The concept of the population attributable risk (PAR) percent has found widespread application in public health research. This quantity describes the proportion of a disease which could be prevented if a specific exposure were to be eliminated from a target population. We present methods for obtaining point and interval estimates of partial PARs, where the impact on disease burden for some presumably modifiable determinants is estimated in, and applied to, a cohort study. When the disease is multifactorial, the partial PAR must, in general, be used to quantify the proportion of disease which can be prevented if a specific exposure or group of exposures is eliminated from a target population, while the distribution of other modifiable and non-modifiable risk factors is unchanged. The methods are illustrated in a study of risk factors for bladder cancer incidence (Michaud DS et al., New England J Med 340 (1999) 1390). A user-friendly SAS macro implementing the methods described in this paper is available via the worldwide web.

This December 2010 version of the International AIDS Society-USA (IAS-USA) drug resistance mutations list updates the figures last published in December 2009 (Johnson VA et al, Top HIV Med, 2009;17:138-145). This update includes 9 new mutations- E138G and E138K for etravirine (Haddad M et al, CROI, 2010; Abstract 574, and Vingerhoets J et al, Antivir Ther, 2010;15 [Suppl 2]:A125); E92Q for raltegravir (Geretti AM et al, Antivir Ther, 2010;15 [Suppl 2]:A62; Cooper et al, N Engl J Med, 2008;359:355-365; and Malet I et al, Antimicrob Agents Chemother, 2008;52:1351-1358); and M36L, M36V, H69R, L89I, L89M, and L89V for tipranavir/ritonavir. In addition, the tipranavir/ritonavir N83D mutation designation was changed to boldface to indicate its recognition as a major mutation rather than a minor mutation. The mutations I13V, K20M/R, E35G, and L90M were removed from the tipranavir/ritonavir bar, reflecting new understanding. For etravirine, L100I*, K101P*, and Y181C*/I*/V* are denoted with asterisks (instead of bolded) to reflect that these individual mutations each have the greatest impact (ie, highest weighting scores) on reduced phenotypic susceptibility and impaired clinical response when compared with other etravirine mutations (Haddad M et al, CROI, 2010; Abstract 574). In addition, user notes d, n, r, w, and z were revised.

Cytotoxic action of membrane lipid peroxidation product 4-hydroxynonenal (HNE) is due mainly to its facile reactivity with proteins (Esterbauer, H., Schaur, R. J., and Zollner, H. (1991) Free Radical Biol. Med. 11, 77-80). In the present study, the detailed mechanism of HNE modification of a key enzyme in intermediary metabolism, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is studied mainly focusing on the formation of HNE-amino acid adducts in the enzyme. When GAPDH (1 mg/ml) was treated with 0-2 mM HNE in sodium phosphate buffer (pH 7.2) for 2 h at 37 degrees C, the enzyme was inactivated by HNE in a concentration-dependent manner. The loss of enzyme activity was associated with the loss of free sulfhydryl groups. Following its reduction with NaBH4, amino acid analysis of the HNE-modified enzyme demonstrated that histidine and lysine residues were also modified. At concentrations lower than 0.5 mM, HNE reacts preferentially with cysteine and lysine residues. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the HNE-modified enzyme suggested the formation of intra- and intermolecular cross-links of the enzyme subunit. The HNE-dependent loss of amino acid residues was accompanied by the generation of protein-linked carbonyl derivatives as assessed by reduction with NaB[3H]H4 and reaction with 2,4-dinitrophenylhydrazine. Thus, the conjugation of all the amino acids appears to involve Michael addition type reactions in which the carbonyl function of HNE would be preserved. The modified histidine residues were quantitatively recovered as the HNE-histidine adduct. However, only 28% of the missing lysine could be accounted for as the HNE-lysine derivative, and only 15.6% of the modified cysteine could be accounted for as the HNE-cysteine thioether derivative. It is proposed that the carbonyl groups of the HNE-derived Michael addition products may undergo secondary reactions with the amino acid groups of lysine residues to yield inter- and intrasubunit cross-links.

Throughout evolution, exposure to sunlight and the photosynthesis of vitamin D(3) in the skin has been critically important for the evolution of land vertebrates. During exposure to sunlight, the solar UVB photons with energies 290-315 nm are absorbed by 7-dehydrocholesterol in the skin and converted to previtamin D(3). Previtamin D(3) undergoes a rapid transformation within the plasma membrane to vitamin D(3). Excessive exposure to sunlight will not result in vitamin D intoxication because both previtamin D(3) and vitamin D(3) are photolyzed to several noncalcemic photoproducts. During the winter at latitudes above approximately 35 degrees , there is minimal, if any, previtamin D(3) production in the skin. Altitude also has a significant effect on vitamin D(3) production. At 27 degrees N in November, very little ( approximately 0.5%) previtamin D(3) synthesis was detected in Agra (169 m) and Katmandu (1400 m). There was an approximately 2- and 4-fold increase in previtamin D(3) production at approximately 3400 m and at Everest base camp (5300 m), respectively. Increased skin pigmentation, application of a sunscreen, aging, and clothing have a dramatic effect on previtamin D(3) production in the skin. It is estimated that exposure in a bathing suit to 1 minimal erythemal dose (MED) is equivalent to ingesting between 10,000 and 25,000 IU of vitamin D(2). The importance of sunlight for providing most humans with their vitamin D requirement is well documented by the seasonal variation in circulating levels of 25-hydroxyvitamin D [25(OH)D]. Vitamin D deficiency [i.e., 25(OH)D < 20 ng/ml] is common in both children and adults worldwide. Exposure to lamps that produce UVB radiation is an excellent source for producing vitamin D(3) in the skin and is especially efficacious in patients with fat malabsorption syndromes. The major cause of vitamin D deficiency globally is an underappreciation of sunlight's role in providing humans with their vitamin D(3) requirement. Very few foods naturally contain vitamin D, and those that do have a very variable vitamin D content. Recently it was observed that wild caught salmon had between 75% and 90% more vitamin D(3) compared with farmed salmon. The associations regarding increased risk of common deadly cancers, autoimmune diseases, infectious diseases, and cardiovascular disease with living at higher latitudes and being prone to vitamin D deficiency should alert all health care professionals about the importance of vitamin D for overall health and well being.

The search for the genetic factors contributing to Alzheimer disease (AD) has evolved tremendously throughout the years. It started from the discovery of fully penetrant mutations in Amyloid precursor protein, Presenilin 1, and Presenilin 2 as a cause of autosomal dominant AD, the identification of the ɛ4 allele of Apolipoprotein E as a strong genetic risk factor for both early-onset and late-onset AD, and evolved to the more recent detection of at least 21 additional genetic risk loci for the genetically complex form of AD emerging from genome-wide association studies and massive parallel resequencing efforts. These advances in AD genetics are positioned in light of the current endeavor directing toward translational research and personalized treatment of AD. We discuss the current state of the art of AD genetics and address the implications and relevance of AD genetics in clinical diagnosis and risk prediction, distinguishing between monogenic and multifactorial AD. Furthermore, the potential and current limitations of molecular reclassification of AD to streamline clinical trials in drug development and biomarker studies are addressed.Genet Med 18 5, 421-430.

Phase-encoded multishot SPIRAL approaches were used to acquire true 3D cerebral blood flow images of the human head using arterial spin tagging approaches. Multiple-inversion background suppression techniques, which suppress phase noise due to interacquisition fluctuations in the static magnetic field, reduced the temporal standard deviation of true 3D delta M images acquired using arterial spin tagging approaches by approximately 50%. Background suppressed arterial spin tagging (ASSIST) approaches were used to obtain high-resolution isotropic true 3D cerebral blood flow images, and to obtain true 3D activation images during cognitive (working memory) tasks. Magn Reson Med 44:92-100, 2000. Published 2000 Wiley-Liss, Inc.

OBJECTIVE

We introduced self-service access to the medical literature database, MEDLINE, into clinical settings to assess the frequency, patterns, purposes, and success of use.

METHODS

Longitudinal descriptive study.

METHODS

Inpatient and outpatient services of a university medical center.

METHODS

All trainees and attending staff working at the service sites were invited to participate; 158 (84%) did so.

METHODS

Free online access was provided to MEDLINE through GRATEFUL MED software. Participants were offered a 2-hour introduction to online searching and 2 hours of free search time.

RESULTS

For each search, a computer program requested identification of the user and the question to be addressed. Search transactions were recorded automatically. Interviews were conducted after a random sample of searches, and search questions were given to more expert searchers to run for comparison with the original. Eighty-one percent of participants did searches on study computers, at a mean rate of 2.7 searches per month. On comparison searches, participants retrieved 55% of the number of relevant articles retrieved by reference librarians (P = 0.024) and 50% more irrelevant articles (P less than 0.001). Forty-seven percent of searches on patient problems affected clinical decisions, but often on scanty information.

CONCLUSIONS

MEDLINE searching from clinical settings is feasible with brief training and affects clinical decisions. However, inexperienced searchers miss many relevant citations and search inefficiently. Further studies are needed to assess the impact of searching on physician performance and patient care.

In response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor alpha, cord blood CD34+ hematopoietic progenitor cells differentiate along two unrelated dendritic cell (DC) pathways: (1) the Langerhans cells (LCs), which are characterized by the expression of CD1a, Birbeck granules, the Lag antigen, and E cadherin; and (2) CD14+ cell-derived DCs, characterized by the expression of CD1a, CD9, CD68, CD2, and factor XIIIa (Caux et al, J Exp Med 184:695, 1996). The present study investigates the functions of each population. Although the two populations are equally potent in stimulating naive CD45RA cord blood T cells through apparently identical mechanisms, each also displays specific activities. In particular CD14-derived DCs show a potent and long-lasting (from day 8 to day 13) antigen uptake activity (fluorescein isothiocyanate dextran or peroxidase) that is about 10-fold higher than that of CD1a+ cells, which is restricted to the immature stage (day 6). The antigen capture is exclusively mediated by receptors for mannose polymers. The high efficiency of antigen capture of CD14-derived cells is coregulated with the expression of nonspecific esterase activity, a tracer of lysosomial compartment. In contrast, the CD1a+ population never expresses nonspecific esterase activity. The most striking difference is the unique capacity of CD14-derived DCs to induce naive B cells to differentiate into IgM-secreting cells, in response to CD40 triggering and interleukin-2. Thus, although the two populations can allow T-cell priming, initiation of humoral responses might be preferentially regulated by the CD14-derived DCs. Altogether, those results show that different pathways of DC development might exist in vivo: (1) the LC type, which might be mainly involved in cellular immune responses, and (2) the CD14-derived DC related to dermal DCs or circulating blood DCs, which could be involved in humoral immune responses.

While inflammation is a crucial component of atherothrombosis and patients with elevated inflammatory biomarkers such as high sensitivity C-reactive protein (hsCRP) are at increased vascular risk, it remains unknown whether inhibition of inflammation per se will lower vascular event rates. The recently completed JUPITER (N Engl J Med 2008, 359, 2195) trial demonstrates that statins reduce myocardial infarction, stroke, and all-cause mortality among healthy individuals with low cholesterol and elevated hsCRP. However, a direct test of the inflammatory hypothesis of atherothrombosis requires an agent that inhibits inflammation without impacting other components of the atherothrombotic process, and has an acceptable safety profile for a trial setting. On this basis, the cardiovascular inflammation reduction trial (CIRT) proposes to allocate 7000 stable coronary artery disease patients with persistent elevations of hsCRP to placebo or very-low-dose-methotrexate (VLDM, 10 mg weekly), a proven anti-inflammatory regimen that reduces TNFalpha, IL-6, and CRP levels and is in wide use among rheumatoid arthritis patients. If successful, CIRT would both confirm the inflammatory hypothesis of atherothrombosis and open novel approaches to the treatment and prevention of cardiovascular disorders.

BACKGROUND

Participation of women in the medical profession has increased during the past four decades, but issues of concern persist regarding disparities between the sexes in academic medicine. Advancement is largely driven by peer-reviewed original research, so we sought to determine the representation of female physician-investigators among the authors of selected publications during the past 35 years.

METHODS

Original articles from six prominent medical journals--the New England Journal of Medicine (NEJM), the Journal of the American Medical Association (JAMA), the Annals of Internal Medicine (Ann Intern Med), the Annals of Surgery (Ann Surg), Obstetrics & Gynecology (Obstet Gynecol), and the Journal of Pediatrics (J Pediatr)--were categorized according to the sex of both the first and the senior (last listed) author. Sex was also determined for the authors of guest editorials in NEJM and JAMA. Data were collected for the years 1970, 1980, 1990, 2000, and 2004. The analysis was restricted to authors from U.S. institutions holding M.D. degrees.

RESULTS

The sex was determined for 98.5 percent of the 7249 U.S. authors of original research with M.D. degrees. The proportion of first authors who were women increased from 5.9 percent in 1970 to 29.3 percent in 2004 (P<0.001), and the proportion of senior authors who were women increased from 3.7 percent to 19.3 percent (P<0.001) during the same period. The proportion of authors who were women increased most sharply in Obstet Gynecol (from 6.7 percent of first authors and 6.8 percent of senior authors in 1970 to 40.7 percent of first authors and 28.0 percent of senior authors in 2004) and J Pediatr (from 15.0 percent of first authors and 4.3 percent of senior authors in 1970 to 38.9 percent of first authors and 38.0 percent of senior authors in 2004) and remained low in Ann Surg (from 2.3 percent of first authors and 0.7 percent of senior authors in 1970 to 16.7 percent of first authors and 6.7 percent of senior authors in 2004). In 2004, 11.4 percent of the authors of guest editorials in NEJM and 18.8 percent of the authors of guest editorials in JAMA were women.

CONCLUSIONS

Over the past four decades, the proportion of women among both first and senior physician-authors of original research in the United States has significantly increased. Nevertheless, women still compose a minority of the authors of original research and guest editorials in the journals studied.

Daptomycin is a lipopeptide antibiotic that has recently been approved for treatment of gram-positive bacterial infections. The mode of action of daptomycin is not yet entirely clear. To further understand the mechanism transcriptomic analysis of changes in gene expression in daptomycin-treated Staphylococcus aureus was carried out. The expression profile indicated that cell wall stress stimulon member genes (B. J. Wilkinson, A. Muthaiyan, and R. K. Jayaswal, Curr. Med. Chem. Anti-Infect. Agents 4:259-276, 2005) were significantly induced by daptomycin and by the cell wall-active antibiotics vancomycin and oxacillin. Comparison of the daptomycin response of a two-component cell wall stress stimulon regulator VraSR mutant, S. aureus KVR, to its parent N315 showed diminished expression of the cell wall stress stimulon in the mutant. Daptomycin has been proposed to cause membrane depolarization, and the transcriptional responses to carbonyl cyanide m-chlorophenylhydrazone (CCCP) and nisin were determined. Transcriptional profiles of the responses to these antimicrobial agents showed significantly different patterns compared to those of the cell wall-active antibiotics, including little or no induction of the cell wall stress stimulon. However, there were a significant number of genes induced by both CCCP and daptomycin that were not induced by oxacillin or vancomycin, so the daptomycin transcriptome probably reflected a membrane depolarizing activity of this antimicrobial also. The results indicate that inhibition of peptidoglycan biosynthesis, either directly or indirectly, and membrane depolarization are parts of the mode of action of daptomycin.

The process of compound selection and prioritization is crucial for both combinatorial chemistry (CBC) and high throughput screening (HTS). Compound libraries have to be screened for unwanted chemical structures, as well as for unwanted chemical properties. Property extrema can be eliminated by using property filters, in accordance with their actual distribution. Property distribution was examined in the following compound databases: MACCS-II Drug Data Report (MDDR), Current Patents Fast-alert, Comprehensive Medicinal Chemistry, Physician Desk Reference, New Chemical Entities, and the Available Chemical Directory (ACD). The ACDF and MDDRF subsets were created by removing reactive functionalities from the ACD and MDDR databases, respectively. The ACDF subset was further filtered by keeping only molecules with a 'drug-like' score [Ajay et al., J. Med. Chem., 41 (1998) 3314; Sadowski and Kubinyi, J. Med. Chem., 41 (1998) 3325] below 0.8. The following properties were examined: molecular weight (MW), the calculated octanol/water partition coefficient (CLOGP), the number of rotatable (RTB) and rigid bonds (RGB), the number of rings (RNG), and the number of hydrogen bond donors (HDO) and acceptors (HAC). Of these, MW and CLOGP follow a Gaussian distribution, whereas all other descriptors have an asymmetric (truncated Gaussian) distribution. Four out of five compounds in ACDF and MDDRF pass the 'rule of 5' test, a probability scheme that estimates oral absorption proposed by Lipinski et al. [Adv. Drug Deliv. Rev., 23 (1997) 3]. Because property distributions of HDO, HAC, MW and CLOGP (used in the 'rule of 5' test) do not differ significantly between these datasets, the 'rule of 5' does not distinguish 'drugs' from 'nondrugs'. Therefore, Pareto analyses were performed to examine skewed distributions in all compound collections. Seventy percent of the 'drug-like' compounds were found between the following limits: 0 < or = HDO < or = 2, 2 < or = HAC < or = 9, 2 < or = RTB < or = 8, and 1 < or = RNG < or = 4, respectively. The number of launched drugs in MDDR having 0 < or = HDO < or = 2 is 4.8 times higher than the number of drugs having 3 < or = HDO < or = 5. Skewed distributions can be exploited to focus on the 'drug-like space': 62.68% of ACDF ('nondrug-like') compounds have 0 < or = RNG < or = 2, and RGB < or = 17, while 28.88% of ACDF compounds have 3 < or = RNG < or = 13, and 18 < or = RGB < or = 56. By contrast, 61.22% of MDDRF compounds have RNG>> or = 3, and RGB>> or = 18, and only 24.73% of MDDRF compounds have 0 < or = RNG < or = 2 rings, and RGB < or = 17. The probability of identifying 'drug-like' structures increases with molecular complexity.

A novel human complex that can either repress activator-dependent transcription mediated by PC4, or, at limiting TFIIH, act synergistically with PC4 to enhance activator-dependent transcription has been purified. This complex contains homologs of a subset of yeast mediator/holoenzyme components (including SRB7, SRB10, SRB11, MED6, and RGR1), homologs of other yeast transcriptional regulatory factors (SOH1 and NUT2), and, significantly, some components (TRAP220, TRAP170/hRGR1, and TRAP100) of a human thyroid hormone receptor-associated coactivator complex. The complex shows direct activator interactions but, unlike yeast mediator, can act independently of the RNA polymerase II CTD. These findings demonstrate both positive and negative functional capabilities for the human complex, emphasize novel (CTD-independent) regulatory mechanisms, and link the complex to other human coactivator complexes.

A number of studies have indicated that central nervous system-derived cells can be infected with human immunodeficiency virus type 1 (HIV-1). To determine whether CD4, the receptor for HIV-1 in lymphoid cells, was responsible for infection of neural cells, we characterized infectable human central nervous system tumor lines and primary fetal neural cells and did not detect either CD4 protein or mRNA. We then attempted to block infection with anti-CD4 antibodies known to block infection of lymphoid cells; we noted no effect on any of these cultured cells. The results indicate that CD4 is not the receptor for HIV-1 infection of the glioblastoma line U373-MG, medulloblastoma line MED 217, or primary human fetal neural cells.

The mouse neurological mutant 'motor endplate disease' (med) is characterized by early onset progressive paralysis of the hind limbs, severe muscle atrophy, degeneration of Purkinje cells and juvenile lethality. We have isolated a voltage-gated sodium channel gene, Scn8a, from the flanking region of a transgene-induced allele of med. Scn8a is expressed in brain and spinal cord but not in skeletal muscle or heart, and encodes a predicted protein of 1,732 amino acids. An intragenic deletion at the transgene insertion site results in loss of expression. Scn8a is closely related to other sodium channel alpha subunits, with greatest similarity to a brain transcript from the pufferfish Fugu rubripes. The human homologue, SCN8A, maps to chromosome 12q13 and is a candidate gene for inherited neurodegenerative disease.

Hematopoietic stem cell (HSC) niches have been reported at the endosteum or adjacent to bone marrow (BM) vasculature. To investigate functional attributes of these niches, mice were perfused with Hoechst 33342 (Ho) in vivo before BM cell collection in presence of pump inhibitors and antibody stained. We report that the position of phenotypic HSCs, multipotent and myeloid progenitors relative to blood flow, follows a hierarchy reflecting differentiation stage, whereas mesenchymal stromal cells are perivascular. Furthermore, during granulocyte colony-stimulating factor-induced mobilization, HSCs migrated closer to blood flow, whereas stromal cells did not. Interestingly, phenotypic Lin(-)Sca1(+)KIT(+)CD41(-)CD48(-)CD150(+) HSCs segregated into 2 groups (Ho(neg) or Ho(med)), based on degree of blood/Ho perfusion of their niche. HSCs capable of serial transplantation and long-term bromodeoxyuridine label retention were enriched in Ho(neg) HSCs, whereas Ho(med) HSCs cycled more frequently and only reconstituted a single host. This suggests that the most potent HSC niches are enriched in locally secreted factors and low oxygen tension due to negligible blood flow. Importantly, blood perfusion of niches correlates better with HSC function than absolute distance from vasculature. This technique enables prospective isolation of serially reconstituting HSCs distinct from other less potent HSCs of the same phenotype, based on the in vivo niche in which they reside.

Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen [lsqb]HLA[rsqb] A, B, and C) may affect susceptibility to and severity of severe acute respiratory syndrome 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We execute a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA -A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explore the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome is successfully sampled and presented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (Lin M, Tseng H-K, Trejaut JA, Lee H-L, Loo J-H, Chu C-C, Chen P-J, Su Y-W, Lim KH, Tsai Z-U, Lin R-Y, Lin R-S, Huang C-H. BMC Med Genet 4:9. 2003.). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting it could enable cross-protective T-cell based immunity. Finally, we report global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of viral severity in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.

CD4+CD25+ T regulatory cells (Treg) are thought to be important in the peripheral tolerance. Recent evidence suggests that human peripheral blood CD4+CD25+ T cells are heterogeneous and contain both CD4+CD25(high) T cells with potent regulatory activity and many more CD4+CD25(low/med) nonregulatory T cells. In this study, we found that virtually all peripheral blood CD4+CD25(high)Foxp3+ Treg expressed high levels of the chemokine receptor CCR4. In addition, 80% of Treg expressed cutaneous lymphocyte Ag (CLA) and 73% expressed CCR6. These molecules were functional, as CLA+ Treg showed CD62E ligand activity and demonstrable chemotactic responses to the CCR4 ligands CCL22 and CCL17 and to the CCR6 ligand CCL20. The phenotype and chemotactic response of these Treg were significantly different from those of CD4+CD25(med) nonregulatory T cells. We further demonstrated that blood CLA+ Treg inhibited CD4+CD25- T cell proliferation induced by anti-CD3. Based on homing receptor profile, CLA+ Treg should enter normal skin. We next isolated CD4+CD25(high) T cells directly from normal human skin; these cells suppressed proliferation of skin CD4+CD25- T cells. Therefore, the majority of true circulating Treg express functional skin-homing receptors, and human Treg may regulate local immune responses in normal human skin.

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.

BACKGROUND

A recent increase in the incidence of hepatocellular carcinoma was reported in the United States. The cause of this witnessed rise remains unknown.

METHODS

We examined the temporal changes in both age-specific and age-standardized hospitalization rates of primary liver cancer associated with hepatitis C, hepatitis B, and alcoholic cirrhosis in the Department of Veterans Affairs Medical Center's Patient Treatment File.

RESULTS

A total of 1605 patients were diagnosed with primary liver cancer between 1993 and 1998. The overall age-adjusted proportional hospitalization rate for primary liver cancer increased from 36.4 per 100,000 (95% confidence interval [CI], 34.0-38.9) between 1993 and 1995 to 47.5 per 100,000 (95% CI, 44.6-50.1) between 1996 and 1998. There was a 3-fold increase in the age-adjusted rates for primary liver cancer associated with hepatitis C virus, from 2.3 per 100,000 (95% CI, 1. 8-3.0) between 1993 and 1995 to 7.0 per 100,000 (95% CI, 5.9-8.1) between 1996 and 1998. Concomitant with this rise, the age-specific rates for primary liver cancer associated with hepatitis C also shifted toward younger patients. During the same periods, the age-adjusted rates for primary liver cancer associated with either hepatitis B virus (2.2 vs 3.1 per 100,000) or alcoholic cirrhosis (8. 4 vs 9.1 per 100,000) remained stable. The rates for primary liver cancer without risk factors also remained without a statistically significant change, from 17.5 (95% CI, 15.8-19.1) between 1993 and 1995 to 19.0 per 100,000 (95% CI, 17.3-20.7) between 1996 and 1998.

CONCLUSIONS

Hepatitis C virus infection accounts for most of the increase in the number of cases of primary liver cancer among US veterans. The rates of primary liver cancer associated with alcoholic cirrhosis and hepatitis B virus infection have remained stable. Arch Intern Med. 2000;160:3227-3230.

The pathogenesis of central nervous system disease during human immunodeficiency virus type 1 (HIV-1) infection revolves around productive viral infection of brain macrophages and microglia. Neuronal losses in the cortex and subcortical gray matter accompany macrophage infection. The question of how viral infection of brain macrophages ultimately leads to central nervous system (CNS) pathology remains unanswered. Our previous work demonstrated high-level production of tumor necrosis factor alpha, interleukin 1 beta, arachidonic acid metabolites, and platelet-activating factor (PAF) from HIV-infected monocytes and astroglia (H. E. Gendelman, P. Genis, M. Jett, and H. S. L. M. Nottet, in E. Major, ed., Technical Advances in AIDS Research in the Nervous System, in press; P. Genis, M. Jett, E. W. Bernton, H. A. Gelbard, K. Dzenko, R. Keane, L. Resnick, D. J. Volsky, L. G. Epstein, and H. E. Gendelman, J. Exp. Med. 176:1703-1718, 1992). These factors, together, were neurotoxic. The relative role(s) of each of these candidate neurotoxins in HIV-1-related CNS dysfunction was not unraveled by these initial experiments. We now report that PAF is produced during HIV-1-infected monocyte-astroglia interactions. PAF was detected at high levels in CSF of HIV-1-infected patients with immunosuppression and signs of CNS dysfunction. The biologic significance of the results for neurological disease was determined by addition of PAF to cultures of primary human fetal cortical or rat postnatal retinal ganglion neurons. Here, PAF at concentrations of>> or = 300 pg/ml produced neuronal death. The N-methyl-D-aspartate receptor antagonist MK-801 or memantine partially blocked the neurotoxic effects of PAF. The identification of PAF as an HIV-1-induced neurotoxin provides new insights into how HIV-1 causes neurological impairment and how it may ultimately be ameliorated.

BACKGROUND

There is a dearth of validated information about lesbian and bisexual women's health. To better understand some of these issues, we used population-based data to assess variations in health behaviors, health status, and access to and use of health care based on sexual orientation.

METHODS

Our study population was drawn from a population-based sample of women, the 1997 Los Angeles County Health Survey. Participants reported their sexual orientation and these analyses included 4697 women: 4610 heterosexual women, 51 lesbians, and 36 bisexual women. We calculated adjusted relative risks to assess the effect of sexual orientation on important health issues.

RESULTS

Lesbians and bisexual women were more likely than heterosexual women to use tobacco products and to report any alcohol consumption, but only lesbians were significantly more likely than heterosexual women to drink heavily. Lesbians and bisexual women were less likely than heterosexual women to have health insurance, more likely to have been uninsured for health care during the preceding year, and more likely to have had difficulty obtaining needed medical care. During the preceding 2 years, lesbians, but not bisexual women, were less likely than heterosexual women to have had a Papanicolaou test and a clinical breast examination.

CONCLUSIONS

In this first population-based study of lesbian and bisexual women's health, we found that lesbians and bisexual women were more likely than heterosexual women to have poor health behaviors and worse access to health care. These findings support our hypothesis that sexual orientation has an independent effect on health behaviors and receipt of care, and indicate the need for the increased systematic study of the relationship between sexual orientation and various aspects of health and health care. Arch Fam Med. 2000;9:1043-1051

OBJECTIVE

Studies have shown that there is an association between depression and male erectile dysfunction (MED). However. these earlier studies suffer considerable methodological flaws including: a) lack of a multidisciplinary approach; b) poor sampling techniques; and finally, c) poor and variable measures of MED and depression. Our objectives are: a) to determine whether MED is associated with depressive symptoms and b) to determine whether this association is independent of aging and para-aging factors.

METHODS

Data were obtained from the Massachusetts Male Aging Study (MMAS). The MMAS was a cross-sectional, population-based multidisciplinary survey of health in normally aging men (aged 40-70 years) conducted from 1986 to 1989. In the analytic model, depressive symptoms, as measured by a score of 16 or greater on the Center for Epidemiological Studies-Depression (CES-D) scale, was used as a predictor of MED, which was assessed with a self-administered questionnaire.

RESULTS

MED was associated with depressive symptoms after controlling for potential confounders (odds ratio (OR) 1.82, 95% confidence interval (Ct) 1.21-2.73).

CONCLUSIONS

We conclude that the relationship between depressive symptoms and MED in middle-aged men is robust and independent of important aging and para-aging confounders, such as demographic, anthropometric and lifestyle factors, health status, medication use, and hormones.

A number of 3-alkyl analogues of the experimental antitumor drug mitozolomide [8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H )-one] have been screened against murine tumors in vivo. Only the compounds with a 3-methyl- or 3-bromoethyl group possessed significant antitumor activity against the TLX5 lymphoma. The 3-methyl analogue, 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045), was investigated further and found to possess good activity, when administered i.p., against the L1210 and P388 leukemias, the M5076 reticulum cell sarcoma, B16 melanoma, and ADJ/PC6A plasmacytoma. The drug was also active when administered p.o. to mice bearing the L1210 leukemia. A daily for 5 days schedule of 100 mg/kg CCRG 81045 produced increases of survival time of treated animals compared to controls of 176 and greater than 235% against the P388 and L1210 leukemias, respectively. In the female C57BL x DBA/2 F1 mouse the 10% lethal dose was 125 mg/kg daily for 5 days. CCRG 81045 was found to undergo mild alkaline hydrolysis and ring fission to form the linear triazene 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide, which is the putative metabolite formed upon metabolic activation of the antitumor drug dacarbazine [5-(3,3-dimethyltriazen-1-yl)imidazole-4-carboxamide]. The half-life of CCRG 81045 at 37 degrees C in 0.2 M phosphate buffer (pH 7.4) was 1.24 h, whereas that of 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide at 25 degrees C was reported to be 8 min (F. H. Shealy and C. A. Krauth, J. Med. Chem., 9:34-37, 1966). The half-life of CCRG 81045 in human plasma in vitro at 37 degrees C was 0.42 h. Pharmacokinetic experiments conducted in BALB/c mice produced plasma profiles of CCRG 81045, administered i.p. or p.o., which showed a rapid absorption phase, elimination half-lives of 1.13 h (i.p.) and 1.29 h (p.o.), and a bioavailability of 0.98.