Divergent responses of Atlantic coastal and oceanic Synechococcus to iron limitation.
Marine Synechococcus are some of the most diverse and ubiquitous phytoplankton, and iron (Fe) is an essential micronutrient that limits productivity in many parts of the ocean. To investigate how coastal and oceanic Atlantic Synechococcus strains acclimate to Fe availability, we compared the growth, photophysiology, and quantitative proteomics of two Synechococcus strains from different Fe regimes. Synechococcus strain WH8102, from a region in the southern Sargasso Sea that receives substantial dust deposition, showed impaired growth and photophysiology as Fe declined, yet used few acclimation responses. Coastal WH8020, from the dynamic, seasonally variable New England shelf, displayed a multitiered, hierarchical cascade of acclimation responses with different Fe thresholds. The multitiered response included changes in Fe acquisition, storage, and photosynthetic proteins, substitution of flavodoxin for ferredoxin, and modified photophysiology, all while maintaining remarkably stable growth rates over a range of Fe concentrations. Modulation of two distinct ferric uptake regulator (Fur) proteins that coincided with the multitiered proteome response was found, implying the coastal strain has different regulatory threshold responses to low Fe availability. Low nitrogen (N) and phosphorus (P) availability in the open ocean may favor the loss of Fe response genes when Fe availability is consistent over time, whereas these genes are retained in dynamic environments where Fe availability fluctuates and N and P are more abundant.


Intramolecular telomeric G-quadruplexes dramatically inhibit DNA synthesis by replicative and translesion polymerases, revealing their potential to lead to genetic change.
Recent research indicates that hundreds of thousands of G-rich sequences within the human genome have the potential to form secondary structures known as G-quadruplexes. Telomeric regions, consisting of long arrays of TTAGGG/AATCCC repeats, are among the most likely areas in which these structures might form. Since G-quadruplexes assemble from certain G-rich single-stranded sequences, they might arise when duplex DNA is unwound such as during replication. Coincidentally, these bulky structures when present in the DNA template might also hinder the action of DNA polymerases. In this study, single-stranded telomeric templates with the potential to form G-quadruplexes were examined for their effects on a variety of replicative and translesion DNA polymerases from humans and lower organisms. Our results demonstrate that single-stranded templates containing four telomeric GGG runs fold into intramolecular G-quadruplex structures. These intramolecular G quadruplexes are somewhat dynamic in nature and stabilized by increasing KCl concentrations and decreasing temperatures. Furthermore, the presence of these intramolecular G-quadruplexes in the template dramatically inhibits DNA synthesis by various DNA polymerases, including the human polymerase δ employed during lagging strand replication of G-rich telomeric strands and several human translesion DNA polymerases potentially recruited to sites of replication blockage. Notably, misincorporation of nucleotides is observed when certain translesion polymerases are employed on substrates containing intramolecular G-quadruplexes, as is extension of the resulting mismatched base pairs upon dynamic unfolding of this secondary structure. These findings reveal the potential for blockage of DNA replication and genetic changes related to sequences capable of forming intramolecular G-quadruplexes.


Prevalence of tuberculosis infection among patients with Takayasu arteritis: a meta-analysis of observational studies.
To clarify the risk of tuberculosis (TB) infection in patients with Takayasu arteritis (TAK). In this study, we conducted a comprehensive search across multiple databases, including PubMed, Web of Science, Embase, Cochrane, and Medline, from the inception of the Literature Library to May 16, 2023. Using a specific set of keywords, including "Takayasu Arteritis", "Tuberculosis", and "Mycobacterium tuberculosis", the main objective of this search was to identify all relevant observational studies, including case-control studies, cohort studies, and cross-sectional studies, that report the prevalence of TB in individuals diagnosed with TAK. Two independent evaluators rigorously screened the studies, extracted data, and assessed the study quality using the Joanna Briggs Institute (JBI) critical appraisal tools. Statistical analyses were conducted using R software version 4.3.0, which allowed for the synthesis of prevalence and subgroup analyses. Subgroup analyses were stratified based on quality scores, World Health Organization regional categorizations, and TB categories. Assessment of publication bias was performed using a funnel plot. The study included a total of 30 studies with 5548 participants. The findings showed that individuals with TAK exhibited an average prevalence of TB infection at 31.27% (95% CI 20.48-43.11%). Significantly, the prevalence of TB infection demonstrated notable regional disparities, ranging from 16.93% (95% CI 7.71-28.76%) in the Western Pacific Region to 63.58% (95% CI 35.70-87.66%) in the African Region. Moreover, the study revealed that patients with TAK displayed a high prevalence of latent TB infection (LTBI) at 50.01% (95% CI 31.25-68.77%) and active TB at 14.40% (95% CI 9.03-20.68%). The high heterogeneity observed in the data highlights significant variability in TB infection rates among the populations studied, with the African Region exhibiting the highest rates. The study concludes that there is a high prevalence of TB infection in the TAK population, with regional variations. Consideration should be given to implementing rigorous TB screening measures and preventive interventions specifically tailored for the TAK population.


Boilerbaisse: an outbreak of methemoglobinemia in New Jersey in 1992.
On October 20, 1992, > 40 children from one elementary school visited the school nurse due to the acute onset of blue lips and hands, vomiting, and headache during and after the school lunch periods. Forty-nine children were seen by physicians that day and 14 were hospitalized. Laboratory analysis revealed methemoglobinemia in many of the children. All recovered in 36 hours. A case-control study was supplemented by environmental and laboratory investigations to determine the outbreak source. Cases were selected based on the laboratory diagnosis of methemoglobinemia (methemoglobin level > 2%). Children whose methemoglobin levels were missing or < 2% were excluded from analysis. Controls were obtained by selecting every third name from a school roster. The parents of 29 students who met the case definition and 52 controls were interviewed. All 29 cases and 33% (17/52) of the controls ate soup during the school lunch (odds ratio undefined, lower 95% confidence limit 16.1). Two pots of soup were prepared from ready-to-serve cans, which were diluted with water and enriched with a commercially prepared flavor enhancer. The school's boiler, dormant during the previous 5 months, was restarted on the morning of the outbreak. The boiler also served as a tankless hot water heater. Laboratory analysis of the soup identified abnormally high quantities of nitrite (459 ppm) and sodium metaborate, major components of the boiler water treatment solution. Undiluted soup from the same lot had 2.0 ppm nitrites; the flavor enhancer had 2.2 ppm nitrites. Nitrites were present in the hot potable water system (4 to 10 ppm) and absent in the cold potable water system. This outbreak of methemoglobinemia due to nitrite poisoning was traced to soup contaminated by nitrites in a boiler additive. Nitrites are ubiquitous and potentially hazardous inorganic ions. Extreme caution should be used when the possibility for toxic human exposure to nitrites exists.


Proteasome dysfunction mediates obesity-induced endoplasmic reticulum stress and insulin resistance in the liver.
Chronic endoplasmic reticulum (ER) stress is a major contributor to obesity-induced insulin resistance in the liver. However, the molecular link between obesity and ER stress remains to be identified. Proteasomes are important multicatalytic enzyme complexes that degrade misfolded and oxidized proteins. Here, we report that both mouse models of obesity and diabetes and proteasome activator (PA)28-null mice showed 30-40% reduction in proteasome activity and accumulation of polyubiquitinated proteins in the liver. PA28-null mice also showed hepatic steatosis, decreased hepatic insulin signaling, and increased hepatic glucose production. The link between proteasome dysfunction and hepatic insulin resistance involves ER stress leading to hyperactivation of c-Jun NH₂-terminal kinase in the liver. Administration of a chemical chaperone, phenylbutyric acid (PBA), partially rescued the phenotypes of PA28-null mice. To confirm part of the results obtained from in vivo experiments, we pretreated rat hepatoma-derived H4IIEC3 cells with bortezomib, a selective inhibitor of the 26S proteasome. Bortezomib causes ER stress and insulin resistance in vitro--responses that are partly blocked by PBA. Taken together, our data suggest that proteasome dysfunction mediates obesity-induced ER stress, leading to insulin resistance in the liver.


Hip Arthroscopy: extra-articular Procedures.
Hip preservation is one of the fastest growing fields in orthopaedics and indications of intra-articular procedures are well established. In the last decade, extra-articular procedures have gained momentum and arthroscopic solutions to peri-articular hip pathologies have been offered. It should be noted that many of these pathologies are well-treated conservatively and only those who fail conservative management should be treated operatively. These indications can be divided into 5 categories: greater trochanteric pain syndrome; internal hip snapping; anterior inferior iliac spine/sub-spine impingement; sciatic nerve entrapment; and proximal hamstring injuries. This article reviews the anatomy, patient history and physical examination, imaging, non-operative treatment, endoscopic operative treatment and outcomes of each category. While indications for hip arthroscopy, specifically extra-articular procedures, are rising steadily, there is not enough data to support its superiority over open procedures. Current literature consists of case studies, case reports, and expert opinions and lacks large, randomised control studies.


Nutrition care quality indicators in hospitals and nursing homes: A systematic literature review and critical appraisal of current evidence.
Quality indicators (QIs) can be used to assess and improve the quality of care in health care institutions. Although QIs about nutrition care in hospitals and nursing homes have been used in studies, no systematic catalogue exists to date. This systematic literature review identifies nutrition care QIs in hospitals and nursing homes and maps them according to QI type, stakeholder level and nutrition care theme. We also assess the level of consensus between studies and critically appraise the QIs presented therein based on two conceptual frameworks. Ovid, Scopus and grey literature were searched from 1995 to 2016 including studies in English and German. Papers were considered if they presented, developed, assessed, rated or applied nutrition care QIs in hospitals or nursing homes. We used Donabedian's framework to define structure, process and outcome indicators, the WHO (World Health Organization) definition to describe stakeholder levels, and a structured table to map indicators within themes. Further, we used the Institute of Medicine (IOM) and the Organisation for Economic Cooperation and Development (OECD) frameworks' key dimensions to measure the conceptual quality of the QIs. Results are summarised and presented tabulated and narratively. From 536 identified studies, 46 were included. Eight hundred and twenty-two QIs were extracted and mapped into 19 themes and 151 sub-themes. Half were process indicators (49%) and about a quarter were outcome (28%) and structure (23%) indicators, respectively. The vast majority (71%) targeted micro level, while 28% meso level and only 1% macro level information. The nutrition themes meals/mealtimes (12%), treatment (adherence) (12%), nutrition screening (7%), assessment (7%) and monitoring (7%) were most frequently covered. 69% of indicators were cited by more than one study. Most frequent framework dimensions were patient-centeredness (33%), timeliness (30%), validity (30%) and actionability/feasibility (30%). The large number of nutrition care QIs in hospitals and nursing homes indicates the high interest in and importance of better nutrition care provision in institutions. However, the great variability indicates little consensus of the nutrition community on how to best assess and measure the quality of nutrition care. The limited methodological and conceptual validity of presented QIs and the low representation of QIs at macro and meso levels make international consensus finding complicated. Increased efforts including all stakeholder levels and using conceptual frameworks to define a limited number of key QIs with high methodological validity, actionability and stakeholder relevance are needed. Registration in clinicaltrials.gov: Identifier: NCT02820246.


Dynamic visual noise reduces confidence in short-term memory for visual information.
Previous research has shown effects of the visual interference technique, dynamic visual noise (DVN), on visual imagery, but not on visual short-term memory, unless retention of precise visual detail is required. This study tested the prediction that DVN does also affect retention of gross visual information, specifically by reducing confidence. Participants performed a matrix pattern memory task with three retention interval interference conditions (DVN, static visual noise and no interference control) that varied from trial to trial. At recall, participants indicated whether or not they were sure of their responses. As in previous research, DVN did not impair recall accuracy or latency on the task, but it did reduce recall confidence relative to static visual noise and no interference. We conclude that DVN does distort visual representations in short-term memory, but standard coarse-grained recall measures are insensitive to these distortions.


NTP Toxicology and Carcinogenesis Studies of Benzyl Alcohol (CAS No. 100-51-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Toxicology and carcinogenesis studies of technical-grade benzyl alcohol (99% pure), a textile dye additive, solvent, and food flavoring agent, were conducted by administering the chemical by gavage in corn oil vehicle to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Short-Term Studies: In 16-day studies, all five male and five female rats and mice dosed with 2,000 mg/kg benzyl alcohol died. Two of five male and 3/5 female rats and 1/5 male and 2/5 female mice dosed with 1,000 mg/kg died. Rats and mice of each sex in the two highest dose groups were lethargic after dosing. Other toxic responses to benzyl alcohol in these dose groups included blood around the mouth and nose, subcutaneous hemorrhages, and blood in the urinary and gastrointestinal tracts of rats and blood in the urinary bladder of mice. Animals administered lower doses of benzyl alcohol (125, 250, or 500 mg/kg) had no compound-related histologic lesions. Doses selected for the 13-week studies were 0, 50, 100, 200, 400, and 800 mg/kg for rats and mice. Eight of 10 male rats dosed with 800 mg/kg died during weeks 7 and 8; four of these deaths were described as gavage related. Rats dosed with 800 mg/kg exhibited clinical signs indicative of neurotoxicity including staggering, respiratory difficulty, and lethargy. Hemorrhages occurred around the mouth and nose, and there were histologic lesions in the brain, thymus, skeletal muscle, and kidney. In mice, deaths were scattered among all dose levels, but none occurred in vehicle controls. Four male and six female mice died after being dosed; all deaths but one were described as gavage related. Staggering after dosing also occurred during the first 2 weeks of the studies in mice dosed with 800 mg/kg. Some of the deaths in the rats and mice may have been caused by a combination of the gavage procedure and chemical toxicity, since there was evidence that benzyl alcohol induced neurotoxic effects. There were reductions in relative weight gain in male rats dosed with 800 mg/kg benzyl alcohol, in female rats dosed with 200 mg/kg or more, in male mice dosed with 400 or 800 mg/kg, and in female mice dosed with 200 mg/kg or more. No notable changes in body weight gain or compound-related histopathologic lesions were observed in rats or mice from the lower dose groups. Based on mortality, reduction in relative body weight gain, and the histopathologic lesions, doses selected for 2-year studies in rats were 0, 200, and 400 mg/kg. Doses selected for 2-year studies in mice were 0, 100, and 200 mg/kg, based on mortality and depression in relative body weight gain. Body Weight and Survival in the Two-Year Studies: Fifty animals of each species and sex were administered benzyl alcohol in corn oil by gavage 5 days per week for 103 weeks. Administration of benzyl alcohol did not affect survival in male rats (final survival rates: vehicle control, 28/50; low dose, 27/50; high dose, 24/50) but reduced survival of dosed female rats by half (36/50; 18/50; 17/50). Many of the early deaths were considered related to the gavage procedure. Survival in mice was not affected by benzyl alcohol administration (male: 34/50; 33/50; 35/50; female: 26/50; 32/50; 36/50). No effect of benzyl alcohol on body weight gain in rats or mice was observed. In the third month of the studies, clinical signs of sialodacryoadenitis virus infection were observed in rats. A positive serologic reaction for rat coronavirus was observed in sentinel animals at 6 months and again at 18 months. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: No apparent compound-related nonneoplastic responses were observed. Dose-related negative trends in the incidences of anterior pituitary gland neoplasms were seen in female rats (vehicle control, 29/50; low dose, 17/47; high dose, 9/49) and of harderian gland adenomas in male mice (8/50; 3/50; 2/50). Adenomas of the adrenal cortex occurred at an increased incidence in high dose male mice (0/48; 0/44; 3/48), but this slight increase was not considered to be related to chemical expcal exposure. Genetic Toxicology: Benzyl alcohol was not mutagenic when tested by the preincubational protocol in the presence or absence of exogenous metabolic activation in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537. In the mouse L5178Y/TK± lymphoma assay, benzyl alcohol induced an increase in trifluorothymidine (Tft)-resistant cells in the absence, but not in the presence, of S9; the effect was associated with toxicity. In cytogenetic assays with Chinese hamster ovary (CHO) cells, treatment with benzyl alcohol produced an increase in sister chromatid exchanges (SCEs) which was judged to be equivocal both with and without S9; a significant increase in chromosomal aberrations was observed after exposure to benzyl alcohol in the presence, but not the absence, of S9. Audit: The data, documents, and pathology materials from the 2-year studies of benzyl alcohol have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of benzyl alcohol for male or female F344/N rats dosed with 200 or 400 mg/kg. Survival in both dose groups of female rats was 50% that of vehicle controls, primarily due to an increased number of gavage-related deaths. There was no evidence of carcinogenic activity of benzyl alcohol for male or female B6C3F1 mice dosed with 100 or 200 mg/kg for 2 years. Synonyms: benzenemethanol; phenylcarbinol; phenylmethanol; a-hydroxytoluene; benzenecarbinol; phenolcarbinol; a-toluenol


ARACNE: an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context.
Elucidating gene regulatory networks is crucial for understanding normal cell physiology and complex pathologic phenotypes. Existing computational methods for the genome-wide "reverse engineering" of such networks have been successful only for lower eukaryotes with simple genomes. Here we present ARACNE, a novel algorithm, using microarray expression profiles, specifically designed to scale up to the complexity of regulatory networks in mammalian cells, yet general enough to address a wider range of network deconvolution problems. This method uses an information theoretic approach to eliminate the majority of indirect interactions inferred by co-expression methods. We prove that ARACNE reconstructs the network exactly (asymptotically) if the effect of loops in the network topology is negligible, and we show that the algorithm works well in practice, even in the presence of numerous loops and complex topologies. We assess ARACNE's ability to reconstruct transcriptional regulatory networks using both a realistic synthetic dataset and a microarray dataset from human B cells. On synthetic datasets ARACNE achieves very low error rates and outperforms established methods, such as Relevance Networks and Bayesian Networks. Application to the deconvolution of genetic networks in human B cells demonstrates ARACNE's ability to infer validated transcriptional targets of the cMYC proto-oncogene. We also study the effects of misestimation of mutual information on network reconstruction, and show that algorithms based on mutual information ranking are more resilient to estimation errors. ARACNE shows promise in identifying direct transcriptional interactions in mammalian cellular networks, a problem that has challenged existing reverse engineering algorithms. This approach should enhance our ability to use microarray data to elucidate functional mechanisms that underlie cellular processes and to identify molecular targets of pharmacological compounds in mammalian cellular networks.


Incidence of pyramidal thyroid lobe in the university college hospital Ibadan.
The pyramidal lobe of the thyroid gland is derived from remnant of the thyroglossal duct. Its presence may be missed clinically; however radiologic and intra-operative findings reveal its presence in up to 50% of cases. The incidence of pyramidal lobe is however not clearly known in Sub-Saharan Africa, particularly in Nigeria. Our aim is to determine the incidence and histological variation of pyramidal lobe of the thyroid gland among surgical patients who underwent thyroid surgery in the University College Hospital, Ibadan. Consecutive surgical patients that underwent total thyroidectomy in the Endocrine Surgery Division, Department of Surgery, University College Hospital, Ibadan between April 2013 and April 2017 were recruited irrespective of age, sex and clinical diagnosis. The presence, anatomy and subsequent histological diagnosis of the pyramidal lobe were noted. One hundred sixty thyroid surgeries were done. Pyramidal lobe was found in 70 patients (44.0%). The presence of the pyramidal lobe was most often associated with multinodular goitres 42 (61.8%) and least found in thyroids with malignant tumours 3 (4.4%). The pyramidal lobe originated commonly from the midline (50.0%) and least from the right (10.3%). The length of the pyramidal lobes ranged from 8 to 80 mm (average 50 mm) in males and 5 to 54 mm (average 42 mm) in females. The presence of a pyramidal lobe is not uncommon in people of southwestern Nigeria with its morphologic and histologic profile akin to what obtains in other geographical locations of the world.


Discriminative analysis of schizophrenia using support vector machine and recursive feature elimination on structural MRI images.
Structural abnormalities in schizophrenia (SZ) patients have been well documented with structural magnetic resonance imaging (MRI) data using voxel-based morphometry (VBM) and region of interest (ROI) analyses. However, these analyses can only detect group-wise differences and thus, have a poor predictive value for individuals. In the present study, we applied a machine learning method that combined support vector machine (SVM) with recursive feature elimination (RFE) to discriminate SZ patients from normal controls (NCs) using their structural MRI data. We first employed both VBM and ROI analyses to compare gray matter volume (GMV) and white matter volume (WMV) between 41 SZ patients and 42 age- and sex-matched NCs. The method of SVM combined with RFE was used to discriminate SZ patients from NCs using significant between-group differences in both GMV and WMV as input features. We found that SZ patients showed GM and WM abnormalities in several brain structures primarily involved in the emotion, memory, and visual systems. An SVM with a RFE classifier using the significant structural abnormalities identified by the VBM analysis as input features achieved the best performance (an accuracy of 88.4%, a sensitivity of 91.9%, and a specificity of 84.4%) in the discriminative analyses of SZ patients. These results suggested that distinct neuroanatomical profiles associated with SZ patients might provide a potential biomarker for disease diagnosis, and machine-learning methods can reveal neurobiological mechanisms in psychiatric diseases.


Parallel sequencing of porA reveals a complex pattern of Campylobacter genotypes that differs between broiler and broiler breeder chickens.
Chicken meat represents an important source of Campylobacter infections of humans world-wide. A better understanding of Campylobacter epidemiology in commercial chicken flocks will facilitate the development of more effective intervention strategies. We developed a gene-specific parallel sequencing approach that efficiently indicated genetic diversity in farm-derived samples and revealed Campylobacter genotypes that would not be detected using microbiological culture. Parallel sequencing of the porA nucleotide fragment identified a different pattern of diversity in broiler flocks compared with broiler-breeder flocks at both individual bird and flock levels. Amongst the flocks tested, broiler flocks and individual birds were dominated by one or two porA fragment types whereas co-dominance with up to six porA fragment types was evident in breeder birds. A high proportion (83.6-93.3%) of porA variants were shared between broiler and breeder flocks. The porA-based diversity profiling could be a useful addition to the repertoire of tools employed to attribute potential sources of contamination for broiler flocks, including the environment, wild animals or other chickens. This approach can be extended to include other loci within Campylobacter and developed for molecular epidemiology studies of other bacterial species.


Circulating D-dimers as a marker of disease activity in pulmonary sarcoidosis.
The search is on to find an easily measurable marker of disease activity in sarcoidosis. The present study was carried out to evaluate the utility of plasma D-dimer as a marker of disease activity in sarcoidosis. Thirty newly diagnosed cases of sarcoidosis with clinical indications for treatment and an equal number of matched healthy controls were studied for the presence of D-dimers (DD) in the plasma before starting treatment with oral prednisolone and after clinical remission. Semi-quantitative estimations of DD were done using the latex agglutination slide test method (Commercial Kit - Diagnostica Stago, France) as per the manufacturer's recommendations. The mean age of cases and controls were 45.43 +/- 8.5 (range 34-60) and 46.16 +/- 8.07 (range 32-61) years, respectively. Of the 30 patients, nine (30%) were DD positive at baseline. The DD positive patients presented more often with dyspnoea, had radiological stage III (7 out of 9) disease and abnormal spirometry compared to patients with no detectable DD in their plasma. Of the 16 patients re-evaluated after clinical remission, eight (50%) were D-dimer positive. Two of the five patients initially DD positive had become negative and five additional patients who were negative at baseline had become positive. Plasma D-dimers, which were positive in 30% of untreated patients of sarcoidosis, indicate patients with significant pulmonary parenchymal involvement; but have no correlation with clinical disease remission.


Plasma gelsolin is decreased and correlates with rate of decline in Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder where definite diagnosis can only be made postmortem, and for which the most promising peripheral markers of disease state and severity have been found in the cerebrospinal fluid. However, recent results suggest that differences in the levels of certain plasma proteins do exist between AD patients and non-demented controls (NDC). Herein, we undertook an untargeted discovery study using isobaric mass tagging to compare the plasma protein levels between slow cognitive declining AD patients, rapid cognitive declining AD patients (RCD) and NDC subjects. Subsequent relative quantification and statistical analysis identified a list of candidate proteins able to distinguish RCD from NDC groups based on multivariate analysis. Selected proteins were then validated by western blot analysis in an independent sample set of 60 AD and 35 NDC subjects. In this cohort, AD patients displayed significantly lower plasma gelsolin levels compared to NDC subjects. Additionally, gelsolin levels correlated with disease progression rate estimated by Mini-Mental Status Examination decline per year. In order to further investigate gelsolin expression, three different brain regions from an additional cohort of 23 subjects and their respective plasma samples were analysed. No significant change in brain gelsolin levels could be established between AD and control subjects. Interestingly, this study reveals yet another condition where plasma gelsolin levels are decreased and our findings, together with the reported interaction of gelsolin and amyloid-beta, makes plasma gelsolin an attractive candidate for further studies targeted at better understanding disease progression in AD.


Seeing facial expressions enhances placebo analgesia.
The strength of the placebo effect is influenced by social contexts and individual personality. Although facial expressions provide important contextual cues, no study of their influence on the placebo response has been performed hitherto. Here we tested (1) whether the observation of facial expressions with different emotional content (Neutral, Pain, and Happy) affects the magnitude of placebo analgesia, and (2) whether interindividual differences in personality traits interact with any modulation of placebo response induced by facial expression. Twenty-seven healthy participants underwent classical placebo conditioning, and subsequently rated the intensity and unpleasantness of their pain experience associated with nociceptive-specific laser pulses delivered to the right hand dorsum. On each trial, different visual cues signalled the occurrence of a laser stimulus alone or of a laser stimulus accompanied by a sham analgesic treatment. In the conditioning period, cues signalling the sham treatment were followed by laser stimuli whose intensity was surreptitiously lowered. In the test period, either cue was followed by laser stimuli of the same intensity. The observation of facial expressions with different emotional content enhanced significantly the placebo analgesia. In particular, a significantly greater analgesic effect was observed when facial expressions with emotional content were presented concomitantly to the nociceptive stimulation. The enhancement of placebo analgesia during the observation of facial expressions was not correlated with personality traits like empathy and behavioural activation/inhibition. These findings quantify for the first time the effect of facial expressions on the magnitude of placebo analgesia.


Selective arterial spin labeling (SASL): perfusion territory mapping of selected feeding arteries tagged using two-dimensional radiofrequency pulses.
To date, most perfusion magnetic resonance imaging (MRI) methods using arterial spin labeling (ASL) have employed slab-selective inversion pulses or continuous labeling within a plane in order to obtain maps derived from all major blood vessels entering the brain. However, there is great potential for gaining additional information on the territories perfused by the major vessels if individual feeding arteries could be tagged. This study demonstrates noninvasive arterial perfusion territory maps obtained using two-dimensional (2D) selective inversion pulses. This method is designated "selective ASL" (SASL). The SASL method was used to tag the major arteries below the circle of Willis. A combination of 2D selective tagging and multislice readout allows perfusion territories to be clearly visualized, with likely applications to cerebrovascular disease and stroke.


Effects of the structurally novel opioid 14 alpha, 14' beta-[dithiobis [(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydromorphinone) on schedule-controlled behavior and thermal nociception in rhesus monkeys.
The in vivo pharmacology of the structurally novel opioid 14 alpha, 14' beta-[dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydromorphinon e) (TAMO) was examined in rhesus monkeys with assays of schedule-controlled behavior and thermal nociception. TAMO (0.032-1.8 mg/kg) produced dose-dependent decreases in response rates maintained under a fixed-ratio 30 schedule of food delivery (n = 3) and increases in tail-withdrawal latencies in a warm-water tail-withdrawal procedure (n = 3). Both the rate-decreasing and antinociceptive effects of TAMO (1.0 mg/kg) were maximal after 40 to 80 min and lasted at least 160 min. Pretreatment with the mu-selective opioid antagonist quadazocine (0.001-0.1 mg/kg) antagonized the effects of TAMO and shifted the TAMO dose-effect curves to the right. Schild analysis yielded in vivo apparent pA2 values (mean +/- S.E.M.) of 8.8 +/- 0.072 and 8.7 +/- 0.40 for quadazocine antagonism of the rate-decreasing and antinociceptive effects, respectively, of TAMO, which suggests that the effects of TAMO were mediated by mu-opioid receptors. In addition, quadazocine (0.1-1.0 mg/kg) reversed the behavioral effects of TAMO (1.0 mg/kg) when quadazocine was administered immediately after TAMO had attained its maximal effect. Twenty-four-hour pretreatment with 1.0 mg/kg TAMO did not significantly after the rate-decreasing or antinociceptive effects of fentanyl or the rate-decreasing effects of morphine. The dose-effect curve for morphine antinociception was shifted 4-fold to the right 24 hr after pretreatment with 1.0 mg/kg TAMO. However, 24-hr pretreatment with an equiactive dose of morphine (10.0 mg/kg) also produced a small (2-fold) but significant rightward shift in the dose-effect curve for morphine antinociception. Twenty-four-hour pretreatment with 1.8 mg/kg TAMO had no effect on the antinociceptive effects of U69,593 (0.0032-0.1 mg/kg). These results suggest that TAMO acts as a reversible mu agonist with a relatively slow onset and a duration of action and relative efficacy similar to those of morphine in rhesus monkeys. Twenty-four hours after TAMO administration, the highest doses of TAMO that could be safely administered produced little or no mu antagonist effects and no kappa antagonist effects.


Involvement of the caudate nucleus head and its networks in sporadic amyotrophic lateral sclerosis-frontotemporal dementia continuum.
We investigated common structural and network changes across the sporadic amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD) continuum. Based on cluster analysis using the frontotemporal assessment battery, 51 patients with sporadic ALS were subdivided into three groups: 25 patients with ALS with cognitive deficiency (ALS-CD); seven patients who satisfied FTD criteria (ALS-FTD), and 19 patients with ALS with normal cognitive function (ALS-NC). Compared with the controls, gray matter images from patients with ALS-FTD showed atrophic changes in the following order of severity: caudate head, medial frontal gyrus, thalamus, amygdala, putamen, and cingulate gyrus (peak level, uncorrected p < 0.001). The caudate head was significant at the cluster level using FWE correction (p < 0.05). Diffusion tensor imaging with tract-based spatial statistics revealed white matter changes in the areas surrounding the caudate head, the internal capsule, and the anterior horn of the lateral ventricle in the ALS-CD and ALS-FTD. Probabilistic diffusion tractography showed a significant decrease in structural connectivity between the caudate head and the dorsomedial frontal cortex and the lateral orbitofrontal cortex, even in the ALS-NC. Our results indicated that the caudate head and its networks were the most vulnerable to lesion in sporadic ALS-FTD-spectrum patients associated with cognitive decline with FTD features.


Retrospective evaluation of circulating thyroid hormones in critically ill dogs with systemic inflammatory response syndrome.
Critical illness can be associated with transient alterations in circulating thyroid hormone concentrations, indicating the presence of non-thyroidal illness (NTI). NTI is well described in humans, but there are few reports on its occurrence and prognostic significance in dogs. This retrospective study assessed the occurrence of NTI in a population of dogs with systemic inflammatory response syndrome (SIRS) and investigated its association with disease severity (APPLEfast scores). A total of 41 SIRS dogs were included and were divided by SIRS origin (non-septic SIRS, n = 10; septic SIRS, n = 41) and final outcome (survivors, n = 37; non-survivors, n = 4). Healthy, age-matched dogs (n = 15) were included as controls. Serum thyroid hormone levels including total T3, free T3, total T4, and reverse T3 were measured upon admission. Compared to controls, there were significant changes in serum thyroid hormone concentrations in SIRS dogs, suggesting the presence of NTI. Septic SIRS dogs had higher APPLEfast scores and lower serum thyroid hormones concentrations than those in non-septic SIRS and control dogs. In conclusion, NTI was frequent in dogs with SIRS and may be associated with the presence of sepsis or high illness severity.


Retrieving seawater-backscattering profiles from coupling Raman and elastic lidar data.
We propose a technique for retrieving seawater-backscattering profiles that is based on the joint use of elastic and Raman lidar returns. We suggest using two lidar channels: the Raman channel and the elastic channel with a light frequency equal to a half-sum of initial and Raman-shifted frequencies of the Raman channel. These specific wavelengths provide the same attenuation laws for elastic and Raman signals if absorption and scattering spectra can be approximated by a power law. In particular, seawater supplies such a possibility in the region of 400-500 nm if extremely bioproductive waters are not considered and the chlorophyll absorption peak at 440 nm does not come out of the background of dissolved organic matter absorption. With these specific initial wavelengths, the elastic and Raman lidar returns differ only in the backscattering coefficients. Because the Raman-backscattering coefficient is constant along the profile, the (elastic-to-Raman) ratio of these lidar returns directly produces the profile of the elastic-backscattering coefficient. This technique stays valid even under multiple-scattering conditions, which is of great importance for seawater sounding.


Breast-feeding counselling in a diarrhoeal disease hospital.
Lactation counsellors were trained to advise mothers of partially breast-fed infants who were admitted to hospital because of diarrhoea, so that they could start exclusive breast-feeding during their hospital stay. Infants (n = 250) up to 12 weeks of age were randomized to intervention and control groups. Mothers in the intervention group were individually advised by the counsellors while mothers in the control group received only routine group health education. During follow-up at home by the counsellors a week later, only the mothers in the intervention group were counselled. All the mothers were evaluated for infant feeding practices at home two weeks after discharge. Among the 125 mother-infant pairs in each group, 60% of mothers in the intervention group were breast-feeding exclusively at discharge compared with only 6% in the control group (P < 0.001); two weeks later, these rates rose to 75% and 8% in the intervention and control groups, respectively (P < 0.001). However, 49% of mothers in the control group reverted back to bottle-feeding compared with 12% in the intervention group (P < 0.001). Thus, individual counselling had a positive impact on mothers to start exclusive breast-feeding during hospitalization and to continue the practice at home. Maternal and child health facilities should include lactation counselling as an integral part of their programme to improve infant feeding practices.


Why are Some Games More Addictive than Others: The Effects of Timing and Payoff on Perseverance in a Slot Machine Game.
Manipulating different behavioral characteristics of gambling games can potentially affect the extent to which individuals persevere at gambling, and their transition to problematic behaviors. This has potential impact for mobile gambling technologies and responsible gambling interventions. Two laboratory models pertinent to this are the partial reinforcement extinction effect (PREE) and the trial spacing effect. Both of these might speed up or delay the acquisition and extinction of conditioned behavior. We report an experiment that manipulated the rate of reinforcement and inter trial interval (ITI) on a simulated slot machine where participants were given the choice between gambling and skipping on each trial, before perseverative gambling was measured in extinction, followed by measurements of the illusion of control, depression and impulsivity. We hypothesized that longer ITI's in conjunction with the low rates of reinforcement observed in gambling would lead to greater perseverance. We further hypothesized, given that timing is known to be important in displaying illusory control and potentially in persevering in gambling, that prior exposure to longer intervals might affect illusions of control. An interaction between ITI and rate of reinforcement was observed, as low reinforced gamblers with a long ITI gambled for longer. Respondents also displayed extinction and a PREE. Gamblers exposed to a higher rate of reinforcement gambled for longer in acquisition. Impulsivity was associated with extended perseverance in extinction, and more depressed gamblers in the high reinforcement short ITI group persevered for longer. Performance in the contingency judgment failed to support the second hypothesis: the only significant contrast observed was that participants became better calibrated as the task progressed.


A stringent limit on a drifting proton-to-electron mass ratio from alcohol in the early universe.
The standard model of physics is built on the fundamental constants of nature, but it does not provide an explanation for their values, nor require their constancy over space and time. Here we set a limit on a possible cosmological variation of the proton-to-electron mass ratio μ by comparing transitions in methanol observed in the early universe with those measured in the laboratory. From radio-astronomical observations of PKS1830-211, we deduced a constraint of Δμ/μ = (0.0 ± 1.0) × 10(-7) at redshift z = 0.89, corresponding to a look-back time of 7 billion years. This is consistent with a null result.


Autocrine and paracrine regulation of human T cell IL-10 production.
We confirm that IL-10 is produced comparatively late after the activation of human T cells via CD3 stimulation, after IL-2 and IFN-gamma. Furthermore we show that IL-10 production by human T cell lines, such as IFN-gamma and IL-2, is inhibited by the immunosuppressive drugs cyclosporin A and FK506. However, a third immunosuppressive drug, rapamycin, normally associated with inhibiting the effects, but not the production, of cytokines, inhibited IL-10, but not IFN-gamma, production. This implies that IL-10 induction may be a secondary event in T cell activation. Since IL-2 is the major growth factor for T cells and is detected before IL-10, we focused on this factor as a potential activator of IL-10 production. We showed that IL-10 production by human T cell lines stimulated by immobilized anti-CD3 in the presence of neutralizing Abs to IL-2 and IL-2R (anti-CD25) was inhibited, whereas addition of exogenous IL-2 enhanced IL-10 production, indicating that IL-10 production by human T cells can be driven by stimulation via IL-2. As the IL-2R shares the common gamma-chain component with IL-4, IL-7, and IL-15, we investigated the possibility that they may all enhance anti-CD3-induced IL-10 production and established that this was the case. Since IL-10 has been previously described as a direct inhibitor of Ag presentation and of IL-2 production, our finding that IL-2 is capable of inducing its own inhibitor demonstrates a feedback mechanism within the immune system that could limit ongoing T cell activation and possibly inflammation.


Generation and characterization of a recombinant antibody fragment that binds to the coat protein of grapevine leafroll-associated virus 3.
Pathogen-specific recombinant antibodies have been used to characterize pathogen infections and to engineer resistance in crops. We selected a single-chain antibody fragment (scFvLR3cp-1) specific for the coat protein of grapevine leafroll-associated virus 3 (GLRaV-3), one of the agents of grapevine leafroll (GLR) disease, from a phage display library. The antibody binds specifically to the entire length of GLRaV-3 particles and has a high binding affinity value (K(D)) of 42 nM. The amino acid motif AQEPPRQ located at the N terminus of the GLRaV-3 coat protein was identified as the antibody-binding epitope by PEPSCAN analysis. To evaluate scFv stability in the reducing environment of the plant cell cytosol, transient expression assays were performed using Nicotiana benthamiana as a model plant. Capture ELISA demonstrated that the scFv fragment was produced and retained its antigen-binding capacity in the plant cytosol. Further functional assays showed that scFvLR3cp-1 binds with high specificity to at least four members of the family Closteroviridae. Therefore, the GLRaV-3-specific scFv fragment could be an ideal candidate for mediating broad-spectrum virus resistance if produced in transgenic grapevine plants.


Predictors of community women's osteoporosis prevention intention--a pilot study.
The main purpose of this pilot study was to identify the predictors of community women's osteoporosis prevention intention. The osteoporosis assessment scales were self-developed and contained 5 scales: a demographics scale, a health status scale, an osteoporosis health belief scale (OHBS), a knowledge scale, and a prevention intention scale. The content validity of the five scales ranged from.90 to 1.00. Test-retest was used to examine the reliability of the demographic characteristics scale and the health status scale, which ranged from.9 to 1.0. Meanwhile, the reliability coefficients of the OHBS comprising perceived susceptibility, perceived seriousness, perceived benefit, and perceived barrier were .75, .90, .80, and .72. In this pilot study, the coefficient of KR-20 for osteoporosis knowledge was .88. The value of Cronbach 's Coefficient Alpha for prevention intention was .85. The results of this research were : (1) The averaged scores of the OHBS comprising perceived susceptibility, perceived seriousness, perceived benefit, and perceived barrier were 2.8 (SD = 0.5), 2.2 (SD = 0.7), 1.9 (SD = 0.4), and 2.9 (SD = 0.7). Meanwhile, the averaged score for women's knowledge on osteoporosis was 10.0 (SD = 2.8). The averaged score for women's intentions for the prevention of osteoporosis was 2.5 (SD = 0.6). (2) There were some significant correlations between OHBS and demographics, health status, knowledge, and prevention intention. (3) Knowledge was positively correlated with perceived barriers, prevention intention, age, self-rated score for health, breast feeding time, and amount of calcium intake. (4) Prevention intention was positively correlated with knowledge, number of children, age of fracture, and hormone replacement therapy. (5) The major factors influencing intention for community women were, in order, knowledge, educational level (high school graduate), number of children (n = 2), self-rated health score, experience of bone density examination (yes), hormone replacement therapy (yes), and kyphosis (yes). These seven items accounted for 45.8% of the variation in intention. The results of this pilot study can help community health professionals evaluate, implement and improve community women's health beliefs regarding prevention of osteoporosis.


A review of current knowledge on toxic benthic freshwater cyanobacteria--ecology, toxin production and risk management.
Benthic cyanobacteria are found globally in plethora of environments. Although they have received less attention than their planktonic freshwater counterparts, it is now well established that they produce toxins and reports of their involvement in animal poisonings have increased markedly during the last decade. Most of the known cyanotoxins have been identified from benthic cyanobacteria including: the hepatotoxic microcystins, nodularins and cylindrospermopsins, the neurotoxic saxitoxins, anatoxin-a and homoanatoxin-a and dermatotoxins, such as lyngbyatoxin. In most countries, observations of toxic benthic cyanobacteria are fragmented, descriptive and in response to animal toxicosis events. Only a limited number of long-term studies have aimed to understand why benthic proliferations occur, and/or how toxin production is regulated. These studies have shown that benthic cyanobacterial blooms are commonly a mixture of toxic and non-toxic genotypes and that toxin concentrations can be highly variable spatially and temporally. Physiochemical parameters responsible for benthic proliferation vary among habitat type with physical disturbance (e.g., flow regimes, wave action) and nutrients commonly identified as important. As climatic conditions change and anthropogenic pressures on waterways increase, it seems likely that the prevalence of blooms of benthic cyanobacteria will increase. In this article we review current knowledge on benthic cyanobacteria: ecology, toxin-producing species, variables that regulate toxin production and bloom formation, their impact on aquatic and terrestrial organisms and current monitoring and management strategies. We suggest research needs that will assist in filling knowledge gaps and ultimately allow more robust monitoring and management protocols to be developed.


Interaction between satellite cells and skeletal muscle fibers.
Single myofibers with attached satellite cells isolated from adult rats were used to study the influence of the mature myofiber on the proliferation of satellite cells. The satellite cells remain quiescent when cultured in serum containing medium but proliferate when exposed to mitogen from an extract of crushed adult muscle. The response of satellite cells to mitogen was measured under three situations with respect to cell contact: (1) in contact with a viable myofiber and its basal lamina, (2) detached from the myofiber by centrifugal force and deposited on the substratum and (3) beneath the basal lamina of a Marcaine killed myofiber. The results show that satellite cells in contact with the plasmalemma of a viable myofiber have reduced mitogenic response. Since inhibiting growth may induce differentiation, I tested whether satellite cells proliferating on the surface of a myofiber would fuse. Although the satellite cell progeny were fusion competent, they did not fuse with the myofiber. To determine whether fusion competence of the myofiber changes with time in culture, embryonic myoblasts were challenged to fuse with myofibers that had been stripped of satellite cells and cultured for several days. The myoblasts fused with pseudopodial sprouts growing from the ends of the myofiber, but did not fuse with the original myofiber surface. These results indicate that contact with the surface of a mature myofiber suppresses proliferation of myogenic cells but the cells do not fuse with the myofiber.


Generation of the squamous epithelial roof of the 4th ventricle.
We use the transparency of zebrafish embryos to reveal the de novo generation of a simple squamous epithelium and identify the cellular architecture in the epithelial transition zone that ties this squamous epithelium to the columnar neuroepithelium within the embryo's brain. The simple squamous epithelium of the rhombencephalic roof plate is pioneered by distinct mesenchymal cells at the dorsal midline of the neural tube. Subsequently, a progenitor zone is established at the interface between columnar epithelium of the rhombic lip and the expanding squamous epithelium of the roof plate. Surprisingly, this interface consists of a single progenitor cell type that we have named the veil cell. Veil cells express gdf6a and constitute a lineage restricted stem zone that generates the squamous roof plate by direct transformation and asymmetrically fated divisions. Experimental restriction of roof plate expansion leads to extrusion of veil cell daughters and squamous cells, suggesting veil cell fate is regulated by the space available for roof plate growth.


Nanofocusing optics for synchrotron radiation made from polycrystalline diamond.
Diamond possesses many extreme properties that make it an ideal material for fabricating nanofocusing x-ray optics. Refractive lenses made from diamond are able to focus x-ray radiation with high efficiency but without compromising the brilliance of the beam. Electron-beam lithography and deep reactive-ion etching of silicon substrates have been used in a transfer-molding technique to fabricate diamond optics with vertical and smooth sidewalls. Latest generation compound refractive lenses have seen an improvement in the quality and uniformity of the optical structures, resulting in an increase in their focusing ability. Synchrotron beamline tests of two recent lens arrays, corresponding to two different diamond morphologies, are described. Focal line-widths down to 210 nm, using a nanocrystalline diamond lens array and a beam energy of E = 11 keV, and 230 nm, using a microcrystalline diamond lens at E = 15 keV, have been measured using the Diamond Light Source Ltd. B16 beamline. This focusing prowess is combined with relatively high transmission through the lenses compared with silicon refractive designs and other diffractive optics.


Research Review: The effectiveness of multidimensional family therapy in treating adolescents with multiple behavior problems - a meta-analysis.
Multidimensional family therapy (MDFT) is a well-established treatment for adolescents showing both substance abuse and/or antisocial behavior. The effectiveness of MDFT in reducing adolescents' substance abuse, delinquency, externalizing and internalizing psychopathology, and family malfunctioning was examined by means of a (three-level) meta-analysis, summarizing 61 effect sizes from 19 manuscripts (N = 1,488 participants). Compared with other therapies, the overall effect size of MDFT was significant, albeit small in magnitude (d = 0.24, p < .001), and similar across intervention outcome categories. Moderator analysis revealed that adolescents with high severity problems, including severe substance abuse and disruptive behavior disorder, benefited more from MDFT than adolescents with less severe conditions. It can be concluded that MDFT is effective for adolescents with substance abuse, delinquency, and comorbid behavior problems. Subsequently, it is important to match specific characteristics of the adolescents, such as extent of impairment, with MDFT.


Pilot Study of Propofol-induced Slow Waves as a Pharmacologic Test for Brain Dysfunction after Brain Injury.
Slow waves (less than 1 Hz) are the most important electroencephalogram signatures of nonrapid eye movement sleep. While considered to have a substantial importance in, for example, providing conditions for single-cell rest and preventing long-term neural damage, a disturbance in this neurophysiologic phenomenon is a potential indicator of brain dysfunction. Since, in healthy individuals, slow waves can be induced with anesthetics, the authors tested the possible association between hypoxic brain injury and slow-wave activity in comatose postcardiac arrest patients (n = 10) using controlled propofol exposure. The slow-wave activity was determined by calculating the low-frequency (less than 1 Hz) power of the electroencephalograms recorded approximately 48 h after cardiac arrest. To define the association between the slow waves and the potential brain injury, the patients' neurologic recovery was then followed up for 6 months. In the patients with good neurologic outcome (n = 6), the low-frequency power of electroencephalogram representing the slow-wave activity was found to substantially increase (mean ± SD, 190 ± 83%) due to the administration of propofol. By contrast, the patients with poor neurologic outcome (n = 4) were unable to generate propofol-induced slow waves. In this experimental pilot study, the comatose postcardiac arrest patients with poor neurologic outcome were unable to generate normal propofol-induced electroencephalographic slow-wave activity 48 h after cardiac arrest. The finding might offer potential for developing a pharmacologic test for prognostication of brain injury by measuring the electroencephalographic response to propofol.


Lower capillary density but no difference in VEGF expression in obese vs. lean young skeletal muscle in humans.
Obesity is associated with lower skeletal muscle capillarization and lower insulin sensitivity. Vascular endothelial growth factor (VEGF) is important for the maintenance of the skeletal muscle capillaries. To investigate whether VEGF and VEGF receptor [kinase insert domain-containing receptor (KDR) and Flt-1] expression are lower with obesity, vastus lateralis muscle biopsies were obtained from eight obese and eight lean young sedentary men before and 2 h after a 1-h submaximal aerobic exercise bout for the measurement of VEGF, KDR, Flt-1, and skeletal muscle fiber and capillary characteristics. There were no differences in VEGF or VEGF receptor mRNA at rest between lean and obese muscle. Exercise increased VEGF (10-fold), KDR (3-fold), and Flt-1 (5-fold) mRNA independent of group. There were no differences in VEGF, KDR, or Flt-1 protein between groups. Compared with lean skeletal muscle, the number of capillary contacts per fiber was the same, but lower capillary density (CD), greater muscle cross sectional area, and lower capillary-to-fiber area ratio were observed in both type I and II fibers in obese muscle. Multiple linear regression revealed that 49% of the variance in insulin sensitivity (homeostasis model assessment) could be explained by percentage of body fat (35%) and maximal oxygen uptake per kilogram of fat-free mass (14%). Linear regression revealed significant relationships between maximal oxygen uptake and both CD and capillary-to-fiber perimeter exchange. Although differences may exist in CD and capillary-to-fiber area ratio between lean and obese skeletal muscle, the present results provide evidence that VEGF and VEGF receptor expression are not different between lean and obese muscle.


Clinical outcome of leukemia patients with intracranial hemorrhage. Clinical article.
Intracranial hemorrhage (ICH) is a frequent complication found in leukemia patients with thrombocytopenia. At the University of Texas MD Anderson Cancer Center, when a leukemia patient is found to have ICH, a platelet transfusion is generally recommended until 50,000/μl is reached. The authors examine the feasibility and outcome of their intervention strategy in this study. Records were reviewed from 76 consecutive leukemia patients with newly diagnosed ICH at the University of Texas MD Anderson Cancer Center from January 1, 2007, to December 31, 2009. Variables of interest included age, platelet count at presentation, leukemia subtype, history of trauma, Glasgow Coma Scale score at presentation, whether the 50,000/μl goal was reached after transfusion, and whether the patient was a transfusion responder (platelet count increase > 2000/μl/unit transfused). Outcome parameters were mortality rates at 72 hours and 30 days and imaging-documented hemorrhage progression. Thrombocytopenia was prevalent at the time of presentation (68 of 76 patients had platelet levels < 50,000/μl at presentation). Despite an aggressive transfusion protocol, only 24 patients reached the 50,000/μl target after an average of 16 units of transfusion. Death due to ICH occurred in 15 patients within the first 72 hours (mortality rate 19.7%). Death correlated with the presenting Glasgow Coma Scale score (p = 0.0075) but not with other transfusion-related parameters. A significant mortality rate was again observed after 30 days (32.7%). The 30-day mortality rate, however, was largely attributable to non-ICH related causes and correlated with patient age (p = 0.032) and whether the patient was a transfusion responder (p = 0.022). Reaching and maintaining a platelet count > 50,000/μl did not positively correlate with the 30-day mortality rate (p = 0.392 and 0.475, respectively). Platelet transfusion in the setting of ICH in leukemia patients is undoubtedly necessary, but whether the transfusion threshold should be 50,000/μl remains unclear. Factors other than thrombocytopenia likely contribute to the overall poor prognosis.


Insights into EB1 structure and the role of its C-terminal domain for discriminating microtubule tips from the lattice.
End-binding proteins (EBs) comprise a conserved family of microtubule plus end-tracking proteins. The concerted action of calponin homology (CH), linker, and C-terminal domains of EBs is important for their autonomous microtubule tip tracking, regulation of microtubule dynamics, and recruitment of numerous partners to microtubule ends. Here we report the detailed structural and biochemical analysis of mammalian EBs. Small-angle X-ray scattering, electron microscopy, and chemical cross-linking in combination with mass spectrometry indicate that EBs are elongated molecules with two interacting CH domains, an arrangement reminiscent of that seen in other microtubule- and actin-binding proteins. Removal of the negatively charged C-terminal tail did not affect the overall conformation of EBs; however, it increased the dwell times of EBs on the microtubule lattice in microtubule tip-tracking reconstitution experiments. An even more stable association with the microtubule lattice was observed when the entire negatively charged C-terminal domain of EBs was replaced by a neutral coiled-coil motif. In contrast, the interaction of EBs with growing microtubule tips was not significantly affected by these C-terminal domain mutations. Our data indicate that long-range electrostatic repulsive interactions between the C-terminus and the microtubule lattice drive the specificity of EBs for growing microtubule ends.


A mechanism for the segregation of age in mammalian neural stem cells.
Throughout life, neural stem cells (NSCs) generate neurons in the mammalian brain. Using photobleaching experiments, we found that during cell division in vitro and within the developing mouse forebrain, NSCs generate a lateral diffusion barrier in the membrane of the endoplasmic reticulum, thereby promoting asymmetric segregation of cellular components. The diffusion barrier weakens with age and in response to impairment of lamin-associated nuclear envelope constituents. Weakening of the diffusion barrier disrupts asymmetric segregation of damaged proteins, a product of aging. Damaged proteins are asymmetrically inherited by the nonstem daughter cell in embryonic and young adult NSC divisions, whereas in the older adult brain, damaged proteins are more symmetrically distributed between progeny. Thus, these data identify a mechanism of how damage that accumulates with age is asymmetrically distributed during somatic stem cell division.


Explaining differential vulnerability to climate change: A social science review.
The varied effects of recent extreme weather events around the world exemplify the uneven impacts of climate change on populations, even within relatively small geographic regions. Differential human vulnerability to environmental hazards results from a range of social, economic, historical, and political factors, all of which operate at multiple scales. While adaptation to climate change has been the dominant focus of policy and research agendas, it is essential to ask as well why some communities and peoples are disproportionately exposed to and affected by climate threats. The cases and synthesis presented here are organized around four key themes (resource access, governance, culture, and knowledge), which we approach from four social science fields (cultural anthropology, archaeology, human geography, and sociology). Social scientific approaches to human vulnerability draw vital attention to the root causes of climate change threats and the reasons that people are forced to adapt to them. Because vulnerability is a multidimensional process rather than an unchanging state, a dynamic social approach to vulnerability is most likely to improve mitigation and adaptation planning efforts. This article is categorized under:Vulnerability and Adaptation to Climate Change > Values-Based Approach to Vulnerability and Adaptation.


The kinesin-like protein CENP-E is kinetochore-associated throughout poleward chromosome segregation during anaphase-A.
The kinesin-like protein CENP-E transiently associates with kinetochores following nuclear envelope breakdown in late prophase, remains bound throughout metaphase, but sometime after anaphase onset it releases and by telophase becomes bound to interzonal microtubules of the mitotic spindle. Inhibition of poleward chromosome movement in vitro by CENP-E antibodies and association of CENP-E with minus-end directed microtubule motility in vitro have combined to suggest a key role for CENP-E as an anaphase chromosome motor. For this to be plausible in vivo depends on whether CENP-E remains kinetochore associated during anaphase. Using Indian muntjac cells whose seven chromosomes have large, easily tracked kinetochores, we now show that CENP-E is kinetochore-associated throughout the entirety of anaphase-A (poleward chromosome movement), relocating gradually during spindle elongation (anaphase-B) to the interzonal microtubules. These observations support roles for CENP-E not only in the initial alignment of chromosomes at metaphase and in spindle elongation in anaphase-B, but also in poleward chromosome movement in anaphase-A.


Amplification and re-generation of LNA-modified libraries.
Locked nucleic acids (LNA) confer high thermal stability and nuclease resistance to oligonucleotides. The discovery of polymerases that accept LNA triphosphates has led us to propose a scheme for the amplification and re-generation of LNA-containing oligonucleotide libraries. Such libraries could be used for in vitro selection of e.g., native LNA aptamers. We maintained an oligonucleotide library encoding 40 randomized positions with LNA ATP, GTP, CTP, and TTP for 7 rounds of 'mock' in vitro selection in the absence of a target and analyzed the sequence composition after rounds 1, 4 and 7. We observed a decrease in LNA-A content from 20.5% in round 1 to 6.6% in round 7. This decrease was accompanied by a substantial bias against successive LNA-As (poly-LNA adenosine tracts) and a relative over-representation of single LNA-As. Maintaining a library with LNA TTP yielded similar results. Together, these results suggest that dispersed LNA monomers are tolerated in our in vitro selection protocol, and that LNA-modified libraries can be sustained for up to at least seven selection rounds, albeit at reduced levels. This enables the discovery of native LNA aptamers and similar oligonucleotide structures.


Phase unwrapping by varying the reconstruction distance in digital holographic microscopy.
We present a digital holographic phase-unwrapping method based on comparison of phase images obtained by using various reconstruction distances. By utilizing information from multiple reconstruction planes, this method can effectively bypass the areas of phase noise. We demonstrate that this method performs better than the traditional phase-unwrapping approaches, even in the case of a complex topology where the data contains high levels of noise.


Signals of eye-muscle proprioception modulate perceived motion smear.
Achieving clear perception during eye movements is one of the major challenges that the human visual system has to face every day. Like most light sensitive mechanisms, the human visual system has a finite integration time that may cause moving images to appear smeared. By comparing the perceived motion smear during ongoing eye movements and fixation, previous studies indicated that smear is reduced by a neural compensation mechanism that uses "extra-retinal information" about eye movements. However, it is not clear whether eye-muscle proprioception (afferent input), internal copies of efferent oculomotor commands (efference copy), or both contribute to the smear reduction. The present study found that similar reductions of perceived motion smear occur during passive eye movement (which is signaled only by eye-muscle proprioception) and during active pursuit tracking (for which efference copy signals exist as well). These results reveal a novel neural contribution for maintaining visual clarity and stand in contrast to previous reports that eye-muscle proprioception makes only a minor contribution to visual perception.


Heavy rainfall events and diarrhea incidence: the role of social and environmental factors.
The impact of heavy rainfall events on waterborne diarrheal diseases is uncertain. We conducted weekly, active surveillance for diarrhea in 19 villages in Ecuador from February 2004 to April 2007 in order to evaluate whether biophysical and social factors modify vulnerability to heavy rainfall events. A heavy rainfall event was defined as 24-hour rainfall exceeding the 90th percentile value (56 mm) in a given 7-day period within the study period. Mixed-effects Poisson regression was used to test the hypothesis that rainfall in the prior 8 weeks, water and sanitation conditions, and social cohesion modified the relationship between heavy rainfall events and diarrhea incidence. Heavy rainfall events were associated with increased diarrhea incidence following dry periods (incidence rate ratio = 1.39, 95% confidence interval: 1.03, 1.87) and decreased diarrhea incidence following wet periods (incidence rate ratio = 0.74, 95% confidence interval: 0.59, 0.92). Drinking water treatment reduced the deleterious impacts of heavy rainfall events following dry periods. Sanitation, hygiene, and social cohesion did not modify the relationship between heavy rainfall events and diarrhea. Heavy rainfall events appear to affect diarrhea incidence through contamination of drinking water, and they present the greatest health risks following periods of low rainfall. Interventions designed to increase drinking water treatment may reduce climate vulnerability.


Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents.
Action potentials in many central neurons are followed by a prolonged afterhyperpolarization (AHP) that influences firing frequency and affects neuronal integration. In hippocampal CA1 pyramidal neurons, the current ascribed to the AHP (IAHP) has three kinetic components. The IfastAHP is predominantly attributable to voltage-dependent K+ channels, whereas Ca2+-dependent and voltage-independent K+channels contribute to the ImediumAHP (ImAHP) and IslowAHP (IsAHP). Apamin, which selectively suppresses a component of the mAHP, increases neuronal excitability and facilitates the induction of synaptic plasticity at Schaffer collateral synapses and hippocampal-dependent learning. The Ca2+-dependent components of the AHP have been attributed to the activity of small conductance Ca2+-activated K+ (SK) channels. Examination of transgenic mice, each lacking one of the three SK channel genes expressed in the CNS, reveals that mice without the SK2 subunit completely lack the apamin-sensitive component of the ImAHP in CA1 neurons, whereas the IsAHP is not different in any of the SK transgenic mice. In each of the transgenic lines, the expression levels of the remaining SK genes are not changed. The results demonstrate that only SK2 channels are necessary for the ImAHP, and none of the SK channels underlie the IsAHP.


Creating an evidence-based admissions formula for a new dental school: University of Nevada, Las Vegas, School of Dental Medicine.
This article reports development of an evidence-based admissions formula that effectively incorporates the admissions criteria most likely to influence dental school performance. This study utilized peer-reviewed literature and analysis of admissions and performance data from the first three classes of students at the University of Nevada, Las Vegas, School of Dental Medicine (UNLV-SDM). We used Pearson's correlation, linear regression, and ANOVA to determine the strength and direction of association between admissions variables, both singly and in combination, and performance measures. Our initial results revealed no significant relationship between our previous admissions formula, which was adapted from other dental admissions offices, and student performance for our first class and National Board Dental Examination Part I (NBDE-I) (R=.288) or dental school grade point average (DS-GPA) (R=0.193). After using the combined data from the first three classes of students at UNLV-SDM, we confirmed no significant relationship between our previous admissions formula and DS-GPA (R=0.207) and a slight increase in correlation to NBDE-I (R=0.303). More detailed analysis of the admissions variables within the formula revealed that some Dental Admission Test scores, such as Reading Comprehension, Quantitative Analysis, and Biology, were significantly correlated with dental school performance at UNLV-SDM, allowing for revision of the admissions formula to a formula score that is now significantly correlated with student performance for the first class to NBDE-I (R=0.458) and DS-GPA (R=0.368), as well as the combined data from the first three cohorts at UNLV-SDM (R=0.361, 0.218, respectively). In addition, this reformulation did not significantly impact the overall ranking of females or minorities. Although formulaic data can never perfectly predict student performance, this study demonstrated that constant review and revision of relevant admissions criteria are needed for each school to maintain an evidence-based admissions program that provides for fair and effective comparison of student admissions data.


Allogeneic haematopoietic stem cell transplantation in myelodysplastic syndromes.
Allogeneic haematopoietic stem cell transplantation remains the only curative treatment for myelodysplastic syndrome. We highlight the various issues to consider in the pretransplant, transplant and posttransplant periods with emphasis on the management of relapse following transplant. Cytogenetic and molecular characteristics are becoming more important in predicting transplant outcome. Hypomethylating agents are effective in the pretransplant setting to reduce disease burden. Haploidentical and umbilical cord blood donations may be valid transplant options for patients without human leukocyte antigen-identical sibling or match unrelated donor options. A preemptive management approach to patients at high risk of relapse is more effective. Adjusting the timing and dose of donor lymphocyte infusion reduces the risk of graft-versus-host disease without jeopardizing the graft-versus-leukaemia effect of donor lymphocyte infusion. Allogeneic haematopoietic stem cell transplantation is curative in up to 40% of myelodysplastic syndrome patients. Appropriate patient selection, modification of conditioning regimes and donor selection should be considered carefully. A preemptive approach for the management of patients at high risk of relapse should be employed following transplant, with the use of immune modulating therapies such as donor lymphocyte infusion and azacitidine.


The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity.
Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential. Here, we show that dynamic epigenetic states defined by the linker histone H1.0 determine which cells within a tumor can sustain the long-term cancer growth. Numerous cancer types exhibit high inter- and intratumor heterogeneity of H1.0, with H1.0 levels correlating with tumor differentiation status, patient survival, and, at the single-cell level, cancer stem cell markers. Silencing of H1.0 promotes maintenance of self-renewing cells by inducing derepression of megabase-sized gene domains harboring downstream effectors of oncogenic pathways. Self-renewing epigenetic states are not stable, and reexpression of H1.0 in subsets of tumor cells establishes transcriptional programs that restrict cancer cells' long-term proliferative potential and drive their differentiation. Our results uncover epigenetic determinants of tumor-maintaining cells.


Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation.
Increasing evidence implicates Aβ peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting Aβ aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with Aβ42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the β-sheet conformation of Aβ42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance π-π stacking/hydrophobic interactions with amino acids of Aβ42. The efficacy of these compounds on inhibiting Aβ fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of Aβ42 leading to decreased cell toxicity.


Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load.
Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/10(6) PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied.


Monocyte-selective transendothelial migration: dissection of the binding and transmigration phases by an in vitro assay.
We describe a quantitative assay of transendothelial migration (TEM) that allows us to selectively study the interaction of monocytes with confluent human endothelial cell (HEC) monolayers. The HEC are grown on hydrated collagen gels; the monocytes need not be purified. 100% of monocytes transmigrated the monolayer within 1 h at 37 degrees C and accumulated in the subendothelial collagen; TEM of lymphocytes was not detected within this time. Migration of neutrophils from the same donor was much slower and incomplete, with only 14% of PMN transmigrating in 2 h. This rapid TEM occurs in the absence of exogenous chemoattractants, and HEC in this system do not express cytokine-inducible leukocyte adhesion molecules. A slight modification of the TEM assay allowed us to separate binding to the apical HEC surface from TEM. We found that tight apical surface binding was the rate-limiting step for TEM. Two-thirds of this binding and TEM could be blocked by a monoclonal antibody against the leukocyte beta 2 integrin chain CD18. This assay will allow us to dissect the mechanisms of both the binding and transmigration stages of diapedesis.


Effects of synchronization treatments on ovarian follicular dynamics, corpus luteum growth, and circulating steroid hormone concentrations in lactating dairy cows.
Lactating dairy cows (n=57) ≥45 d postpartum at first service were enrolled in a randomized complete block design study to evaluate treatments to synchronize estrus and ovulation. At 10 d before artificial insemination (AI), animals were randomly assigned to 1 of 3 treatments: (1) d -10 GnRH (GnRH1; 10 μg of buserelin, i.m.) and controlled internal drug release insert [CIDR, 1.38 g of progesterone (P4)]; d -3 PGF(2α) (PGF; 25 mg of dinoprost, i.m.); d -2 CIDR out; and AI at observed estrus (CIDR_OBS); (2) same as CIDR_OBS, but GnRH (GnRH2) 36 h after CIDR out and timed AI (TAI) 18 h later (CIDR_TAI); or (3) same as CIDR_TAI, but no CIDR (Ovsynch). Transrectal ultrasound was used to assess follicle size before ovulation and on d 4, 8, and 15 after the presumptive day of estrus (d 0) to measure the corpus luteum (CL). Blood samples were collected to determine concentrations of estradiol (E2; d -10, -9, -3, -2, -1, and 0) and P4 (d -10, -9, -2, -1, 0, 1, 4, 6, 8, 11, and 15). No treatment differences were observed in either circulating concentrations of P4 or the ovulatory response to GnRH1 at the onset of synchronization treatments. Circulating concentrations of P4 were greater for CIDR_OBS and CIDR_TAI compared with Ovsynch at 24 h after CIDR insertion (5.34 and 4.98 vs. 1.75 ng/mL) and immediately before CIDR removal (1.65 and 1.48 vs. 0.40 ng/mL). Peak circulating concentrations of E2 were greater for CIDR_OBS compared with Ovsynch (3.85 vs. 2.39 pg/mL), but CIDR_TAI (2.82 pg/mL) did not differ from either CIDR_OBS or Ovsynch. The interval from PGF injection to peak circulating E2 did not differ between CIDR_TAI and Ovsynch (52.1 vs. 49.8 h). Both CIDR_TAI and Ovsynch, however, had shorter intervals from PGF injection to peak circulating E2 concentrations compared with CIDR_OBS (67.8 h). The diameter of the dominant follicle before ovulation was greater for CIDR_OBS compared with Ovsynch (18.5 vs. 16.0 mm) but CIDR_TAI (17.1 mm) did not differ from either of the other treatments. The mean interval from PGF to ovulation was longer for CIDR_OBS (100.0 h) compared with CIDR_TAI and Ovsynch (84.4 and 83.2 h, respectively). Use of CIDR_OBS resulted in increased preovulatory follicle size and greater circulating concentrations of E2 due to a longer period of preovulatory follicle growth. Progesterone supplementation during synchronization and GnRH on the day before TAI affected ovulatory follicle size, and periovulatory circulating concentrations of P4 and E2. No differences, however, in postovulatory P4 or luteal volume profiles were observed.


Assessment of online self-testing and self-sampling service providers for sexually transmitted infections against national standards in the UK in 2020.
Online testing for STIs may help overcome barriers of traditional face-to-face testing, such as stigma and inconvenience. However, regulation of these online tests is lacking, and the quality of services is variable, with potential short-term and long-term personal, clinical and public health implications. This study aimed to evaluate online self-testing and self-sampling service providers in the UK against national standards. Providers of online STI tests (self-sampling and self-testing) in the UK were identified by an internet search of Google and Amazon (June 2020). Website information on tests and associated services was collected and further information was requested from providers via an online survey, sent twice (July 2020, April 2021). The information obtained was compared with British Association for Sexual Health and HIV and Faculty of Sexual and Reproductive Healthcare guidelines and standards for diagnostics and STI management. 31 providers were identified: 13 self-test, 18 self-sample and 2 laboratories that serviced multiple providers. Seven responded to the online survey. Many conflicts with national guidelines were identified, including: lack of health promotion information, lack of sexual history taking, use of tests licensed for professional-use only marketed for self-testing, inappropriate infections tested for, incorrect specimen type used and lack of advice for postdiagnosis management. Very few online providers met the national STI management standards assessed, and there is concern that this will also be the case for service provision aspects that were not covered by this study. For-profit providers were the least compliant, with concerning implications for patient care and public health. Regulatory change is urgently needed to ensure that all online providers are compliant with national guidelines to ensure high-quality patient care, and providers are held to account if non-compliant.


Personality and Risk of Frailty: the English Longitudinal Study of Ageing.
There is evidence that the personality traits conscientiousness, extraversion and neuroticism are associated with health behaviours and with risk of various health outcomes. We hypothesised that people who are lower in conscientiousness or extraversion or higher in neuroticism may be at greater risk of frailty in later life. We used general linear models to examine the prospective relation between personality, assessed using the Midlife Development Inventory, and change in frailty, modelled by a frailty index, in 5314 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing. Men and women with higher levels of neuroticism or lower levels of extraversion or conscientiousness had an increased frailty index score at follow-up. After adjustment for potential confounding or mediating variables, including frailty index score at baseline, the frailty index score at follow-up-which potentially ranges from 0 to 1-was higher by 0.035 (95 % confidence interval 0.018, 0.052) for a standard deviation increase in neuroticism and lower by 0.061 (0.031, 0.091) or 0.045 (0.020, 0.071) for a standard deviation increase in extraversion or conscientiousness, respectively. There was some evidence that the association between extraversion and frailty may be due to reverse causation whereby poorer health affected responses to items in the personality inventory. Higher levels of neuroticism or lower levels of conscientiousness or extraversion may be risk factors for the onset or progression of frailty. Future studies need to replicate these observations in other populations and explore the mechanisms underlying these associations.


The economic pre-treatment of coal mine drainage water with caustic and ozone.
Coal mine drainage waters are low in pH with varying amounts of iron and manganese and are generally brackish. The Austar Coal Mine in NSW, Australia, sought alternatives to their current lime dosing as the pre-treatment before the downstream reverse osmosis plant. Undesirable operating aspects of the current system include manganese and gypsum scaling/fouling, the need for anti-scalants and reduced water recovery. Thirteen processes for acid mine drainage were initially considered. The preferred process of caustic and ozone for Mn(II) oxidation was pilot tested at up to 0.74 kL/hr at the mine site. Under proper conditions and no aeration, about 81 per cent of the Fe could be removed (initially at 156 mg/L) as green rust. Supplemental aeration followed first-order kinetics and allowed 99.9 per cent Fe(II) oxidation and removal but only with a hydraulic residence time of about 47 minutes. The addition of supplemental Cu catalyst improved Fe removal. Ozone applied after caustic was effective in stoichiometrically oxidising recalcitrant Mn(II) and any remaining Fe(II). Control of the ozonation was achieved using the oxidation reduction potential during oxidation of the Mn(II) species. The use of caustic, followed by ozone, proved economically comparable to the current lime pre-treatment.


Telemedicine is a useful tool to deliver care to patients with Amyotrophic Lateral Sclerosis during COVID-19 pandemic: results from Southern Italy.
Teleneurology is an effective tool for the rapid evaluation of patients in remote locations with a well-established use in stroke and epilepsy. To date its adoption for Amyotrophic Lateral Sclerosis (ALS) care is still in a preliminary stage. We evaluated the feasibility of multidisciplinary assessment of patients with ALS, using telememedicine during the emergency determined by the COVID-19 pandemic. Methods: All patients included in this survey had received a diagnosis of ALS according to international criteria after a complete clinical and paraclinical assessment during 2019. A structured questionnaire was used by the neurologist with the patient or the caregiver. A video interaction was offered but refused by all patients because they did not feel comfortable or did not have smartphone. Results: Out of 31 clinical interviews 8 were completed directly with the patients and 23 with patients' caregivers. In a successive survey, most of patients were satisfied with the neurological interview (85%), the possibility to interact directly with the clinician being at home (85%) and reduction of economic and time costs because they avoided unnecessary travel to the clinic. Most of subjects expressed their willingness to continue to be included in remote evaluation programs (90%). Notably, none of the patients presented index symptoms of Covid-19 infection. Conclusion: Our study indicates that telemedicine is a valid tool to triage patients with ALS to increase practice outreach and efficiency. Delivery of care via telemedicine was effective and successful in people with ALS in the dramatic and sudden crisis determined by Covid-19 outbreak.


On the value of Burmese amber for understanding insect evolution: Insights from †Heterobathmilla - an exceptional stem group genus of Strepsiptera (Insecta).
Burmese amber and amber from other periods and regions became a rich source of new extinct insect species and yielded important insights in insect evolution in the dimension of time. Amber fossils have contributed to the understanding of the phylogeny, biology, and biogeography of insects and other groups, and have also gained great importance for dating molecular trees. Another major potential is the documentation of faunal, floral and climatic shifts. Evolutionary transitions can be well-documented in amber fossils and can reveal anatomical transformations and the age of appearance of structural features. Here, using a new stem group species of Strepsiptera from Burmite, we evaluate this potential of amber insect fossils to assess the current phylogeny of Strepsiptera, with the main emphasis on the early splitting events in the stem group. Amber fossils have greatly contributed to the understanding of the evolution of Strepsiptera in the late Mesozoic and the Cenozoic. †Heterobathmilla kakopoios Pohl and Beutel gen. et sp. n. described here is placed in the stem group of the order, in a clade with †Kinzelbachilla (†Kinzelbachillidae) and †Phthanoxenos (†Phthanoxenidae). †Phthanoxenidae has priority over †Kinzelbachillidae, and the latter is synonymised. The superb details available from this new fossil allowed us to explore unique features of the antennae, mouthparts, and male copulatory apparatus, and to provide a phylogenetic hypothesis for the order. The younger †Protoxenos from Eocene Baltic amber was confirmed as sister to all remaining extinct and extant groups of Strepsiptera, whereas the position of the Cretaceous †Cretostylops in the stem group remains ambivalent. While the value of Burmite and amber from other periods has a recognized impact on our knowledge of the evolution in various lineages, this new fossil does not fundamentally change our picture of the phylogeny and evolution of early Strepsiptera. However, it offers new insights into the morphological diversity in the early evolution of the group.


Human papilloma virus screening by hybrid capture II in Chinese women of Jiangsu Province.
To survey Human Papilloma Virus (HPV) infection in Chinese Women of Jiangsu Province and discuss the relationship between HPV and the biology of cervical cancer. Two thousand, one hundred and fifty-three sexually active women (including 66 cases of cervical cancer) were selected for high-risk human papilloma virus DNA test with Hybrid Capture II (HCII). The overall HPV prevalence was 32.6% (701/2153) with higher positive rates in cervical carcinoma and Cervical Interstitial Neoplasia (CIN) [93.9% and 54.6%] respectively. For women aged 40-59 years, the overall high-risk HPV prevalence was higher than those of other age groups. Compared with CIN I, the positivity rate and viral load of HPV DNA in CIN III is much higher (80.2% vs. 29.9%, 11.89 vs. 0.53). Ninety-four per cent (64/66) of patients with Cervical cancer were detected to be HPV positive. There was no significant difference in HPV DNA among each clinical stage and pathologic grade. But the positive rates and the value of HPV DNA were higher in the patients with cervical interstitial incursion. Eighty per cent of patients (20/25) could become negative within six months after operation. High-risk HPV DNA test is effective in screening for cervical diseases. HCII is an effective method to detect HPV DNA.


Pediatric Hospitalist Workload and Sustainability in University-Based Programs: Results from a National Interview-Based Survey.
Wide variability exists in the clinical workload of pediatric hospitalists without an accepted standard for benchmarking purposes. By using data obtained from interviews of pediatric hospital medicine (PHM) program leaders, we describe the clinical workload of university-based programs and report on the program sustainability perceived by PHM program leaders. The median clinical hours reported for a full-time pediatric hospitalist were 1800 hours per year, with a median of 15 weekends worked per year. Furthermore, program leaders reported an ideal number of clinical hours as 1700 hours per year. Half of the interviewed program leaders perceived their current models as unsustainable. Programs perceived as unsustainable were more likely than those perceived as sustainable to require a higher number of weekends worked per year or to be university employed. Further research should focus on establishing benchmarks for the workloads of pediatric hospitalists and on evaluating factors that can affect sustainability.


Targeting α-synuclein for PD Therapeutics: A Pursuit on All Fronts.
Parkinson's Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.