CYR61, regulated by miR-22-3p and MALAT1, promotes autophagy in HK-2 cell inflammatory model.
Renal tubular epithelial cells play an important role in renal function and are a major site of injury from inflammation. Emerging evidence suggests that CYR61 is involved in the regulation of autophagy. However, there are few studies on CYR61 in nephropathy and associated inflammation. This study aimed to clarify how CYR61 regulates autophagy in human renal epithelial cells while in an inflammatory state and regulates the upstream pathway of CYR61 levels. The human renal tubular epithelial cells (HK-2) cell line treated by lipopolysaccharide (LPS) was used as an inflammatory model of human epithelial cells. Short hairpin RNA (shRNA) was used to down-regulate CYR61, and the changes in the transcription and expression levels of related molecules, as well as the morphological changes of HK-2 cells, were detected by quantitative real time-PCR (qRT-PCR), western blot (WB), and transmission electron microscopy. Either CYR61 or MALAT1 were up-regulated by overexpression vectors, or MALAT1 was down-regulated by miR-22-3p mimics. Subsequently, the levels of CYR61, MALAT1, related inflammatory factors, and autophagy factors were measured by qPCR, WB, and enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was detected by flow cytometry and acridine-orange assay. We observed that down-regulation of CYR61 could down-regulate 1B-light chain 3 (LC3) level and inhibit autophagy in the LPS-induced inflammation model of HK-2 cells. The expression levels of CYR61, Beclin1, Atg5, LC3, interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were significantly increased by upregulating CYR61 or MALAT1 by overexpression vector, while the expression level of p62 was significantly decreased, intracellular reactive oxygen species (ROS) content was increased, and the proportion of autophagy and apoptosis was increased. The use of miR-22-3p mimics significantly reversed the changes induced by up-regulation of CYR61 or MALAT1 at the molecular and cellular levels. Our data indicated that CYR61 positively regulates autophagy of HK-2 cells under an inflammatory state, and was negatively regulated by miR-22-3p, while miR-22-3p and MALAT1 were negatively regulated by each other.


Predictors of psychological morbidity in liver transplant assessment candidates: is alcohol abuse or dependence a factor?
Orthotopic liver transplantation candidates with depressive and other symptoms report poorer perceived quality of life when compared with nondepressed patients, and are also significantly more likely to die while awaiting transplantation. Alcohol abuse and dependence have been associated with increased levels of psychological co-morbidity. This article presents data about psychological morbidity from a prospective study of patients being assessed for liver transplantation in Birmingham, UK, and explores whether those with a diagnosis of alcohol abuse or dependence are at increased risk of psychological symptoms. Of 399 consecutive patients assessed for liver transplantation between July 2004 and July 2005, a sample of 155 was included in the study. Eighty-three (53.5%) patients were identified as having general psychological distress that merited referral for specialist assessment using the Symptom Checklist-90-Revised instrument. The alcohol-dependent group achieved the highest overall 'caseness' rates, with 72% (n = 26) compared with 52% (n = 12) of the alcohol-abuse group and 47% (n = 45) of those with no alcohol-related diagnosis. However, alcohol abuse or dependence was not the significant predictor of psychological symptoms in the final regression model. Higher rates of psychological distress were associated with greater severity of liver disease, being unemployed, and being a tobacco smoker. Possible reasons for these findings and potential future management strategies are discussed.


Effects of Maytenus ilicifolia on reproduction and embryo-fetal development in Wistar rats.
Maytenus ilicifolia (Celastraceae), popularly known as espinheira-santa, is a native plant from the Atlantic forest and is commonly used in popular medicine to treat inflammation and as an abortifacient. To evaluate the effects of M. ilicifolia on pregnant rats during the organogenic period (T1) or throughout the gestational period (T2), an extract obtained using an acetone-water mixture at a 70:30 ratio was administered via gavage at a dose of 15.11 mg·kg(-1)·day(-1) over 2 treatment periods (T1 and T2). No clinical signs of maternal toxicity were observed. Term fetuses did not present malformations or anomalies as the number of implantations, reabsorptions, live, and dead fetuses were similar to the control group. In conclusion, M. ilicifolia hydroacetonic extract is non-toxic to pregnant rats and appears to not interfere with the progress of embryo-fetal development.


Left ventricular mechanics related to the local distribution of oxygen demand throughout the wall.
The complex interactions between left ventricular mechanics and the oxygen demand is studied by relating the left ventricular transmural oxygen demand to the myocardial structural and dynamic characteristics. The study utilizes a recent model of left ventricular contraction, which is based on a nested shell spheroidal geometry, a fan-like fibrous structure, the twisting motion of the left ventricle over its long axis, a transmural electrical activation propagation and the basic laws of sarcomere dynamics. The local "axial" stress (in the direction of the fibers) and the instantaneous sarcomere length are used to calculate the spatial distribution of the intramural oxygen demand per beat Vo2(y), where y is the distance from the endocardium. The normalized local sarcomere stress-length area SLAn(y) is related linearly to Vo2(y) by: Vo2(y) = K1 X SLAn(y) + K2, where K1 and K2 are constants. The calculations show a transmural metabolic gradient which is characterized by higher values of Vo2(y) in the endocardial layers than in the epicardial layers. Shorter endocardial sarcomeres and the twisting motion of the left ventricle around the long axis decrease the metabolic gradient across the wall, while a slow transmural electrical propagation wave as well as a wider angle of distribution of the fan-like fiber architecture increases the transmural metabolic gradient. Integration of the local oxygen demand across the left ventricular wall yields global values in agreement with those based on Suga's pressure-volume area approach. The model thus provides a qualitative and quantitative tool to assess the relation of the local and global oxygen demand to the complex left ventricular structure, fiber mechanics, and the dynamics of contraction.


Management of tuberculosis infection in Victorian children: A retrospective clinical audit of factors affecting treatment completion.
Tuberculosis preventive treatment (TPT) is strongly recommended for children following infection with Mycobacterium tuberculosis because of their high risk of progression to active tuberculosis, including severe disseminated disease. We describe the implementation of TPT for children and adolescents with evidence of tuberculosis infection (TBI) at Victoria's largest children's hospital and examine factors affecting treatment completion. We conducted a retrospective clinical audit of all children and adolescents aged <18 years diagnosed with latent TBI at the Royal Children's Hospital, Melbourne, between 2010 and 2016 inclusive. The primary outcome was treatment completion, defined as completing TPT to within one month of a target duration for the specified regimen (for instance, at least five months of a six-month isoniazid course), confirmed by the treating clinician. Factors associated with treatment adherence were evaluated by univariate and multivariate analysis. Of 402 participants with TBI, 296 (74%) met the criteria for treatment "complete". The most common TPT regimen was six months of daily isoniazid (377, 94%). On multivariate logistic regression analysis, treatment completion was more likely among children and adolescents who had refugee health screening performed (OR 2.31, 95%CI 1.34-4.00) or who were also treated for other medical conditions (OR 1.67 95%CI 1.0-2.85), and less likely among those who experienced side-effects (OR 0.32, 95%CI 0.11-0.94). However, TPT was generally well tolerated with side-effects reported in 15 participants (3.7%). Identification of factors associated with TPT completion and deficiencies in the existing care pathway have informed service provision changes to further improve outcomes for Victorian children and adolescents with TBI.


Initial Mild Traumatic Brain Injury Characteristics and Recovery Patterns Among Females Across the United States Military Service Academies: A Report from the NCAA-DoD CARE Consortium.
Mild traumatic brain injury (mTBI) has been described in the United States (US) military service academy cadet population, but female-specific characteristics and recovery outcomes are poorly characterized despite sex being a confounder. Our objective was to describe female cadets' initial characteristics, assessment performance, and return-to-activity outcomes post-mTBI. Female cadets (n = 472) from the four US military service academies who experienced a mTBI completed standardized mTBI assessments from pre-injury to acute initial injury and unrestricted return-to-duty (uRTD). Initial injury presentation characteristics (e.g., delayed symptoms, retrograde amnesia) and return-to-activity outcomes [i.e., return-to-learn, initiate return-to-duty protocol (iRTD), uRTD] were documented. Descriptive statistics summarized female cadets' injury characteristics, return-to-activity outcomes, and post-mTBI assessment performance change categorization (worsened, unchanged, improved) relative to pre-injury baseline using established change score confidence rank criteria for each assessment score. The median (interquartile range) days to return-to-learn (n = 157) was 7.0 (3.0-14.0), to iRTD (n = 412) was 14.7 (8.6-25.8), and to uRTD (n = 431) was 26.0 (17.7-41.8). The majority experienced worse SCAT total symptom severity (77.8%) and ImPACT reaction time (97.0%) acutely < 24-h versus baseline, but unchanged BESS total errors (75.2%), SAC total score (72%), BSI-18 total score (69.6%), and ImPACT verbal memory (62.3%), visual memory (58.4%), and visual motor speed (52.5%). We observed similar return-to-activity times in the present female cadet cohort relative to the existing female-specific literature. Confidence ranks categorizing post-mTBI performance were heterogenous and indicate multimodal assessments are necessary. Our findings provide clinically relevant insights to female cadets experiencing mTBI across the US service academies for stakeholders providing healthcare.


Motor innervation of the guinea pig interarytenoid muscle: reinnervation process following unilateral denervation.
The authors investigated the process of denervation and reinnervation of the interarytenoid (IA) muscle in the guinea pig using transmission electron microscopy and glycogen depletion technique after unilateral transection of the recurrent laryngeal nerve (RLN) and superior laryngeal nerve to clarify the innervation pattern of the unpaired IA muscle. Anastomosis between the bilateral arytenoid branches was confirmed in the belly of the IA muscle. Five weeks after transection, all of the IA muscle fibers appeared to have been reinnervated by the contralateral RLN. As the arytenoid branch of the RLN runs together with that of the contralateral RLN in a single intramuscular nerve funiculus, it is possible that collateral sprouting branches grow and extend into the adjacent denervated Schwann's sheaths. The authors conclude that the unpaired IA muscle, as a whole, receives specific motor nerve supply from the bilateral RLNs, although each muscle fiber is innervated unilaterally.


Immune defenses of healthy, bleached and diseased Montastraea faveolata during a natural bleaching event.
One prominent hypothesis regarding climate change and scleractinian corals is that thermal stress compromises immune competence. To test this hypothesis we tracked how the immune defenses of bleached, apparently healthy and yellow band disease (YBD) diseased Montastraea faveolata colonies varied with natural thermal stress in southwestern Puerto Rico. Colonies were monitored for 21 mo from the peak of the bleaching event in October 2005 to August 2007. Since sea surface temperature was significantly higher in summer and fall 2005 than 2006, year of collection was used as a proxy for temperature stress, and colony fragments collected in 2005 were compared with those collected in 2006. Mortality rate was high (43% overall) and all colonies (except one) either died or became infected with YBD by August 2007. YBD-infected tissue did not bleach (i.e. expel zooxanthellae) during the 2005 bleaching event, even when healthy tissue of these colonies bleached. Immune activity was assayed by measuring prophenoloxidase (PPO), peroxidase (POX), lysozyme-like (LYS) and antibacterial (AB) activity. Immune activity was variable between all coral samples, but there was a significant elevation of PPO activity in bleached colonies collected in 2005 relative to apparently healthy and YBD-diseased corals in 2006. In YBD-diseased colonies, LYS and AB activity were elevated in both healthy and infected tissue, indicating a systemic response; activity levels in these colonies were higher compared to those that appeared healthy. In both these immune parameters, there was a trend for suppression of activity in corals that were bleached in 2005. These data, while complicated by between-genet variability, illustrate the complex interaction between disease and temperature stress on immune function.


Techniques in recording centric relation.
1. Muscle seated centric registration is a reproducible method of obtaining centric relation (Wood, 1994). 2. The muscle-seated CR record provides a consistent, accurate, less technique-sensitive CR record of condylar position.


Mammalian gut immunity.
The mammalian intestinal tract is the largest immune organ in the body and comprises cells from non-hemopoietic (epithelia, Paneth cells, goblet cells) and hemopoietic (macrophages, dendritic cells, T-cells) origin, and is also a dwelling for trillions of microbes collectively known as the microbiota. The homeostasis of this large microbial biomass is prerequisite to maintain host health by maximizing beneficial symbiotic relationships and minimizing the risks of living in such close proximity. Both microbiota and host immune system communicate with each other to mutually maintain homeostasis in what could be called a "love-hate relationship." Further, the host innate and adaptive immune arms of the immune system cooperate and compensate each other to maintain the equilibrium of a highly complex gut ecosystem in a stable and stringent fashion. Any imbalance due to innate or adaptive immune deficiency or aberrant immune response may lead to dysbiosis and low-grade to robust gut inflammation, finally resulting in metabolic diseases.


Telomere length as a predictor of response to Pioglitazone in patients with unremitted depression: a preliminary study.
We studied peripheral leukocyte telomere length (LTL) as a predictor of antidepressant response to PPAR-γ agonist in patients with unremitted depression. In addition we examined correlation between LTL and the insulin resistance (IR) status in these subjects. Forty-two medically stable men and women ages 23-71 with non-remitted depression participated in double-blind placebo-controlled add-on of Pioglitazone to treatment-as-usual. Oral glucose tolerance tests were administered at baseline and at 12 weeks. Diagnostic evaluation of psychiatric disorders was performed at baseline and mood severity was followed weekly throughout the duration of the trial. At baseline, no differences in LTL were detected by depression severity, duration or chronicity. LTL was also not significantly different between insulin-resistant and insulin-sensitive subjects at baseline. Subjects with longer telomeres exhibited greater declines in depression severity in the active arm, but not in a placebo arm, P=0.005, r=-0.63, 95% confidence interval (95% CI)=(-0.84,-0.21). In addition, LTL predicted improvement in insulin sensitivity in the group overall and did not differ between intervention arms, P=0.036, r=-0.44, 95% CI=(-0.74,0.02) for the active arm, and P=0.026, r=-0.50, 95% CI=(-0.78,-0.03) for the placebo arm. LTL may emerge as a viable predictor of antidepressant response. An association between insulin sensitization and LTL regardless of the baseline IR status points to potential role of LTL as a non-specific moderator of metabolic improvement in these patients.


A fatal cytauxzoonosis-like disease in cats.
A cytauxzoon-like agent caused fatal disease in 4 domestic cats from separate, rural, heavily wooded premises in southwestern Missouri. Clinical signs included lethargy; pale, icteric mucous membranes; fever; and dehydration. One case of fatal cytauxzoonosis occurred in early September, 1973, and another in September, 1974. Two additional cases were detected in June, 1975. Tick infestations were reported from a variety of animals, including cats, on all premises. Necropsy revealed generalized icterus and petechial and ecchymotic hemorrhages over the surfaces of the heart and lungs. The pericardial sac was distended with clear yellow serous fluid. Large numbers of schizonts characteristic of Cytauxzoon spp were discovered in specimens of liver, lung, spleen, and lymph nodes of all cats. Infection of vascular endothelial cells, a characteristic of cytauxzoonosis, was observed in all organs examined. Piroplasms or ring forms of the agent were observed in erythrocytes of affected cats.


Th17 Cells in Helicobacter pylori Infection: a Dichotomy of Help and Harm.
Helicobacter pylori is a Gram-negative bacterium that infects the gastric epithelia of its human host. Everyone who is colonized with these pathogenic bacteria can develop gastric inflammation, termed gastritis. Additionally, a small proportion of colonized people develop more adverse outcomes, including gastric ulcer disease, gastric adenocarcinoma, or gastric mucosa-associated lymphoid tissue lymphoma. The development of these adverse outcomes is dependent on the establishment of a chronic inflammatory response. The development and control of this chronic inflammatory response are significantly impacted by CD4+ T helper cell activity. Noteworthy, T helper 17 (Th17) cells, a proinflammatory subset of CD4+ T cells, produce several proinflammatory cytokines that activate innate immune cell antimicrobial activity, drive a pathogenic immune response, regulate B cell responses, and participate in wound healing. Therefore, this review was written to take an intricate look at the involvement of Th17 cells and their affiliated cytokines (interleukin-17A [IL-17A], IL-17F, IL-21, IL-22, and IL-26) in regulating the immune response to H. pylori colonization and carcinogenesis.


Melanoma and non-melanoma skin cancer in inflammatory bowel disease patients following tumor necrosis factor-α inhibitor monotherapy and in combination with thiopurines: analysis of the Food and Drug Administration Adverse Event Reporting System.
Reports have shown an increased risk of melanoma skin cancer (MSC) with exposure to tumor necrosis factor alpha (TNF-α) inhibitors and non-melanoma skin cancer (NMSC) with thiopurine exposure in inflammatory bowel disease (IBD) patients. Using the Food and Drug Administration Adverse Event Reporting System (FAERS) we sought to evaluate the odds of developing MSC and NMSC for patients on TNF-α inhibitors as monotherapy and in combination therapy with thiopurines and/or steroids. The FAERS was queried for reports between January 2003 and June 2012. A proportional reporting ratio (PRR) metric analyses was performed on the data to determine the odds of developing MSC and NMSC. The PRR analysis showed increased odds of developing MSC and NMSC for patients on a TNF-α inhibitor (p-value = 0.035 and p-value = 0.03, respectively) and those on a TNF-α inhibitor in combination with a thiopurine (p-value < 0.001 and p-value < 0.001). TNF-α inhibitor monotherapy or use with concomitant thiopurines in patients with IBD is associated with higher odds of developing MSC and NMSC.


Widespread environmental contamination associated with patients with diarrhea and methicillin-resistant Staphylococcus aureus colonization of the gastrointestinal tract.
Patients colonized with methicillin-resistant Staphylococcus aureus (MRSA) may contaminate their immediate environment with this organism. However, the extent to which gastrointestinal colonization with MRSA affects environmental contamination is not known. We investigated the frequency of environmental contamination in the rooms of patients with diarrheal stools and heavy gastrointestinal colonization with MRSA. Prospective observational study. A 500-bed teaching hospital. Stool specimens submitted for Clostridium difficile toxin assays were inoculated onto colistin-naladixic acid agar. MRSA was identified with standard methods. Samples from a standardized list of 10 environmental surfaces were cultured, from the rooms of 8 patients who had diarrhea that yielded heavy growth of MRSA (case patients) and from the rooms of 6 MRSA-positive patients with stool cultures negative for MRSA (control patients). MRSA isolates from 13 patients (8 case patients and 5 control patients) and 64 of the environmental isolates recovered from their rooms were compared by pulsed-field gel electrophoresis (PFGE). One clinical isolate from a control patient was excluded because there was no corresponding environmental MRSA isolate with which to compare it. Overall, MRSA were recovered from 47 (58.8%) of 80 surfaces in the rooms of case patients, compared with 14 (23.3%) of 60 surfaces in the rooms of control patients (58.8% [95% CI, 47.8-68.9] vs 23.3% [95% CI, 14.3-35.5]; P<.0001). The items most commonly contaminated were bedside rails, blood pressure cuffs, television remote controls, and toilet seats. Seventy-eight percent of the environmental isolates in patients' rooms had PFGE types that were indistinguishable or closely related to those recovered from the patients' clinical specimens. Patients who have diarrheal stools and heavy gastrointestinal colonization with MRSA are associated with significantly greater environmental MRSA contamination than patients without MRSA in their stool, and they are likely to be the source of that contamination.


Consent and recruitment: the reporting of paediatric trials published in 2012.
We evaluated 300 paediatric trials to determine: the consent and recruitment strategies used, who trial information was targeted to, how incentives were used and if they achieved their recruitment targets. For this cross-sectional evaluation, we searched the Cochrane Central Register of Controlled Trials for paediatric trials published in 2012 and randomly selected 300 that reported on outcomes for participants aged ≤21 years. We collected data on consent and recruitment procedures for each trial and undertook descriptive analyses in SPSS statistics V.23. All but one trial (99.7%) used a standard recruitment strategy. Most (92%) trials reported that consent was obtained but only 13% reported who obtained consent. Two-thirds (65%) of trials included school-aged participants, and of these 68% reported obtaining assent. Half (50%) of the trials reported who the trial information was targeted to. Most trials (75%) of school-aged participants targeted information towards children or children and their parents. Fourteen per cent of trials reported using incentives, half (50%) of which were in the form of compensation. Only 48% of trials reported sufficient data to determine if their recruitment targets were achieved. Of these, 70% achieved their targets. Notable reporting shortcomings included: how families were recruited into the trial, who obtained consent and/or assent and how, who trial information was directed to, whether incentives were used and sufficient data to determine if the recruitment target was achieved. Forthcoming paediatric-specific reporting standards may improve reporting in this priority area. Our data provide a baseline for ongoing monitoring of the state of the research.


Pineal photoreceptor cells are required for maintaining the circadian rhythms of behavioral visual sensitivity in zebrafish.
In non-mammalian vertebrates, the pineal gland functions as the central pacemaker that regulates the circadian rhythms of animal behavior and physiology. We generated a transgenic zebrafish line [Tg(Gnat2:gal4-VP16/UAS:nfsB-mCherry)] in which the E. coli nitroreductase is expressed in pineal photoreceptor cells. In developing embryos and young adults, the transgene is expressed in both retinal and pineal photoreceptor cells. During aging, the expression of the transgene in retinal photoreceptor cells gradually diminishes. By 8 months of age, the Gnat2 promoter-driven nitroreductase is no longer expressed in retinal photoreceptor cells, but its expression in pineal photoreceptor cells persists. This provides a tool for selective ablation of pineal photoreceptor cells, i.e., by treatments with metronidazole. In the absence of pineal photoreceptor cells, the behavioral visual sensitivity of the fish remains unchanged; however, the circadian rhythms of rod and cone sensitivity are diminished. Brief light exposures restore the circadian rhythms of behavioral visual sensitivity. Together, the data suggest that retinal photoreceptor cells respond to environmental cues and are capable of entraining the circadian rhythms of visual sensitivity; however, they are insufficient for maintaining the rhythms. Cellular signals from the pineal photoreceptor cells may be required for maintaining the circadian rhythms of visual sensitivity.


Genetic structure and diversity among sheep breeds in the United States: identification of the major gene pools.
Understanding existing levels of genetic diversity of sheep breeds facilitates in situ and ex situ conservation activities. A comprehensive evaluation of US sheep breeds has not been previously performed; therefore, we evaluated the genetic diversity among and within 28 US sheep breeds. Both major and minor breeds were included in the analysis and consisted of 666 animals from 222 producers located in 38 states. The level of within-breed genetic diversity was variable and not dependent upon status of a breed as a major or minor breed. Bayesian cluster analysis indicated the breeds were grouped more by physiological differences (meat vs. wool production) rather than geographic origin. Results suggest several actionable items to improve in situ and ex situ conservation. The results clearly identify breeds in need of increased in situ and ex situ management (e.g., Hog Island and Karakul) and allow several suggestions for in situ management of flocks. Conversely, several of the breeds appear genetically similar and therefore require less emphasis on collecting germplasm samples for the gene bank. Commercially important breeds (e.g., Rambouillet and Suffolk) were found to have substantial variation, which should enable breeders to proceed, unencumbered by genetic diversity concerns, with selection strategies that maximize profit.


Modulation of microRNome by Human Cytomegalovirus and Human Herpesvirus 6 Infection in Human Dermal Fibroblasts: Possible Significance in the Induction of Fibrosis in Systemic Sclerosis.
Human cytomegalovirus (HCMV) and Human herpesvirus 6 (HHV-6) have been reportedly suggested as triggers of the onset and/or progression of systemic sclerosis (SSc), a severe autoimmune disorder characterized by multi-organ fibrosis. The etiology and pathogenesis of SSc are still largely unknown but virological and immunological observations support a role for these beta-herpesviruses, and we recently observed a direct impact of HCMV and HHV-6 infection on the expression of cell factors associated with fibrosis at the cell level. Since miRNA expression has been found profoundly deregulated at the tissue level, here we aimed to investigate the impact on cell microRNome (miRNome) of HCMV and HHV-6 infection in in vitro infected primary human dermal fibroblasts, which represent one of the main SSc target cells. The analysis, performed by Taqman arrays detecting and quantifying 754 microRNAs (miRNAs), showed that both herpesviruses significantly modulated miRNA expression in infected cells, with evident early and late effects and deep modulation (>10 fold) of >40 miRNAs at each time post infection, including those previously recognized for their key function in fibrosis. The correlation between these in vitro results with in vivo observations is strongly suggestive of a role of HCMV and/or HHV-6 in the multistep pathogenesis of fibrosis in SSc and in the induction of fibrosis-signaling pathways finally leading to tissue fibrosis. The identification of specific miRNAs may open the way to their use as biomarkers for SSc diagnosis, assessment of disease progression and possible antifibrotic therapies.


Hospital admissions for unintentional poisoning in preschool children in England; 2000-2011.
We conducted a population based time-trend analysis of all unplanned admissions to National Health Service hospitals for poisoning in preschool children (aged <5 years) in England, between 2000 and 2011. Hospital admission rates for poisoning (medicinal and non-medicinal) decreased overall from 179 per 100 000 in 2000 to 139 per 100 000 in 2011 (rate ratio 0.77, 95% CI 0.74 to 0.81). The relative risk of hospital admission from the most deprived quintile compared with the least deprived quintile reduced from 2.37 (95% CI 2.15 to 2.60) in 2001 to 1.54 (95% CI 1.40 to 1.70) in 2011. Poisoning admissions in preschool children have decreased by 23% over the past decade. Although social gradients have narrowed, those from the most deprived areas are at higher risk of poisoning, and may benefit from targeted schemes of home safety education in deprived areas.


Microbend fiber-optic sensor.
Intensity modulation induced by microbending in multimode fibers is considered as a transduction mechanism for detecting environmental changes such as pressure, temperature, acceleration, and magnetic and electric fields. A generic microbend sensor has been defined and studied, and its components, such as sensing fiber, light source, optical fiber leads, and detector, have been examined and optimized. Finally, the generic microbend sensor has been tested demonstrating good performance.


Biodegradation of Quinalphos by a Soil Bacterium-Bacillus subtilis.
A widely used pesticide quinalphos (O, O-diethyl O-quinoxalin-2-yl phosphorothioate) may be an undesirable and persistent pollutant to non-target environments like rivers and other ecosystems. The objective of this study was to isolate a potential degradant bacterium of quinalphos from polluted soils and test its fitness under various culture conditions. A soil bacterium strain, capable of utilizing quinalphos as its sole source of carbon and energy was isolated from soil by enrichment method on a minimal salts medium (MSM). On the basis of morphological, biochemical and 16S rRNA gene sequence analysis the bacterium is a species of the genus Bacillus and it was closely related to Bacillus subtilis. Quinalphos degrading capabilities of this bacterium were assessed under different culture conditions. Quinalphos degradation data were analysed byusing a two-way ANOVA analysis with the Statistica v.10. Bacillus subtilis grew on quinalphos with a generation time of 32.34 min or 0.54 h in the logarithmic phase. Maximum degradation of quinalphos was observed with an inoculum of 1.0 optical density, around pH-7.5 and at an optimum temperature of 35-37°C. Among the additional carbon and nitrogen sources, carbon source-glucose and nitrogen source-yeast extract marginally improved the rate of degradation of quinalphos. Gas chromatography-mass spectrometry (GC-MS) analysis of the culture of B. subtilis grown on quinalphos indicated the formation of one main metabolite-quinoxaline. The B. subtilis strain discovered in this study has a unique combination of abilities to degrade quinalphos and it is therefore suitable candidate bioremediator of quinalphos polluted environments.


Transforming healthcare through a digital revolution: A review of digital healthcare technologies and solutions.
The COVID-19 pandemic has put a strain on the entire global healthcare infrastructure. The pandemic has necessitated the re-invention, re-organization, and transformation of the healthcare system. The resurgence of new COVID-19 virus variants in several countries and the infection of a larger group of communities necessitate a rapid strategic shift. Governments, non-profit, and other healthcare organizations have all proposed various digital solutions. It's not clear whether these digital solutions are adaptable, functional, effective, or reliable. With the disease becoming more and more prevalent, many countries are looking for assistance and implementation of digital technologies to combat COVID-19. Digital health technologies for COVID-19 pandemic management, surveillance, contact tracing, diagnosis, treatment, and prevention will be discussed in this paper to ensure that healthcare is delivered effectively. Artificial Intelligence (AI), big data, telemedicine, robotic solutions, Internet of Things (IoT), digital platforms for communication (DC), computer vision, computer audition (CA), digital data management solutions (blockchain), digital imaging are premiering to assist healthcare workers (HCW's) with solutions that include case base surveillance, information dissemination, disinfection, and remote consultations, along with many other such interventions.


Discerning intra-tuber differences in textural properties in cooked Solanum tuberosum group Tuberosum and group Phureja tubers.
The textural properties of potato tubers influence their acceptability and palatability and these properties differ between varieties, groups and progeny. The aim of this study was to compare the textural properties of cooked tubers of Solanum tuberosum group Phureja with those of group Tuberosum. To assess intra-tuber differences, the textural properties of seven cubes from defined positions along the longitudinal axis of tubers of four Tuberosum group cultivars and three Phureja group lines were tested after cooking using an amended wedge fracture method. Tuberosum group tubers gave consistently higher peak force and work done values during fracture than the Phureja group tubers. Moreover, the values for cubes 1-6 from any tuber were not significantly different and only cube 7, from the stem end, gave higher values. Therefore, the use of any of cubes 1-6 is a valid measurement of the tuber as a whole but the central cube 4 may be most conveniently located. The dry matter content of the cubes did not influence the textural properties of the cubes, which suggested that starch swelling is not the main driving force for textural differences. Total pectin methyl esterase (PME) activity was consistently higher in cubes of the Tuberosum group cultivars over the Phureja group lines. The method developed is valid and consistent for assessing textural differences within potato germplasm. The relationship between PME activity and enhanced resistance to fracture suggests that PME may modulate pectin cohesiveness, perhaps through increasing Ca(2+)-bridges, to provide greater resistance to fracture.


A Severe Acute Respiratory Syndrome Extranet: supporting local communication and information dissemination.
The objective of this study was to explore the use and perceptions of a local Severe Acute Respiratory Syndrome (SARS) Extranet and its potential to support future information and communication applications. The SARS Extranet was a single, managed electronic and limited access system to manage local, provincial and other SARS control information. During July, 2003, a web-based and paper-based survey was conducted with 53 SARS Steering Committee members in Hamilton. It assessed the use and perceptions of the Extranet that had been built to support the committee during the SARS outbreak. Before distribution, the survey was user-tested based on a think-aloud protocol, and revisions were made. Quantitative and qualitative questions were asked related to frequency of use of the Extranet, perceived overall usefulness of the resource, rationale for use, potential barriers, strengths and limitations, and potential future uses of the Extranet. The response rate was 69.4% (n = 34). Of all respondents, 30 (88.2%) reported that they had visited the site, and rated it highly overall (mean = 4.0; 1 = low to 5 = high). However, the site was rated 3.4 compared with other communications strategies used during the outbreak. Almost half of all respondents (44.1%) visited the site at least once every few days. The two most common reasons the 30 respondents visited the Extranet were to access SARS Steering Committee minutes (63.3%) and to access Hamilton medical advisories (53.3%). The most commonly cited potential future uses for the Extranet were the sending of private emails to public health experts (63.3%), and surveillance (63.3%). No one encountered personal barriers in his or her use of the site, but several mentioned that time and duplication of email information were challenges. Despite higher rankings of various communication strategies during the SARS outbreak, such as email, meetings, teleconferences, and other web sites, users generally perceived a local Extranet as a useful support for the dissemination of local information during public health emergencies.


Advanced glycation endproducts and their receptor in different body compartments in COPD.
Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by chronic airway inflammation and emphysema, and is caused by exposure to noxious particles or gases, e.g. cigarette smoke. Smoking and oxidative stress lead to accelerated formation and accumulation of advanced glycation end products (AGEs), causing local tissue damage either directly or by binding the receptor for AGEs (RAGE). This study assessed the association of AGEs or RAGE in plasma, sputum, bronchial biopsies and skin with COPD and lung function, and their variance between these body compartments. Healthy smoking and never-smoking controls (n = 191) and COPD patients (n = 97, GOLD stage I-IV) were included. Autofluorescence (SAF) was measured in the skin, AGEs (pentosidine, CML and CEL) and sRAGE in blood and sputum by ELISA, and in bronchial biopsies by immunohistochemistry. eQTL analysis was performed in bronchial biopsies. COPD patients showed higher SAF values and lower plasma sRAGE levels compared to controls and these values associated with decreased lung function (p <0.001; adjusting for relevant covariates). Lower plasma sRAGE levels significantly and independently predicted higher SAF values (p < 0.001). One SNP (rs2071278) was identified within a region of 50 kB flanking the AGER gene, which was associated with the gene and protein expression levels of AGER and another SNP (rs2071278) which was associated with the accumulation of AGEs in the skin. In COPD, AGEs accumulate differentially in body compartments, i.e. they accumulate in the skin, but not in plasma, sputum and bronchial biopsies. The association between lower sRAGE and higher SAF levels supports the hypothesis that the protective mechanism of sRAGE as a decoy-receptor is impaired in COPD.


Numerical and Experimental Analyses of Three- Dimensional Unsteady Flow around a Micro-Pillar Subjected to Rotational Vibration.
The steady streaming (SS) phenomenon is gaining increased attention in the microfluidics community, because it can generate net mass flow from zero-mean vibration. We developed numerical simulation and experimental measurement tools to analyze this vibration-induced flow, which has been challenging due to its unsteady nature. The validity of these analysis methods is confirmed by comparing the three-dimensional (3D) flow field and the resulting particle trajectories induced around a cylindrical micro-pillar under circular vibration. In the numerical modeling, we directly solved the flow in the Lagrangian frame so that the substrate with a micro-pillar becomes stationary, and the results were converted to a stationary Eulerian frame to compare with the experimental results. The present approach enables us to avoid the introduction of a moving boundary or infinitesimal perturbation approximation. The flow field obtained by the micron-resolution particle image velocimetry (micro-PIV) measurement supported the three-dimensionality observed in the numerical results, which could be important for controlling the mass transport and manipulating particulate objects in microfluidic systems.


Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis.
Glucocorticoid (GC) therapy has been shown to prevent Graves' ophthalmopathy (GO) progression following radioactive iodine (RAI) treatment. However, the optimal regimen is controversial, with studies from recent years suggesting the use of lower doses and shorter GC treatment courses. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and retrospective controlled trials comparing GC regimens versus placebo, no treatment, or other GC regimens. Eight trials evaluating 850 patients fulfilled inclusion criteria. In patients with preexisting GO, standard dose prednisone (0.4-0.5 mg/kg tapered over 3 months) was very effective for prevention of GO progression (OR 0.14 [CI 0.06-0.35], p<0.01) in patients with mild to moderate GO. Two studies evaluated low-dose prednisone (0.2-0.3 mg/kg for 4-6 weeks) in patients with mild GO or risk factors, but were limited by not including patients with preexisting GO in the control groups. Therefore, the two low-dose groups were evaluated using indirect comparisons with control groups matched for age and clinical activity score, showing excellent efficacy versus no treatment or placebo (OR 0.20 [CI 0.07-0.60], p=0.004) and no significant difference compared with standard dose (OR 1.7 [CI 0.52-5.52], p=0.47). In patients without preexisting GO, steroid prophylaxis had no beneficial effect (OR 1.87 [CI 0.81-4.3]), though there were insufficient data regarding patients with risk factors for GO development. GC prophylaxis had no impact on hyperthyroidism resolution (OR 1.05 [CI 0.69-1.58]), and GC side effects were common but mild. Current evidence supports a three-tier approach for prevention of GO progression following RAI. Standard dose prednisone is the best validated regimen and should be used in patients with mild to moderate GO who have high risk of progression, while low dose prednisone can be used in patients with mild GO, and in patients without preexisting GO who have risk factors and are selected for GC prophylaxis. Patients without preexisting GO and without risk factors should not be treated with GC prophylaxis.


Active roles of electrically coupled bipolar cell network in the adult retina.
Gap junctions are frequently observed in the adult vertebrate retina. It has been shown that gap junctions function as passive electrotonic pathways and play various roles, such as noise reduction, synchronization of electrical activities, regulation of the receptive field size, and transmission of rod signals to cone pathways. The presence of gap junctions between bipolar cells has been reported in various species but their functions are not known. In the present study, we applied dual whole-cell clamp techniques to the adult goldfish retina to elucidate the functions of gap junctions between ON-type bipolar cells with a giant axon terminal (Mb1-BCs). Electrophysiological and immunohistochemical experiments revealed that Mb1-BCs were coupled with each other through gap junctions that were located at the distal dendrites. The coupling conductance between Mb1-BCs under light-adapted conditions was larger than that under dark-adapted conditions. The gap junctions showed neither rectification nor voltage dependence, and behaved as a low-pass filter. Mb1-BCs could generate Ca(2+) spikes in response to depolarization, especially under dark-adapted conditions. The Ca(2+) spike evoked electrotonic depolarization through gap junctions in neighboring Mb1-BCs, and the depolarization in turn could trigger Ca(2+) spikes with a time lag. A brief depolarizing pulse applied to an Mb1-BC evoked a long-lasting EPSC in the postsynaptic ganglion cell. The EPSC was shortened in duration when gap junctions were pharmacologically or mechanically impaired. These results suggest that the spread of Ca(2+) spikes through gap junctions between bipolar cells may play a key role in lateral interactions in the adult retina.


Simulation of Na channel inactivation by thiazine dyes.
Some dyes of the methylene blue family serve as artificial inactivators of the sodium channels when present inside squid axons at a concentration of approximately 0.1 mM. The dyes restore a semblance of inactivation after normal inactivation has been destroyed by pronase. In fibers that inactivate normally, the dyes hasten the decay of sodium current. Many dye-blocked channels conduct transiently on exit of the dye molecule after repolarization to the holding potential. In contrast, normally inactivated channels do not conduct during recovery from inactivation. Kinetic evidence shows that inactivation of a dye-blocked channel is unlikely or impossible, which suggests that dye molecules compete with inactivation "particles" for the same site. In the absence of tetrodotoxin, the dyes do not affect the ON gating current unless the interpulse interval is very short. If sufficient equilibration time is allowed during a pulse, the initial amplitude of the OFF gating current is reduced to near zero. This suggests that a dye molecule is a Na channel completely blocks that channel's gating current, even the fraction that is resistant to normal inactivation. Dyes block INa and Ig with the same time course. This provides the strongest evidence to date that virtually all of recorded "gating current" is associated with Na channels. Tetrodotoxin greatly slows dissociation of dye molecules from Na channels and reduced gating current during both opening and closing of the channels.


Functional composition and diversity of leaf traits in subalpine versus alpine vegetation in the Apennines.
Mediterranean high mountain grasslands are shaped by climatic stress and understanding their functional adaptations can contribute to better understanding ecosystems' response to global change. The present work analyses the plant functional traits of high-elevation grasslands growing in Mediterranean limestone mountains to explore, at the community level, the presence of different plant strategies for resource use (conservative vs. acquisitive) and functional diversity syndromes (convergent or divergent). Thus, we compared the functional composition and diversity of the above-ground traits related to resource acquisition strategies of subalpine and alpine calcareous grasslands in the central Apennines, a mountain region characterized by a dry-summer Mediterranean climate. We used georeferenced vegetation plots and field-measured plant functional traits (plant maximum height, specific leaf area and leaf dry matter content) for the dominant species of two characteristic vegetation types: the subalpine Sesleria juncifolia community and the alpine Silene acaulis community. Both communities are of particular conservation concern and are rich in endemic species for which plant functional traits are measured here for the first time. We analysed the functional composition and diversity using the community-weighted mean trait index and the functional diversity using Rao's function, and we assessed how much the observed pattern deviated from a random distribution by calculating the respective standardized effect sizes. The results highlighted that an acquisitive resource use strategy and relatively higher functional diversity of leaf traits prevail in the alpine S. acaulis community, optimizing a rapid carbon gain, which would help overcome the constraints exerted by the short growing season. The divergent functional strategy underlines the co-occurrence of different leaf traits in the alpine grasslands, which shows good adaptation to a microhabitat-rich environment. Conversely, in the subalpine S. juncifolia grassland, a conservative resource use strategy and relatively lower functional diversity of the leaf traits are likely related to a high level resistance to aridity over a longer growing season. Our outcomes indicate the preadaptation strategy of the subalpine S. juncifolia grassland to shift upwards to the alpine zone that will become warmer and drier as a result of anthropogenic climate change.


Practice patterns in ordering a voiding cystourethrogram for pediatric patients among different specialties in a Middle Eastern tertiary care center.
Voiding cystourethrogram (VCUG) is a very popular test performed to evaluate genitourinary tract anomalies. Nevertheless, this test can be overused and can lead to unnecessary patient discomfort, radiation exposure, and cost. We sought to study the practice patterns in ordering a VCUG in a Middle Eastern tertiary care center. Over a period of 3 years, a retrospective analysis of all VCUG images done for pediatric patients in a single center was made. Further clinical details were extracted from the electronic health records. The specialty of an ordering physician and the reported indication for the procedure were noted. Indications for VCUG were recorded based on the AAP 2011 guidelines, NICE guidelines 2007, and ACR 2011 guidelines. Based on these criteria, patients were analyzed. A total of 92 VCUGs were evaluated. Of all VCUGs done, pediatricians ordered the most VCUGs (50/92), followed by pediatric infectious disease (16/92), pediatric nephrology (9/92), pediatric urology (7/92), adult urology (5/92), pediatric surgery (3/92), obstetrician-gynecologist (1/92), and emergency medicine (1/92). Properly indicated VCUGs were 50% by general pediatrics, 55% by pediatric infectious disease, 45% by pediatric nephrology, 40% by adult urology, 33% by pediatric surgery, and 100% by pediatric urology. VCUG is utilized differently by different specialties. In some centers, adult specialties may order a pediatric VCUG. General pediatricians order VCUG the most with a tendency for misuse in up to 50%. Pediatric urology is not the most ordering specialty of VCUG; however, it utilizes it most appropriately. The noted practice patterns may be improved with awareness of the indications and limitations of the study and with proper referral.


Longer Residence of Ecuadorian and Colombian Migrant Workers in Spain Associated with New Episodes of Common Mental Disorders.
The healthy migrant effect and its impact on mental health has been reported in the general population of many countries. Information is limited about its impact on working populations. The aim of this study is to estimate the incidence of common mental disorders over a one-year follow-up period among a cohort of Colombian and Ecuadorian employees in Spain, taking into account the duration of residence and comparing with Spanish-born workers. Data was from the Longitudinal Studies on Immigrant Families Project (PELFI), a follow-up survey of immigrants and Spanish-born workers interviewed in 2015 and 2016. Mental health was assessed using the 12-item general health questionnaire (GHQ-12). Crude and adjusted odds ratios (ORas) for common mental disorders by sociodemographic and employment characteristics were created. There were differences for immigrants with time of residence less than or equal to 15 years (time of residence 11-15 years: ORa = 0.06, 95% CI = (0.26-0.01); time of residence 1-10 years: ORa = 0.06, 95% CI = (0.36-0.01)). There was evidence of a healthy immigrant worker effect, as newer arrivals from Ecuador and Columbia to Spain had a lower incidence of common mental disorders than either the Spanish-born or immigrant workers who had lived in Spain for more than 15 years.


Picosecond self-diffusion in ethanol-water mixtures.
We report the self-diffusion in ethanol-water mixtures as a function of the water-ethanol ratio measured at different temperatures using quasi-elastic neutron spectroscopy (QENS). For our protiated samples, QENS is mainly sensitive to the dominant ensemble-averaged incoherent scattering from the hydrogen atoms of the liquid mixtures. The energy range and resolution render our experiment sensitive to the picosecond time scale and nanometer length scale. These observation scales complement different scales accessible by nuclear magnetic resonance techniques. Subsequent to testing different models, we find that a simple jump-diffusion model averaging over both types of molecules, water and ethanol, best fits our data.


Measurement and characteristics of neurotransmitter receptor surface trafficking (Review).
Neurotransmitter receptor trafficking in and out synapses has emerged as a key process to regulate synaptic transmission during synaptic development and plasticity both at excitatory and inhibitory synapses. Lateral diffusion of surface neurotransmitter receptors has recently emerged as a key pathway to regulate receptor trafficking to and from synapses. Receptors enter and exit synapses mainly by lateral diffusion within the plane of the membrane while their retrieval and addition from and to the plasma membrane by endo and exocytotic processes occur largely at extrasynaptic sites. As a consequence, regulation of receptor surface trafficking is likely to be a major process to regulate receptor numbers at synapses. Measurement of receptor surface diffusion has required the development of new experimental approaches to specifically label and track surface receptor with appropriate time- and space-resolutions. In this review, we first discuss the approaches that have been used to measure receptor surface diffusion, such as the ensemble approach that measure average diffusion of a defined surface receptor population and the single molecule/particle approaches that measure the surface diffusion of isolated receptors. To date, surface diffusion has been described for a variety of neurotransmitter receptors that exhibit common as well as specific features. These points are discussed in a comparative manner and emerging rules of surface trafficking as well as potential interplay between receptor classes are further commented. Because our knowledge on neurotransmitter receptor surface diffusion is fairly recent, open questions and experimental challenges facing the field are highlighted throughout the review.


Safety of Street-Vended Soy Wara in Nigeria.
Soy wara is a common ready-to-eat food whose production and sale are currently unregulated. Microbiological sampling indicated that 21% of the samples had standard plate counts exceeding 100,000 CFU/g, and 14% had Staphylococcus aureus counts higher than 100,000 CFU/g. The occurrence of S. aureus at these levels can result in food poisoning. Listeria monocytogenes was isolated in 14.4% of the samples, although the counts were generally low, typically <1,000 CFU/g. Although counts of L. monocytogenes were low, immunocompromised individuals and children may particularly be at risk of listeriosis. All samples showed low counts of Bacillus cereus (< 10,000 CFU/g). Escherichia coli and Salmonella enterica were detected in 5.6 and 2.2% of all samples, respectively, indicating fecal contamination and possible links to gastroenteritis and enteric fever. Fungal counts were variable, ranging from 6.0 × 10(3) to 2.0 × 10(4) CFU/g, with Alternaria spp., Fusarium spp., and Rhizopus spp. being the predominant species. Aluminum content was as high as 0.776 mg of Al per g in soy wara processed with alum. Significantly higher aluminum contents were observed in alum-processed soy wara compared with those processed with lime or ogi (an acid-fermented gruel of either maize [Zea mays], sorghum [Sorghum bicolor], or millet [Pennisetum glaucum]) (P < 0.05). These results indicate the need to improve personal hygiene and environmental sanitation in the production and preparation of soy wara, and further studies are warranted for the implication of the accumulation of aluminum.


Effect of different solutes, natural organic matter, and particulate Fe(III) on ferrate(VI) decomposition in aqueous solutions.
This study investigated the impacts of buffer ions, natural organic matter (NOM), and particulate Fe(III) on ferrate(VI) decomposition and characterized Fe(VI) decomposition kinetics and exposure in various waters. Homogeneous and heterogeneous Fe(VI) decomposition can be described as a second- and first-order reaction with respect to Fe(VI), respectively. Fe(VI) decay was catalyzed by Fe(VI) decomposition products. Solutes capable of forming complexes with iron hydroxides retarded Fe(VI) decay. Fractionation of the resulting solutions from Fe(VI) self-decay and ferric chloride addition in borate- and phosphate-buffered waters showed that phosphate could sequester Fe(III). The nature of the iron precipitate from Fe(VI) decomposition was different from that of freshly precipitated ferric hydroxide from ferric chloride solutions. The stabilizing effects of different solutes on Fe(VI) are in the following order: phosphate > bicarbonate > borate. The constituents of colored and alkaline waters (NOM and bicarbonate) inhibited the catalytic effects of Fe(VI) decomposition products and stabilized Fe(VI) in natural waters. Because of the stabilizing effects of solutes, moderate doses of Fe(VI) added to natural waters at pH 7.5 resulted in exposures that have been shown to be effective for inactivation of target pathogens. Preformed ferric hydroxide was less effective than freshly dosed ferric chloride in accelerating Fe(VI) decomposition.


3-hydroxy-3-methylglutaryl-coenzyme A reductase A comparison of the modulation in vitro by phosphorylation and dephosphorylation to modulation of enzyme activity by feeding cholesterol- or cholestryamine-supplemented diets.
The activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (hydroxymethylglutaryl-CoA reductase) was considerably inhibited during incubation with ATP+Mg(2+). The inactivated enzyme was reactivated on further incubation with partially purified cytosolic phosphoprotein phosphatase. The inactivation was associated with a decrease in the apparent K(m) of the reductase for hydroxymethylglutaryl-CoA, and this was reversed on reactivation. The slight increase in activity observed during incubation of microsomal fraction without ATP was not associated with a change in apparent K(m) and, unlike the effect of the phosphatase, was not inhibited by NaF. Liver microsomal fraction from rats given cholesterol exhibited a low activity of hydroxymethylglutaryl-CoA reductase with a low apparent K(m) for hydroxymethylglutaryl-CoA. Mícrosomal fraction from rats fed cholestyramine exhibited a high activity with a high K(m). To discover whether these changes had resulted from phosphorylation and dephosphorylation of the reductase, microsomal fraction from rats fed the supplemented diets and the standard diet were inactivated with ATP and reactivated with phosphoprotein phosphatase. Inactivation reduced the maximal activity of the reductase in each microsomal preparation and also reduced the apparent K(m) for hydroxymethylglutaryl-CoA. There was no difference between the preparations in the degree of inactivation produced by ATP. Treatment with phosphatase restored both the maximal activity and the apparent K(m) of each preparation, but never significantly increased the activity above that observed with untreated microsomal fraction. It is concluded that hydroxymethylglutaryl-CoA reductase in microsomal fraction prepared by standard procedures is almost entirely in the dephosphorylated form, and that the difference in kinetic properties in untreated microsomal fraction from rats fed the three diets cannot be explained by differences in the degree of phosphorylation of the enzyme.


Tumour calcitonin. Interaction with specific calcitonin receptors.
The human epidermoid bronchial carcinoma (BEN) cell line has been shown to have specific membrane binding sites for calcitonin and to secrete high-molecular-weight forms (ranging from 40000 to 10000) of immunoreactive calcitonin. Synthetic salmon and human calcitonins and a thyroid extract of porcine calcitonin have been shown to displace 125I-labelled salmon calcitonin from the receptors in a dose-related fashion. The binding to these receptors of calcitonins derived from the BEN cell line and a medullary thyroid carcinoma with molecular weights ranging from 28000 to 3500 (both separated by gel-filtration chromatography) has been investigated. Neither major peaks of BEN-cell-line calcitonin showed receptor binding activity. Only one form of medullary thyroid carcinoma calcitonin, that which co-eluted with synthetic calcitonin monomer on gel-filtration chromatography, caused any significant displacement of labelled hormone from the receptors.


A Multilevel Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia.
The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25, rs6039769, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the SNAP25b/SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.SIGNIFICANCE STATEMENT Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.


[Ouabain and intracellular potassium activity in the papillary muscle of the rabbit].
Ionic activity on both sides of the cardiac cell membrane is an essential parameter for determining the mechanism responsible for the positive inotropic effect of cardiotonic glucosides. The intracellular activity of K (aiK) was therefore measured using selective microelectrodes, in the papillary muscles of a rabbit, for both a low concentration (10(-8) M) and a toxic concentration (10(-6) M) of ouabain. The ouabain at low concentration (10(-8) M) had no significant effect with respect to aiK, the values derived with and without ouabain being 85.4 mequiv./L and 84.2 mequiv./L respectively. The use of selective microelectrodes for measuring K, paired with a microelectrode filled with KC1, made it possible to study aiK in terms of time in the presence of a toxic concentration of ouabain (10(-6) M). In such a case, ouabain results in a reversible lessening of aiK.


Three theories of stroboscopic motion detection.
The three theories derive from three different paradigms. Suprathreshold judgements of perceived quality of motion in multi-flash displays are modelled by space-time Fourier analysis of the motion stimulus. Stroboscopic motion is perceived as being different from real motion to the extent that the additional Fourier components in stroboscopic motion are detectable. Stroboscopic motion of dots along conflicting paths leads to perceptual competition. The theory to describe perceptual I solution derives and proves the uniqueness of strength functions computed only from the time and from the distance between successive points on each path. Time-strength and motion-strength add to determine path-strength; only the strongest path is perceived. Motion-direction detection in continuously drifting two-flash combinations of sinusoidal gratings is described by elaborated Reichardt detectors (ERDs) that compute the covariance of temporal events in two adjacent locations. Other apparently different, detectors that account for direction-detection data are shown to be equivalent to ERDs.


Repair of double-strand breaks by homologous recombination in mismatch repair-defective mammalian cells.
Chromosomal double-strand breaks (DSBs) stimulate homologous recombination by several orders of magnitude in mammalian cells, including murine embryonic stem (ES) cells, but the efficiency of recombination decreases as the heterology between the repair substrates increases (B. Elliott, C. Richardson, J. Winderbaum, J. A. Nickoloff, and M. Jasin, Mol. Cell. Biol. 18:93-101, 1998). We have now examined homologous recombination in mismatch repair (MMR)-defective ES cells to investigate both the frequency of recombination and the outcome of events. Using cells with a targeted mutation in the msh2 gene, we found that the barrier to recombination between diverged substrates is relaxed for both gene targeting and intrachromosomal recombination. Thus, substrates with 1.5% divergence are 10-fold more likely to undergo DSB-promoted recombination in Msh2(-/-) cells than in wild-type cells. Although mutant cells can repair DSBs efficiently, examination of gene conversion tracts in recombinants demonstrates that they cannot efficiently correct mismatched heteroduplex DNA (hDNA) that is formed adjacent to the DSB. As a result, >20-fold more of the recombinants derived from mutant cells have uncorrected tracts compared with recombinants from wild-type cells. The results indicate that gene conversion repair of DSBs in mammalian cells frequently involves mismatch correction of hDNA rather than double-strand gap formation. In cells with MMR defects, therefore, aberrant recombinational repair may be an additional mechanism that contributes to genomic instability and possibly tumorigenesis.


Supernumerary teeth in a Turkish population.
Our aim in this study was to investigate the frequency, distribution, sex differences, and characteristics of supernumerary teeth in a referred Turkish population. A total of 2599 patients' panoramic radiographs (1360 girls, 1239 boys) were evaluated, including children in both the mixed and the permanent dentitions. Their mean age was 8.6 +/- 0.23 years. Number, location, classification, side, and impaction of supernumerary teeth were evaluated. Furthermore, the development of these teeth was evaluated. Eighty-four supernumerary teeth were found on 69 radiographs; 9 were deciduous and 75 were permanent teeth. Most supernumerary teeth were in the premaxillary region (67%). Mesiodens (n = 43) was the most frequent supernumerary tooth (51.2%). This was followed by the maxillary lateral incisor (15.5%), the mandibular premolar (14.3%), the maxillary canine (9.5%), the maxillary premolar (6%), the mandibular lateral incisor (2.4%), and the mandibular canine (1.2%). Sixty-two (73.8%) supernumerary teeth were impacted. The male-female ratio was 1.13:1, which was not statistically significant. The prevalence of supernumerary teeth in Turkish children was 2.7% in this study.


ComplexEye: a multi-lens array microscope for high-throughput embedded immune cell migration analysis.
Autonomous migration is essential for the function of immune cells such as neutrophils and plays an important role in numerous diseases. The ability to routinely measure or target it would offer a wealth of clinical applications. Video microscopy of live cells is ideal for migration analysis, but cannot be performed at sufficiently high-throughput (HT). Here we introduce ComplexEye, an array microscope with 16 independent aberration-corrected glass lenses spaced at the pitch of a 96-well plate to produce high-resolution movies of migrating cells. With the system, we enable HT migration analysis of immune cells in 96- and 384-well plates with very energy-efficient performance. We demonstrate that the system can measure multiple clinical samples simultaneously. Furthermore, we screen 1000 compounds and identify 17 modifiers of migration in human neutrophils in just 4 days, a task that requires 60-times longer with a conventional video microscope. ComplexEye thus opens the field of phenotypic HT migration screens and enables routine migration analysis for the clinical setting.


Fanconi Anemia complementation group C protein in metabolic disorders.
Given importance of 22-Fanconi Anemia (FA) proteins together to act in a signaling pathway in preventing deleterious clinical symptoms, e.g. severe bone marrow failure, congenital defects, an early onset of aging and cancer, studies on each FA protein become increasingly attractive. However, an unbiased and systematic investigation of cellular effects resulting from each FA protein is missing. Here, we report roles of FA complementation C group protein (FANCC) in the protection from metabolic disorders. This study was prompted by the diabetes-prone feature displayed in FANCC knockout mice, which is not typically shown in patients with FA. We found that in cells expressing FANCC at different levels, there are representative alterations in metabolites associated with aging (glycine, citrulline, ornithine, L-asparagine, L-tyrosine, L-arginine, L-glutamine, L-leucine, L-isoleucine, L-valine, L-proline and L-alanine), Diabetes Mellitus (DM) (carbon monoxide, collagens, fatty acids, D-glucose, fumaric acid, 2-oxoglutaric acid, C3), inflammation (inosine, L-arginine, L-isoleucine, L-leucine, L-lysine, L-phenylalanine, hypoxanthine, L-methionine), and cancer ( L-methionine, sphingomyelin, acetyl-L-carnitine, L-aspartic acid, L-glutamic acid, niacinamide, phospho-rylethanolamine). We also found that FANCC can act in an FA-pathway-independent manner in tumor suppression. Collectively, featured-metabolic alterations are readouts of functional mechanisms underlying reduced tumorigenicity driven by FANCC, demonstrating close links among cancer, aging, inflammation and DM.


Pelvic Phlebolith: A Trivial Pursuit for the Urologist?
Pelvic phleboliths are commonly encountered on plain and CT imaging and remain a source of frustration when attempting to differentiate them from ureteral calculi. Given their frequency, surprising little is known about their significance. We review the literature on pelvic phleboliths, specifically in relation to their history, demography, clinical significance, and methods to distinguish them from ureteral calculi. A comprehensive literature search was performed for all articles concerning pelvic phleboliths. Pelvic phleboliths were first described in 19th century when the presence of calcified intravenous nodules was observed in human dissection. With the discovery of X-ray imaging in 1895, they have caused much diagnostic controversies since. Histologically they are composed of calcified laminated fibrous tissue, with a surface layer continuous with vein endothelium. Prevalence of pelvic phleboliths in adults is reported to be 38.9%-48%. They are more common in adults aged over 40, and appear to equally affect both genders. They may be associated with diverticulitis, vascular abnormalities, and are more commonly seen in individuals from economically developed countries. The soft-tissue "rim"sign (50%-77% sensitivity and 92%-100% specificity) and a geometric shape (100% positive predictive value [PPV]) are radiological signs predictive of ureteral calculi on unenhanced CT scanning. Radiological signs suggestive of phleboliths include the presence of central lucency (8%-60% sensitivity and 100% specificity), rounded shape (91% PPV), and the comet-tail sign (21%-65% sensitivity and 100% specificity). Phleboliths appear to have a significantly lower Hounsfield unit enhancement than ureteral calculi (160-350 HU). Pelvic phleboliths are a common radiological finding, especially in the older population, which continue to present diagnostic challenges in those with suspected ureteral calculi. With greater awareness, the uncertainty can be overcome by identifying defining characteristics when interpreting radiological investigations.


Fetal thyroid hyperplasia, rhesus isoimmunisation, and amniography.
Thyroid hyperplasia was identified at necropsy in 16 of 70 cases of haemolytic disease of the newborn due to rhesus isoimmunisation dying in the years 1959--76. No hyperplasia was found in the thyroids from 140 nonrhesus-affected infants matched for date of birth, bodyweight and length, and gestation, or in cases of haemolytic disease born before 1966. All 16 infants with thyroid hyperplasia had received intrauterine transfusions and the iodine-containing contrast media used for preliminary amniography were the only goitrogenic factors identified. Lipiodol, first used in 1966, was considered to have the greatest effect. The 16 infants with hyperplastic thyroids were less mature and smaller than 22 infants with normal thyroids who had been similarly exposed to contrast media. The high incidence of hyperplasia may be due to immaturity of the adaptive mechanisms which allow most normal individuals to escape the goitrogenic effects of iodine compounds.


Expression of heat-stable enterotoxin STb by adherent Escherichia coli is not sufficient to cause severe diarrhea in neonatal pigs.
The role of Escherichia coli heat-stable enterotoxin B (STb) in neonatal porcine diarrhea caused by enterotoxigenic E. coli was examined by comparing adherent isogenic strains with or without STb. The cloned STb gene (in the plasmid pRAS1) was electroporated into a nonenterotoxigenic strain (226M) which expresses the F41 adhesin. Strain 226M pRAS1 adhered and expressed STb in vivo, causing fluid secretion in ligated ileal loops in neonatal pigs. Although strain 226M pRAS1 caused very mild diarrhea in some orally inoculated neonatal pigs, the weight loss in these pigs was similar to that caused by the parental strain without STb. We conclude that STb does not significantly contribute to diarrhea caused by enterotoxigenic E. coli in neonatal pigs.


Pedicle Screw Placement Using Augmented Reality Surgical Navigation With Intraoperative 3D Imaging: A First In-Human Prospective Cohort Study.
Prospective observational study. The aim of this study was to evaluate the accuracy of pedicle screw placement using augmented reality surgical navigation (ARSN) in a clinical trial. Recent cadaveric studies have shown improved accuracy for pedicle screw placement in the thoracic spine using ARSN with intraoperative 3D imaging, without the need for periprocedural x-ray. In this clinical study, we used the same system to place pedicle screws in the thoracic and lumbosacral spine of 20 patients. The study was performed in a hybrid operating room with an integrated ARSN system encompassing a surgical table, a motorized flat detector C-arm with intraoperative 2D/3D capabilities, integrated optical cameras for augmented reality navigation, and noninvasive patient motion tracking. Three independent reviewers assessed screw placement accuracy using the Gertzbein grading on 3D scans obtained before wound closure. In addition, the navigation time per screw placement was measured. One orthopedic spinal surgeon placed 253 lumbosacral and thoracic pedicle screws on 20 consenting patients scheduled for spinal fixation surgery. An overall accuracy of 94.1% of primarily thoracic pedicle screws was achieved. No screws were deemed severely misplaced (Gertzbein grade 3). Fifteen (5.9%) screws had 2 to 4 mm breach (Gertzbein grade 2), occurring in scoliosis patients only. Thirteen of those 15 screws were larger than the pedicle in which they were placed. Two medial breaches were observed and 13 were lateral. Thirteen of the grade 2 breaches were in the thoracic spine. The average screw placement time was 5.2 ± 4.1 minutes. During the study, no device-related adverse event occurred. ARSN can be clinically used to place thoracic and lumbosacral pedicle screws with high accuracy and with acceptable navigation time. Consequently, the risk for revision surgery and complications could be minimized. 3.


Current concepts in robotic total hip arthroplasty.
Total hip replacement provides mostly fair functional and clinical results. Many factors play an essential role in hip stability and long-term outcomes. Surgical positioning remains fundamental for obtaining accurate implant fit and prevent hip dislocation or impingement. Different categories of robotic assistance have been established throughout the previous years and all of the technologies target accuracy and reliability to reduce complications, and enhance clinical outcomes. An overview is proposed over the principles of robotic assistance in hip arthroplasty surgery. Accuracy, reliability, management of the bone stock, clinical outcomes, constraints and limits of this technology are reported, based on recent literature. Potential advantages regarding pre-operative planning accuracy, cup positioning, maintenance of the center of rotation, preservation of an adequate bone stock nay clinical short- and mid-term outcomes are balanced with some reported disadvantages and limits like hip anatomical specificity, cost-effectiveness, engineering dependence. The use of robotic-assisted THA presents clear and evident benefits related to accurate implant positioning and maintenance of a minimal bone while allowing. For some authors, an early improvement in functional results and patient's recovery. This technology demonstrated a shorter surgical time and a short learning curve required to optimize its use and this technology presents promising outcomes and results and potential use in routine clinical application but its limitation of use is still present especially the cost of the robot, the need for the presence of an engineer during the surgery, its availability of use in all hospitals as well as the difficulty presented in dysplastic or dysmorphic hip joints.


An accurate metalloprotein-specific scoring function and molecular docking program devised by a dynamic sampling and iteration optimization strategy.
Metalloproteins, particularly zinc metalloproteins, are promising therapeutic targets, and recent efforts have focused on the identification of potent and selective inhibitors of these proteins. However, the ability of current drug discovery and design technologies, such as molecular docking and molecular dynamics simulations, to probe metal-ligand interactions remains limited because of their complicated coordination geometries and rough treatment in current force fields. Herein we introduce a robust, multiobjective optimization algorithm-driven metalloprotein-specific docking program named MpSDock, which runs on a scheme similar to consensus scoring consisting of a force-field-based scoring function and a knowledge-based scoring function. For this purpose, in this study, an effective knowledge-based zinc metalloprotein-specific scoring function based on the inverse Boltzmann law was designed and optimized using a dynamic sampling and iteration optimization strategy. This optimization strategy can dynamically sample and regenerate decoy poses used in each iteration step of refining the scoring function, thus dramatically improving both the effectiveness of the exploration of the binding conformational space and the sensitivity of the ranking of the native binding poses. To validate the zinc metalloprotein-specific scoring function and its special built-in docking program, denoted MpSDockZn, an extensive comparison was performed against six universal, popular docking programs: Glide XP mode, Glide SP mode, Gold, AutoDock, AutoDock4Zn, and EADock DSS. The zinc metalloprotein-specific knowledge-based scoring function exhibited prominent performance in accurately describing the geometries and interactions of the coordination bonds between the zinc ions and chelating agents of the ligands. In addition, MpSDockZn had a competitive ability to sample and identify native binding poses with a higher success rate than the other six docking programs.


Genomic Distance with High Indel Costs.
We determine complexity of computing the DCJ-indel distance, when DCJ and indel operations have distinct constant costs, by showing an exact formula that can be computed in linear time for any choice of (constant) costs for DCJ and indel operations. We additionally consider the problem of triangular inequality disruption and propose an algorithmically efficient correction on each member of the family of DCJ-indel.


Change in blood eosinophils following treatment with inhaled corticosteroids may predict long-term clinical response in COPD.
There is an emerging role for blood eosinophil count (EOS) as a biomarker to guide inhaled corticosteroid (ICS) therapy in COPD. Since ICS administration could influence EOS, we hypothesised that change in EOS following treatment with ICS may predict outcomes of long-term therapy.In a post hoc analysis of ISOLDE, a 3-year, double-blind trial comparing 500 µg fluticasone propionate twice daily with placebo in 751 patients with moderate-to-severe COPD, we evaluated whether the initial changes in EOS during ICS treatment were predictive of ICS treatment response.EOS change within 1 year after the introduction of ICS was strongly predictive of treatment response. A suppressed EOS was associated with treatment effect. Characteristically, in patients with EOS suppression of ≥200 cells·μL-1, ICS use was associated with a decelerated rate of decline of forced expiratory volume in 1 s (FEV1), by 32 mL·year-1, and a 30% reduction in the exacerbation rate. In contrast, in patients experiencing an increase in EOS of ≥200 cells·μL-1, ICS use was associated with an accelerated rate of decline of FEV1, by 37 mL·year-1 and an 80% increase in the exacerbation rate (p<0.0001). EOS change was not predictive of clinical response with regards to health status evaluated using the St George's Respiratory Questionnaire.These findings suggest that EOS change after ICS administration may predict clinical response to ICS therapy in patients with moderate-to-severe COPD at risk of exacerbations. ICS administration may be associated with more frequent exacerbations and an accelerated lung function decline in the 20% of patients in whom EOS increases after the administration of ICS. These hypothesis-generating observations will need validation in prospectively designed studies.The ISOLDE trial was conducted before the ICJME recommended a prospective registration of RCT protocols.


Large-scale vibrating coil magnetometer for the magnetic characterization of bulk superconductors.
This work presents the design and validation of a vibrating coil magnetometer for the characterization of the field dependence of the critical current density of centimeter-sized bulk superconductors as an alternative to the destructive methods typically used. The magnetometer is also shown to be capable of measuring the magnetic moment in an applied field of up to 5 T for diverse magnetic materials, such as soft and hard ferromagnets and high-temperature superconducting pellets. The vibrating coil magnetometer was first optimized using finite element simulations and calibrated using a commercial vibrating sample magnetometer. The vibrating coil magnetometer was benchmarked with hysteresis measurements of a Nd2Fe14B disk made with a commercial hysteresisgraph, showing good agreement between the different setups. The magnetic hysteresis of a YBa2Cu3O7-x superconducting pellet was measured at 77 K, showing a penetration field of 1 T and an irreversibility field of 4 T. The field dependent critical current density of the superconductor was then inferred from the magnetic hysteresis measurements and extrapolated at low fields. Finally, the resulting critical current density was used to successfully reproduce the measured magnetization curve of the pellet at 2 T with finite element simulations.


Histopathological diagnostic discrepancies in soft tissue tumours referred to a specialist centre: reassessment in the era of ancillary molecular diagnosis.
Introduction. Soft tissue tumour pathology is a highly specialised area of surgical pathology, but soft tissue neoplasms can occur at virtually all sites and are therefore encountered by a wide population of surgical pathologists. Potential sarcomas require referral to specialist centres for review by pathologists who see a large number of soft tissue lesions and where appropriate ancillary investigations can be performed. We have previously assessed the types of diagnostic discrepancies between referring and final diagnosis for soft tissue lesions referred to our tertiary centre. We now reaudit this 6 years later, assessing changes in discrepancy patterns, particularly in relation to the now widespread use of ancillary molecular diagnostic techniques which were not prevalent in our original study. Materials and Methods. We compared the sarcoma unit's histopathology reports with referring reports on 348 specimens from 286 patients with suspected or proven soft tissue tumours in a one-year period. Results. Diagnostic agreement was seen in 250 cases (71.8%), with 57 (16.4%) major and 41 (11.8%) minor discrepancies. There were 23 cases of benign/malignant discrepancies (23.5% of all discrepancies). 50 ancillary molecular tests were performed, 33 for aiding diagnosis and 17 mutational analyses for gastrointestinal stromal tumour to guide therapy. Findings from ancillary techniques contributed to 3 major and 4 minor discrepancies. While the results were broadly similar to those of the previous study, there was an increase in frequency of major discrepancies. Conclusion. Six years following our previous study and notably now in an era of widespread ancillary molecular diagnosis, the overall discrepancy rate between referral and tertiary centre diagnosis remains similar, but there is an increase in frequency of major discrepancies likely to alter patient management. A possible reason for the increase in major discrepancies is the increasing lack of exposure to soft tissue cases in nonspecialist centres in a time of subspecialisation. The findings support the national guidelines in which all suspected soft tissue tumour pathology specimens should be referred to a specialist sarcoma unit.


Feto-maternal haemorrhage in Kenya.
Six hundred and twenty antenatal, 40 post normal delivery 40 post caesarian section, 4 patients with placenta previa and 3 with fresh still section, 4 patients with placenta previa and 3 with fresh still births were investigated for feto maternal haemorrhage. The prevalence of feto maternal haemorrhage was 32.2% for antenatal patients, 45% for post caesarian section ones and 25% after normal delivery. All the values were higher than in Caucasian studies. Antenatal prevalence increased with gestation being 15.4% in first trimester, 29.5% in second and 38% in third trimester (p 0.05). Maternal age, parity, number of previous abortions and marital status did not influence the prevalence. Increased feto maternal haemorrhage was associated with history of vaginal bleeding or trauma but not pre-eclampsia. Feto maternal macrotransfusion was detected in 1% of antenatal patients, two patients with abruptio placenta, one with still birth and eight delivered by caesarian section. The mode of delivery did not influence the frequency but affected the volume of feto maternal transfusion. Probable changes in the timing of prophylactic anti D-gammaglobulin are discussed.


The magnitude and selectivity of natural and multiple anthropogenic mortality causes in hunted brown bears.
1. The population dynamic and evolutionary effects of harvesting are receiving growing attention among biologists. Cause-specific estimates of mortality are necessary to determine and compare the magnitude and selectivity of hunting and other types of mortalities. In addition to the logistic and financial constraints on longitudinal studies, they are complicated by the fact that nonhunting mortality in managed populations usually consists of a mix of natural and human-caused factors. 2. We used multistate capture-recapture (MCR) models to estimate cause-specific survival of brown bears (Ursus arctos) in two subpopulations in Sweden over a 23-year period. In our analysis, we distinguished between legal hunting and other sources of mortality, such as intraspecific predation, accidents, poaching, and damage control removals. We also tested whether a strong increase in harvest quotas after 1997 in one of the subpopulations affected vulnerability to legal hunting. 3. Although only a fraction of mortalities other than legal hunting could be considered natural, this group of causes showed a general pattern of demographic selectivity expected from natural mortality regimes in populations of long-lived species, namely greater vulnerability of young animals. On the other hand, demographic effects on hunting vulnerability were weak and inconsistent. Our findings support the assumption that hunting and other mortalities were additive. 4. As expected, an increase in hunting pressure coincided with a correspondingly large increase in vulnerability to hunting in the affected subpopulation. Because even unbiased harvest can lead to selective pressures on life-history traits, such as size at primiparity, increasing harvest quotas may not only affect population growth directly, but could also alter optimal life-history strategies in brown bears and other carnivores. 5. Legal hunting is the most conveniently assessed and the most easily managed cause of mortality in many wild populations of large mammals. Although legal hunting is the single-most important cause of mortality for brown bears in Sweden, the combined mortality from other causes is of considerable magnitude and additionally shows greater selectivity in terms of sex and age than legal hunting. Therefore, its role in population dynamics and evolution should not be underestimated.


Free flaps for coverage of the foot and ankle.
Coverage of complex soft tissue injuries to the foot and ankle is difficult and often can be achieved only by the use of free flaps. Selection of the appropriate flap must be patient-oriented. Indications for composite tissue transfer are presented. In addition, the vascular anatomy and characteristics of commonly used flaps--the groin flap, the scapular flap, and the latissimus dorsi, tensor fascia lata, and gracilis flaps are presented along with case histories illustrating their utilization.


Posttranscriptional regulation of expression of plasminogen activator inhibitor type-1 by sphingosine 1-phosphate in HepG2 liver cells.
Altered expression of plasminogen activator inhibitor type-1 (PAI-1), a major physiologic inhibitor of fibrinolysis, is implicated in the progression of atherosclerosis. Sphingosine 1-phosphate (S1P) regulates expression of diverse genes and alters expression of PAI-1 in several types of cells. However, the nature of posttranscriptional regulation of expression of PAI-1 by S1P has not yet been thoroughly elucidated. The present study was undertaken to determine whether S1P has important effects on the posttranscriptional regulation of PAI-1 expression. To evaluate this possibility, we determined promoter activity, mRNA levels, 3'-untranslated region (UTR) activity, and protein levels of PAI-1 in HepG2 cells. S1P increased PAI-1 promoter activity and the expression of PAI-1 mRNA within 4h of exposure. It decreased the expression of PAI-1 mRNA and the accumulation of PAI-1 protein into the media in 24h. Human PAI-1 mRNA exists in two subspecies (3.2 and 2.2kb). S1P decreased the baseline luciferase activity of the 1kb fragment of the 3' terminus (+2177 to 3176nt) of the 3'-UTR of the 3.2kb PAI-1 mRNA [3'-UTR (+2177-3176)]. S1P decreased expression of PAI-1 protein, presumably by regulating PAI-1 expression at the posttranscriptional level thereby affecting mRNA stability. SERPINE1 mRNA binding protein (SERBP1) and ARE3 in the 3'-UTR were involved in the posttranscriptional regulation by S1P. Our data suggest that S1P can destabilize 3.2kb PAI-1 mRNA through specific effects on the 3'-UTR. These effects appear to involve SERBP1 leading to decreased expression of PAI-1 protein.


Deletions in the 3' part of the NFIX gene including a recurrent Alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of Marshall-Smith syndrome.
Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.


Weight management using a meal replacement strategy: meta and pooling analysis from six studies.
Although used by millions of overweight and obese consumers, there has not been a systematic assessment on the safety and effectiveness of a meal replacement strategy for weight management. The aim of this study was to review, by use of a meta- and pooling analysis, the existing literature on the safety and effectiveness of a partial meal replacement (PMR) plan using one or two vitamin/mineral fortified meal replacements as well as regular foods for long-term weight management. A PMR plan was defined as a program that prescribes a low calorie (>800<or=1600 kcal/day) diet whereby one or two meals are replaced by commercially available, energy-reduced product(s) that are vitamin and mineral fortified, and includes at least one meal of regular foods. Randomized, controlled PMR interventions of at least 3 months duration, with subjects 18 y of age or older and a BMI>or=25 kg/m(2), were evaluated. Studies with self-reported weight and height were excluded. Searches in Medline, Embase, and the Cochrane Clinical Trials Register from 1960 to January 2001 and from reference lists identified 30 potential studies for analysis. Of these, six met all of the inclusion criteria and used liquid meal replacement products with the associated plan. Overweight and obese subjects were randomized to the PMR plan or a conventional reduced calorie diet (RCD) plan. The prescribed calorie intake was the same for both groups. Authors of the six publications were contacted and asked to supply primary data for analysis. Primary data from the six studies were used for both meta- and pooling analyses. Subjects prescribed either the PMR or RCD treatment plans lost significant amounts of weight at both the 3-month and 1-year evaluation time points. All methods of analysis indicated a significantly greater weight loss in subjects receiving the PMR plan compared to the RCD group. Depending on the analysis and follow-up duration, the PMR group lost approximately 7-8% body weight and the RCD group lost approximately 3-7% body weight. A random effects meta-analysis estimate indicated a 2.54 kg (P<0.01) and 2.43 kg (P=0.14) greater weight loss in the PMR group for the 3-month and 1-y periods, respectively. A pooling analysis of completers showed a greater weight loss in the PMR group of 2.54 kg (P<0.01) and 2.63 kg (P<0.01) during the same time period. Risk factors of disease associated with excess weight improved with weight loss in both groups at the two time points. The degree of improvement was also dependent on baseline risk factor levels. The dropout rate for PMR and RCD groups was equivalent at 3 months and significantly less in the PMR group at 1 y. No reported adverse events were attributable to either weight loss regimen. This first systematic evaluation of randomized controlled trials utilizing PMR plans for weight management suggests that these types of interventions can safely and effectively produce significant sustainable weight loss and improve weight-related risk factors of disease.