Pseudotyping of HIV-1 with Human T-Lymphotropic Virus 1 (HTLV-1) Envelope Glycoprotein during HIV-1-HTLV-1 Coinfection Facilitates Direct HIV-1 Infection of Female Genital Epithelial Cells: Implications for Sexual Transmission of HIV-1.

Female genital epithelial cells cover the genital tract and provide the first line of protection against infection with sexually transmitted pathogenic viruses. These cells normally are impervious to HIV-1. We report that coinfection of cells by HIV-1 and another sexually transmitted virus, human T-lymphotropic virus 1 (HTLV-1), led to production of HIV-1 that had expanded cell tropism and was able to directly infect primary vaginal and cervical epithelial cells. HIV-1 infection of epithelial cells was blocked by neutralizing antibodies against the HTLV-1 envelope (Env) protein, indicating that the infection was mediated through HTLV-1 Env pseudotyping of HIV-1. Active replication of HIV-1 in epithelial cells was demonstrated by inhibition with anti-HIV-1 drugs. We demonstrated that HIV-1 derived from peripheral blood of HIV-1-HTLV-1-coinfected subjects could infect primary epithelial cells in an HTLV-1 Env-dependent manner. HIV-1 from subjects infected with HIV-1 alone was not able to infect epithelial cells. These results indicate that pseudotyping of HIV-1 with HTLV-1 Env can occur in vivo Our data further reveal that active replication of both HTLV-1 and HIV-1 is required for production of pseudotyped HIV-1. Our findings indicate that pseudotyping of HIV-1 with HTLV-1 Env in coinfected cells enabled HIV-1 to directly infect nonpermissive female genital epithelial cells. This phenomenon may represent a risk factor for enhanced sexual transmission of HIV-1 in regions where virus coinfection is common.IMPORTANCE Young women in certain regions of the world are at very high risk of acquiring HIV-1, and there is an urgent need to identify the factors that promote HIV-1 transmission. HIV-1 infection is frequently accompanied by infection with other pathogenic viruses. We demonstrate that coinfection of cells by HIV-1 and HTLV-1 can lead to production of HIV-1 pseudotyped with HTLV-1 Env that is able to directly infect female genital epithelial cells both in vitro and ex vivo Given the function of these epithelial cells as genital mucosal barriers to pathogenic virus transmission, the ability of HIV-1 pseudotyped with HTLV-1 Env to directly infect female genital epithelial cells represents a possible factor for increased risk of sexual transmission of HIV-1. This mechanism could be especially impactful in settings such as Sub-Saharan Africa and South America, where HIV-1 and HTLV-1 are both highly prevalent.

Infection of female primary lower genital tract epithelial cells after natural pseudotyping of HIV-1: possible implications for sexual transmission of HIV-1.

The global AIDS pandemic continues to expand and in some regions of the world, such as southern Africa, the prevalence of HIV-1 infection exceeds 20%. The devastating spread of the virus in young women in these countries appears disproportional to overall risk of infection. Regions with high prevalence of HIV-1 are often also highly endemic for other pathogenic viruses including HSV, CMV and HTLV. We propose that acquisition by HIV-1 of the envelope glycoproteins of other viruses, in a process we call "natural pseudotyping," expands the cellular tropism of HIV-1, enabling it to infect female genital epithelial cells directly and thereby dramatically increasing risk of infection during sexual intercourse. In this proof-of-concept study, we demonstrate that when HIV-1 co-infects T cells along with the gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV), progeny HIV-1 particles are produced capable of infecting primary vaginal, ectocervical and endocervical epithelial cells. These cell types are normally resistant to HIV-1 infection. Infection of primary genital cells was neutralized by antisera against the XMRV glycoprotein, confirming that infection was mediated by the XMRV glycoprotein acquired through pseudotyping of HIV. Inhibition by AZT showed that active replication of HIV-1 occurred in these cells and ruled out non-specific endocytic uptake of the virus. These results demonstrate that natural pseudotyping can expand the tropism of HIV-1 to include genital epithelial cells and have potential implications for sexual transmission of the virus.

Surgical and therapy update on the management of Dupuytren's disease.

Advancements in surgical and therapy management for Dupuytren's disease are highlighted. Indications for treatment and various surgical options for Dupuytren's disease are described. Non-surgical techniques are also presented. Therapy interventions are reviewed. Treatment techniques for the management of secondary problems resulting from prolonged digit flexion are presented. The benefits, limitations and outcomes of treatments are reviewed to assist the reader to link patient specific problems and goals to the most appropriate treatment choice.

Evidence for Gardnerella vaginalis uptake and internalization by squamous vaginal epithelial cells: implications for the pathogenesis of bacterial vaginosis.

Bacterial vaginosis (BV), a common condition seen in premenopausal women, is associated with preterm labor, pelvic inflammatory disease, and delivery of low birth weight infants. Gardnerella vaginalis is the predominant bacterial species associated with BV, although its exact role in the pathology of BV is unknown. Using immunofluorescence, confocal and transmission electron microscopy, we found that VK2 vaginal epithelial cells take up G. vaginalis after exposure to the bacteria. Confocal microscopy also indicated the presence of internalized G. vaginalis within vaginal epithelial cells obtained from a subject with BV. Using VK2 cells and (35)S labeled bacteria in an invasion assay, we found that a 1 h uptake of G. vaginalis was 21.8-fold higher than heat-killed G. vaginalis, 84-fold compared to Lactobacillus acidophilus and 6.6-fold compared to Lactobacillus crispatus. Internalization was inhibited by pre-exposure of cells to cytochalasin-D. In addition, the cytoskeletal protein vimentin was upregulated in VK2 cells exposed to G. vaginalis, but there was no change in actin cytoskeletal polymerization/rearrangements or vimentin subcellular relocalization post exposure. Cytoskeletal protein modifications could represent a potential mechanism for G. vaginalis mediated internalization by vaginal epithelial cells. Finally, understanding vaginal bacteria/host interactions will allow us to better understand the underlying mechanisms of BV pathogenesis.

Racial influence on the polycystic ovary syndrome phenotype: a black and white case-control study.

OBJECTIVE: To estimate racial disparities in the polycystic ovary syndrome (PCOS) phenotype between white and black women with PCOS. DESIGN: Case-control study. SETTING: Two academic medical centers. PATIENT(S): A total of 242 women not taking confounding medications in otherwise good health. INTERVENTION(S): Phenotyping during the follicular phase or anovulation after an overnight fast in women. MAIN OUTCOME MEASURE(S): Biometric, serum hormones, glycemic and metabolic parameters, and body composition by dual-energy x-ray absorptiometry. RESULT(S): We studied 77 white and 43 black women with PCOS and 35 white and 87 black controls. Black women with PCOS were similar reproductively to white women with PCOS. Black women with PCOS had lower levels of serum transaminases, higher high-density lipoprotein cholesterol levels (mean difference [MD], 18.2 mg/dL; 95% confidence intervals [CI], 14.3, 22.1 mg/dL), lower triglyceride levels (MD, -43.2 mg/dL; 95% CI, -64.5, -21.9), and enhanced insulinogenic index on the oral glucose tolerance test compared with white women with PCOS. Black women with PCOS had higher bone mineral density (MD, 0.1 g/cm(2); 95% CI, 0.1, 0.2 g/cm(2)), lower percent body fat on dual-energy x-ray absorptiometry (MD, -2.8%; 95% CI, -5.1%, -0.5%), and overall a higher quality of life. Although most of these findings disappeared when the differences with racially matched controls were compared, black women with PCOS compared with black controls had lower estradiol levels than white women with PCOS compared with white controls (MD, -12.9 pg/mL; 95% CI, -24.9, -0.8 pg/mL), higher systolic blood pressure (MD, 9.1 mm Hg; 95% CI, 0.8, 17.4 mm Hg), and lower fasting glucose levels (MD, -12.0 mg/dL; 95% CI, -22.3, -1.7 mg/dL). CONCLUSION(S): Racial disparities in PCOS phenotype are minor and mixed. Future studies should explore if race impacts treatment effects.

Effects of metformin in adolescents with polycystic ovary syndrome undertaking lifestyle therapy: a pilot randomized double-blind study.

Our small study does not support the addition of metformin to the lifestyle of adolescents. Although there are favorable trends toward hyperandrogenism with metformin, these must be balanced against the increased rate of gastrointestinal side effects. However, other treatments were associated with an improved quality of life.

The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study.

OBJECTIVE: To determine if the combination of lifestyle (caloric restriction and exercise) and metformin (MET) would be superior to lifestyle and placebo (PBO) in improving the polycystic ovary syndrome (PCOS) phenotype. DESIGN: Double-blind randomized 6-month trial of MET versus PBO. SETTING: Two academic medical centers. PATIENT(S): One hundred fourteen subjects with PCOS were randomized to MET (N = 55) or PBO (N = 59). INTERVENTION(S): Subjects collected urine daily for ovulation monitoring, had monthly monitoring of hormones and weight and determination of body composition by dual-energy x-ray absorptiometry, glucose tolerance, and were evaluated for quality of life at baseline and completion. MAIN OUTCOME MEASURE(S): Ovulation rates and testosterone levels. RESULT(S): Dropout rates were high. There was no significant difference in ovulation rates. Testosterone levels were significantly lower compared with baseline in the MET group at 3 mos but not at 6 mos. There were no differences in weight loss between groups, but MET showed a significant decline at 6 months compared with baseline (-3.4 kg, 95% confidence interval -5.3 to -1.5 kg). We noted divergent effects of MET versus PBO on oral glucose tolerance test indices of insulin sensitivity (increased) and secretion (worsened). Total bone mineral density increased significantly in MET. There were no differences in quality of life measures between the groups. The MET group had increased diarrhea and headache, but fewer bladder infections and musculoskeletal complaints. CONCLUSION(S): The addition of metformin to lifestyle therapy produced little reproductive or glycemic benefit in women with PCOS, although our study had limited power owing to a high dropout rate. It is not possible at baseline to identify women likely to drop out.

Does polycystic ovary syndrome increase the disparity in metabolic syndrome and cardiovascular-related health for African-American women?

There have been few formal studies of differences in the phenotype of PCOS among women of African-American ancestry. Generally, African-American women tend to have an adverse cardiovascular risk profile when compared with women of other racial groups. The metabolic syndrome is a clinical disorder that identifies individuals at risk for diabetes and cardiovascular disease. Preliminary studies support that both African-American and White women with PCOS have similar prevalences of the metabolic syndrome, suggesting that the diagnosis may not be associated with racial differences in cardiovascular risk factors.

A comparison of methods and results in recruiting white and black women into reproductive studies: the MMC-PSU cooperative center on reproduction experience.

Establishing a holistic approach for the enrollment of subjects into clinical trials that includes strategies for the recruitment of non-traditional and minority populations has been an elusive task. The existence of such a design, that is understood and embraced by investigators and the target communities, would streamline the current level of commitment of time, energy and resources. This is necessary to successfully encourage individual and community participation in research studies. The Center for Research in Reproduction at Meharry set out to recruit a large number of African American women volunteers of reproductive age into clinical trials. The experience, of recruiting volunteers from the African American community for clinical trials in the Meharry Medical College/Pennsylvania State University (MMC/PSU)'s Cooperative Center for Research in Reproduction at Meharry, is presented.

Distal intersection tenosynovitis of the wrist: a lesser-known extensor tendinopathy with characteristic MR imaging features.

OBJECTIVE: To present the MRI imaging findings of extensor tenosynovitis at the distal intersection or crossover between the second (extensor carpi radialis longus (ECRL) and brevis (ECRB)) and third (extensor pollicis longus (EPL)) extensor compartment tendons, and the anatomical details that may play a role in the pathogenesis of this condition. DESIGN AND PATIENTS: The imaging studies and clinical records of five patients (three females and two males, with ages ranging between 22 and 78 years; mean age, 49 years) presenting with pain on the dorsal and radial aspect of the wrist were reviewed by two musculoskeletal radiologists in consensus. Three cases were identified serendipitously during routine clinical reading sessions; a follow-up computerized database search for additional cases reported in the prior two years yielded two additional cases. The overall number of cases screened was 1,031. The diagnosis of tendinopathy affecting the second and third compartment extensor tendons was made on the basis of MRI findings and clinical follow-up, or synovectomy. RESULTS: All patients showed signs of tenosynovitis: in four patients both the tendons of the second and third extensor compartments were affected; the fifth patient showed signs of tenosynovitis of the EPL tendon, and tendinosis of the extensor carpi radialis tendons. Three patients showed tenosynovitis proximal and distal to the point of intersection; and in two of them, a discrete point of constriction was appreciated at the crossover site in relation to the extensor retinaculum. Two patients showed tenosynovitis limited to the segment distal to the point of decussation. Tendinosis tended to follow the presence of tenosynovitis. In one of the patients, subtendinous reactive marrow edema in Lister's tubercle was noted. CONCLUSION: Distal intersection tenosynovitis may be related to the biomechanical pulley effect exerted by Lister's tubercle on the EPL tendon as it leaves the third compartment and crosses over the extensor carpi radialis tendons, as well as the constraining effect of the extensor retinaculum. These anatomical features determine the presence of characteristic MR imaging findings.

Preiser's disease: identification of two patterns.

PURPOSE: A large series of patients with Preiser's disease was reviewed to compare 2 potentially different categories of this disorder: complete versus partial vascular impairment of the scaphoid bone as determined by magnetic resonance imaging (MRI). METHODS: Nineteen patients with Preiser's disease were identified retrospectively from 2 institutions. Using MRI criteria, 2 disease patterns were identified: diffuse necrosis and/or ischemia of the scaphoid (type 1 disease, 11 cases) and segmental vascular impairment of the scaphoid (type 2 disease, 8 cases). Risk factors for osteonecrosis, treatment methods, and serial radiographs were reviewed in all cases. Sixteen patients were examined for the purpose of this study at an average follow-up of 25 months. RESULTS: MRI signal changes of necrosis and/or ischemia involved 100% of the scaphoid in type 1 cases and on average approximately 42% in type 2 cases (range, 33% to 66%). In type 1 cases, regardless of the treatment used, the scaphoid typically fragmented and collapsed. In type 2 cases, scaphoid architecture was altered minimally after similar treatment methods. A history of wrist trauma was significantly more common in type 2 cases, and the results of treatment were generally better in this group of patients (mean Mayo modified wrist scores, 86 vs 58 points). CONCLUSIONS: This study supports the concept of 2 patterns of scaphoid involvement in Preiser's disease. Type 1 cases are characterized by MRI signal changes of necrosis and/or ischemia involving the entire scaphoid bone. Patients in this group have a propensity for scaphoid deterioration. Type 2 cases have MRI signal changes involving only part of the scaphoid. These patients commonly report a history of wrist trauma, show fewer tendencies toward scaphoid fragmentation, and may have a more favorable clinical outcome.