Influence of antiretroviral therapy and cardiovascular disease on the immature platelet fraction in patients living with HIV.

Cardiovascular disease is an important contributor to morbidity and mortality in people living with HIV . The immature platelet fraction (IPF) is increased in HIV-negative patients with cardiovascular disease and evidence suggests that an enlarged IPF is associated with adverse cardiovascular events. In this multi-center observational study, we aimed to investigate how the IPF in people living with HIV is influenced by antiretroviral therapy and cardiovascular disease. Subjects without cardiovascular disease that received antiretroviral therapy showed a smaller IPF accompanied by lower D-dimer and C-reactive protein (CRP) levels compared to therapy-naïve subjects (mean IPF: 2.9% vs. 3.9%, p = .016; median D-dimer: 252 µg/L vs. 623 µg/L, p < .001; median CRP: 0.2 mg/dL vs. 0.5 mg/dL, p = .004). No significant differences for the IPF, D-dimer or CRP were found between subjects on antiretroviral therapy with documented cardiovascular disease and therapy-naïve subjects. In conclusion, we observed a reduction in the IPF among subjects on therapy only in the absence of cardiovascular disease. In contrast, subjects receiving therapy that had documented cardiovascular disease showed an IPF comparable to therapy-naïve subjects. Future studies are needed to investigate if an enlarged IPF may serve as a biomarker in predicting adverse cardiovascular events in people living with HIV.

Evaluation of anal carcinoma screening in male and female HIV patients at an interdisciplinary HIV therapy centre.

BACKGROUND: Incidence of anal carcinoma is increased in people living with HIV (PLWH). Due to the improved life expectancy in PLWH, identifying appropriate prevention strategies for non-AIDS-defining cancer types such as anal carcinoma has become a priority in managing PLWH today. OBJECTIVE: We aimed to evaluate anal cytology assessment as screening tool for anal dysplasia and/or carcinoma in PLWH, regardless of gender or sexual orientation. Additionally, we investigated the correlation between cancer risk factors and abnormal screening results in our patient cohort. METHODS: People living with HIV from the Interdisciplinary HIV Centre of the University Hospital rechts der Isar in Munich, Germany (IZAR), were screened for anal carcinoma by single cytobrush examination and anal Papanicolaou (PAP) smear assessment from 2013 to 2015. Patients with abnormal PAP smear result were offered a follow-up examination after 12 months. Differences between two groups were tested for statistical significance using Student's t-test and Mann-Whitney U-test, as appropriate. RESULTS: In total, 101 PLWH were included. 26.7% of subjects (n = 27) were PAP IIID, and 9.9% (n = 10) were PAP IVa. Seven female subjects had an abnormal finding at screening. Smoking was significantly associated with abnormal findings at screening (P = 0.005). In addition, our study found an association between sexually transmitted infections (STI) and anal dysplasia. Condylomata acuminata were increased in subjects with PAP IIID/PAP IVa (P = 0.045). Reactive syphilis serology was found to be significantly associated with abnormal screening results (P = 0.016), respectively. CONCLUSION: Our results demonstrate that smoking and two common STIs, condylomata acuminata and syphilis, are risk factors associated with advanced anal intraepithelial neoplasia (AIN) stages in our PLWH cohort. While further analysis is needed to determine diagnostic guidelines concerning AIN in PLWH, these results suggest that interdisciplinary lifestyle prevention strategies are required to reduce the risk factors for AIN in PLWH in an outpatient setting.

Simple method of modulating Q-band microwaves.

In this note a novel method of modulating microwave power at Q-band is presented.

[Ophthalmological alterations at the initial diagnosis of HIV infection]. / Ophthalmologische Veränderungen im Rahmen der Erstdiagnose einer HIV-Infektion.

Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV), is one of the most important infectious causes of death in the twentieth and twenty-first centuries. Ocular manifestations can appear in particular when the CD4 cell count is low. This article presents a case report of a 38-year-old homosexual man in whom HIV microangiopathy retinopathy syndrome (MAPS) was found during the assessment of the initial HIV diagnosis. Typical findings in MAPS are conjunctival and retinal vessel abnormalities, cotton wool spots as well as intraretinal hemorrhages. Loss of vision is a rare complication but MAPS shows an impairment of the immune status and is also associated with a higher mortality.

Influence of anesthetics on pharyngeal flap surgery: a 23-year study.

This study assessed the influence of anesthetics on early complications after pharyngeal flap surgery. A 23-year retrospective chart review was carried out of all patients at the authors' institution who underwent superiorly based pharyngeal flap surgery. Variables analyzed were gender, age at the time of surgery, cleft type, anesthesia procedure used and complications in the early postoperative period. 2299 patients (50% male; 50% female) who underwent pharyngeal flap surgery between 1980 and 2003 were reviewed. The highest number of surgeries was performed in patients aged 11-20 years. There were 1042 patients with at least one type of complication. Of these, 39 required reoperation to control complications such as bleeding and airway obstruction. There were no records of death. Vomiting and pain were the most frequent postoperative complications (16% and 14% of patients, respectively). Lower complication rates were observed when anesthesia protocols included sevoflurane, propofol and opioids.

Circadian output, input, and intracellular oscillators: insights into the circadian systems of single cells.

Circadian output comprises the business end of circadian systems in terms of adaptive significance. Work on Neurospora pioneered the molecular analysis of circadian output mechanisms, and insights from this model system continue to illuminate the pathways through which clocks control metabolism and overt rhythms. In Neurospora, virtually every strain examined in the context of rhythms bears the band allele that helps to clarify the overt rhythm in asexual development. Recent cloning of band showed it to be an allele of ras-1 and to affect a wide variety of signaling pathways yielding enhanced light responses and asexual development. These can be largely phenocopied by treatments that increase levels of intracellular reactive oxygen species. Although output is often unidirectional, analysis of the prd-4 gene provided an alternative paradigm in which output feeds back to affect input. prd-4 is an allele of checkpoint kinase-2 that bypasses the requirement for DNA damage to activate this kinase; FRQ is normally a substrate of activated Chk2, so in Chk2(PRD-4), FRQ is precociously phosphorylated and the clock cycles more quickly. Finally, recent adaptation of luciferase to fully function in Neurospora now allows the core FRQ/WCC feedback loop to be followed in real time under conditions where it no longer controls the overt rhythm in development. This ability can be used to describe the hierarchical relationships among FRQ-Less Oscillators (FLOs) and to see which are connected to the circadian system. The nitrate reductase oscillator appears to be connected, but the oscillator controlling the long-period rhythm elicited upon choline starvation appears completely disconnected from the circadian system; it can be seen to run with a very long noncompensated 60-120-hour period length under conditions where the circadian FRQ/WCC oscillator continues to cycle with a fully compensated circadian 22-hour period.

A circadian clock in Neurospora: how genes and proteins cooperate to produce a sustained, entrainable, and compensated biological oscillator with a period of about a day.

Neurospora has proven to be a tractable model system for understanding the molecular bases of circadian rhythms in eukaryotes. At the core of the circadian oscillatory system is a negative feedback loop in which two transcription factors, WC-1 and WC-2, act together to drive expression of the frq gene. WC-2 enters the promoter region of frq coincident with increases in frq expression and then exits when the cycle of transcription is over, whereas WC-1 can always be found there. FRQ promotes the phosphorylation of the WCs, thereby decreasing their activity, and phosphorylation of FRQ then leads to its turnover, allowing the cycle to reinitiate. By understanding the action of light and temperature on frq and FRQ expression, the molecular basis of circadian entrainment to environmental light and temperature cues can be understood, and recently a specific role for casein kinase 2 has been found in the mechanism underlying circadian temperature-compensation. These data promise molecular explanations for all of the canonical circadian properties of this model system, providing biochemical answers and regulatory logic that may be extended to more complex eukaryotes including humans.

Localization and light-dependent phosphorylation of white collar 1 and 2, the two central components of blue light signaling in Neurospora crassa.

In Neurospora crassa only two white collar (wc) mutants, wc-1 and wc-2, have been described that seem to be insensitive to light. The pleiotropic phenotypes of these mutants suggest that they represent two central components of blue light signal transduction. The WC proteins have several characteristics of transcription factors consistent with an involvement in transcriptional control of light-regulated genes. Here, we present a biochemical analysis of WC1 and WC2 polypeptides in N. crassa. Using specific antisera against WC1 and WC2, respectively, the subcellular localization of the WC polypeptides was investigated. The WC1 protein was localized exclusively in the nucleus, whereas WC2 was detected in both the nuclear and cytoplasmic fractions. The nuclear localization of WC1 and WC2 was shown to be independent of light and dimerization between the two proteins. In addition, WC1 and WC2 are phosphorylated in response to light. The phosphorylation of WC1 and WC2 was dependent on functional WC1 and WC2 proteins, respectively, which clearly indicated a correlation between the light-dependent phosphorylation and the function of WC1 and WC2 in blue light signaling. However, the light-specific phosphorylation of the WC proteins revealed different kinetics. The phosphorylation of WC1 was transient whereas the WC2 phosphorylation was shown to be stable under constant light conditions. The analysis of the light-dependent phosphorylation of WC1 and WC2 in wc-2 and wc-1 mutants revealed an epistatic relationship for WC1 and WC2 with WC2 acting downstream of WC1 in the signal transduction pathway of blue light.

Blue light adaptation and desensitization of light signal transduction in Neurospora crassa.

The ascomycete Neurospora crassa has the capacity of adapting to a given light quantity, leading to transient blue light responses under continuous light conditions. Here, we present an investigation of this photoadaptation phenomenon. We demonstrated previously that two proteins of the Neurospora blue light signal transduction chain, WC1 and WC2, are subject to light-dependent phosphorylation. WC1 was phosphorylated in parallel with the transient increase in transcript levels of light-regulated genes. Using the light-dependent phosphorylation of WC1 as a marker for an active signalling state of WC1, we show that the transiency of Neurospora blue light responses results from desensitization of the photoreceptor and/or the signalling cascade. Furthermore, a Neurospora mutant was characterized that revealed a specific defect in photoadaptation. In this mutant, the transient expression of light-regulated genes under continuous light, the temporary insensitivity after a light pulse and the capability of differentiating between and adapting to low and high light intensities were abolished. The corresponding protein seems to represent a central component of a negative feedback desensitization mechanism. This negative feedback regulation requires continuous and light-dependent protein de novo biosynthesis.

Overexpression of White Collar-1 (WC-1) activates circadian clock-associated genes, but is not sufficient to induce most light-regulated gene expression in Neurospora crassa.

Many processes in fungi are regulated by light, but the molecular mechanisms are not well understood. The White Collar-1 (WC-1) protein is required for all known blue-light responses in Neurospora crassa. In response to light, WC-1 levels increase, and the protein is transiently phosphorylated. To test the hypothesis that the increase in WC-1 levels after light treatment is sufficient to activate light-regulated gene expression, we used microarrays to identify genes that respond to light treatment. We then overexpressed WC-1 in dark-grown tissue and used the microarrays to identify genes regulated by an increase in WC-1 levels. We found that 3% of the genes were responsive to light, whereas 7% of the genes were responsive to WC-1 overexpression in the dark. However, only four out of 22 light-induced genes were also induced by WC-1 overexpression, demonstrating that changes in the levels of WC-1 are not sufficient to activate all light-responsive genes. The WC proteins are also required for circadian rhythms in dark-grown cultures and for light entrainment of the circadian clock, and WC-1 protein levels show a circadian rhythm in the dark. We found that representative samples of the mRNAs induced by over-expression of WC-1 show circadian fluctuations in their levels. These data suggest that WC-1 can mediate both light and circadian responses, with an increase in WC-1 levels affecting circadian clock-responsive gene regulation and other features of WC-1, possibly its phosphorylation, affecting light-responsive gene regulation.