Publications

OBJECTIVE

To examine the predictors of transmission risk among HIV-infected men who have sex with men (MSM) in 4 US cities.

METHOD

Individual computer-assisted interviews assessing psychologic measures and sexual behavior with the 5 most recent male and female partners were conducted with a diverse sample of 1910 HIV-infected MSM recruited from community and clinic settings in San Francisco, New York, Los Angeles, and Milwaukee. Transmission-risk events were defined as unprotected vaginal or anal sex with a partner who was HIV negative or of unknown status.

RESULTS

A small but not insignificant proportion of MSM (12.7%) reported at least 1 transmission-risk event in the previous 3 months, with 57% of those events taking place with casual as opposed to steady partners. Multivariate predictors of transmission risk with casual partners were stimulant (eg, crystal methamphetamine) and other drug use, having low coping self-efficacy, and not having disclosed one's HIV serostatus to all partners. Stimulant use and failing to disclosing one's serostatus to all partners were associated with risk in primary relationships.

CONCLUSIONS

Responding to HIV transmission risk in MSM requires different strategies for primary and casual partners.

GspB and Hsa are homologous serine-rich surface glycoproteins of Streptococcus gordonii strains M99 and Challis, respectively, that mediate the binding of these organisms to platelet membrane glycoprotein (GP) Ibalpha. Both GspB and Hsa consist of an N-terminal putative signal peptide, a short serine-rich region, a region (BR) that is rich in basic amino acids, a longer serine-rich region and a C-terminal cell wall anchoring domain. To further assess the mechanisms for GspB and Hsa binding, we investigated the binding of the BRs of GspB and Hsa (expressed as glutathione S-tranferase fusion proteins) to sialylated glycoproteins in vitro. Both fusion proteins showed significant levels of binding to sialylated moieties on fetuin and GPIbalpha. In contrast, the corresponding region of a GspB homologue of Streptococcus agalactiae, which is acidic rather than basic, showed no binding to either fetuin or GPIbalpha. As measured by surface plasmon resonance kinetic analysis, GspB- and Hsa-derived fusion proteins had high affinity for GPIbalpha, but with somewhat different dissociation constants. Dot blot analysis using a panel of synthesized oligosaccharides revealed that the BR of Hsa can bind both alpha(2-3) sialyllactosamine [NeuAcalpha(2-3)Galbeta(1-4)GlcNAc] and sialyl-T antigen [NeuAcalpha(2-3)Galbeta(1-3)GalNAc], whereas the BR of GspB only bound sialyl-T antigen. Moreover, far Western blotting using platelet membrane proteins revealed that GPIbalpha is the principal receptor for GspB and Hsa on human platelets. The combined results indicate that the BRs of GspB and Hsa are the binding domains of these adhesins. However, the subsets of carbohydrate structures on GPIbalpha recognized by the binding domains appear to be different between the two proteins.

Antimicrobial stewardship programs in hospitals seek to optimize antimicrobial prescribing in order to improve individual patient care as well as reduce hospital costs and slow the spread of antimicrobial resistance. With antimicrobial resistance on the rise worldwide and few new agents in development, antimicrobial stewardship programs are more important than ever in ensuring the continued efficacy of available antimicrobials. The design of antimicrobial management programs should be based on the best current understanding of the relationship between antimicrobial use and resistance. Such programs should be administered by multidisciplinary teams composed of infectious diseases physicians, clinical pharmacists, clinical microbiologists, and infection control practitioners and should be actively supported by hospital administrators. Strategies for changing antimicrobial prescribing behavior include education of prescribers regarding proper antimicrobial usage, creation of an antimicrobial formulary with restricted prescribing of targeted agents, and review of antimicrobial prescribing with feedback to prescribers. Clinical computer systems can aid in the implementation of each of these strategies, especially as expert systems able to provide patient-specific data and suggestions at the point of care. Antibiotic rotation strategies control the prescribing process by scheduled changes of antimicrobial classes used for empirical therapy. When instituting an antimicrobial stewardship program, a hospital should tailor its choice of strategies to its needs and available resources.

BACKGROUND

Data on associations of body composition with HIV disease characteristics are limited.

OBJECTIVE

We compared sex-specific associations between HIV disease characteristics and body composition in an racially-ethnically diverse cohort of antiretroviral-naive patients.

DESIGN

The study was a cross-sectional analysis of participants enrolled in a metabolic substudy of a multicenter trial. Regional fat was measured, and total body fat (TBF) was derived by using the Durnin-Womersley formula (DWF) and bioelectrical impedance analysis (BIA). Body cell mass (BCM) was measured by BIA.

RESULTS

Among 422 participants, 22% were women, 60% were African American, and 36% had prior AIDS-defining illnesses. Mean (+/-SD) age was 38.2 +/- 9.6 y, CD4+ count was 215 +/- 184 cells/mm3, and HIV RNA log10 was 5.0 +/- 0.8 copies/mL. On multivariate analysis, women with AIDS-defining illness had significantly (P < 0.005) lower regional body fat and TBF (BIA: -9.5 kg; DWF: -7.3 kg) but nonsignificantly lower BCM (-1.3 kg) than did women without such illnesses, whereas men with AIDS-defining illness had significantly (P < 0.005) lower BCM (-1.7 kg) but nonsignificantly lower TBF (BIA: -1.3 kg; DWF: -1.83 kg) than did men without such illnesses (P < 0.05 for sex differences in TBF). Significant negative associations of HIV RNA with BCM (-0.9 kg/log RNA; P = 0.03), TBF by BIA (-1.4 kg/log RNA; P = 0.05) and by DWF (-1.6 kg/log RNA; P = 0.01), and regional fat were observed in men only.

CONCLUSIONS

The effect of prior AIDS illness on body fat differed significantly between the sexes: women with prior AIDS-defining illness had significantly less fat than did women without such illnesses. An independent effect of HIV viremia on BCM and fat was seen in men. These distinctions may be due to inherent biological differences between the sexes.

OBJECTIVE

Both peripheral fat loss and central fat gain have been reported in HIV infection. Which changes are specific to HIV were determined by comparison with control subjects and the associations among different adipose tissue depots were determined.

METHODS

Cross-sectional analysis of HIV-positive and control men from the study of Fat Redistribution and Metabolic Change in HIV Infection. Lipoatrophy or lipohypertrophy was defined as concordance between participant report of change and examination. Regional adipose tissue volume was measured by magnetic resonance imaging (MRI).

RESULTS

HIV-positive men reported more fat loss than controls in all peripheral and most central depots. Peripheral lipoatrophy was more frequent in HIV-positive men than in controls (38.3% vs. 4.6%, P < 0.001), whereas central lipohypertrophy was less frequent (40.2% vs. 55.9%, P = 0.001). Among HIV-positive men, the presence of central lipohypertrophy was not positively associated with peripheral lipoatrophy (odds ratio = 0.71, CI: 0.47 to 1.06, P = 0.10). On MRI, HIV-positive men with clinical peripheral lipoatrophy had less subcutaneous adipose tissue (SAT) in peripheral and central sites and less visceral adipose tissue (VAT) than HIV-positive men without peripheral lipoatrophy. HIV-positive men both with and without lipoatrophy had less SAT than controls, with legs and lower trunk more affected than upper trunk. Use of the antiretroviral drugs stavudine or indinavir was associated with less leg SAT but did not appear to be associated with more VAT; nevirapine use was associated with less VAT.

CONCLUSION

Both peripheral and central subcutaneous lipoatrophy was found in HIV infection. Lipoatrophy in HIV-positive men is not associated with reciprocally increased VAT.

Mutations in the Melanocortin 4 receptor are implicated in 1-6% of early onset or severe adult obesity cases. Most of the patients carry heterozygous missense mutations. Arguments for the pathogenicity of these mutations are based on the frequency of rare functionally relevant non-synonymous mutations in severely obese children and adults versus non-obese controls, the segregation of mutations with obesity in the family of the probands (although with incomplete penetrance) and the relevant functional defects described for these mutations. We have developed new assays to study the functional characteristics of these obesity-associated MC4R mutations. Systematic and comparative functional study of over 50 different obesity-associated mutations suggests that multiple functional alterations contribute to their pathogenicity. These studies also lead to new insights into the structure-function relationship of MC4R, provide novel hypotheses for the genetic predisposition to common obesity in humans and allow the development of new molecular tools for studying the physiological role of GPCRs.

BACKGROUND

We examined the link between functioning and psychological status among persons with chronic obstructive pulmonary disease (COPD), using measures of both general functional status and performance of life activities.

METHODS

334 persons with COPD were interviewed by telephone. Functioning was assessed with two measures of difficulty with specific types of activities (self-care, recreational activities/hobbies) and a general measure of functional status (SF-12 Physical Component Score (PCS)).

RESULTS

About 16.2% of the sample had SF-12 Mental Component Score (MCS) scores indicative of psychological distress (MCS < 35). In separate regression models, difficulty with self-care and recreational activities was associated with an increased likelihood of distress (self-care: OR=2.9, 95%CI 1.3, 6.6; recreation: OR=7.5 [2.4, 23.7]), while PCS scores were not. In a model including all three predictors, difficulty with recreation was strongly associated with distress (OR=7.7 [2.1, 29.2]), difficulty with self-care was less strongly associated with distress (OR=2.1 [0.8, 5.5]), and PCS did not contribute significantly to the predictive ability of the model. However, low functioning as measured by the PCS was a significant risk factor for difficulty performing activities.

CONCLUSIONS

Measures of activity difficulty were independent predictors of psychological distress, while general physical function was not. Poor general physical function was a risk factor for activity difficulties, suggesting an indirect relationship between low PCS and psychological distress, with activity difficulties as the intermediate variable.

OBJECTIVE

To investigate breast cancer risk according to metabolizing genes polymorphisms in older women.

METHODS

A subset (43.8%) of 4248 older, white women from the Study of Osteoporotic Fractures (SOF) were genotyped for the catechol-O-methyltransferase (COMT) Val108Met polymorphism and the CYP1A1*2C locus. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between genotypes and breast cancer while controlling for potential confounders.

RESULTS

During a mean follow up of 12.4 years, 252 women (5.9%) developed breast cancer. The HR (95% CI) for breast cancer was 1.24 (0.87-1.75) for COMT(Val/Met) and 1.35 (0.93-1.97) for COMT(Met/Met). No interactions with lifestyle and reproductive factors were found. The HR associated with the CYP1A1*2C Val allele was 0.80 (0.46, 1.39) with little evidence for interactions with lifestyle or reproductive factors.

CONCLUSIONS

Among older white women, neither the COMT Val108/158Met polymorphism nor the CYP1A*2C Val allele plays a major role in breast cancer risk either alone or in combination with lifestyle and reproductive factors.

OBJECTIVES

ABCB1 (multidrug resistance 1 polypeptide, MDR1, Pgp) is a multispecific efflux transporter of drugs and xenobiotics. Among numerous polymorphisms in human ABCB1, the synonymous SNP 3435C > T has been associated with decreased mRNA and protein levels, via unknown mechanisms.

METHODS

To search for cis-acting polymorphism affecting transcription or mRNA processing, we used 3435C > T as a marker single nucleotide polymorphism (SNP), for measuring differences in allelic mRNA expression. Ratios of allelic abundance in genomic DNA and mRNA (after conversion to cDNA) were measured quantitatively with a primer extension assay, in human liver samples.

RESULTS

mRNA expression of the 3435C allele was significantly higher than that of the 3435T allele (3435C/3435T ratios ranging from 1.06-1.61). Cotransfection of equal amounts of ABCB1 expression plasmids containing 3435C or 3435T also revealed higher 3435C mRNA expression. Increasing 3435C/3435T ratios after cessation of transcription indicated that the 3435C > T substitution decreases mRNA stability. 3435C > T is in strong linkage disequilibrium with two other coding SNPs (1236C > T and 2677G > T) forming two abundant haplotypes (ABCB1*1 and ABCB1*13). Transfection of all possible combinations of these three SNPs demonstrated that only 3435T is associated with lower mRNA levels. Calculations of mRNA folding, using Mfold, suggested an effect on mRNA secondary structure.

CONCLUSIONS

the abundant 3435C > T SNP appears to be a main factor in allelic variation of ABCB1 mRNA expression in the liver, by changing mRNA stability.

Since the first minimally invasive colon resection 15 years ago, laparoscopic colectomy has been implemented as techniques have evolved. Like the laparoscopic approach for other operations, minimally invasive colectomy has potential benefits of improved short-term outcomes. Questions have been raised, however, regarding its use for colorectal cancer resection. Until recently, it was unclear whether minimally invasive surgery for colonic malignancies would achieve adequate oncologic resection. This review provides an overview of laparoscopic colectomy and techniques and examines recent data from randomized, controlled trials that report the short- and long-term outcomes after laparoscopic colectomy for cancer.