NEJM â Collection Updates for Genetics

CORRESPONDENCE: Transfusion of RhD-Positive Blood in âAsia Typeâ DEL Recipients

Chao-Peng Shao, M.D. — Thu, 04Â FebÂ 2010 00:00:00 -05:00

To the Editor: The RhD status of transfusion recipients and donors is routinely matched for red-cell transfusion. This worldwide practice is due to the potent immunogenicity of RhD. In East...

CORRESPONDENCE: Somatic Mutations of and in the Leukemic Transformation of Myeloproliferative Neoplasms

Anthony Green, F.R.C.Path., F.Med.Sci. and Philip Beer, F.R.C.Path., Ph.D. — Thu, 28Â JanÂ 2010 00:00:00 -05:00

To the Editor: Somatic mutations affecting the R132 residue of isocitrate dehydrogenase 1 (IDH1) and the homologous IDH2 R172 occur in central nervous system tumors.12 Recently (in the Sept. 10...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Î±-Adrenergic Receptors and Type 2 Diabetes

Fiona M. Gribble, D.Phil., B.M., B.Ch. — Thu, 28Â JanÂ 2010 00:00:00 -05:00

The global epidemic of type 2 diabetes mellitus is undoubtedly driven by soaring levels of obesity. Although increased body fat impairs the action of insulin, the risk of type 2...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 3-2010 â A 5-Month-Old Boy with Developmental Delay and Irritability

Thu, 28Â JanÂ 2010 00:00:00 -05:00

A 4.5-month-old boy was seen in the pediatric neurology clinic of this hospital because of developmental delay and an abnormal neurologic examination.

The patient had been born at full-term by normal...

CORRESPONDENCE: Lovastatin in X-Linked Adrenoleukodystrophy

Thu, 21Â JanÂ 2010 00:00:00 -05:00

To the Editor: As reported previously in the Journal, lovastatin lowers levels of very-long-chain fatty acids in plasma in patients with X-linked adrenoleukodystrophy (X-ALD).1 Further studies did not reproduce this...

EDITORIAL: Achondrogenesis Type 1A â From Mouse to Human

Hudson H. Freeze, Ph.D. — Thu, 21Â JanÂ 2010 00:00:00 -05:00

In this issue of the Journal, Smits et al.1 describe how they identified the cause of a rare human skeletal dysplasia, achondrogenesis type 1A. In so doing, they have provided...

REVIEW ARTICLE: WilliamsâBeuren Syndrome

Barbara R. Pober, M.D. — Thu, 21Â JanÂ 2010 00:00:00 -05:00

WilliamsâBeuren syndrome (also known as Williams' syndrome; Online Mendelian Inheritance in Man [OMIM] number, 194050), a multisystem disorder, is caused by deletion of the WilliamsâBeuren syndrome chromosome region, spanning 1.5...

ORIGINAL ARTICLE: Lethal Skeletal Dysplasia in Mice and Humans Lacking the Golgin GMAP-210

Thu, 21Â JanÂ 2010 00:00:00 -05:00

Background: Establishing the genetic basis of phenotypes such as skeletal dysplasia in model organisms can provide insights into biologic processes and their role in human disease.

Methods: We screened mutagenized mice...

CORRESPONDENCE: Lack of Population Diversity in Commonly Used Human Embryonic Stem-Cell Lines

Thu, 14Â JanÂ 2010 00:00:00 -05:00

To the Editor: Human embryonic stem-cell research may lead to new methods of drug discovery, insights into mechanisms of disease, and eventually, cellular therapies. The potential benefit to patient populations...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: A Seminal Finding for Prostate Cancer?

Jiaoti Huang, M.D., Ph.D., and Owen N. Witte, M.D. — Thu, 14Â JanÂ 2010 00:00:00 -05:00

The traditional view is that prostate cancer arises from mature luminal cells of the prostate gland.1 Studies of other cancers, however, have implicated more primitive stem and progenitor cells as...

ORIGINAL ARTICLE: Variants of Associated with Asthma in Children

Thu, 07Â JanÂ 2010 00:00:00 -05:00

Background: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown.

Methods: We carried out a genomewide association study...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Aging â Lost in Translation?

Pankaj Kapahi, Ph.D., and Jan Vijg, Ph.D. — Thu, 31Â DecÂ 2009 00:00:00 -05:00

Extending the span of a healthy life has fascinated humanity ever since Gilgamesh failed to prevent his dying friend Enkidu from descending into the horrific netherworld, as described in the...

EDITORIAL: A Common Genetic Fingerprint in Leprosy and Crohn's Disease?

Erwin Schurr, Ph.D., and Philippe Gros, Ph.D. — Thu, 31Â DecÂ 2009 00:00:00 -05:00

The cause-and-effect relationship between severe infections and death suggests that microbial pathogens are evolutionary sculptors of the genome. However, the genetic component of susceptibility to infections in the general population...

EDITORIAL: Matrix Metalloproteinase 12, Asthma, and COPD

Guy G. Brusselle, M.D., Ph.D. — Thu, 31Â DecÂ 2009 00:00:00 -05:00

Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway diseases that involve chronic inflammation of the lower respiratory tract. They differ from each other in the pattern of inflammation,...

ORIGINAL ARTICLE: Genomewide Association Study of Leprosy

Thu, 31Â DecÂ 2009 00:00:00 -05:00

Background: The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host...

ORIGINAL ARTICLE: Lung Function, and COPD in High-Risk Populations

Thu, 31Â DecÂ 2009 00:00:00 -05:00

Background: Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups.

Methods: We tested for an...

EDITORIAL: Lp(a) Lipoprotein Redux â From Curious Molecule to Causal Risk Factor

Sekar Kathiresan, M.D. — Thu, 24Â DecÂ 2009 00:00:00 -05:00

Lp(a) lipoprotein, which was initially described in 1963,1 is a circulating macromolecule consisting of a low-density lipoprotein (LDL) particle that is covalently linked to a protein called apolipoprotein(a). Plasma Lp(a)...

ORIGINAL ARTICLE: Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease

Thu, 24Â DecÂ 2009 00:00:00 -05:00

Background: An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Gene Therapy for Color Blindness

Jean Bennett, M.D., Ph.D. — Thu, 17Â DecÂ 2009 00:00:00 -05:00

The inability to distinguish particular color combinations, or âcolor blindness,â is one of the most common and best understood inherited anomalies, having first been self-diagnosed more than 200 years ago...

REVIEW ARTICLE: Molecular Basis of Colorectal Cancer

Sanford D. Markowitz, M.D., Ph.D., and Monica M. Bertagnolli, M.D. — Thu, 17Â DecÂ 2009 00:00:00 -05:00

Every year in the United States, 160,000 cases of colorectal cancer are diagnosed, and 57,000 patients die of the disease, making it the second leading cause of death from cancer...

REVIEW ARTICLE: Telomere Diseases

Rodrigo T. Calado, M.D., Ph.D., and Neal S. Young, M.D. — Thu, 10Â DecÂ 2009 00:00:00 -05:00

Elizabeth Blackburn, Jack Szostak, and Carol Greider were recently awarded the Nobel Prize in Physiology or Medicine for their elucidation of the structure and maintenance of telomeres (the tips of...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: The Hedgehog Pathway and Pancreatic Cancer

Manuel Hidalgo, M.D., and Anirban Maitra, M.D. — Thu, 19Â NovÂ 2009 00:00:00 -05:00

Aberrant activation of the hedgehog pathway has been observed in multiple human cancers, including pancreatic cancer. For this reason, several small-molecule inhibitors of the pathway have been advanced to clinical...

EDITORIAL: Interleukin-10 in Inflammatory Bowel Disease

Brian Kelsall, M.D. — Thu, 19Â NovÂ 2009 00:00:00 -05:00

In this issue of the Journal, Glocker et al.1 provide the first substantial support for a functional role for the immunosuppressive cytokine interleukin-10 in the pathogenesis of inflammatory bowel disease...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 36-2009 â A 23-Year-Old Man with Cough, Hoarseness, and Abnormalities on Chest Imaging

Thu, 19Â NovÂ 2009 00:00:00 -05:00

Dr. David T. Ting (Medical Oncology): A 23-year-old man was transferred to this hospital because of cough, hoarseness, fever, and abnormalities on chest imaging.

The patient had been well until 1...

REVIEW ARTICLE: Inflammatory Bowel Disease

Clara Abraham, M.D., and Judy H. Cho, M.D. — Thu, 19Â NovÂ 2009 00:00:00 -05:00

The idiopathic inflammatory bowel diseases comprise two types of chronic intestinal disorders: Crohn's disease and ulcerative colitis. Accumulating evidence suggests that inflammatory bowel disease results from an inappropriate inflammatory response...

ORIGINAL ARTICLE: A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure

Thu, 19Â NovÂ 2009 00:00:00 -05:00

Background: Kuru is a devastating epidemic prion disease that affected a highly restricted geographic area of the Papua New Guinea highlands; at its peak, it predominantly affected adult women and...

ORIGINAL ARTICLE: Combined Immunodeficiency Associated with Mutations

Thu, 19Â NovÂ 2009 00:00:00 -05:00

Background: Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown.

Methods: We...

ORIGINAL ARTICLE: Inflammatory Bowel Disease and Mutations Affecting the Interleukin-10 Receptor

Thu, 19Â NovÂ 2009 00:00:00 -05:00

Background: The molecular cause of inflammatory bowel disease is largely unknown.

Methods: We performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected...

ORIGINAL ARTICLE: Normal Spermatogenesis in a Man with Mutant Luteinizing Hormone

Thu, 05Â NovÂ 2009 00:00:00 -05:00

Men with mutations in LHB, the gene encoding the beta subunit of luteinizing hormone (LHB), have azoospermia with absent or few fetal Leydig cells. We report a mutation in LHB...

EDITORIAL: Yeast Infections â Human Genetics on the Rise

Steven M. Holland, M.D., and Donald C. Vinh, M.D. — Thu, 29Â OctÂ 2009 00:00:00 -05:00

We lead inextricably mycotic lives: yeasts leaven our bread, ferment our wine and beer, and inhabit our skins, mouths, and gastrointestinal tracts; however, not all is harmony. Hippocrates reported aphthous...

ORIGINAL ARTICLE: Human Dectin-1 Deficiency and Mucocutaneous Fungal Infections

Thu, 29Â OctÂ 2009 00:00:00 -05:00

Mucocutaneous fungal infections are typically found in patients who have no known immune defects. We describe a family in which four women who were affected by either recurrent vulvovaginal candidiasis...

ORIGINAL ARTICLE: A Homozygous Mutation in a Family with Susceptibility to Fungal Infections

Thu, 29Â OctÂ 2009 00:00:00 -05:00

Background: Chronic mucocutaneous candidiasis may be manifested as a primary immunodeficiency characterized by persistent or recurrent infections of the mucosa or the skin with candida species. Most cases are sporadic,...

CORRESPONDENCE: FOXP3 Forkhead Domain Mutation and Regulatory T Cells in the IPEX Syndrome

Thu, 22Â OctÂ 2009 00:00:00 -05:00

To the Editor: The immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a rare disorder characterized by multiorgan autoimmunity, often results in death in infancy.1 The IPEX syndrome results from mutations...

ORIGINAL ARTICLE: X-Linked Thrombophilia with a Mutant Factor IX (Factor IX Padua)

Thu, 22Â OctÂ 2009 00:00:00 -05:00

We report a case of juvenile thrombophilia associated with a substitution of leucine for arginine at position 338 (R338L) in the factor IX gene (factor IXâR338L). The level of the...

ORIGINAL ARTICLE: Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease

Thu, 22Â OctÂ 2009 00:00:00 -05:00

Background: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to...

PERSPECTIVE: When Diseases Disappear â The Case of Familial Dysautonomia

Thu, 22Â OctÂ 2009 00:00:00 -05:00

The success of genetic-screening programs raises an intriguing possibility: some dread diseases of the 20th century may soon become history. A representative example is familial dysautonomia, a severe neurologic condition,...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 32-2009 â A 27-Year-Old Man with Progressive Dyspnea

Andrew M. Tager, M.D., Amita Sharma, M.D., and Eugene J. Mark, M.D. — Thu, 15Â OctÂ 2009 00:00:00 -05:00

A 27-year-old man was seen in the outpatient pulmonary division of this hospital because of progressive dyspnea and decreased exercise tolerance.

Approximately 2 years earlier, the patient noted a slight decrease...

REVIEW ARTICLE: Cell Death

Thu, 15Â OctÂ 2009 00:00:00 -05:00

All multicellular organisms require apoptosis, the controlled death of cells. Without apoptosis, 2 tons of bone marrow and lymph nodes and a 16-km intestine would probably accumulate in a human...

EDITORIAL: Micromanaging Cancer

Judy Lieberman, M.D., Ph.D. — Thu, 08Â OctÂ 2009 00:00:00 -05:00

The discovery of RNA interference triggered a âsilentâ revolution that overturned our understanding of how gene expression is regulated.1 The previous model was that gene expression was activated during transcription,...

REVIEW ARTICLE: DNA Damage, Aging, and Cancer

Jan H.J. Hoeijmakers, Ph.D. — Thu, 08Â OctÂ 2009 00:00:00 -05:00

DNA damage has emerged as a major culprit in cancer and many diseases related to aging. The stability of the genome is supported by an intricate machinery of repair, damage...

ORIGINAL ARTICLE: MicroRNA Expression, Survival, and Response to Interferon in Liver Cancer

Thu, 08Â OctÂ 2009 00:00:00 -05:00

Background: Hepatocellular carcinoma is a common and aggressive cancer that occurs mainly in men. We examined microRNA expression patterns, survival, and response to interferon alfa in both men and women...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Rendering the Leukemia Cell Susceptible to Attack

Dorothy A. Sipkins, M.D., Ph.D. — Thu, 24Â SepÂ 2009 00:00:00 -05:00

The cytokine interferon-Î± is thought to exert its antitumor effects through pleiotropic mechanisms, including the modulation of immune responses and the inhibition of angiogenesis.1 In addition, interferon-Î± inhibits growth and...

CORRESPONDENCE: A Classic Twin Study of External Ear Malformations, Including Microtia

Thu, 17Â SepÂ 2009 00:00:00 -05:00

To the Editor: The pathogenesis of microtia, a rare congenital malformation of the external ear, remains elusive. Phenotypes range from minor deformities, such as preauricular tags, to anotia, the complete...

EDITORIAL: Following the Hedgehog to New Cancer Therapies

Andrzej A. Dlugosz, M.D., and Moshe Talpaz, M.D. — Thu, 17Â SepÂ 2009 00:00:00 -05:00

Two studies in this issue of the Journal12 describe a new drug, GDC-0449, that inhibits the hedgehog signaling pathway. This pathway orchestrates numerous processes throughout embryogenesis, and although the pathway...

ORIGINAL ARTICLE: Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449

Thu, 17Â SepÂ 2009 00:00:00 -05:00

Medulloblastoma is the most common malignant brain tumor in children. Aberrant activation of the hedgehog signaling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old...

ORIGINAL ARTICLE: Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma

Thu, 17Â SepÂ 2009 00:00:00 -05:00

Background: Mutations in hedgehog pathway genes, primarily genes encoding patched homologue 1 (PTCH1) and smoothened homologue (SMO), occur in basal-cell carcinoma. In a phase 1 clinical trial, we assessed the...

ORIGINAL ARTICLE: Sex HormoneâBinding Globulin and Risk of Type 2 Diabetes in Women and Men

Thu, 17Â SepÂ 2009 00:00:00 -05:00

Background: Circulating sex hormoneâbinding globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain.

Methods: We performed a...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Understanding Abdominal Aortic Aneurysm

Neal L. Weintraub, M.D. — Thu, 10Â SepÂ 2009 00:00:00 -05:00

Abdominal aortic aneurysms occur in up to 9% of adults older than 65 years of age, and the rupture of these aneurysms accounts for about 15,000 deaths in the United...

EDITORIAL: Cancer Genomes â Continuing Progress

James R. Downing, M.D. — Thu, 10Â SepÂ 2009 00:00:00 -05:00

Cancer is believed to result from the acquisition of mutations and epigenetic changes that work collaboratively to induce the malignant growth of a cell. The field of cancer genomics has...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 28-2009 â A 68-Year-Old Man with Fatigue, Cough, and Peripheral-Blood Monocytosis

Thu, 10Â SepÂ 2009 00:00:00 -05:00

Dr. Alfred Ian Lee (Oncology): A 68-year-old man was seen in the cancer center of this hospital because of fatigue, cough, and peripheral-blood monocytosis.

The patient had been well until approximately...

ORIGINAL ARTICLE: Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome

Thu, 10Â SepÂ 2009 00:00:00 -05:00

Background: The full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known.

Methods: We used massively parallel DNA sequencing to obtain...

ORIGINAL ARTICLE: Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer

Thu, 03Â SepÂ 2009 00:00:00 -05:00

Background: Activating mutations in the epidermal growth factor receptor gene (EGFR) confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced nonâsmall-cell lung cancer. We evaluated...

ORIGINAL ARTICLE: Gefitinib or CarboplatinâPaclitaxel in Pulmonary Adenocarcinoma

Thu, 03Â SepÂ 2009 00:00:00 -05:00

Background: Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with nonâsmall-cell lung cancer.

Methods: In this phase 3, open-label study, we randomly assigned...

EDITORIAL: Personalized Medicine and Inhibition of Signaling in Lung Cancer

Adi F. Gazdar, M.D. — Thu, 03Â SepÂ 2009 00:00:00 -05:00

The concept underlying much of cancer therapy is that patients with specific types and stages of cancer should be treated according to standardized, predetermined protocols. However, recent advances in drug...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Finding the Weakness in Cancer

Julian Downward, Ph.D. — Thu, 27Â AugÂ 2009 00:00:00 -05:00

By the time the sequencing of the human genome was completed 6 years ago, expectations were huge that this knowledge would soon have an impact on our ability to treat...

CORRESPONDENCE: Codeine, Ultrarapid-Metabolism Genotype, and Postoperative Death

Thu, 20Â AugÂ 2009 00:00:00 -05:00

To the Editor: Obstructive sleep apnea is not rare in children with hypertrophic tonsils, and the common curative procedure is adenotonsillectomy.1 Codeine is commonly prescribed for pain after adenotonsillectomy.2 The...

CORRESPONDENCE: Vision 1 Year after Gene Therapy for Leber's Congenital Amaurosis

Thu, 13Â AugÂ 2009 00:00:00 -05:00

To the Editor: Leber's congenital amaurosis, a common cause of blindness in infants and children,1 recently became the first human genetic retinal disease to show improved vision in response to...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Master Regulators of Female Fertility

Nava Dekel, Ph.D. — Thu, 13Â AugÂ 2009 00:00:00 -05:00

Ovulation, initiated by the proestrus surge of the pituitary luteinizing hormone, culminates in the rupture of the ovarian follicle and is followed by the delivery of a mature oocyte. This...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 25-2009 â A 36-Year-Old Woman with Hormone-ReceptorâPositive Breast Cancer

Thu, 13Â AugÂ 2009 00:00:00 -05:00

Dr. Barbara L. Smith (Surgical Oncology): A 36-year-old woman was seen in the multidisciplinary breast cancer clinic of this hospital for management of hormone-receptorâpositive breast cancer.

Approximately 3 months earlier she...

EDITORIAL: Genetic Trickery â Escape of Leukemia from Immune Attack

John Barrett, M.D., and Bruce R. Blazar, M.D. — Thu, 30Â JulÂ 2009 00:00:00 -05:00

It is increasingly clear that neoplastic cells and the immune system are locked in a struggle in which each attempts to outmaneuver its opponent. One tactic that tumors use to...

ORIGINAL ARTICLE: AGC1 Deficiency Associated with Global Cerebral Hypomyelination

Thu, 30Â JulÂ 2009 00:00:00 -05:00

The mitochondrial aspartateâglutamate carrier isoform 1 (AGC1), specific to neurons and muscle, supplies aspartate to the cytosol and, as a component of the malateâaspartate shuttle, enables mitochondrial oxidation of cytosolic...

IMAGES IN CLINICAL MEDICINE: Myotonic Dystrophy

Luis M. Franco, M.D. and Josh C. Skorupski, M.D. — Thu, 23Â JulÂ 2009 00:00:00 -05:00

A 36-year-old woman was seen in the clinic after congenital myotonic dystrophy was diagnosed in her newborn son. The neonate had profound hypotonia, areflexia, and bradycardia and required mechanical ventilation....

BOOK REVIEW:

Thu, 23Â JulÂ 2009 00:00:00 -05:00

A decade ago, a textbook linking the human genome and diseases of the kidney would have contained more questions than answers. This is probably the first textbook dedicated to the...

CORRESPONDENCE: Muscle Glycogenosis Due to Phosphoglucomutase 1 Deficiency

Thu, 23Â JulÂ 2009 00:00:00 -05:00

To the Editor: Muscle glycogen storage diseases are rare inborn diseases caused by errors of metabolism associated with either dynamic, exercise-related symptoms or permanent muscle weakness. The most common glycogen...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 23-2009 â A 13-Year-Old Boy with Headache, Nausea, Seizures, and Hypertension

Thu, 23Â JulÂ 2009 00:00:00 -05:00

A 13-year-old boy was admitted to the hospital because of headache, nausea, seizures, renal failure, and hypertension.

The patient had been well until approximately 3 weeks earlier, when intermittent left-sided headaches...

ORIGINAL ARTICLE: Hearing Improvement after Bevacizumab in Patients with Neurofibromatosis Type 2

Thu, 23Â JulÂ 2009 00:00:00 -05:00

Background: Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve. There...

ORIGINAL ARTICLE: Thrombomodulin Mutations in Atypical HemolyticâUremic Syndrome

Thu, 23Â JulÂ 2009 00:00:00 -05:00

Background: The hemolyticâuremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxinâproducing bacteria...

EDITORIAL: Effect of Genetic Testing for Risk of Alzheimer's Disease

Rosalie A. Kane, Ph.D., and Robert L. Kane, M.D. — Thu, 16Â JulÂ 2009 00:00:00 -05:00

Genetic testing can be considered a complex variant of diagnostic testing. If the results are not actionable, the findings may lead to anxiety or even life-disrupting actions with little offsetting...

ORIGINAL ARTICLE: Longitudinal Modeling of Age-Related Memory Decline and the Îµ4 Effect

Thu, 16Â JulÂ 2009 00:00:00 -05:00

Background: The APOE Îµ4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE Îµ4...

ORIGINAL ARTICLE: Disclosure of Genotype for Risk of Alzheimer's Disease

Thu, 16Â JulÂ 2009 00:00:00 -05:00

Background: The apolipoprotein E (APOE) genotype provides information on the risk of Alzheimer's disease, but the genotyping of patients and their family members has been discouraged. We examined the effect...

PERSPECTIVE: The Persistent Legacy of the 1918 Influenza Virus

Thu, 16Â JulÂ 2009 00:00:00 -05:00

It is not generally appreciated that descendents of the H1N1 influenza A virus that caused the catastrophic and historic pandemic of 1918â1919 have persisted in humans for more than 90...

HEALTH LAW, ETHICS, AND HUMAN RIGHTS: Protecting Privacy and the Public â Limits on Police Use of Bioidentifiers in Europe

George J. Annas, J.D., M.P.H. — Thu, 09Â JulÂ 2009 00:00:00 -05:00

Since 9/11, police and military around the world have sought to increase their arsenals of bioidentifiers, and privacy advocates have sought to cabin their use. In what may turn out...

EDITORIAL: Gene Therapy â Still a Work in Clinical and Regulatory Progress

Elizabeth L. Hohmann, M.D. — Thu, 09Â JulÂ 2009 00:00:00 -05:00

In this issue of the Journal, Frank and colleagues present the case history and autopsy results of a widely publicized death in the summer of 2007 of a young woman...

EDITORIAL: Synthetic Lethality â A New Direction in Cancer-Drug Development

J. Dirk Iglehart, M.D., and Daniel P. Silver, M.D., Ph.D. — Thu, 09Â JulÂ 2009 00:00:00 -05:00

In this issue of the Journal, Fong et al. report the results of a phase 1 trial of a new cancer therapy involving 60 patients (ClinicalTrials.gov number, NCT00516373).1 Readers may...

ORIGINAL ARTICLE: Investigation of the Cause of Death in a Gene-Therapy Trial

Thu, 09Â JulÂ 2009 00:00:00 -05:00

We present a case of disseminated histoplasmosis, complicated by retroperitoneal bleeding and leading to death, in a patient who was receiving systemic immunosuppressive therapy for rheumatoid arthritis and who was...

ORIGINAL ARTICLE: Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from Mutation Carriers

Thu, 09Â JulÂ 2009 00:00:00 -05:00

Background: The inhibition of poly(adenosine diphosphate [ADP]âribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers...

PERSPECTIVE: Geographic Dependence, Surveillance, and Origins of the 2009 Influenza A (H1N1) Virus

Thu, 09Â JulÂ 2009 00:00:00 -05:00

In April 2009, a new strain of human H1N1 influenza A virus was identified in Mexico. According to the World Health Organization (www.who.int/csr/don/2009_05_25), as of May 25, 2009, the virus...

CORRESPONDENCE: Mutation in Metastatic Colorectal Cancer

Thu, 02Â JulÂ 2009 00:00:00 -05:00

To the Editor: We recently found that progression-free survival was shorter among patients with metastatic colorectal cancer treated with chemotherapy, bevacizumab, and cetuximab (CBC regimen) than among patients who received...

CLINICAL PROBLEM-SOLVING: A Fragile Balance

Thu, 02Â JulÂ 2009 00:00:00 -05:00

A 31-year-old man presented to the emergency department with pain in the left shoulder. He had tripped over the shoulder strap of his backpack earlier in the day and noted...

CORRESPONDENCE: Molecular Outcome Prediction in Diffuse Large-B-Cell Lymphoma

Thu, 25Â JunÂ 2009 00:00:00 -05:00

To the Editor: Lenz et al. (Nov. 27 issue)1 report the results of an important study of gene expression and survival in patients with diffuse large-B-cell lymphoma. We reassessed the...

EDITORIAL: Cancer Genomes on a Shoestring Budget

Jay Shendure, M.D., Ph.D., and Colin J. Stewart, M.B., Ch.B. — Thu, 25Â JunÂ 2009 00:00:00 -05:00

In a remarkably short time, the use of massively parallel technologies has greatly reduced the cost of DNA sequencing.1 Already, these technologies have permitted the whole-genome sequencing of several persons234...

CLINICAL PRACTICE: Alpha-Antitrypsin Deficiency

Edwin K. Silverman, M.D., Ph.D., and Robert A. Sandhaus, M.D., Ph.D. — Thu, 25Â JunÂ 2009 00:00:00 -05:00

A 60-year-old white man presents for evaluation of progressive dyspnea. He is a former smoker with a 20-pack-year smoking history and a 10-year history of diagnosed chronic obstructive pulmonary disease...

ORIGINAL ARTICLE: Isolated Familial Hypogonadotropic Hypogonadism and a Mutation

Thu, 25Â JunÂ 2009 00:00:00 -05:00

We investigated whether mutations in the gene encoding gonadotropin-releasing hormone 1 (GNRH1) might be responsible for idiopathic hypogonadotropic hypogonadism (IHH) in humans. We identified a homozygous GNRH1 frameshift mutation, an...

ORIGINAL ARTICLE: Mutation of in Granulosa-Cell Tumors of the Ovary

Thu, 25Â JunÂ 2009 00:00:00 -05:00

Background: Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cordâstromal tumor (SCST). The pathogenesis of these tumors is unknown. Moreover, their histopathological diagnosis can be challenging,...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: A New Target for Tumor Therapy

Rakesh K. Jain, Ph.D. — Thu, 18Â JunÂ 2009 00:00:00 -05:00

Vascular normalization, or restoration of the normal structure and function in blood vessels, has emerged as a strategy to treat cancer and other vascular disorders.1 Mazzone et al.2 have recently...

ORIGINAL ARTICLE: Immunodeficiency Associated with Mutation and Ficolin-3 Deficiency

Thu, 18Â JunÂ 2009 00:00:00 -05:00

Ficolin-3, encoded by the FCN3 gene and expressed in the lung and liver, is a recognition molecule in the lectin pathway of the complement system. Heterozygosity for an FCN3 frameshift...

CLINICAL PRACTICE: Prenatal Screening for Aneuploidy

Deborah A. Driscoll, M.D., and Susan Gross, M.D. — Thu, 11Â JunÂ 2009 00:00:00 -05:00

A 37-year-old woman, gravida 1, seeks prenatal care at 8 weeks' gestation. Her family history and medical history are unremarkable. What would you advise regarding her risk of fetal chromosomal...

ORIGINAL ARTICLE: Primary Biliary Cirrhosis Associated with and Variants

Thu, 11Â JunÂ 2009 00:00:00 -05:00

Background: Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary...

EDITORIAL: Interleukin-1Î² and the Autoinflammatory Diseases

Charles A. Dinarello, M.D. — Thu, 04Â JunÂ 2009 00:00:00 -05:00

Interleukin-1 is a highly active proinflammatory cytokine that causes not only fever, anorexia, and other constitutional symptoms but also tissue damage and remodeling. All these effects â including joint destruction,...

ORIGINAL ARTICLE: An Autoinflammatory Disease Due to Homozygous Deletion of the Locus

Thu, 04Â JunÂ 2009 00:00:00 -05:00

We describe a patient with an autoinflammatory disease in which the main clinical features are pustular rash, marked osteopenia, lytic bone lesions, respiratory insufficiency, and thrombosis. Genetic studies revealed a...

ORIGINAL ARTICLE: An Autoinflammatory Disease with Deficiency of the Interleukin-1âReceptor Antagonist

Thu, 04Â JunÂ 2009 00:00:00 -05:00

Background: Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1âreceptor antagonist, with...

BOOK REVIEW:

Thu, 28Â MayÂ 2009 00:00:00 -05:00

Few conditions are more devastating to the physical, emotional, and social health of an infant or child than epidermolysis bullosa. The disease is actually a group of congenital abnormalities of...

EDITORIAL: A Common Genetic Mechanism in Malignant Bone Marrow Diseases

Ross L. Levine, M.D., and Martin Carroll, M.D. — Thu, 28Â MayÂ 2009 00:00:00 -05:00

The myelodysplastic syndromes, myeloproliferative disorders, and acute myeloid leukemia (AML) are seemingly unrelated diseases except for their origin in hematopoietic precursor cells in bone marrow. A principal feature of the...

ORIGINAL ARTICLE: Inactivating Mutations in a Patient with Premature Pubarche

Thu, 28Â MayÂ 2009 00:00:00 -05:00

Dehydroepiandrosterone (DHEA) sulfotransferase, known as SULT2A1, converts the androgen precursor DHEA to its inactive sulfate ester, DHEAS, thereby preventing the conversion of DHEA to an active androgen. SULT2A1 requires 3â²-phosphoadenosine-5â²-phosphosulfate...

ORIGINAL ARTICLE: Mutation in in Myeloid Cancers

Thu, 28Â MayÂ 2009 00:00:00 -05:00

Background: The myelodysplastic syndromes and myeloproliferative disorders are associated with deregulated production of myeloid cells. The mechanisms underlying these disorders are not well defined.

Methods: We conducted a combination of molecular,...

BOOK REVIEW:

Thu, 14Â MayÂ 2009 00:00:00 -05:00

Diagnostic molecular pathology took shape as a field in the early 1980s, primarily on the basis of the use of nucleic acid hybridization probes for three purposes: the detection of...

CORRESPONDENCE: Bevacizumab in Hereditary Hemorrhagic Telangiectasia

Prithviraj Bose, M.D., Jennifer L. Holter, M.D., and George B. Selby, M.D. — Thu, 14Â MayÂ 2009 00:00:00 -05:00

To the Editor: Hereditary hemorrhagic telangiectasia (HHT) (also known as the OslerâWeberâRendu syndrome) is an inherited vascular dysplasia whose main features are mucocutaneous telangiectasias, epistaxis, gastrointestinal bleeding, and iron-deficiency anemia.1...

BOOK REVIEW:

Thu, 07Â MayÂ 2009 00:00:00 -05:00

This is not a straightforward textbook on Huntington's disease, a condition that causes much distress to patients and their relatives by virtue of the combination of cognitive decline and involuntary...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: The Origins of Brown Adipose Tissue

Sven EnerbÃ¤ck, M.D., Ph.D. — Thu, 07Â MayÂ 2009 00:00:00 -05:00

What is the source of brown adipose tissue? During the formation of the three germ layers (gas trulation), the mesoderm fills the void between the outer shell (ectoderm) and the...

EDITORIAL: Membrane Physiology â Bridging the Gap between Medical Disciplines

Markus Bleich, M.D. — Thu, 07Â MayÂ 2009 00:00:00 -05:00

The general separation between medical disciplines has, for decades, been a strange tradition. For example, neurologists and nephrologists have each had their defined patient groups, and many are barely interested,...

ORIGINAL ARTICLE: Mutation Associated with a Syndrome of Immunodeficiency and Autoimmunity

Thu, 07Â MayÂ 2009 00:00:00 -05:00

A mutation in ORAI1, the gene encoding the pore-forming subunit of the Ca2+-releaseâactivated Ca2+ (CRAC) channel, abrogates the store-operated entry of Ca2+ into cells and impairs lymphocyte activation. Stromal interaction...

ORIGINAL ARTICLE: Epilepsy, Ataxia, Sensorineural Deafness, Tubulopathy, and Mutations

Thu, 07Â MayÂ 2009 00:00:00 -05:00

Background: Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis. We...

CORRESPONDENCE: Mutations in a Thiamine-Transporter Gene and Wernicke's-like Encephalopathy

Thu, 23Â AprÂ 2009 00:00:00 -05:00

To the Editor: We report on two previously healthy Japanese brothers with a newly discovered recessively inherited syndrome similar to Wernicke's encephalopathy that developed in the second decade of life;...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Crohn's Disease, Autophagy, and the Paneth Cell

Daniel J. Klionsky, Ph.D. — Thu, 23Â AprÂ 2009 00:00:00 -05:00

Because of its very nature, the gastrointestinal tract is potentially subject to inflammation and infection. Much of its surface is designed to be highly exposed and absorptive, yet it faces...

IMAGES IN CLINICAL MEDICINE: Pulmonary Arteriovenous Fistula

Nils Kraemer, M.D. and Gabriele A. Krombach, M.D. — Thu, 23Â AprÂ 2009 00:00:00 -05:00

A 50-year-old woman presented with mild exercise-induced shortness of breath; she reported being otherwise healthy. Her family history was notable for her mother's having the OslerâWeberâRendu syndrome, also called hereditary...

REVIEW ARTICLE: Genomewide Association Studies and Human Disease

John Hardy, Ph.D., and Andrew Singleton, Ph.D. — Thu, 23Â AprÂ 2009 00:00:00 -05:00

For 20 years, genetic linkage combined with positional cloning has offered a rational and increasingly straightforward route to finding gene mutations that lead to monogenic disease, such as cystic fibrosis...

ORIGINAL ARTICLE: Association of HTRA1 Mutations and Familial Ischemic Cerebral Small-Vessel Disease

Thu, 23Â AprÂ 2009 00:00:00 -05:00

Background: The genetic cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is characterized by ischemic, nonhypertensive, cerebral small-vessel disease with associated alopecia and spondylosis, is...

ORIGINAL ARTICLE: Genomewide Association Studies of Stroke

Thu, 23Â AprÂ 2009 00:00:00 -05:00

Background: The genes underlying the risk of stroke in the general population remain undetermined.

Methods: We carried out an analysis of genomewide association data generated from four large cohorts composing the...

PERSPECTIVE: Genetic Risk Prediction â Are We There Yet?

Thu, 23Â AprÂ 2009 00:00:00 -05:00

A major goal of the Human Genome Project was to facilitate the identification of inherited genetic variants that increase or decrease the risk of complex diseases. The completion of the...

PERSPECTIVE: Genomewide Association Studies â Illuminating Biologic Pathways

Thu, 23Â AprÂ 2009 00:00:00 -05:00

Human geneticists seek to understand the inherited basis of human biology and disease, aiming either to gain insights that could eventually improve treatment or to produce useful diagnostic or predictive...

PERSPECTIVE: Common Genetic Variation and Human Traits

Thu, 23Â AprÂ 2009 00:00:00 -05:00

The human genome has been cracked wide open in recent years and is spilling many of its secrets. More than 100 genomewide association studies have been conducted for scores of...

CORRESPONDENCE: Revertant Mosaicism â Patchwork in the Skin

Marcel F. Jonkman, M.D., Ph.D. and Anna M.G. Pasmooij, Ph.D. — Thu, 16Â AprÂ 2009 00:00:00 -05:00

To the Editor: Revertant mosaicism occurs when an inherited disease-causing mutation is corrected by a spontaneous genetic event within a somatic cell, followed by expansion of this reverted cell.1 This...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 12-2009 â A 46-Year-Old Man with Migraine, Aphasia, and Hemiparesis and Similarly Affected Family Members

Thu, 16Â AprÂ 2009 00:00:00 -05:00

A 46-year-old man was seen in the neurology clinic because of hemiparesis, aphasia, and abnormalities on neuroimaging studies.

The patient had been well, except for migraine headaches, until 4 years earlier,...

REVIEW ARTICLE: Genetics of Type 1A Diabetes

Thu, 16Â AprÂ 2009 00:00:00 -05:00

In 1976, the noted human geneticist James Neel titled a book chapter âDiabetes Mellitus: A Geneticist's Nightmare.â1 Over the past 30 years, however, the phenotypic and genetic heterogeneity of diabetes...

ORIGINAL ARTICLE: Inhibitors of Factor VIII in Black Patients with Hemophilia

Thu, 16Â AprÂ 2009 00:00:00 -05:00

Background: Black patients with hemophilia A (factor VIII deficiency) are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy. There are six...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Limiting Fibrosis after Myocardial Infarction

Bodh I. Jugdutt, M.D., D.M. — Thu, 09Â AprÂ 2009 00:00:00 -05:00

A recent study by Kobayashi and colleagues1 showed that a secreted protein may be a therapeutic target for limiting fibrosis and improving function after myocardial infarction. Myocardial infarction is a...

ORIGINAL ARTICLE: Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer

Thu, 02Â AprÂ 2009 00:00:00 -05:00

Background: We investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer and sought associations between the mutation status of the KRAS...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: A Lesson in Tolerance â Maternal Instruction to Fetal Cells

William J. Burlingham, Ph.D. — Thu, 26Â MarÂ 2009 00:00:00 -05:00

Most people would agree that mothers are influential in shaping their children's outlook on life. A recent study by Mold and colleagues1 discloses a new facet of maternal influence: maternal...

ORIGINAL ARTICLE: Genetic Compensation in a Human Genomic Disorder

Thu, 19Â MarÂ 2009 00:00:00 -05:00

Cytogenetic studies of the parents of a girl with the DiGeorge (or velocardiofacial) syndrome, who carried a deletion at 22q11.2, revealed an unexpected rearrangement of both 22q11.2 regions in the...

ORIGINAL ARTICLE: Mutations in Associated with Ovarian Insufficiency

Thu, 19Â MarÂ 2009 00:00:00 -05:00

Background: The genetic causes of nonsyndromic ovarian insufficiency are largely unknown. A nuclear receptor, NR5A1 (also called steroidogenic factor 1), is a key transcriptional regulator of genes involved in the...

BOOK REVIEW:

Thu, 12Â MarÂ 2009 00:00:00 -05:00

In 1925, a patient who was being treated by Alfred S. Warthin told him she was terrified she would die of âcancer of my female organs or bowels,â which she...

PERSPECTIVE: Serotonin Rising â The Bone, Brain, Bowel Connection

Thu, 05Â MarÂ 2009 00:00:00 -05:00

In a recent article, Yadav et al.1 elucidated the regulation of gut-produced serotonin by low-density lipoprotein receptorârelated protein 5 (Lrp5) and the deleterious effect of serotonin on bone mass. This...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Acute Promyelocytic Leukemia â Weapons of Mass Differentiation

Jonathan D. Licht, M.D. — Thu, 26Â FebÂ 2009 00:00:00 -05:00

Acute myeloid leukemia (AML) involves the immortalization of immature myeloid progenitors and is a heterogeneous disease. Current clinical practice separates AML into low-, intermediate-, and high-risk categories according to cytogenetic...

EDITORIAL: The Will-o'-the-Wisp of Genetics â Hunting for the Azoospermia Factor Gene

Chris Tyler-Smith, Ph.D., and Csilla Krausz, M.D., Ph.D. — Thu, 26Â FebÂ 2009 00:00:00 -05:00

It has been known for decades that the Y chromosome carries genes required for spermatogenesis and male fertility. But it has been frustratingly difficult to pin down the relevant genes,...

ORIGINAL ARTICLE: Spermatogenesis in a Man with Complete Deletion of

Thu, 26Â FebÂ 2009 00:00:00 -05:00

Deletions in the azoospermia factor region AZFa on the human Y chromosome and, more specifically, in the region that encompasses the ubiquitin-specific peptidase 9, Y-linked gene USP9Y have been implicated...

ORIGINAL ARTICLE: C3 Polymorphisms and Allograft Outcome in Renal Transplantation

Thu, 26Â FebÂ 2009 00:00:00 -05:00

Background: Complement activation plays a role in the development of chronic allograft nephropathy, a common cause of late allograft loss. The role of two complement component 3 (C3) allotypes, called...

CORRESPONDENCE: Bezafibrate for an Inborn Mitochondrial Beta-Oxidation Defect

Thu, 19Â FebÂ 2009 00:00:00 -05:00

To the Editor: Carnitine palmitoyltransferase II (CPT2) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid oxidation. The most common form of this disorder is characterized by muscle...

EDITORIAL: Metabolic Enzymes as Oncogenes or Tumor Suppressors

Craig B. Thompson, M.D. — Thu, 19Â FebÂ 2009 00:00:00 -05:00

Whether mutations in metabolic pathways contribute to the pathogenesis of cancer is controversial.12 Cancer cells have long been noted to preferentially metabolize glucose through glycolysis, a discovery that has been...

EDITORIAL: Pharmacogenetics â Tailoring Treatment for the Outliers

Janet Woodcock, M.D., and Lawrence J. Lesko, Ph.D., F.C.P. — Thu, 19Â FebÂ 2009 00:00:00 -05:00

Over the past half century, biomedical science has developed randomized, controlled clinical-trial methods that can distinguish treatment effects from the noise of human variability. Positive results from tests of a...

REVIEW ARTICLE: Gene-Expression Signatures in Breast Cancer

Christos Sotiriou, M.D., D.Phil., and Lajos Pusztai, M.D., D.Phil. — Thu, 19Â FebÂ 2009 00:00:00 -05:00

Gene-expression profiling with the use of DNA microarrays allows measurement of thousands of messenger RNA (mRNA) transcripts in a single experiment. Results of such studies have confirmed that breast cancer...

ORIGINAL ARTICLE: and Mutations in Gliomas

Thu, 19Â FebÂ 2009 00:00:00 -05:00

Background: A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such...

ORIGINAL ARTICLE: Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data

The International Warfarin Pharmacogenetics Consortium — Thu, 19Â FebÂ 2009 00:00:00 -05:00

Background: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic...

CORRESPONDENCE: A Family with Complete Resistance to Thyrotropin-Releasing Hormone

Thu, 12Â FebÂ 2009 00:00:00 -05:00

To the Editor: We report on a family with recessive resistance to the action of thyrotropin-releasing hormone (TRH) due to a nonsense homozygous mutation in the TRH receptor (TRHR) gene...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Inflammatory Bowel Disease, Stress, and the Endoplasmic Reticulum

Hans Clevers, M.D., Ph.D. — Thu, 12Â FebÂ 2009 00:00:00 -05:00

The causes of Crohn's disease and ulcerative colitis are poorly understood, despite having been defined many decades ago on the basis of their clinical manifestations. Experiments involving transgenic mice and...

EDITORIAL: Not an HIV Cure, but Encouraging New Directions

Jay A. Levy, M.D. — Thu, 12Â FebÂ 2009 00:00:00 -05:00

The history of infectious diseases frequently includes people who were resistant to a pathogen. Such a phenomenon helped the Spanish, who had resistance to smallpox, in their conquest of South...

EDITORIAL: The Secret Lives of Monoclonal B Cells

Robert F. Vogt, Jr., Ph.D., and Robert A. Kyle, M.D. — Thu, 12Â FebÂ 2009 00:00:00 -05:00

It seems that B cells, the lymphocytes responsible for producing antibodies, are eager to share their secrets. Their revelations were first uncovered indirectly in serum through reactions with microbes, cells,...

ORIGINAL ARTICLE: Long-Term Control of HIV by Delta32/Delta32 Stem-Cell Transplantation

Thu, 12Â FebÂ 2009 00:00:00 -05:00

Infection with the human immunodeficiency virus type 1 (HIV-1) requires the presence of a CD4 receptor and a chemokine receptor, principally chemokine receptor 5 (CCR5). Homozygosity for a 32-bp deletion...

ORIGINAL ARTICLE: B-Cell Clones as Early Markers for Chronic Lymphocytic Leukemia

Thu, 12Â FebÂ 2009 00:00:00 -05:00

Background: Otherwise healthy persons with a small number of B-cell clones circulating in the peripheral blood have been designated as having monoclonal B-cell lymphocytosis (MBL). Hospital-based series indicate an excess...

CORRESPONDENCE: Prevalence of Mitochondrial 1555AâG Mutation in Adults of European Descent

Thu, 05Â FebÂ 2009 00:00:00 -05:00

To the Editor: Sensorineural hearing loss is the most common type of sensory impairment worldwide.1 We have found that pathogenic mitochondrial DNA (mtDNA) mutations, such as the m.3243AâG mutation associated...

CORRESPONDENCE: Prevalence of Mitochondrial 1555AâG Mutation in European Children

Thu, 05Â FebÂ 2009 00:00:00 -05:00

To the Editor: Aminoglycoside antibiotics are used worldwide to treat gram-negative sepsis. Since these drugs are ototoxic and nephrotoxic, drug levels are closely monitored. However, their effect on patients with...

ORIGINAL ARTICLE: Mutations in in Autosomal Nonsyndromic Mental Retardation

Thu, 05Â FebÂ 2009 00:00:00 -05:00

Although autosomal forms of nonsyndromic mental retardation account for the majority of cases of mental retardation, the genes that are involved remain largely unknown. We sequenced the autosomal gene SYNGAP1,...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Getting to the Heart of Proteomics

Peipei Ping, Ph.D. — Thu, 29Â JanÂ 2009 00:00:00 -05:00

Chen and colleagues1 recently described mitochondrial aldehyde dehydrogenase type 2 (ALDH2) as a target in protecting the heart against ischemic insult. Their study provides insights into cardiovascular biology and may...

EDITORIAL: Acute Lymphoblastic Leukemia â On the Wings of IKAROS

Katia Georgopoulos, Ph.D. — Thu, 29Â JanÂ 2009 00:00:00 -05:00

Acute lymphoblastic leukemia (ALL) with an immature B-cell immunophenotype (B-cellâprogenitor ALL) is a common cancer in children and adolescents, and it also occurs in adults. Cure rates of B-cellâprogenitor ALL...

EDITORIAL: Gene Therapy Fulfilling Its Promise

Donald B. Kohn, M.D., and Fabio Candotti, M.D. — Thu, 29Â JanÂ 2009 00:00:00 -05:00

From its earliest conception, gene therapy held the promise of correcting inherited diseases by inserting a normal copy of the relevant gene into somatic cells.1 Common monogenic diseases of blood...

ORIGINAL ARTICLE: Deletion of and Prognosis in Acute Lymphoblastic Leukemia

Thu, 29Â JanÂ 2009 00:00:00 -05:00

Background: Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number...

ORIGINAL ARTICLE: Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency

Thu, 29Â JanÂ 2009 00:00:00 -05:00

Background: We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency.

Methods:...

EDITORIAL: Clopidogrel, Genetics, and Drug Responsiveness

Jane E. Freedman, M.D., and Elaine M. Hylek, M.D., M.P.H. — Thu, 22Â JanÂ 2009 00:00:00 -05:00

Despite great progress in the diagnosis and treatment of unstable coronary syndromes, it is estimated that 785,000 Americans will have new acute cardiac events and 470,000 will have recurrent events...

ORIGINAL ARTICLE: Genetic Determinants of Response to Clopidogrel and Cardiovascular Events

Thu, 22Â JanÂ 2009 00:00:00 -05:00

Background: Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. The effect of these determinants on clinical outcomes after...

ORIGINAL ARTICLE: Cytochrome P-450 Polymorphisms and Response to Clopidogrel

Thu, 22Â JanÂ 2009 00:00:00 -05:00

Background: Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function.

Methods:...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: The Crossroads of Oncogenesis and Metastasis

Isidro SÃ¡nchez-GarcÃa, M.D., Ph.D. — Thu, 15Â JanÂ 2009 00:00:00 -05:00

The treatment of cancer is generally based on histologic grade, resectability, and the presence or absence of metastasis. Because interventions after the manifestation of metastasis are notoriously ineffective for most...

CORRESPONDENCE: Elimination of Antibodies to Recombinant Enzyme in Pompe's Disease

Thu, 08Â JanÂ 2009 00:00:00 -05:00

To the Editor: Infantile Pompe's disease is due to a deficiency of lysosomal acid alpha glucosidase (GAA). In patients in whom GAA is not produced, a status called cross-reacting immunologic...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 1-2009 â A 57-Year-Old Man with Progressive Cognitive Decline

Thu, 08Â JanÂ 2009 00:00:00 -05:00

Dr. Matthew T. Bianchi (Neurology): A 57-year-old man was transferred to this hospital because of progressive cognitive decline. He had a history of recurrent malignant melanoma of the right conjunctiva...

ORIGINAL ARTICLE: Modulation of Blood Pressure by Central Melanocortinergic Pathways

Thu, 01Â JanÂ 2009 00:00:00 -05:00

Background: Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood pressure...

ORIGINAL ARTICLE: A Syndrome with Congenital Neutropenia and Mutations in

Thu, 01Â JanÂ 2009 00:00:00 -05:00

Background: The main features of severe congenital neutropenia are the onset of severe bacterial infections early in life, a paucity of mature neutrophils, and an increased risk of leukemia. In...

PERSPECTIVE: The Many Causes of Severe Congenital Neutropenia

Thu, 01Â JanÂ 2009 00:00:00 -05:00

In 1956, Rolf Kostmann, a Swedish pediatrician, described an autosomal recessive disorder that he called infantile genetic agranulocytosis â which is now called severe congenital neutropenia. The Kostmann form of...

CORRESPONDENCE: Concordance for Islet Autoimmunity among Monozygotic Twins

Thu, 25Â DecÂ 2008 00:00:00 -05:00

To the Editor: The risk of type 1 diabetes among the monozygotic twins of patients with type 1 diabetes is reported to be as low as 30%; this percentage is...

CORRESPONDENCE: Cardiac Amyloidosis with the Mutation of the Fibrinogen A Î±-Chain

Georges Mourad, M.D., Jean-Philippe Delabre, M.D., and ValÃ©rie Garrigue, M.D. — Thu, 25Â DecÂ 2008 00:00:00 -05:00

To the Editor: Proteinuria developed in a 48-year-old man in 2003. His mother had died 10 years earlier from renal amyloidosis. Laboratory tests showed isolated nephrotic-range proteinuria (urinary protein excretion,...

EDITORIAL: Shared Genetic Risk Factors for Type 1 Diabetes and Celiac Disease

Robert M. Plenge, M.D., Ph.D. — Thu, 25Â DecÂ 2008 00:00:00 -05:00

Some families seem to be afflicted with more than their fair share of chronic illness â and sometimes more than one. Why does a particular disease develop in some members...

REVIEW ARTICLE: Molecular Basis of Metastasis

Anne C. Chiang, M.D., Ph.D., and Joan MassaguÃ©, Ph.D. — Thu, 25Â DecÂ 2008 00:00:00 -05:00

Metastasis is the end product of an evolutionary process in which diverse interactions between cancer cells and their microenvironment yield alterations that allow these cells to transcend their programmed behavior....

ORIGINAL ARTICLE: Inhibition of the Bcl-x Deamidation Pathway in Myeloproliferative Disorders

Thu, 25Â DecÂ 2008 00:00:00 -05:00

Background: The myeloproliferative disorders are clonal disorders with frequent somatic gain-of-function alterations affecting tyrosine kinases. In these diseases, there is an increase in DNA damage and a risk of progression...

ORIGINAL ARTICLE: Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease

Thu, 25Â DecÂ 2008 00:00:00 -05:00

Background: Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Boosting Beta-Cell Numbers

Harry Heimberg, Ph.D. — Thu, 18Â DecÂ 2008 00:00:00 -05:00

The restoration of functional beta-cell mass by cell therapy is possibly the most realistic current option for curing type 1 diabetes mellitus. The transplantation of human islet cells has been...

EDITORIAL: MicroRNA in Cancer Prognosis

Frank J. Slack, Ph.D., and Joanne B. Weidhaas, M.D., Ph.D. — Thu, 18Â DecÂ 2008 00:00:00 -05:00

Ovarian cancer is the leading cause of deaths from gynecologic cancer, and although there are nomograms that use pathological variables to predict outcome for advanced-stage disease,1 few if any molecular...

IMAGES IN CLINICAL MEDICINE: Postpartum Venous Thromboembolism

Ronen Zalts, M.D. and Tony Hayek, M.D. — Thu, 18Â DecÂ 2008 00:00:00 -05:00

A previously healthy 34-year-old woman, gravida 7, para 5, presented on postpartum day 14 with severe low back pain, chest pain, dyspnea, and substantial swelling of both legs after an...

ORIGINAL ARTICLE: Mutation and Congenital Erythrocytosis with Paraganglioma

Thu, 18Â DecÂ 2008 00:00:00 -05:00

Prolyl hydroxylase domain (PHD) proteins play a major role in regulating the hypoxia-inducible factor (HIF) that induces expression of genes involved in angiogenesis, erythropoiesis, and cell metabolism, proliferation, and survival....

ORIGINAL ARTICLE: Dicer, Drosha, and Outcomes in Patients with Ovarian Cancer

Thu, 18Â DecÂ 2008 00:00:00 -05:00

Background: We studied Dicer and Drosha, components of the RNA-interference machinery, in ovarian cancer.

Methods: We measured messenger RNA (mRNA) levels of Dicer and Drosha in specimens of invasive epithelial ovarian...

EDITORIAL: Energy In, Energy Out, and the Effects of Obesity-Related Genes

Rudolph L. Leibel, M.D. — Thu, 11Â DecÂ 2008 00:00:00 -05:00

More than 100 genes have been implicated in the determination of body weight. These genes, acting primarily in or through the central nervous system (primarily the hypothalamus and brain stem),...

ORIGINAL ARTICLE: An Obesity-Associated Gene Variant and Increased Energy Intake in Children

Thu, 11Â DecÂ 2008 00:00:00 -05:00

Background: Variation in the fat mass and obesityâassociated (FTO) gene has provided the most robust associations with common obesity to date. However, the role of FTO variants in modulating specific...

CORRESPONDENCE: Osteosarcoma Derived from Donor Stem Cells Carrying the Norrie's Disease Gene

Thu, 04Â DecÂ 2008 00:00:00 -05:00

To the Editor: There have been few reports of osteosarcoma after allogeneic bone marrow transplantation.1 We report the development of osteosarcoma in a recipient 17 years after stem-cell transplantation.

A 23-month-old...

CORRESPONDENCE: Triglyceride Deposit Cardiomyovasculopathy

Thu, 27Â NovÂ 2008 00:00:00 -05:00

To the Editor: A 41-year-old man was admitted to our hospital with ventricular tachycardia in 2003. Biopsy specimens obtained from the right ventricle showed neutral lipid deposition in cardiomyocytes. In...

EDITORIAL: The Genetics of Speech and Language Impairments

Karin Stromswold, M.D., Ph.D. — Thu, 27Â NovÂ 2008 00:00:00 -05:00

Without instruction, most children master the complexities of spoken language by the age of 6 or 7 years. About 5% of apparently healthy children, however, struggle to acquire basic competence...

EDITORIAL: Microenvironmental Protection in Diffuse Large-B-Cell Lymphoma

Charis Eng, M.D., Ph.D. — Thu, 27Â NovÂ 2008 00:00:00 -05:00

The recent coming of age of genomic techniques and bioinformatics tools has led to an unprecedented proliferation of publications on genomewide association studies and expression profiling for use in genetic...

ORIGINAL ARTICLE: A Functional Genetic Link between Distinct Developmental Language Disorders

Thu, 27Â NovÂ 2008 00:00:00 -05:00

Background: Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific...

ORIGINAL ARTICLE: Stromal Gene Signatures in Large-B-Cell Lymphomas

Thu, 27Â NovÂ 2008 00:00:00 -05:00

Background: The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Attenuation by a Thousand Cuts

John M. Coffin, Ph.D. — Thu, 20Â NovÂ 2008 00:00:00 -05:00

Vaccination with live attenuated virus can be highly effective for the induction of protective immunity and is critical in the prevention of once devastating epidemic diseases. Vaccines containing live attenuated...

ORIGINAL ARTICLE: Clinical Risk Factors, DNA Variants, and the Development of Type 2 Diabetes

Thu, 20Â NovÂ 2008 00:00:00 -05:00

Background: Type 2 diabetes mellitus is thought to develop from an interaction between environmental and genetic factors. We examined whether clinical or genetic factors or both could predict progression to...

ORIGINAL ARTICLE: Genotype Score in Addition to Common Risk Factors for Prediction of Type 2 Diabetes

Thu, 20Â NovÂ 2008 00:00:00 -05:00

Background: Multiple genetic loci have been convincingly associated with the risk of type 2 diabetes mellitus. We tested the hypothesis that knowledge of these loci allows better prediction of risk...

PERSPECTIVE: The Genetic Privacy of Presidential Candidates

Thu, 20Â NovÂ 2008 00:00:00 -05:00

In the wake of the often bitter presidential election, with its emphasis on negative campaigning and intermittent controversies over the release of candidates' health information, it is not too soon...

REVIEW ARTICLE: Inherited Susceptibility to Common Cancers

William D. Foulkes, M.B., B.S., Ph.D. — Thu, 13Â NovÂ 2008 00:00:00 -05:00

Rare, large families with multiple cases of early-onset cancer affecting several generations provide clear evidence that inherited factors are important causes of cancer.1 The range of cancers, the age at...

EDITORIAL: Recurrence of Hepatocellular Carcinoma

Morris Sherman, M.B., B.Ch., Ph.D. — Thu, 06Â NovÂ 2008 00:00:00 -05:00

Although the treatment of hepatocellular carcinoma is evolving, hepatic resection remains the treatment of choice for many patients. Resection is associated with a 5-year survival rate of 50% but also...

EDITORIAL: 17q21 Variants and Asthma â Questions and Answers

John W. Holloway, Ph.D., and Gerard H. Koppelman, M.D., Ph.D. — Thu, 06Â NovÂ 2008 00:00:00 -05:00

It has long been established that many common diseases are the result of interactions between genetic susceptibility and environmental exposure. The identification of genetic variants that underlie susceptibility to diseases...

IMAGES IN CLINICAL MEDICINE: Ankylosing Spondylitis

Kyung-Su Park, M.D. and Young-Seok Cho, M.D. — Thu, 06Â NovÂ 2008 00:00:00 -05:00

A 40-year-old man presented with a 3-day history of increasing abdominal pain. On physical examination, rebound tenderness was present, and both hip joints were fixed in flexion state with no...

ORIGINAL ARTICLE: Gene Expression in Fixed Tissues and Outcome in Hepatocellular Carcinoma

Thu, 06Â NovÂ 2008 00:00:00 -05:00

Background: It is a challenge to identify patients who, after undergoing potentially curative treatment for hepatocellular carcinoma, are at greatest risk for recurrence. Such high-risk patients could receive novel interventional...

ORIGINAL ARTICLE: Effect of 17q21 Variants and Smoking Exposure in Early-Onset Asthma

Thu, 06Â NovÂ 2008 00:00:00 -05:00

Background: A genomewide association study has shown an association between variants at chromosome 17q21 and an increased risk of asthma. To elucidate the relationship between this locus and disease, we...

BOOK REVIEW:

Thu, 30Â OctÂ 2008 00:00:00 -05:00

Molecular epidemiology extends traditional epidemiology studies based on questionnaires by incorporating genetic and molecular measures as biomarkers of exposure, risk, and prognosis. The explosion of genetic information and laboratory methods...

BOOK REVIEW:

Thu, 30Â OctÂ 2008 00:00:00 -05:00

The death in July 2008 of Victor A. McKusick marked the end of an era. McKusick, widely considered to be the founding father of medical genetics, gave both a name...

EDITORIAL: Elevated C-Reactive Protein in Atherosclerosis â Chicken or Egg?

Heribert Schunkert, M.D., and Nilesh J. Samani, M.D., F.Med.Sci. — Thu, 30Â OctÂ 2008 00:00:00 -05:00

One of the most debated topics in cardiovascular medicine is whether C-reactive protein (CRP), a component of the acute-phase response, is a causal factor in the pathogenesis of atherosclerosis.12 If...

ORIGINAL ARTICLE: Genetically Elevated C-Reactive Protein and Ischemic Vascular Disease

Thu, 30Â OctÂ 2008 00:00:00 -05:00

Background: Elevated levels of C-reactive protein (CRP) are associated with increased risks of ischemic heart disease and ischemic cerebrovascular disease. We tested whether this is a causal association.

Methods: We studied...

BOOK REVIEW:

Thu, 23Â OctÂ 2008 00:00:00 -05:00

Recent progress in human and medical genetics has been nothing short of astonishing in its breadth, complexity, and speed. There have been few comprehensive reviews of the ethical and social...

BOOK REVIEW:

Thu, 23Â OctÂ 2008 00:00:00 -05:00

This book introduces an evolutionary approach to medicine and offers the reader extensive coverage of medical topics to which evolutionary principles can be applied. The book's 23 chapters were written...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: The Exercise Pill â Too Good to Be True?

Laurie J. Goodyear, Ph.D. — Thu, 23Â OctÂ 2008 00:00:00 -05:00

Regular physical exercise has undisputed health benefits in the prevention â and in some cases, the treatment â of many diseases. The problem is that for the great majority of...

EDITORIAL: Polymorphisms and the Risk of Invasive Fungal Infections

Eric G. Pamer, M.D. — Thu, 23Â OctÂ 2008 00:00:00 -05:00

Allogeneic hematopoietic stem-cell transplantation is a potentially lifesaving cancer therapy that, at least temporarily, renders patients highly immunocompromised and vulnerable to infection. Aspergillus fumigatus, a common environmental fungus that causes...

EDITORIAL: Targeting EGFR in Colorectal Cancer

Wells A. Messersmith, M.D., and Dennis J. Ahnen, M.D. — Thu, 23Â OctÂ 2008 00:00:00 -05:00

In the United States, cancer is the most common cause of death among people under the age of 85 years, and colorectal cancer is the second most common cause of...

ORIGINAL ARTICLE: Toll-like Receptor 4 Polymorphisms and Aspergillosis in Stem-Cell Transplantation

Thu, 23Â OctÂ 2008 00:00:00 -05:00

Background: Toll-like receptors (TLRs) are essential components of the immune response to fungal pathogens. We examined the role of TLR polymorphisms in conferring a risk of invasive aspergillosis among recipients...

ORIGINAL ARTICLE: Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer

Thu, 23Â OctÂ 2008 00:00:00 -05:00

Background: Treatment with cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer...

EDITORIAL: Cytogenetic Technology â Genotype and Phenotype

David H. Ledbetter, Ph.D. — Thu, 16Â OctÂ 2008 00:00:00 -05:00

In this issue of the Journal, Mefford et al.1 describe an association between a microdeletion at 1q21.1 and a diverse range of impairments: mental retardation associated with microcephaly, cardiac abnormalities,...

ORIGINAL ARTICLE: Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes

Thu, 16Â OctÂ 2008 00:00:00 -05:00

Background: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic...

CLINICAL PRACTICE: Autosomal Dominant Polycystic Kidney Disease

Jared J. Grantham, M.D. — Thu, 02Â OctÂ 2008 00:00:00 -05:00

Autosomal dominant polycystic kidney disease is an inherited systemic disorder with major renal manifestations and, in some cases, abnormalities in the liver, the pancreas, the brain, the arterial blood vessels,...

ORIGINAL ARTICLE: Toll-like Receptor 3 and Geographic Atrophy in Age-Related Macular Degeneration

Thu, 02Â OctÂ 2008 00:00:00 -05:00

Background: Age-related macular degeneration is the most common cause of irreversible visual impairment in the developed world. Advanced age-related macular degeneration consists of geographic atrophy and choroidal neovascularization. The specific...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Cell Therapies for Muscular Dystrophy

Helen M. Blau, Ph.D. — Thu, 25Â SepÂ 2008 00:00:00 -05:00

Duchenne's muscular dystrophy is a devastating, progressive, X-linked muscle-wasting disease. It is the most common form of muscular dystrophy, affecting 1 in 3500 boys. With an onset in early childhood,...

EDITORIAL: Calcific Aortic Stenosis â Time to Look More Closely at the Valve

Catherine M. Otto, M.D. — Thu, 25Â SepÂ 2008 00:00:00 -05:00

Calcific aortic stenosis is a progressive disease that results in stiff valve leaflets with eventual obstruction to left ventricular outflow. Once symptoms occur, valve replacement is the only effective treatment,...

REVIEW ARTICLE: Lung Cancer

Thu, 25Â SepÂ 2008 00:00:00 -05:00

Lung cancer is the leading cause of cancer deaths in the United States1 and worldwide. The two major forms of lung cancer are nonâsmall-cell lung cancer (about 85% of all...

CORRESPONDENCE: Mutation with Primary Hyperparathyroidism and Undetectable Intact PTH

Thu, 11Â SepÂ 2008 00:00:00 -05:00

To the Editor: We describe a case of hypercalcemia associated with the secretion of an abnormally truncated parathyroid hormone (PTH) from a parathyroid adenoma. A 59-year-old postmenopausal woman presenting with...

EDITORIAL: Renal PhosphateâTransporter Regulatory Proteins and Nephrolithiasis

Moshe Levi, M.D., and Sophia Breusegem, Ph.D. — Thu, 11Â SepÂ 2008 00:00:00 -05:00

Nephrolithiasis is a common disorder, and idiopathic hypercalciuria is the most frequent metabolic disorder associated with nephrolithiasis.1 Several studies have shown that subjects with idiopathic hypercalciuria have phosphaturia or renal...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 28-2008 â An 8-Day-Old Infant with Congenital Deafness, Lethargy, and Hypothermia

Thu, 11Â SepÂ 2008 00:00:00 -05:00

Dr. Sarah M. Barnett (Neurology): An 8-day-old boy was admitted to the neonatal intensive care unit of this hospital because of weakness and lethargy.

The patient was born after a full-term...

ORIGINAL ARTICLE: Mutations and Responsiveness of Renal Parathyroid Hormone

Thu, 11Â SepÂ 2008 00:00:00 -05:00

Impaired renal phosphate reabsorption, as measured by dividing the tubular maximal reabsorption of phosphate by the glomerular filtration rate (TmP/GFR), increases the risks of nephrolithiasis and bone demineralization. Data from...

CLINICAL PRACTICE: Hereditary Angioedema

Bruce L. Zuraw, M.D. — Thu, 04Â SepÂ 2008 00:00:00 -05:00

A 19-year-old woman presents to the emergency department with light-headedness, severe abdominal pain, and intractable nausea and vomiting that began 12 hours earlier. The patient reports previous episodes of abdominal...

BOOK REVIEW:

Thu, 28Â AugÂ 2008 00:00:00 -05:00

In 1875, the newly graduated Cambridge polymath Joseph Jacobs wrote a review of George Eliot's last completed novel, Daniel Deronda, the story of a young English gentleman who discovers his...

ORIGINAL ARTICLE: Brain-Derived Neurotrophic Factor and Obesity in the WAGR Syndrome

Thu, 28Â AugÂ 2008 00:00:00 -05:00

Background: Brain-derived neurotrophic factor (BDNF) has been found to be important in energy homeostasis in animal models, but little is known about its role in energy balance in humans. Heterozygous,...

PERSPECTIVE: The Power of the Extreme in Elucidating Obesity

Thu, 28Â AugÂ 2008 00:00:00 -05:00

Despite the worrisome statistics that 16% of children in the United States are obese and that the number of adults with a body-mass index (the weight in kilograms divided by...

EDITORIAL: Pharmacogenomics and Drug Toxicity

Yusuke Nakamura, M.D., Ph.D. — Thu, 21Â AugÂ 2008 00:00:00 -05:00

In the United States alone, it is estimated that adverse drug reactions affect nearly 2 million patients and kill about 100,000 people each year.1 Adverse drug reactions are often classified...

ORIGINAL ARTICLE: Variants and Statin-Induced Myopathy â A Genomewide Study

The SEARCH Collaborative Group — Thu, 21Â AugÂ 2008 00:00:00 -05:00

Background: Lowering low-density lipoprotein cholesterol with statin therapy results in substantial reductions in cardiovascular events, and larger reductions in cholesterol may produce larger benefits. In rare cases, myopathy occurs in...

BOOK REVIEW:

Thu, 14Â AugÂ 2008 00:00:00 -05:00

More than 218,000 new cases of prostate cancer are diagnosed every year in the United States. Great improvements in diagnosis and treatment have been made over the past two decades,...

REVIEW ARTICLE: Chromosomal Abnormalities in Cancer

Stefan FrÃ¶hling, M.D., and Hartmut DÃ¶hner, M.D. — Thu, 14Â AugÂ 2008 00:00:00 -05:00

Cytogenetic abnormalities are a characteristic attribute of cancer cells. To date, clonal chromosome aberrations have been found in all major tumor types from more than 54,000 patients (http://cgap.nci.nih.gov/Chromosomes/Mitelman), and their...

EDITORIAL: Monoclonal B-Cell Lymphocytosis â A Frequent Premalignant Condition

Guillaume Dighiero, M.D., Ph.D. — Thu, 07Â AugÂ 2008 00:00:00 -05:00

Chronic lymphocytic leukemia (CLL), a lymphoproliferative disorder of B cells, is the commonest form of leukemia in Western countries, with an incidence of 6 cases per 100,000 persons in North...

ORIGINAL ARTICLE: Monoclonal B-Cell Lymphocytosis and Chronic Lymphocytic Leukemia

Thu, 07Â AugÂ 2008 00:00:00 -05:00

Background: A diagnosis of chronic lymphocytic leukemia (CLL) requires a count of over 5000 circulating CLL-phenotype cells per cubic millimeter. Asymptomatic persons with fewer CLL-phenotype cells have monoclonal B-cell lymphocytosis...

IMAGES IN CLINICAL MEDICINE: Horizontal Pendular Nystagmus in a Patient with Ocular Albinism

Ariel D. Teitel, M.D. and Josh Rubin, M.D. — Thu, 31Â JulÂ 2008 00:00:00 -05:00

A 32-year-old Hispanic woman with ocular albinism presented with a congenital horizontal pendular nystagmus (see video). Other than being fair-skinned, the patient had no cutaneous manifestations of albinism, and pigmentation...

EDITORIAL: Noninvasive Monitoring of Tumors

Joan H. Schiller, M.D. — Thu, 24Â JulÂ 2008 00:00:00 -05:00

The treatment of nonâsmall-cell lung cancer has made limited but clinically significant progress during the past two decades of clinical research. Through carefully designed clinical trials, investigators have identified several...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 23-2008 â A 26-Year-Old Man with Back Pain and a Mass in the Lung

Thu, 24Â JulÂ 2008 00:00:00 -05:00

A 26-year-old man was admitted to this hospital because of back pain and a mass in the lung. He had been well until 17 days before admission, when he bent...

ORIGINAL ARTICLE: Detection of Mutations in in Circulating Lung-Cancer Cells

Thu, 24Â JulÂ 2008 00:00:00 -05:00

Background: The use of tyrosine kinase inhibitors to target the epidermal growth factor receptor gene (EGFR) in patients with nonâsmall-cell lung cancer is effective but limited by the emergence of...

ORIGINAL ARTICLE: Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection

Thu, 24Â JulÂ 2008 00:00:00 -05:00

Background: We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with...

IMAGES IN CLINICAL MEDICINE: Bifid Uvula and Aortic Aneurysm

Isidre Vilacosta, M.D. and Victoria CaÃ±adas Godoy, M.D. — Thu, 10Â JulÂ 2008 00:00:00 -05:00

A 24-year-old man was hospitalized for evaluation of an aortic-root aneurysm. He had a family history of aortic disease. Physical examination revealed proptosis, retrognathia, bifid uvula (Panel A), and pectus...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 21-2008 â An 11-Month-Old Boy with Fever and Pulmonary Infiltrates

Thu, 10Â JulÂ 2008 00:00:00 -05:00

An 11-month-old boy was admitted to this hospital because of fevers and pulmonary infiltrates. One month before admission, a month after beginning a visit to India with his parents, daily...

ORIGINAL ARTICLE: Atrial Natriuretic Peptide Frameshift Mutation in Familial Atrial Fibrillation

Thu, 10Â JulÂ 2008 00:00:00 -05:00

Atrial fibrillation is a common arrhythmia that is hereditary in a small subgroup of patients. In a family with 11 clinically affected members, we mapped an atrial fibrillation locus to...

ORIGINAL ARTICLE: Familial Myeloma

Thu, 10Â JulÂ 2008 00:00:00 -05:00

We describe a family with five cases of multiple myeloma, three cases of monoclonal gammopathy of undetermined significance (MGUS), and five cases of prostate cancer in two generations. The putative...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Removing the Golden Coat of

Robert S. Daum, M.D. — Thu, 03Â JulÂ 2008 00:00:00 -05:00

Infections caused by Staphylococcus aureus, particularly those that are resistant to methicillin and all available Î²-lactam antibiotics â the so-called methicillin-resistant S. aureus (MRSA) infections â have been declared a...

REVIEW ARTICLE: Effect of In Utero and Early-Life Conditions on Adult Health and Disease

Thu, 03Â JulÂ 2008 00:00:00 -05:00

A long latency period between an environmental trigger and the onset of subsequent disease is widely recognized in the etiology of certain cancers, yet this phenomenon is not generally considered...

BOOK REVIEW:

Thu, 03Â JulÂ 2008 00:00:00 -05:00

It must have been a daunting task to produce a comprehensive account of the extraordinary advances in the genetics, molecular mechanisms, diagnosis, and treatment of cardiac arrhythmias. Ihor Gussak and...

EDITORIAL: A Small Molecule for a Large Disease

Reed E. Pyeritz, M.D., Ph.D. — Thu, 26Â JunÂ 2008 00:00:00 -05:00

Almost three decades ago, Victor McKusick and I reviewed Marfan's syndrome in the Journal and advised traditional medical and surgical approaches to management.1 The holy grail at that time was...

SPECIAL ARTICLE: Polygenes, Risk Prediction, and Targeted Prevention of Breast Cancer

Thu, 26Â JunÂ 2008 00:00:00 -05:00

Background: New developments in the search for susceptibility alleles in complex disorders provide support for the possibility of a polygenic approach to the prevention and treatment of common diseases.

Methods: We...

ORIGINAL ARTICLE: Angiotensin II Blockade and Aortic-Root Dilation in Marfan's Syndrome

Thu, 26Â JunÂ 2008 00:00:00 -05:00

Background: Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome...

PERSPECTIVE: From Darwin's Finches to Canaries in the Coal Mine â Mining the Genome for New Biology

Thu, 26Â JunÂ 2008 00:00:00 -05:00

The observations of finches that Charles Darwin made while in the Galapagos contributed to his theory of the origins of interspecies differences, ultimately leading to our understanding of mutation and...

PERSPECTIVE: Keeping Pace with the Times â The Genetic Information Nondiscrimination Act of 2008

Thu, 19Â JunÂ 2008 00:00:00 -05:00

When the first federal legislation to prevent the misuse of genetic information was introduced in 1995, many in the health care, research, and policy communities considered the measure to be...

EDITORIAL: Neuroblastoma â Linking a Common Allele to a Rare Disease

Brian H. Kushner, M.D., and Nai-Kong V. Cheung, M.D., Ph.D. — Thu, 12Â JunÂ 2008 00:00:00 -05:00

Neuroblastoma has a notorious reputation among solid tumors of childhood because of its frequently massive and widespread tumor burden. Yet stage for stage, this embryonal neoplasm of the sympathetic nervous...

ORIGINAL ARTICLE: Chromosome 6p22 Locus Associated with Clinically Aggressive Neuroblastoma

Thu, 12Â JunÂ 2008 00:00:00 -05:00

Background: Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known.

Methods: We performed a...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Metabolism and Therapeutic Angiogenesis

Peter Carmeliet, M.D., Ph.D., and Myriam Baes, Ph.D. — Thu, 05Â JunÂ 2008 00:00:00 -05:00

Despite great expectations, therapeutic angiogenesis with the vascular endothelial growth factor (VEGF) and related molecules for the treatment of ischemic heart and peripheral arterial occlusive disease has thus far failed...

EDITORIAL: Bona Fide Genetic Associations with Bone Mineral Density

Joel N. Hirschhorn, M.D., Ph.D., and Luigi Gennari, M.D., Ph.D. — Thu, 29Â MayÂ 2008 00:00:00 -05:00

Osteoporosis is a common skeletal disorder characterized by compromised bone strength and increased bone fragility, affecting up to 40% of postmenopausal women and 15% of men.1 Its clinical significance lies...

ORIGINAL ARTICLE: Multiple Genetic Loci for Bone Mineral Density and Fractures

Thu, 29Â MayÂ 2008 00:00:00 -05:00

Background: Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated...

EDITORIAL: Preliminary Results of Gene Therapy for Retinal Degeneration

Joan W. Miller, M.D. — Thu, 22Â MayÂ 2008 00:00:00 -05:00

In this issue of the Journal, two groups of investigators â Bainbridge et al.1 and Maguire et al.2 â describe the first results of separate clinical trials investigating the short-term...

ORIGINAL ARTICLE: Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis

Thu, 22Â MayÂ 2008 00:00:00 -05:00

Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epitheliumâspecific...

ORIGINAL ARTICLE: Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis

Thu, 22Â MayÂ 2008 00:00:00 -05:00

Early-onset, severe retinal dystrophy caused by mutations in the gene encoding retinal pigment epitheliumâspecific 65-kD protein (RPE65) is associated with poor vision at birth and complete loss of vision in...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: A New Weapon for Attacking Tumor Blood Vessels

Gregg L. Semenza, M.D., Ph.D. — Thu, 08Â MayÂ 2008 00:00:00 -05:00

The approval by the Food and Drug Administration of bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF),1 sparked enormous excitement among oncologists. Bevacizumab, the first cancer therapy...

REVIEW ARTICLE: Tumor Angiogenesis

Robert S. Kerbel, Ph.D. — Thu, 08Â MayÂ 2008 00:00:00 -05:00

The current era of research in antiangiogenic therapy for cancer began in earnest in 1971 with the publication of Folkman's imaginative hypothesis,1 but 33 years would elapse before the first...

ORIGINAL ARTICLE: An Immunodeficiency Disease with Mutations and Granulomas

Thu, 08Â MayÂ 2008 00:00:00 -05:00

We describe three unrelated girls who had an immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. All three girls had severe complications after viral infections, including...

EDITORIAL: Diagnosis and Prognosis in Acute Myeloid Leukemia â The Art of Distinction

Bob LÃ¶wenberg, M.D., Ph.D. — Thu, 01Â MayÂ 2008 00:00:00 -05:00

The days when the microscope was the principal tool for classifying the various forms of acute myeloid leukemia (AML) and predicting the outcome of affected patients seem long past. The...

ORIGINAL ARTICLE: MicroRNA Expression in Cytogenetically Normal Acute Myeloid Leukemia

Thu, 01Â MayÂ 2008 00:00:00 -05:00

Background: A role of microRNAs in cancer has recently been recognized. However, little is known about the role of microRNAs in acute myeloid leukemia (AML).

Methods: Using microRNA expression profiling, we...

ORIGINAL ARTICLE: Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia

Thu, 01Â MayÂ 2008 00:00:00 -05:00

Background: Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT/enhancer binding protein Î±...

ORIGINAL ARTICLE: Shared Genetic Causes of Cardiac Hypertrophy in Children and Adults

Thu, 01Â MayÂ 2008 00:00:00 -05:00

Background: The childhood onset of idiopathic cardiac hypertrophy that occurs without a family history of cardiomyopathy can portend a poor prognosis. Despite morphologic similarities to genetic cardiomyopathies of adulthood, the...

EDITORIAL: Reduce, Recycle, Reuse â Iodotyrosine Deiodinase in Thyroid Iodide Metabolism

Peter A. Kopp, M.D. — Thu, 24Â AprÂ 2008 00:00:00 -05:00

Thyroid hormones are essential for normal brain development, growth, and metabolism. Their synthesis is dependent on a normally developed thyroid gland, an adequate nutritional intake of iodide, and a series...

EDITORIAL: A Malaria Fingerprint in the Human Genome?

Johanna P. Daily, M.D., and Pardis Sabeti, M.D., Ph.D. — Thu, 24Â AprÂ 2008 00:00:00 -05:00

Malaria, a tremendously successful pathogen that is responsible for more than 300 million cases and 1 million deaths annually,1 has had a large impact on the shape of the human...

ORIGINAL ARTICLE: Mutations in the Iodotyrosine Deiodinase Gene and Hypothyroidism

Thu, 24Â AprÂ 2008 00:00:00 -05:00

DEHAL1 has been identified as the gene encoding iodotyrosine deiodinase in the thyroid, where it controls the reuse of iodide for thyroid hormone synthesis. We screened patients with hypothyroidism who...

ORIGINAL ARTICLE: Pyruvate Kinase Deficiency and Malaria

Thu, 24Â AprÂ 2008 00:00:00 -05:00

Malaria that is caused by Plasmodium falciparum is a significant global health problem. Genetic characteristics of the host influence the severity of disease and the ultimate outcome of infection, and...

ORIGINAL ARTICLE: Effect of Variation in on Serum YKL-40 Level, Risk of Asthma, and Lung Function

Thu, 17Â AprÂ 2008 00:00:00 -05:00

Background: The chitinase-like protein YKL-40 is involved in inflammation and tissue remodeling. We recently showed that serum YKL-40 levels were elevated in patients with asthma and were correlated with severity,...

ORIGINAL ARTICLE: Gene Identification for the cblD Defect of Vitamin B Metabolism

Thu, 03Â AprÂ 2008 00:00:00 -05:00

Background: Vitamin B12 (cobalamin) is an essential cofactor in several metabolic pathways. Intracellular conversion of cobalamin to its two coenzymes, adenosylcobalamin in mitochondria and methylcobalamin in the cytoplasm, is necessary...

ORIGINAL ARTICLE: Polymorphisms Associated with Cholesterol and Risk of Cardiovascular Events

Thu, 20Â MarÂ 2008 00:00:00 -05:00

Background: Common single-nucleotide polymorphisms (SNPs) that are associated with blood low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol modestly affect lipid levels. We tested the hypothesis that a combination of...

REVIEW ARTICLE: Epigenetics in Cancer

Manel Esteller, M.D., Ph.D. — Thu, 13Â MarÂ 2008 00:00:00 -05:00

Classic genetics alone cannot explain the diversity of phenotypes within a population. Nor does classic genetics explain how, despite their identical DNA sequences, monozygotic twins1 or cloned animals2 can have...

ORIGINAL ARTICLE: DNA Methylation Markers and Early Recurrence in Stage I Lung Cancer

Thu, 13Â MarÂ 2008 00:00:00 -05:00

Background: Despite optimal and early surgical treatment of nonâsmall-cell lung cancer (NSCLC), many patients die of recurrent NSCLC. We investigated the association between gene methylation and recurrence of the tumor.

Methods:...

ORIGINAL ARTICLE: Genetic Determinants of Response to Warfarin during Initial Anticoagulation

Thu, 06Â MarÂ 2008 00:00:00 -05:00

Background: Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9), and of a key pharmacologic target of warfarin, vitamin K epoxide reductase (VKORC1), contribute to differences in...

ORIGINAL ARTICLE: A New Arenavirus in a Cluster of Fatal Transplant-Associated Diseases

Thu, 06Â MarÂ 2008 00:00:00 -05:00

Background: Three patients who received visceral-organ transplants from a single donor on the same day died of a febrile illness 4 to 6 weeks after transplantation. Culture, polymerase-chain-reaction (PCR) and...

PERSPECTIVE: The New Age of Molecular Diagnostics for Microbial Agents

Thu, 06Â MarÂ 2008 00:00:00 -05:00

How, in this era of molecular diagnostic tests, can we best determine whether there is a causal relationship between the presence of a genetic signature of an infectious agent and...

EDITORIAL: Pharmacogenomics â Ready for Prime Time?

Susan B. Shurin, M.D., and Elizabeth G. Nabel, M.D. — Thu, 06Â MarÂ 2008 00:00:00 -05:00

Pharmacogenomics is receiving a great deal of attention in scientific circles and, increasingly, in the popular press because of the promise of personalized medicine. Short of being able to cure...

ORIGINAL ARTICLE: Autoimmune Polyendocrine Syndrome Type 1 and NALP5, a Parathyroid Autoantigen

Thu, 06Â MarÂ 2008 00:00:00 -05:00

Background: Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: A New Dawn for Stem-Cell Therapy

Douglas R. Higgs, M.D., D.Sc. — Thu, 28Â FebÂ 2008 00:00:00 -05:00

Recently, the potential use of stem cells for regenerative medicine and for the treatment of genetic disease has rarely been out of the news. Discussion has focused mainly on the...

EDITORIAL: Complexities of Prostate-Cancer Risk

Edward P. Gelmann, M.D. — Thu, 28Â FebÂ 2008 00:00:00 -05:00

As men age, prostate epithelial cells are subjected to substantial stresses, and these stresses can damage DNA, thereby causing cellular transformation. The aging prostate gland acquires numerous foci of cancer...

EDITORIAL: Collaboration, Genetic Associations, and Lupus Erythematosus

Mary K. Crow, M.D. — Thu, 28Â FebÂ 2008 00:00:00 -05:00

Systemic lupus erythematosus (SLE), a disease that preferentially targets women during the reproductive years, is considered by many clinicians and investigators to be the prototypic autoimmune disease. Among clinicians, this...

ORIGINAL ARTICLE: Cumulative Association of Five Genetic Variants with Prostate Cancer

Thu, 28Â FebÂ 2008 00:00:00 -05:00

Background: Single-nucleotide polymorphisms (SNPs) in five chromosomal regions â three at 8q24 and one each at 17q12 and 17q24.3 â have been associated with prostate cancer. Each SNP has only...

ORIGINAL ARTICLE: Association of Systemic Lupus Erythematosus with and

Thu, 28Â FebÂ 2008 00:00:00 -05:00

Background: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Structural Genomic Variation and Personalized Medicine

Charles Lee, Ph.D., and Cynthia C. Morton, Ph.D. — Thu, 14Â FebÂ 2008 00:00:00 -05:00

The ultimate goal of personalized medicine is to comprehensively identify genetic differences among persons and to correlate specific genetic features (or combinations of genetic features) with the differential risk of...

EDITORIAL: A Hot Spot of Genetic Instability in Autism

Evan E. Eichler, Ph.D., and Andrew W. Zimmerman, M.D. — Thu, 14Â FebÂ 2008 00:00:00 -05:00

Sixty-five years after Leo Kanner first described autism,1 we are beginning to move beyond description of this clinically heterogeneous neurobehavioral syndrome toward a deeper understanding of its biologic complexity. In...

ORIGINAL ARTICLE: A -Activating Mutation in a Patient with Central Precocious Puberty

Thu, 14Â FebÂ 2008 00:00:00 -05:00

Gonadotropin-dependent, or central, precocious puberty is caused by early maturation of the hypothalamicâpituitaryâgonadal axis. In girls, this condition is most often idiopathic. Recently, a G proteinâcoupled receptor, GPR54, and its...

ORIGINAL ARTICLE: Association between Microdeletion and Microduplication at 16p11.2 and Autism

Thu, 14Â FebÂ 2008 00:00:00 -05:00

Background: Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role.

Methods: As a first component of a genomewide association study of families...

EDITORIAL: Pharmacogenomic Biomarkers for Prediction of Severe Adverse Drug Reactions

Magnus Ingelman-Sundberg, Ph.D., B.Sc.Med. — Thu, 07Â FebÂ 2008 00:00:00 -05:00

The accumulating knowledge of human genomic variation is being used for the development of personalized medicine, with the aims of decreasing the number of adverse drug reactions and increasing the...

CLINICAL PROBLEM-SOLVING: What's the Connection? â A 26-year-old white man presented to our referral hospital with a 1-month history of persistent cough productive of white sputum, which was occasionally tinged with blood

Thu, 07Â FebÂ 2008 00:00:00 -05:00

A 26-year-old white man presented to our referral hospital with a 1-month history of persistent cough productive of white sputum, which was occasionally tinged with blood. He reported mild pleuritic...

ORIGINAL ARTICLE: Neonatal Diagnosis and Treatment of Menkes Disease

Thu, 07Â FebÂ 2008 00:00:00 -05:00

Background: Menkes disease is a fatal neurodegenerative disorder of infancy caused by diverse mutations in a copper-transport gene, ATP7A. Early treatment with copper injections may prevent death and illness, but...

ORIGINAL ARTICLE: Phenotype and Course of HutchinsonâGilford Progeria Syndrome

Thu, 07Â FebÂ 2008 00:00:00 -05:00

Background: HutchinsonâGilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or...

ORIGINAL ARTICLE: HLA-B*5701 Screening for Hypersensitivity to Abacavir

Thu, 07Â FebÂ 2008 00:00:00 -05:00

Background: Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the...

PERSPECTIVE: HutchinsonâGilford Progeria Syndrome, Aging, and the Nuclear Lamina

Thu, 07Â FebÂ 2008 00:00:00 -05:00

We are living in a time that will probably be remembered as a golden age of discovery in human genetics. Most of the recent excitement has focused on the identification...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Inflammatory Bowel Disease â Live Transmission

Gail A. Hecht, M.D. — Thu, 31Â JanÂ 2008 00:00:00 -05:00

Inflammatory bowel disease results from a dysregulated immunologic response to commensal microbial flora residing in the intestinal lumen. Although this response is probably due at least in part to a...

EDITORIAL: Molecular Origins of Cancer

Harold J. Burstein, M.D., Ph.D., and Robert S. Schwartz, M.D. — Thu, 31Â JanÂ 2008 00:00:00 -05:00

Over the past decade, insights into the origins and behavior of human cancers have reshaped our understanding of these diseases and have generated advances in clinical care. The seminal feature...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 4-2008 â A 33-Year-Old Pregnant Woman with Swelling of the Left Breast and Shortness of Breath

Lawrence N. Shulman, M.D., Rachel A. Hitt, M.D., and Judith A. Ferry, M.D. — Thu, 31Â JanÂ 2008 00:00:00 -05:00

A 33-year-old pregnant woman was admitted to the hospital at 30.7 weeks' gestation because of swelling of the left breast, shortness of breath, and tachycardia.

The patient had received prenatal care...

REVIEW ARTICLE: Oncogenes and Cancer

Carlo M. Croce, M.D. — Thu, 31Â JanÂ 2008 00:00:00 -05:00

Cancer is caused by alterations in oncogenes, tumor-suppressor genes, and microRNA genes. These alterations are usually somatic events, although germ-line mutations can predispose a person to heritable or familial cancer....

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 3-2008 â An 80-Year-Old Woman with Cutaneous Basal-Cell Carcinomas and Cysts of the Jaws

Ervin H. Epstein, M.D., Jo-Anne O. Shepard, M.D., and Thomas J. Flotte, M.D. — Thu, 24Â JanÂ 2008 00:00:00 -05:00

Dr. Gabriela Rolz-Cruz (Dermatology): An 80-year-old woman was seen in the outpatient clinic of this hospital for management of recurrent ulcerated skin lesions on the scalp.

When the patient was approximately...

ORIGINAL ARTICLE: HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression

Thu, 24Â JanÂ 2008 00:00:00 -05:00

08012430.xml 08012430.xml 08012430.xml 08012430.xml Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a...

EDITORIAL: Clinical Penetrance of Hereditary Hemochromatosis

Bruce R. Bacon, M.D., and Robert S. Britton, Ph.D. — Thu, 17Â JanÂ 2008 00:00:00 -05:00

In 1996, Feder and colleagues1 showed that homozygosity for a mutation (C282Y) in the HFE gene is responsible for the majority of cases of typical phenotypic hereditary hemochromatosis. At that...

IMAGES IN CLINICAL MEDICINE: Leukemic Gingival Infiltration

Aparna Mani, M.S. and David A. Lee, M.D. — Thu, 17Â JanÂ 2008 00:00:00 -05:00

An otherwise healthy 36-year-old man presented with a 6-day history of bleeding gums and abdominal pain in the left upper quadrant. He reported having had fevers, fatigue, decreased appetite, and...

ORIGINAL ARTICLE: Iron-OverloadâRelated Disease in Hereditary Hemochromatosis

Thu, 17Â JanÂ 2008 00:00:00 -05:00

Background: Most persons who are homozygous for C282Y, the HFE allele most commonly asssociated with hereditary hemochromatosis, have elevated levels of serum ferritin and transferrin saturation. Diseases related to iron...

EDITORIAL: Efficacy of Sirolimus in Treating Tuberous Sclerosis and Lymphangioleiomyomatosis

Elahna Paul, M.D., Ph.D., and Elizabeth Thiele, M.D., Ph.D. — Thu, 10Â JanÂ 2008 00:00:00 -05:00

Owing to their immunosuppressive and antiproliferative effects, sirolimus (also called rapamycin) and related drugs are being evaluated as part of many transplant immunosuppresion regimens, as well as for a plethora...

IMAGES IN CLINICAL MEDICINE: Spontaneous Pneumothorax in Tuberous Sclerosis

Rajeev L. Narayan, M.D. — Thu, 10Â JanÂ 2008 00:00:00 -05:00

A 28-year-old woman with tuberous sclerosis presented with sudden onset of dyspnea and discomfort in the right chest and back. On examination she had tachycardia, tachypnea, and hypoxia, with an...

CLINICAL PRACTICE: Long-QT Syndrome

Dan M. Roden, M.D. — Thu, 10Â JanÂ 2008 00:00:00 -05:00

After the sudden death of a 13-year-old girl while she was playing basketball, her family comes to the clinic for medical evaluation (Figure 1). Her parents' resting electrocardiograms (ECGs) are...

ORIGINAL ARTICLE: A Gain-of-Function Mutation in the Gene in Familial Erythrocytosis

Thu, 10Â JanÂ 2008 00:00:00 -05:00

Hypoxia-inducible factor (HIF) Î±, which has three isoforms, is central to the continuous balancing of the supply and demand of oxygen throughout the body. HIF-Î± is a transcription factor that...

ORIGINAL ARTICLE: Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis

Thu, 10Â JanÂ 2008 00:00:00 -05:00

Background: Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin...

PERSPECTIVE: Letting the Genome Out of the Bottle â Will We Get Our Wish?

Thu, 10Â JanÂ 2008 00:00:00 -05:00

It may happen soon. A patient, perhaps one you have known for years, who is overweight and does not exercise regularly, shows up in your office with an analysis of...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: B-Cell Identity â Commitment Is Not Forever

Stephen L. Nutt, Ph.D. — Thu, 03Â JanÂ 2008 00:00:00 -05:00

A general rule of cell biology is that once a cell commits to a particular differentiation pathway, there is no turning back. It is thought that the event triggering differentiation...

EDITORIAL: Skipping toward Personalized Molecular Medicine

Eric P. Hoffman, Ph.D. — Thu, 27Â DecÂ 2007 00:00:00 -05:00

âPersonalized molecular medicine.â As with other catchy terms for big ideas, such as âreversing global warmingâ and ârenewable energy,â the concept of personalized molecular medicine is certainly important, but the...

ORIGINAL ARTICLE: Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and Muscle Cramps

Thu, 27Â DecÂ 2007 00:00:00 -05:00

Background: COL4A3, COL4A4, and COL4A5 are the only collagen genes that have been implicated in inherited nephropathies in humans. However, the causative genes for a number of hereditary multicystic kidney...

ORIGINAL ARTICLE: Local Dystrophin Restoration with Antisense Oligonucleotide PRO051

Thu, 27Â DecÂ 2007 00:00:00 -05:00

Background: Duchenne's muscular dystrophy is associated with severe, progressive muscle weakness and typically leads to death between the ages of 20 and 35 years. By inducing specific exon skipping during...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Small RNAs and Large DNA Viruses

Jay A. Nelson, Ph.D. — Thu, 20Â DecÂ 2007 00:00:00 -05:00

Although most human cytomegalovirus (CMV) infections are asymptomatic, CMV is a significant pathogen in immunosuppressed patients such as patients with AIDS and those who receive immunosuppressive therapy after solid-organ or...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 39-2007 â A 5-Month-Old Girl with Skin Lesions

Melissa M. Burnett, M.D., Mary S. Huang, M.D., and Rania M. Seliem, M.D. — Thu, 20Â DecÂ 2007 00:00:00 -05:00

Dr. Ruth Ann Vleugels (Dermatology): A 5-month-old girl was seen in the pediatric dermatology clinic because of a rash. She had been well until 3 months of age, when her...

ORIGINAL ARTICLE: Mutations and Survival in Squamous-Cell Carcinoma of the Head and Neck

Thu, 20Â DecÂ 2007 00:00:00 -05:00

Background: The abrogation of function of the tumor-suppressor protein p53 as a result of mutation of its gene, TP53, is one of the most common genetic alterations in cancer cells....

ORIGINAL ARTICLE: Breast-Cancer Stromal Cells with Mutations and Nodal Metastases

Thu, 20Â DecÂ 2007 00:00:00 -05:00

Background: The importance of cross-talk between a cancer and its microenvironment has been increasingly recognized. We hypothesized that mutational inactivation of the tumor-suppressor gene TP53 and genomic alterations in stromal...

PERSPECTIVE: p53 â Master and Commander

Thu, 20Â DecÂ 2007 00:00:00 -05:00

The gene known variously as p53, TP53, and Trp53 is currently featured in nearly 45,000 published articles listed in PubMed â a remarkable number suggesting that the protein product of...

PERSPECTIVE: Stromal Effects in Breast Cancer

Thu, 20Â DecÂ 2007 00:00:00 -05:00

Investigations into the interaction between epithelial cancer cells and adjacent stroma have revealed paracrine interactions that enhance the tumorigenic characteristics of the cancer cell.1 Tumor-associated stroma have been reported to...

PERSPECTIVE: Knock Out, Knock In, Knock Down â Genetically Manipulated Mice and the Nobel Prize

Thu, 13Â DecÂ 2007 00:00:00 -05:00

In Stockholm this fall, the Nobel Prize in Medicine or Physiology was awarded to Martin Evans, Oliver Smithies, and Mario Capecchi for their discoveries of âprinciples for introducing specific gene...

CLINICAL PROBLEM-SOLVING: The Leading Diagnosis â A 23-year-old black woman presented to the emergency department with diffuse, colicky abdominal pain of 1 hour's duration

Thomas E. Baudendistel, M.D., Amy K. Haase, M.D., and Faith Fitzgerald, M.D. — Thu, 06Â DecÂ 2007 00:00:00 -05:00

A 23-year-old black woman presented to the emergency department with diffuse, colicky abdominal pain of 1 hour's duration. The pain was followed by nausea and episodes of bilious vomiting and...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: The Liver X Receptor and Atherosclerosis

James Scott, M.B., B.S. — Thu, 22Â NovÂ 2007 00:00:00 -05:00

Cardiovascular disease is the leading cause of death in the developed world, and it is poised to become the most widespread health problem worldwide. Atherosclerosis is the major cause of...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Hepatocellular Carcinoma and Sex

Jack Wands, M.D. — Thu, 08Â NovÂ 2007 00:00:00 -05:00

Hepatocellular carcinoma is an important disease worldwide, with an increasing incidence in the United States. The large majority of cases occur in patients with chronic infection with hepatitis B virus...

REVIEW ARTICLE: Celiac Disease

Peter H.R. Green, M.D., and Christophe Cellier, M.D., Ph.D. — Thu, 25Â OctÂ 2007 00:00:00 -05:00

Celiac disease is a unique autoimmune disorder, unique because the environmental precipitant is known. The disorder was previously called celiac sprue, based on the Dutch word sprue, which was used...

EDITORIAL: STAT3 Signaling and the Hyper-IgE Syndrome

David E. Levy, Ph.D., and Cynthia A. Loomis, M.D., Ph.D. — Thu, 18Â OctÂ 2007 00:00:00 -05:00

The Janus kinase (JAK)âsignal transducer and activator of transcription (STAT) signaling pathway has emerged over the past decade as a major relay between cell-surface receptors and cytokine responses. The human...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 32-2007 â A 62-Year-Old Woman with a Second Breast Cancer

Thu, 18Â OctÂ 2007 00:00:00 -05:00

Dr. David A. Barbie (Medical Oncology): A 62-year-old woman came to this hospital for management of breast cancer.

Six years earlier, a routine mammogram had revealed calcifications in the left breast....

IMAGES IN CLINICAL MEDICINE: FLT3 Mutation and Acute Myelogenous Leukemia with Leukostasis

Katherine A. Thornton, M.D. and Mark Levis, M.D., Ph.D. — Thu, 18Â OctÂ 2007 00:00:00 -05:00

A 59-year-old man presented with a sudden onset of abdominal pain in the left upper quadrant, associated with low-grade fever and shortness of breath. He had had a recent relapse...

ORIGINAL ARTICLE: Mutations in the Hyper-IgE Syndrome

Thu, 18Â OctÂ 2007 00:00:00 -05:00

Background: The hyper-IgE syndrome (or Job's syndrome) is a rare disorder of immunity and connective tissue characterized by dermatitis, boils, cyst-forming pneumonias, elevated serum IgE levels, retained primary dentition, and...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Periostin and Myocardial Repair, Regeneration, and Recovery

Gerald W. Dorn II, M.D. — Thu, 11Â OctÂ 2007 00:00:00 -05:00

Early reperfusion therapy for myocardial infarction has transformed the treatment of this disease. The restoration of blood flow to the heart within hours after thrombotic coronary occlusion reduces infarct size,...

ORIGINAL ARTICLE: Cardiomyopathy and Exercise Intolerance in Muscle Glycogen Storage Disease 0

Thu, 11Â OctÂ 2007 00:00:00 -05:00

Storage of glycogen is essential for glucose homeostasis and for energy supply during bursts of activity and sustained muscle work. We describe three siblings with profound muscle and heart glycogen...

PERSPECTIVE: Pluripotency Redux â Advances in Stem-Cell Research

Thu, 11Â OctÂ 2007 00:00:00 -05:00

Acell's ability to give to rise to all the cell types of the embryo and the adult organism is called pluripotency. Pluripotent cells are found within mammalian blastocysts and persist...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Viral Infections and Nonspecific Protection â Good or Bad?

Emil R. Unanue, M.D. — Thu, 27Â SepÂ 2007 00:00:00 -05:00

Viruses, like many microbes, have complex and diverse relationships with the immune system. We need to kill or control viruses to survive as a species, but under special circumstances, we...

ORIGINAL ARTICLE: Evidence of MEN-2 in the Original Description of Classic Pheochromocytoma

Thu, 27Â SepÂ 2007 00:00:00 -05:00

The first description of pheochromocytoma in 1886 has been attributed to Felix FrÃ¤nkel, who described an 18-year-old woman with bilateral adrenal âsarcoma and angio-sarcoma.â We reviewed the publication and then...

EDITORIAL: Lessons from a Genomewide Association Study of Rheumatoid Arthritis

Kazuhiko Yamamoto, M.D., Ph.D., and Ryo Yamada, M.D., Ph.D. — Thu, 20Â SepÂ 2007 00:00:00 -05:00

Rheumatoid arthritis is a chronic inflammatory disorder in which the articular joints are gradually destroyed. Occasionally there is systemic involvement, which can include vasculitis in various organs and pulmonary fibrosis....

ORIGINAL ARTICLE: A Polymorphism in the Promoter Region Associated with Systemic Sclerosis

Thu, 20Â SepÂ 2007 00:00:00 -05:00

Background: Systemic sclerosis (scleroderma) is a life-threatening autoimmune disease that is characterized by the presence of specific autoantibodies and fibrosis of the skin and major internal organs.

Methods: We genotyped a...

ORIGINAL ARTICLE: as a Risk Locus for Rheumatoid Arthritis â A Genomewide Study

Thu, 20Â SepÂ 2007 00:00:00 -05:00

Background: Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently....

CLINICAL IMPLICATIONS OF BASIC RESEARCH: On Prions, Proteasomes, and Mad Cows

Alfred L. Goldberg, Ph.D. — Thu, 13Â SepÂ 2007 00:00:00 -05:00

All cells have the capacity to selectively degrade misfolded intracellular proteins, which, if they accumulated, could interfere with normal function and could be toxic. Such proteins may arise by mutation,...

ORIGINAL ARTICLE: and the Risk of Rheumatoid Arthritis and Systemic Lupus Erythematosus

Thu, 06Â SepÂ 2007 00:00:00 -05:00

Background: Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q.

Methods: We tested single-nucleotide polymorphisms (SNPs)...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: A Tale about Tau

Karen H. Ashe, M.D., Ph.D. — Thu, 30Â AugÂ 2007 00:00:00 -05:00

During the next few decades, millions of baby boomers will enter their 70s, 80s, and 90s, quadrupling the number of patients with Alzheimer's disease, the leading cause of dementia in...

EDITORIAL: Experiments of Nature â A Glimpse into the Mysteries of the Pubertal Clock

Shalender Bhasin, M.D. — Thu, 30Â AugÂ 2007 00:00:00 -05:00

In an extraordinary display of nature's myriad intricacies, in higher mammals the gonadotropin-releasing hormone (GnRH) pulse generator, which drives the pulsatile secretion of gonadotropin and sex steroids, is kept in...

EDITORIAL: Old Suspects Found Guilty â The First Genome Profile of Multiple Sclerosis

Leena Peltonen, M.D., Ph.D. — Thu, 30Â AugÂ 2007 00:00:00 -05:00

High-resolution genomewide association studies using panels of 300,000 to 1 million single-nucleotide polymorphisms (SNPs) aim to define genetic risk profiles of common diseases. These studies herald a fundamentally new opportunity...

ORIGINAL ARTICLE: Luteinizing Hormone Beta Mutation and Hypogonadism in Men and Women

Thu, 30Â AugÂ 2007 00:00:00 -05:00

Selective luteinizing hormone deficiency due to mutations in the luteinizing hormone beta-subunit gene (LHB) is a rare cause of hypogonadism. We describe the clinical features of a consanguineous family in...

ORIGINAL ARTICLE: Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study

The International Multiple Sclerosis Genetics Consortium — Thu, 30Â AugÂ 2007 00:00:00 -05:00

Background: Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis.

Methods: We used DNA microarray technology...

IMAGES IN CLINICAL MEDICINE: PeutzâJeghers Syndrome

Elizabeth Cureton, M.D. and Sunghoon Kim, M.D. — Thu, 23Â AugÂ 2007 00:00:00 -05:00

A previously healthy 12-year-old boy presented with abdominal pain, vomiting, and abdominal distention of 3 days' duration. On physical examination, hyperpigmented macules were seen on his lips (Panel A). A...

EDITORIAL: Understanding the Causes of Amyotrophic Lateral Sclerosis

Richard W. Orrell, M.D. — Thu, 23Â AugÂ 2007 00:00:00 -05:00

Amyotrophic lateral sclerosis (ALS) is a human disease resulting from the degeneration of motor neurons in the brain, spinal cord, and peripheral nervous system. The resultant clinical features include weakness...

ORIGINAL ARTICLE: Whole-Genome Analysis of Sporadic Amyotrophic Lateral Sclerosis

Thu, 23Â AugÂ 2007 00:00:00 -05:00

Background: Approximately 90% of persons with amyotrophic lateral sclerosis (ALS) have the sporadic form, which may be caused by the interaction of multiple environmental factors and previously unknown genes.

Methods: We...

EDITORIAL: Periodic Limb Movements in Sleep â Endophenotype for Restless Legs Syndrome?

John W. Winkelman, M.D., Ph.D. — Thu, 16Â AugÂ 2007 00:00:00 -05:00

Today, 350 years after its first description, the restless legs syndrome (RLS) is strangely controversial. Experts and patients alike describe RLS both as a miserably impairing disorder and as âthe...

ORIGINAL ARTICLE: A Genetic Risk Factor for Periodic Limb Movements in Sleep

Thu, 16Â AugÂ 2007 00:00:00 -05:00

Background: The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb...

ORIGINAL ARTICLE: Complement C3 Variant and the Risk of Age-Related Macular Degeneration

Thu, 09Â AugÂ 2007 00:00:00 -05:00

Background: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Changing the Trajectory of Cognitive Decline?

Marilyn S. Albert, Ph.D. — Thu, 02Â AugÂ 2007 00:00:00 -05:00

Delaying the onset of cognitive decline and reducing cognitive decline once it has begun have become increasingly important with the aging of the population. Age-related changes in cognitive functions such...

EDITORIAL: Scanning the Genome for Coronary Risk

Anthony Rosenzweig, M.D. — Thu, 02Â AugÂ 2007 00:00:00 -05:00

Coronary artery disease remains an enormous clinical problem, affecting more than 15 million people in the United States alone, where it is the most common cause of death (accounting for...

EDITORIAL: Publishing Genomewide Association Studies

Jeffrey M. Drazen, M.D., and Elizabeth G. Phimister, Ph.D. — Thu, 02Â AugÂ 2007 00:00:00 -05:00

On July 18, 2007, two original research articles appeared on the Journal's Web site (and will be published in this and later print issues) conveying the results of âgenomewide association...

ORIGINAL ARTICLE: Genomewide Association Analysis of Coronary Artery Disease

Thu, 02Â AugÂ 2007 00:00:00 -05:00

Background: Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease.

Methods: We first...

PERSPECTIVE: Drinking from the Fire Hose â Statistical Issues in Genomewide Association Studies

Thu, 02Â AugÂ 2007 00:00:00 -05:00

The past 3 months have seen the publication of a series of studies examining the inherited genetic underpinnings of common diseases such as prostate cancer, breast cancer, diabetes, and in...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Rational Design of Cancer-Drug Combinations

Sridhar Ramaswamy, M.D. — Thu, 19Â JulÂ 2007 00:00:00 -05:00

Advanced tumors cannot be cured with single drugs. They often are resistant to single agents, and even if they are initially sensitive, their molecular heterogeneity usually guarantees the secondary outgrowth...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 22-2007 â A Woman with a Family History of Gastric and Breast Cancer

Thu, 19Â JulÂ 2007 00:00:00 -05:00

A 38-year-old woman was seen in the Gastrointestinal Cancer Genetics Clinic of this hospital because of a family history of breast and gastric cancer.

Approximately 15 months earlier, mild chronic gastrointestinal...

CLINICAL THERAPEUTICS: BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myelogenous Leukemia

Charles A. Schiffer, M.D. — Thu, 19Â JulÂ 2007 00:00:00 -05:00

A 28-year-old woman is referred for advice about the management of recently diagnosed chronic myelogenous leukemia (CML). She was in excellent overall health but was incidentally found to have an...

EDITORIAL: Genes, Cancer Risks, and Clinical Outcomes

Patricia Hartge, Sc.D. — Thu, 12Â JulÂ 2007 00:00:00 -05:00

Learning whether a patient who has just been given a diagnosis of breast cancer also bears one of the cancer-causing mutations in the BRCA1 or BRCA2 genes may add little...

CLINICAL PRACTICE: Management of an Inherited Predisposition to Breast Cancer

Mark Robson, M.D., and Kenneth Offit, M.D., M.P.H. — Thu, 12Â JulÂ 2007 00:00:00 -05:00

A healthy 33-year-old woman comes to establish care. She reports no breast symptoms, her age at menarche was 14, and she has no children. She notes a family history of...

ORIGINAL ARTICLE: Clinical Outcomes of Breast Cancer in Carriers of and Mutations

Thu, 12Â JulÂ 2007 00:00:00 -05:00

Background: Some features of breast cancer in women with a BRCA1 mutation suggest that hereditary breast cancer has a poor outcome. We conducted a national population-based study of Israeli women...

ORIGINAL ARTICLE: In Vitro Fertilization with Preimplantation Genetic Screening

Thu, 05Â JulÂ 2007 00:00:00 -05:00

Background: Pregnancy rates in women of advanced maternal age undergoing in vitro fertilization (IVF) are disappointingly low. It has been suggested that the use of preimplantation genetic screening of cleavage-stage...

EDITORIAL: Preimplantation Genetic Screening in Older Mothers

John A. Collins, M.D. — Thu, 05Â JulÂ 2007 00:00:00 -05:00

Preimplantation genetic diagnosis, first described in 1990,1 involves removing one or two cells from an embryo for genetic testing in order to prevent transmission of genetic disorders from a parent...

REVIEW ARTICLE: Trastuzumab â Mechanism of Action and Use in Clinical Practice

Clifford A. Hudis, M.D. — Thu, 05Â JulÂ 2007 00:00:00 -05:00

Overexpression of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErbB-2), a 185-kD receptor first described more than two decades ago,1 occurs in 20...

EDITORIAL: Teratogenicity of SSRIs â Serious Concern or Much Ado about Little?

Michael F. Greene, M.D. — Thu, 28Â JunÂ 2007 00:00:00 -05:00

In the fall of 2005, GlaxoSmithKline called attention to recently collected safety data indicating an increased risk of major congenital malformations among infants exposed during organogenesis to GlaxoSmithKline's selective serotonin...

ORIGINAL ARTICLE: Allogeneic Bone Marrow Transplantation in Mevalonic Aciduria

Thu, 28Â JunÂ 2007 00:00:00 -05:00

Mevalonic aciduria is a rare, inborn error of isoprene biosynthesis characterized by severe, periodic attacks of fever and inflammation, developmental delay, ataxia, and dysmorphic features. This autosomal recessive disease is...

ORIGINAL ARTICLE: Use of Selective Serotonin-Reuptake Inhibitors in Pregnancy and the Risk of Birth Defects

Thu, 28Â JunÂ 2007 00:00:00 -05:00

Background: Information regarding the safety of selective serotonin-reuptake inhibitors (SSRIs) in human pregnancy is sparse. Concern has been raised about the risk of congenital heart defects associated with the use...

ORIGINAL ARTICLE: First-Trimester Use of Selective Serotonin-Reuptake Inhibitors and the Risk of Birth Defects

Thu, 28Â JunÂ 2007 00:00:00 -05:00

Background: The risk of birth defects after antenatal exposure to selective serotonin-reuptake inhibitors (SSRIs) remains controversial.

Methods: We assessed associations between first-trimester maternal use of SSRIs and the risk of birth...

PERSPECTIVE: Mevalonate Kinase Deficiency and Autoinflammatory Disorders

Thu, 28Â JunÂ 2007 00:00:00 -05:00

A deficiency of mevalonate kinase resulting in mevalonic aciduria was the first inherited defect in cholesterol and nonsterol isoprene biosynthesis to be recognized.1 Nine other enzyme deficiencies have since been...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: MicroRNAs and the Failing Heart

Douglas L. Mann, M.D. — Thu, 21Â JunÂ 2007 00:00:00 -05:00

The search for the basic mechanisms responsible for the development and progression of heart failure has been exhaustive. Despite the elucidation of several clinically relevant signal transduction pathways that can...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: A Healthy Tan?

Gregory Barsh, M.D., Ph.D., and Laura D. Attardi, Ph.D. — Thu, 24Â MayÂ 2007 00:00:00 -05:00

For the past 500 million years or so, the tumor suppressor and transcription factor known as p53 has been the guardian of the genome in multicellular organisms. It mediates the...

PERSPECTIVE: The Mixed Promise of Genetic Medicine

Thu, 17Â MayÂ 2007 00:00:00 -05:00

In the early decades of the 20th century, most Americans considered cosmetic surgery to be just a few steps removed from quackery. Many observers saw the desire for cosmetic surgery...

PERSPECTIVE: Prohibiting Genetic Discrimination

Thu, 17Â MayÂ 2007 00:00:00 -05:00

Even before the sequencing of the human genome began in earnest, Americans started worrying about how information about their genetic makeup might be used in harmful ways, and policymakers began...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Cancer Regression by Senescence

Manuel Serrano, Ph.D. — Thu, 10Â MayÂ 2007 00:00:00 -05:00

Three recent reports123 have shown that cancers in mice can be eliminated through the activation of a single gene, Tp53, which encodes the protein p53. The power of p53 with...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Tolls and Beyond â Many Roads to Vaccine Immunity

Bali Pulendran, Ph.D. — Thu, 26Â AprÂ 2007 00:00:00 -05:00

Of all the public health measures against infections, vaccination is arguably the most cost-effective. Most successful vaccines can be divided into two types â live attenuated vaccines and nonreplicating vaccines....

ORIGINAL ARTICLE: A Lethal Defect of Mitochondrial and Peroxisomal Fission

Thu, 26Â AprÂ 2007 00:00:00 -05:00

We report on a newborn girl with microcephaly, abnormal brain development, optic atrophy and hypoplasia, persistent lactic acidemia, and a mildly elevated plasma concentration of very-long-chain fatty acids. We found...

PERSPECTIVE: Mitochondrial Dynamics in Disease

Thu, 26Â AprÂ 2007 00:00:00 -05:00

Mitochondria are subcellular organelles that coordinate numerous metabolic reactions, including those of the respiratory complexes that produce the ATP that powers cellular reactions. They have often been depicted as static,...

ORIGINAL ARTICLE: Targeted Therapy for Inherited GPI Deficiency

Thu, 19Â AprÂ 2007 00:00:00 -05:00

Disrupted binding of the transcription factor Sp1 to the mutated promoter region of the mannosyl transferaseâencoding gene PIGM causes inherited glycosylphosphatidylinositol (GPI) deficiency characterized by splanchnic vein thrombosis and epilepsy....

ORIGINAL ARTICLE: Mutations in Associated with Neural-Tube Defects

Thu, 05Â AprÂ 2007 00:00:00 -05:00

Neural-tube defects such as anencephaly and spina bifida constitute a group of common congenital malformations caused by complex genetic and environmental factors. We have identified three mutations in the VANGL1...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Idiopathic Pulmonary Fibrosis â New Insights

Subodh Verma, M.D., Ph.D., and Arthur S. Slutsky, M.D. — Thu, 29Â MarÂ 2007 00:00:00 -05:00

âDeath occurred about three months and a half after the onset of the acute disease and the lung was two thirds of the normal size, grayish in color, and hard...

ORIGINAL ARTICLE: Telomerase Mutations in Families with Idiopathic Pulmonary Fibrosis

Thu, 29Â MarÂ 2007 00:00:00 -05:00

Background: Idiopathic pulmonary fibrosis is progressive and often fatal; causes of familial clustering of the disease are unknown. Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase...

EDITORIAL: Modern Genetics, Ancient Defenses, and Potential Therapies

Peter K. Gregersen, M.D. — Thu, 22Â MarÂ 2007 00:00:00 -05:00

Autoimmunity is the reflection of a basic problem confronting all living organisms â how to defend against foreign invasion while maintaining control of the defending forces. The B-cell and T-cell...

ORIGINAL ARTICLE: in Vitiligo-Associated Multiple Autoimmune Disease

Thu, 22Â MarÂ 2007 00:00:00 -05:00

Background: Autoimmune and autoinflammatory diseases involve interactions between genetic risk factors and environmental triggers. We searched for a gene on chromosome 17p13 that contributes to a group of epidemiologically associated...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Structural Variation in the Human Genome

James R. Lupski, M.D., Ph.D. — Thu, 15Â MarÂ 2007 00:00:00 -05:00

The completion of the Human Genome Project was a remarkable feat and provided 3 billion bases of reference nucleotides for comparative studies. An analogy often used to conceptualize human genetic...

PERSPECTIVE: What Genome-wide Association Studies Can Do for Medicine

Thu, 15Â MarÂ 2007 00:00:00 -05:00

As researchers have explored the environmental and inherited causes of common diseases, they have often amassed clinical and laboratory data collected from people with common complex disorders. Many have also...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Bugging Tumors to Put Drugs on Target

Rudy Juliano, Ph.D. — Thu, 01Â MarÂ 2007 00:00:00 -05:00

Targeting drugs to tumors has been a key goal of cancer pharmacology for decades. Newer technologies such as monoclonal antibodies engineered to target tumors, as well as liposomal or nanoparticle...

ORIGINAL ARTICLE: Missense Mutations in the Gene as a Cause of the BjÃ¶rnstad Syndrome

Thu, 22Â FebÂ 2007 00:00:00 -05:00

Background: The BjÃ¶rnstad syndrome, an autosomal recessive disorder associated with sensorineural hearing loss and pili torti, is caused by mutation of a previously unidentified gene on chromosome 2q34â36.

Methods: Refined genetic...

ORIGINAL ARTICLE: DNA Synthesis and Repair Genes and in Lung Cancer

Thu, 22Â FebÂ 2007 00:00:00 -05:00

Background: RRM1, the regulatory subunit of ribonucleotide reductase, is involved in carcinogenesis, tumor progression, and the response of nonâsmall-cell lung cancer to treatment.

Methods: We developed an automated quantitative determination of...

PERSPECTIVE: DNA Repair and Survival in Lung Cancer â The Two Faces of Janus

Thu, 22Â FebÂ 2007 00:00:00 -05:00

Lung cancer, the most common cause of cancer deaths globally, results in about 1 million deaths each year. Despite advances in treatment over the past two decades, the improvement in...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: A Closer Look at Follicular Lymphoma

Louis M. Staudt, M.D., Ph.D. — Thu, 15Â FebÂ 2007 00:00:00 -05:00

A majority of healthy persons have, in their normal B cells, the defining event of follicular lymphoma â a t(14;18) translocation that brings together BCL2 and the gene encoding the...

EDITORIAL: Genetics and Epigenetics â Nature's Pen-and-Pencil Set

Roger G. Gosden, Ph.D., D.Sc., and Andrew P. Feinberg, M.D. — Thu, 15Â FebÂ 2007 00:00:00 -05:00

The sequence of the four nucleotides of the genetic code is like an indelible ink that, with rare exceptions, is faithfully transcribed from cell to cell and from generation to...

ORIGINAL ARTICLE: Inheritance of a Cancer-Associated Germ-Line Epimutation

Thu, 15Â FebÂ 2007 00:00:00 -05:00

Persons who have hypermethylation of one allele of MLH1 in somatic cells throughout the body (a germ-line epimutation) have a predisposition for the development of cancer in a pattern typical...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Huntington's Disease â Making Connections

J. Timothy Greenamyre, M.D., Ph.D. — Thu, 01Â FebÂ 2007 00:00:00 -05:00

When the causative gene for Huntington's disease was identified in 1993, there was great anticipation and hope that key disease-causing mechanisms would be identified quickly and that rational neuroprotective treatments...

ORIGINAL ARTICLE: Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis

Thu, 01Â FebÂ 2007 00:00:00 -05:00

Background: The V617F mutation, which causes the substitution of phenylalanine for valine at position 617 of the Janus kinase (JAK) 2 gene (JAK2), is often present in patients with polycythemia...

PERSPECTIVE: Mutations in Polycythemia Vera â Molecular Mechanisms and Clinical Applications

Thu, 01Â FebÂ 2007 00:00:00 -05:00

Janus kinase 2 (JAK2) is a cytoplasmic tyrosine kinase that transduces signals, especially those triggered by hematopoietic growth factors such as erythropoietin, in normal and neoplastic cells. In March and...

EDITORIAL: Sorting Out Breast-Cancer Gene Signatures

Joan MassaguÃ©, Ph.D. — Thu, 18Â JanÂ 2007 00:00:00 -05:00

The advent of technology for the analysis of human tissue samples for the activity of the entire genome initiated a quest for the molecular profiling of tumors. The aim of...

ORIGINAL ARTICLE: Clinical and Molecular Genetic Spectrum of Congenital Deficiency of the Leptin Receptor

Thu, 18Â JanÂ 2007 00:00:00 -05:00

Background: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has...

ORIGINAL ARTICLE: The Prognostic Role of a Gene Signature from Tumorigenic Breast-Cancer Cells

Thu, 18Â JanÂ 2007 00:00:00 -05:00

Background: Breast cancers contain a minority population of cancer cells characterized by CD44 expression but low or undetectable levels of CD24 (CD44+CD24â/low) that have higher tumorigenic capacity than other subtypes...

ORIGINAL ARTICLE: Inhibition of Microsomal Triglyceride Transfer Protein in Familial Hypercholesterolemia

Thu, 11Â JanÂ 2007 00:00:00 -05:00

Background: Patients with homozygous familial hypercholesterolemia have markedly elevated cholesterol levels, which respond poorly to drug therapy, and a very high risk of premature cardiovascular disease. Inhibition of the microsomal...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: p53 and Tumor Suppression

Terry Van Dyke, Ph.D. — Thu, 04Â JanÂ 2007 00:00:00 -05:00

The p53 tumor-suppressor protein is dysfunctional in most human cancers. Even when p53 is not itself mutant, its regulators â such as p14ARF â are often altered. Moreover, for any...

EDITORIAL: Molecular Signatures of Lung Cancer â Toward Personalized Therapy

Roy S. Herbst, M.D., Ph.D., and Scott M. Lippman, M.D. — Thu, 04Â JanÂ 2007 00:00:00 -05:00

Lung cancer is the deadliest cancer in the world. Relapses are frequent after primary and adjuvant therapy and often evolve into lethal metastatic disease. Currently, lung-cancer staging rests on histopathological...

ORIGINAL ARTICLE: A Five-Gene Signature and Clinical Outcome in NonâSmall-Cell Lung Cancer

Thu, 04Â JanÂ 2007 00:00:00 -05:00

Background: Current staging methods are inadequate for predicting the outcome of treatment of nonâsmall-cell lung cancer (NSCLC). We developed a five-gene signature that is closely associated with survival of patients...

IMAGES IN CLINICAL MEDICINE: Adults with Osteogenesis Imperfecta

Janet Reeder, M.S., P.A.-C. and Eric Orwoll, M.D. — Thu, 28Â DecÂ 2006 00:00:00 -05:00

Osteogenesis imperfecta is a heritable disorder caused by mutations in the gene for type I collagen. The Sillence classification of osteogenesis imperfecta (types I through IV) is based on clinical...

ORIGINAL ARTICLE: Deficiency of Cartilage-Associated Protein in Recessive Lethal Osteogenesis Imperfecta

Thu, 28Â DecÂ 2006 00:00:00 -05:00

Classic osteogenesis imperfecta, an autosomal dominant disorder associated with osteoporosis and bone fragility, is caused by mutations in the genes for type I collagen. A recessive form of the disorder...

ORIGINAL ARTICLE: Female Predominance and Transmission Distortion in the Long-QT Syndrome

Thu, 28Â DecÂ 2006 00:00:00 -05:00

Background: Congenital long-QT syndrome is a disorder resulting in ventricular arrhythmias and sudden death. The most common forms of the long-QT syndrome, types 1 and 2, are caused by mutations...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: The Persistence of Memory

Mark R. Cookson, Ph.D., and John Hardy, Ph.D. — Thu, 21Â DecÂ 2006 00:00:00 -05:00

We often do not realize how much we need something until it is gone â and Alzheimer's disease shows us how debilitating it is to lose memory. Although we now...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Another Look at Imatinib Mesylate

Klaus Strebhardt, Ph.D., and Axel Ullrich, Ph.D. — Thu, 07Â DecÂ 2006 00:00:00 -05:00

Genetic abnormalities that occur during neoplastic transformation can cause the dysregulation of protein kinases â a critical event in tumorigenesis. The inhibition of protein kinases is one of the most...

REVIEW ARTICLE: The Myeloproliferative Disorders

Thu, 07Â DecÂ 2006 00:00:00 -05:00

The myeloproliferative disorders comprise several clonal hematologic diseases that are thought to arise from a transformation in a hematopoietic stem cell. The main clinical features of these diseases are the...

PERSPECTIVE: Exploring the Uses of RNAi â Gene Knockdown and the Nobel Prize

Thu, 07Â DecÂ 2006 00:00:00 -05:00

The Nobel Prize in Physiology or Medicine was awarded this year to Andrew Fire (Stanford University School of Medicine) and Craig Mello (University of Massachusetts Medical School) for their discovery...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 37-2006 â A 19-Year-Old Woman with Thyroid Cancer and Lower Gastrointestinal Bleeding

Thu, 30Â NovÂ 2006 00:00:00 -05:00

A 19-year-old woman was seen in the outpatient gastroenterology division because of painless rectal bleeding.

The patient had been well until 8 months earlier, when a diagnosis of papillary carcinoma was...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Connecting the Dots Using Gene-Expression Profiles

Steven R. Gullans, Ph.D. — Thu, 09Â NovÂ 2006 00:00:00 -05:00

Imagine you had a database of the gene-expression signatures of human diseases and their responses to therapeutic drugs. Its use could result in an unprecedented understanding of the interconnectivity of...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: A Reversal of Misfortune for Myotonic Dystrophy?

Thomas A. Cooper, M.D. — Thu, 26Â OctÂ 2006 00:00:00 -05:00

Myotonic dystrophy, the most common cause of adult-onset muscular dystrophy, is a dominantly inherited disorder in which death is usually caused by the wasting of skeletal muscle and defects in...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 33-2006 â A 43-Year-Old Man with Diabetes, Hypogonadism, Cirrhosis, Arthralgias, and Fatigue

Raymond T. Chung, M.D., Joseph Misdraji, M.D., and Dushyant V. Sahani, M.D. — Thu, 26Â OctÂ 2006 00:00:00 -05:00

A 43-year-old white man was seen at this hospital because of hypogonadism.

The patient had felt well until 6 months earlier, when he noted the gradual onset of fatigue, decreased libido,...

ORIGINAL ARTICLE: The Genotype of the Original Wiskott Phenotype

Thu, 26Â OctÂ 2006 00:00:00 -05:00

The WiskottâAldrich syndrome is an X-linked hereditary disorder associated with combined immunodeficiency, thrombocytopenia, small platelets, eczema, and increased susceptibility to autoimmune disorders and cancers. It is caused by mutations in...

PERSPECTIVE: Lessons from the WiskottâAldrich Syndrome

Thu, 26Â OctÂ 2006 00:00:00 -05:00

The WiskottâAldrich syndrome is a well-recognized triad of eczema, bleeding diathesis, and recurrent infections that occurs in boys. Although it is rare (with an estimated incidence of less than 1...

HEALTH POLICY REPORT: FDA Regulation of Stem-CellâBased Therapies

Dina Gould Halme, Ph.D., and David A. Kessler, M.D. — Thu, 19Â OctÂ 2006 00:00:00 -05:00

In the interest of public safety, the Food and Drug Administration (FDA) has jurisdiction over the production and marketing of any stem-cellâbased therapy involving the transplantation of human cells into...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Amyotrophic Lateral Sclerosis â Are Microglia Killing Motor Neurons?

David R. Borchelt, Ph.D. — Thu, 12Â OctÂ 2006 00:00:00 -05:00

Amyotrophic lateral sclerosis (ALS) is a disease characterized by the selective degeneration of motor neurons. The only known genetic cause of the disease, which accounts for about 2% of cases,...

ORIGINAL ARTICLE: Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion

Thu, 05Â OctÂ 2006 00:00:00 -05:00

Background: Severe, often refractory anemia is characteristic of the myelodysplastic syndrome associated with chromosome 5q31 deletion. We investigated whether lenalidomide (CC5013) could reduce the transfusion requirement and suppress the abnormal...

ORIGINAL ARTICLE: Immunotherapy with a RagweedâToll-Like Receptor 9 Agonist Vaccine for Allergic Rhinitis

Thu, 05Â OctÂ 2006 00:00:00 -05:00

Background: Conjugating immunostimulatory sequences of DNA to specific allergens offers a new approach to allergen immunotherapy that reduces acute allergic responses.

Methods: We conducted a randomized, double-blind, placebo-controlled phase 2 trial...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: Key Role for a Viral Lytic Gene in Kaposi's Sarcoma

Robert Yarchoan, M.D. — Thu, 28Â SepÂ 2006 00:00:00 -05:00

Several types of cancer, including the majority of those typically associated with AIDS, are caused by gammaherpesviruses. Herpesviruses undergo both latent and lytic infection; most research on herpesvirus-induced tumors has...

REVIEW ARTICLE: The Tuberous Sclerosis Complex

Thu, 28Â SepÂ 2006 00:00:00 -05:00

The tuberous sclerosis complex (TSC), a multisystem, autosomal dominant disorder affecting children and adults, results from mutations in one of two genes, TSC1 (encoding hamartin) or TSC2 (encoding tuberin) (see...

PERSPECTIVE: Telomeres, Telomerase, and Human Disease

Thu, 21Â SepÂ 2006 00:00:00 -05:00

Telomeres, the genetic segments that appear at a chromosome's ends, have been known since the 1930s to have special properties that protect these ends. They were first isolated in the...

PERSPECTIVE: Bit Player or Powerhouse? China and Stem-Cell Research

Thu, 21Â SepÂ 2006 00:00:00 -05:00

For more than a decade, China has been shocking the West. Although it is still poor and officially Communist, the world's most populous country has turned old convictions on their...

PERSPECTIVE: The Politics and Promise of Stem-Cell Research

Thu, 21Â SepÂ 2006 00:00:00 -05:00

On July 19, 2006, President George W. Bush exercised his constitutional prerogative to veto a congressional act for the first time in the 6 years he has been in office....

CLINICAL IMPLICATIONS OF BASIC RESEARCH: A Critical New Pathway for Toxin Secretion?

Timothy L. Yahr, Ph.D. — Thu, 14Â SepÂ 2006 00:00:00 -05:00

Vaccines that are composed of inactivated bacterial toxins work well for diseases such as diphtheria and tetanus, in which a single secreted toxin is the primary mediator of disease. Pathogens...

ORIGINAL ARTICLE: DNA Repair by ERCC1 in NonâSmall-Cell Lung Cancer and Cisplatin-Based Adjuvant Chemotherapy

Thu, 07Â SepÂ 2006 00:00:00 -05:00

Background: Adjuvant cisplatin-based chemotherapy improves survival among patients with completely resected nonâsmall-cell lung cancer, but there is no validated clinical or biologic predictor of the benefit of chemotherapy.

Methods: We used...

EDITORIAL: ERCC1 Measurements in Clinical Oncology

Eddie Reed, M.D. — Thu, 07Â SepÂ 2006 00:00:00 -05:00

Clinical oncology has struggled for decades with the predicament of the toxicity of chemotherapy for the treatment of malignant disease. For example, cisplatin and its analogues, carboplatin and oxaliplatin, are...

REVIEW ARTICLE: Oncogene-Induced Cell Senescence â Halting on the Road to Cancer

W.J. Mooi, M.D., and D.S. Peeper, Ph.D. — Thu, 07Â SepÂ 2006 00:00:00 -05:00

In many tissues, there are numerous small and inconspicuous neoplastic lesions that rarely become overt cancers. In these small lesions, clonality and oncogenic mutations have been identified. These lesions include...

CLINICAL IMPLICATIONS OF BASIC RESEARCH: RNA Interference as Potential Therapy â Not So Fast

Philip A. Marsden, M.D. — Thu, 31Â AugÂ 2006 00:00:00 -05:00

The 1989 Nobel Prize in Chemistry was awarded to Sidney Altman and Thomas Cech for the discovery that RNA is not only a molecule of heredity, it is also a...

ORIGINAL ARTICLE: Marburg Hemorrhagic Fever Associated with Multiple Genetic Lineages of Virus

Thu, 31Â AugÂ 2006 00:00:00 -05:00

Background: An outbreak of Marburg hemorrhagic fever was first observed in a gold-mining village in northeastern Democratic Republic of the Congo in October 1998.

Methods: We investigated the outbreak of Marburg...

EDITORIAL: Marfan's Syndrome and Related Disorders â More Tightly Connected Than We Thought

Bruce D. Gelb, M.D. — Thu, 24Â AugÂ 2006 00:00:00 -05:00

Reviewing the entry on Marfan's syndrome in my medical schoolâera edition of Harrison's Principles of Internal Medicine, circa 1980, reminded me anew of the transformative potential of molecular medicine. In...

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL: Case 26-2006 â A 19-Year-Old Woman with Difficulty Walking

Nagagopal Venna, M.D., Katherine B. Sims, M.D., and P. Ellen Grant, M.D. — Thu, 24Â AugÂ 2006 00:00:00 -05:00

Dr. Roy N. Alcalay (Neurology): A 19-year-old right-handed woman was referred to the neurology clinic because of slowly worsening difficulty walking and painful spasms in her legs and arms. When...

ORIGINAL ARTICLE: Aneurysm Syndromes Caused by Mutations in the TGF-Î² Receptor

Thu, 24Â AugÂ 2006 00:00:00 -05:00

Background: The LoeysâDietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and...

EDITORIAL: Molecular Signatures Predict Outcomes of Breast Cancer

Joyce A. O'Shaughnessy, M.D. — Thu, 10Â AugÂ 2006 00:00:00 -05:00

Breast cancer is classified and managed largely on the basis of anatomy â in contrast with lymphoma, which has been classified and treated according to grade for more than 20...

ORIGINAL ARTICLE: Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1Î² Inhibition