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Data on suppression of HIV replication in the CNS and on the subsequent risk of neurocognitive impairment using monotherapy with boosted protease inhibitors are limited.Ours was an exploratory cross-sectional study in patients on lopinavir/ritonavir-based monotherapy (LPV/r-MT) or standard triple therapy (LPV/r-ART) for at least 96 weeks who maintained a plasma viral load

We investigated the effect of food on the steady-state pharmacokinetics of a proprietary fixed-dose combination (FDC) tablet containing tenofovir disoproxil fumarate (TDF)/emtricitabine/efavirenz. Fifteen Ugandan HIV-1 patients at steady-state dosing with TDF/emtricitabine/efavirenz were admitted for 24-hour intensive pharmacokinetic sampling after dosing in the fasting state. Blood sampling was repeated seven days later with TDF/emtricitabine/efavirenz administered with food (19 g fat). Drug concentrations in plasma were determined by liquid chromatography and tandem mass spectrometry. Geometric mean ratios (GMRs) and confidence intervals (CIs) of parameters were calculated (reference, fasting). For efavirenz, GMRs (90% CIs) for Cmax, AUC0-24, and C24 were 1.47 (1.24–1.75), 1.13 (1.03–1.23), and 1.01 (0.91–1.11), respectively. Corresponding GMRs were 1.04 (0.84–1.27), 1.19 (1.10–1.29), and 0.99 (0.82–1.19) for tenofovir, 0.83 (0.76–0.92), 0.87 (0.78–0.97), and 0.91 (0.73–1.14) for emtricitabine. Stable patients may take the FDC without meal restrictions. The FDC should be taken without food by patients experiencing central nervous system toxicities.

Clinically significant drug-drug interactions (CSDIs) involving antiretrovirals are frequent and under-recognized in developed countries, but data are lacking for developing countries.To investigate the prevalence of CSDIs between antiretrovirals and coadministered drugs, we surveyed prescriptions dispensed in a large HIV clinic in Kenya. Of 1040 consecutive patients screened, 996 were eligible for inclusion. CSDIs were defined as 'major' (capable of causing severe or permanent damage, contraindicated, avoid or not recommended by the manufacturer, or requiring dose modification) or 'moderate' (manufacturers advise caution, or close monitoring, or capable of causing clinical deterioration). A total of 334 patients (33.5%) were at risk for a CSDI, potentially lowering antiretroviral drug concentrations in 120 (12%) patients. Major interactions most frequently involved rifampicin (12.4%, mostly with efavirenz) and azoles (2.7%) whereas moderate interactions were frequently azoles (13%), steroids (11%), and antimalarials (3%). Multivariable analyses suggested that patients at risk for CSDIs had lower CD4 counts (P = 0.006) and baseline weight (P = 0.023) and WHO Stage 3 or 4 disease (P≤0.007). Risk for CSDIs was not associated with particular regimens, although only 116 (11.6%) patients were receiving WHO second line regimens.One in three patients receiving antiretrovirals in our programme were at risk of CSDIs. Strategies need to be urgently developed to avoid important drug interactions, to identify early markers of toxicity and to manage unavoidable interactions safely in order to reduce risk of harm, and to maximize the effectiveness of mass antiretroviral deployment in Africa.

Abstract Background Reports of freezing of gait (FoG) in idiopathic normal pressure hydrocephalus (iNPH) are few and results are variable. This study’s objective was to evaluate the frequency of FoG in a large cohort of iNPH patients, identify FoG-associated factors, and assess FoG’s responsiveness to shunt surgery. Methods Videotaped standardized gait protocols with iNPH patients pre- and post-shunt surgery (n = 139; median age 75 (71–79) years; 48 women) were evaluated for FoG episodes by two observers (Cohens kappa = 0.9, p

Phytophthora root rot (PRR) of chickpea (Cicer arietinum) caused by Phytophthora medicaginis is an important disease. Partial resistance to PRR is sourced from Cicer echinospermum. In this study, we evaluated if lines with low levels of PRR foliage symptoms in two contrasting recombinant inbred line (RIL) populations parented by chickpea cultivars (Yorker and Rupali) and 04067-81-2-1-1 (C. echinospermum, interspecific breeding line) had a significant drag on yield parameters. For the Yorker × 04067-81-2-1-1 population with the highest level of PRR resistance, in the absence of PRR, low foliage symptom RIL had significantly later flowering and podding, lower grain yields, and lighter seed and shorter plant phenotypes than high foliage symptom RIL. A quantitative trait locus analysis identified significant QTL for flowering, height, 100-seed weight, and yield, and there was a significantly higher frequency of alleles for the negative agronomic traits (i.e., drag) from the 04067-81-2-1-1 parent in low foliage symptom RIL than in high foliage symptom RIL. For the Rupali × 04067-81-2-1-1 population with lower levels of PRR resistance, in the absence of PRR, low foliage symptom RIL had significantly lighter seed and shorter plants than high foliage symptom RIL. Significant QTL were detected, the majority were for the timing of flowering and podding (n = 18), others were for plant height, yield, and 100-seed weight. For this second population, the frequency of alleles for the negative agronomic traits from the 04067-81-2-1-1 parent did not differ between low and high foliage symptom RIL. The 100 seed weight of RIL under moderate PRR disease pressure showed some promise as a yield component trait to identify phenotypes with both high levels of PRR resistance and grain yield potential for further seed number evaluations. We identified that large population sizes are required to enable selection among chickpea × C. echinospermum crosses for high levels of PRR resistance without a significant drag on yield.

Abstract Background Whether there was clinical superiority for the single‐radius prosthesis over the multi‐radius prothesis in total knee arthroplasty (TKA) still remains to be clarified. We updated a meta‐analysis including prospective randomized controlled trials (RCTs) to compare the clinical prognosis of patients receiving single‐radius TKA (SR‐TKA) or multi‐radius TKA (MR‐TKA). Methods We searched the databases of PubMed, Web of Science, EMBASE, Cochrane Library, MEDLINE for eligible RCTs. Two reviewers evaluated the study quality according to the Risk of Bias tool of the Cochrane Library and extracted the data in studies individually. The extracted data included the baseline data and clinical outcome. The baseline data include the author's name, country, and year of included studies, the name of knee prosthesis used in studies, sample size, follow‐up time, and BMI of patients. The clinical data comprised primary indicators including postoperative knee range of motion (ROM), sit‐to‐stand rest, severe postoperative scorings, such as visual analog scale (VAS), American Knee Society knee score (AKS), Oxford knee scoring (OKS), and SF‐36 Quality of Life Scale, as well as various secondary indicators of complications including anterior knee pain, postoperative infection, aseptic prosthesis loosening, and prosthesis revision. The data analysis was performed using Review Manager 5.3 software and STATA 12.0. The sensitivity analysis was performed using STATA 12.0. Results A total of 13 RCTs, along with 1720 patients and 1726 knees, were finally included in our present meta‐analysis. We found that patients in SR‐TKA group performed better in the sit‐to‐stand test (OR = 1.89, 95% CI: 1.05–3.41, p = 0.03) and satisfaction evaluation (OR = 3.27, 95% CI: 1.42–7.53, p = 0.005), which were only evaluated in two included RCTs. While no significant difference was found between SR‐TKA and MR‐TKA groups in terms of postoperative ROM, VAS scoring, AKS scoring, SF‐36 scoring, OKS scoring, and various complications including anterior knee pain, postoperative infection, aseptic prosthesis loosening, and prosthesis revision. Conclusion In conclusion, our present meta‐analysis indicated that SR implants were noninferior to MR implants in TKA, and SR implants could be an alternative choice over MR implants, since patients after SR‐TKA felt more satisfied and performed better in the sit‐to‐stand test, with no significant difference in complications between SR‐TKA and MR‐TKA groups. While more relevant clinical trials with long‐term follow‐up time and specific tests evaluating the function of knee extension mechanism should be carried out to further investigate the clinical performance of SR implants.

Phytophthora root rot caused by Phytophthora medicaginis is an important disease of chickpeas (Cicer arietinum) in Australia with limited management options, increasing reliance on breeding for improved levels of genetic resistance. Resistance based on chickpea–Cicer echinospermum crosses is partial with a quantitative genetic basis provided by C. echinospermum and some disease tolerance traits originating from C. arietinum germplasm. Partial resistance is hypothesised to reduce pathogen proliferation, while tolerant germplasm may contribute some fitness traits, such as an ability to maintain yield despite pathogen proliferation. To test these hypotheses, we used P. medicaginis DNA concentrations in the soil as a parameter for pathogen proliferation and disease assessments on lines of two recombinant inbred populations of chickpea–C. echinospermum crosses to compare the reactions of selected recombinant inbred lines and parents. Our results showed reduced inoculum production in a C. echinospermum backcross parent relative to the C. arietinum variety Yorker. Recombinant inbred lines with consistently low levels of foliage symptoms had significantly lower levels of soil inoculum compared to lines with high levels of visible foliage symptoms. In a separate experiment, a set of superior recombinant inbred lines with consistently low levels of foliage symptoms was tested for soil inoculum reactions relative to control normalised yield loss. The in-crop P. medicaginis soil inoculum concentrations across genotypes were significantly and positively related to yield loss, indicating a partial resistance-tolerance spectrum. Disease incidence and the rankings for in-crop soil inoculum were correlated strongly to yield loss. These results indicate that soil inoculum reactions may be useful to identify genotypes with high levels of partial resistance.

Background: Sex-specific differences in heart disease outcomes are influenced by the levels of the steroid hormones, estrogen and testosterone. While the roles of estrogen receptors in cardiac disease are well-studied in animals and humans, respective research on androgen receptors (AR) is limited. Here we investigate AR protein and mRNA expression in human myocardium of various cardiac diseases. Methods: AR expression was analyzed by western blotting in myocardium from human non-failing hearts (NF, n = 6) and patients with aortic stenosis (AS, n = 6), hypertrophic cardiomyopathy (HCM, n = 7), dilated cardiomyopathy (DCM, n = 7), and ischemic cardiomyopathy (ICM, n = 7). Using an AR45-specific antibody, a subsequent western blot assessed samples from male and female patients with HCM (n = 10) and DCM (n = 10). The same sample set was probed for full-length AR and AR45 mRNA expression. Immunohistochemistry (IHC) localized AR in myocardium from HCM and AS hearts. Results: Full-length AR was notably enriched in AS and HCM hearts compared to ICM, DCM, and NF. Similarly, AR45 was more abundant in HCM than in DCM. In contrast to the pattern observed for AR protein, full-length AR mRNA levels were lower in HCM compared to DCM, with no discernible difference for the AR45 isoform. Although gender differences in AR expression were not detected in western blots or qRT-PCR, IHC showed stronger nuclear AR signals in males than in females. Conclusions: Our findings indicate disease-specific regulation of AR mRNA and/or AR protein in cardiac hypertrophy, underscoring a potential role in this cardiac pathology.

Abstract Background Cognitive decline and dementia are common in Parkinson’s disease (PD). Cognitive deficits have been linked to the depletion of dopamine in the nigrostriatal pathway, but pharmacological treatments for PD have little evidence of improving or delaying cognitive decline. Therefore, exploring non-pharmacological treatment options is important. There have been some promising results of cognitive training interventions in PD, especially for improvements in working memory and executive functions. Yet, existing studies are often underpowered, lacking appropriate control condition, long term follow-up, a thorough description of the intervention and characteristics of the participants. Working memory updating training has previously shown to increase striatal activation in healthy young and old participants as well as dopaminergic neurotransmission in healthy young participants. In the light of dopamine dysfunction in PD, with negative effects on both motor and cognitive functions it is of interest to study if an impaired striatal system can be responsive to a non-invasive, non-pharmacological intervention. Methods and design The iPARK trial is a double-blinded, randomized controlled trial with a parallel-group design that aims to recruit 80 patients with PD (during the period 02/2017–02/2023). Included patients need to have PD, Hoehn and Yahr staging I-III, be between 45 to 75 years of age and not have a diagnosis of dementia. All patients will undergo 30 sessions (6–8 weeks) of web-based cognitive training performed from home. The target intervention is a process-based training program targeting working memory updating. The placebo program is a low dose short-term memory program. A battery of neuropsychological tests and questionnaires will be performed before training, directly after training, and 16 weeks after training. Discussion We expect that the iPARK trial will provide novel and clinically useful information on whether updating training is an effective cognitive training paradigm in PD. Further, it will hopefully contribute to a better understanding of cognitive function in PD and provide answers regarding cognitive plasticity as well as determining critical factors for a responsive striatal system. Trial registration Clinicaltrials.gov registry number: NCT03680170 , registry name: “Cognitive Training in Parkinson’s Disease: the iPARK study”, retrospectively registered on the 21st of September 2018. The inclusion of the first participant was the 1st of February 2017.

IntroductionHereditary transthyretin (ATTRv) amyloidosis caused by the V30M (p. V50M) mutation is a fatal, neuropathic systemic amyloidosis. Liver transplantation has prolonged the survival of patients and central nervous system (CNS) complications, attributed to amyloid angiopathy caused by CNS synthesis of variant transthyretin, have emerged. The study aimed to ascertain amyloid deposition within the brain in long-term ATTRv amyloidosis survivors with neurological symptoms from the CNS.MethodsA total of 20 patients with ATTR V30M having symptoms from the CNS and a median disease duration of 16 years (8–25 years) were included in this study. The cognitive and peripheral nervous functions were determined for 18 patients cross-sectionally at the time of the investigation. Amyloid brain deposits were examined by [18F]flutemetamol PET/CT. Five patients with Alzheimer's disease (AD) served as positive controls.Result60% of the patients with ATTRv had a pathological Z-score in the cerebellum, compared to only 20% in the patients with AD. 75% of the patients with transient focal neurological episodes (TFNEs) displayed a pathological uptake only in the cerebellum. Increased cerebellar uptake was related to an early age of onset of the ATTRv disease. 55% of the patients with ATTRv had a pathological Z-score in the global cerebral region compared to 100% of the patients with AD.ConclusionAmyloid deposition within the brain after long-standing ATTRv amyloidosis is common, especially in the cerebellum. A cerebellar amyloid uptake profile seems to be related to TFNE symptoms.

The Famine Early Warning Systems Network (FEWS NET) has been appraising food security in numerous countries around the world since 1985. Multiple times per year, FEWS NET reports scores for current situation assessments and future projections of food security. The scores are measured on a five-level index scale and gauged for the geographic units of livelihood zones. These zones vary in size and do not remain static, which complicates comparison of food security within and across countries and over time. To facilitate such analysis and interoperability with other sources, we transformed available raw data to the units of geospatial grid-cells that have a uniform, static resolution of 0.5° × 0.5°, a common format of data used in research across diverse disciplines. FEWS NET provides public online access to shapefiles reflecting reports back to 2009. Separate shapefiles capture assessments and projections, with further delineation by the index score. Each shapefile can comprise a complex (multi)polygon, without clear differentiation among livelihood zones. Overlaying a geospatial grid allows disaggregation of the (multi)polygons to standard units. We performed the transformation to grid-cells on the shapefiles for all 25 countries (including Yemen) that FEWS NET tracked within regional groupings of East, Southern, and West Africa from July 2009–October 2020. For each report cycle, each grid-cell was assigned scores of the assessment and near-term and medium-term projections, based on the raw data for the corresponding livelihood zone. In addition, we calculated a value of bias in medium-term projections relative to subsequent assessments, which can be used as a metric for validation of accuracy. This article provides access to the grid-cell data on assessment and projection scores and bias values. In addition, we present time-lapse animated maps as tools to visualize historical patterns and trends in these indicators across Africa. Our related research article employed the grid-cell data to evaluate the accuracy of FEWS NET projections, including as a function of variation in humanitarian assistance, climate conditions, and violent conflict (Backer and Billing [1]). Researchers can likewise use the grid-cell data to conduct further validation of food security projections and to examine the relationship of assessments and projections to potential drivers and consequences. The data and animations are also valuable to stakeholders throughout the international community seeking to learn and disseminate knowledge about the tendencies of food security projections on a broad scale.

In Parkinson’s disease (PD), the fronto-striatal network is involved in motor and cognitive symptoms. Working memory (WM) updating training engages this network in healthy populations, as observed by improved cognitive performance and increased striatal BOLD signal. This two-part study aimed to assess the feasibility of WM updating training in PD and measure change in cognition, movement and functional brain response in one individual with PD after WM updating training. A feasibility and single-subject (FL) study were performed in which patients with PD completed computerized WM updating training. The outcome measures were the pre-post changes in criterion and transfer cognitive tests; cognitive complaints; psychological health; movement kinematics; and task-related BOLD signal. Participants in the feasibility study showed improvements on the criterion tests at post-test. FL displayed the largest improvements on the criterion tests and smaller improvements on transfer tests. Furthermore, FL reported improved cognitive performance in everyday life. A shorter onset latency and smoother upper-limb goal-directed movements were measured at post-test, as well as increased activation within the striatum and decreased activation throughout the fronto-parietal WM network. This two-part study demonstrated that WM updating training is feasible to complete for PD patients and that change occurred in FL at post-test in the domains of cognition, movement and functional brain response.

Abstract Background Dopamine transporter (DAT) imaging may be of diagnostic value in patients with clinically suspected parkinsonian disease. The purpose of this study was to compare the diagnostic performance of DAT imaging with positron emission computed tomography (PET), using the recently developed, highly DAT-selective radiopharmaceutical [18F]FE-PE2I (FE-PE2I), to the commercially available and frequently used method with [123I]FP-CIT (FP-CIT) single-photon emission computed tomography (SPECT) in early-stage idiopathic parkinsonian syndrome (PS). Methods Twenty-two patients with a clinical de novo diagnosis of PS and 28 healthy controls (HC) participating in an on-going clinical trial of FE-PE2I were analyzed in this study. Within the trial protocol, participants are clinically reassessed 2 years after inclusion. A commercially available software was used for automatic calculation of FP-CIT-specific uptake ratio (SUR). MRI-based volumes of interest combined with threshold PET segmentation were used for FE-PE2I binding potential relative to non-displaceable binding (BPND) quantification and specific uptake value ratios (SUVR). Results PET with FE-PE2I revealed significant differences between patients with a clinical de novo diagnosis of PS and healthy controls in striatal DAT availability (p

To better support the transition to more industrial uses of additive manufacturing, this study examined the use of an Arcam Q20+ industrial 3D printer for producing heavily nested Ti-6Al-4V parts with both in-specification (IS) and out of specification (OS) oxygen content in reused grade 5 powder chemistries. Both the OS and IS powder chemistries were evaluated to understand their impact on build integrity and on static and fatigue performance. The results from our evaluations showed that controlling the bed preheat temperature in the Q20+ to relatively low values (326–556 °C) was effective in limiting microstructural coarsening during the long build time and enabled adequate/balanced performance vis à vis the tensile strength and ductility. Overall, the tensile properties of the IS Ti-6Al-4V material in the as-built and machined states fully met the requirements of ASTM F2924-14. By contrast, the ductility was compromised at oxygen levels above 0.2 wt.% (OS) in Ti-6Al-4V produced by EBM. Removal of the surface layer by machining increased the consistency and performance of the IS and OS Ti-6Al-4V materials. The fatigue behaviour of the EBM Ti-6Al-4V material was in the range of properties produced by casting. Due to the strong influence of both the surface finish and oxygen content on the fatigue strength, the IS Ti-6Al-4V material exhibited the highest performance, with results that were in the range of parts that had been cast plus hot isostatically pressed.

Objectives: The amount of ritonavir needed to enhance saquinavir hard gel (hg) plasma concentrations is unclear. Reduced ritonavir dosing may help to reduce ritonavir-related side effects and costs. This study examined the pharmacokinetics of twice-daily saquinavir-hg (1000?mg) in the presence of ritonavir 100?mg, dosed twice-daily and once-daily on one single occasion.Methods: Eighteen HIV-infected adults taking saquinavir/ritonavir 1000/100?mg twice-daily underwent pharmacokinetic (PK) assessment of saquinavir/ritonavir on day 1 following a morning saquinavir/ritonavir dose. On day 2, PK assessment was repeated when subjects took saquinavir without ritonavir. Drug intake (with a standard meal containing 20?g of fat) was timed on days -1, 1 and 2. Geometric mean ratios (GMR) and 95% confidence intervals (CI) were calculated to assess changes in saquinavir PK parameters.Results: Geometric mean saquinavir AUC012, Ctrough, Cmax and elimination half-life on days 1 and 2 were 14 389 and 9590?ngh/mL, 331 and 234?ng/mL, 2503 and 1893?ng/mL and 2.80 and 2.82?h, respectively. The GMR (95% CI) for these parameters were 0.67 (0.530.84), 0.71 (0.481.04), 0.76 (0.580.98) and 1.01 (0.861.18), respectively.Conclusions: Withholding a ritonavir dose significantly reduces overall saquinavir exposure and Cmax, but had no impact on the elimination half-life. These data establish the need to administer saquinavir and ritonavir simultaneously. [ABSTRACT FROM AUTHOR]

Soil nematode populations have the potential to indicate ecosystem disturbances. In response to questions about nematode interactions with soilborne diseases and whether genetically modified cotton altered nematode populations, several fields in the Namoi cotton growing area of Australia were sampled between 2005 and 2007. No significant interactions were observed, but nematodes numbers were low and postulated to be due to the use of the nematicide aldicarb. Aldicarb was removed from the system in 2011 and in 2015 funding allowed some fields to be resampled to determine if there had been a change in the nematode numbers following aldicarb removal. No significant changes in the total nematode numbers were observed, implying that the removal of aldicarb had little impact on the total nematode population size. However, an increase in plant parasitic nematodes was observed in both fields, but the species identified and the levels of change were not considered a threat to cotton production nor driven solely by altered pesticide chemistry. Additionally, greater numbers of higher order coloniser-persisters in the 2015 samples suggests that the current cotton production system is less disruptive to the soil ecosystem than that of a decade ago.

Nitrogen (N) is the most important fertiliser element determining the productivity of wheat. N nutrition is known to affect the level of stripe rust infection, with higher N associated with increased disease severity. Stripe rust, caused by Puccinia striiformis f. sp. tritici, is a major yield-limiting disease of wheat in Australia. This paper describes experiments designed to investigate the agronomic response to the interaction of various levels of N application and stripe rust severity in wheat varieties differing in response. Experimental plots were established in crop seasons 2006 and 2007 on the Liverpool Plains of northern NSW, Australia. Yield, biomass, grain protein content (GPC) and harvest index (HI) data were recorded. Increased rates of N increased the severity of stripe rust during grain filling. N application also increased yield and GPC in all varieties in both years. Stripe rust reduced the yield of the rust-susceptible wheat varieties, and GPC and proportion of added N recovered in the grain were also reduced in one year but not the other. It was evident from our experiment that stripe rust caused yield loss accompanied by either no change or reduction in GPC, indicating that the total amount of N entering the grain was reduced by stripe rust. The effects of stripe rust on N yield are most likely associated with reduced uptake of N during grain filling.

BACKGROUND: Despite calls for the development and evaluation of pain education programs during early medical student training, little research has been dedicated to this initiative.

Congenital permanent dislocation of the patella is a rare disorder of the knee joint in which the patella is permanently displaced, even in extension and is fixed on the lateral aspect of the femoral condyle. The dislocation is irreducible without surgical techniques. This rare condition is usually detected within the first decade of life, because of inability of active extension in the knee and impaired ability during walking. This report presents an unusual case of a 51-year-old man with bilateral congenital permanent dislocation of the patella. The pathology had never been treated because there were few symptoms. The patient presented with right knee pain caused by a fall on the knee during his work. The right knee was painful on the lateral side and the clinical signs were positive for pathology of the lateral meniscus, confirmed by MRI. The clinical and the imaging findings suggested a lesion of the lateral meniscus as the probable cause of the pain. Therefore we performed a knee arthroscopy, whose intra-operative findings confirmed the MRI findings. During the surgery we performed just a selective arthroscopic meniscectomy, without correcting patella dislocation, because the condition was unusually asymptomatic before the trauma.

Bone loss around the knee in the setting of total knee arthroplasty remains a difficult and challenging problem for orthopaedic surgeons. There are a number of options for dealing with smaller and contained bone loss; however, massive segmental bone loss has fewer options. Small, contained defects can be treated with cement, morselized autograft/allograft or metal augments. Segmental bone loss cannot be dealt with through simple addition of cement, morselized autograft/allograft, or metal augments. For younger or higher demand patients, the use of allograft is a good option as it provides a durable construct with high rates of union while restoring bone stock for future revisions. Older patients, or those who are low demand, may be better candidates for a tumour prosthesis, which provides immediate ability to weight bear and mobilize.

Abstract Centrioles are subcellular organelles found at the cilia base with an evolutionarily conserved structure and a shock absorber-like function. In sperm, centrioles are found at the flagellum base and are essential for embryo development in basal animals. Yet, sperm centrioles have evolved diverse forms, sometimes acting like a transmission system, as in cattle, and sometimes becoming dispensable, as in house mice. How the essential sperm centriole evolved to become dispensable in some organisms is unclear. Here, we test the hypothesis that this transition occurred through a cascade of evolutionary changes to the proteins, structure, and function of sperm centrioles and was possibly driven by sperm competition. We found that the final steps in this cascade are associated with a change in the primary structure of the centriolar inner scaffold protein FAM161A in rodents. This information provides the first insight into the molecular mechanisms and adaptive evolution underlying a major evolutionary transition within the internal structure of the mammalian sperm neck.

Lipodystrophy (LD) is a common adverse effect of HIV treatment with highly active antiretroviral therapy, which comprises morphological and metabolic changes. The underlying mechanisms for LD are thought to be due to mitochondrial toxicity and insulin resistance, which results from derangements in levels of adipose tissue-derived proteins (adipocytokines) that are actively involved in energy homeostasis. Several management strategies for combating this syndrome are available, but they all have limitations. They include: switching from thymidine analogues to tenofovir or abacavir in lipoatrophy, or switching from protease inhibitors associated with hyperlipidaemia to a protease-sparing option; injection into the face with either biodegradable fillers such as poly-l-lactic acid and hyaluronic acid (a temporary measure requiring re-treatment) or permanent fillers such as bio-alcamid (with the risk of foreign body reaction or granuloma formation); and structured treatment interruption with the risk of loss of virological control and disease progression. There is therefore a need to explore alternative therapeutic options. Some new approaches including adipocytokines, uridine supplementation, glitazones, growth hormone (or growth hormone-releasing hormone analogues), metformin and statins (used alone or in combination) merit further investigation. [ABSTRACT FROM AUTHOR]