Biogeography of squirrel monkeys (genus Saimiri): South-central Amazon origin and rapid pan-Amazonian diversification of a lowland primate.
The squirrel monkey, Saimiri, is a pan-Amazonian Pleistocene radiation. We use statistical phylogeographic methods to create a mitochondrial DNA-based timetree for 118 squirrel monkey samples across 68 localities spanning all Amazonian centers of endemism, with the aim of better understanding (1) the effects of rivers as barriers to dispersal and distribution; (2) the area of origin for modern Saimiri; (3) whether ancestral Saimiri was a lowland lake-affiliated or an upland forest taxa; and (4) the effects of Pleistocene climate fluctuation on speciation. We also use our topology to help resolve current controversies in Saimiri taxonomy and species relationships. The Rondônia and Inambari centers in the southern Amazon were recovered as the most likely areas of origin for Saimiri. The Amazon River proved a strong barrier to dispersal, and squirrel monkey expansion and diversification was rapid, with all speciation events estimated to occur between 1.4 and 0.6Ma, predating the last three glacial maxima and eliminating climate extremes as the main driver of squirrel monkey speciation. Saimiri expansion was concentrated first in central and western Amazonia, which according to the "Young Amazon" hypothesis was just becoming available as floodplain habitat with the draining of the Amazon Lake. Squirrel monkeys also expanded and diversified east, both north and south of the Amazon, coincident with the formation of new rivers. This evolutionary history is most consistent with a Young Amazon Flooded Forest Taxa model, suggesting Saimiri has always maintained a lowland wetlands niche and was able to greatly expand its range with the transition from a lacustrine to a riverine system in Amazonia. Saimiri vanzolinii was recovered as the sister group to one clade of Saimiri ustus, discordant with the traditional Gothic vs. Roman morphological division of squirrel monkeys. We also found paraphyly within each of the currently recognized species: S. sciureus, S. ustus, and S. macrodon. We discuss evidence for taxonomic revision within the genus Saimiri, and the need for future work using nuclear markers.


How cats lap: water uptake by Felis catus.
Animals have developed a range of drinking strategies depending on physiological and environmental constraints. Vertebrates with incomplete cheeks use their tongue to drink; the most common example is the lapping of cats and dogs. We show that the domestic cat (Felis catus) laps by a subtle mechanism based on water adhesion to the dorsal side of the tongue. A combined experimental and theoretical analysis reveals that Felis catus exploits fluid inertia to defeat gravity and pull liquid into the mouth. This competition between inertia and gravity sets the lapping frequency and yields a prediction for the dependence of frequency on animal mass. Measurements of lapping frequency across the family Felidae support this prediction, which suggests that the lapping mechanism is conserved among felines.


Antiphospholipid antibodies: findings at arteriography.
The purpose of this study was to determine the frequency and types of abnormalities at arteriography in patients with antiphospholipid antibodies (APA) and ischemic cerebrovascular events. Twenty-three patients with APA and ischemic cerebrovascular events who underwent arteriography were identified. Patients over the age of 65 years were excluded. No patients met diagnostic criteria for systemic lupus erythematosus. All angiograms were reviewed by two neuroradiologists. Seventeen patients (74%) between the ages of 28 and 64 years (average age, 40 years) had abnormal angiograms. Sixteen patients had arterial abnormalities and one had dural sinus thrombosis. Ten had solely intracranial abnormalities (nine arterial and one venous), six had solely extracranial arterial abnormalities, and one had both intracranial and extracranial arterial abnormalities. Intracranial arterial abnormalities included stem or branch occlusions of the cerebral or basilar arteries, which were generally solitary (six patients), and findings suggestive of vasculitis (four patients). Four patients had stenoses of the origins of two or more great vessels. Two patients had extracranial internal carotid artery stenoses or occlusions that were not typical of atheromatous disease, considered to be embolic in one patient. In another patient, a stenosis of the origin of the internal carotid artery was present that appeared typical of atheromatous disease. Infarctions were seen on CT or MR studies in 13 of 17 patients with abnormal angiograms. In our group of patients, typical atheromatous lesions at the common carotid artery bifurcation were rare. Some lesions that are infrequent in the general stroke population (eg, vasculitis-like findings and stenoses at the origin of great vessels) were common. Patients with APA and cerebrovascular events appear to differ from the general stroke population with regard to types of arterial abnormalities seen at arteriography.


Is minimally invasive thoracoscopic surgery the new benchmark for treating mitral valve disease?
The treatment of mitral valve disease remains dynamic; surgeons and patients must now choose between many different surgical options when addressing mitral regurgitation and mitral stenosis. Notably, advances in imaging and surgical instrumentation allow surgeons to perform less invasive mitral valve surgery that spares the sternum. With favorable long-term data now emerging, we compare the benefits and risks of thoracoscopic mitral valve surgery with that through conventional sternotomy or surgery that is robot-assisted.


IT Infrastructure for Biomedical Research in North-West Germany.
The efficient use of routine data for biomedical research presupposes an IT infrastructure designed for health care facilities. The objective of this study was to analyse which IT infrastructure is used in hospitals and by general practitioners' (GP) practices in the region Oldenburg-Bremen and to examine how well this supports research projects. To this end, IT managers and GPs were interviewed. The usage of hospital information systems (HIS) and data warehouse systems (DWS) in hospitals is of major importance for the study. Over 90 % use DWS for administration, 42 % for clinical research. None of the hospitals implemented consent for the use of routine data for research. Only a third of the GPs have participated in studies. The GPs' offices based EHR systems in use offer virtually no support for research projects. The study results demonstrate that technical and organisational measures are required for the further usage of routine data in the region.


Impact of source data verification on data quality in clinical trials: an empirical post hoc analysis of three phase 3 randomized clinical trials.
The aim of this project was to perform an empirical evaluation of the impact of on site source data verification (SDV) on the data quality in a clinical trial database to guide an informed decision on selection of the monitoring approach. We used data from three randomized phase III trials monitored with a combination of complete SDV or partial SDV. After database lock, individual subject data were extracted from the clinical database and subjected to post hoc complete SDV. Error rates were calculated with focus on the degree of on study monitoring and relevance and analyzed for potential impact on end points. Data from a total of 2566 subjects including more than 3 million data fields were 100% source data verified post hoc. An overall error rate of 0.45% was found. No sites had 0% errors. 100% SDV yielded an error rate of 0.27% as compared with partial SDV having an error rate of 0.53% (P < 0.0001). Comparing partly and fully monitored subjects, minor differences were identified between variables of major importance to efficacy or safety. The findings challenge the notion that a 0% error rate is obtainable with on site monitoring. Data indicate consistently low error rates across the three trials analyzed. The use of complete vs. partial SDV offers a marginal absolute error rate reduction of 0.26%, i.e. a need to perform complete SDV of about 370 data points to avoid one unspecified error and does not support complete SDV as a means of providing meaningful improvements in data accuracy.


Quantification of HBsAg: basic virology for clinical practice.
Hepatitis B surface antigen (HBsAg) is produced and secreted through a complex mechanism that is still not fully understood. In clinical fields, HBsAg has long served as a qualitative diagnostic marker for hepatitis B virus infection. Notably, advances have been made in the development of quantitative HBsAg assays, which have allowed viral replication monitoring, and there is an opportunity to make maximal use of quantitative HBsAg to elucidate its role in clinical fields. Yet, it needs to be underscored that a further understanding of HBsAg, not only from clinical point of view but also from a virologic point of view, would enable us to deepen our insights, so that we could more widely expand and apply its utility. It is also important to be familiar with HBsAg variants and their clinical consequences in terms of immune escape mutants, issues resulting from overlap with corresponding mutation in the P gene, and detection problems for the HBsAg variants. In this article, we review current concepts and issues on the quantification of HBsAg titers with respect to their biologic nature, method principles, and clinically relevant topics.


Identity Processes and Intrinsic and Extrinsic Goal Pursuits: Directionality of Effects in College Students.
Identity research has mainly focused on the degree to which adolescents and emerging adults engage in exploration and commitment to identity goals and strivings. Somewhat lacking from this research tradition is an explicit focus on the content of the identity goals that individuals deem important and pursue. The present manuscript describes two longitudinal studies sampling college students in which we examine how exploration and commitment processes relate to intrinsic and extrinsic goal pursuits as defined in Self-Determination Theory. Study 1 was a two-wave longitudinal study spanning 6 months (N = 370; 77.4% women; mean age 18.24 years); Study 2 was a three-wave longitudinal study spanning 6 months (N = 458 students; 84.9% women; mean age 18.25 years). Using cross-lagged path analyses, hypotheses were supported to various degrees of convergence between studies, pointing to the extent of which results were replicated across our two independent longitudinal samples. Whereas an intrinsic goal orientation positively predicted commitment making (Study 1) and identification with commitment over time (Studies 1 and 2), an extrinsic goal orientation positively predicted ruminative exploration over time, which led to decreases in intrinsic orientation over time (Study 2). Further, an intrinsic goal orientation negatively predicted ruminative exploration over time (Study 1). The findings in for pro-active exploration processes were inconsistent across both studies, being prospectively related to both intrinsic (Study 2) and extrinsic goal orientations (Study 1). Implications and suggestions for future research are discussed.


META060 protects against diet-induced obesity and insulin resistance in a high-fat-diet fed mouse.
We investigated whether a reduced iso-α acid derived from an extract of Humulus lupulus L., META060, had an effect on weight gain, body composition, and metabolism in a high-fat-diet (HFD) fed mouse model. Weight gain was monitored for up to 20 wk in mice receiving a low-fat diet, an HFD, or an HFD supplemented with META060 or rosiglitazone. Body composition was determined using dual-energy x-ray absorptiometric analysis. Indirect calorimetric measurements were performed to investigate the energy balance in the mice, and oral glucose tolerance tests were administered to examine the effect of META060 on the glycemic response. The HFD-fed mice administered META060 for 14 wk had a significantly lower mean weight than HFD-fed mice (30.58 ± 0.5 versus 37.88 ± 0.7 g, P < 0.05). Indirect calorimetric measurements showed an increased metabolic flexibility in mice supplemented with META060. In addition, glucose tolerance was improved, comparable to the effects of rosiglitazone treatment. META060 has potential therapeutic value for managing obesity and insulin resistance, and further research into the mechanism of action is warranted.


Comparative studies on the infectivity of Theileria parva in ticks fed in vitro and those fed on cattle.
Nymphs of the brown ear tick, Rhipicephalus appendiculatus, were fed on heparinised bovine blood infected with Theileria parva parasites in an in vitro feeding system consisting of rabbit skin membranes. The main feeding and development parameters such as the mean attachment rate, feeding duration and engorgement weights of membrane-fed ticks were not significantly different from nymphs fed on cattle. The moulting rate was also comparable although a slight significant difference was observed. Assessment of infection prevalence and abundance with T. parva in adults indicated that the membrane-fed ticks acquired infection to the same level as those fed on cattle. Stabilates prepared from both the membrane- and cattle-fed adult ticks were found to be infective and caused severe reactions in susceptible cattle. When the immunised cattle were challenged with a lethal homologous dose of T. parva (Marikebuni), they were found to be immune.


Recent developments in the new inorganic solid-state LED phosphors.
Stable and efficient phosphor systems for white light-emitting diodes (LEDs) are highly important with respect to their application in solid-state lighting beyond the technical limitations of traditional lighting technologies. Therefore, inorganic solid-state conversion phosphors must be precisely selected and evaluated with regard to their special material properties and synergistic optical parameters. In this perspective, we present an overview of the recent developments of LED phosphors; firstly, general photoluminescence-controlling strategies for phosphors to match LED applications have been evaluated; secondly, state-of-the-art and emerging new LED phosphors have been demonstrated. Then, methodologies for the discovery of new LED phosphors by mineral-inspired prototype evolution and new phase construction, as well as combinatorial optimization screening, and the single-particle-diagnosis approach, have been analyzed and exemplified. Finally, future developments of LED phosphors have been proposed.


Improved Visual Localization via Graph Filtering.
Vision-based localization is the problem of inferring the pose of the camera given a single image. One commonly used approach relies on image retrieval where the query input is compared against a database of localized support examples and its pose is inferred with the help of the retrieved items. This assumes that images taken from the same places consist of the same landmarks and thus would have similar feature representations. These representations can learn to be robust to different variations in capture conditions like time of the day or weather. In this work, we introduce a framework which aims at enhancing the performance of such retrieval-based localization methods. It consists in taking into account additional information available, such as GPS coordinates or temporal proximity in the acquisition of the images. More precisely, our method consists in constructing a graph based on this additional information that is later used to improve reliability of the retrieval process by filtering the feature representations of support and/or query images. We show that the proposed method is able to significantly improve the localization accuracy on two large scale datasets, as well as the mean average precision in classical image retrieval scenarios.


Metal nanoparticles in liquid phase catalysis; from recent advances to future goals.
Metal nanoparticles have attracted much attention over the last decade owing to their unique properties, different to their bulk counterparts, which pave the way for their application in different fields from materials science and engineering to biomedical applications. Of particular interest, the use of metal nanoparticles in catalysis has brought superior efficiency in terms of activity, selectivity and lifetime to heterogeneous catalysis. This article reviews the recent developments in the synthesis routes and the catalytic performance of metal nanoparticles depending on the solvent used for various organic and inorganic transformations. Additionally, we also discuss the prevalent complications and their possible solutions plus future prospects in the field of nanocatalysis.


Identification of a novel long noncoding RNA that promotes osteoblast differentiation.
Long noncoding RNAs (lncRNAs) are a heterogeneous class of transcripts, longer than 200 nucleotides, 5'-capped, polyadenylated, and poorly conserved among mammalian species. Several studies have shown the contribution of lncRNAs to different cellular processes, including regulation of the chromatin structure, control of messenger RNA translation, regulation of gene transcription, regulation of embryonic pluripotency, and differentiation. Although limited numbers of functional lncRNAs have been identified so far, the immense regulatory potential of these RNAs is already evident, indicating that a functional characterization of lncRNAs is needed. In this study, mouse preosteoblastic cells were induced to differentiate into osteoblasts. At 3 sequential differentiation stages, total RNA was isolated and libraries were constructed for Illumina sequencing. The resulting sequences were aligned and transcript abundances were determined. New lncRNA candidates that displayed differential expression patterns during osteoblast differentiation were identified by combining bioinformatics and reverse transcription polymerase chain reaction analyses. Among these, lncRNA-1 that exhibited increased expression during osteogenesis and was downregulated during myogenesis. Importantly, knockdown of lncRNA-1 expression in primary mouse preosteoblasts was found to inhibit osteogenic differentiation, reflected by a reduced transcription of the Runx2/p57 and Sp7 bone master genes. Together, our results indicate that lncRNA-1 represents a new regulatory RNA that plays a relevant role during the early stages of osteogenesis.


Encephalitis: diagnosis, management and recent advances in the field of encephalitides.
Encephalitis describes inflammation of the brain parenchyma, typically caused by either an infectious agent or through an autoimmune process which may be postinfectious, paraneoplastic or idiopathic. Patients can present with a combination of fever, alterations in behaviour, personality, cognition and consciousness. They may also exhibit focal neurological deficits, seizures, movement disorders and/or autonomic instability. However, it can sometimes present non-specifically, and this combined with its many causes make it a difficult to manage neurological syndrome. Despite improved treatments in some forms of encephalitides, encephalitis remains a global concern due to its high mortality and morbidity. Prompt diagnosis and administration of specific and supportive management options can lead to better outcomes. Over the last decade, research in encephalitis has led to marked developments in the understanding, diagnosis and management of encephalitis. In parallel, the number of autoimmune encephalitis syndromes has rapidly expanded and clinically characteristic syndromes in association with pathogenic autoantibodies have been defined. By focusing on findings presented at the Encephalitis Society's conference in December 2021, this article reviews the causes, clinical manifestations and management of encephalitis and integrate recent advances and challenges of research into encephalitis.


ICTV Virus Taxonomy Profile: Caulimoviridae.
Caulimoviridae is a family of non-enveloped reverse-transcribing plant viruses with non-covalently closed circular dsDNA genomes of 7.1-9.8 kbp in the order Ortervirales. They infect a wide range of monocots and dicots. Some viruses cause economically important diseases of tropical and subtropical crops. Transmission occurs through insect vectors (aphids, mealybugs, leafhoppers, lace bugs) and grafting. Activation of infectious endogenous viral elements occurs in Musa balbisiana, Petunia hybrida and Nicotiana edwardsonii. However, most endogenous caulimovirids are not infectious. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Caulimoviridae, which is available at ictv.global/report/caulimoviridae.


Comparative toxicity of acaricides to honey bee (Hymenoptera: Apidae) workers and queens.
Acaricides are used to treat honey bee (Apis mellifera L.) colonies to control the varroa mite (Varroa destructor Anderson & Trueman), a worldwide threat to honey bee health. Although acaricides control a serious honey bee parasite and mitigate bee loss, they may cause harm to bees as well. We topically applied five acaricides, each with a different mode of action, to young adult queen and worker bees to generate dose-response curves and LD50. Twenty-four hours after treatment, queens were found to be three-times more tolerant of tau-fluvalinate and six-times more tolerant of thymol than workers when adjusted for body weight differences between workers (108 mg) and queens (180 mg). Queens survived the highest administered doses of fenpyroximate (1620 microg/g) and coumaphos (2700 microg/g) indicating that queens are at least 11-fold more tolerant of coumaphos and at least 54-fold more tolerant of fenpyroximate than workers. However, queens treated with as little as 54 microg/g of fenpyroximate exhibited reduced survival over 6 wk after treatment. Amitraz was the only acaricide tested for which queens were not more tolerant than workers. The striking difference in acaricide tolerance of queen and worker honey bees suggests physiological differences in how the two castes are affected by xenobiotics.


Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of β-oxidation.
It has been suggested that some cancer cells rely upon fatty acid oxidation (FAO) for energy. Here we show that when FAO was reduced approximately 90% by pharmacological inhibition of carnitine palmitoyltransferase I (CPT1) with low concentrations of etomoxir, the proliferation rate of various cancer cells was unaffected. Efforts to pharmacologically inhibit FAO more than 90% revealed that high concentrations of etomoxir (200 μM) have an off-target effect of inhibiting complex I of the electron transport chain. Surprisingly, however, when FAO was reduced further by genetic knockdown of CPT1, the proliferation rate of these same cells decreased nearly 2-fold and could not be restored by acetate or octanoic acid supplementation. Moreover, CPT1 knockdowns had altered mitochondrial morphology and impaired mitochondrial coupling, whereas cells in which CPT1 had been approximately 90% inhibited by etomoxir did not. Lipidomic profiling of mitochondria isolated from CPT1 knockdowns showed depleted concentrations of complex structural and signaling lipids. Additionally, expression of a catalytically dead CPT1 in CPT1 knockdowns did not restore mitochondrial coupling. Taken together, these results suggest that transport of at least some long-chain fatty acids into the mitochondria by CPT1 may be required for anabolic processes that support healthy mitochondrial function and cancer cell proliferation independent of FAO.


Direct Behavior Rating: an evaluation of time-series interpretations as consequential validity.
Direct Behavior Rating (DBR) is a repeatable and efficient method of behavior assessment that is used to document teacher perceptions of student behavior in the classroom. Time-series data can be graphically plotted and visually analyzed to evaluate patterns of behavior or intervention effects. This study evaluated the decision accuracy of novice raters who were presented with single-phase graphical plots of DBR data. Three behaviors (i.e., academically engaged, disruptive, and respectful) and three graphical trends (i.e., positive, no trend, and negative) were analyzed by 27 graduate and five undergraduate participants who had minimal visual analysis experience. All graphs were unique, with data points arranged to form one of three "true" trends. Raters correctly classified graphs with positive, no, and negative trends an average of 76, 98, and 67% of instances. The generalized linear mixed model was used to handle significance tests for the categorical data. Results indicate that accuracy was influenced by the trend direction, with the most accurate ratings in the no trend condition. Despite the significant effect for trend direction, the current study provides empirical evidence for accuracy of DBR trends and interpretations. Novice raters and visual analysts yielded accurate decisions regarding the trend of plotted data for student behavior.


Expansion of human mesenchymal stem cells on microcarriers.
The effects on human mesenchymal stem cell growth of choosing either of two spinner flask impeller geometries, two microcarrier concentrations and two cell concentrations (seeding densities) were investigated. Cytodex 3 microcarriers were not damaged when held at the minimum speed, N(JS), for their suspension, using either impeller, nor was there any observable damage to the cells. The maximum cell density was achieved after 8-10 days of culture with up to a 20-fold expansion in terms of cells per microcarrier. An increase in microcarrier concentration or seeding density generally had a deleterious or neutral effect, as previously observed for human fibroblast cultures. The choice of impeller was significant, as was incorporation of a 1 day delay before agitation to allow initial attachment of cells. The best conditions for cell expansion on the microcarriers in the flasks were 3,000 microcarriers ml(-1) (ca. 1 g dry weight l(-1)), a seeding density of 5 cells per microcarrier with a 1 day delay before agitation began at N(JS) (30 rpm), using a horizontally suspended flea impeller with an added vertical paddle. These findings were interpreted using Kolmogorov's theory of isotropic turbulence.


Subsequent cooling-circulation after radiofrequency and microwave ablation avoids secondary indirect damage induced by residual thermal energy.
We aimed to investigate the exact role of residual thermal energy following microwave ablation (MWA) and radiofrequency ablation (RFA) at the final ablation and transition zones and determine whether residual thermal energy could be dissipated by subsequent cooling-circulation. In an ex vivo study, MWA and RFA were performed on fresh porcine liver, and central and border temperatures were compared. In an in vivo study, MWA and RFA were performed to the livers of New Zealand white rabbits. Tissue samples were stained with α-NADH-diaphorase. The coagulation zones (NADH-negative) and transition zones (lightly NADH-stained) of different groups were compared at different time points. In the ex vivo model, the residual thermal energy after MWA and RFA could be dispersed by subsequent cooling-circulation due to the temperature decreasing rapidly. In the in vivo study, the coagulation volume in the ablation group was larger than that in the cooling-circulation group (P < 0.05) 2 days after ablation. In the ablation group, the damaged zone (the transition zone plus the coagulation zone) on α-NADH-diaphorase-stained images increased rapidly within 2 hours after ablation and slowly reached the maximum on day 2. However, the damaged zones did not change significantly at the three time points observed in the cooling-circulation group. The residual thermal energy in MWA and RFA induced secondary damage beyond the direct coagulation zone, and it could be dissipated by subsequent cooling-circulation, contributing to smaller ablation and transition zones.


Comparison of midforceps, low-forceps, and spontaneous vaginal deliveries.
A prospective, six-month study compared various maternal and neonatal parameters among spontaneous vaginal (n = 47), low-forceps (n = 21), and midforceps (n = 15) deliveries. All three groups had good neonatal and maternal outcomes. The only significant differences (P greater than .01) were the one-minute Apgar scores between the low-forceps and midforceps groups and parity between the spontaneous vaginal and low-forceps deliveries. The findings did not reveal poorer neonatal outcomes or excessive maternal morbidity, thus supporting the continued use of forceps in properly selected patients.


Selective maternal-allele loss in human lung cancers of the maternally expressed p57KIP2 gene at 11p15.5.
Genomic imprinting at 11p15 is suggested to play a role in certain pediatric tumors such as Wilms' tumor, based on the findings of selective maternal loss of this chromosomal region. Although the allele loss at 11p15 is also frequent in a number of cancers of adults including lung, breast, and bladder cancers, possible involvement of genomic imprinting in these tumors has not been investigated extensively. p57KIP2, a newly described member of the p21 cyclin-dependent kinase (CDK) inhibitor family which is thought to negatively regulate the cell cycle at the G1 checkpoint, has been mapped to 11p15. In the present study, we searched for somatic p57KIP2 mutations in lung cancer, but failed to find such alterations. Interestingly, however, we found that the p57KIP2 gene is imprinted with maternal expression and that the maternal alleles had been selectively lost in 11 of 13 (85%) lung cancer cases carrying 11p15 deletions, this being a significant bias (p=0.01). These data provide the first evidence that genomic imprinting may play a role in the oncogenesis of not only rare pediatric tumors but also this common cancer of adults, suggesting that the imprinted p57KIP2 CDK inhibitor gene is a potential target for maternally biased 11p15 deletions.


Vascular anastomotic complications in lung transplantation: a single institution's experience.
Lung transplant recipients were reviewed to compare our early and current experience of vascular complications. Since 1995, we have had a policy of early identification and intervention. We undertook a retrospective review of all adult lung transplants performed at our centre. Patients with pulmonary vascular complications before and after 1995 were identified and reviewed to determine changes in management and outcome. We identified a total of 13 patients with either pulmonary artery or venous obstruction out of a total of 720 adult lung transplants (1.8%). There were 9 females and 4 males with an age range of 25-64 years. Complications were more common in patients with fibrotic lung disease and involved 15 vascular anastomoses, most commonly the pulmonary arterial anastomosis. Prior to 1995, 5 cases were identified, all postoperatively. In this group, the mean time for identification of the complication was 9.4 (range 4-14) days. Only 1 patient survived to discharge. After 1995, vascular complications were identified intraoperatively in 4 cases and corrected immediately. Four cases were identified postoperatively (at <1-17 days) by a computed tomography pulmonary angiogram. Three were treated surgically within 24 h of diagnosis (using cardiopulmonary bypass with cold preservation). One patient was managed conservatively. Among patients identified after 1995, 5 survived to discharge. Though rare, pulmonary vascular complications after lung transplantation carry high mortality. In our opinion, early identification and intervention improves outcome. Intraoperative assessment by pressure gradient measurement and transoesophageal echocardiography is recommended. Despite this, mortality remains high and prevention is better than cure.


Dopamine imbalance in Huntington's disease: a mechanism for the lack of behavioral flexibility.
Dopamine (DA) plays an essential role in the control of coordinated movements. Alterations in DA balance in the striatum lead to pathological conditions such as Parkinson's and Huntington's diseases (HD). HD is a progressive, invariably fatal neurodegenerative disease caused by a genetic mutation producing an expansion of glutamine repeats and is characterized by abnormal dance-like movements (chorea). The principal pathology is the loss of striatal and cortical projection neurons. Changes in brain DA content and receptor number contribute to abnormal movements and cognitive deficits in HD. In particular, during the early hyperkinetic stage of HD, DA levels are increased whereas expression of DA receptors is reduced. In contrast, in the late akinetic stage, DA levels are significantly decreased and resemble those of a Parkinsonian state. Time-dependent changes in DA transmission parallel biphasic changes in glutamate synaptic transmission and may enhance alterations in glutamate receptor-mediated synaptic activity. In this review, we focus on neuronal electrophysiological mechanisms that may lead to some of the motor and cognitive symptoms of HD and how they relate to dysfunction in DA neurotransmission. Based on clinical and experimental findings, we propose that some of the behavioral alterations in HD, including reduced behavioral flexibility, may be caused by altered DA modulatory function. Thus, restoring DA balance alone or in conjunction with glutamate receptor antagonists could be a viable therapeutic approach.


Antioxidant and antihyperlipidemic effect of Solanum nigrum fruit extract on the experimental model against chronic ethanol toxicity.
The possible protective effect of Solanum nigrum fruit extract (SNFEt) was investigated for its antioxidant and antihyperlipidemic activity against ethanol-induced toxicity in rats. The experimental animals were intoxicated with 20% ethanol (7.9 g/kg/day) for 30 days via gastric intubation. SNFEt was administered at the dose of 250 mg/kg body weight along with the daily dose of ethanol for 30 days. From the result it was observed that ethanol-induced rats showed a significant elevation in the levels of Thiobarbituric acid reactive substances (TBARS), which lowered the antioxidant defense systems, such as, reduced glutathione (GSH) and vitamins C and E, when compared to the controls. In the lipid profiles, the levels of total cholesterol (TC), triglycerides (TG), low density lipoproteins (LDL), very low density lipoproteins (VLDL), free fatty acids (FFA), and phospholipids were significantly elevated in the ethanol-induced group, whereas, the high density lipoproteins (HDL) were found to be reduced in the plasma, and the phospholipid levels were significantly decreased in the tissues. Supplementation of SNFEt improved the antioxidant status by decreasing the levels of TBARS and altering the lipid profiles to near normal. These activities were also compared to the standard drug silymarin (25 mg/kg body weight). Thus the findings of the present study indicated a significant antioxidant and antihyperlipidemic activity of Solanum nigrum fruits, which offered protection against ethanol-induced toxicity.


Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation.
RUNX2 is an essential transcription factor required for skeletal development and cartilage formation. Haploinsufficiency of RUNX2 leads to cleidocranial displaysia (CCD) a skeletal disorder characterised by gross dysgenesis of bones particularly those derived from intramembranous bone formation. A notable feature of the RUNX2 protein is the polyglutamine and polyalanine (23Q/17A) domain coded by a repeat sequence. Since none of the known mutations causing CCD characterised to date map in the glutamine repeat region, we hypothesised that Q-repeat mutations may be related to a more subtle bone phenotype. We screened subjects derived from four normal populations for Q-repeat variants. A total of 22 subjects were identified who were heterozygous for a wild type allele and a Q-repeat variant allele: (15Q, 16Q, 18Q and 30Q). Although not every subject had data for all measures, Q-repeat variants had a significant deficit in BMD with an average decrease of 0.7SD measured over 12 BMD-related parameters (p = 0.005). Femoral neck BMD was measured in all subjects (-0.6SD, p = 0.0007). The transactivation function of RUNX2 was determined for 16Q and 30Q alleles using a reporter gene assay. 16Q and 30Q alleles displayed significantly lower transactivation function compared to wild type (23Q). Our analysis has identified novel Q-repeat mutations that occur at a collective frequency of about 0.4%. These mutations significantly alter BMD and display impaired transactivation function, introducing a new class of functionally relevant RUNX2 mutants.


Parasite diversity in adult patients with cerebral malaria: a hospital-based, case-control study.
Thirty adult patients with cerebral malaria (CM) were recruited for this study. Two clinical groups were used as controls: those with mild malaria (n = 20) and asymptomatic volunteers (n = 20). Thick and thin blood smears were examined for detection of Plasmodium falciparum and estimating infection intensity. A nested polymerase chain reaction (PCR) using allele-specific primers for merozoite surface protein gene was used to determine the parasite diversity of Plasmodium falciparum causing CM. Plasmodium falciparum was detected in blood smears of all malaria patients. No significant difference in parasite count was found between the groups. Thirteen (65%) of the asymptomatic volunteers had a positive PCR for P. falciparum. Multiple alleles were found in 17 (58.6%) patients with CM, but only in 7 (35.6%) with uncomplicated malaria. Multiple alleles were also found in 6 (46.2%) of the 13 PCR-positive asymptomatic individuals. We could not identify a specific strain or strains of P. falciparum that showed a significant association with disease severity. Therefore, we assume that the development of CM in adults residing in endemic areas is more dependent on strain multiplicity rather than on a specific strain or strains of P. falciparum, and that the parasite intensity has no relationship with disease severity. Asymptomatic adults may repeatedly be exposed to low levels of a wide range of different strains during low transmission season and acquire sub-patent parasitemia. This may also confer premunition that renders them relatively resistant to CM.


Use of additive and pretreatment to control odors in municipal kitchen waste during aerobic composting.
The effects of adding a bulking agent and chemically pretreating municipal kitchen waste before aerobic composting were studied using a laboratory-scale system. The system used 20-L reactors and each test lasted 28days. The objective was to decrease NH3 and H2S emissions during composting. The bulking agent, dry cornstalks, was mixed with the kitchen waste to give a mixture containing 15% (wet weight) bulking agent. A combined treatment was also conducted, in which kitchen waste mixed with the bulking agent was pretreated with ferric chloride (FeCl3). Less leachate was produced by the composted kitchen waste mixed with bulking agent than by the kitchen waste alone, when the materials had reached the required maturity. The presence of cornstalks also caused less H2S to be emitted, but had little impact on the amount of NH3 emitted. The FeCl3 was found to act as an effective chemical flocculant, and its presence significantly decreased the amounts of NH3 and H2S emitted. Kitchen waste mixed with cornstalks and treated with FeCl3 emitted 42% less NH3 and 76% less H2S during composting than did pure kitchen waste.


Plant traits in influencing soil moisture in semiarid grasslands of the Loess Plateau, China.
Large-scale vegetation restoration projects pose threats to water resource security in water-limited regions. Thus, the quantification of how vegetation cover affects soil moisture is of key importance to support effective restoration schemes in drylands. However, the current understanding of such effects remains poor. For this study, an in-situ vegetation-removal experiment was conducted at 36 herbaceous grassland sites having different community compositions and topographical conditions in two adjacent loess watersheds of the Loess Plateau, China. The effects of vegetation cover (vegetation effects) on soil moisture were analyzed across soil profiles (0-180 cm) and two growing seasons. Overall, 13 plant traits and 7 topographic and soil properties were employed to evaluate how community compositions modulated vegetation effects on soil moisture. The results showed that vegetation cover increased soil moisture in the surface layer (0-20 cm) by 6.81% during wet periods (semi-monthly rainfall >30 mm) relative to an in-situ unvegetated control, but primarily induced a decline of soil moisture in the deep soil layer (20-180 cm) by 19.44% across two growing seasons. Redundancy analysis (RDA) and structural equation modeling (SEM) suggested that these vegetation effects on soil moisture were significantly correlated with vegetative height, leaf area, shallow root allocation, and slope gradient. Our study revealed that tall, small-leaved, and shallow-rooted plants on flat topographies were beneficial to soil water retention and replenishment. This implied that current restoration strategies may be significantly improved through the development of optimal communities and diverse terracing measures. Our findings are anticipated to provide effective guidance for soil water conservation, as well as ecosystem rehabilitation in dry and degraded regions.


Periprosthetic osteolysis after total wrist arthroplasty.
Background and Literature Review Periprosthetic osteolysis (PPO) after second- or third-generation total wrist arthroplasty (TWA), with or without evident loosening of the implant components, has previously been reported in the literature, but rarely in a systematic way. Purpose The purpose of this study was to analyze the prevalence, location, and natural history of PPO following a TWA and to determine whether this was associated with prosthetic loosening. Patients and Methods We analyzed 44 consecutive cases in which a RE-MOTION TWA (Small Bone Innovations Inc., Morrisville, PA, USA) had been done. Results We found significant periprosthetic radiolucency (more than 2 mm in width) at the radial component side in 16 of the cases and at the carpal component side in 7. It developed gradually juxta-articularly around the prosthetic components regardless of the primary diagnosis, and seemed to stabilize in most patients after 1-3 years. In a small percentage of the patients, the periprosthetic area of bone resorption was markedly larger. In general, radiolucency was not related to evident loosening of the implant components, and only five carpal components and one radial had subsided or tilted. Conclusion Periprosthetic loosening is frequent following a TWA. In our series it was not necessarily associated with implant loosening and seemed to stabilize within 3 years. Close and continued observation is, however, recommended. Level of Evidence Therapeutic IV.


Erythrocyte aggregation and neutrophil function in an aging population.
There are limited investigations which have examined the relationship between neutrophil activation and erythrocyte aggregation in older persons. The purpose of the present study was to investigate the relationship between neutrophil activation and erythrocyte aggregation (EA) in an aging population. Twenty-eight male and female subjects were allocated into one of four groups with 7 participants in each group (group 1, 20-29 years; group 2, 30-39 years; group 3, 40-49 years; group 4, 50-59 years). EA was determined using the Myrenne aggregometer. Neutrophil function (respiratory burst and phagocytic activity) was assessed using flow cytometry. EA was found to increase with age. An ANOVA showed a significant (p < 0.05) increase for EA in autologous plasma in group 4 compared to groups 1 and 2. An ANOVA and Pearson's correlation showed that phagocytic activity decreased with age. Furthermore, a positive correlation between stimulated phagocytic activity and erythrocyte aggregability at low shear in 3% dextran-70 solution was observed. The current investigation suggests a decrease in neutrophil phagocytic activity with age and EA was increased with age. Additionally, the current study is novel as it suggests a possible relationship between neutrophil phagocytic activity and erythrocyte aggregability.


A 2nd generation linkage map of Heterobasidion annosum s.l. based on in silico anchoring of AFLP markers.
In this study, we present a 2(nd) generation genetic linkage map of a cross between the North American species Heterobasidion irregulare and H. occidentale, based on the alignment of the previously published 1(st) generation map to the parental genomes. We anchored 216 of the original 308 AFLP markers to their respective restriction sites using an in silico-approach. The map resolution was improved by adding 146 sequence-tagged microsatellite markers and 39 sequenced gene markers. The new markers confirmed the positions of the anchored AFLP markers, fused the original 39 linkage groups together into 17, and fully expanded 12 of these to single groups covering entire chromosomes. Map coverage of the genome increased from 55.3% to 92.8%, with 96.3% of 430 markers collinearly aligned with the genome sequence. The anchored map also improved the H. irregulare assembly considerably. It identified several errors in scaffold arrangements and assisted in reducing the total number of major scaffolds from 18 to 15. This denser, more comprehensive map allowed sequence-based mapping of three intersterility loci and one mating type locus. This demonstrates the possibility to utilize an in silico procedure to convert anonymous markers into sequence-tagged ones, as well as the power of a sequence-anchored linkage map and its usefulness in the assembly of a whole genome sequence.


Recommended guidelines for the treatment of cancer treatment-induced diarrhea.
To update and expand on previously published clinical practice guidelines for the treatment of cancer treatment-induced diarrhea. An expert multidisciplinary panel was convened to review the recent literature and discuss recommendations for updating the practice guidelines previously published by this group in the Journal of Clinical Oncology in 1998. MEDLINE searches were performed and the relevant literature published since 1998 was reviewed by all panel members. The treatment recommendations and algorithm were revised by panel consensus. A recent review of early toxic deaths occurring in two National Cancer Institute-sponsored cooperative group trials of irinotecan plus high-dose fluorouracil and leucovorin for advanced colorectal cancer has led to the recognition of a life-threatening gastrointestinal syndrome and highlighted the need for vigilant monitoring and aggressive therapy for this serious complication. Loperamide remains the standard therapy for uncomplicated cases. However, the revised guidelines reflect the need for recognition of the early warning signs of complicated cases of diarrhea and the need for early and aggressive management, including the addition of antibiotics. Management of radiation-induced diarrhea is similar but may not require hospitalization, and chronic low- to intermediate-grade symptoms can be managed with continued loperamide. With vigilant monitoring and aggressive therapy for cancer treatment-induced diarrhea, particularly in patients with early warning signs of severe complications, morbidity and mortality may be reduced.


Longitudinal Associations of the Cystic Fibrosis Airway Microbiome and Volatile Metabolites: A Case Study.
The identification of 16S rDNA biomarkers from respiratory samples to describe the continuum of clinical disease states within persons having cystic fibrosis (CF) has remained elusive. We sought to combine 16S, metagenomics, and metabolomics data to describe multiple transitions between clinical disease states in 14 samples collected over a 12-month period in a single person with CF. We hypothesized that each clinical disease state would have a unique combination of bacterial genera and volatile metabolites as a potential signature that could be utilized as a biomarker of clinical disease state. Taxonomy identified by 16S sequencing corroborated clinical culture results, with the majority of the 109 PCR amplicons belonging to the bacteria grown in clinical cultures (Escherichia coli and Staphylococcus aureus). While alpha diversity measures fluctuated across disease states, no significant trends were present. Principle coordinates analysis showed that treatment samples trended toward a different community composition than baseline and exacerbation samples. This was driven by the phylum Bacteroidetes (less abundant in treatment, log2 fold difference -3.29, p = 0.015) and the genus Stenotrophomonas (more abundant in treatment, log2 fold difference 6.26, p = 0.003). Across all sputum samples, 466 distinct volatile metabolites were identified with total intensity varying across clinical disease state. Baseline and exacerbation samples were rather uniform in chemical composition and similar to one another, while treatment samples were highly variable and differed from the other two disease states. When utilizing a combination of the microbiome and metabolome data, we observed associations between samples dominated Staphylococcus and Escherichia and higher relative abundances of alcohols, while samples dominated by Achromobacter correlated with a metabolomics shift toward more oxidized volatiles. However, the microbiome and metabolome data were not tightly correlated; examining both the metagenomics and metabolomics allows for more context to examine changes across clinical disease states. In our study, combining the sputum microbiome and metabolome data revealed stability in the sputum composition through the first exacerbation and treatment episode, and into the second exacerbation. However, the second treatment ushered in a prolonged period of instability, which after three additional exacerbations and treatments culminated in a new lung microbiome and metabolome.


Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome.
Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05-1.45) and 1.25 (95% CI 1.05-1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07-1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.


Outcomes of HIV-exposed children in western Kenya: efficacy of prevention of mother to child transmission in a resource-constrained setting.
To compare rates of mother to child transmission of HIV and infant survival in women-infant dyads receiving different interventions in a prevention of Mother to Child Transmission (pMTCT) program in western Kenya. Retrospective cohort study using prospectively collected data stored in an electronic medical record system. Eighteen HIV clinics in western Kenya. HIV-exposed infants enrolled between February 2002 and July 2007, at any of the United States Agency for International Development-Academic Model Providing Access To Healthcare partnership clinics. Combined endpoint (CE) of infant HIV status and mortality at 3 and 18 months. Descriptive statistics, chi Fisher exact test, and multivariable modeling. Between February 2002 and July 2007, 2477 HIV-exposed children were registered for care by the United States Agency for International Development-Academic Model Providing Access To Healthcare partnership pMTCT program before 3 months of age. Median age at enrollment was 6.1 weeks; 50.4% infants were male. By 3 months, 31 of 2477 infants (1.3%) were dead and 183 (7.4%) were lost to follow-up. One thousand (40%) underwent HIV DNA Polymerase Chain Reaction virologic test at a median age of 8.3 weeks: 5% were HIV infected, 89% uninfected, and 6% were indeterminate. Of the 968 infants with specific test results or mortality data at 3 months, the CE of HIV infection or death was reached in 84 of 968 (8.7%) infants. The 3-month CE was significantly impacted (A) by maternal prophylaxis [51 of 752 (6.8%) combination antiretroviral therapy (cART); 8 of 69 (11.6%) single-dose nevirapine (sdNVP); and 25 of 147 (17%) no prophylaxis (P < 0.001)] and (B) by feeding method for the 889 of 968 (91.8%) mother-infant pairs for which feeding choice was documented [5 of 29 (17.2%) exclusive breastfeeding; 13 of 110 (11.8%) mixed feeding; and 54 of 750 (7.2%) formula feeding (P = 0.041)]. Of the 1201 infants > or = 18 months of age: 41 (3.4%) were deceased and 329 (27.4%) were lost to follow-up. Of 621 of 831 (74.7%) infants tested, 65 (10.5%) were infected resulting in a CE of 103 of 659 (15.6%). CE differed significantly by maternal prophylaxis [52 of 441 (11.8%) for cART; 13 of 96 (13.5%) for sdNVP; and 38 of 122 (31.2%) no therapy group (P < 0.001)] but not by feeding method for the 638 of 659 (96.8%) children with documented feeding choice [7 of 35 (20%) exclusive breastfeeding, 14 of 63 (22.2%) mixed, and 74 of 540 (13.7%) formula (P = 0.131)]. On multivariate analysis, sdNVP (odds ratio: 0.4; 95% confidence interval: 0.2 to 0.8) and cART (odds ratio: 0.3; 95% confidence interval: 0.2 to 0.6) were associated with fewer CE. At 18 months, feeding method was not significantly associated with the CE. Though ascertainment bias is likely, results strongly suggest a benefit of antiretroviral prophylaxis in reducing infant death and HIV infection, but do not show a benefit at 18-months from the use of formula. There was a high rate of loss to follow up, and adherence to the HIV infant testing protocol was less than 50% indicating the need to address barriers related to infant HIV testing, and to improve outreach and follow-up services.


A Population-Based Surveillance Study of Shared Genotypes of Escherichia coli Isolates from Retail Meat and Suspected Cases of Urinary Tract Infections.
There is increasing evidence that retail food may serve as a source of Escherichia coli that causes community-acquired urinary tract infections, but the impact of this source in a community is not known. We conducted a prospective, population-based study in one community to examine the frequency of recovery of uropathogenic E. coli genotypes from retail meat samples. We analyzed E. coli isolates from consecutively collected urine samples of patients suspected to have urinary tract infections (UTIs) at a university-affiliated health service and retail meat samples from the same geographic region. We genotyped all E. coli isolates by multilocus sequence typing (MLST) and tested them for antimicrobial susceptibility. From 2016 to 2017, we cultured 233 E. coli isolates from 230 (21%) of 1,087 urine samples and 177 E. coli isolates from 120 (28%) of 427 retail meat samples. Urine samples contained 61 sequence types (STs), and meat samples had 95 STs; 12 STs (ST10, ST38, ST69, ST80, ST88, ST101, ST117, ST131, ST569, ST906, ST1844, and ST2562) were common to both. Thirty-five (81%) of 43 meat isolates among the 12 STs were from poultry. Among 94 isolates in the 12 STs, 26 (60%) of 43 retail meat isolates and 15 (29%) of 51 human isolates were pan-susceptible (P < 0.005). We found that 21% of E. coli isolates from suspected cases of UTIs belonged to STs found in poultry. Poultry may serve as a possible reservoir of uropathogenic E. coli (UPEC). Additional studies are needed to demonstrate transmission pathways of these UPEC genotypes and their food sources.IMPORTANCE Community-acquired urinary tract infection caused by Escherichia coli is one of the most common infectious diseases in the United States, affecting approximately seven million women and costing approximately 11.6 billion dollars annually. In addition, antibiotic resistance among E. coli bacteria causing urinary tract infection continues to increase, which greatly complicates treatment. Identifying sources of uropathogenic E. coli and implementing prevention measures are essential. However, the reservoirs of uropathogenic E. coli have not been well defined. This study demonstrated that poultry sold in retail stores may serve as one possible source of uropathogenic E. coli This finding adds to a growing body of evidence that suggests that urinary tract infection may be a food-borne disease. More research in this area can lead to the development of preventive strategies to control this common and costly infectious disease.


Effects of problem-based learning modules within blended learning courses in medical statistics - A randomized controlled pilot study.
Problem-based learning (PBL) allows students to learn medical statistics through problem solving experience. The aim of this study was to assess the efficiency of PBL modules implemented in the blended learning courses in medical statistics through knowledge outcomes and student satisfaction. The pilot study was designed as a randomized controlled trial that included 53 medical students who had completed all course activities. The students were randomized in two groups: the group with access to PBL modules within the blended learning course (hPBL group) and the group without access to PBL modules-only blended learning course (BL group). There were no significant differences between the groups concerning socio-demographic characteristics, previous academic success and modality of access to course materials. Students from hPBL group had a significantly higher problem solving score (p = 0.012; effect size 0.69) and the total medical statistics score (p = 0,046; effect size 0.57). Multivariate regression analysis with problem solving as an outcome variable showed that problem solving was associated with being in hPBL group (p = 0.010) and having higher grade point average (p = 0.037). Multivariate regression analysis with the medical statistics score as an outcome variable showed the association between a higher score on medical statistics with access to PBL modules (p = 0.045) and a higher grade point average (p = 0.021). All students in hPBL group (100.0%) considered PBL modules useful for learning medical statistics. PBL modules can be easily implemented in the existing courses within medical statistics using the Moodle platform, they have high applicability and can complement, but not replace other forms of teaching. These modules were shown to be efficient in learning, to be well accepted among students and to be a potential missing link between teaching and learning medical statistics. The authors of this study are planning to create PBL modules for advanced courses in medical statistics and to conduct this study on other universities with a more representative study sample, with the aim to overcome the limitations of the existing study and confirm its results.


Depression in primary care: review of AHCPR guidelines.
To present an overview and evaluation of the Agency for Health Care Policy and Research (AHCPR) clinical practice guidelines for the treatment of depression. One responsibility of the AHCPR is the development and periodic review and update of clinical practice guidelines. This process is undertaken by an independent panel composed of groups of clinicians and other experts from the private sector. Their findings are published in a four-volume, softcover set of booklets. DATA SOURCE AND EVALUATION: Volume 2 in the four-volume set includes a comprehensive complication, synthesis, and critical evaluation of the studies of different treatments for depression. Studies included for evaluation were randomized, prospective clinical trials that were pertinent to all topics concerning the treatment of depression. In some areas, the opinions of the panel were included due to a paucity of data from well-controlled clinical trials. Each AHCPR guideline was followed by a code that indicated whether the strength of evidence supporting that guideline was based on good or fair research-based evidence, or whether it was based primarily on panel members' opinions. With regard to drug treatment, the guidelines are good. However, since these guidelines were published in 1993 they might be considered somewhat dated because more antidepressants have become available in the interim. Overall, the AHCPR guidelines reflect an extensive review of the literature provided by the panel, as well as input from a highly respected group of reviewers. The panel included physicians, a nurse, a social worker, a psychologist, and a consumer representative. Unfortunately, a pharmacist was not included on the panel. Input from pharmacy practitioners would have been valuable.


Population pharmacokinetics, tolerability, and safety of dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine-piperaquine in pregnant and nonpregnant Papua New Guinean women.
The tolerability, safety, and disposition of dihydroartemisinin (DHA) and piperaquine (PQ) were assessed in 32 pregnant (second/third trimester) and 33 nonpregnant Papua New Guinean women randomized to adult treatment courses of DHA-PQ (three daily doses) or sulfadoxine-pyrimethamine (SP)-PQ (three daily PQ doses, single dose of SP). All dose adminstrations were observed, and subjects fasted for 2 h postdose. Plasma PQ was assayed by using high-performance liquid chromatography, and DHA was assessed by using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models were developed using a population-based approach. Both regimens were well tolerated. There was an expected increase in the rate-corrected electrocardiographic QT interval which was independent of pregnancy and treatment. Two pregnant and two nonpregnant women had Plasmodium falciparum parasitemia which cleared within 48 h, and no other subject became slide positive for malaria during 42 days of follow-up. Of 30 pregnant women followed to delivery, 27 (90%) delivered healthy babies and 3 (10%) had stillbirths; these obstetric outcomes are consistent with those in the general population. The area under the plasma PQ concentration-time curve (AUC0-∞) was lower in the pregnant patients (median [interquartile range], 23,721 μg · h/liter [21,481 to 27,951 μg · h/liter] versus 35,644 μg · h/liter [29,546 to 39,541 μg · h/liter]; P < 0.001) in association with a greater clearance relative to bioavailability (73.5 liters/h [69.4 to 78.4] versus 53.8 liters/h [49.7 to 58.2]; P < 0.001), but pregnancy did not influence the pharmacokinetics of DHA. The apparent pharmacokinetic differences between the present study and results from other studies of women with uncomplicated malaria that showed no effect of pregnancy on the AUC0-∞ of PQ and greater bioavailability may reflect differences in postdose fat intake, proportions of women with malaria, and/or racial differences in drug disposition.


MR image segmentation using a power transformation approach.
This study proposes a segmentation method for brain MR images using a distribution transformation approach. The method extends traditional Gaussian mixtures expectation-maximization segmentation to a power transformed version of mixed intensity distributions, which includes Gaussian mixtures as a special case. As MR intensities tend to exhibit non-Gaussianity due to partial volume effects, the proposed method is designed to fit non-Gaussian tissue intensity distributions. One advantage of the method is that it is intuitively appealing and computationally simple. To avoid performance degradation caused by intensity inhomogeneity, different methods for correcting bias fields were applied prior to image segmentation, and their correction effects on the segmentation results were examined in the empirical study. The partitions of brain tissues (i.e., gray and white matter) resulting from the method were validated and evaluated against manual segmentation results based on 38 real T1-weighted image volumes from the internet brain segmentation repository, and 18 simulated image volumes from BrainWeb. The Jaccard and Dice similarity indexes were computed to evaluate the performance of the proposed approach relative to the expert segmentations. Empirical results suggested that the proposed segmentation method yielded higher similarity measures for both gray matter and white matter as compared with those based on the traditional segmentation using the Gaussian mixtures approach.


An objective approach for Burkholderia pseudomallei strain selection as challenge material for medical countermeasures efficacy testing.
Burkholderia pseudomallei is the causative agent of melioidosis, a rare disease of biodefense concern with high mortality and extreme difficulty in treatment. No human vaccines are available that protect against B. pseudomallei infection, and with the current limitations of antibiotic treatment, the development of new preventative and therapeutic interventions is crucial. Although clinical trials could be used to test the efficacy of new medical countermeasures (MCMs), the high mortality rates associated with melioidosis raises significant ethical issues concerning treating individuals with new compounds with unknown efficacies. The US Food and Drug Administration (FDA) has formulated a set of guidelines for the licensure of new MCMs to treat diseases in which it would be unethical to test the efficacy of these drugs in humans. The FDA "Animal Rule" 21 CFR 314 calls for consistent, well-characterized B. pseudomallei strains to be used as challenge material in animal models. In order to facilitate the efficacy testing of new MCMs for melioidosis using animal models, we intend to develop a well-characterized panel of strains for use. This panel will comprise of strains that were isolated from human cases, have a low passage history, are virulent in animal models, and are well-characterized phenotypically and genotypically. We have reviewed published and unpublished data on various B. pseudomallei strains to establish an objective method for selecting the strains to be included in the panel of B. pseudomallei strains with attention to five categories: animal infection models, genetic characterization, clinical and passage history, and availability of the strain to the research community. We identified 109 strains with data in at least one of the five categories, scored each strain based on the gathered data and identified six strains as candidate for a B. pseudomallei strain panel.


Terlipressin and hepatorenal syndrome: what is important for nephrologists and hepatologists.
Hepatorenal syndrome (HRS) is a reversible form of functional renal failure that occurs with advanced hepatic cirrhosis and liver failure. Despite mounting research in HRS, its etiology and medical therapy has not been resolved. HRS encompasses 2 distinct types. Type 1 is characterized by the rapid development of renal failure that occurs within 2 wk and involves a doubling of initial serum creatinine. Type 2 has a more insidious onset and is often associated with ascites. Animal studies have shown that both forms, in particular type 1 HRS, are often precipitated by bacterial infections and circulatory changes. The prognosis for HRS remains very poor. Type 1 and 2 both have an expected survival time of 2 wk and 6 mo, respectively. Progression of liver cirrhosis and the resultant portal hypertension leads to the pooling of blood in the splanchnic vascular bed. The ensuing hyperdynamic circulation causes an ineffective circulatory volume which subsequently activates neurohormonal systems. Primarily the sympathetic nervous system and the renin angiotensin system are activated, which, in the early stages of HRS, maintain adequate circulation. Both advanced cirrhosis and prolonged activation of neurohormonal mechanisms result in fatal complications. Locally produced nitric oxide may have the potential to induce a deleterious vasodilatory effect on the splanchnic circulation. Currently medical therapy is aimed at reducing splanchnic vasodilation to resolve the ineffective circulation and maintain good renal perfusion pressure. Terlipressin, a vasopressin analogue, has shown potential benefit in the treatment of HRS. It prolongs both survival time and has the ability to reverse HRS in the majority of patients. In this review we aim to focus on the pathogenesis of HRS and its treatment with terlipressin vs other drugs.


Has the tobacco industry evaded the FDA's ban on 'Light' cigarette descriptors?
Under the Family Smoking Prevention and Tobacco Control Act (FSPTCA), the Food and Drug Administration (FDA) banned the use of "Lights" descriptors or similar terms on tobacco products that convey messages of reduced risk. Manufacturers eliminated terms explicitly stated and substituted colour name descriptors corresponding to the banned terms. This paper examines whether the tobacco industry complied with or circumvented the law and potential FDA regulatory actions. Philip Morris retailer manuals, manufacturers' annual reports filed with the Massachusetts Department of Public Health, a national public opinion survey, and market-wide cigarette sales data were examined. Manufacturers substituted "Gold" for "Light" and "Silver" for "Ultra-light" in the names of Marlboro sub-brands, and "Blue", "Gold", and "Silver" for banned descriptors in sub-brand names. Percent filter ventilation levels, used to generate the smoke yield ranges associated with "Lights" categories, appear to have been reassigned to the new colour brand name descriptors. Following the ban, 92% of smokers reported they could easily identify their usual brands, and 68% correctly named the package colour associated with their usual brand, while sales for "Lights" cigarettes remained unchanged. Tobacco manufacturers appear to have evaded a critical element of the FSPTCA, the ban on misleading descriptors that convey reduced health risk messages. The FPSTCA provides regulatory mechanisms, including banning these products as adulterated (Section 902). Manufacturers could then apply for pre-market approval as new products and produce evidence for FDA evaluation and determination whether or not sales of these products are in the public health interest.


In vitro and in vivo activities of novel, semisynthetic thiopeptide inhibitors of bacterial elongation factor Tu.
Recently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC(90) ≤ 0.25 μg/ml) but weaker against the streptococci (MIC(90) ≥ 4 μg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in the tuf gene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureus infections with 50% effective doses (ED(50)) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalis infections with ED(50) of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitro and in vivo activity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy.


Quality of life and satisfaction with treatment in subjects with type 2 diabetes: results from primary health care in Turkey.
The aim of this study was to assess the quality of life and degree of satisfaction with the treatment of patients with type 2 diabetes mellitus (T2DM) in primary health care in Turkey. A total of 180 adults with type 2 diabetes mellitus from the Family Medicine out-patient clinic were included in the study. Participants were asked to fill out a self-report survey to collect data via two well validated scales, including the Turkish version of the Audit of Diabetes Dependent Quality of Life (ADDQoL) instrument and the Diabetes Treatment Satisfaction Questionnaire (DTSQ). Overall average weighted impact score for the study group was -2.73 ± 2.56. Diabetes mellitus has the largest impact on enjoyment of food (mean ± SD impact rating: -1.63 ± 1.50). The mean score of the DTSQ was 21.02 ± 8.07 (range from better to worse: 36 to 0) for the entire group. Presence of diabetes-related complication was significantly related with lower treatment satisfaction scores (mean ± SD = 23.08 ± 7.32 without complications; mean ± SD = 18.48 ± 8.36 with complications, P = 0.003). Physicians working in primary care should be equipped with more recent knowledge of diabetes treatment in order to tailor more appropriate treatment strategies from current guidelines.


Preventing early child maltreatment: implications from a longitudinal study of maternal abuse history, substance use problems, and offspring victimization.
In the interest of improving child maltreatment prevention science, this longitudinal, community based study of 499 mothers and their infants tested the hypothesis that mothers' childhood history of maltreatment would predict maternal substance use problems, which in turn would predict offspring victimization. Mothers (35% White/non-Latina, 34% Black/non-Latina, 23% Latina, 7% other) were recruited and interviewed during pregnancy, and child protective services records were reviewed for the presence of the participants' target infants between birth and age 26 months. Mediating pathways were examined through structural equation modeling and tested using the products of the coefficients approach. The mediated pathway from maternal history of sexual abuse to substance use problems to offspring victimization was significant (standardized mediated path [ab] = .07, 95% CI [.02, .14]; effect size = .26), as was the mediated pathway from maternal history of physical abuse to substance use problems to offspring victimization (standardized mediated path [ab] = .05, 95% CI [.01, .11]; effect size = .19). There was no significant mediated pathway from maternal history of neglect. Findings are discussed in terms of specific implications for child maltreatment prevention, including the importance of assessment and early intervention for maternal history of maltreatment and substance use problems, targeting women with maltreatment histories for substance use services, and integrating child welfare and parenting programs with substance use treatment.


Prevalence of body-focused repetitive behaviors in three large medical colleges of Karachi: a cross-sectional study.
Body-focused repetitive behaviors (BFRBs) that include skin picking (dermatillomania), hair pulling (trichotillomania) and nail biting (onychophagia), lead to harmful physical and psychological sequelae.The objective was to determine the prevalence of BFRBs among students attending three large medical colleges of Karachi. It is imperative to come up with frequency to design strategies to decrease the burden and adverse effects associated with BFRBs among medical students. A cross-sectional study was conducted among 210 students attending Aga Khan University, Dow Medical College and Sind Medical College, Karachi, in equal proportion. Data were collected using a pre tested tool, "Habit Questionnaire". Diagnoses were made on the criteria that a student must be involved in an activity 5 times or more per day for 4 weeks or more. Convenience sampling was done to recruit the participants aged 18 years and above after getting written informed consent. The overall prevalence of BFRBs was found to be 46 (22%). For those positive for BFRBs, gender distribution was as follows: females 29 (13.9%) and males 17 (8.1%). Among these students, 19 (9.0%) were engaged in dermatillomania, 28 (13.3%) in trichotillomania and 13 (6.2%) in onychophagia. High proportions of BFRBs are reported among medical students of Karachi. Key health messages and interventions to reduce stress and anxiety among students may help in curtailing the burden of this disease which has serious adverse consequences.


Structural and functional multi-platform MRI series of a single human volunteer over more than fifteen years.
We present MRI data from a single human volunteer consisting in over 599 multi-contrast MR images (T1-weighted, T2-weighted, proton density, fluid-attenuated inversion recovery, T2* gradient-echo, diffusion, susceptibility-weighted, arterial-spin labelled, and resting state BOLD functional connectivity imaging) acquired in over 73 sessions on 36 different scanners (13 models, three manufacturers) over the course of 15+ years (cf. Data records). Data included planned data collection acquired within the Consortium pour l'identification précoce de la maladie Alzheimer - Québec (CIMA-Q) and Canadian Consortium on Neurodegeneration in Aging (CCNA) studies, as well as opportunistic data collection from various protocols. These multiple within- and between-centre scans over a substantial time course of a single, cognitively healthy volunteer can be useful to answer a number of methodological questions of interest to the community.


Parametric soliton laser.
The parametric soliton laser is described. It operates through parametric four-photon mixing in a synchronously pumped ring cavity. A dispersion-shifted single-mode fiber at 1.525 microm is used, and the pump wavelength is set at the wavelength of zero chromatic dispersion. Clear evidence of a threshold was found, and a pulse width of 210 fsec was obtained. An intensity-dependent carrier frequency was observed and is explained by phase matching through the nonlinear index.


The reflection of histology in MR imaging of Pelizaeus-Merzbacher disease.
Pelizaeus-Merzbacher disease is a rare disease of infants and young children in which there is an arrest of myelination of the CNS. The cause of the disorder is unknown. Three cases are reported, representing the connatal and classical forms of the disease. The MR images obtained of these children are compared with histologic findings as reported in the literature. In the connatal form a complete absence of myelin in the brain is demonstrated. In the classical form an arrest of myelination in an early stage of development is shown in combination with progressive abnormalities of the unmyelinated white matter and possibly a slow degradation of some myelin. MR imaging appears to be a unique diagnostic method for assessing the degree of hypomyelination, the core of Pelizaeus-Merzbacher disease, and for contributing to the understanding of the underlying pathology of this disorder.


Inhibition of eicosanoid biosynthesis by glucocorticoids in humans.
Therapeutic doses of glucocorticoids are thought to inhibit prostaglandin and leukotriene formation in humans. Several studies in animals, however, have failed to demonstrate modulation of eicosanoid biosynthesis by steroids in vivo. We administered prednisone (60 mg/day) to eight healthy volunteers and measured eicosanoid formation by a variety of cell types in vivo and ex vivo, using sensitive and specific physicochemical assays. We found that the in vivo course of prednisone failed to inhibit the synthesis of thromboxane A2, prostaglandin I2 (prostacyclin), prostaglandin E2, and leukotriene E4 in vivo and of leukotriene B4 ex vivo. Biosynthesis of leukotriene B4, thromboxane B2, and prostaglandins F2 and E2 by macrophage-rich bronchoalveolar lavage cells was strongly suppressed. These findings indicate that therapeutic regimens of glucocorticoids suppress eicosanoid biosynthesis in human macrophages but not in a number of other cell types with steroid receptors, the capacity for eicosanoid formation, and lipocortin-like material.


The dopant type and amount governs the electrochemical performance of graphene platforms for the antioxidant activity quantification.
Graphene doped with heteroatoms can show new or improved properties as compared to the original undoped material. It has been reported that the type of heteroatoms and the doping conditions can have a strong influence on the electronic and electrochemical properties of the resulting material. Here, we wish to compare the electrochemical behavior of two n-type and two p-type doped graphenes, namely boron-doped graphenes and nitrogen-doped graphenes containing different amounts of heteroatoms. We show that the boron-doped graphene containing a higher amount of dopants provides the best electroanalytical performance in terms of calibration sensitivity, selectivity and linearity of response for the detection of gallic acid normally used as the standard probe for the quantification of antioxidant activity of food and beverages. Our findings demonstrate that the type and amount of heteroatoms used for the doping have a profound influence on the electrochemical detection of gallic acid rather than the structural properties of the materials such as amounts of defects, oxygen functionalities and surface area. This finding has a profound influence on the application of doped graphenes in the field of analytical chemistry.


Caffeine administration does not alter salivary α-amylase activity in young male daily caffeine consumers.
To follow up on a recent report from our lab [Hum Psychopharmacol 25:359-367, 2010.] we examined the effects of caffeine on salivary α-amylase (sAA) activity in response to an engaging, non-stressful task in healthy young males (age 18-30 yrs) who consumed caffeine on a daily basis. Using a placebo-controlled, double-blind, between-subjects design, 45 men received either placebo, 200 mg or 400 mg of caffeine (Vivarin®). Participants then rested for 20 minutes, and performed a 20-minute computerized air traffic controller-like task that was cognitively engaging but not stressful. Saliva samples (assayed for sAA and cortisol), blood pressure, and heart rate were taken before (baseline) and 15 minutes after the computerized task. Systolic and diastolic blood pressure and sAA activity increased across the laboratory session (F's > 9.20, p's < 0.05); salivary cortisol levels decreased (F = 16.17, p < 0.05). There were no main effects for caffeine administration on sAA, salivary cortisol, or cardiovascular measures, and caffeine did not interact with the task to alter these measures. Laboratory administered caffeine does not alter sAA activity, even when sAA activity is stimulated by participating in a cognitively engaging task. These data demonstrate that caffeine administration does not affect sAA activity, at least in healthy young men who regularly consume caffeine. Results support recent findings that basal caffeine levels in habitual caffeine users are not associated with basal sAA activity and that daily caffeine intake and diurnal sAA activity are not related.


RIFM fragrance ingredient safety assessment, dodecane, CAS Registry Number 112-40-3.
Dodecane was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog nonane (CAS # 111-84-2) show that dodecane is not expected to be genotoxic. Data on read-across analog undecane (CAS # 1120-21-4) provide a calculated Margin of Exposure (MOE) >100 for the repeated dose toxicity and reproductive toxicity endpoints. The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/vis) spectra; dodecane is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to dodecane is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; dodecane was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.


Learning improvement after PI3K activation correlates with de novo formation of functional small spines.
PI3K activation promotes the formation of synaptic contacts and dendritic spines, morphological features of glutamatergic synapses that are commonly known to be related to learning processes. In this report, we show that in vivo administration of a peptide that activates the PI3K signaling pathway increases spine density in the rat hippocampus and enhances the animals' cognitive abilities, while in vivo electrophysiological recordings show that PI3K activation results in synaptic enhancement of Schaffer and stratum lacunosum moleculare inputs. Morphological characterization of the spines reveals that subjecting the animals to contextual fear-conditioning training per se promotes the formation of large spines, while PI3K activation reverts this effect and favors a general change toward small head areas. Studies using hippocampal neuronal cultures show that the PI3K spinogenic process is NMDA-dependent and activity-independent. In culture, PI3K activation was followed by mRNA upregulation of glutamate receptor subunits and of the immediate-early gene Arc. Time-lapse studies confirmed the ability of PI3K to induce the formation of small spines. Finally, we demonstrate that the spinogenic effect of PI3K can be induced in the presence of neurodegeneration, such as in the Tg2576 Alzheimer's mouse model. These findings highlight that the PI3K pathway is an important regulator of neuronal connectivity and stress the relationship between spine size and learning processes.


Sexual Partner Typologies Among Single Young Men Who Have Sex with Men.
Using data from a sample of single young men who have sex with men (N = 1,359, ages 18-24, 65 % White, 93 % gay), we examined whether the number of unprotected anal intercourse (UAI) partners with differed across relationship typologies (e.g., friends with benefits, hookups, romantic interests). We then examined how safer sex self-efficacy, decisional balance to forego condoms, ideal relationship attributes (i.e., intimacy, passion and commitment), and limerence were associated with UAI. Different partner types were associated with greater UAI partners; single partner types were associated with fewer UAI partners, irrespective of how they were categorized. UAI partners was associated with decisional balance (OR = 1.89, p < 0.001), passion ideation (OR = 1.38, p < 0.001), and difficulty negotiating safer sex with romantic partners (OR = 1.16, p < 0.001). Odds of UAI partners decreased with higher scores of commitment ideation (OR = 0.91, p < 0.05) and difficulty negotiating safer sex with casual partners (OR = 0.96, p < 0.05). We discuss the importance of acknowledging how different sexual partnerships, alongside its motivational correlates, influence UAI risk in order to inform HIV-prevention interventions.


Walk this way: approaching bodies can influence the processing of faces.
A highly familiar type of movement occurs whenever a person walks towards you. In the present study, we investigated whether this type of motion has an effect on face processing. We took a range of different 3D head models and placed them on a single, identical 3D body model. The resulting figures were animated to approach the observer. In a first series of experiments, we used a sequential matching task to investigate how the motion of an approaching person affects immediate responses to faces. We compared observers' responses following approach sequences to their performance with figures walking backwards (receding motion) or remaining still. Observers were significantly faster in responding to a target face that followed an approach sequence, compared to both receding and static primes. In a second series of experiments, we investigated long-term effects of motion using a delayed visual search paradigm. After studying moving or static avatars, observers searched for target faces in static arrays of varying set sizes. Again, observers were faster at responding to faces that had been learned in the context of an approach sequence. Together these results suggest that the context of a moving body influences face processing, and support the hypothesis that our visual system has mechanisms that aid the encoding of behaviourally-relevant and familiar dynamic events.


Effect of adenosine on Na+ and Cl- currents in A6 monolayers. Receptor localization and messenger involvement.
The effect of adenosine regulation on sodium and chloride transport was examined in cultured A6 renal epithelial cells. Adenosine and its analogue N6-cyclopentyladenosine (CPA) had different effects on short-circuit current (Isc) depending on the side of addition. Basolateral CPA addition induced an approximately threefold increase of the Isc that reached a maximum effect 20 min after addition and was completely inhibited by preincubation with either an A2 selective antagonist, CSC, or the sodium channel blocker, amiloride. Apical CPA addition induced a biphasic Isc response characterized by a rapid fourfold transient increase over its baseline followed by a decline and a plateau phase that were amiloride insensitive. The A1 adenosine antagonist, CPX, completely prevented this response. This Isc response to apical CPA was also strongly reduced in Cl--free media and was significantly inhibited either by basolateral bumetanide or apical DPC preincubation. Only basolateral CPA addition was able to induce an increase in cAMP level. CPA, added to cells in suspension, caused a rapid rise in [Ca2+]i that was antagonized by CPX, not affected by CSC and prevented by thapsigargin preincubation. These data suggest that basolateral CPA regulates active sodium transport via A2 adenosine receptors stimulating adenylate cyclase while apical CPA regulates Cl- secretion via A1 receptor-mediated changes in [Ca2+]i.


Analysis of T-cell clones in systemic lupus erythematosus.
It is fairly well established that T-helper (TH)((1)) cells play a role in the pathogenesis of organ-specific autoimmune diseases, while their role and their relationship with TH((2)) cells is far from being defined in systemic lupus erythematosus (SLE). To address this issue, six female patients who fulfilled the American Rheumatism Association criteria for the diagnosis of SLE were studied. We analyzed the intracellular production of cytokines by T-cells from the peripheral blood (PB). Then, we established T-cell clones (TCC) from the peripheral blood (PB) of all cases as well as from the synovial fluid of one patient with an articular flare-up. The percentages of IL-4 positive and IFN-g positive PB T-cells were not different between SLE patients and normal controls. When 93 TCC (67 CD4(+), 23 CD8(+)) from the PB of 5 different SLE patients were compared to 118 TCC (94 CD4(+), 23 CD8(+)) from 5 healthy controls no statistical difference was observed between SLE and controls in terms of TH((1)), TH((2)) or TH((0)) phenotype. However, SLE clones showed a reduced ability to secrete IL-10 (p = 0. 002). In contrast, the analysis of the 30 clones obtained from synovial fluid revealed that 11/23 CD4(+) clones were TH((1)), 12/23 were TH((0)), 2/7 CD8(+ )clones were TH((1)) and 5/7 were TH((0)). No TH((2)) clones were obtained from the synovial fluid. The data suggest that the T-cell subsets operating in actively inflamed organs of SLE may belong to the TH((1)) and TH((0)) subsets.


Status of hepatocellular carcinoma in South Korea.
In South Korea, liver cancer is the 4th most common cancer in men and 6th most common cancer in women. However, the incidences of liver cancer among Korean men and women have been declining from 1999 to 2010. The reason for the declining incidence appears secondary to decreased hepatitis B virus (HBV) infection, which is the leading risk factor for hepatocellular carcinoma (HCC), with successful implementation of HBV vaccination since 1983. Despite recent advances in the treatment of HCC, including liver transplantation (LT), radiofrequency ablation (RFA), transarterial embolization, and the use of molecularly targeted agents, many patients cannot be cured due to the advanced stage of HCC at the time of diagnosis in South Korea. While the 5-year survival rate of HCC patients in Korea is relatively lower than other cancers, it has been gradually increased from the early 1990s to the late 2000s. The reason for the improvement in 5-year survival rates is attributed that early detection of HCC becomes possible by well-established surveillance program in high-risk populations for HCC in Korea. In Korea, national surveillance program for HCC was established in 2003, in which repeated applications of screening tests [serum α-fetoprotein (AFP) and liver ultrasound] at 6-month intervals have been recommended in patients at high risk for developing HCC, such as men and women older than 40 years of age with positive hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) or underlying liver cirrhosis. It is essential that the nationwide surveillance program for HCC should be effectively executed in high-risk patients for developing HCC. Optimal application of multidisciplinary team approach and active involvement in clinical studies with new agents in HCC patients are critically important not only for the management of advanced HCC patients but also for the improvement in natural history and therapeutic outcomes of HCC patients in the future.


Sledding: how fast can they go?
Sledding, a fun and easily accessible winter sport, can potentially generate significant speed and energy posing a risk of injury. The objective of this study was to determine the speeds and potential kinetic energy generated by sledders. Observational study conducted of single sledders at sledding hills located in Monroe County, NY during February 2007. Participant's weight, age, and sled type were recorded. Speeds were recorded using Stalker police grade radar guns. Multiple runs by each sledder were measured. The kinetic energy for each run was calculated. Investigators recorded observations about injuries, near misses, and other safety issues. Seventy-six participants were enrolled with ages ranging from 4 year old to adult, including 54 children (18 years) with median age 9 years (range, 4-14 years). Of the 145 runs by single riders, 54 were on inner tubes, 89 on plastic/hard foam sleds, and 2 on other. The average speed was 19 mph (range, 14-25 mph). The average kinetic energy was 1,872 J (range, 329-6,441 J). Sledders on inner tubes went faster and generated more kinetic energy than those on plastic/hard foam sleds; mean 20.3 mph (95% CI 19.5-21.0) versus 18.3 mph (95% CI 17.8-18.7), p < 0.0001 and mean 2,136 J (95% CI 1,752-2,520) versus 1,707 J (95% CI 1,478-1,936), p < 0.05, respectively. None of the sledder wore a helmet and no injuries were observed. The potential for injury with sledding increases with weight and use of inner tubes, thus safe sledding practices and helmet use should be encouraged.


Ambient Air Pollution and Respiratory Health in Sub-Saharan African Children: A Cross-Sectional Analysis.
Ambient air pollution is projected to become a major environmental risk in sub-Saharan Africa (SSA). Research into its health impacts is hindered by limited data. We aimed to investigate the cross-sectional relationship between particulate matter with a diameter ≤ 2.5 μm (PM2.5) and prevalence of cough or acute lower respiratory infection (ALRI) among children under five in SSA. Data were collected from 31 Demographic and Health Surveys (DHS) in 21 SSA countries between 2005-2018. Prior-month average PM2.5 preceding the survey date was assessed based on satellite measurements and a chemical transport model. Cough and ALRI in the past two weeks were derived from questionnaires. Associations were analysed using conditional logistic regression within each survey cluster, adjusting for child's age, sex, birth size, household wealth, maternal education, maternal age and month of the interview. Survey-specific odds ratios (ORs) were pooled using random-effect meta-analysis. Included were 368,366 and 109,664 children for the analysis of cough and ALRI, respectively. On average, 20.5% children had reported a cough, 6.4% reported ALRI, and 32% of children lived in urban areas. Prior-month average PM2.5 ranged from 8.9 to 64.6 μg/m3. Pooling all surveys, no associations were observed with either outcome in the overall populations. Among countries with medium-to-high Human Development Index, positive associations were observed with both cough (pooled OR: 1.022, 95%CI: 0.982-1.064) and ALRI (pooled OR: 1.018, 95%CI: 0.975-1.064) for 1 μg/m3 higher of PM2.5. This explorative study found no associations between short-term ambient PM2.5 and respiratory health among young SSA children, necessitating future analyses using better-defined exposure and health metrics to study this important link.