Johns Hopkins University School of Medicine

About: Johns Hopkins University School of Medicine is a healthcare organization based out in Baltimore, Maryland, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 44277 authors who have published 79222 publications receiving 4788882 citations.

Full-Length Human Immunodeficiency Virus Type 1 Genomes from Subtype C-Infected Seroconverters in India, with Evidence of Intersubtype Recombination

Abstract: According to World Health Organization estimates, India will have the greatest number of human immunodeficiency virus (HIV)-infected individuals of any country by the end of this decade (1, 6). High rates of sexually transmitted diseases, rapidly increasing seroprevalence in female commercial sex workers, and inadequate facilities for HIV testing, counseling, and prevention are the major contributing factors in the recent explosive increases in the numbers of HIV infections (5, 6, 24, 29). While antiretroviral drugs have reduced mortality from AIDS in developed nations, their effect will be negligible elsewhere due to their cost. For most communicable diseases, vaccines offer the most cost-effective control strategy. It is likely that development of a vaccine for HIV will require knowledge of the viral variants being transmitted in the target population. Despite India’s impending predominance in the worldwide pandemic, little is known of the genetic diversity of HIV-1 in India. The HIV-1 sequence database is growing exponentially, but the distribution of submitted sequences is not representative of the worldwide picture. Subtype C has been reported in nearly every region affected by HIV-1 (11, 23, 28) and predominates in India, and it also causes 74% of infections in southern Africa and 96% of infections in northern Africa (11, 18, 32). Given the combined population of India and the other regions affected, subtype C is likely to be the most commonly transmitted HIV-1 subtype worldwide. In contrast, 7% of the available HIV-1 sequence data is from subtype C-infected individuals (37), and of the 46 completely sequenced HIV-1 genomes (excluding multiple derivatives of HIV-1LAI), only two are of subtype C, one from a 1992 Brazilian sample and the other from a 1986 Ethiopian sample (37). In November 1997, an analysis of cross-clade epitope variation (9) excluded the C clade from evaluation of p24gag epitopes because of a lack of sequence data, whereas there was sufficient data to analyze subtypes A, B, D, F, G, and H (no HIV-1 harboring a subtype E gag gene has been found). Further sequence data from subtype C is needed, but the past approach of generating data from small subgenomic amplicons is no longer sufficient. Recent developments have made full-genome characterization of HIV-1 isolates both important and feasible. First, the recognition of intersubtype recombination in a significant proportion of HIV-1 sequences (44, 45) has led to detection of mosaic genomes in many regions of the world affected by multiple subtypes (14, 17, 31). Subtypes A, B, and C in India have been reported (4, 22, 30, 31, 59), but mosaic HIV-1 there has not been reported. The existence of such recombinants makes characterization of variants by analyzing subgenomic segments incomplete. Second, immune responses to vaccines based on single genes such as env have been limited (13), and attention is being shifted toward multivalent vaccines that incorporate other gene products. Third, interactions among discontinuous regions of the genome, such as between the long terminal repeat (LTR) and pol (26), can be detected only when such regions can be analyzed from the same template. In an effort to characterize subtype C virus genomes being transmitted currently in India, viral isolates were obtained from individuals with seroincident infections in India. Three of the isolates (collected in 1994 and 1995) were known to be non-syncytium inducing (NSI) and therefore resembled viruses transmitted through unprotected sexual contact, which account for 75 to 85% of new infections (2, 15, 61). These isolates were cloned, and nearly full-length genomic sequences were determined. Detailed sequence analysis was performed, as was an analysis of variation in characterized cytotoxic T lymphocyte (CTL) epitopes.

A model for p53-induced apoptosis

Abstract: The inactivation of the p53 gene in a large proportion of human cancers has inspired an intense search for the encoded protein's physiological and biological properties. Expression of p53 induces either a stable growth arrest or programmed cell death (apoptosis). In human colorectal cancers, the growth arrest is dependent on the transcriptional induction of the protein p21WAF1/CIP1(ref. 1), but the mechanisms underlying the development of p53-dependent apoptosis are largely unknown2. As the most well documented biochemical property of p53 is its ability to activate transcription of genes, we examined in detail the transcripts induced by p53 expression before the onset of apoptosis. Of 7,202 transcripts identified, only 14 (0.19%) were found to be markedly increased in p53-expressing cells compared with control cells. Strikingly, many of these genes were predicted to encode proteins that could generate or respond to oxidative stress, including one that is implicated in apoptosis in plant meristems. These observations stimulated additional biochemical and pharmacological experiments suggesting that p53 results in apoptosis through a three-step process: (1) the transcriptional induction of redox-related genes; (2) the formation of reactive oxygen species; and (3) the oxidative degradation of mitochondrial components, culminating in cell death.

Longitudinal Effects of Aging on Serum Total and Free Testosterone Levels in Healthy Men

Abstract: Many studies have shown cross-sectional (and two small studies, longitudinal) declines in total and/or free testosterone (T) levels, with age, in men. The extent to which decline in T is the result of the aging process per se, as opposed to chronic illness, medication use, and other age-related factors, remains controversial. The frequency with which aging leads to T levels consistent with hypogonadism has also not been defined. These issues bear on the potential use of T replacement in aging men, because aging and hypogonadism have, in common, reduced bone and lean body mass and muscle strength and increased total and abdominal fat. We measured T and sex hormone-binding globulin (SHBG), by RIA, in stored samples from 890 men in the Baltimore Longitudinal Study on Aging. Using a mixed-effects model, we found independent effects of age and date of sampling to reduce T levels. After compensating for date effects, which investigation suggested was artifactual, we observed significant, independent, age-invariant, longitudinal effects of age on both T and free T index (free T index = T/SHBG), with an average change of -0.124 nmol/L.yr and -0.0049 nmol T/nmol SHBG.yr. T, but not free T index, also decreased with increasing body mass index. Use of beta-blocking drugs was associated with higher T and higher free T index levels. Using total T criteria, incidence of hypogonadal T levels increased to about 20% of men over 60, 30% over 70 and 50% over 80 yr of age, and even greater percentages when free T index criteria were employed. Our observations of health factor independent, age-related longitudinal decreases in T and free T, resulting in a high frequency of hypogonadal values, suggest that further investigation of T replacement in aged men, perhaps targeted to those with the lowest serum T concentrations, are justified.