GNE: a deep learning framework for gene network inference by aggregating biological information.
The topological landscape of gene interaction networks provides a rich source of information for inferring functional patterns of genes or proteins. However, it is still a challenging task to aggregate heterogeneous biological information such as gene expression and gene interactions to achieve more accurate inference for prediction and discovery of new gene interactions. In particular, how to generate a unified vector representation to integrate diverse input data is a key challenge addressed here. We propose a scalable and robust deep learning framework to learn embedded representations to unify known gene interactions and gene expression for gene interaction predictions. These low- dimensional embeddings derive deeper insights into the structure of rapidly accumulating and diverse gene interaction networks and greatly simplify downstream modeling. We compare the predictive power of our deep embeddings to the strong baselines. The results suggest that our deep embeddings achieve significantly more accurate predictions. Moreover, a set of novel gene interaction predictions are validated by up-to-date literature-based database entries. The proposed model demonstrates the importance of integrating heterogeneous information about genes for gene network inference. GNE is freely available under the GNU General Public License and can be downloaded from GitHub ( https://github.com/kckishan/GNE ).


Non-colinear polyketide biosynthesis in the aureothin and neoaureothin pathways: an evolutionary perspective.
Aureothin and neoaureothin (spectinabilin) represent rare nitroaryl-substituted polyketide metabolites from Streptomyces thioluteus and Streptomyces orinoci, respectively, which only differ in the lengths of the polyene backbones. Cloning and sequencing of the 39 kb neoaureothin (nor) biosynthesis gene cluster and its comparison with the aureothin (aur) pathway genes revealed that both polyketide synthase (PKS) assembly lines are remarkably similar. In both cases the module architecture breaks with the principle of colinearity, as individual PKS modules are used in an iterative fashion. Parsimony and neighbour-joining phylogenetic studies provided insights into the evolutionary process that led to the programming of these unusual type I PKS systems and to prediction of which modules act iteratively. The iterative function of the first module in the neoaureothin pathway, NorA, was confirmed by a successful cross-complementation.


Adjuvant Chemotherapy for Patients with T2N0M0 NSCLC.
Adjuvant chemotherapy improves survival in patients with completely resected stage II and III NSCLC. However, its role in patients with stage IB NSCLC disease remains unclear. We evaluated the role of adjuvant chemotherapy in a large data set of patients with completely resected T2N0M0 NSCLC. Patients with pathologic stage T2N0M0 NSCLC who underwent complete (R0) resection between 2004 and 2011 were identified from the National Cancer Data Base and classified into four groups based on tumor size: 3.1 to 3.9 cm, 4 to 4.9 cm, 5 to 5.9 cm, and 6 to 7 cm. Patients who died within 1 month after their operation were excluded. Survival curves were estimated by the Kaplan-Meier product-limit method and compared by log-rank test. Among the 25,267 patients who met the inclusion criteria, there were 4996 (19.7%) who received adjuvant chemotherapy. Adjuvant chemotherapy was associated with improved median and 5-year overall survival compared with observation for all tumor size groups. In patients with T2 tumors smaller than 4 cm, adjuvant chemotherapy was associated with improved median and 5-year overall survival in univariate (101.6 versus 68.2 months [67% versus 55%], hazard ratio [HR] = 0.66, 95% confidence interval [CI]: 0.61-0.72, p < 0.0001) and multivariable analysis (HR = 0.77, 95% CI: 0.70-0.83, p < 0.001) as well as propensity-matched score (101.6 versus 78.9 months [68% versus 60%], HR = 0.75, 95% CI: 0.70-0.86; p < 0.0001). In patients with completely resected T2N0M0, adjuvant chemotherapy is associated with improved survival in all tumor size groups. The benefit in patients with tumors smaller than 4 cm strongly suggests a role for chemotherapy in this patient population and counters its current status as an exclusion criteria for adjuvant trials.


Comparing Adult Hippocampal Neurogenesis Across Species: Translating Time to Predict the Tempo in Humans.
Comparison of neurodevelopmental sequences between species whose initial period of brain organization may vary from 100 days to 1,000 days, and whose progress is intrinsically non-linear presents large challenges in normalization. Comparing adult timelines when lifespans stretch from 1 year to 75 years, when underlying cellular mechanisms under scrutiny do not scale similarly, presents challenges to simple detection and comparison. The question of adult hippocampal neurogenesis has generated numerous controversies regarding its simple presence or absence in humans versus rodents, whether it is best described as the tail of a distribution centered on early neural development, or is several distinct processes. In addition, adult neurogenesis may have substantially changed in evolutionary time in different taxonomic groups. Here, we extend and adapt a model of the cross-species transformation of early neurodevelopmental events which presently reaches up to the equivalent of the third human postnatal year for 18 mammalian species (www.translatingtime.net) to address questions relevant to hippocampal neurogenesis, which permit extending the database to adolescence or perhaps to the whole lifespan. We acquired quantitative data delimiting the envelope of hippocampal neurogenesis from cell cycle markers (i.e., Ki67 and DCX) and RNA sequencing data for two primates (macaque and humans) and two rodents (rat and mouse). To improve species coverage in primates, we gathered the same data from marmosets (Callithrix jacchus), but additionally gathered data on a number of developmental milestones to find equivalent developmental time points between marmosets and other species. When all species are so modeled, and represented in a common time frame, the envelopes of hippocampal neurogenesis are essentially superimposable. Early developmental events involving the olfactory and limbic system start and conclude possibly slightly early in primates than rodents, and we find a comparable early conclusion of primate hippocampal neurogenesis (as assessed by the relative number of Ki67 cells) suggesting a plateau to low levels at approximately 2 years of age in humans. Marmosets show equivalent patterns within neurodevelopment, but unlike macaque and humans may have wholesale delay in the initiation of neurodevelopment processes previously observed in some precocial mammals such as the guinea pig and multiple large ungulates.


Classifying gene expression profiles from pairwise mRNA comparisons.
We present a new approach to molecular classification based on mRNA comparisons. Our method, referred to as the top-scoring pair(s) (TSP) classifier, is motivated by current technical and practical limitations in using gene expression microarray data for class prediction, for example to detect disease, identify tumors or predict treatment response. Accurate statistical inference from such data is difficult due to the small number of observations, typically tens, relative to the large number of genes, typically thousands. Moreover, conventional methods from machine learning lead to decisions which are usually very difficult to interpret in simple or biologically meaningful terms. In contrast, the TSP classifier provides decision rules which i) involve very few genes and only relative expression values (e.g., comparing the mRNA counts within a single pair of genes); ii) are both accurate and transparent; and iii) provide specific hypotheses for follow-up studies. In particular, the TSP classifier achieves prediction rates with standard cancer data that are as high as those of previous studies which use considerably more genes and complex procedures. Finally, the TSP classifier is parameter-free, thus avoiding the type of over-fitting and inflated estimates of performance that result when all aspects of learning a predictor are not properly cross-validated.


Calcitonin gene-related peptide prevents disuse-induced sprouting of rat motor nerve terminals.
Calcitonin gene-related peptide (CGRP) coexists with acetylcholine (ACh) in motor nerve terminals. Externally applied CGRP has been shown to increase the synthesis of ACh receptors in cultured myotubes by a mechanism independent of muscle activity. Thus, CGRP is suggested to be a neurotrophic factor that may regulate the expression of several long-term events occurring at the neuromuscular junction. We have examined the effect of CGRP on the sprouting of motor nerve terminals induced by chronic block of nerve-muscle activity in adult rats. Daily treatment with CGRP suppressed the disuse-induced terminal sprouting in a dose-dependent manner, whereas the morphology of motor nerve terminals in active muscles was unaffected by CGRP. CGRP may be a possible candidate for an antisprouting agent which has been postulated to exist in nerve terminals. The disuse-induced outgrowth of terminal sprouts was accompanied by an increase in the mean quantum content of end-plate potentials, as well as in the frequency of spontaneous miniature end-plate potentials. This increased transmitter release was still maintained at the junctions in which disuse-induced terminal sprouting had been suppressed by CGRP. It is suggested that the formation of terminal sprouts per se is not responsible for the plastic change of transmitter release induced by prolonged disuse of the neuromuscular junction.


Defining Remoteness from Health Care: Integrated Research on Accessing Emergency Maternal Care in Indonesia.
The causes of maternal death are well known, and are largely preventable if skilled health care is received promptly. Complex interactions between geographic and socio-cultural factors affect access to, and remoteness from, health care but research on this topic rarely integrates spatial and social sciences. In this study, modeling of travel time was integrated with social science research to refine our understanding of remoteness from health care. Travel time to health facilities offering emergency obstetric care (EmOC) and population distribution were modelled for a district in eastern Indonesia. As an index of remoteness, the proportion of the population more than two hours estimated travel time from EmOC was calculated. For the best case scenario (transport by ambulance in the dry season), modelling estimated more than 10,000 fertile aged women were more than two hours from EmOC. Maternal mortality ratios were positively correlated with the remoteness index, however there was considerable variation around this relationship. In a companion study, ethnographic research in a subdistrict with relatively good access to health care and high maternal mortality identified factors influencing access to EmOC, including some that had not been incorporated into the travel time model. Ethnographic research provided information about actual travel involved in requesting and reaching EmOC. Modeled travel time could be improved by incorporating time to deliver request for care. Further integration of social and spatial methods and the development of more dynamic travel time models are needed to develop programs and policies to address these multiple factors to improve maternal health outcomes.


The influence of social class, strain and social support on symptoms of anxiety and depression in mothers of toddlers.
The aim of the study was to identify risk and protective factors for anxiety and depression among mothers of toddlers. A population-based sample of 921 Norwegian mothers with 18-month-old children completed a questionnaire designed to examine the impact of socioeconomic and demographic factors, somatic health problems, negative life events, chronic strain and social support on symptoms of anxiety and depression (HSCL-25). There was a moderate aversive effect of negative life events and chronic strain and a moderate protective effect of social support on the symptom level, but no interaction effects were found between the risk and protective factors. Behaviour problems among the children clearly seemed to affect the mothers' symptom level. The symptom level varied with background factors like the mothers' education, employment status and age even after controlling for the effect of strain and social support. The largest effect of the background factors seemed to be indirect, however, mediated through their effect on the risk and protective factors. Although problems with the children's behaviour and child care arrangements were observed to have a strong impact on the mothers' symptom level, the frequencies of such problems appeared to be less dependent on socioeconomic conditions than did other types of strain.


Enhancing the Kinetic Stability of Polymeric Nanomicelles (PLGA) Using Nano-Montmorillonite for Effective Targeting of Cancer Tumors.
The toxic profile of chemical cross-linkers used in enhancing the stability of self-assembled nanomicelles made of amphiphilic polymeric materials hinders their use in clinical applications. This study was aimed to use the layered structure of Na-montmorillonite (MMT) as a stabilizer for nanomicelles made of poly(d,l-lactide-co-glycolide) (PLGA) amphiphilic polymer. The size of Na-MMT was reduced below 40 nm (nano-MMT) by processing in an attritor prior to its incorporation with PLGA. Hybrid PLGA nano-MMT (PM) nanoparticles (NPs) were prepared using dialysis nanoprecipitation. The size distribution was measured using dynamic light scattering (DLS). Loading 1250 μg of the model drug molecule curcumin to PM (PMC) resulted in obtaining 88 nm-sized particles, suitable for passive targeting of cancer tumors. The structure of nano-MMT and its position in PMC were investigated using FT-IR, differential scanning chalorimetry (DSC), XRF, XRD, ESEM, and EDAX assays, all of which showed the exfoliated structure of nano-MMT incorporated with both hydrophilic and hydrophobic blocks of PLGA. Curcumin was mutually loaded to PLGA and nano-MMT. This firm incorporation caused a serious extension in the release of curcumin from PMC compared to PLGA (PC). Fitting the release profile to different mathematical models showed the remarkable role of nano-MMT in surface modification of PLGA NPs. The ex vivo dynamic model showed the enhanced stability of PMC in simulated blood flow, while cytotoxicity assays showed that nano-MMT does not aggravate the good toxic profile of PLGA but improves the anticancer effect of payload. Nano-MMT could be used as an effective nontoxic stabilizer agent for self-assembled NPs.


Phosphorus in runoff assessed by anion exchange resin extraction and an algal assay.
Eutrophication of surface waters can be accelerated by agricultural inputs of phosphorus (P), provided that P is in a form that can be utilized by aquatic algae. We studied anion exchange resin (AER) extraction and a dual culture algal assay (DCAA) for the determination of potentially algal-available P in water samples without sediment preconcentration. Our material consisted of agricultural and forest runoff and wastewaters. The results obtained by the two methods were essentially equal when the samples contained only small amounts of particulate phosphorus (PP) in relation to dissolved molybdate-reactive phosphorus (DRP). However, in turbid agricultural runoff, P extracted with AER averaged 72% (n = 17) of the P yield of the 3-wk DCAA (R2 = 0.94). When the runoff samples were diluted for the AER extraction in the same manner as for the DCAA, the AER-P yield increased to 85% (n = 5) of DCAA-P. The minimum detectable value was greater for the AER test (41 microg L(-1) AER-extractable P) than for the DCAA (7 microg L(-1) DCAA-P). At concentrations greater than about 50 microg L(-1) AER-P or DCAA-P, the accuracy of the methods was satisfactory, with the coefficient of variation in replicated analyses being less than 10% for the AER test and less than 20% for the DCAA. Other anions competing for the exchange sites of the AER decreased P recovery by 15 to 20% when their equivalent concentration exceeded about 4 mmol, L(-1), and this effect was relatively constant over a large concentration range. We consider that AER extraction is a suitable low-cost method to estimate the algal availability of P in runoff samples.


Effect of aging on microleakage of restorative systems.
This study evaluated the sealing properties of AP.H/Prisma Universal Bond 3, Z100/Scotchbond MultiPurpose, AP.H/Imperva Bond, Charisma/Denthesive, Bisfil M/All-Bond 2, resin composite/dentin adhesive systems and Fuji II LC light-cured glass ionomer, in Class V preparations following 6 months of storage in a 37 degrees C water bath. The Class V preparations extended just beyond the cemento-enamel junction of extracted human molars. The restored teeth were placed in 37 degrees C water for 24 hours and then thermally stressed for 100 temperature cycles. Half of the specimens were tested for microleakage at this time. The other specimens were returned to water storage and thermally stressed every 30 days during the following 6 months and then assessed for microleakage by dye penetration. AP.H/Imperva Bond, Z100/Scotchbond Multi-Purpose and Fuji II LC were not affected by the storage, while AP.H/Prisma Universal Bond 3, Charisma/Denthesive and Bisfil M/All-Bond 2 revealed some increase in microleakage at the dentin/cememtum margin.


A comparative study of Mycobacterium avium subsp. avium and Mycobacterium avium subsp. hominissuis in experimentally infected pigs.
Mycobacterium avium subsp. avium (Maa) and Mycobacterium avium subsp. hominissuis (Mah) are opportunistic pathogens that may infect several species, including humans and pigs. Mah is however more frequently isolated from pigs than Maa, and it is unclear if this is due to difference in virulence or in exposure to the two organisms. Clinical isolates of each subspecies were administered perorally to ten domestic pigs, respectively. The animals were sacrificed at six and 12 weeks after inoculation. At necropsy, macroscopic lesions were recorded, and tissue samples were collected for mycobacterial culture, IS1245 real time PCR and histopathological examination. Culturing was also performed on faecal samples collected at necropsy. Macroscopic and histopathological lesions were detected in pigs infected with each subspecies, and bacterial growth and histopathological changes were demonstrated, also in samples from organs without gross pathological lesions. Six weeks after inoculation, live Mah was detected in faeces, as opposed to Maa. The presence of live mycobacteria was also more pronounced in Mah infected tonsils. In comparison, the Maa isolate appeared to have a higher ability of intracellular replication in porcine macrophages compared to the Mah isolate. The study shows that both subspecies were able to infect pigs. Additionally, the more extensive shedding of Mah might cause pig-to-pig transmission and contribute to the higher incidence of infection caused by this subspecies.


DNA methylation. The effect of minor bases on DNA-protein interactions.
DNA methylation is found almost ubiquitously in nature and the methyltransferases show evidence of a common evolutionary origin. It will be a fascinating study in protein evolution to follow the ways in which the structures of the various enzymes have developed. Although methylation may have a direct effect on DNA structure the evidence for the importance of this in vivo is accumulating only slowly. In contrast, there is now abundant evidence that methylation of DNA affects DNA-protein interactions and so may have a function in all processes in which such interactions occur. The binding of nucleases is affected in the processes of mismatch repair, DNA restriction and possibly demethylation during differentiation in vertebrates. The binding of transcription factors is affected by DNA methylation and the association of DNA with packaging and segregation proteins may play a part in the control of transcription and replication. The interplay of these effects makes DNA methylation a complex but rewarding area for study. Perhaps we should no longer refer to methylcytosine and methyladenine as minor bases, but rather as key bases which help regulate the functions of DNA.


The role of neuropeptides in the regulation of adrenal vascular tone: effects of vasoactive intestinal polypeptide, substance P, neuropeptide Y, neurotensin, Met-enkephalin, and Leu-enkephalin on perfusion medium flow rate in the intact perfused rat adrenal.
There is evidence that adrenal blood flow may be regulated in part by neuropeptides released from the capsular region of the adrenal gland in response to splanchnic nerve stimulation. The present study investigated the effects of various neuropeptides on the rate of perfusion medium flow through an intact in situ perfused rat adrenal preparation. Vasoactive intestinal polypeptide (VIP) had the greatest effect, causing a 136% increase in flow at the highest dose used (10 nmol in a 200 microliters bolus). Of the other peptides tested Met-enkephalin caused a 50% increase in flow, and the others (Leu-enkephalin, neurotensin and substance P) had only a minor effect, increasing perfusion medium flow rate by no more than around 35%. Neuropeptide Y, in contrast, caused a significant decrease in perfusion medium flow rate: the maximum effect was a 30% decrease with a dose of 1 nmol in a 200 microliters bolus. The significance of this observation awaits elucidation. It is clear from the actions of the neuropeptides tested that they may have a significant role in the regulation of adrenal blood flow. In view of the findings of other authors: that VIP is released in response to splanchnic nerve stimulation, and that it is specifically localised in the capsular region of the adrenal, it seems most likely that VIP is the major peptide involved in mediating the increased adrenal blood flow following splanchnic nerve stimulation.


The surgical treatment of severe Scheuermann's kyphosis.
To report the surgical outcome of patients with severe Scheuermann's kyphosis treated using a consistent technique and perioperative management. We reviewed 88 consecutive patients with a severe Scheuermann's kyphosis who had undergone posterior spinal fusion with closing wedge osteotomies and hybrid instrumentation. There were 55 males and 33 females with a mean age of 15.9 years (12.0 to 24.7) at the time of surgery. We recorded their demographics, spinopelvic parameters, surgical correction, and perioperative data, and assessed the impact of surgical complications on outcome using the Scoliosis Research Society (SRS)-22 questionnaire. The mean follow-up was 8.4 years (2 to 14.9). There were 85 patients (96.6%) with a thoracic deformity. Posterior spinal fusion with closing-wedge osteotomies and hybrid instrumentation was used in 86 patients; two patients underwent combined anterior and posterior spinal fusion. The mean kyphosis was corrected from 94.5° to 47.5° (p < 0.001). Coronal and sagittal balance returned to normal. The rate of complications was 12.5%: there were no neurological deficits, implant failure, or revision surgery. SRS-22 scores improved from a mean 3.6 (1.3 to 4.1) to 4.6 (4.2 to 5.0) at two years (p < 0.001) with a high rate of patient satisfaction. Non-smokers and patients with lower preoperative SRS-22 scores showed greater improvement in their quality of life. Sagittal pelvic balance did not change after correction of the kyphosis and correlated with lumbar lordosis but not with thoracic or thoracolumbar kyphosis. Posterior spinal fusion using hybrid instrumentation, closing-wedge osteotomies, and iliac bone grafting achieves satisfactory correction of a severe kyphosis resulting in improvements in physical and mental health and a high degree of patient-reported satisfaction. Cite this article: Bone Joint J 2021;103-B(1):148-156.


Clinical problems in the long-term care of patients with chronic depression.
This paper is a report of a study to explore problems encountered by mental health professionals in the long-term care of patients with chronic depression. Patients who do not profit from psychopharmacological or psychotherapeutic treatment often need long-term care. Although they experience severe symptoms and loss of functioning, little is known about these people and the care they receive. Experts in chronic depression (n = 8) participated in a four-phase Delphi study in 2006-2007. Problems were elicited through a focus group interview (first round) which was analysed using thematic analysis. The resulting problem list was validated (second round) and scored twice on a 7-point Likert scale (third and fourth rounds) by the participants. Urgency and changeability scores of 35 problems were obtained and a hierarchy of problems was set. In addition, qualitative data from the focus group interview were used to frame the results in the context of long-term care for patients with chronic depression. Problems were subdivided into five areas. Relapses by the patient, a pessimistic attitude by the professional and demoralization in both were major problems. Also noted were the negative societal connotations of chronic depression and the lack of a coherent view on treatment within mental health care. Chronicity of depression may be denied by both patients and professionals, resulting in an overly strong focus on cure and a limited quality of care. The results may be used as a starting point for construction of a best-practice programme to improve long-term care.


Can we build it? Yes we can, but should we use it? Assessing the quality and value of a very large phylogeny of campanulid angiosperms.
The study of very large and very old clades holds the promise of greater insights into evolution across the tree of life. However, there has been a fair amount of criticism regarding the interpretations and quality of studies to date, with some suggesting that detailed studies carried out on smaller, tractable scales should be preferred over the increasingly grand syntheses of these data. We provided in detail our trials and tribulations of compiling a large, sparsely sampled matrix from GenBank data and inferring a well-supported, time-calibrated phylogeny of Campanulidae. We also used a simulation approach to assess tree quality and to study the value of using very large, comprehensive phylogenies in a comparative context. A robust and well-supported phylogeny can be produced as long as automated procedures are supplemented with some human intervention. In the case of campanulids, the overall topology may be driven not only by particular genes, but also particular sequences for a gene. We also determined that estimates of divergence times should be fairly robust to issues related to clade-specific heterogeneity. Finally, we demonstrated how relying on results from smaller, younger clades are prone to produce biased interpretations of tropical to temperate evolution across campanulids as a whole. While we were both surprised and encouraged by the robust and fairly well-resolved, comprehensive phylogeny of campanulids, challenges still remain. Nevertheless, large phylogenies are inherently valuable in a comparative context if only to attenuate the issue of ascertainment bias.


[Comparison of Cookgas and Fastrach intubating laryngeal mask airway with fiberoptic bronchoscope in anticipated difficult airway management].
To compare the clinical effectiveness of fiberoptic bronchoscope (FOB)-guided intubation through the Cookgas intubating laryngeal airway(CILA)and the Fastrach intubating laryngeal mask airway (FT-LMA) in the management of anticipated difficult airways. Sixty patients with all three difficult intubation criterion (thyromental distance<60 mm, interincisor distance<35 mm, and Mallampati class 3 or 4) undergoing elective plastic surgery under general anesthesia were randomly allocated into CILA group (n=30) and FT-LMA group (n=30). After anesthesia being induced and CILA or FT-LMA being inserted, the patients were treated with FOB-guided intubation through CILA or FT-LMA. The success of the intubating laryngeal airway(ILA)insertion and FOB-guided intubation, the number of attempts, and the duration of the successful attempt were recorded. The ILA was inserted successfully in 30 patients from CILA group and 27 patients from FT-LMA group. Three failed cases in FT-LMA group were inserted successfully with CILA. In CILA group, the first FOB-guided intubation attempt succeeded in 26 patients, and 4 cases were intubated at the second attempt. In 27 patients of FT-LMA group, 20 cases were intubated successfully at the first attempt, 4 cases at the second attempt, and 3 cases failed; of these three failed patients, two patients were intubated smoothly with FOB through CILA at the first attempt, one was intubated by FOB via CILA at the second attempt. The duration of FT-LMA insertion [(35.3±12.8)s] was significantly longer when compared with CILA [(23.9±17.5)s] (P<0.05). However, the duration of FOB-guided intubation through CILA and FT-LMA [(48.6±13.5)s vs.(53.2±14.2)s] and the time of ILA removal [(40.4±10.2)s vs. (38.5±11.3)s] were not significantly different between these two groups (P>0.05). The adverse events during and after intubtion were not significantly different between these two groups. FOB-guided intubation through CILA and FT-LMA is safe and feasible for the management of anticipated difficult airways. However, in patients with severe scar contracture of face and neck and those with huge expander in neck, the CILA insertion and FOB-guided intubation via CILA is superior to FT-LMA.


Application of a methicillin-resistant Staphylococcus aureus risk score for community-onset pneumonia patients and outcomes with initial treatment.
Community-onset (CO) methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is an evolving problem, and there is a great need for a reliable method to assess MRSA risk at hospital admission. A new MRSA prediction score classifies CO-pneumonia patients into low, medium, and high-risk groups based on objective criteria available at baseline. Our objective was to assess the effect of initial MRSA therapy on mortality in these three risk groups. We conducted a retrospective cohort study using data from the Veterans Health Administration (VHA). Patients were included if they were hospitalized with pneumonia and received antibiotics within the first 48 h of admission. They were stratified into MRSA therapy and no MRSA therapy treatment arms based on antibiotics received in the first 48 h. Multivariable logistic regression was used to adjust for potential confounders. A total of 80,330 patients met inclusion criteria, of which 36% received MRSA therapy and 64% did not receive MRSA therapy. The majority of patients were classified as either low (51%) or medium (47%) risk, with only 2% classified as high-risk. Multivariable logistic regression analysis demonstrated that initial MRSA therapy was associated with a lower 30-day mortality in the high-risk group (adjusted odds ratio 0.57; 95% confidence interval 0.42-0.77). Initial MRSA therapy was not beneficial in the low or medium-risk groups. This study demonstrated improved survival with initial MRSA therapy in high-risk CO-pneumonia patients. The MRSA risk score might help spare MRSA therapy for only those patients who are likely to benefit.


Acid pH in tumors and its potential for therapeutic exploitation.
Measurement of pH in tissue has shown that the microenvironment in tumors is generally more acidic than in normal tissues. Major mechanisms which lead to tumor acidity probably include the production of lactic acid and hydrolysis of ATP in hypoxic regions of tumors. Further reduction in pH may be achieved in some tumors by administration of glucose (+/- insulin) and by drugs such as hydralazine which modify the relative blood flow to tumors and normal tissues. Cells have evolved mechanisms for regulating their intracellular pH. The amiloride-sensitive Na+/H+ antiport and the DIDS-sensitive Na+-dependent HCO3-/Cl- exchanger appear to be the major mechanisms for regulating pHi under conditions of acid loading, although additional mechanisms may contribute to acid extrusion. Mitogen-induced initiation of proliferation in some cells is preceded by cytoplasmic alkalinization, usually triggered by stimulation of Na+/H+ exchange; proliferation of other cells can be induced without prior alkalinization. Mutant cells which lack Na+/H+ exchange activity have reduced or absent ability to generate solid tumors; a plausible explanation is the failure of such mutant cells to withstand acidic conditions that are generated during tumor growth. Studies in tissue culture have demonstrated that the combination of hypoxia and acid pHe is toxic to mammalian cells, whereas short exposures to either factor alone are not very toxic. This interaction may contribute to cell death and necrosis in solid tumors. Acidic pH may influence the outcome of tumor therapy. There are rather small effects of pHe on the response of cells to ionizing radiation but acute exposure to acid pHe causes a marked increase in response to hyperthermia; this effect is decreased in cells that are adapted to low pHe. Acidity may have varying effects on the response of cells to conventional anticancer drugs. Ionophores such as nigericin or CCCP cause acid loading of cells in culture and are toxic only at low pHc; this toxicity is enhanced by agents such as amiloride or DIDS which impair mechanisms involved in regulation of pHi. It is suggested that acid conditions in tumors might allow the development of new and relatively specific types of therapy which are directed against mechanisms which regulate pHi under acid conditions.


Amaryllidaceae and Sceletium alkaloids.
Covering: July 2010 to June 2012. Previous review: Nat. Prod. Rep., 2011, 28, 1126-1142. Recent progress on the isolation, identification, biological activity and synthetic studies of structurally diverse alkaloids from plants of the family Amaryllidaceae is summarized in this review. In addition, the structurally related alkaloids isolated from Sceletium species are discussed as well.


Structure and characterisation of a duplicated human alpha 1 acid glycoprotein gene.
Human alpha 1-acid glycoprotein (AGP), also known as orosomucoid, is a major acute-phase plasma protein. The amino acid sequence of AGP, which was determined by sequencing from protein isolated from pooled plasma, contained amino acid substitutions in 21 different positions. Genomic and cDNA clones which correspond to one of the possible amino acid sequences have been previously reported. In this paper we present the complete nucleotide sequence of a second gene, AGP2 which is located approx. 3.3 kb downstream from AGP1. The derived amino acid sequence of AGP2 contains 19 of the possible alternative amino acid substitutions as well as two additional differences. It is clear from the results presented here that the AGP in human plasma is the product of two separate gene loci.


Sport-Specific Agility and Change of Direction in Water Polo: The Reliability and Validity of Two Newly Developed Tests.
Dong, L, Paradelo, D, Delorme, A, Oliveira, J, Parillo, B, Croteau, F, Romeas, T, Dubé, E, Bieuzen, F, Billaut, F, and Berryman, N. Sport-specific agility and change of direction in water polo: The reliability and validity of two newly developed tests. J Strength Cond Res 35(12S): S111-S118, 2021-There is a gap in water-based agility testing that considers both the change-of-direction (COD) and perceptive-reactive components of agility. This study sought to develop easily implementable, sport-specific in-water agility tests for water polo and to verify the reliability and validity of these new tests: the in-water Stop and Go (SG) and Jump and Go (JG). Female water polo athletes at the Senior (n = 12, age = 22.1 ± 2.1 years), Junior (n = 19, age = 18.5 ± 1.0 years), and Youth (n = 11, age = 16.5 ± 0.8 years) national levels performed 3 trials of each of the SG, JG, and the existing Functional Test for Agility Performance (FTAP). Senior athletes performed an additional experimental session to assess reliability parameters. Relative reliability for agility and COD versions of the SG and JG was high or very high (intraclass correlation coefficient [ICC] = 0.76-0.95). For construct validity analyses, significant between-group differences for each of the new tests (p < 0.05) were found. In contrast, the FTAP was moderately reliable (ICC = 0.57) and was unsuccessful in discriminating between playing levels. Considering the favorable metrological properties of the SG and JG, their fidelity to in-game demands, and their accessible setups, these new tests represent viable options to implement at grassroots and elite levels for the assessment and training of water polo-specific agility.


Extragenic suppressors that rescue defects in the heat stress response of the budding yeast mutant tom1.
The TOM1 gene codes for a so-called HECT protein, a putative ubiquitin ligase, in Saccharomyces cerevisiae. Deletion of the entire gene (tom1-10) or the sequence encoding the HECT domain (tom1-2) causes temperature sensitivity for growth. Here we report the isolation of extragenic, recessive suppressors of tom1-2, which were designated tmr (for tom1 revertant) mutations. These were classified into eight complementation groups and six of the genes were identified: tmr1/cyr1, tmnr2/sch9, tmr3/zuo1, tmr4, tmr5/mot1, tmr6/sse1, tmr7 and tmr8/kre6. These results suggested that the tom1 phenotype can be rescued by down-regulating the cAMP/PKA pathway. It was found that the temperature sensitivity of the tom1-2 mutant is indeed suppressed by multiple copies of PDE2 or BCY1, which encode negative regulators of the cAMP/PKA pathway. The MSN2 gene, which encodes a zinc-finger transcription factor involved in the general stress response is also a multicopy suppressor of tom1. It was found that induction levels of both STRE-mediated (general stress response) and HSE-mediated gene expression (heat shock response) upon shift to high temperature are reduced by more than half in the tom1 mutant. Most of the isolated tmr mutations rescued one of the defects seen in both types of heat stress response in the tom1 mutant.


Livestock water and land productivity in Kenya and their implications for future resource use.
Population growth and rising affluence increase the demand for agricultural commodities. Associated growth in production increases dependency on natural resources in countries that attempt to meet part or all of the new demand locally. This study assesses the impact of changing meat and milk production on natural resource use in Kenya under three plausible scenarios of socio-economic development, namely Business-As-Usual (BAU), Sustainable Development (SDP) and Kenya Vision 2030 (V2030) scenarios. The IMPACT model is used to estimate projected cattle, sheep, goats and camel production parameters for meat and milk. The BAU and SDP represent standard scenarios for Kenya of a global economic model, IMPACT, while V2030 incorporates in the model features specific to Kenya's medium-term national development plan. We use calculations of water footprint and land footprint as resource use indicators to quantify the anticipated appropriation of water and land resources for meat and milk production and trade by 2040. Though camel dairy production numbers increase the most by quadrupling between 2005 and 2040, it is cattle dairy production that significantly determined gains in production between the scenarios. Productivity gains under the SDP scenario does not match the investments made thereby leading to only slightly better values for water and land productivity than those achieved under the BAU scenario. Relative to the BAU scenario, improvement in land productivity under the V2030 scenario is the most dramatic for shoat milk production in the arid and semi-arid systems but the least marked for cattle milk production in the humid system. By quantifying water and land productivity across heterogenous production systems, our findings can aid decision-makers in Kenya and other developing countries to understand the implications of strategies aimed at increasing domestic agricultural and livestock production on water and land resources both locally and through trade with other countries.


Assessments of pulmonary macrophage clearance responses to inhaled particulates.
An integrated bioassay program is being developed to evaluate the toxicity of inhaled particulate materials. The multi-disciplined approach combines studies on lung clearance mechanisms with pulmonary macrophage functional assessments based on cellular biology, biochemical and cytochemical evaluations on lung specimens from exposed animals. To validate this method, animals were exposed to asbestos, iron-treated asbestos, fiberglass, Mt. St. Helens ash or carbonyl iron particles. Deposition patterns, macrophage migration and phagocytosis were monitored in vivo at selected time periods after exposure. Our results showed that chemotactic factor generation by particles in vitro correlated with the corresponding macrophage recruitment responses in vivo. In addition, macrophage morphologic and functional characteristics were evaluated following exposures to aerosolized dusts. Our results suggest that scanning electron microscopy (SEM) techniques for investigating particle deposition and macrophage clearance provide an important component for evaluating the toxicity of inhaled particulate materials.


Sports injuries in physical education teacher education students.
Sports injuries could be highly detrimental to the career of a physical education teacher education (PETE) student. To enable the development of future sports injury prevention programs, sports injuries in 128 first-year academic bachelor PETE students were registered prospectively during one academic year. Common risk factors for sports injuries, taken from the literature, were also evaluated by means of logistic regression analysis. We found an incidence rate of 1.91 and an injury risk of 0.85, which is higher than generally found in a sports-active population. Most injuries involved the lower extremities, were acute, newly occurring injuries, and took place in non-contact situations. More than half of all injuries lead to an inactivity period of 1 week or more and over 80% of all injuries required medical attention. A major part of these injuries happened during the intracurricular sports classes. Few differences were seen between women and men. A history of injury was a significant risk factor (P = 0.018) for the occurrence of injuries, and performance of cooling-down exercises was significantly related to a lower occurrence of ankle injuries (P = 0.031). These data can inform future programs for the prevention of sports injuries in PETE students.


Neurobiology of schizophrenia: search for the elusive correlation with symptoms.
In the last half-century, human neuroscience methods provided a way to study schizophrenia in vivo, and established that it is associated with subtle abnormalities in brain structure and function. However, efforts to understand the neurobiological bases of the clinical symptoms that the diagnosis is based on have been largely unsuccessful. In this paper, we provide an overview of the conceptual and methodological obstacles that undermine efforts to link the severity of specific symptoms to specific neurobiological measures. These obstacles include small samples, questionable reliability and validity of measurements, medication confounds, failure to distinguish state and trait effects, correlation-causation ambiguity, and the absence of compelling animal models of specific symptoms to test mechanistic hypotheses derived from brain-symptom correlations. We conclude with recommendations to promote progress in establishing brain-symptom relationships.


[Therapy of idiopathic Parkinson syndrome 1817 to 2001. A success story?].
It lasted some 150 years after the first description by James Parkinson in 1817 until levodopa, the first really efficacious treatment, was available for Parkinson's disease. Previously only anticholinergic substances and stereotaxic operations, both acting merely exclusively on tremor, were used for many and a few years respectively. Even today the treatment is purely symptomatic. There is no treatment in sight which would cure the disease or at least stop or slow down its progression.


Hepatocyte growth factor promotes endogenous repair and functional recovery after spinal cord injury.
Many therapeutic interventions using neurotrophic factors or pharmacological agents have focused on secondary degeneration after spinal cord injury (SCI) to reduce damaged areas and promote axonal regeneration and functional recovery. Hepatocyte growth factor (HGF), which was identified as a potent mitogen for mature hepatocytes and a mediator of inflammatory responses to tissue injury, has recently been highlighted as a potent neurotrophic and angiogenic factor in the central nervous system (CNS). In the present study, we revealed that the extent of endogenous HGF up-regulation was less than that of c-Met, an HGF receptor, during the acute phase of SCI and administered exogenous HGF into injured spinal cord using a replication-incompetent herpes simplex virous-1 (HSV-1) vector to determine whether HGF exerts beneficial effects and promotes functional recovery after SCI. This treatment resulted in the significant promotion of neuron and oligodendrocyte survival, angiogenesis, axonal regrowth, and functional recovery after SCI. These results suggest that HGF gene delivery to the injured spinal cord exerts multiple beneficial effects and enhances endogenous repair after SCI. This is the first study to demonstrate the efficacy of HGF for SCI.


Cases from the aerospace medicine residents' teaching file. Case #38. A navigator with nonischemic central retinal vein occlusion progressing to ischemic central retinal vein occlusion.
A case report of a young USAF navigator with nonischemic central retinal vein occlusion progressing to ischemic central retinal vein occlusion is presented. This young man was treated with hyperbaric oxygen therapy early in the course of his disease with complete resolution of his condition. Two years later his vision remained 20/17. This is the first known case of central retinal vein occlusion being treated with hyperbaric oxygen.


Peptides in the parabrachial nucleus modulate visceral input to the thalamus.
The role of neuropeptides in ascending visceral pathways was investigated by recording the changes in the response of thalamic neuronal activity evoked by vagal stimulation before and after peptide injection in the parabrachial nucleus (PB). Male Wistar rats (n = 25) were anesthetized with chloral hydrate and ventilated, and blood pressure and heart rate were continuously monitored. The left cervical vagus nerve was stimulated at submaximal current intensities to elicit changes in single and multiunit activity in the parvocellular visceral relay nuclei in the ventral basal thalamus. Peristimulustime histograms of thalamic activity were made before and after 200-nl injections of peptides or artificial cerebrospinal fluid (CSF) controls in the PB. Injection of calcitonin gene-related peptide (CGRP) at 5 mM or substance P (SP) at 2 mM into the PB significantly attenuated the evoked response of thalamic neuronal activity by 87-100% and 85-100%, respectively. Injections of somatostatin (SOM; 1 mM) did not significantly alter the response evoked by vagal stimulation but significantly inhibited the spontaneous firing of thalamic units, resulting in a 10-fold increase in the response-to-background ratio. This suggests that SOM in the PB inhibits cells in a parallel pathway that terminates on thalamic visceral neurons but that are not part of the ascending visceral sensory pathway. Spontaneous thalamic neuronal activity and vagally evoked responses were significantly enhanced (278-508%) by injection of 1 mM neurotensin (NT) in the PB. Cholecystokinin (CCK) at low doses (0.0002-0.2 mM) attenuated while the highest dose, 2 mM, briefly excited the spontaneous activity of thalamic units before inhibiting their activity.(ABSTRACT TRUNCATED AT 250 WORDS)


A dual-ion accepting vanadium carbide nanowire cathode integrated with carbon cloths for high cycling stability.
Herein, we report vanadium carbide (V8C7) nanowires (NWs) axially grown on carbon cloths (CCs) as a dual-ion accepting cathode for both lithium (LIBs) and sodium-ion batteries (SIBs). Using a facile hydrothermal method, we grew V2O3 NWs on CCs and subsequently reduced them to V8C7 by annealing with carbon sources under a H2/Ar atmosphere. In striking contrast to V2O5 NW cathodes obtained by annealing under air, the V8C7 NWs exhibit outstanding cycling stability during 500 cycles, and good rate capability for both LIBs and SIBs. V8C7 NWs as cathode active materials for LIBs exhibited 203.9 mA h g-1 specific capacity at 0.1 C after 500 cycles, 91.12% cycling retention and a coulombic efficiency of 99.84%. As cathodes in SIBs, the V8C7 NWs delivered 176.34 mA h g-1 specific capacity at 0.1 C during 300 cycles. Their defect sites by removal of the oxygen framework in V2O3 NWs have a high surface area (183.27 m2 g-1) and the unique 1D NW structure highly mitigates the volume changes during charge and discharge showing a superior electrochemical performance. Compared to commercially available cathodes, V8C7 nanowires have very good cycling stability and enhanced electrical conductivity. Moreover, the synergistic effect with 3D CCs utilized here as a current collector provides a large number of cation-accessible active sites in conjunction with high electrical conductivity and chemical stability.


Population genetics and forensic applications using multiplex PCR (CSF1PO, TPOX, and TH01) loci in the Basque Country.
A population study in a sample of 200 unrelated individuals from the Basque Country (Northern Spain) was carried out using the GenePrint STR Multiplex System. The PCR products were electrophorized on a denaturing polyacrylamide gel and visualized by silver staining. The loci are TH01, TPOX, and CSF1PO. All loci meet Hardy-Weinberg expectations, and independence of alelles at these STR loci was found. A comparison with other population groups appeared to indicate that frequencies are well conserved in Caucasians, but differ from those of other racial groups. We have also calculated Fst as a measure of population subdivision. No appreciable genetic subdivision in the Caucasian populations studied here was found. Some statistical parameters of forensic interest (Pex, PM and PD) were also calculated. No exclusions were found in 100 mother-child and father-child meiosis. To evaluate the applicability of these systems to forensic casework, we studied the minimum quantity of DNA which can be used applying the multiplex methodology, and the minimum quantity that can be typed in a mixed sample. We also examined several samples such as hair roots, semen stains, vaginal swabs, blood stains and temporary teeth, each of these of varying ages.


Combined analysis of the tobacco metabolites cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in human urine.
Two of the most widely measured compounds in the urine of people who use tobacco products are cotinine, a major metabolite of the addictive constituent nicotine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of the powerful lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Thousands of analyses have been reported in the literature, carried out exclusively, to the best of our knowledge, by separate methods. In the study reported here, we have developed a sensitive, accurate, and precise liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring method for the combined analysis of total cotinine (the sum of cotinine and its glucuronide) and total NNAL (the sum of NNAL and its glucuronide). The new method quantifies naturally occurring [(13)C]cotinine to minimize problems associated with the vast differences in concentration of total cotinine and total NNAL in urine. This method should greatly facilitate future determinations of these important compounds.


Healthy behaviors, risk factor control and awareness of chronic kidney disease.
The association between chronic kidney disease (CKD) awareness and healthy behaviors is unknown. We examined whether CKD self-recognition is associated with healthy behaviors and achieving risk-reduction targets known to decrease risk of cardiovascular morbidity and CKD progression. CKD awareness, defined as a 'yes' response to 'Has a doctor or other health professional ever told you that you had kidney disease?', was examined among adults with CKD (eGFR <60 ml/min/1.73 m(2)) who participated in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Odds of participation in healthy behaviors (tobacco avoidance, avoidance of regular nonsteroidal anti-inflammatory drug use, and physical activity) and achievement of risk-reduction targets (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, systolic blood pressure control and glycemic control among those with diabetes) among those aware versus unaware of their CKD were determined by logistic regression, controlling for sociodemographics, access to care and comorbid conditions. Systolic blood pressure control was defined as <130 mm Hg (primary definition) or <140 mm Hg (secondary definition). Of 2,615 participants, only 6% (n = 166) were aware of having CKD. Those who were aware had 82% higher odds of tobacco avoidance compared to those unaware (adjusted OR = 1.82, 95% CI 1.02-3.24). CKD awareness was not associated with other healthy behaviors or achievement of risk-reduction targets. Awareness of CKD was only associated with participation in one healthy behavior and was not associated with achievement of risk-reduction targets. To encourage adoption of healthy behaviors, a better understanding of barriers to participation in CKD-healthy behaviors is needed.


A Safety and Feasibility Trial of Ultrasound-Guided Radiofrequency Ablation of Parotid Warthin's Tumor.
To determine if ultrasound-guided (USG) radiofrequency ablation (RFA) of Parotid Warthin's tumor under local anesthesia is a safe and effective procedure. Safety and feasibility study. Tertiary academic medical center. This is an IDEAL phase 2a trial in a tertiary referral center. Twenty patients with Parotid Warthin's tumor were recruited. RFA was done between September and December 2021 for all 20 patients using a CoATherm AK-F200 machine with a disposable, 18G × 7 mm radiofrequency electrode. Results and follow-up statistics were compared with a historic sample of patients with parotid Warthin's tumor who underwent parotidectomy between 2019 and 2021 in the same center. Nineteen patients were included in the analysis as 1 patient dropped out after 4 weeks of follow-up. The mean age for the RFA group was 67 years old with most of them being male smokers. At a median of 45 weeks (44-47 weeks) postprocedure there was a 7.48 mL (68.4%) volume reduction compared to baseline. Three patients had transient facial nerve (FN) paresis, 1 recovered within hours, and the other 2 by 12 weeks follow-up. Three patients had great auricular nerve numbness; 1 patient had infected hematoma treated in an out-patient manner. Compared to a historic cohort of parotidectomy patients for Warthin's tumor, there was no significant difference in FN paresis and other minor complications between the 2 treatment modalities. The current analysis suggests that USG RFA of Warthin's Tumor is a safe alternative to parotidectomy with shorter operative time and length of stay.


The Peripheral Flicker Illusion.
A new illusion is reported. A visual object suddenly appearing on a red background sometimes causes an impression of flicker or double flash. In Experiment 1, a red, green, or blue object was presented on a red, green, blue, or gray background. Participants evaluated the illusion strength in reference to the physical flicker of a gray object presented in central vision. The results show that the green or blue object presented on the red background caused the illusion. In Experiment 2, the effect of retinal eccentricity on the illusion was tested. The results showed that the illusion was weak in central vision but became stronger as the retinal eccentricity of the objects' presentation increased. In Experiment 3, optimal luminance conditions for the illusion were explored with the green and blue objects. The illusion was strong when object luminance was lower than background luminance and the optimal luminance for the blue object was lower than that for the green object. We propose a tentative theory for the illusion and discuss its cause.


Alien hand syndrome: neural correlates of movements without conscious will.
The alien hand syndrome is a striking phenomenon characterized by purposeful and autonomous movements that are not voluntarily initiated. This study aimed to examine neural correlates of this rare neurological disorder in a patient with corticobasal degeneration and alien hand syndrome of the left hand. We employed functional magnetic resonance imaging to investigate brain responses associated with unwanted movements in a case study. Results revealed that alien hand movements involved a network of brain activations including the primary motor cortex, premotor cortex, precuneus, and right inferior frontal gyrus. Conscious and voluntary movements of the alien hand elicited a similar network of brain responses but lacked an activation of the inferior frontal gyrus. The results demonstrate that alien and unwanted movements may engage similar brain networks than voluntary movements, but also imply different functional contributions of prefrontal areas. Since the inferior frontal gyrus was uniquely activated during alien movements, the results provide further support for a specific role of this brain region in inhibitory control over involuntary motor responses. We discuss the outcome of this study as providing evidence for a distributed neural network associated with unwanted movements in alien hand syndrome, including brain regions known to be related to movement execution and planning as well as areas that have been linked to inhibition control (inferior frontal gyrus) and experience of agency (precuneus).


Preservation techniques for heart transplantation: comparison of hypothermic storage and hypothermic perfusion.
Preservation of the donor heart is an important and controversial subject in heart transplantation. This study compares simple hypothermic storage and hypothermic perfusion in a swine model of heart transplantation (n = 14). The donor hearts of group A (n = 7) were placed in simple hypothermic storage for 5 hours. The donor hearts of group B (n = 7) were placed onto a perfusion apparatus for 5 hours, with pressure maintained at 28 cm of H2O and a myocardial temperature of 8 to 10 degrees C. In both groups the hearts were initially protected with isosmolar potassium cardioplegic solution. The perfusate in group B contained moderate sodium, mannitol, glucose, insulin, and oxygen. The ischemic interval within both groups was 6 hours including orthotopic transplantation. Investigation was conducted at three time periods: prepreservation, postpreservation, and immediately after loading. For both groups there was nonsignificant depression of myocardial function (cardiac index, stroke index, stroke work index, ejection fraction, and wall stress) at the postpreservation period. After volume loading, for the hypothermic perfusion group there was significant improvement of myocardial function (cardiac index, p less than 0.01; stroke index, p less than 0.01) with no significant change in heart rate, systemic vascular resistance, and systolic blood pressure. There was also significant improvement in myocardial performance (p less than 0.05) for the hypothermic perfusion group after volume loading. Ultrastructural changes were minimal for both groups, and there were no major heart transplantation after 6 hours of ischemia; however, hearts retain their contractile capacity better after hypothermic perfusion than after simple hypothermic storage.(ABSTRACT TRUNCATED AT 250 WORDS)


NEW BACTERIAL POLYSACCHARIDE FROM ARTHROBACTER.
A bacterial strain (NRRL B-1973) isolated from soil at Guatemala City and tentatively identified as an Arthrobacter species produced a polysaccharide with unusual properties. Conditions were studied for the production of this microbial gum in shaken flasks and 20-liter fermentors. Suitable nutrients for optimal polysaccharide production included 3% glucose, 0.3% enzyme-hydrolyzed casein, magnesium sulfate, manganese sulfate, and potassium phosphate buffer (pH 7.0). Polysaccharide yields ranged from 40 to 45%, based on initial dextrose in the medium in 3- or 4-day fermentations. The gum was readily recovered from culture fluid by alcohol precipitation in the presence of an electrolyte. The Arthrobacter gum exhibited characteristics unique for a polyelectrolyte. Viscosity of solutions was not decreased by heating in the presence of salt, and the gum withstood a temperature of 121 C for 30 min. At polysaccharide levels above 0.75%, gels were formed when solutions were autoclaved with KCl. There was no significant change in viscosity over a pH range of 5.0 to 10.0.


Precision of mean transit time measurements in 99Tcm-DTPA renal scintigraphy: a Monte Carlo study.
The precision of renal mean transit time (MTT) measurements by 99Tcm-DTPA scintigraphy was studied by a Monte Carlo procedure. Data were obtained from twenty mild essential hypertensives with normal renal function. An ensemble of equivalent data sequences was constructed for each renal time-activity curve (TAC), assuming the dominant noise in the data to be Poisson in character. TACS were deconvolved by the matrix method and MTT was inferred from retention functions by a procedure entailing a nonlinear least-squares minimization. For every ensemble of data sequences a distribution of MTTs was generated. The population-averaged coefficients of variation for these distributions were 1.6% and 2.6%, for whole-kidney and cortical data, respectively. We conclude that the precision of MTT determination from clinical data is comparable to that from simulated data. MTT measurements may be useful for detecting functional changes in individual kidneys following an intervention such as angiotensin-converting-enzyme inhibition.


Mapping recombinant events with molecular markers in hemochromatosis pedigrees.
The gene responsible for hereditary hemochromatosis (HH) is tightly linked to the class I region of the human leukocyte antigen (HLA) complex. Initial studies designed to map the disease locus have relied on serological markers for the class I antigens. Molecular markers from this region can now be used in combination with HLA serotyping for mapping studies. We previously reported two pedigrees in which serological data indicated recombinant events within the class I region. These data suggested a location for the HH locus between HLA-A and HLA-B. Molecular mapping studies have allowed us to demonstrate that an apparent recombination in one pedigree did not occur. This approach has also produced a more precise centromeric boundary for the region containing the disease locus, telomeric of HLA-C. These results emphasize the importance of including both serological and molecular markers in pedigree studies aimed at fine mapping the HH locus.


Human benign prostatic hyperplasia stromal cells as inducers and targets of chronic immuno-mediated inflammation.
Benign prostatic hyperplasia (BPH), a highly prevalent prostatic condition, could involve an inflammatory component in disease pathogenesis. In this study, we show that human stromal prostate cells obtained from BPH tissue can actively contribute to the inflammatory process by secreting proinflammatory cytokines as well as chemokines able to recruit lymphomonuclear cells and by acting as APCs. BPH cells express all of the TLRs and their ligation leads to the secretion of CXCL8/IL-8, CXCL10, and IL-6. In addition, BPH cells express costimulatory as well as class I and class II MHC molecules, which activate alloreactive CD4(+) cells that in turn markedly up-regulate IL-12/IL-23p40 and IL-12p75 secretion by BPH cells. Alloreactive CD4(+) cells activated by BPH cells secrete IFN-gamma and IL-17. These cytokines up-regulate IL-6, IL-8, and CXCL10 production by BPH cells, creating a positive feedback loop that can amplify inflammation. IL-8 induces autocrine/paracrine proliferation of BPH cells, indicating also a growth-promoting activity of this chemokine in disease pathogenesis. These results show that human BPH cells represent nonprofessional APCs able to induce and sustain chronic inflammatory processes, supporting the relevance of inflammation in BPH pathogenesis.


A computational study of the hemodynamic impact of open- versus closed-cell stent design in carotid artery stenting.
The aim of this study is to analyze the shape and flow changes of a patient-specific carotid artery after carotid artery stenting (CAS) performed using an open-cell (stent-O) or a closed-cell (stent-C) stent design. First, a stent reconstructed from micro-computed tomography (microCT) is virtually implanted in a left carotid artery reconstructed from CT angiography. Second, an objective analysis of the stent-to-vessel apposition is used to quantify the lumen cross-sectional area and the incomplete stent apposition (ISA). Third, the carotid artery lumen is virtually perfused in order to quantify its resistance to flow and its exposure to atherogenic or thrombogenic hemodynamic conditions. After CAS, the minimum cross-sectional area of the internal carotid artery (ICA) (external carotid artery [ECA]) changes by +54% (-12%) with stent-O and +78% (-17%) with stent-C; the resistance to flow of the ICA (ECA) changes by -21% (+13%) with stent-O and -26% (+18%) with stent-C. Both stent designs suffer from ISA but the malapposed stent area is larger with stent-O than stent-C (29.5 vs. 14.8 mm(2) ). The untreated vessel is not exposed to atherogenic flow conditions whereas an area of 67.6 mm(2) (104.9) occurs with stent-O (stent-C). The area of the stent surface exposed to thrombogenic risk is 5.42 mm(2) (7.7) with stent-O (stent-C). The computer simulations of stenting in a patient's carotid artery reveal a trade-off between cross-sectional size and flow resistance of the ICA (enlarged and circularized) and the ECA (narrowed and ovalized). Such a trade-off, together with malapposition, atherogenic risk, and thrombogenic risk is stent-design dependent.


Syndemic Conditions and Their Association with HIV/STI Sexual Risk Behaviors Among Transgender Women and Cisgender Men Sex Workers in Catalonia: The SexCohort Project.
Transgender women and cisgender men sex workers are vulnerable to HIV and sexually transmitted infections (STIs). This study aimed to explore in depth the prevalence of syndemic conditions and their association with the sexual risk behaviors for HIV/STI acquisition in cis men and trans women sex workers in Barcelona (Catalonia, Spain). We conducted a study between 2014 and 2018 to determine whether syndemic conditions (frequent alcohol consumption and polydrug use (> 2) during sex with clients; experience of violence; and lack of healthcare access) are associated with HIV/STI sexual risk behaviors. A "syndemic index" was calculated based on the cumulative number of syndemic conditions (0 to 4). In the last year (2018), 78.8% of cisgender men and 68.1% of transgender women reported at least one syndemic condition. The most prevalent syndemic factor in both cisgender men and transgender women was violence (38.8% and 43.6% respectively). In multivariable analysis, an association was found between condomless anal sex and violence (aOR = 1.81), and frequent alcohol consumption and violence with reporting > 10 clients/week (aOR = 2.73 and 1.88, respectively). The higher the number of syndemic factors, the greater probability of having > 10 clients/week and reporting condomless anal sex with clients. Psychosocial conditions have a syndemic effect on risky sexual behaviors highlighting the need for a more holistic approach to HIV/STI prevention targeting these populations.


Consistent and reproducible long-term in vitro growth of health and disease-associated oral subgingival biofilms.
Several in vitro oral biofilm growth systems can reliably construct oral microbiome communities in culture, yet their stability and reproducibility through time has not been well characterized. Long-term in vitro growth of natural biofilms would enable use of these biofilms in both in vitro and in vivo studies that require complex microbial communities with minimal variation over a period of time. Understanding biofilm community dynamics in continuous culture, and whether they maintain distinct signatures of health and disease, is necessary to determine the reliability and applicability of such models to broader studies. To this end, we performed next-generation sequencing on biofilms grown from healthy and disease-site subgingival plaque for 80 days to assess stability and reliability of continuous oral biofilm growth. Biofilms were grown from subgingival plaque collected from periodontitis-affected sites and healthy individuals for ten eight-day long generations, using hydroxyapatite disks. The bacterial community in each generation was determined using Human Oral Microbe Identification by Next-Generation Sequencing (HOMINGS) technology, and analyzed in QIIME. Profiles were steady through the ten generations, as determined by species abundance and prevalence, Spearman's correlation coefficient, and Faith's phylogenetic distance, with slight variation predominantly in low abundance species. Community profiles were distinct between healthy and disease site-derived biofilms as demonstrated by weighted UniFrac distance throughout the ten generations. Differentially abundant species between healthy and disease site-derived biofilms were consistent throughout the generations. Healthy and disease site-derived biofilms can reliably maintain consistent communities through ten generations of in vitro growth. These communities maintain signatures of health and disease and of individual donors despite culture in identical environments. This subgingival oral biofilm growth and perpetuation model may prove useful to studies involving oral infection or cell stimulation, or those measuring microbial interactions, which require the same biofilms over a period of time.


Functional diversity in vascular endothelial cells: role in coxsackievirus tropism.
Six plaque-purified virus isolates were obtained from liver and heart tissues of a DBA/2 mouse infected 7 days earlier with 10(4) PFU of coxsackievirus group B type 3. Each virus isolate was assayed in vitro for infectivity to vascular endothelial cells (VEC) of the liver, lungs, and heart. Both the percentage of VEC infected and the mean progeny PFU produced per infected VEC were determined. Virus isolates from the heart showed greater infectivity and replication in heart VEC than in VEC derived from either the liver or lungs. Similarly, virus isolated from the liver preferentially infected liver VEC. Virus receptor expression varied between VEC populations, as demonstrated by binding studies with a [35S]methionine-radiolabeled heart virus and by enzyme-linked immunoadsorption assay studies with a monoclonal antibody to the coxsackievirus group B type 3 receptor on heart tissue. Finally, the heart and liver virus isolates were injected (10(4) PFU) intraperitoneally into BALB/c mice. After 7 days, the animals were sacrificed, and the hearts, livers, and lungs were evaluated for tissue injury and virus concentrations. Viruses originally isolated from the heart preferentially infected the heart when reinjected into animals and caused severe myocarditis. Viruses originally derived from the liver most consistently reinfected the liver, although significant virus concentrations were also detected in the heart. The liver virus isolates, however, were incapable of causing myocarditis. Thus, selective tropism of viruses for particular organs in vivo corresponds to the ability of these isolates to infect VEC in vitro.


Ischemic preconditioning of musculocutaneous flaps: effects of ischemia cycle length and number of cycles.
Previous work in our laboratory has indicated that ischemic preconditioning improves musculocutaneous flap survival 2.5 times that of the control flap area when the flaps are subsequently subjected to 4 hours of global ischemia. The preconditioning protocol used in this study was arbitrarily designed to be 10 minutes of pedicle clamping followed by 10 minutes of reperfusion. This sequence was repeated for three cycles with a total preconditioning time of 1 hour. There are no published works comparing different preconditioning protocols in musculocutaneous flaps. The goal of this study was to determine if the ischemic cycle time and the number of cycles influenced the effectiveness of ischemic preconditioning. Fifty-one male Sprague-Dawley rats were divided into one control and six treatment groups of 6 to 10 animals in each group. A transverse rectus abdominis musculocutaneous flap based on the inferior epigastric vessels was elevated in each animal. Flaps were preconditioned by pedicle clamping and reperfusion for either 5 or 10 minutes per cycle. This was repeated for one, two, or three cycles. Controls were simply perfused for 30 minutes. Each flap was then subjected to 4 hours of global ischemia. Flap surface survival area was calculated on the fifth postoperative day by computerized video planimetry. Differences in survival areas between control and preconditioned flaps were compared using analysis of variance and t-tests. There was an overall statistical significance in the comparison of flap survival of preconditioned flaps with that of controls. A single 5-minute cycle improved flap survival 2.5 times the mean control area. Two and three 5-minute cycles resulted in a reduction of the preconditioning effect, with flap survival no different than controls. Ten-minute preconditioning cycles increased flap survival 1.5 to 3 times the mean control area. Flap survival was improved by increasing the number of 10-minute cycles. Cycle time and number of cycles have definite effects on the survival areas of preconditioned musculocutaneous flaps. Ischemic preconditioning with 10-minute cycles is superior to 5-minute cycles. Three cycles of 10-minute preconditioning is statistically superior to one or two cycles. Future studies are planned to study four or more cycles and longer cycle times.


Reconstruction of the nasal soft triangle subunit.
Of all nine subunits, the soft triangle is perhaps the most challenging to recreate. The complexity of soft triangle reconstruction resides in its proximity to such important structures as the nasal tip, nasal ala, and distal columella. If the soft triangle is not properly reconstructed, problems with nasal function and aesthetics often arise. Anatomical asymmetries in the lower third and abnormal shadowing can occur following insufficient restoration. A retrospective review was completed of all patients undergoing reconstruction of the nasal soft triangle subunit at the University of Texas Southwestern Medical Center in Dallas, Texas, from 1995 to 2010. Defects with only external skin intact were classified as type I. Defects involving both skin and underlying soft tissue with intact mucosa were classified as type II. Finally, transmural defects with violated mucosa were classified as type III. Surgical outcomes were graded on a scale of I to IV. Grades given were based on the complexity of the existing defect and restoration of the soft triangle, with higher grades given when adjacent structures were not distorted. Of the 14 cases reviewed, two (14 percent) were type I defects, nine (64 percent) were type II defects, and three (21 percent) were type III defects. Three patients (21 percent) required revision with subsequent resurfacing and two (14 percent) required resurfacing alone. All but one patient (93 percent) had a grade of 2.0 or better, with the one patient opting not to undergo revision. The authors believe their method of soft triangle reconstruction using the proposed algorithm is an easy approach to soft triangle reconstruction that will yield consistent surgical and clinical success from aesthetic and functional perspectives. Furthermore, the authors were able to achieve excellent aesthetic outcomes without compromise or facing any structural complications. Therapeutic, IV.


Estrogen receptors α and β in the central amygdala and the ventromedial nucleus of the hypothalamus: Sociosexual behaviors, fear and arousal in female rats during emotionally challenging events.
Estrogens receptors (ER) are involved in several sociosexual behaviors and fear responses. In particular, the ERα is important for sexual behaviors, whereas ERβ modulates anxiolytic responses. Using shRNA directed either against the ERα or the ERβ RNAs (or containing luciferase control) encoded within an adeno-associated viral vector, we silenced these receptors in the ventromedial nucleus of the hypothalamus (VMN) and the central amygdala (CeA). We exposed ovariectomized female rats, sequentially treated with estradiol benzoate and progesterone, to five stimuli, previously reported to elicit positive and negative affect. The subjects were housed in groups of 4 females and 3 males in a seminatural environment for several days before hormone treatment. We analyzed the frequency of a large number of behavior patterns. In addition, we performed analyses of co-occurrence in order to detect changes in the structure of behavior after infusion of the vectors. Silencing the ERα in the VMN disrupted lordosis and showed some anxiolytic properties in aversive situations, whereas silencing of the ERβ in this structure had no effect. This was also the case after silencing the ERα in the CeA. Silencing of the ERβ in this structure increased risk assessment, an expression of anxiety, and increased olfactory exploration of the environment. We hypothesize that the ERβ in the CeA has an important role in the well-established anxiolytic effects of estrogens, and that it may modulate arousal level. Furthermore, it seems that the ERα in the VMN is anxiogenic in aversive or threatening situations, in agreement with other studies.


Two-month stop in mammographic screening significantly impacts on breast cancer stage at diagnosis and upfront treatment in the COVID era.
The present analysis aims to evaluate the consequences of a 2-month interruption of mammographic screening on breast cancer (BC) stage at diagnosis and upfront treatments in a region of Northern Italy highly affected by the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) virus. This retrospective single-institution analysis compared the clinical pathological characteristics of BC diagnosed between May 2020 and July 2020, after a 2-month screening interruption, with BC diagnosed in the same trimester of 2019 when mammographic screening was regularly carried out. The 2-month stop in mammographic screening produced a significant decrease in in situ BC diagnosis (-10.4%) and an increase in node-positive (+11.2%) and stage III BC (+10.3%). A major impact was on the subgroup of patients with BC at high proliferation rates. Among these, the rate of node-positive BC increased by 18.5% and stage III by 11.4%. In the subgroup of patients with low proliferation rates, a 9.3% increase in stage III tumors was observed, although node-positive tumors remained stable. Despite screening interruption, procedures to establish a definitive diagnosis and treatment start were subsequently carried out without delay. Our data showed an increase in node-positive and stage III BC after a 2-month stop in BC screening. These findings support recommendations for a quick restoration of BC screening at full capacity, with adequate prioritization strategies to mitigate harm and meet infection prevention requirements.


Comprehensive Quality Management (CQM) in the PLCO Trial.
The NCI imbedded the notion of comprehensive quality control and assurance (CQA) in the design concept for the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. PLCO implemented a comprehensive, adaptable quality assurance and control program to span more than 20 years of data collection, coordinate multiple institutions and committees, and integrate a wide variety of complex protocols. CQA concepts, practices, and procedures traced through all aspects of trial management, governance, and operations of PLCO. The driving force behind CQA in PLCO was scientific and clinical credibility of trial data and findings. CQA as implemented in PLCO was operationally analogous to the concept of Total Quality Management (TQM) described in the management literature. This paper describes CQA actualization in PLCO.


Regulating the Fast-Food Landscape: Canadian News Media Representation of the Healthy Menu Choices Act.
With the rapid rise of fast food consumption in Canada, Ontario was the first province to legislate menu labelling requirements via the enactment of the Healthy Menu Choice Act (HMCA). As the news media plays a significant role in policy debates and the agenda for policymakers and the public, the purpose of this mixed-methods study was to clarify the manner in which the news media portrayed the strengths and critiques of the Act, and its impact on members of the community, including consumers and stakeholders. Drawing on data from Canadian regional and national news outlets, the major findings highlight that, although the media reported that the HMCA was a positive step forward, this was tempered by critiques concerning the ineffectiveness of using caloric labelling as the sole measure of health, and its predicted low impact on changing consumption patterns on its own. Furthermore, the news media were found to focus accountability for healthier eating choices largely on the individual, with very little consideration of the role of the food industry or the social and structural determinants that affect food choice. A strong conflation of health, weight and calories was apparent, with little acknowledgement of the implications of menu choice for chronic illness. The analysis demonstrates that the complex factors associated with food choice were largely unrecognized by the media, including the limited extent to which social, cultural, political and corporate determinants of unhealthy choices were taken into account as the legislation was developed. Greater recognition of these factors by the media concerning the HMCA may evoke more meaningful and long-term change for health and food choices.


Dimethylsulfoxide (DMSO) clusters dataset: DFT relative energies, non-covalent interactions, and cartesian coordinates.
Theoretical understanding of dimethylsulfoxide (DMSO) liquid depends on the understanding of the DMSO clusters. In this work, we provide the structures and the energetics of the DMSO clusters. The structures have been generated using ABCluster and further optimized at the MP2/aug-cc-pVDZ level of theory. The final structures have been optimized at two different levels of theory: PW6B95D3/aug-cc-pVDZ and ω B97XD/aug-cc-pVDZ. The Cartesian coordinates of the structures optimized at the MP2/aug-cc-pVDZ level of theory are also reported. The relative energies of the structures can be used to locate the most favorable structures of the DMSO clusters. The Cartesian coordinates of the structures can be used for further investigations on DMSO clusters. In addition, we report the data related to the quantum theory of atoms in molecule (QTAIM) analysis of the investigated clusters. The QTAIM data reported in this work can be used to understand and determine the nature of non-covalent interactions in DMSO clusters. For further reading and discussion on the data reported here, please report to the original manuscript Malloum and Conradie (2022) [1].


Current Cigarette Smoking Among Adults - United States, 2016.
The U.S. Surgeon General has concluded that the burden of death and disease from tobacco use in the United States is overwhelmingly caused by cigarettes and other combusted tobacco products (1). Cigarettes are the most commonly used tobacco product among U.S. adults, and about 480,000 U.S. deaths per year are caused by cigarette smoking and secondhand smoke exposure (1). To assess progress toward the Healthy People 2020 target of reducing the proportion of U.S. adults aged ≥18 years who smoke cigarettes to ≤12.0% (objective TU-1.1),* CDC analyzed data from the 2016 National Health Interview Survey (NHIS). In 2016, the prevalence of current cigarette smoking among adults was 15.5%, which was a significant decline from 2005 (20.9%); however, no significant change has occurred since 2015 (15.1%). In 2016, the prevalence of cigarette smoking was higher among adults who were male, aged 25-64 years, American Indian/Alaska Native or multiracial, had a General Education Development (GED) certificate, lived below the federal poverty level, lived in the Midwest or South, were uninsured or insured through Medicaid, had a disability/limitation, were lesbian, gay, or bisexual (LGB), or had serious psychological distress. During 2005-2016, the percentage of ever smokers who quit smoking increased from 50.8% to 59.0%. Proven population-based interventions are critical to reducing the health and economic burden of smoking-related diseases among U.S. adults, particularly among subpopulations with the highest smoking prevalences (1,2).


[Meningeal carcinomatosis in giant cell lung cancer].
A case of patient with symptoms of L3-L4 roots affliction and IV cranial nerve lesion, caused by meningeal carcinomatosis secondary to giant cell lung cancer, is presented. The clinical features, diagnosis methods, and therapeutic possibilities in this case are commented on.


Long-term results of combined surgical and radiological intervention in complicated aortic dissection type-A. A case report.
We report the long-term results of combined surgical and radiological intervention in a patient with complicated aortic dissection, type-A. Following surgical graft-repair of a dissected part of the ascending aorta, embolization of the splenic artery, and stenting of the major abdominal arteries and of the left renal artery, was performed. The patient was able to return to normal active life, and all stented arteries remained patent after 32 months. A stent that was mispositioned across the aortic lumen did not cause any symptoms.


Juvenile Spondyloarthritis: focus on uveitis.
Juvenile spondyloarthritis (JSpA) represents a group of inflammatory arthritides with several distinctive features (enthesitis, involvement of spine and sacroiliac joint, HLA-B27 association and development of uveitis). There are limited data on the course of uveitis in children with JSpA. This study aims to estimate the prevalence of uveitis and to look at the presence of HLA-B27 in relation to uveitis occurrence and ocular symptoms in a cohort of JSpA patients. This is a cross sectional/retrospective study involving patients with JSpA followed in a tertiary referral hospital. Two hundred twenty-three patients were enrolled in the study. The prevalent diagnosis was enthesitis-related arthritis (ERA) (62%) followed by juvenile psoriatic arthritis (PsA), undifferentiated arthritis (UA), and the arthropathies associated with inflammatory bowel disease (IBD-A) (18, 14, 6%, respectively). Uveitis was reported in twenty-four patients (11%) of the JSpA cohort (JSpA-U). ERA patients had the highest uveitis prevalence (ERA-U) (13%) with similar prevalences in UA, PsA and in IBD-A (7% each). The prevalence of HLA-B27 positivity was similar amongst the entire JSpA-U cohort (N = 22, 45%) and those with ERA-U (N = 8, 44%). The overall prevalence of symptomatic uveitis was 79%. Neither the likelihood of uveitis, nor of symptomatic uveitis, varied by HLA-B27 status either in the entire cohort nor in those with ERA. About one-tenth of patients developed uveitis, the majority of which was symptomatic. Fewer than half of the patients with uveitis were HLA-B27 positive. HLA-B27 status was not statistically associated with either the development of uveitis or symptomaticity of uveitis.


Behavioral disinhibition and depression in amphetaminized rats: a comparison of risperidone, ocaperidone and haloperidol.
The mixed serotonin-2/dopamine-D2 antagonists risperidone and ocaperidone were compared with the specific D2 antagonist haloperidol for their ability to antagonize amphetamine (10 mg/kg, s.c.)-induced stereotypy in rats. Four successive stages of amphetamine antagonism were differentiated: 1) disinhibition: reversal of stationary stereotypy into the hyperactivity normally observed with lower doses of amphetamine; 2) inhibition: the first significant reduction of activity; 3) normalization: reduction of activity to the level of nonamphetaminized rats; and 4) suppression: reduction of activity to 50% of the level of nonamphetaminized rats. Ocaperidone and risperidone were equipotent with haloperidol for disinhibition (0.0062-0.011 mg/kg). However, the disinhibition was maintained over a wider dose range with risperidone (factor 84) than with haloperidol (9.0) and ocaperidone (4.1) and was also more pronounced in magnitude with risperidone. Ocaperidone was equipotent with haloperidol for inhibition (0.013-0.025 mg/kg) and normalization (0.074-0.080 mg/kg) but 4.4 times less potent for suppression of activity (0.71 vs. 0.16 mg/kg). Risperidone became progressively less potent than haloperidol: 4.4 times for inhibition, 9.6 times for normalization and 22 times for suppression of activity. The present data are consistent with the hypothesis that serotonin-2 antagonism compensates for the functional consequences of D2 receptor blockade. The implications for the clinical application of the compounds are discussed.


Homer1a Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Stress After Ischemic Reperfusion Injury by Inhibiting the PERK Pathway.
Homer1a is the short form of a scaffold protein that plays a protective role in many forms of stress. However, the role of Homer1a in cerebral ischemia/reperfusion (I/R) injury and its potential mechanism is still unknown. In this study, we found that Homer1a was upregulated by oxygen and glucose deprivation (OGD) and that overexpression of Homer1a alleviated OGD-induced lactate dehydrogenase (LDH) release and cell death in cultured cortical neurons. After OGD treatment, the overexpression of Homer1a preserved mitochondrial function, as evidenced by less cytochrome c release, less reactive oxygen species (ROS) production, less ATP and mitochondrial membrane potential (MMP) loss, less caspase-9 activation, and inhibition of endoplasmic reticulum (ER) stress confirmed by the decreased expression of phosphate-PKR-like ER Kinase (p-PERK)/PERK and phosphate- inositol-requiring enzyme 1 (p-IRE1)/IRE1 and immunofluorescence (IF) staining. In addition, mitochondrial protection of Homer1a was blocked by the ER stress activator Tunicamycin (TM) with a re-escalated ROS level, increasing ATP and MMP loss. Furthermore, Homer1a overexpression-induced mitochondrial stress attenuation was significantly reversed by activating the PERK pathway with TM and p-IRE1 inhibitor 3,5-dibromosalicylaldehyde (DBSA), as evidenced by increased cytochrome c release, increased ATP loss and a higher ROS level. However, activating the IRE1 pathway with TM and p-PERK inhibitor GSK2656157 showed little change in cytochrome c release and exhibited a moderate upgrade of ATP loss and ROS production in neurons. In summary, these findings demonstrated that Homer1a protects against OGD-induced injury by preserving mitochondrial function through inhibiting the PERK pathway. Our finding may reveal a promising target of protecting neurons from cerebral I/R injury.


Hardware accelerated segmentation of complex volumetric filament networks.
We present a framework for segmenting and storing filament networks from scalar volume data. Filament networks are encountered more and more commonly in biomedical imaging due to advances in high-throughput microscopy. These data sets are characterized by a complex volumetric network of thin filaments embedded in a scalar volume field. High-throughput microscopy volumes are also difficult to manage since they can require several terabytes of storage, even though the total volume of the embedded structure is much smaller. Filaments in microscopy data sets are difficult to segment because their diameter is often near the sampling resolution of the microscope, yet these networks can span large regions of the data set. We describe a novel method to trace filaments through scalar volume data sets that is robust to both noisy and undersampled data. We use graphics hardware to accelerate the tracing algorithm, making it more useful for large data sets. After the initial network is traced, we use an efficient encoding scheme to store volumetric data pertaining to the network.


Nonrelated living-donor kidney transplantation: medical and ethical aspects.
Several patients with end-stage renal disease went to Bombay for renal transplantation from nonrelated living donors and then returned to Turkey for posttransplantation follow-up. The aims of this study are to evaluate the long-term results of renal transplantation from nonrelated living donors in Turkish patients with end-stage renal disease and to discuss the ethical and social aspects of nonrelated kidney donation. One hundred and twenty-seven patients (89 males, 38 females; mean age 38.1, range 17-63 years) were investigated retrospectively. None of the patients went to Bombay on our advice. All transplantations were performed between 1991 and 1995. The mean follow-up period after transplantation was 34.2 (range 1-68) months. Graft survival rates were 85, 83, and 57% after 3 months and 1 and 5 years, respectively. Patient survival rates were 94, 93, and 92% after 3 months and 1 and 5 years, respectively. Seven patients died within the first 3 months after the transplantation. Surgical problems, infections, acute rejection, ciclosporin nephrotoxicity, and hepatic problems were common complications. We conclude that medical and surgical complications occur frequently in paid kidney transplantation, but most of these complications can be prevented by adequate preoperative management, and precautionary measures should be taken to prevent commercialization of renal transplantation before the spread of emotionally related living kidney donation.


Perioperative outcomes of robotic surgery for the treatment of lung cancer compared to a conventional video-assisted thoracoscopic surgery (VATS) technique.
To conduct a meta-analysis to determine the relative merits between robotic video-assisted thoracoscopic surgery (R-VATS) and conventional video-assisted thoracoscopic surgery (VATS) for lung cancer. Fifteen studies matched the selection criterion, which reported 8827 subjects, of whom 1704 underwent R-VATS and 7123 underwent VATS. Compared the perioperative outcomes with VATS, reports of R-VATS indicated unfavorable outcomes considering the operative time (SMD = 0.48, 95% CI 0.15 to 0.81). Meanwhile, the number of dissected lymph nodes (SMD = 0.12, 95% CI -0.27 to 0.51) and hospital stay following surgery (SMD = -0.1; 95% CI -0.27 to 0.07), conversion (RR = 0.68; 95% CI 0.42 to 1.11), morbidity (RR = 0.99, 95% CI 0.92 to 1.07) and mortality (RR = 0.33, 95% CI 0.1 to 1.09) were similar for both procedures. A literature search was performed to identify comparative studies reporting perioperative outcomes for R-VATS and VATS for lung cancer. Pooled risk ratio (RR) and standardized mean differences (SMDs) with 95% confidence intervals (95% CIs) were calculated using either the fixed effects model or the random effects model. There is no difference in terms of perioperative outcomes between R-VATS and VATS except for the operative time which is significantly high for R-VATS. Further studies are required to confirm these results.


Mental health first aid training of the public in a rural area: a cluster randomized trial [ISRCTN53887541].
A Mental Health First Aid course has been developed which trains members of the public in how to give initial help in mental health crisis situations and to support people developing mental health problems. This course has previously been evaluated in a randomized controlled trial in a workplace setting and found to produce a number of positive effects. However, this was an efficacy trial under relatively ideal conditions. Here we report the results of an effectiveness trial in which the course is given under more typical conditions. The course was taught to members of the public in a large rural area in Australia by staff of an area health service. The 16 Local Government Areas that made up the area were grouped into pairs matched for size, geography and socio-economic level. One of each Local Government Area pair was randomised to receive immediate training while one served as a wait-list control. There were 753 participants in the trial: 416 in the 8 trained areas and 337 in the 8 control areas. Outcomes measured before the course started and 4 months after it ended were knowledge of mental disorders, confidence in providing help, actual help provided, and social distance towards people with mental disorders. The data were analysed taking account of the clustered design and using an intention-to-treat approach. Training was found to produce significantly greater recognition of the disorders, increased agreement with health professionals about which interventions are likely to be helpful, decreased social distance, increased confidence in providing help to others, and an increase in help actually provided. There was no change in the number of people with mental health problems that trainees had contact with nor in the percentage advising someone to seek professional help. Mental Health First Aid training produces positive changes in knowledge, attitudes and behaviour when the course is given to members of the public by instructors from the local health service.