Assessment of the antimalarial potential of tetraoxane WR 148999.
The antimalarial peroxide, dispiro-1,2,4,5-tetraoxane WR 148999, was synergistic with chloroquine, quinine, mefloquine, and artemisinin against both D6 and W2 clones of Plasmodium falciparum. In consideration of the contrasting antagonism between artemisinin and chloroquine, these drug combination data imply that WR 148999 and artemisinin may not share a common mechanism of action. For Plasmodium berghei-infected mice given oral, subcutaneous, and intraperitoneal doses of WR 148999 ranging from 2 to 1024 mg/kg in the Thompson test, median survival times were 8.8, 11.8, and 27.5 days, respectively, compared to 8 days for control animals. Using subcutaneous administration, WR 148999 had a considerably longer duration of action than did artemisinin against P. berghei. WR 148999 did not significantly inhibit cytochrome P450 isozymes CYP 2C9, 2C19, 2D6, 2E1, or 3A4 (IC50 >500 microM) but did inhibit CYP 1A2 with an IC50 value of 36 microM, suggesting that WR 148999 may be metabolized by the latter CYP isozyme. These results combined with previous observations that formulation strategies and incorporation of polar functional groups in a series of WR 148999 analogs both failed to enhance tetraoxane oral antimalarial activity suggest that oral bioavailability of tetraoxane WR 148999 is more likely a function of extensive first-pass metabolism rather than solubility-limited dissolution.


Predicting Virological Response to HIV Treatment Over Time: A Tool for Settings With Different Definitions of Virological Response.
Definitions of virological response vary from <50 up to 1000 copies of HIV-RNA/mL. Our previous models estimate the probability of HIV drug combinations reducing the viral load to <50 copies/mL, with no indication of whether higher thresholds of response may be achieved. Here, we describe the development of models that predict absolute viral load over time. Two sets of random forest models were developed using 50,270 treatment change episodes from more than 20 countries. The models estimated viral load at different time points following the introduction of a new regimen from variables including baseline viral load, CD4 count, and treatment history. One set also used genotypes in their predictions. Independent data sets were used for evaluation. Both models achieved highly significant correlations between predicted and actual viral load changes (r = 0.67-0.68, mean absolute error of 0.73-0.74 log10 copies/mL). The models produced curves of virological response over time. Using failure definitions of <100, 400, or 1000 copies/mL, but not 50 copies/mL, both models were able to identify alternative regimens they predicted to be effective for the majority of cases where the new regimen prescribed in the clinic failed. These models could be useful for selecting the optimum combination therapy for patients requiring a change in therapy in settings using any definition of virological response. They also give an idea of the likely response curve over time. Given that genotypes are not required, these models could be a useful addition to the HIV-TRePS system for those in resource-limited settings.


Measurements of light at night (LAN) for a sample of female school teachers.
Epidemiological studies have shown an association between rotating shiftwork and breast cancer (BC) risk. Recently, light at night (LAN) measured by satellite photometry and by self-reports of bedroom brightness has been shown to be associated with BC risk, irrespective of shiftwork history. Importance has been placed on these associations because retinal light exposures at night can suppress the hormone melatonin and/or disrupt circadian entrainment to the local 24-h light-dark cycle. The present study examined whether it was valid to use satellite photometry and self-reports of brightness to characterize light, as it might stimulate the circadian system and thereby affect BC incidence. Calibrated photometric measurements were made at the bedroom windows and in the bedrooms of a sample of female school teachers, who worked regular dayshifts and lived in a variety of satellite-measured sky brightness categories. The light levels at both locations were usually very low and were independent of the amount of satellite-measured light. Calibrated photometric measurements were also obtained at the corneas of these female school teachers together with calibrated accelerometer measurements for seven consecutive days and evenings. Based upon these personal light exposure and activity measurements, the female teachers who participated in this study did not have disrupted light-dark cycles like those associated with rotating shiftworkers who do exhibit a higher risk for BC. Rather, this sample of female school teachers had 24-h light-dark and activity-rest patterns very much like those experienced by dayshift nurses examined in an earlier study who are not at an elevated risk of BC. No relationship was found between the amount of satellite-measured light levels and the 24-h light-dark patterns these women experienced. It was concluded from the present study that satellite photometry is unrelated to personal light exposures as they might affect melatonin suppression and/or circadian disruption. More generally, photometric devices calibrated in terms of the operational characteristics of the human circadian system must be used to meaningfully link LAN and BC incidence.


A Genome-Centric Approach Reveals a Novel Glycosyltransferase from the GA A07 Strain of Bacillus thuringiensis Responsible for Catalyzing 15-O-Glycosylation of Ganoderic Acid A.
Strain GA A07 was identified as an intestinal Bacillus bacterium of zebrafish, which has high efficiency to biotransform the triterpenoid, ganoderic acid A (GAA), into GAA-15-O-β-glucoside. To date, only two known enzymes (BsUGT398 and BsUGT489) of Bacillus subtilis ATCC 6633 strain can biotransform GAA. It is thus worthwhile to identify the responsible genes of strain GA A07 by whole genome sequencing. A complete genome of strain GA A07 was successfully assembled. A phylogenomic analysis revealed the species of the GA A07 strain to be Bacillus thuringiensis. Forty glycosyltransferase (GT) family genes were identified from the complete genome, among which three genes (FQZ25_16345, FQZ25_19840, and FQZ25_19010) were closely related to BsUGT398 and BsUGT489. Two of the three candidate genes, FQZ25_16345 and FQZ25_19010, were successfully cloned and expressed in a soluble form in Escherichia coli, and the corresponding proteins, BtGT_16345 and BtGT_19010, were purified for a biotransformation activity assay. An ultra-performance liquid chromatographic analysis further confirmed that only the purified BtGT_16345 had the key biotransformation activity of catalyzing GAA into GAA-15-O-β-glucoside. The suitable conditions for this enzyme activity were pH 7.5, 10 mM of magnesium ions, and 30 °C. In addition, BtGT_16345 showed glycosylation activity toward seven flavonoids (apigenein, quercetein, naringenein, resveratrol, genistein, daidzein, and 8-hydroxydaidzein) and two triterpenoids (GAA and antcin K). A kinetic study showed that the catalytic efficiency (kcat/KM) of BtGT_16345 was not significantly different compared with either BsUGT398 or BsUGT489. In short, this study identified BtGT_16345 from B. thuringiensis GA A07 is the catalytic enzyme responsible for the 15-O-glycosylation of GAA and it was also regioselective toward triterpenoid substrates.


Metabolic syndrome and retinal microvascular calibre in a high cardiovascular disease risk cohort.
To investigate the independent associations between metabolic syndrome and retinal vessel calibre in a high cardiovascular risk cohort, and to determine whether these associations also exist in patients without diabetes, hypertension or coronary artery disease (CAD). The Australian Heart Eye Study is an observational study that surveyed 1680 participants who presented to a tertiary referral hospital for the evaluation of potential CAD by coronary angiography. Metabolic syndrome was defined according to the Third Report of the National Cholesterol Education Program. Retinal arteriolar calibre narrowing and retinal venular calibre widening were measured from retinal photographs. CAD was quantified using severity (Gensini) and extent scores. Diabetes and hypertension were defined from clinical investigation (fasting plasma glucose >7.0 mmol/L and blood pressure >130/85 mm Hg) or from self-reported clinical diagnosis, including the use of medications. A total of 979 participants had complete information on metabolic syndrome components and were included in cross-sectional analyses. After adjusting for age, sex, smoking status and fellow vessel calibre, persons with metabolic syndrome (compared with persons without metabolic syndrome) had narrower retinal arteriolar calibre (mean difference 4.3 µm, p<0.0001). No significant difference in venular calibre was observed (p=0.05). This association persisted in persons without diabetes (mean arteriolar calibre difference 4.4 µm, p=0.0006) but not in participants without CAD and those without hypertension. Metabolic syndrome is independently associated with narrower retinal arterioles but not wider retinal venules among those at high risk of CAD. The association between metabolic syndrome and narrower retinal arterioles is likely due to the presence of CAD or hypertension in individuals with this syndrome, as the association is not significant in individuals without hypertension or without CAD.


Metabolomics: Applications and Promise in Mycobacterial Disease.
Until recently, the study of mycobacterial diseases was trapped in culture-based technology that is more than a century old. The use of nucleic acid amplification is changing this, and powerful new technologies are on the horizon. Metabolomics, which is the study of sets of metabolites of both the bacteria and host, is being used to clarify mechanisms of disease, and can identify changes leading to better diagnosis, treatment, and prognostication of mycobacterial diseases. Metabolomic profiles are arrays of biochemical products of genes in their environment. These complex patterns are biomarkers that can allow a more complete understanding of cell function, dysfunction, and perturbation than genomics or proteomics. Metabolomics could herald sweeping advances in personalized medicine and clinical trial design, but the challenges in metabolomics are also great. Measured metabolite concentrations vary with the timing within a condition, the intrinsic biology, the instruments, and the sample preparation. Metabolism profoundly changes with age, sex, variations in gut microbial flora, and lifestyle. Validation of biomarkers is complicated by measurement accuracy, selectivity, linearity, reproducibility, robustness, and limits of detection. The statistical challenges include analysis, interpretation, and description of the vast amount of data generated. Despite these drawbacks, metabolomics provides great opportunity and the potential to understand and manage mycobacterial diseases.


New innovative techniques in radiotherapy for breast cancer.
Breast-conserving surgery (BCS) followed by adjuvant whole breast radiotherapy (WBRT) is an established treatment for early-stage breast cancer. Long-term follow-up has demonstrated equivalent survival to mastectomy. However, standard WBRT to the conserved breast requires daily radiation treatment, 5 days per week, for 5-7 weeks. This schedule imposes a considerable burden on breast cancer patients and healthcare systems alike. For the last decade, there has been considerable interest in lessening the volume of breast treated with radiotherapy and reducing the number of fractions of radiation treatment. Accelerated partial breast irradiation (APBI), including intraoperative radiotherapy (IORT), delivers high-dose radiation immediately surrounding the lumpectomy cavity, with relative sparing of the majority of the ipsilateral breast. Hypofractionated WBRT delivers radiation to the entire ipsilateral breast; however, this is achieved using a smaller number of fractions and total dose of radiotherapy. The attraction of less invasive or demanding radiotherapy schedules has led to the widespread introduction of APBI before its long-term results have been established. In the past 5 years, data from prospective trials of hypofractionated WBRT and IORT compared to standard WBRT have become available. Additionally, a large, prospective randomized study of APBI versus WBRT is nearing accrual. In this review article, we will discuss these new innovative techniques in radiotherapy for breast cancer. We will also discuss the recently completed and ongoing prospective studies that will provide a robust evaluation of the safety and efficacy of these techniques.


William Burchell's medical challenges: a 19th-century natural philosopher in the field.
Two hundred years ago, the naturalist William John Burchell departed from Cape Town on extensive travels in South Africa 'solely for the purpose of acquiring knowledge'. An intelligent observer who was exceptionally skilled at recording his observations in words and pictures, he is remembered for numerous contributions to the country as scientist, artist and ethnographer. The medical perspective on his travels has yet to receive attention. He identified and recorded illnesses of the indigenous peoples with whom he came into contact. He also described the medical care he administered to his companions and to himself; in doing so, he revealed a profound care for his 'fellow creatures'. His vivid and sometimes poignant descriptions remind us of some of the health risks endured by early travellers in the country. One of the most riveting is his successful care of an assistant whose left hand was severely mutilated when a firearm exploded in his hands. Burchell was probably the first person to include the materia medica of the Khoi in an essentially European approach to the non-surgical management of such a serious condition.


Food supply and bioenergy production within the global cropland planetary boundary.
Supplying food for the anticipated global population of over 9 billion in 2050 under changing climate conditions is one of the major challenges of the 21st century. Agricultural expansion and intensification contributes to global environmental change and risks the long-term sustainability of the planet. It has been proposed that no more than 15% of the global ice-free land surface should be converted to cropland. Bioenergy production for land-based climate mitigation places additional pressure on limited land resources. Here we test normative targets of food supply and bioenergy production within the cropland planetary boundary using a global land-use model. The results suggest supplying the global population with adequate food is possible without cropland expansion exceeding the planetary boundary. Yet this requires an increase in food production, especially in developing countries, as well as a decrease in global crop yield gaps. However, under current assumptions of future food requirements, it was not possible to also produce significant amounts of first generation bioenergy without cropland expansion. These results suggest that meeting food and bioenergy demands within the planetary boundaries would need a shift away from current trends, for example, requiring major change in the demand-side of the food system or advancing biotechnologies.


Replacement of the torn posterior cruciate ligament with a mid-third patellar tendon graft with use of a modified tibial inlay method.
The tibial inlay method for reconstruction of the posterior cruciate ligament has been performed with the patient in the prone or lateral decubitus position. The purpose of this report is to present a modification of this method wherein the patient is positioned supine throughout the procedure. Between May 1995 and September 1998, twelve patients who had an isolated tear of the posterior cruciate ligament underwent reconstruction with use of the modified tibial inlay technique. Eleven patients were evaluated after a minimum duration of follow-up of two years. Stability was measured on posterior stress radiographs and with a maximum manual displacement test performed with a KT-1000 arthrometer. Clinical evaluation was carried out with use of the scoring systems of the Orthopädische Arbeitsgruppe Knie and the International Knee Documentation Committee. Second-look arthroscopy was performed in five patients at the time of follow-up. The mean side-to-side difference in displacement (and standard deviation) was reduced from 10.8 +/- 1.9 mm preoperatively to 3.4 +/- 2.4 mm at the time of follow-up as measured on the stress radiographs, and it was reduced from 9.0 +/- 2.1 mm preoperatively to 1.8 +/- 1.2 mm at the time of follow-up as measured with the KT-1000 arthrometer. The average Orthopädische Arbeitsgruppe Knie score was improved from 71.6 +/- 6.8 to 92.5 +/- 4.8 points. All eleven patients had a satisfactory clinical outcome at the time of the final clinical evaluation. The second-look arthroscopic examination in the five patients showed no evidence of partial tearing or abrasion of the graft. Use of our modified tibial inlay technique for reconstruction of the posterior cruciate ligament achieved a good clinical result in eleven of twelve patients. The advantages of the technique are (1) minimal tendon abrasion at the posterior opening of the tibial tunnel, and (2) elimination of the need to change the patient's position during surgery.


Endophthalmitis caused by staphylococcus epidermidis: in vitro antibiotic susceptibilities and clinical outcomes.
To investigate the antibiotic sensitivities and clinical outcomes of eyes with endophthalmitis caused by methicillin-sensitive versus methicillin-resistant Staphylococcus epidermidis (MSSE/MRSE). A retrospective, consecutive case series of all patients with endophthalmitis caused by S. epidermidis from January 1, 1996, through July 1, 2004, was conducted. The antibiotic sensitivities and clinical outcomes were obtained from the corresponding medical records. The study included 86 eyes of 86 patients with S. epidermidis endophthalmitis (34 MSSE and 52 MRSE). Endophthalmitis categories included cataract surgery (58), glaucoma surgery (12), trauma (7), vitrectomy (4), penetrating keratoplasty (4), and corneal suture ulcer (1). In vitro testing revealed that all MSSE and MRSE isolates were sensitive to vancomycin, 67% of MSSE isolates and 67% of MRSE isolates were sensitive to gatifloxacin, and 73% of MSSE isolates and 67% of MRSE isolates were sensitive to moxifloxacin (overall 68% sensitive). All eyes were treated with intravitreal vancomycin and either ceftazidime or amikacin. Visual acuity improved to a median of 20/80 at 3 months and 20/60 at 1 year. I CONCLUSIONS: In the current study, all MSSE and MRSE isolates were sensitive to vancomycin and 68% were sensitive to the fourth-generation fluoroquinolones. There were no significant differences in visual acuity outcomes of endophthalmitis caused by MSSE versus MRSE isolates.


Explaining the homogeneous diffusion of COVID-19 nonpharmaceutical interventions across heterogeneous countries.
We analyze the adoption of nonpharmaceutical interventions in the Organisation for Economic Co-operation and Development (OECD) countries during the early phase of the coronavirus disease 2019 (COVID-19) pandemic. Given the complexity associated with pandemic decisions, governments are faced with the dilemma of how to act quickly when their core decision-making processes are based on deliberations balancing political considerations. Our findings show that, in times of severe crisis, governments follow the lead of others and base their decisions on what other countries do. Governments in countries with a stronger democratic structure are slower to react in the face of the pandemic but are more sensitive to the influence of other countries. We provide insights for research on international policy diffusion and research on the political consequences of the COVID-19 pandemic.


A computational framework to study sub-cellular RNA localization.
RNA localization is a crucial process for cellular function and can be quantitatively studied by single molecule FISH (smFISH). Here, we present an integrated analysis framework to analyze sub-cellular RNA localization. Using simulated images, we design and validate a set of features describing different RNA localization patterns including polarized distribution, accumulation in cell extensions or foci, at the cell membrane or nuclear envelope. These features are largely invariant to RNA levels, work in multiple cell lines, and can measure localization strength in perturbation experiments. Most importantly, they allow classification by supervised and unsupervised learning at unprecedented accuracy. We successfully validate our approach on representative experimental data. This analysis reveals a surprisingly high degree of localization heterogeneity at the single cell level, indicating a dynamic and plastic nature of RNA localization.


Cross-sectional association between polyfluoroalkyl chemicals and cognitive limitation in the National Health and Nutrition Examination Survey.
Our limited understanding of how polyfluoroalkyl chemicals (PFCs) may impact on human health suggests the potential for a protective impact on brain health. This study was designed to explore the association between PFCs and cognitive ability in older adults. We assessed the association between four PFCs, perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS), and self-reported limitation due to difficulty remembering or periods of confusion using data from participants aged 60-85 years from the 1999-2000 and 2003-2008 National Health and Nutrition Examination Surveys. We also considered whether diabetic status or diabetic medication use modifies this association in light of in vitro evidence that PFCs may act on the same receptors as some diabetic medications. In multivariable adjusted models, point estimates suggest a protective association between PFCs and self-reported cognitive limitation (odds ratio, OR; 95% confidence interval, CI) for a doubling in PFC concentration: PFOS (OR, 0.90; 95% CI, 0.78, 1.03), PFOA (OR, 0.92; 95% CI, 0.78, 1.09), PFNA (OR, 0.91; 95% CI, 0.79, 1.04) and PFHxS (OR, 0.93; 95% CI, 0.82, 1.06). The protective association was concentrated in diabetics, with strong, significant protective associations in nonmedicated diabetics. This cross-sectional study suggests that there may be a protective association between exposure to PFCs and cognition in older adults, particularly diabetics.


Efficient screening of fungal cellobiohydrolase class I enzymes for thermostabilizing sequence blocks by SCHEMA structure-guided recombination.
We describe an efficient SCHEMA recombination-based approach for screening homologous enzymes to identify stabilizing amino acid sequence blocks. This approach has been used to generate active, thermostable cellobiohydrolase class I (CBH I) enzymes from the 390 625 possible chimeras that can be made by swapping eight blocks from five fungal homologs. Constructing and characterizing the parent enzymes and just 32 'monomeras' containing a single block from a homologous enzyme allowed stability contributions to be assigned to 36 of the 40 blocks from which the CBH I chimeras can be assembled. Sixteen of 16 predicted thermostable chimeras, with an average of 37 mutations relative to the closest parent, are more thermostable than the most stable parent CBH I, from the thermophilic fungus Talaromyces emersonii. Whereas none of the parent CBH Is were active >65°C, stable CBH I chimeras hydrolyzed solid cellulose at 70°C. In addition to providing a collection of diverse, thermostable CBH Is that can complement previously described stable CBH II chimeras (Heinzelman et al., Proc. Natl Acad. Sci. USA 2009;106:5610-5615) in formulating application-specific cellulase mixtures, the results show the utility of SCHEMA recombination for screening large swaths of natural enzyme sequence space for desirable amino acid blocks.


Influence of perturbation velocity on balance control in Parkinson's disease.
Underlying somatosensory processing deficits of joint rotation velocities may cause patients with Parkinson's disease (PD) to be more unstable for fast rather than slow balance perturbations. Such deficits could lead to reduced proprioceptive amplitude feedback triggered by perturbations, and thereby to smaller or delayed stabilizing postural responses. For this reason, we investigated whether support surface perturbation velocity affects balance reactions in PD patients. We examined postural responses of seven PD patients (OFF medication) and eight age-matched controls following backward rotations of a support-surface platform. Rotations occurred at three different speeds: fast (60 deg/s), medium (30 deg/s) or slow (3.8 deg/s), presented in random order. Each subject completed the protocol under eyes open and closed conditions. Full body kinematics, ankle torques and the number of near-falls were recorded. Patients were significantly more unstable than controls following fast perturbations (26% larger displacements of the body's centre of mass; P<0.01), but not following slow perturbations. Also, more near-falls occurred in patients for fast rotations. Balance correcting ankle torques were weaker for patients than controls on the most affected side, but were stronger than controls for the least affected side. These differences were present both with eyes open and eyes closed (P<0.01). Fast support surface rotations caused greater instability and discriminated Parkinson patients better from controls than slow rotations. Although ankle torques on the most affected side were weaker, patients partially compensated for this by generating larger than normal stabilizing torques about the ankle joint on the least affected side. Without this compensation, instability may have been greater.


Elasticity of agr-Cristobalite: A Silicon Dioxide with a Negative Poisson's Ratio.
Laser Brillouin spectroscopy was used to determine the adiabatic single-crystal elastic stiffness coefficients of silicon dioxide (SiO(2)) in the alpha-cristobalite structure. This SiO(2) polymorph, unlike other silicas and silicates, exhibits a negative Poisson's ratio; alpha-cristobalite contracts laterally when compressed and expands laterally when stretched. Tensorial analysis of the elastic coefficients shows that Poisson's ratio reaches a maximum value of -0.5 in some directions, whereas averaged values for the single-phased aggregate yield a Poisson's ratio of -0.16.


Community collective efficacy is associated with reduced physical intimate partner violence (IPV) incidence in the rural province of Mpumalanga, South Africa: findings from HPTN 068.
Intimate partner violence (IPV) is a human rights violation and is associated with a variety of adverse physical and mental health outcomes. Collective efficacy, defined as mutual trust among community members and willingness to intervene on the behalf of the common good, has been associated with reduced neighbourhood violence. Limited research has explored whether community collective efficacy is associated with reduced incidence of IPV. This is of particular interest among adolescent girls and young women (AGYW) in sub-Saharan Africa, where the burden of HIV is greatest and IPV is common. We collected longitudinal data among 2533 AGYW (ages 13-20) enrolled in the HPTN 068 cohort in Mpumalanga province, South Africa between 2011 and 2016. We included participants from 26 villages where community surveys were collected during the HPTN 068 study. Collective efficacy was measured at the village level via two population-based cross-sectional surveys in 2012 and 2014. Multivariable Poisson generalised estimating equation regression models estimated the relative risk ratio (RR) between village collective efficacy scores and subsequent physical IPV 12 month incidence, adjusting for village-level clustering and covariates. Thirty-eight per cent of the cohort (n=950) reported at least one episode of recent physical IPV during follow-up. For every SD higher level of collective efficacy, there was a 6% lower level of physical IPV incidence (adjusted RR: 0.94; 95% CI 0.89 to 0.98) among AGYW after adjusting for covariates. Community-level interventions that foster the development of collective efficacy may reduce IPV among AGYW.


Meat quality and muscle fibre type characteristics of Southdown Rams from high and low backfat selection lines.
Characteristics of the meat of 15-18-month Southdown rams from lines selected for high or low backfat depths (assessed ultrasonically at position C over the last rib) were compared. Half of the carcasses were electrically stimulated (ES) and within each carcass post-mortem treatments chosen to produce effects on meat tenderness were ageing periods of 1 or 15 days (Semimembranosus), early or delayed chilling (Biceps femoris), and trimming of the s.c. fat cover (Longissimus dorsi). These treatments had the expected effects on shear values, but the sizes of the effects were little affected by selection line or ES treatment. Selection line did not have any direct effects on shear values, reflectance values at several wavelengths, waterholding capacity, cooking loss or sarcomere length. The Semitendinosus muscle had a higher proportion of predominantly oxidative fibres for the high-backfat line, based on succinic dehydrogenase activity (P < 0·05), but there was no line difference in alkaline-stable ATPase activity in the same muscle. Muscle fibre diameter was similar for the two lines.


Automated Plasmodium detection by the Sysmex XN hematology analyzer.
Malaria is a potentially severe disease affecting nearly 200 million people per year. Early detection of the parasite even in unsuspected patients remains the challenging aim for effective patient care. Automated complete blood counts that are usually performed for any febrile patient might represent a tool to ascertain malaria infection. To evaluate the ability of the new generation of the Sysmex hematology analyzer (XN-series) to detect malaria. We retrospectively studied 100 blood samples performed with the recent Sysmex XN analyzer that were positive for Plasmodium and explored its ability to detect the parasite. 100 samples from patients uninfected by malaria were used as control group. Specific abnormalities such as additional events in the mature neutrophil/eosinophil area of the white blood cells differential (WDF) scattergram were noted for 1.1% of Plasmodium falciparum samples and 56.2% of other Plasmodium species samples. Mature parasite stages (schizonts or gametocytes) were observed on blood smears among those samples. WDF scattergrams were able to detect 80.0% (12/15) of Plasmodium mature stages. Furthermore, the differential in white blood counts between WDF and white cell nucleated (WNR) channels was a predictive signal of Plasmodium mature stages in 73.3% (11/15) of samples and may be explained by a differential destruction of particles with the analyzer reagent. Associated to thrombocytopaenia, a Sysmex XN Plasmodium pattern may represent a useful warning for Plasmodium detection in unsuspected patients, particularly when mature parasite stages are present.


Hippocampal CA1 apical neuropil atrophy and memory performance in Alzheimer's disease.
Memory loss is often the first and most prominent symptom of Alzheimer's disease (AD), coinciding with the spread of neurofibrillary pathology from the entorhinal cortex (ERC) to the hippocampus. The apical dendrites of hippocampal CA1 pyramidal neurons, in the stratum radiatum/stratum lacunosum-moleculare (SRLM), are among the earliest targets of this pathology, and atrophy of the CA1-SRLM is apparent in postmortem tissue from patients with mild AD. We previously demonstrated that CA1-SRLM thinning is also apparent in vivo, using ultra-high field 7-Tesla (7T) MRI to obtain high-resolution hippocampal microstructural imaging. Here, we hypothesized that CA1-SRLM thickness would correlate with episodic memory performance among patients with mild AD. We scanned nine patients, using an oblique coronal T2-weighted sequence through the hippocampal body with an in-plane resolution of 220 μm, allowing direct visual identification of subfields - dentate gyrus (DG)/CA3, CA2, CA1, and ERC - and hippocampal strata - SRLM and stratum pyramidale (SP). We present a novel semi-automated method of measuring stratal width that correlated well with manual measurements. We performed multi-domain neuropsychological evaluations that included three tests of episodic memory, yielding composite scores for immediate recall, delayed recall, and delayed recognition memory. Strong correlations occurred between delayed recall performance and the widths of CA1-SRLM (r(2)=0.69; p=0.005), CA1-SP (r(2)=0.5; p=0.034), and ERC (r(2)=0.62; p=0.012). The correlation between CA1-SRLM width and delayed recall lateralized to the left hemisphere. DG/CA3 size did not correlate significantly with any aspect of memory performance. These findings highlight a role for 7T hippocampal microstructural imaging in revealing focal structural pathology that correlates with the central cognitive feature of AD.


High-fat feeding impairs nutrient sensing and gut brain integration in the caudomedial nucleus of the solitary tract in mice.
Hyperphagic obesity is characterized in part by a specific increase in meal size that contributes to increased daily energy intake, but the mechanisms underlying impaired activity of meal size regulatory circuits, particularly those converging at the caudomedial nucleus of the solitary tract in the hindbrain (cmNTS), remain poorly understood. In this paper, we assessed the consequences of high-fat (HF) feeding and diet-induced obesity (DIO) on cmNTS nutrient sensing and metabolic integration in the control of meal size. Mice maintained on a standard chow diet, low-fat (LF) diet or HF diet for 2 weeks or 6 months were implanted with a bilateral brain cannula targeting the cmNTS. Feeding behavior was assessed using behavioral chambers and meal-pattern analysis following cmNTS L-leucine injections alone or together with ip CCK. Molecular mechanisms implicated in the feeding responses were assessed using western blot, immunofluorescence and pharmacological inhibition of the amino acid sensing mTORC1 pathway (mammalian target of rapamycin complex 1). We found that HF feeding blunts the anorectic consequences of cmNTS L-leucine administration. Increased baseline activity of the L-leucine sensor P70 S6 kinase 1 and impaired L-leucine-induced activation of this pathway in the cmNTS of HF-fed mice indicate that HF feeding is associated with an impairment in cmNTS mTOR nutritional and hormonal sensing. Interestingly, the acute orexigenic effect of the mTORC1 inhibitor rapamycin was preserved in HF-fed mice, supporting the assertion that HF-induced increase in baseline cmNTS mTORC1 activity underlies the defect in L-leucine sensing. Last, the synergistic feeding-suppressive effect of CCK and cmNTS L-leucine was abrogated in DIO mice. These results indicate that HF feeding leads to an impairment in cmNTS nutrient sensing and metabolic integration in the regulation of meal size.


Consistent Two-Flow Network for Tele-Registration of Point Clouds.
Rigid registration of partial observations is a fundamental problem in various applied fields. In computer graphics, special attention has been given to the registration between two partial point clouds generated by scanning devices. State-of-the-art registration techniques still struggle when the overlap region between the two point clouds is small, and completely fail if there is no overlap between the scan pairs. In this article, we present a learning-based technique that alleviates this problem, and allows registration between point clouds, presented in arbitrary poses, and having little or even no overlap, a setting that has been referred to as tele-registration. Our technique is based on a novel neural network design that learns a prior of a class of shapes and can complete a partial shape. The key idea is combining the registration and completion tasks in a way that reinforces each other. In particular, we simultaneously train the registration network and completion network using two coupled flows, one that register-and-complete, and one that complete-and-register, and encourage the two flows to produce a consistent result. We show that, compared with each separate flow, this two-flow training leads to robust and reliable tele-registration, and hence to a better point cloud prediction that completes the registered scans. It is also worth mentioning that each of the components in our neural network outperforms state-of-the-art methods in both completion and registration. We further analyze our network with several ablation studies and demonstrate its performance on a large number of partial point clouds, both synthetic and real-world, that have only small or no overlap.


Distribution of prostaglandins E2 and 6-keto-F1 alpha production in dog kidneys.
Little is known about the distribution of prostaglandin E2 (PGE2) and prostacyclin (PGI2) production in the canine kidney. To determine the basal and stimulated profiles of PGE2 and PGI2 production along the corticomedullary axis of the dog kidney, a slice (0.5 mm thick, 10-50 mg) was obtained from six equally spaced zones along the axis (zone 1, medullary crest; zones 2 and 3, inner medulla; zone 4, outer medulla; and zones 5 and 6, cortex) and was divided into equal halves. One half of the slice was incubated with Krebs-Ringer buffer containing arachidonic acid (6.6 x 10(-4) M), bradykinin (9.4 x 10(-6) M), or indomethacin (10(-5) M), whereas the remaining half of each slice was similarly incubated in Krebs-Ringer buffer alone. The production of PGE2 and 6-keto-PGF1 alpha (the stable metabolite of PGI2) was determined by radioimmunoassay. Under basal conditions, both PGE2 and 6-keto-PGF1 alpha were highest in the innermost zones of the inner medulla (PGE2, 3,328 +/- 549 pg/mg; 6-keto-PGF 1 alpha, 1,611 +/- 129 pg/mg) and decreased exponentially to low levels in the cortex (PGE2, undetectable; 6-keto-PGF1 alpha, 13 +/- 2 pg/mg); this production was inhibited by indomethacin. Arachidonic acid significantly increased the production of PGE2 in all zones of the kidney and the production of 6-keto-PGF1 alpha only in zones 3-6.(ABSTRACT TRUNCATED AT 250 WORDS)


Come together, right now: dynamic overwriting of an object's history through common fate.
The objects around us constantly move and interact, and the perceptual system needs to monitor on-line these interactions and to update the object's status accordingly. Gestalt grouping principles, such as proximity and common fate, play a fundamental role in how we perceive and group these objects. Here, we investigated situations in which the initial object representation as a separate item was updated by a subsequent Gestalt grouping cue (i.e., proximity or common fate). We used a version of the color change detection paradigm, in which the objects started to move separately, then met and stayed stationary, or moved separately, met, and then continued to move together. We monitored the object representations on-line using the contralateral delay activity (CDA; an ERP component indicative of the number of maintained objects), during their movement, and after the objects disappeared and became working memory representations. The results demonstrated that the objects' representations (as indicated by the CDA amplitude) persisted as being separate, even after a Gestalt proximity cue (when the objects "met" and remained stationary on the same position). Only a strong common fate Gestalt cue (when the objects not just met but also moved together) was able to override the objects' initial separate status, creating an integrated representation. These results challenge the view that Gestalt principles cause reflexive grouping. Instead, the object initial representation plays an important role that can override even powerful grouping cues.


Lack of impact of radiologic septal measurements upon patient symptoms and performance of septoplasty during endoscopic sinus surgery.
Recent literature suggests that concurrent septoplasty during endoscopic sinus surgery (ESS) improves patient outcomes, however, the underlying indications for performing concurrent septoplasty are unknown. The objective of this study was to investigate the relationship between objective radiologic measures of nasal septal deviation with preoperative patient symptomatology and measures of CRS disease severity. We also sought to understand the association of objective radiologic measurements with surgeon performance of concurrent septoplasty during ESS. Seventy-four patients with CRS undergoing ESS were prospectively enrolled. Angles of septal deviation, intranasal areas and volumes were assessed on preoperative computed tomography (CT) scans and correlated with a robust battery of patient reported outcomes measures (PROMs), objective measures of CRS severity including olfaction scores, radiologic and endoscopic staging, and performance of septoplasty. Intranasal areas and volumes demonstrated only weak linear associations with patient-reported nasal congestion, however, angles of septal deviation alone did not correlate with congestion or any other PROM measure. Meanwhile, radiologic septal-related measurements did not correlate with objective measures of CRS disease severity or the performance of a concurrent septoplasty. Though prior studies demonstrate improved patient outcomes in the setting of concurrent septoplasty during ESS, this study failed to establish an association between preoperative radiologic septal-related measurements and patient symptomatology or surgeon decision to perform septoplasty. Although objective factors to identify patients most likely to benefit from concurrent septoplasty remain unidentified, the potential improvement of surgical recommendations and patient outcomes makes this an important area of continued investigation.


Sexual function and satisfaction in the treatment of chronic major depression with nefazodone, psychotherapy, and their combination.
Changes in sexual interest/satisfaction and function are frequently associated with major depression and the use of some antidepressant treatments. This study compares the effects of antidepressant medication, psychotherapy, and combined treatment on sexual interest/satisfaction and function in patients with chronic major depression. Outpatients with chronic forms of DSM-IV major depressive disorder (N = 681) were randomly assigned to 12 weeks of nefazodone, Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or combined nefazodone/CBASP. The Modified Rush Sexual Inventory was used to assess sexual functioning, and the 24-item Hamilton Rating Scale for Depression was used to assess depressive symptoms. At baseline, 65% of men and 48% of women reported some sexual dysfunction. Statistically significant linear improvement in sexual interest/satisfaction was noted across all 3 treatment groups (p < .001). Additionally, significant improvement in sexual function was observed across all 3 treatment groups on a composite measure of female sexual function (p < .001). Controlling for depressive symptoms and gender, combined treatment produced greater improvement in total sexual interest/satisfaction than CBASP alone (p = .007), but was not significantly different from nefazodone alone. Improvement in depressive symptoms was associated with improved sexual interest/satisfaction for men and women and, for men, improved sexual functioning. Chronic depression is associated with high rates of sexual dysfunction. Treatment with nefazodone, CBASP, and combined treatment improved sexual interest/satisfaction, with greatest improvement observed with combined treatment.


Pretreatment assessment and predictors of hepatitis C virus treatment in US veterans coinfected with HIV and hepatitis C virus.
The US Department of Veterans Affairs (VA) cares for many human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients. VA treatment recommendations indicate that all HIV/HCV-coinfected patients undergo evaluation for HCV treatment and list pretreatment assessment tests. We compared clinical practice with these recommendations. We identified 377 HIV/HCV-coinfected veterans who began HCV therapy with pegylated interferon and ribavirin and 4135 HIV/HCV-coinfected veterans who did not but were in VA care at the same facilities during the same period. We compared laboratory and clinical characteristics of the two groups and estimated multivariate logistic regression models of receipt of HCV treatment. Overall, patients had high rates of receipt of tests necessary for HCV pretreatment assessment. Patients starting HCV treatment had higher alanine aminotransferase (ALT), lower creatinine, higher CD4 counts and lower HIV viral loads than patients not starting HCV treatment. In the multivariate model, positive predictors of starting HCV treatment included being non-Hispanic whites, having higher ALTs, lower creatinines, higher HCV viral loads, higher CD4 counts, undetectable HIV viral loads and receiving HIV antiretrovirals. A history of chronic mental illness and a history of hard drug use were negative predictors. Most HIV/HCV-coinfected patients received the necessary HCV pretreatment assessments, although rates of screening for hepatitis A and B immunity can be improved. Having well-controlled HIV disease is by far the most important modifiable factor affecting the receipt of HCV treatment. More research is needed to determine if the observed racial differences in starting HCV treatment reflect biological differences, provider behaviour or patient preference.


Fatigue creep damage at the cement-bone interface: an experimental and a micro-mechanical finite element study.
The goal of this study was to quantify the micromechanics of the cement-bone interface under tensile fatigue loading using finite element analysis (FEA) and to understand the underlying mechanisms that play a role in the fatigue behavior of this interface. Laboratory cement-bone specimens were subjected to a tensile fatigue load, while local displacements and crack growth on the specimen's surface were monitored. FEA models were created from these specimens based upon micro-computed tomography data. To accurately model interfacial gaps at the interface between the bone and cement, a custom-written erosion algorithm was applied to the bone model. A fatigue load was simulated in the FEA models while monitoring the local displacements and crack propagation. The results showed the FEA models were able to capture the general experimental creep damage behavior and creep stages of the interface. Consistent with the experiments, the majority of the deformation took place at the contact interface. Additionally, the FEA models predicted fatigue crack patterns similar to experimental findings. Experimental surface cracks correlated moderately with FEA surface cracks (r(2)=0.43), but did not correlate with the simulated crack volume fraction (r(2)=0.06). Although there was no relationship between experimental surface cracks and experimental creep damage displacement (r(2)=0.07), there was a strong relationship between the FEA crack volume fraction and the FEA creep damage displacement (r(2)=0.76). This study shows the additional value of FEA of the cement-bone interface relative to experimental studies and can therefore be used to optimize its mechanical properties.


Utilizing descriptive statements from the biodiversity heritage library to expand the Hymenoptera Anatomy Ontology.
Hymenoptera, the insect order that includes sawflies, bees, wasps, and ants, exhibits an incredible diversity of phenotypes, with over 145,000 species described in a corpus of textual knowledge since Carolus Linnaeus. In the absence of specialized training, often spanning decades, however, these articles can be challenging to decipher. Much of the vocabulary is domain-specific (e.g., Hymenoptera biology), historically without a comprehensive glossary, and contains much homonymous and synonymous terminology. The Hymenoptera Anatomy Ontology was developed to surmount this challenge and to aid future communication related to hymenopteran anatomy, as well as provide support for domain experts so they may actively benefit from the anatomy ontology development. As part of HAO development, an active learning, dictionary-based, natural language recognition tool was implemented to facilitate Hymenoptera anatomy term discovery in literature. We present this tool, referred to as the 'Proofer', as part of an iterative approach to growing phenotype-relevant ontologies, regardless of domain. The process of ontology development results in a critical mass of terms that is applied as a filter to the source collection of articles in order to reveal term occurrence and biases in natural language species descriptions. Our results indicate that taxonomists use domain-specific terminology that follows taxonomic specialization, particularly at superfamily and family level groupings and that the developed Proofer tool is effective for term discovery, facilitating ontology construction.


Genome Assembly and Annotation of the Trichoplusia ni Tni-FNL Insect Cell Line Enabled by Long-Read Technologies.
Trichoplusiani derived cell lines are commonly used to enable recombinant protein expression via baculovirus infection to generate materials approved for clinical use and in clinical trials. In order to develop systems biology and genome engineering tools to improve protein expression in this host, we performed de novo genome assembly of the Trichoplusiani-derived cell line Tni-FNL. By integration of PacBio single-molecule sequencing, Bionano optical mapping, and 10X Genomics linked-reads data, we have produced a draft genome assembly of Tni-FNL. Our assembly contains 280 scaffolds, with a N50 scaffold size of 2.3 Mb and a total length of 359 Mb. Annotation of the Tni-FNL genome resulted in 14,101 predicted genes and 93.2% of the predicted proteome contained recognizable protein domains. Ortholog searches within the superorder Holometabola provided further evidence of high accuracy and completeness of the Tni-FNL genome assembly. This first draft Tni-FNL genome assembly was enabled by complementary long-read technologies and represents a high-quality, well-annotated genome that provides novel insight into the complexity of this insect cell line and can serve as a reference for future large-scale genome engineering work in this and other similar recombinant protein production hosts.


Honey bee Apis mellifera parasites in the absence of Nosema ceranae fungi and Varroa destructor mites.
Few areas of the world have western honey bee (Apis mellifera) colonies that are free of invasive parasites Nosema ceranae (fungi) and Varroa destructor (mites). Particularly detrimental is V. destructor; in addition to feeding on host haemolymph, these mites are important vectors of several viruses that are further implicated as contributors to honey bee mortality around the world. Thus, the biogeography and attendant consequences of viral communities in the absence of V. destructor are of significant interest. The island of Newfoundland, Province of Newfoundland and Labrador, Canada, is free of V. destructor; the absence of N. ceranae has not been confirmed. Of 55 Newfoundland colonies inspected visually for their strength and six signs of disease, only K-wing had prevalence above 5% (40/55 colonies = 72.7%). Similar to an earlier study, screenings again confirmed the absence of V. destructor, small hive beetles Aethina tumida (Murray), tracheal mites Acarapis woodi (Rennie), and Tropilaelaps spp. ectoparasitic mites. Of a subset of 23 colonies screened molecularly for viruses, none had Israeli acute paralysis virus, Kashmir bee virus, or sacbrood virus. Sixteen of 23 colonies (70.0%) were positive for black queen cell virus, and 21 (91.3%) had some evidence for deformed wing virus. No N. ceranae was detected in molecular screens of 55 colonies, although it is possible extremely low intensity infections exist; the more familiar N. apis was found in 53 colonies (96.4%). Under these conditions, K-wing was associated (positively) with colony strength; however, viruses and N. apis were not. Furthermore, black queen cell virus was positively and negatively associated with K-wing and deformed wing virus, respectively. Newfoundland honey bee colonies are thus free of several invasive parasites that plague operations in other parts of the world, and they provide a unique research arena to study independent pathology of the parasites that are present.


Gender, internet experience, Internet identification, and internet anxiety: a ten-year followup.
In 2002, we found gender differences in the use of the Internet. Since then, however, the Internet has changed considerably. We therefore conducted a follow-up study in 2012. The study involved 501 students (389 females and 100 males, 12 participants unspecified gender) and we measured Internet use, Internet anxiety, and Internet identification. We found that males had a greater breadth of Internet use; they used the Internet more for games and entertainment than females. The differentiation between males and females in terms of Internet use is evident, and in some ways is even more distinct than 10 years ago. In our previous research we had found no gender differences in the use of the Internet for communication, whereas in the current study we have found that females use the Internet for communication than males and were using social network sites more than males. We also found, consistent with our previous study, that Internet identification and Internet anxiety were related to Internet use.


Comparison of blood and lymph node cells after intramuscular injection with HIV envelope immunogens.
Harnessing CD4+ T cell help in the lymph nodes through rational antigen design could enhance formation of broadly neutralizing antibodies (bNAbs) during experimental HIV immunization. This process has remained hidden due to difficulty with direct study, with clinical studies instead focusing on responses in the blood as a proxy for the secondary lymphoid tissue. To address this, lymph node cells (LNC) were collected using ultrasound guided fine needle aspiration of axillary lymph nodes from 11 HIV negative participants in an experimental HIV immunogen study (European AIDS Vaccine Initiative EAVI2020_01 study, NCT04046978). Cells from lymph node and blood (PBMC), were collected after intramuscular injection with HIV Env Mosaic immunogens based on HIV Envelope glycoprotein and combined with a liposomal toll-like receptor-4 adjuvant; monophosphoryl lipid A. Simultaneously sampled cells from both blood and lymph node in the same donors were compared for phenotype, function, and antigen-specificity. Unsupervised cluster analysis revealed tissue-specific differences in abundance, distribution, and functional response of LNC compared with PBMC. Monocytes were virtually absent from LNC, which were significantly enriched for CD4+ T cells compared with CD8+ T cells. T follicular helper cells with germinal center features were enriched in LNC, which contained specific CD4+ and CD8+ T cell subsets including CD4+ T cells that responded after a single injection with HIV Env Mosaic immunogens combined with adjuvant. Tissue-specific differences in response to an MHC-II dependent superantigen, staphylococcal enterotoxin B, indicated divergence in antigen presentation function between blood and lymph node. LNC are phenotypically and functionally distinct from PBMC, suggesting that whole blood is only a limited proxy of the T cell lymphatic response to immunization. HIV-specific CD4+ T cells in the lymph node are rapidly inducible upon experimental injection with HIV immunogens. Monitoring evolution of CD4+ T cell memory in LNC with repeated experimental HIV immunization could indicate the strategies most likely to be successful in inducing HIV-specific bNAbs.


The Vaginal Microbiota Among Adolescent Girls in Tanzania Around the Time of Sexual Debut.
The aetiology of bacterial vaginosis (BV) is not well-understood, and prevalence appears to be higher among women living in sub-Saharan Africa. A recent conceptual model implicates three main bacteria (Gardnerella vaginalis; Atopobium vaginae; and Prevotella bivia), sexual activity, sialidase activity, and biofilm formation in the pathogenesis of BV. We describe the vaginal microbiota, presence of the putative sialidase A gene of G. vaginalis, and biofilm among 386 adolescent girls aged 17 and 18 years in a cross-sectional study in Mwanza, Tanzania around the time of expected sexual debut. Vaginal swabs were collected and tested by quantitative polymerase chain reaction (qPCR) for five Lactobacillus species, G. vaginalis, A. vaginae, P. bivia, the sialidase A gene of G. vaginalis, and by fluorescence in situ hybridisation (FISH) for evidence of G. vaginalis and A. vaginae biofilm. We conducted a risk factor analysis of G. vaginalis, A. vaginae and P. bivia, and explored the associations between biofilm, the presence of the sialidase A gene, and non-optimal vaginal microbiota (Nugent 4-7). L. crispatus and L. iners were detected in 69 and 82% of girls, respectively. The prevalence of L. crispatus was higher than previously reported in earlier studies among East and Southern African women. G. vaginalis, A. vaginae, P. bivia were independently associated with reported penile-vaginal sex. Samples with all three BV-associated bacteria made up the highest proportion of samples with Nugent-BV compared to samples with each bacterium alone or together in pairs. Of the 238 girls with G. vaginalis, 63% had the sialidase A gene detected, though there was no difference by reported sexual activity (p = 0.197). Of the 191 girls with results for sialidase A gene and FISH, there was strong evidence for an increased presence of sialidase A gene among those with evidence of a biofilm (p < 0.001). There was a strong association between biofilm and non-optimal microbiota (aOR67.00; 95% CI 26.72-190.53). These results support several of the steps outlined in the conceptual model, although the role of sexual activity is less clear. We recommend longitudinal studies to better understand changes in vaginal microbiota and biofilm formation around the time of sexual debut.


Patterns of genetic diversity in southern and southeastern Araucaria angustifolia (Bert.) O. Kuntze relict populations.
Habitat fragmentation and a decrease in population size may lead to a loss in population genetic diversity. For the first time, the reduction in genetic diversity in the northernmost limit of natural occurence (southeastern Brazil) of Araucaria angustifolia in comparison with populations in the main area of the species continuous natural distribution (southern Brazil), was tested. The 673 AFLPs markers revealed a high level of genetic diversity for the species (Ht = 0.27), despite anthropogenic influence throughout the last century, and a decrease of H in isolated populations of southeastern Brazil (H = 0.16), thereby indicating the tendency for higher genetic diversity in remnant populations of continuous forests in southern Brazil, when compared to natural isolated populations in the southeastern region. A strong differentiation among southern and southeastern populations was detected (AMOVA variance ranged from 10%-15%). From Bayesian analysis, it is suggested that the nine populations tested form five "genetic clusters" (K = 5). Five of these populations, located in the northernmost limit of distribution of the species, represent three "genetic clusters". These results are in agreement with the pattern of geographic distribution of the studied populations.


Timing of onset of cognitive decline: results from Whitehall II prospective cohort study.
To estimate 10 year decline in cognitive function from longitudinal data in a middle aged cohort and to examine whether age cohorts can be compared with cross sectional data to infer the effect of age on cognitive decline. Prospective cohort study. At study inception in 1985-8, there were 10,308 participants, representing a recruitment rate of 73%. Civil service departments in London, United Kingdom. 5198 men and 2192 women, aged 45-70 at the beginning of cognitive testing in 1997-9. Tests of memory, reasoning, vocabulary, and phonemic and semantic fluency, assessed three times over 10 years. All cognitive scores, except vocabulary, declined in all five age categories (age 45-49, 50-54, 55-59, 60-64, and 65-70 at baseline), with evidence of faster decline in older people. In men, the 10 year decline, shown as change/range of test × 100, in reasoning was -3.6% (95% confidence interval -4.1% to -3.0%) in those aged 45-49 at baseline and -9.6% (-10.6% to -8.6%) in those aged 65-70. In women, the corresponding decline was -3.6% (-4.6% to -2.7%) and -7.4% (-9.1% to -5.7%). Comparisons of longitudinal and cross sectional effects of age suggest that the latter overestimate decline in women because of cohort differences in education. For example, in women aged 45-49 the longitudinal analysis showed reasoning to have declined by -3.6% (-4.5% to -2.8%) but the cross sectional effects suggested a decline of -11.4% (-14.0% to -8.9%). Cognitive decline is already evident in middle age (age 45-49).


Evaluation of a short interspersed nucleotide element in the 3' untranslated region of the defective dystrophin gene of dogs with muscular dystrophy.
To determine the distribution of a 231-base pair (bp) element in the dystrophin gene 3' untranslated region (UTR) in a colony of Golden Retrievers with muscular dystrophy and other unrelated dogs and to estimate the frequency of recombination for the canine dystrophin gene. 77 dogs from the Golden Retriever Muscular Dystrophy (GRMD) colony at the Murdoch Veterinary School and 30 unrelated dogs from the Murdoch University Veterinary Clinic. Samples of blood or hair from dogs were used for amplification of DNA, using primers to the canine dystrophin 3' UTR. The DNA from affected dogs generated a larger PCR product than that obtained from clinically normal dogs. Products were cloned and sequenced, and the difference in size was found to be attributable to a 231-bp short interspersed nucleotide element (SINE). The SINE was found in all affected dogs in the colony but not in most unaffected puppies in the colony. Eighteen of 19 dogs in the colony were heterozygous for the GRMD mutation, and 7 of 30 unrelated dogs also were heterozygous for the SINE. Evidence of recombination between the GRMD mutation and the SINE was observed in only 4 dogs (2 sets of littermates) in the GRMD colony. Incidence of this SINE in a few unrelated dogs suggests that this particular insertion into the dystrophin gene may have been a recent event. The SINE in the dystrophin 3' UTR did not have an apparent influence on dystrophin mRNA concentrations.


Effects of composite formulation on the mechanical properties of biodegradable poly(propylene fumarate)/bone fiber scaffolds.
The objective of our study was to determine the effects of composite formulation on the compressive modulus and ultimate strength of a biodegradable, in situ polymerizable poly(propylene fumarate) (PPF) and bone fiber scaffold. The following parameters were investigated: the incorporation of bone fibers (either mineralized or demineralized), PPF molecular weight, N-vinyl pyrrolidinone (NVP) crosslinker amount, benzoyl peroxide (BP) initiator amount, and sodium chloride porogen amount. Eight formulations were chosen based on a resolution III two level fractional factorial design. The compressive modulus and ultimate strength of these formulations were measured on a materials testing machine. Absolute values for compressive modulus varied from 21.3 to 271 MPa and 2.8 to 358 MPa for dry and wet samples, respectively. The ultimate strength of the crosslinked composites varied from 2.1 to 20.3 MPa for dry samples and from 0.4 to 16.6 MPa for wet samples. Main effects of each parameter on the measured property were calculated. The incorporation of mineralized bone fibers and an increase in PPF molecular weight resulted in higher compressive modulus and ultimate strength. Both mechanical properties also increased as the amount of benzoyl peroxide increased or the NVP amount decreased in the formulation. Sodium chloride had a dominating effect on the increase of mechanical properties in dry samples but showed little effects in wet samples. Demineralization of bone fibers led to a decrease in the compressive modulus and ultimate strength. Our results suggest that bone fibers are appropriate as structural enforcement components in PPF scaffolds. The desired orthopaedic PPF scaffold might be obtained by changing a variety of composite formulation parameters.


The application of proteomics to the human alcoholic brain.
Alcoholism results in changes in the human brain that reinforce the cycle of craving and dependency, and these changes are manifest in the pattern of expression of proteins in key cells and brain areas. Described here is a proteomics-based approach aimed at determining the identity of proteins in the superior frontal cortex (SFC) of the human brain that show different levels of expression in autopsy samples taken from healthy and long-term alcohol abuse subjects. Soluble protein fractions constituting pooled samples combined from SFC biopsies of four well-characterized chronic alcoholics (mean consumption > 80 g ethanol/day throughout adulthood) and four matched controls (<20 g/day) were generated. Two-dimensional electrophoresis was performed in triplicate on alcoholic and control samples and the resultant protein profiles analyzed for differential expression. Overall, 182 proteins differed by the criterion of twofold or more between case and control samples. Of these, 139 showed significantly lower expression in alcoholics, 35 showed significantly higher expression, and 8 were new or had disappeared. To date, 63 proteins have been identified using MALDI-MS and MS-MS. The finding that the expression level of differentially expressed proteins is preponderantly lower in the alcoholic brain is supported by recent results from parallel studies using microarray mRNA transcript.


Triiodothyronine stimulates cystatin C production in bone cells.
Thyroid hormones increase cystatin C levels in vivo. To study whether 3,3',5-triiodo-l-thyronine (T(3)) stimulates the production of cystatin C in vitro, we used a T(3)-responsive osteoblastic cell line (PyMS) which can be kept in serum-free culture. We compared the effects of T(3) on cystatin C mRNA expression (by Northern) and on protein release (by Western and ELISA) with those of dexamethasone (dex). Triiodothyronine increased cystatin C mRNA expression and cystatin C accumulation in culture media in a dose- and time-dependent manner, 1.5-fold at 1 nmol/l after 4d; dex (100 nmol/l) was more potent and increased cystatin C accumulation 3-fold after 4d. Triiodothyronine but not dex stimulated glucose uptake. Our in vitro findings explain in vivo observations. Triiodothyronine-induced increase in the production of cystatin C may be related to an increased cell metabolism and proteolysis control demand.


Venous thromboembolism during pregnancy or postpartum: findings from the RIETE Registry.
Venous thromboembolism (VTE) occurs infrequently during pregnancy, and issues concerning its natural history, prevention and therapy remain unresolved. RIETE is an ongoing registry of consecutive patients with objectively confirmed, symptomatic acute VTE. In this analysis, we compared the clinical characteristics and outcome for all enrolled pregnant and postpartum women with acute VTE, and all non-pregnant women in the same age range. Up to May 2005, 11,630 patients were enrolled in RIETE, of whom 848 (7.3%) were women aged <47 years. Of them, 72 (8.5%) were pregnant, 64 (7.5%) postpartum. Pregnant women presented less often with symptomatic pulmonary embolism (11%) than non-pregnant women (39%). VTE developed during the first trimester in 29 (40%) pregnant patients; in the second in 13; in the third in 30. Thrombophilia tests were more often positive in women who had VTE during the first trimester (odds ratio [OR]: 4.4; 95% CI: 0.9-2.4; p=0.037). Most patients in all three groups were initially treated with low-molecular-weight heparin (LMWH). As for long-term therapy, 75% of pregnant women received LMWH until delivery. There were no maternal deaths, and no pregnant patient had recurrence or bled before delivery. However, after delivery one patient (1.4%) developed recurrent thrombosis, four (5.6%) had major bleeding. In conclusion, VTE developed during the first trimester in 40% of the pregnant women, thus suggesting that thromboprophylaxis, when indicated during pregnancy, should start in the first trimester. No patient showed recurrence or bled before delivery, but after delivery the risk of bleeding exceeded the risk of recurrences.


Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies.
To investigate the use of a nonmyeloablative fludarabine-based preparative regimen to produce sufficient immunosuppression to allow engraftment of allogeneic stem cells and induction of graft-versus-leukemia/lymphoma (GVL) as the primary treatment modality for patients with chronic lymphocytic leukemia (CLL) and lymphoma. Fifteen patients were studied. Six patients were in advanced refractory relapse, and induction therapy had failed in two patients. Patients with CLL or low-grade lymphoma received fludarabine 90 to 150 mg/m2 and cyclophosphamide 900 to 2,000 mg/m2. Patients with intermediate-grade lymphoma or in Richter's transformation received cisplatin 25 mg/m2 daily for 4 days; fludarabine 30 mg/m2; and cytarabine 500 mg/m2 daily for 2 days. Chemotherapy was followed by allogeneic stem-cell infusion from HLA-identical siblings. Patients with residual malignant cells or mixed chimerism could receive a donor lymphocyte infusion of 0.5 to 2 x 10(8) mononuclear cells/kg 2 to 3 months posttransplantation if graft-versus-host disease (GVHD) was not present. Eleven patients had engraftment of donor cells, and the remaining four patients promptly recovered autologous hematopoiesis. Eight of 11 patients achieved a complete response (CR). Five of six patients (83.3%) with chemosensitive disease continue to be alive compared with two of nine patients (22.2%) who had refractory or untested disease at the time of study entry (P = .04). These findings indicate the feasibility of allogeneic hematopoietic transplantation with a nonablative preparative regimen to produce engraftment and GVL against lymphoid malignancies. The ability to induce remissions with donor lymphocyte infusion in patients with CLL, Richter's, and low-grade and intermediate-grade lymphoma is direct evidence of GVL activity against these diseases. This approach appears to be most promising in patients with chemotherapy-responsive disease and low tumor burden.


Leptin induces hippocampal synaptogenesis via CREB-regulated microRNA-132 suppression of p250GAP.
Leptin acts in the hippocampus to enhance cognition and reduce depression and anxiety. Cognitive and emotional disorders are associated with abnormal hippocampal dendritic spine formation and synaptogenesis. Although leptin has been shown to induce synaptogenesis in the hypothalamus, its effects on hippocampal synaptogenesis and the mechanism(s) involved are not well understood. Here we show that leptin receptors (LepRs) are critical for hippocampal dendritic spine formation in vivo because db/db mice lacking the long form of the leptin receptor (LepRb) have reduced spine density on CA1 and CA3 neurons. Leptin promotes the formation of mature spines and functional glutamate synapses on hippocampal pyramidal neurons in both dissociated and slice cultures. These effects are blocked by short hairpin RNAs specifically targeting the LepRb and are absent in cultures from db/db mice. Activation of the LepR leads to cAMP response element-binding protein (CREB) phosphorylation and initiation of CREB-dependent transcription via the MAPK kinase/Erk pathway. Furthermore, both Mek/Erk and CREB activation are required for leptin-induced synaptogenesis. Leptin also increases expression of microRNA-132 (miR132), a well-known CREB target, which is also required for leptin-induced synaptogenesis. Last, leptin suppresses the expression of p250GAP, a miR132 target, and this suppression is obligatory for leptin's effects as is the downstream target of p250GAP, Rac1. LepRs appear to be critical in vivo as db/db mice have lowered hippocampal miR132 levels and elevated p250GAP expression. In conclusion, we identify a novel signaling pathway by which leptin increases synaptogenesis through inducing CREB transcription and increasing microRNA-mediated suppression of p250GAP activity, thus removing a known inhibitor of Rac1-stimulated synaptogenesis.


Interfacial and structural characteristics of polyelectrolyte multilayers used as cushions for supported lipid bilayers.
The surface properties of polyelectrolyte multilayers (PEMs) obtained via sequential adsorption of oppositely charged polyions from their solutions and used as cushions for supported lipid bilayers were investigated. Five types of polyelectrolytes were used: cationic polyethyleneimine (PEI), poly(diallyldimethylammonium)chloride (PDADMAC), and poly-l-lysine hydrobromide (PLL); and anionic polysodium 4-styrenesulfonate (PSS) and poly-l-glutamic acid sodium (PGA). The wettability and surface free energy of the PEMs were determined by contact angle measurements using sessile drop analysis. Electrokinetic characterisation of the studied films was performed by streaming potential measurements of selected multilayers and the structure of the polyelectrolyte multilayer was characterized by synchrotron X-ray reflectometry. The examined physicochemical properties of the PEMs were correlated with the kinetics of the formation of supported lipid bilayers atop the PEM cushion.


Role of the morphogenetic furrow in establishing polarity in the Drosophila eye.
The Drosophila retina is a crystalline array of 800 ommatidia whose organization and assembly suggest polarization of the retinal epithelium along anteroposterior and dorsoventral axes. The retina develops by a stepwise process following the posterior-to-anterior progression of the morphogenetic furrow across the eye disc. Ectopic expression of hedgehog or local removal of patched function generates ectopic furrows that can progress in any direction across the disc leaving in their wake differentiating fields of ectopic ommatidia. We have studied the effect of these ectopic furrows on the polarity of ommatidial assembly and rotation. We find that the anteroposterior asymmetry of ommatidial assembly parallels the progression of ectopic furrows, regardless of their direction. In addition, ommatidia developing behind ectopic furrows rotate coordinately, forming equators in various regions of the disc. Interestingly, the expression of a marker normally restricted to the equator is induced in ectopic ommatidial fields. Ectopic equators are stable as they persist to adulthood, where they can coexist with the normal equator. Our results suggest that ectopic furrows can impart polarity to the disc epithelium, regarding the direction of both assembly and rotation of ommatidia. We propose that these processes are polarized as a consequence of furrow propagation, while more global determinants of dorsoventral and anteroposterior polarity may act less directly by determining the site of furrow initiation.


Entry into puberty is reflected in changes in hormone production but not in testicular receptor expression in Atlantic salmon (Salmo salar).
Puberty in male Atlantic salmon in aquaculture can start as early as after the first winter in seawater, stunts growth and entails welfare problems due to the maturation-associated loss of osmoregulation capacity in seawater. A better understanding of the regulation of puberty is the basis for developing improved cultivation approaches that avoid these problems. Our aim here was to identify morphological and molecular markers signaling the initiation of, and potential involvement in, testis maturation. In the first experiment, we monitored for the first time in large Atlantic salmon males several reproductive parameters during 17 months including the first reproductive cycle. Since testicular growth accelerated after the Winter solstice, we focused in the second experiment on the 5 months following the winter solstice, exposing fish from February 1 onwards to the natural photoperiod (NL) or to continuous additional light (LL). In the first experiment, testis weight, plasma androgens and pituitary gonadotropin transcript levels increased with the appearance of type B spermatogonia in the testis, but testicular transcript levels for gonadotropin or androgen receptors did not change while being clearly detectable. In the second experiment, all males kept under NL had been recruited into puberty until June. However, recruitment into puberty was blocked in ~ 40% of the males exposed to LL. The first morphological sign of recruitment was an increased proliferation activity of single spermatogonia and Sertoli cells. Irrespective of the photoperiod, this early sign of testis maturation was accompanied by elevated pituitary gnrhr4 and fshb and testicular igf3 transcript levels as well as increased plasma androgen levels. The transition into puberty occurred again with stable testicular gonadotropin and androgen receptor transcript levels. The sensitivity to reproductive hormones is already established before puberty starts and up-regulation of testicular hormone receptor expression is not required to facilitate entry into puberty. The increased availability of receptor ligands, on the other hand, may result from an up-regulation of pituitary Gnrh receptor expression, eventually activating testicular growth factor and sex steroid release and driving germ and Sertoli cell proliferation and differentiation.


Redox events in HTLV-1 Tax-induced apoptotic T-cell death.
A number of studies implicate reactive oxygen intermediates in the induction of DNA damage and apoptosis. Recent studies suggest that the human T-cell leukemia virus type 1 (HTLV-1) Tax protein induces oxidative stress and apoptotic T-cell death. Activation of the T-cell receptor/CD3 pathway enhances the Tax-mediated oxidative and apoptotic effects. Tax-mediated apoptosis and oxidative stress as well as activation of nuclear factor-kappaB can be potently suppressed by antioxidants. This review focuses on Tax-dependent changes in the intracellular redox status and their role in Tax-mediated DNA damage and apoptosis. The relevance of these observations to HTLV-1 virus-mediated T-cell transformation and leukemogenesis are discussed.


Diagnosis of cirrhosis in patients with chronic hepatitis C genotype 4: Role of ABCB11 genotype polymorphism and plasma bile acid levels.
Chronic hepatitis C (CHC)-related mortality generally results from cirrhosis and subsequent complications. We aimed to investigate the potential role of plasma bile acid levels and ABCB11 1331T > C (V444A, rs2287622) (ATP-binding cassette subfamily B, member 11) gene polymorphism in fibrosis prediction in CHC genotype 4 patients. This case control study included 85 healthy control and the following 225 subjects: 170 adult patients infected with hepatitis C virus (HCV) and categorized into three groups according to liver biopsy; no fibrosis group (F0) (n=33), early fibrosis group (F1-F2) (n=61), and advanced fibrosis group (F3-F4) (n=76). Fasting bile acid levels, hepatitis C virus (HCV) genotyping, and ABCB11 1331T > C gene polymorphism were assessed. The frequency of the variant homozygote genotype CC in advanced fibrosis was significantly higher than that in early fibrosis (48.7% vs. 36.1%) (odd ratio, OR =2.58; 95% confidence interval, CI=1.07-6.20; p=0.03). C allele was significantly represented in advanced fibrosis (65.8%) compared with that in early fibrosis (51.6%) (OR=1.80, 95% CI=1.10-2.93, p=0.01). A significant elevation of plasma bile acid levels in advanced fibrosis was observed compared with those in early fibrosis (p≤0.001). Receiver operating characteristic curve for plasma bile acid levels at cutoff value of 75.5 μmol/L had a 59% specificity and 97.4% sensitivity as a predictor of advanced hepatic fibrosis (AUROC=0.78%). We concluded that Egyptian patients having chronic hepatitis C genotype 4 with CC genotype of ABCB11 SNP 1331T > C and high plasma bile acid levels at cutoff value of 75.5 μmol/L were associated with advanced hepatic fibrosis.


Clinical heterogeneity of polish patients with KAT6B-related disorder.
Say-Barber-Biesecker-Young-Simpson (SBBYSS) variant of Ohdo syndrome is a rare, autosomal dominant and clinically heterogenous disorder, caused by pathogenic variants in the KAT6B gene located on chromosome 10q22.2. KAT6B encodes a highly conserved histone acetyltransferase belonging to the MYST family. Currently, diseases caused by pathogenic variants in KAT6B (KAT6B-related disorders) comprise two allelic entities: SBBYSS variant of Ohdo syndrome and genitopatellar syndrome (GPS). Increase in the number of cases with overlapping GPS/SBBYSS phenotype which makes it necessary to redefine this group of phenotypes as KAT6B-related disorders or KAT6B spectrum disorders. Individuals with SBBYSS usually present with facial abnormalities, hypotonia, joint laxity, feeding problems, and long thumbs/great toes. This syndrome also typically involves skeletal problems including patellar hypoplasia/agenesis. Here we report six SBBYS syndrome patients with the same dysmorphic features but a different course of the disease. One known and five novel KATB6 pathogenic variants were identified by molecular diagnostics using Next Generation Sequencing (NGS). We present a detailed phenotypic analysis of six individuals with KAT6B-related disorders, in whom a heterozygous pathogenic variant in KAT6B gene was found. In all of our patients facial dysmorphism as well as developmental and speech delay were present. Additionally, all but one patients presented with hypotonia, ocular abnormalities and long thumbs. Most of our probands showed blepharophimosis and skeletal (mainly knee) defects. Contrary to previously reported severe patellar defects (hypoplasia/agenesis) anomalies presented by our patients were less severe (dysplasia, habitual dislocation, subluxation) referring to KAT6B-related disorders. While most of the anomalies found in our patients comply with SBBYSS criteria, phenotypic differences in our probands support a broader spectrum of the disease phenotype. To establish the range of this spectrum, a detailed analysis of clinical variability among patients with SBBYSS requires further investigation.


Early childhood predictors of boys' antisocial and violent behavior in early adulthood.
Research on early childhood predictors of violent behaviors in early adulthood is limited. The current study investigated whether individual, family, and community risk factors from 18 to 42 months of age were predictive of violent criminal arrests during late adolescence and early adulthood using a sample of 310 low-income male participants living in an urban community. In addition, differences in trajectories of overt conduct problems (CP), hyperactivity/attention problems (HAP), and co-occurring patterns of CP and HAP from age 1½ to 10 years were investigated in regard to their relationship to violent and nonviolent behaviors, depression, and anxiety at age 20. Results of multivariate analyses indicated that early childhood family income, home environment, emotion regulation, oppositional behavior, and minority status were all significant in distinguishing violent offending boys from those with no criminal records. In addition, trajectories of early childhood CP, but not attention deficit hyperactivity disorder, were significantly related to self-reports of violent behavior, depressive symptoms, and anxiety symptoms. Implications for the prevention of early childhood risk factors associated with adolescent and adult violent behavior for males are discussed.


Persons with disabilities as experts-by experience: using personal narratives to affect community attitudes in Kilifi, Kenya.
The last decade has seen improved public awareness of disability in sub-Saharan Africa. However, negative and stereotypical views of disability still persist in many communities. We conducted a study to promote awareness of disability in rural Kenya, using a process of reflection and education. This paper reports on the second aspect - education. The research question was: How can personal narratives of living with disability affect community attitudes and responses to disability? A qualitative phenomenological approach was adopted. Twenty community-based groups involving 249 participants took part. Each group participated in one focus group discussion at baseline, to explore the members' personal experiences and views of disability. The intervention involved three adults with disabilities sharing their personal narratives with each group. After the intervention, repeat focus group discussions were conducted with each group. Thematic analysis was carried out according to the framework method. The emergent framework consisted of four main themes, organised as opposing constructs: 'burden' and 'agency', 'sub-human' and 'human'. 'Burden' focused on the perceived hopelessness of the situation. Post-intervention revealed greater support for the 'agency' of persons with disabilities, evidenced by what the person could do, rather than their inability, and the relevance of support. The 'sub-human' to 'human' construct captured dehumanising and discriminating practice towards persons with disabilities on one side, and recognition of the person and inclusion in the community on the other. Whilst support and empathy were evident at the pre-intervention stage, post-intervention revealed greater recognition of people with disabilities as fellow human beings. This study provides a proof of concept regarding the deployment of persons with disabilities as agents for change. Exposure to experts-by-experience provided community groups with opportunities to reflect on, examine and adjust their views on disability in this rural part of Kenya. The sharing of personal narratives appeared to resonate with group members, to encourage recognition of the person and not just the disability, and to move their resolve toward ideas for collective action. Further research is needed to assess the effects of such interventions.


Bereavement in critical care: A narrative review and practice exploration of current provision of support services and future challenges.
This special article outlines the background to bereavement in critical care and scopes the current provision and evidence for bereavement support following death in critical care. Co-authored by a family member and former critical care patient, we aim to draw out the current challenges and think about how and where support can be implemented along the bereavement pathway. We draw on the literature to examine different trajectories of dying in critical care and explore how these might impact bereavement, highlighting important points and risk factors for complicated grief. We present graphic representation of the critical junctures for bereavement in critical care. Adjustment disorders around grief are explored and the consequences for families, including the existing evidence base. Finally, we propose new areas for research in this field.


Firing rate models for gamma oscillations.
Gamma oscillations are readily observed in a variety of brain regions during both waking and sleeping states. Computational models of gamma oscillations typically involve simulations of large networks of synaptically coupled spiking units. These networks can exhibit strongly synchronized gamma behavior, whereby neurons fire in near synchrony on every cycle, or weakly modulated gamma behavior, corresponding to stochastic, sparse firing of the individual units on each cycle of the population gamma rhythm. These spiking models offer valuable biophysical descriptions of gamma oscillations; however, because they involve many individual neuronal units they are limited in their ability to communicate general network-level dynamics. Here we demonstrate that few-variable firing rate models with established synaptic timescales can account for both strongly synchronized and weakly modulated gamma oscillations. These models go beyond the classical formulations of rate models by including at least two dynamic variables per population: firing rate and synaptic activation. The models' flexibility to capture the broad range of gamma behavior depends directly on the timescales that represent recruitment of the excitatory and inhibitory firing rates. In particular, we find that weakly modulated gamma oscillations occur robustly when the recruitment timescale of inhibition is faster than that of excitation. We present our findings by using an extended Wilson-Cowan model and a rate model derived from a network of quadratic integrate-and-fire neurons. These biophysical rate models capture the range of weakly modulated and coherent gamma oscillations observed in spiking network models, while additionally allowing for greater tractability and systems analysis. NEW & NOTEWORTHY Here we develop simple and tractable models of gamma oscillations, a dynamic feature observed throughout much of the brain with significant correlates to behavior and cognitive performance in a variety of experimental contexts. Our models depend on only a few dynamic variables per population, but despite this they qualitatively capture features observed in previous biophysical models of gamma oscillations that involve many individual spiking units.


Colloidal suspensions in one-phase mixed solvents under shear flow.
We numerically studied the behaviour of colloidal suspensions in one-phase binary liquid mixtures under shear flows. Far from the phase-separation point, the colloidal particles are well dispersed and the suspension exhibits a Newtonian viscosity. When the mixture is close to the coexistence curve, the colloidal particles aggregate by attractive interactions due to the concentration heterogeneity caused by surface wetting, and the viscosity of the suspension increases. Near the phase-separation point, the viscosity increases when the fraction of species favoured by the surface of a colloid particle is small. The mixture also exhibits shear thinning behaviour, since the aggregated structure is rearranged into small clusters due to the shear flow. Our simulations indicate that the concentration profile around each particle is not significantly disturbed by the shear flow at the onset of the structural rearrangements. The effective interaction is independent of the shear flow and remains isotropic.


The Effectiveness of the Latarjet Procedure in Patients with Chronic Locked Anterior Shoulder Dislocation: A Retrospective Study.
Chronic locked anterior shoulder dislocation is a difficult clinical problem for patients and surgeons. Prior studies have proposed a variety of surgical techniques to address this problem; however, the failure rate is high. To our knowledge, there have been no previously published studies on the clinical outcome of the Latarjet procedure for the treatment of chronic locked anterior shoulder dislocation. The purpose of this study was to evaluate the short-term subjective, objective, and radiographic outcomes of patients with chronic locked anterior shoulder dislocation after a Latarjet procedure. From January 2005 to January 2013, 43 patients with chronic locked anterior shoulder dislocation were treated surgically in our institution. Open Latarjet procedures were performed in 35 patients. A subscapularis tenotomy or split was chosen on the basis of the ability to achieve open reduction. Outcomes were assessed preoperatively and postoperatively with the American Shoulder and Elbow Surgeons (ASES) score, the visual analog scale (VAS) for pain, the University of California Los Angeles (UCLA) shoulder rating scale, and the Constant-Murley rating scale. A comparison of the clinical outcomes among the patients who underwent subscapularis tenotomy and repair, those who underwent a procedure that used the subscapularis-splitting technique, and those who underwent a concomitant humeral head replacement was performed. Twenty-five shoulders of 25 patients were available for a mean follow-up of 31.6 months. At the time of the latest follow-up, the range of motion and the shoulder functional evaluations (VAS [p = 0.02], ASES [p = 0.01], Constant score [p = 0.01], and UCLA score [p = 0.04]) were significantly improved. The overall redislocation or subluxation rate was 48% (12 of 25): 0% (0 of 5) for the subscapularis-splitting group, 53% (8 of 15) for the subscapularis tenotomy and repair group, and 80% (4 of 5) for the humeral head replacement group. The ASES score (p = 0.006), UCLA score (p = 0.014), Constant score (p = 0.046), and external rotation (p = 0.048) were significantly better, and less severe glenohumeral osteoarthritis was found in patients who had undergone a Latarjet procedure with subscapularis-splitting compared with those who had undergone subscapularis tenotomy and repair. The Latarjet procedure for the treatment of chronic locked anterior shoulder dislocation can be successful if the shoulder reduction can be performed without requiring a subscapularis tenotomy. If this reduction is not possible, then other surgical reconstruction should be considered. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Immune responses to abacavir in antigen-presenting cells from hypersensitive patients.
A potentially life-threatening hypersensitive reaction accompanies the use of HIV nucleoside analogue abacavir (ABC) in 4-8% of Caucasian individuals. HLA-B*5701 and Hsp70 493T alleles have been shown to predict susceptibility to this hypersensitivity. This study was undertaken to provide a mechanistic understanding of the highly significant genetic association of HLA Class I and Hsp70 alleles with ABC hypersensitivity. In this study an ABC-induced localization of intracellular HSP70 to endosomal vesicles of antigen-presenting cells was demonstrated. This ABC-stimulated redistribution of endogenous HSP70 was substantially higher in the genetically homogenous HLA-B*5701, Hsp70 493T ABC-hypersensitive individuals and ABC-naive individuals in comparison with the heterogeneous tolerant patients (P = 0.023). Increased expression of HSP70 was also detected in the hypersensitive group as measured by flow cytometry (P = 0.032). Blocking of HSP70 and HSP70 cell surface receptors CD14 and TLR2 abrogated ABC-stimulated HSP70 redistribution in sensitized individuals to basal levels (P < 0.004). In addition, the use of TcRalphabeta and HLA-B57/58 antibodies also ablated the expression of HSP70. Cells expressing the activation markers CD40 were increased after ABC stimulation in the hypersensitive patients (P = 0.006). ABC-stimulated interferon-gamma levels were higher in hypersensitive patients in comparison with ABC-tolerant individuals with a mean of 123.54 versus 0 pg/ml (P = 0.001). The present data indicates that ABC stimulates an innate immune response and activates antigen-presenting cells via the endogenous HSP70-mediated Toll-like receptor pathway in genetically susceptible individuals potentially initiating the immuno-pathological hypersensitive response.


Influence of carbohydrate, intense exercise, and rest intervals on hormonal and oxidative changes.
This study compared effects of carbohydrate (CHO) and rest on oxidative stress during exercise. Cyclists (N = 12) completed 4 randomized trials at 64% Wattsmax under 2 conditions (continuous cycling for 2 h [C] and cycling with 3-min rest every 10 min for 2.6 h [R]). Subjects cycled under each condition while receiving 6% CHO and placebo (PLA). CHO and PLA were given preexercise (12 mL/kg) and during exercise (4 mL x kg(-1) x 15 min(-1)). Blood was collected preexercise, postexercise, and 1 h postexercise and assayed for F2-isoprostanes, hydroperoxides (LH), nitrite, antioxidant capacity, glucose, insulin, cortisol, and epinephrine. F2-isoprostanes and LH were lower in CHO. Glucose, cortisol, and epinephrine exhibited significant effects, with postexercise levels of glucose higher and cortisol and epinephrine lower in CHO during the R condition. This pattern was identical in the C condition (21). Oxidative stress during cycling was unaffected by use of short rest intervals but was diminished by CHO.


Discordant Dose-Dependent Metabolic Effects of Eicosapentanoic Acid in Diet-Induced Obese Mice.
Obesity is a widespread epidemic that increases the risk for several metabolic diseases. Despite several beneficial health effects of eicosapentaenoic acid (C20:5n-3, EPA), previous studies have used very high doses of EPA. In this study, dose-dependent effects of EPA on metabolic outcomes were determined in diet-induced obese mice. We used B6 male mice, fed high-fat diet (HF, 45% kcal fat) or HF diet supplemented with 9, 18, and 36 g/kg of EPA-enriched fish oil for 14 weeks. We conducted metabolic phenotyping during the feeding period, and harvested tissues and blood at termination. Only mice fed 36 g/kg of EPA significantly (p < 0.05) lowered body weight, fat content and epididymal fat pad weight, compared to HF. Both 18 and 36 g/kg doses of EPA significantly increased glucose clearance and insulin sensitivity, compared to HF or 9 g/kg of EPA. Locomotor activity was significantly increased with both 18 and 36 g/kg doses of EPA. Interestingly, all doses of EPA compared to HF, significantly increased energy expenditure and oxygen consumption and significantly reduced serum insulin, leptin, and triglycerides levels. These results demonstrate weight- and adiposity-independent metabolic benefits of EPA, at doses comparable to those currently used to treat hypertriglyceridemia.