Showing papers by "Johns Hopkins University School of Medicine published in 1995"
TL;DR: An approach for genome analysis based on sequencing and assembly of unselected pieces of DNA from the whole chromosome has been applied to obtain the complete nucleotide sequence of the genome from the bacterium Haemophilus influenzae Rd.
Abstract: An approach for genome analysis based on sequencing and assembly of unselected pieces of DNA from the whole chromosome has been applied to obtain the complete nucleotide sequence (1,830,137 base pairs) of the genome from the bacterium Haemophilus influenzae Rd. This approach eliminates the need for initial mapping efforts and is therefore applicable to the vast array of microbial species for which genome maps are unavailable. The H. influenzae Rd genome sequence (Genome Sequence DataBase accession number L42023) represents the only complete genome sequence from a free-living organism.
5,944 citations
TL;DR: Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells.
Abstract: Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells. We show that both HIF-1 subunits are basic-helix-loop-helix proteins containing a PAS domain, defined by its presence in the Drosophila Per and Sim proteins and in the mammalian ARNT and AHR proteins. HIF-1 alpha is most closely related to Sim. HIF-1 beta is a series of ARNT gene products, which can thus heterodimerize with either HIF-1 alpha or AHR. HIF-1 alpha and HIF-1 beta (ARNT) RNA and protein levels were induced in cells exposed to 1% O2 and decayed rapidly upon return of the cells to 20% O2, consistent with the role of HIF-1 as a mediator of transcriptional responses to hypoxia.
5,729 citations
TL;DR: Comparison of the Mycoplasma genitalium genome to that of Haemophilus influenzae suggests that differences in genome content are reflected as profound differences in physiology and metabolic capacity between these two organisms.
Abstract: The complete nucleotide sequence (580,070 base pairs) of the Mycoplasma genitalium genome, the smallest known genome of any free-living organism, has been determined by whole-genome random sequencing and assembly. A total of only 470 predicted coding regions were identified that include genes required for DNA replication, transcription and translation, DNA repair, cellular transport, and energy metabolism. Comparison of this genome to that of Haemophilus influenzae suggests that differences in genome content are reflected as profound differences in physiology and metabolic capacity between these two organisms.
2,565 citations
TL;DR: Hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in some adults with three or more painful crises per year and Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect.
Abstract: Background In a previous open-label study of hydroxyurea therapy, the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia, with only mild myelotoxicity. By inhibiting sickling, increased levels of fetal hemoglobin might decrease the frequency of painful crises. Methods In a double-blind, randomized clinical trial, we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year. The trial was stopped after a mean follow-up of 21 months. Results Among 148 men and 151 women studied at 21 clinics, the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo (median, 2.5 vs. 4.5 crises per year, P<0.001). The median times to the first crisis (3.0 vs. 1.5 months, P = 0.01) and the second crisis (8.8 vs. 4.6 months, P<0.001) were longer with hydroxyurea treatment. Fewer patients assigned to hydroxyurea had chest syndrome (25 vs. 51, P<0.001), and...
2,062 citations
TL;DR: The biochemical purification of HIF-1 from Epo-producing Hep3B cells and non-Epo-producing HeLa S3 cells concludes that in both cobalt chloride-treated HeLa cells and hypoxic Hep3 B cells HIF -1 is composed of two different subunits: 120-kDa Hif-1α and 91-94-k da HIF,1β.
1,976 citations
TL;DR: Mutations in Cu/Zn superoxide dismutase cause a subset of cases of familial amyotrophic lateral sclerosis, and four lines of mice accumulating one of these mutant proteins (G37R) develop severe, progressive motor neuron disease.
1,470 citations
Johns Hopkins University School of Medicine1, Johns Hopkins University2, National Institutes of Health3, Western Pennsylvania Hospital4, University of California, Los Angeles5, Northwestern University6, McGill University7, University of Toronto8, University of Alabama at Birmingham9, University of Texas Southwestern Medical Center10
TL;DR: Interstitial chemotherapy delivered with polymers directly to brain tumours at the time of surgery seems to be a safe and effective treatment for recurrent malignant gliomas.
1,330 citations
TL;DR: Analysis of the deduced amino acid sequence indicates a region of homology with alpha-spectrin, and observations suggest that Arc may play a role in activity-dependent plasticity of dendrites.
1,197 citations
971 citations
TL;DR: The results suggest that the induction of floor plate cells and motor neurons by the notochord in vivo is mediated by exposure of neural plate cells to different concentrations of the amino-terminal product of SHH autoproteolytic cleavage.
959 citations
Journal Article•
TL;DR: Some retinal ganglion cells injured by glaucoma and by axotomy die by apoptosis, possibly because of the small proportion of cells that were dying at any given time.
Abstract: Purpose To investigate whether retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Methods Chronic elevated eye pressure was produced in 20 monkey eyes, and the optic nerve was transected unilaterally in the orbit of 10 monkeys and 14 rabbits. Sixteen monkey and 14 rabbit eyes were studied as normal controls. Analytic methods included light and electron microscopy, histochemistry for DNA fragmentation (TUNEL method), and DNA electrophoresis in agarose gels. Results Dying ganglion cells in the experimental retinas exhibited morphologic features of apoptosis, including chromatin condensation and formation of apoptotic bodies. Cells with a positive reaction for DNA fragmentation were observed in eyes subjected to axotomy and experimental glaucoma but were only rarely encountered in control eyes. No evidence of internucleosomal fragmentation was detected electrophoretically, possibly because of the small proportion of cells that were dying at any given time. Conclusion Some retinal ganglion cells injured by glaucoma and by axotomy die by apoptosis.
Journal Article•
TL;DR: The technique of laparoscopic live donor nephrectomy has resulted in improved postoperative recovery and shorter convalescence, with no effect on recipient renal function.
Abstract: A laparoscopic live-donor nephrectomy was performed on a 40-year-old man. The kidney was removed intact via a 9-cm infraumbilical midline incision. Warm ischemia was limited to less than 5 min. Immediately upon revascularization, the allograft produced urine. By the second postoperative day, the recipient's serum creatinine had decreased to 0.7 mg/dl. The donor's postoperative course was uneventful. He experienced minimal discomfort and was discharged home on the first postoperative day. We conclude that laparoscopic donor nephrectomy is feasible. It can be performed without apparent deleterious effects to either the donor or the recipient. The limited discomfort and rapid convalescence enjoyed by our patient indicate that this technique may prove to be advantageous.
TL;DR: Pneumonia has been recognized as a common and potentially lethal condition for nearly two centuries as discussed by the authors, and community-acquired pneumonia (as distinguished from that acquired nosocomially or in a nursing home) continues to be a very serious illness.
Abstract: Pneumonia has been recognized as a common and potentially lethal condition for nearly two centuries. Comprehensive studies of the disease in the pre-antibiotic era showed mortality rates of about 1 per 1000 per year; over 80 percent of the cases were due to Streptococcus pneumoniae, and mortality rates were generally reported at 20 to 40 percent.1,2 Community-acquired pneumonia (as distinguished from that acquired nosocomially or in a nursing home) continues to be a common and serious illness. Current estimates for the United States are 4 million cases annually, an attack rate of 12 per 1000 adults per year, about . . .
TL;DR: Chronic gastrointestinal symptoms and histological changes of the esophagus unresponsive to standard treatments for gastroesophageal reflux were improved by the use of elemental formulas.
TL;DR: Regression analyses indicated that both factors accounted for unique variance associated with body image and eating dysfunction, however, internalization of standards was a stronger predictor of disturbance.
Abstract: The Sociocultural Attitudes Towards Appearance Questionnaire-3 (SATAQ-3) and its earlier versions are measures designed to assess societal and interpersonal aspects of appearance ideals. Correlational, structural equation modeling, and prospective studies of the SATAQ-3 have shown consistent and significant associations with measures of body image disturbance and eating pathology. In the current investigation, the SATAQ-3 was revised to improve upon some conceptual limitations and was evaluated in 4 U.S. and 3 international female samples, as well as a U.S. male sample. In Study 1, exploratory and confirmatory factor analyses for a sample of women from the Southeastern United States (N = 859) indicated a 22-item scale with 5 factors: Internalization: Thin/Low Body Fat, Internalization: Muscular/Athletic, Pressures: Family, Pressures: Media, Pressures: Peers. This scale structure was confirmed in 3 independent and geographically diverse samples of women from the United States (East Coast N = 440, West Coast N = 304, and North/Midwest N = 349). SATAQ-4 scale scores demonstrated excellent reliability and good convergent validity with measures of body image, eating disturbance, and self-esteem. Study 2 replicated the factorial validity, reliability, and convergent validity of the SATAQ-4 in an international sample of women drawn from Italy, England, and Australia (N = 362). Study 3 examined a sample of college males from the United States (N = 271); the 5-factor solution was largely replicated, yet there was some evidence of an underlying structure unique to men. Future research avenues include additional item testing and modification of the scale for men, as well as adaptation of the measure for children and adolescents.
TL;DR: In this article, the reproducibility of this phenotype among mice with segmental trisomy 16 (Ts65Dn mice) indicates that dosage imbalance for a gene or genes in this region contributes to this impairment.
Abstract: Trisomy 21 or Down syndrome (DS) is the most frequent genetic cause of mental retardation, affecting one in 800 live born human beings. Mice with segmental trisomy 16 (Ts65Dn mice) are at dosage imbalance for genes corresponding to those on human chromosome 21q21-22.3--which includes the so-called DS 'critical region'. They do not show early-onset of Alzheimer disease pathology; however, Ts65Dn mice do demonstrate impaired performance in a complex learning task requiring the integration of visual and spatial information. The reproducibility of this phenotype among Ts65Dn mice indicates that dosage imbalance for a gene or genes in this region contributes to this impairment. The corresponding dosage imbalance for the human homologues of these genes may contribute to cognitive deficits in DS.
TL;DR: D-Serine appears to be the endogenous ligand for the glycine site of NMDA receptors, suggesting a mechanism by which astrocyte-derived D-serine could modulate neurotransmission.
Abstract: Using an antibody highly specific for D-serine conjugated to glutaraldehyde, we have localized endogenous D-serine in rat brain. Highest levels of D-serine immunoreactivity occur in the gray matter of the cerebral cortex, hippocampus, anterior olfactory nucleus, olfactory tubercle, and amygdala. Localizations of D-serine immunoreactivity correlate closely with those of D-serine binding to the glycine modulatory site of the N-methyl-D-aspartate (NMDA) receptor as visualized by autoradiography and are inversely correlated to the presence of D-amino acid oxidase. D-Serine is enriched in process-bearing glial cells in neuropil with the morphology of protoplasmic astrocytes. In glial cultures of rat cerebral cortex, D-serine is enriched in type 2 astrocytes. The release of D-serine from these cultures is stimulated by agonists of non-NMDA glutamate receptors, suggesting a mechanism by which astrocyte-derived D-serine could modulate neurotransmission. D-Serine appears to be the endogenous ligand for the glycine site of NMDA receptors.
TL;DR: The prevalence of domestic violence among female patients presenting to four community-based, primary care, adult medicine practices that serve patients of diverse socioeconomic background was determined and demographic and clinical differences between currently abused patients and patients not currently being abused were identified.
Abstract: Objectives: To determine the prevalence of domestic violence among female patients and to identify clinical characteristics that are associated with current domestic violence. Design: Cross-section...
TL;DR: To understand the in vivo function of APP and its processing, an APP-null mutation is generated in mice and it is shown that the APP-deficient mice exhibited a decreased locomotor activity and forelimb grip strength, indicating a compromised neuronal or muscular function.
TL;DR: No statistically significant correlations were found between the pattern of disease, AMAN or AIDP, anti-glycolipid antibodies, or C. jejuni antibodies.
Abstract: Guillain-Barre syndrome has been considered to be primarily an acute inflammatory demyelinating polyneuropathy (AIDP). Our experience with Guillain-Barre syndrome in northern China differs from the traditional concept. Electrophysiologically and pathologically, most of our patients have motor axonal degeneration with minimal cellular inflammation, which we have termed 'acute motor axonal neuropathy' (AMAN). The current studies were undertaken to characterize prospectively the clinical, electrophysiological, and serological features of Guillain-Barre syndrome, defined clinically, in northern China. In 1991 and 1992, we characterized by electrodiagnostic criteria 129 Chinese patients with Guillain-Barre syndrome. The AMAN form was present in 65% of patients, the AIDP form in 24% and 11% were unclassifiable. For the 38 patients who presented from January to October, 1992, we performed serological assays for antibodies to Campylobacter jejuni and to glycolipids. Of these 38 patients, 55% had AMAN, 32% had AIDP and 13% were unclassifiable. Sixty-six percent of the 38 had serological evidence of recent C. jejuni infection as compared with 16% of village controls (P = 0.001). Seventy-six percent of AMAN patients and 42% of AIDP patients were seropositive. IgG anti-GM1 antibodies were more frequent in Guillain-Barre syndrome patients compared with village controls (42% versus 6%; P < 0.01). However, no statistically significant correlations were found between the pattern of disease, AMAN or AIDP, anti-glycolipid antibodies, or C. jejuni antibodies. Based on electrophysiological criteria, Guillain-Barre syndrome in northern China can be divided into two predominant forms: AIDP and AMAN. The AMAN form is more common and predominates in the yearly summer outbreaks of Guillain-Barre syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: It is suggested that because of viral cytopathic effects and/or host effector mechanisms, productively infected CD4+ T cells do not generally survive for long enough to revert to a resting memory state in vivo.
Abstract: Although it is presumed that the integration of HIV-1 into the genome of infected CD4+ T lymphocytes allows viral persistence, there has been little direct evidence that CD4+ T cells with integrated provirus function as a latent reservoir for HIV-1 in infected individuals. Using resting CD4+ T-cell populations of extremely high purity and a novel assay that selectively and unambiguously detects integrated HIV-1, we show that resting CD4+ T cells harbouring integrated provirus are present in some infected individuals. However, these cells do not accumulate within the circulating pool of resting CD4+ T cells in the early stages of HIV-1 infection and do not accumulate even after prolonged periods in long-term survivors of HIV-1 infection. These results suggest that because of viral cytopathic effects and/or host effector mechanisms, productively infected CD4+ T cells do not generally survive for long enough to revert to a resting memory state in vivo.
TL;DR: Molecular analysis of surgical margins and lymph nodes can augment standard histopathological assessment and may improve the prediction of local tumor recurrence.
Abstract: Background Surgical oncologists rely heavily on the histopathological assessment of surgical margins to ensure total excision of the tumor in patients with head and neck cancer. However, current techniques may not detect small numbers of cancer cells at the margins of resection or in cervical lymph nodes. Methods We used molecular techniques to determine whether clonal populations of infiltrating tumor cells harboring mutations of the p53 gene could be detected in histopathologically negative surgical margins and cervical lymph nodes of patients with squamous-cell carcinoma of the head and neck. Results We identified 25 patients with primary squamous-cell carcinoma of the head and neck containing a p53 mutation who appeared to have had complete tumor resection on the basis of a negative histopathological assessment. In 13 of these 25 patients, molecular analysis was positive for a p53 mutation in at least one tumor margin. In 5 of 13 patients with positive margins by this method (38 percent), the carcinom...
TL;DR: These studies indicate that the immune system can interact with peripheral sensory-nerve endings to inhibit pain and intrinsic modulation of nociception can occur at the peripheral terminals of afferent nerves.
Abstract: Pain can be effectively diminished by various endogenous mechanisms within the central nervous system One region where these mechanisms have been well characterized is the dorsal horn of the spina
TL;DR: The results suggest that POAG is associated with an alteration in factors related to ocular blood flow and a breakdown of autoregulation, with a sixfold excess for those in the lowest category of perfusion pressure.
Abstract: Objective: To evaluate the association of vascular factors with primary open-angle glaucoma (POAG). Design: A population-based prevalence survey of ocular disease among black and white residents. Setting: Communities of east Baltimore, Md. Participants: A stratified cluster sample of 5308 residents 40 years of age or older. Main Outcome Measures: Primary open-angle glaucoma as defined by demonstrable glaucomatous optic nerve damage based on visual fields and/or optic disc findings. Intraocular pressure level was not a criterion for diagnosis. Results: Systolic and diastolic blood pressure showed modest, positive association with POAG. The effect of blood pressure on POAG was modified by age, with a stronger association among older subjects. Lower perfusion pressure (blood pressure-intraocular pressure) was strongly associated with an increased prevalence of POAG, with a sixfold excess for those in the lowest category of perfusion pressure. Conclusion: These results suggest that POAG is associated with an alteration in factors related to ocular blood flow and a breakdown of autoregulation.
TL;DR: The results suggest that CFTR functions to regulate other Cl- secretory pathways in addition to itself conducting Cl-.
TL;DR: The identification of a protein (huntingtin-associated protein (HAP)-l) that binds to huntingtin is reported, enhanced by an expanded polyglutamine repeat, the length of which is also known to correlate with the age of disease onset19–21.
Abstract: HUNTINGTON's disease (HD) is an autosomal dominant neuro-degenerative disorder caused by an expanding polyglutamine repeat in the IT 15 or huntingtin gene1. Although this gene is widely expressed2–9 and is required for normal development10–12, the pathology of HD is restricted to the brain, for reasons that remain poorly understood. The huntingtin gene product is expressed at similar levels in patients and controls, and the genetics of the disorder13,14 suggest that the expansion of the polyglutamine repeat induces a toxic gain of function, perhaps through interactions with other cellular proteins15–18. Here we report the identification of a protein (huntingtin-associated protein (HAP)-l) that binds to huntingtin. This binding is enhanced by an expanded polyglutamine repeat, the length of which is also known to correlate with the age of disease onset19–21. The HAP-1 protein is enriched in the brain, suggesting a possible basis for the selective brain pathology of HD.
TL;DR: It is found that small homozygous deletions represent the predominant mechanism of inactivation at 9p21 in bladder tumours and are present in other tumour types, including breast and prostate cancer.
Abstract: Many tumour types have been reported to have deletion of 9p21 (refs 1-6). A candidate target suppressor gene, p16 (p16INK4a/MTS-1/CDKN2), was recently identified within the commonly deleted region in tumour cell lines. An increasing and sometimes conflicting body of data has accumulated regarding the frequency of homozygous deletion and the importance of p16 in primary tumours. We tested 545 primary tumours by microsatellite analysis with existing and newly cloned markers around the p16 locus. We have now found that small homozygous deletions represent the predominant mechanism of inactivation at 9p21 in bladder tumours and are present in other tumour types, including breast and prostate cancer. Moreover, fine mapping of these deletions implicates a 170 kb minimal region that includes p16 and excludes p15.
TL;DR: The results suggest that apoptosis occurs in both HD and excitotoxic animal models and that apoptotic and necrotic mechanisms of neuronal death may occur simultaneously within individual dying cells in the excitOToxically injured brain.
Abstract: Huntington disease (HD) is an inherited neurodegenerative disorder characterized by selective death of striatal medium spiny neurons. Intrastriatal injections of glutamate receptor agonists (excitotoxins) recapitulate some neuropathological features of this disorder. Although this model suggests that excitotoxic injury may be involved in HD, the exact mechanisms of cell death in HD and its models are unknown. The present study was designed to test the hypothesis that HD can develop via the activation of an apoptotic mechanism of cell death and to examine whether excitotoxic striatal lesions with quinolinic acid in rats represent accurate models of HD. To characterize cell death, we employed DNA electrophoresis, electron microscopy (EM), and the terminal transferase-mediated (TdT) deoxyuridine triphosphate (d-UTP)-biotin nick end labeling (TUNEL) method for the in situ detection of DNA strand breaks. In the neostriatum of individuals with HD, patterns of distribution of TUNEL-positive neurons and glia were reminiscent of those seen in apoptotic cell death during normal development of the nervous system; in the same areas, nonrandom DNA fragmentation was detected occasionally. Following excitotoxic injury of the rat striatum, internucleosomal DNA fragmentation (evidence of apoptosis) was seen at early time intervals and random DNA fragmentation (evidence of necrosis) at later time points. In addition, EM detected necrotic profiles of medium spiny neurons in the lesioned rats. In concert, these results suggest that apoptosis occurs in both HD and excitotoxic animal models and that apoptotic and necrotic mechanisms of neuronal death may occur simultaneously within individual dying cells in the excitotoxically injured brain. However, the distribution of dying neurons in the neostriatum, the degree of glial degeneration, and the involvement of striatofugal pathways are very different between HD and excitotoxically damaged striatum. The present study suggests that multiple methods should be employed for a proper characterization of neuronal cell death in vivo.
TL;DR: A role for tobacco in the molecular progression of squamous-cell carcinoma of the head and neck and support the epidemiologic evidence that abstinence from smoking is important to preventHead and neck cancer are suggested.
Abstract: Background Although epidemiologic studies have long associated tobacco and alcohol use with the development of squamous-cell carcinoma of the head and neck, the molecular targets of these carcinogens have yet to be identified. We performed a molecular analysis to determine the pattern of mutations in the p53 gene in neoplasms from patients with squamous-cell carcinoma of the head and neck and a history of tobacco or alcohol use. Methods Sequence analysis of the conserved regions of the p53 gene was performed in tumor samples from 129 patients with primary squamous-cell carcinoma of the head and neck. We then used statistical analysis to identify any patient characteristics associated with mutation of the p53 gene. Results We found p53 mutations in 42 percent of the patients (54 of 129). Fifty-eight percent of the patients who smoked cigarettes and used alcohol (37 of 64; 95 percent confidence interval, 45 to 70 percent), 33 percent of the patients who smoked but abstained from alcohol (13 of 39; 95 percen...
TL;DR: Pima subjects homozygous for the Trp64Arg beta 3-adrenergic-receptor mutation have an earlier onset of NIDDM and tend to have a lower resting metabolic rate.
Abstract: Background The β3-adrenergic receptor is expressed in visceral adipose tissue and is thought to contribute to the regulation of the resting metabolic rate and lipolysis. Methods To investigate whether mutations in the gene for the β3-adrenergic receptor predispose patients to obesity and non-insulin-dependent diabetes mellitus (NIDDM), we studied this gene in 10 Pima Indians by analysis of single-stranded conformational polymorphisms and dideoxy sequence analysis. Association studies were performed in 642 Pima subjects (390 with NIDDM and 252 without NIDDM). Results A missense mutation was identified in the gene for the β3-adrenergic receptor that results in the replacement of tryptophan by arginine (Trp64Arg) in the first intracellular loop of the receptor. This mutation was detected with allelic frequencies of 0.31 in Pima Indians, 0.13 in 62 Mexican Americans, 0.12 in 49 blacks, and 0.08 in 48 whites in the United States. Among Pimas, the frequency of the Trp64Arg mutation was similar in nondiabetic an...