Effective self-stretching of carpal ligament for the treatment of carpal tunnel syndrome: A double-blinded randomized controlled study.

INTRODUCTION: Carpal tunnel syndrome (CTS) is the most common nerve entrapment syndrome worldwide. There are limited studies on the effectiveness of carpal ligament stretching on symptomatic and electrophysiologic outcomes. PURPOSE OF THE STUDY: The purpose of this study was to evaluate the effect of self-myofascial stretching of the carpal ligament on symptom outcomes and nerve conduction findings in persons with CTS. STUDY DESIGN: This is a prospective, double-blinded, randomized, placebo-controlled trial. METHODS: Eighty-three participants diagnosed with median mononeuropathy across the wrist by nerve conduction study were randomized 1:1 to sham treatment or self-carpal ligament stretching. Participants were instructed to perform the self-treatment four times a day for six weeks. Seventeen participants in the sham treatment group and 19 participants in the carpal ligament stretching group completed the study. Pre- and post-treatment outcome measures included subjective complaints, strength, nerve conduction findings, and functional scores. RESULTS: Groups were balanced on age, sex, hand dominance, symptom duration, length of treatment, presence of nocturnal symptoms, and compliance with treatment. Even though the ANOVA analyses were inconclusive about group differences, explorative post hoc analyses revealed significant improvements in numbness (P = .011, Cohen's d = .53), tingling (P = .007, Cohen's d = .60), pinch strength (P = .007, Cohen's d = -.58), and symptom severity scale (P = .007, Cohen's d = .69) for the treatment group only. CONCLUSIONS: The myofascial stretching of the carpal ligament showed statistically significant symptom improvement in persons with CTS. Larger comparative studies that include other modalities such as splinting should be performed to confirm the effectiveness of this treatment option.

HIV Exploits Antiviral Host Innate GCN2-ATF4 Signaling for Establishing Viral Replication Early in Infection.

Antiviral innate host defenses against acute viral infections include suppression of host protein synthesis to restrict viral protein production. Less is known about mechanisms by which viral pathogens subvert host antiviral innate responses for establishing their replication and dissemination. We investigated early innate defense against human immunodeficiency virus (HIV) infection and viral evasion by utilizing human CD4+ T cell cultures in vitro and a simian immunodeficiency virus (SIV) model of AIDS in vivo Our data showed that early host innate defense against the viral infection involves GCN2-ATF4 signaling-mediated suppression of global protein synthesis, which is exploited by the virus for supporting its own replication during early viral infection and dissemination in the gut mucosa. Suppression of protein synthesis and induction of protein kinase GCN2-ATF4 signaling were detected in the gut during acute SIV infection. These changes diminished during chronic viral infection. HIV replication induced by serum deprivation in CD4+ T cells was linked to the induction of ATF4 that was recruited to the HIV long terminal repeat (LTR) to promote viral transcription. Experimental inhibition of GCN2-ATF4 signaling either by a specific inhibitor or by amino acid supplementation suppressed the induction of HIV expression. Enhancing ATF4 expression through selenium administration resulted in reactivation of latent HIV in vitro as well as ex vivo in the primary CD4+ T cells isolated from patients receiving suppressive antiretroviral therapy (ART). In summary, HIV/SIV exploits the early host antiviral response through GCN2-ATF4 signaling by utilizing ATF4 for activating the viral LTR transcription to establish initial viral replication and is a potential target for HIV prevention and therapy.IMPORTANCE Understanding how HIV overcomes host antiviral innate defense response in order to establish infection and dissemination is critical for developing prevention and treatment strategies. Most investigations focused on the viral pathogenic mechanisms leading to immune dysfunction following robust viral infection and dissemination. Less is known about mechanisms that enable HIV to establish its presence despite rapid onset of host antiviral innate response. Our novel findings provide insights into the viral strategy that hijacks the host innate response of the suppression of protein biosynthesis to restrict the virus production. The virus leverages transcription factor ATF4 expression during the GCN2-ATF4 signaling response and utilizes it to activate viral transcription through the LTR to support viral transcription and production in both HIV and SIV infections. This unique viral strategy is exploiting the innate response and is distinct from the mechanisms of immune dysfunction after the critical mass of viral loads is generated.

Short-stay transurethral prostate surgery: A randomized controlled trial comparing transurethral resection in saline bipolar transurethral vaporization of the prostate with monopolar transurethral resection.

OBJECTIVES: The aim of the present study was to establish the safety and efficacy profile of transurethral resection in saline (TURis) bipolar vaporization of the prostate relative to monopolar transurethral resection of prostate (TURP) and to test the hospital stay efficiency after TURis vaporization. MATERIALS AND METHODS: in this multicenter, double-blinded, prospective, randomized controlled trial, men aged 50-75 years old were randomized into two arms: TURis bipolar vaporization and monopolar TURP. Intraoperative details, perioperative parameters, and postoperative functional outcomes were assessed after intervention. Follow-up with symptom score assessment, prostate volume measurement, and uroflowmetry were performed at 3 and 6 months. RESULTS: Eighty-four patients (mean age, 65.0 ± 5.6 years) were randomized into each study arm. TURis bipolar vaporization had a longer operative time than monopolar TURP (51.6 ± 24.5 vs 38.5 ± 20.3 min, P < 0.001). Postoperatively, the TURis group had a shorter catheter time (33.6 ± 23.7 vs 40.8 ± 29.4 h, P = 0.013) and a shorter length of hospital stay (43.14 ± 18.79 vs 52.33 ± 30.58 h, P = 0.013). The postoperative dysuria score was higher in the TURis vaporization arm. There was no statistically significant difference between the two arms in terms of hemoglobin change and postoperative complication. No significant difference was observed in quality of life score at 3 and 6 months. CONCLUSIONS: TURis bipolar vaporization of the prostate is a safe and comparable alternative to monopolar TURP. It leads to a reduction in both catheter time and length of hospital stay.

Early virologic failure and the development of antiretroviral drug resistance mutations in HIV-infected Ugandan children.

BACKGROUND: Without virologic testing, HIV-infected African children starting antiretroviral (ARV) therapy are at risk for undetected virologic failure and the development of ARV resistance. We sought to determine the prevalence of early virologic failure (EVF), to characterize the evolution of ARV-resistance mutations and to predict the impact on second-line therapy. METHODS: The prevalence of EVF (HIV RNA >400 copies/mL on sequential visits after 6 months of therapy) was identified among 120 HIV-infected Ugandan children starting ARV therapy. ARV mutations were identified by population sequencing of HIV-1 pol in sequential archived specimens. Composite discrete genotypic susceptibility scores were determined for second-line ARV regimens. RESULTS: EVF occurred in 16 children (13%) and persisted throughout a median (interquartile ratio) 938 (760-1066) days of follow-up. M184V and nonnucleoside reverse transcriptase inhibitor-associated mutations emerged within 6 months of EVF; thymidine-analog-mutations arose after 12 months. Worse discrete genotypic susceptibility scores correlated with increasing duration of failure (Spearman R = -0.47; P = 0.001). Only 1 child met World Health Organization CD4 criteria for ARV failure at the time of EVF or during the follow-up period. CONCLUSIONS: A significant portion of HIV-infected African children experience EVF that would be undetected using CD4/clinical monitoring and resulted in the accumulation of ARV mutations that could compromise second-line therapy options.

Suspensions for intravenous (IV) injection: a review of development, preclinical and clinical aspects.

There has been growing interest in nanoparticles as an approach to formulate poorly soluble drugs. Besides enhanced dissolution rates, and thereby, improved bioavailability, nanoparticles can also provide targeting capabilities when injected intravenously. The latter property has led to increased research and development activities for intravenous suspensions. The first intravenously administered nanoparticulate product, Abraxane (a reformulation of paclitaxel), was approved by the FDA in 2006. Additional clinical trials have been conducted or are ongoing for multiple other indications such as oncology, infective diseases, and restenosis. This article reviews various challenges associated with developing intravenous nanosuspension dosage forms. In addition, various formulation considerations specific to intravenous nanosuspensions as well as reported findings from various clinical studies have been discussed.

An unusual S-adenosylmethionine synthetase gene from dinoflagellate is methylated.

BACKGROUND: S-Adenosylmethionine synthetase (AdoMetS) catalyzes the formation of S-Adenosylmethionine (AdoMet), the major methyl group donor in cells. AdoMet-mediated methylation of DNA is known to have regulatory effects on DNA transcription and chromosome structure. Transcription of environmental-responsive genes was demonstrated to be mediated via DNA methylation in dinoflagellates. RESULTS: A full-length cDNA encoding AdoMetS was cloned from the dinoflagellate Crypthecodinium cohnii. Phylogenetic analysis suggests that the CcAdoMetS gene, is associated with the clade of higher plant orthrologues, and not to the clade of the animal orthrologues. Surprisingly, three extra stretches of residues (8 to 19 amino acids) were found on CcAdoMetS, when compared to other members of this usually conserved protein family. Modeled on the bacterial AdeMetS, two of the extra loops are located close to the methionine binding site. Despite this, the CcAdoMetS was able to rescue the corresponding mutant of budding yeast. Southern analysis, coupled with methylation-sensitive and insensitive enzyme digestion of C. cohnii genomic DNA, demonstrated that the AdoMetS gene is itself methylated. The increase in digestibility of methylation-sensitive enzymes on AdoMet synthetase gene observed following the addition of DNA methylation inhibitors L-ethionine and 5-azacytidine suggests the presence of cytosine methylation sites within CcAdoMetS gene. During the cell cycle, both the transcript and protein levels of CcAdoMetS peaked at the G1 phase. L-ethionine was able to delay the cell cycle at the entry of S phase. A cell cycle delay at the exit of G2/M phase was induced by 5-azacytidine. CONCLUSION: The present study demonstrates a major role of AdoMet-mediated DNA methylation in the regulation of cell proliferation and that the CcAdoMetS gene is itself methylated.