Synapse-specific adaptations to inactivity in hippocampal circuits achieve homeostatic gain control while dampening network reverberation.
Synaptic homeostasis, induced by chronic changes in neuronal activity, is well studied in cultured neurons, but not in more physiological networks where distinct synaptic circuits are preserved. We characterized inactivity-induced adaptations at three sets of excitatory synapses in tetrodotoxin-treated organotypic hippocampal cultures. The adaptation to inactivity was strikingly synapse specific. Hippocampal throughput synapses (dentate-to-CA3 and CA3-to-CA1) were upregulated, conforming to homeostatic gain control in order to avoid extreme limits of neuronal firing. However, chronic inactivity decreased mEPSC frequency at CA3-to-CA3 synapses, which were isolated pharmacologically or surgically. This downregulation of recurrent synapses was opposite to that expected for conventional homeostasis, in apparent conflict with typical gain control. However, such changes contributed to an inactivity-induced shortening of reverberatory bursts generated by feedback excitation among CA3 pyramids, safeguarding the network from possible runaway excitation. Thus, synapse-specific adaptations of synaptic weight not only contributed to homeostatic gain control, but also dampened epileptogenic network activity.


[Periprosthetic joint infections: a practical overview for family physicians].
Periprosthetic joint infection is a rare but serious complication. Its management requires the collaboration between general practitioner, orthopaedic surgeon and infectious disease specialist. A delay in the diagnosis can result in complications, requiring complex surgical procedures. Identification of the causative pathogen and its susceptibility pattern is crucial, because it guides both the choice of antimicrobial treatment and the surgical strategy. Antimicrobial treatment without proper micro- biological sampling must be avoided. Swabs from open wounds are not helpful, because microorganisms belonging to the skin flora will grow. The target audience of this review article on periprosthetic joint infections is the general practitioner.


Dual-force ISOMAP: a new relevance feedback method for medical image retrieval.
With great potential for assisting radiological image interpretation and decision making, content-based image retrieval in the medical domain has become a hot topic in recent years. Many methods to enhance the performance of content-based medical image retrieval have been proposed, among which the relevance feedback (RF) scheme is one of the most promising. Given user feedback information, RF algorithms interactively learn a user's preferences to bridge the "semantic gap" between low-level computerized visual features and high-level human semantic perception and thus improve retrieval performance. However, most existing RF algorithms perform in the original high-dimensional feature space and ignore the manifold structure of the low-level visual features of images. In this paper, we propose a new method, termed dual-force ISOMAP (DFISOMAP), for content-based medical image retrieval. Under the assumption that medical images lie on a low-dimensional manifold embedded in a high-dimensional ambient space, DFISOMAP operates in the following three stages. First, the geometric structure of positive examples in the learned low-dimensional embedding is preserved according to the isometric feature mapping (ISOMAP) criterion. To precisely model the geometric structure, a reconstruction error constraint is also added. Second, the average distance between positive and negative examples is maximized to separate them; this margin maximization acts as a force that pushes negative examples far away from positive examples. Finally, the similarity propagation technique is utilized to provide negative examples with another force that will pull them back into the negative sample set. We evaluate the proposed method on a subset of the IRMA medical image dataset with a RF-based medical image retrieval framework. Experimental results show that DFISOMAP outperforms popular approaches for content-based medical image retrieval in terms of accuracy and stability.


The effect of responsiveness to speech-generating device input on spoken language in children with autism spectrum disorder who are minimally verbal†.
The use of speech-generating devices (SGD) in early interventions for children with autism spectrum disorder (ASD) can improve communication and spoken language outcomes. The purpose of this study was to describe children's responsiveness to SGD input modeled by a social partner during adult-child play interactions over a 24-week intervention trial and explore the effect of that responsiveness on spoken language growth. This secondary analysis consisted of 31 children with less than 20 functional words at study entry who received a blended behavioral intervention (JASPER + EMT) as part of a randomized controlled trial. Significant improvements were seen in rate of responsiveness to both adult SGD models and adult natural speech models; only rate of responsiveness to SGD models at entry was a significant predictor of frequency of commenting and was a more robust predictor of number of different words post-intervention. Lastly, at entry, children with more joint attention and language responded to SGD models at significantly higher rates. Attention and responsiveness to SGD output may be important mechanisms of language growth and children who have more joint attention skills may particularly benefit from use of an SGD.


DNA damage-induced apoptosis suppressor (DDIAS), a novel target of NFATc1, is associated with cisplatin resistance in lung cancer.
In a previous study, we reported that DNA damage induced apoptosis suppressor (DDIAS; hNoxin), a human homolog of mouse Noxin, functions as an anti-apoptotic protein in response to DNA repair. Here we reveal that DDIAS is a target gene of nuclear factor of activated T cells 2 (NFATc1) and is associated with cisplatin resistance in lung cancer cells. In the DDIAS promoter analysis, we found that NFATc1 activated the transcription of DDIAS through binding to NFAT consensus sequences in the DDIAS promoter. In addition, tissue array immunostaining revealed a correlation between DDIAS and NFATc1 expression in human lung tumors. NFATc1 knockdown or treatment with the NFAT inhibitor cyclosporine A induced apoptosis and led to growth inhibition of lung cancer cells, indicating the functional relevance of both the proteins. In contrast, DDIAS overexpression overcame this NFATc1 knockdown-induced growth inhibition, supporting the cancer-specific role of DDIAS as a target gene of NFATc1. NFATc1 or DDIAS inhibition clearly enhanced apoptosis induced by cisplatin in NCI-H1703 and A549 cells. Conversely, DDIAS overexpression rescued NCI-H1703 cells from cisplatin-mediated cell death and caspase-3/7 activation. These results suggest that NFATc1-induced DDIAS expression contributes to cisplatin resistance, and targeting DDIAS or NFATc1 impairs the mechanism regulating cisplatin resistance in lung cancer cells. Taken together, DDIAS is a target of NFATc1 and is associated with cisplatin resistance in lung cancer cells.


Box Hill Hospital resuscitation trolley.
A resuscitation trolley has been designed to meet the following requirements. Continuous oxygen supply from the trolley for the duration of the emergency; medical suction of similar strength to that of an ICU treatment bay and provision of equipment and drugs in a modular form, which is uniform across the institution, and which allows immediate replacement from stock. These requirements have been fulfilled whilst maintaining a total trolley weight and manoeuvrability similar to that of commercially manufactured trolleys available in Australia.


Pacing in preterm with hydrops fetalis due to congenital complete heart block.
Hydrops fetalis due to congenital complete heart block (CCHB) is a rare condition. The outcome of the preterm fetus with hydrops fetalis due to CCHB is poor, and is frequently associated with significant morbidity and mortality. The management of this condition is difficult. We report our experience in a hydropic preterm using staged pacing by applying left ventricular epicardial pacing with a temporary pacemaker and subsequently, left ventricular epicardial pacing with a permanent pacemaker.


Soybean dihydrolipoamide dehydrogenase (ferric leghemoglobin reductase 2) interacts with and reduces ferric rice non-symbiotic hemoglobin 1.
Ferrous oxygenated hemoglobins (Hb2+O2) autoxidize to ferric Hb3+, but Hb3+ is reduced to Hb2+ by enzymatic and non-enzymatic mechanisms. We characterized the interaction between the soybean ferric leghemoglobin reductase 2 (FLbR2) and ferric rice non-symbiotic Hb1 (Hb13+). Spectroscopic analysis showed that FLbR2 reduces Hb13+. Analysis by tryptophan fluorescence quenching showed that FLbR2 interacts with Hb13+, however the use of ITC and IEF techniques revealed that this interaction is weak. In silico modeling showed that predicted FLbR2 and native Hb13+ interact at the FAD-binding domain of FLbR2 and the CD-loop and helix F of Hb13+.


Genome-wide analysis of C/D and H/ACA-like small nucleolar RNAs in Leishmania major indicates conservation among trypanosomatids in the repertoire and in their rRNA targets.
Small nucleolar RNAs (snoRNAs) are a large group of noncoding RNAs that exist in eukaryotes and archaea and guide modifications such as 2'-O-ribose methylations and pseudouridylation on rRNAs and snRNAs. Recently, we described a genome-wide screening approach with Trypanosoma brucei that revealed over 90 guide RNAs. In this study, we extended this approach to analyze the repertoire of the closely related human pathogen Leishmania major. We describe 23 clusters that encode 62 C/Ds that can potentially guide 79 methylations and 37 H/ACA-like RNAs that can potentially guide 30 pseudouridylation reactions. Like T. brucei, Leishmania also contains many modifications and guide RNAs relative to its genome size. This study describes 10 H/ACAs and 14 C/Ds that were not found in T. brucei. Mapping of 2'-O-methylations in rRNA regions rich in modifications suggests the existence of trypanosomatid-specific modifications conserved in T. brucei and Leishmania. Structural features of C/D snoRNAs, such as copy number, conservation of boxes, K turns, and intragenic and extragenic base pairing, were examined to elucidate the great variation in snoRNA abundance. This study highlights the power of comparative genomics for determining conserved features of noncoding RNAs.


Genetic screening for the next decade: application of present and new technologies.
Molecular genetic technology is diffusing from the research laboratory to the clinical laboratory, where it has already begun to influence prenatal diagnosis and counseling. In the very near future, this technology will be applied more generally, using population-based screening strategies. Pilot programs are beginning to evaluate the technical feasibility and efficacy of recombinant DNA techniques for newborn screening follow-up. DNA-based population screening is being considered for heterozygous carriers of an autosomal recessive disorder such as cystic fibrosis in order to identify carrier couples at risk of having an affected child. We will review the current DNA methodologies in the context of three genetic disorders: sickle-cell disease, Duchenne muscular dystrophy, and cystic fibrosis. We will then consider the requirements for implementation of these new technologies. We will conclude that implementation will require two key factors: machines and people. Machines are required to automate molecular genetic procedures, which are currently personnel-intensive, so that the expense can be reduced and the procedures made more cost-effective. The people who are required are health professionals knowledgeable in the clinical aspects of the target disorders, as well as in the DNA laboratory testing. These professionals will be able to facilitate sample acquisition and information exchange among the laboratory, the primary health care provider, and the families requesting consultation.


[Influence of acupuncture and electroacupuncture on heart rate and extrasystoles (author's transl)].
In 33 patients with constant ventricular extrasystoles the influence of acupuncture and electroacupuncture on the extrasystoles and the heart rate was examined. There was no difference in heart rate between the treatment-conditions and the non-treatment-conditions. Differences were seen however in the frequencies of the ventricular extrasystoles: During acupuncture (normal as well as electric) the total sum of ventricular extrasystoles and the number of subjects with ventricular extrasystoles was lowered significantly in relation to the non-treatment-condition. The findings are discussed as to neurovegetative and neuroendocrine influence of acupuncture.


Internal cardioverter defibrillator: component failure.
Sudden death occurred in a patient with congestive cardiomyopathy, sustained ventricular tachycardia refractory to amiodarone, and an automatic internal cardioverter defibrillator. Interrogation of the AICD at the time of death was indicative of malfunction. Postmortem analysis documented component failure involving a voltage regulating transistor resulting in prolonged charge times.


Cellulose-dependent expression and antibacterial characteristics of surfactin from Bacillus subtilis HH2 isolated from the giant panda.
Surfactin secreted by Bacillus subtilis can confer strong, diverse antipathogenic effects, thereby benefitting the host. Carbon source is an important factor for surfactin production. However, the mechanism that bacteria utilize cellulose, the most abundant substance in the intestines of herbivores, to produce surfactin remains unclear. Here, we used B. subtilis HH2, isolated from the feces of a giant panda, as a model to determine changes in surfactin expression in the presence of different concentrations of cellulose by quantitative polymerase chain reaction and high-performance liquid chromatography. We further investigated the antimicrobial effects of surfactin against three common intestinal pathogens (Escherichia coli, Staphylococcus aureus, and Salmonella enterica) and its resistance to high temperature (60-121°C), pH (1-12), trypsin (100-300 μg/mL, pH 8), and pepsin (100-300 μg/mL, pH 2). The results showed that the surfactin expressed lowest in bacteria cultured in the presence of 1% glucose medium as the carbon source, whereas increased in an appropriate cellulose concentration (0.67% glucose and 0.33% cellulose). The surfactin could inhibit E. coli and Staphylococcus aureus, but did not affect efficiently for Salmonella enterica. The antibacterial ability of surfactin did not differ according to temperature (60-100°C), pH (2-11), trypsin (100-300 μg/mL), and pepsin (100-300 μg/mL; P > 0.05), but decreased significantly at extreme environments (121°C, pH 1 or 12; P < 0.05) compared with that in the control group (37°C, pH = 7, without any protease). In conclusion, our findings indicated that B. subtilis HH2 could increase surfactin expression in an appropriate cellulose environment and thus provide benefits to improve the intestinal health of herbivores.


[Prevention and interventions for suicidal youth considerations for health professionionals in Switzerland].
Adolescence is associated with a dramatic surge in suicide rate. While worldwide age-adjusted suicides rate per 100'000 in under 14-year olds are relatively low around 0.6, a dramatic increase to 7.4 can be observed in 15 – 19 year olds with suicide being one of the three leading causes of mortality in most countries in this age group. From 2000 to 2013 the Swiss annual average of completed suicides in 15 – 19 year olds was 33.1 (minimum 24; maximum 47). This corresponds to an average age-specific death rate of 7.6, which is slightly above the global mean. Suicide prevention and treatment of suicidality in adolescents is a complex underpinning. Subjectively experienced feelings of insufficiency, hopelessness and the feeling of worthlessness combined with concrete suicidal ideations and the capacity to act out are important indicators for assessing suicidal risk. Suicide attempts as the strongest risk factor for suicide should always be taken seriously, even if they occur in the context of situational crisis. Narcissistic personality traits or increased impulsivity are further indicators of risk. The early detection and effective treatment of mental disorders such as depression, anxiety disorders, bipolar-affective disorders or psychotic disorders provide a great opportunity to reduce the frequency of suicide attempts and suicide. Particular caution is required when co-morbid addictions are present. The maintenance or establishment of sustainable relationships with significant others is considered a key protecting factor. Increasing withdrawal from significant others is an important warning sign and needs urgent involvement of experts. In acute suicidality, the admission to a psychiatric hospital must be considered, if necessary against the will of affected adolescent and their relatives. Personality-related recurrent suicidal behavior requires specific treatment approaches taking into account the prevention of iatrogenic worsening of suicidal patterns.


Kidney function and cognitive impairment in US adults: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.
The association between kidney function and cognitive impairment has not been assessed in a national sample with a wide spectrum of kidney disease severity. Cross-sectional. 23,405 participants (mean age, 64.9 +/- 9.6 years) with baseline measurements of creatinine and cognitive function participating in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, a study of stroke risk factors in a large national sample. Estimated glomerular filtration rate (eGFR). Cognitive impairment. Chronic kidney disease (CKD) was defined as eGFR less than 60 mL/min/1.73 m(2). Kidney function was analyzed in 10-mL/min/1.73 m(2) increments in those with CKD, and in exploratory analyses, across the range of kidney function. Cognitive function was assessed using the 6-Item Screener, and participants with a score of 4 or less were considered to have cognitive impairment. CKD was associated with an increased prevalence of cognitive impairment independent of confounding factors (odds ratio, 1.23; 95% confidence interval, 1.06 to 1.43). In patients with CKD, each 10-mL/min/1.73 m(2) decrease in eGFR less than 60 mL/min/1.73 m(2) was associated with an 11% increased prevalence of impairment (odds ratio, 1.11; 95% confidence interval, 1.04 to 1.19). Exploratory analyses showed a nonlinear association between eGFR and prevalence of cognitive impairment, with a significant increased prevalence of impairment in those with eGFR less than 50 and 100 mL/min/1.73 m(2) or greater. Longitudinal measures of cognitive function were not available. In US adults, lower levels of kidney function are associated with an increased prevalence of cognitive impairment. The prevalence of impairment appears to increase early in the course of kidney disease; therefore, screening for impairment should be considered in all adults with CKD.


Thyrotoxic periodic paralysis as the first manifestation of a thyrotropin-secreting pituitary adenoma.
Thyrotoxic Periodic Paralysis (TPP) is a rare manifestation of hyperthyroidism characterized by muscle weakness and hypokalemia. Thyroid-Stimulating Hormone (TSH)-secreting pituitary adenoma is a rare cause of hyperthyroidism. Even more rare is the occurrence of TPP as the first manifestation of a TSH-secreting pituitary adenoma. We report a 31-year-old Asian male patient suffering from TPP caused by a TSH-secreting adenoma, who was evaluated for persistent episodes of muscle paralysis. Laboratory investigation revealed hypokalemia as well as elevated levels of both thyroid hormones and TSH. The Magnetic Resonance Imaging (MRI) of the pituitary gland revealed a microadenoma, thus suggesting the presence of a TSH-secreting adenoma. The patient underwent transphenoidal resection and the pathological investigation confirmed the diagnosis of TSH-secreting pituitary adenoma. After the adenomectomy and the restoration of euthyroidism, the patient did not experience any episode of hypokalemic paralysis or weakness. Despite its rarity, TSH-secreting pituitary adenoma should be included in the differential diagnosis of TPP.


Vitamin A Prophylaxis Programs in Developing Countries: Past Experiences and Future Prospects.
Clinical eye signs are estimated to affect 5-10 million children annually in the developing world. Thus most experience with large-scale prophylaxis programs has been with periodic distribution of high-dose vitamin A supplements directed toward preventing ocular problems. However, subclinical vitamin A depletion affects an estimated five- to 10-fold larger population, and evidence is accumulating for a subclinical protective role of vitamin A against risk of mortality, and perhaps morbidity. Current programs aim to integrate prophylaxis with vitamin A supplements into ongoing programs. Decentralization of distribution of supplements and their integration into community-based programs require careful consideration of dosages and frequency to assure safety and broad coverage. Fortification of foods and condiments has not provided adequate prophylaxis in countries with significant vitamin A deficiency. Other strategies recognized as more sustainable, long-term solutions have received less attention, and their potential has not been evaluated. Such strategies aim to increase dietary intake of vitamin A and/or decrease physiologic requirements; these strategies include horticulture, public health, socioeconomic improvement, and nutrition and health education measures.


COVID-19 in Cirrhotic Patients: Is Portal Vein Thrombosis a Potential Complication?
Several studies have demonstrated that thromboembolic events increased in patients with coronavirus infection, usually occurring in elderly patients with severe illness, associated with comorbid diseases such as diabetes and hypertension. Portal vein thrombosis (PVT) is a rare venous thromboembolic disease occurring typically in patients with an underlying disease such as decompensated cirrhosis with or without hepatocellular carcinoma (HCC). To evaluate incidence of occurrence of acute PVT in cirrhotic patients infected with 2019 coronavirus disease (COVID-19). This cross-sectional, observational study involved 70 patients of the liver cirrhosis: (group A) 28 patients with liver cirrhosis infected with COVID-19, and 42 patients with liver cirrhosis as the control group matched for age and sex (group B). All patients were subjected to thorough medical history, routine investigations (complete blood count, liver, and renal function tests), imaging in the form of abdominal and Doppler ultrasonography to assess the presence of acute PVT, serum ferritin, D-dimer, C-reactive protein, and PCR of COVID-19 for group A only. There was a significant difference between the two groups regarding Doppler ultrasound findings as 3 of the patients in group A had PVT (10.7%), 2 of them had HCC diagnosed by triphasic CT abdomen, and only 1 patient in group B had PVT (2.3%) (p < 0.05). In cirrhotic patients infected with COVID-19, portal vein thrombosis may be a potential complication even in the absence of hepatocellular carcinoma; further prospective studies with longer follow-up may be needed.


Methotrexate/mifepristone-combined with embryo removal in the treatment of caesarean scar pregnancy.
The aim of this study was to compare the effect of different administration modalities of methotrexate (MTX)/mifepristone in the initial medication stage, followed by embryo transfer in the treatment of caesarean scar pregnancy (CSP). A retrospective analysis of 66 CSP patients who received treatment in our hospital from January 2015 to July 2021 was performed, and participants were divided into three groups: Group one (n=14) received mifepristone followed by embryo removal treatment, Group two (n=29) received MTX followed by embryo removal, and Group three (n=23) received a methotrexate/mifepristone combined treatment followed by embryo removal. The basic findings were analysed, along with the curative effects between the three groups. Risk factors predicting additional treatment after initial intervention failure were analysed. There were statistically significant differences in gestational age, hospitalization days, costs, myometrial thickness, cardiac activity, and mean sac diameter between groups (p<0.05) after grouping by eight weeks. The initial intervention success rates were 92.86%, 89.66%, and 65.22% in Group one, two, and three, respectively (p<0.05), while the complication rates were 14.29%, 6.90%, and 26.87%, respectively (p>0.05). After grouping according to eight weeks of gestational age, the difference in initial serum β-hCG between Group two and three was statistically significant (p<0.05). Mean sac diameter was a risk factor for additional treatment after initial intervention failure, with an odds ratio of 1.113 (p<0.05). A cut-off of 22.75 mm was a preferable indicator. MTX/mifepristone followed by embryo removal is a reliable way to treat CSP. Mean sac diameter was a risk factor for additional treatment after initial intervention failure.


Cognitive model of caregiving in psychosis.
There is a long history of research into the attributes of carers of people with psychosis, but few interventions target their distress or their difficulties. To describe an empirically based model of the relationships of those caring for people with psychosis to inform clinical and theoretical advances. We developed a model of informal carer relationships in psychosis, based on an integration of the literature elaborating the concept of expressed emotion. The model accounts for divergent outcomes of three relationship types: positive, overinvolved and critical/hostile relationships. Good evidence supports a number of hypotheses concerning the origin and maintenance of these relationship outcomes, which relate to specific differences in carer attributions, illness perceptions, coping behaviour, social support, distress, depression and low self-esteem predicted by our model. We propose that interventions aimed at modifying the specific maintenance factors involved in the different styles of relationships will optimise therapeutic change both for service users with psychosis and for their carers. Family work in psychosis, which improves relationships through problem-solving, reduces service user relapse. It is now time to consider theory-based interventions focused on improving carer outcomes.


The female sexual function index: reliability and validity in Spanish postmenopausal women.
To examine the reliability and validity of the Spanish version of the Female Sexual Function Index (FSFI) and its ability to discriminate between women with and without female sexual dysfunction (FSD) among Spanish postmenopausal women. A total of 152 postmenopausal women completed the Spanish version of FSFI. Internal consistency, test-retest reliability, and construct validity (exploratory factor analysis) were analyzed. Concurrent and divergent validity were assessed using a visual analog scale for overall satisfaction with sexual life and the Hospital Anxiety and Depression Scale, respectively. To determine the ability and the accuracy of the FSFI total score in discriminating between women with and without FSD, a receiver-operating characteristic curve analysis was performed. Factor analysis suggested a three-factor structure (explained variance 77.77%). The Spanish FSFI showed substantial-to-excellent test-retest reliability, with good internal consistency in the FSFI total score (Cronbach's alpha = 0.964), and also in its three dimensions. The FSFI total and domains scores showed strong (r > 0.50) and significant correlations (P < 0.01) with overall satisfaction with sexual life (concurrent validity), and low correlations with anxiety and depression (divergent validity). The Spanish FSFI total score and dimensions were significantly able to discriminate between women with and without FSD (P < 0.05), with an optimal cut-off point of <24.95 for the FSFI total score (64.15% sensitivity and 75.76% specificity). The Spanish FSFI is a valid and reliable instrument for assessing and discriminating for FSD among Spanish postmenopausal women.


Treatment of Class III Malocclusion: Atypical Extraction Protocol.
The treatment of Angle Class III malocclusion is rather challenging, because the patient's growth pattern determines the success of long-term treatment. Early diagnosis and treatment are still highly discussed issues in orthodontic literature. This type of early intervention has been indicated more frequently in order to eliminate primary etiological factors and prevent an already present malocclusion from becoming severe. However, when a patient is diagnosed in adulthood, manipulation of the bone bases becomes extremely limited, as there is no longer any potential for growth. Treatments are restricted to dental compensations when possible or orthognathic surgery. However, owing to the high cost and inherent risk of the surgical procedure, this treatment option is often denied by the patient; in such a case, the orthodontist has little choice but to perform, where possible, compensatory treatments to restore a functional occlusion and improve facial esthetics. This article reports a case of Class III malocclusion in a patient who opted for compensatory treatment with lower molar extraction that allowed for correction of the midline and the overjet. Good facial esthetics and functional normal occlusion were achieved at the end of the treatment.


The Lin12-notch repeats of pregnancy-associated plasma protein-A bind calcium and determine its proteolytic specificity.
The Lin12-Notch repeat (LNR) module of about 35 residues is a hallmark of the Notch receptor family. Three copies, arranged in tandem, are invariably present in the extracellular portion of the Notch receptors. Although their function is unknown, genetic and biochemical data indicate that the LNR modules participate in the regulation of ligand-induced proteolytic cleavage of the Notch receptor, a prerequisite to intramembrane cleavage and Notch signaling. Outside the Notch receptor family, the LNR module is present only in the metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) and its homologue PAPP-A2, which also contain three copies. Curiously, LNR modules 1 and 2 are present within the proteolytic domain of PAPP-A/A2, but LNR3 is separated from LNR2 by more than 1000 amino acids. The growth factor antagonists insulin-like growth factor-binding protein (IGFBP)-4 and -5 are both substrates of PAPP-A. We provide here evidence that the PAPP-A LNR modules function together to determine the proteolytic specificity of PAPP-A. Analysis of C-terminally truncated PAPP-A mutants followed by the analysis of LNR deletion mutants demonstrated that each of the three PAPP-A LNR modules is strictly required for proteolytic activity against IGFBP-4 but not for proteolytic activity against IGFBP-5. Individual substitution of conserved LNR residues predicted to participate in calcium coordination caused elimination (D341A, D356A, D389A, D1484A, D1499A, and D1502A) or a significant reduction (D359A and E392A) of IGFBP-4 proteolysis, whereas IGFBP-5 proteolysis was unaffected. The activity of the latter mutants against IGFBP-4 could be partially rescued by calcium, and the addition of the calcium-binding protein calbindin D9k to wild-type PAPP-A eliminated activity against IGFBP-4 but not against IGFBP-5, demonstrating that the PAPP-A LNR modules bind calcium ions. We propose a model in which LNR3 is spatially localized in proximity to LNR1 and -2, forming a single functional unit.


Patient-Reported Outcome Measures for Patients Undergoing Inguinal Hernia Repair.
There are many ways to determine the success of an inguinal hernia operation. Traditional measures are hernia recurrence, neuralgia, mesh infection, or rather the absence of these complications. While these traditional measures obviously have their merits, alternative outcomes are emerging, and researchers and clinicians are gaining an increasing interest in patient-reported outcomes and patient reported outcome measures (PROMs). PROMs are patient questionnaires concerning quality of life, chronic pain, disability, or other subjects that are best assessed by the patients. PROMs come in two different forms: generic and condition specific. The generic PROMs concern general symptoms and issues, while the condition-specific PROMs target patients with a certain condition. Inguinal hernia-specific PROMs typically address issues like mesh-related symptoms, groin pain, sexual dysfunction, etc. Clinical measurement instruments such as PROMs should be carefully validated according to standardized guidelines to ensure their psychometric measurement properties. Unfortunately, this type of evidence is often lacking when it comes to inguinal hernia-specific PROMs. In this review, we explain why PROMs are useful for patients with inguinal hernia and why one should use inguinal hernia-specific PROMs as opposed to the generic ones. We address the importance of population-specific validation and explain what type of evidence is lacking. Last, we discuss the future prospects of using PROMs for patients with inguinal hernia.


Current respiratory support practices in premature infants: an observational study.
This study aims to describe longitudinally the current invasive and non-invasive ventilation practices in premature infants in a single neonatal intensive care unit (NICU). It´s a retrospective chart review including 682 babies born at gestational age ≤35 weeks, admitted to the NICU at Erasme Hospital, between 1st of January 2001 and 31st of December 2011, the different ventilatory support used were analyzed. This population was stratified depending on gestational age and the recruitment period on 3 groups. All infants born <28 weeks of GA (group 1) needed some kind of respiratory support of which 22% non-invasive. Among babies born after 28 to 31 weeks (group 2), 10.2% didn´t need any ventilatory support and 42% needed a non-invasive respiratory support. In neonates from 32 to 35 weeks of GA (group 3) respiratory support was needed in 34.9%, 65% of which was non-invasive. The median duration of endotracheal ventilation was: 6, 1 and 2 days, and of non-invasive support: 41, 17 and 2 days in group 1, 2 and 3 respectively. One single premature baby could pass along the first weeks through all modes. In premature infants whose respiratory support was needed, the median age at the end of support was remarkably constant at 33 - 34 weeks of corrected age. We conclude that is an important diversity and a significant complementarity between modes of respiratory support for premature infants. Invasive ventilation decreased significantly for group 2, but is still remarkably long for group 1.


Hemodynamic Changes Are Predictive of Coagulopathic Hemorrhage After Living Donor Liver Transplant.
Our goal was to evaluate the predictors of coagulopathic hemorrhage after living-donor liver transplant. We retrospectively evaluated 161 patients who had undergone living-donor liver transplant from July 2005 to April 2014 at a single medical institution. Of these patients, 32 developed hemorrhage after transplant. Patients were separated into those with coagulopathy-related hemorrhage (n=15) or noncoagulopathy-related hemorrhage (n=17) based on the results of computed tomography images. Predictors of hemorrhage after living-donor liver transplant evaluated in this study included preoperative, perioperative, and posttransplant factors and hemodynamic status. Patients who developed coagulopathy-related hemorrhage had significantly lower pretransplant platelet counts (P = .040), a longer cold-ischemia time (P = .045), more blood loss (P = .040), and earlier onset of hemorrhage (P = .048) than patients who had noncoagulopathy-related hemorrhage after transplant. Results of the generalized estimating equation analysis showed that heart rate and central venous pressure differed significantly between the 2 groups of patients. Heart rates increased significantly during hemorrhage (P < .010). Central venous pressure was higher in the coagulopathic group (P = .005) than in the noncoagulopathic group. Lower pretransplant platelet counts, longer cold ischemia time, more blood loss, earlier onset of hemorrhage, and higher central venous pressure level are indicators of coagulopathic hemorrhage after living-donor liver transplant.


Tetronic(®)-based composite hydrogel scaffolds seeded with rat bladder smooth muscle cells for urinary bladder tissue engineering applications.
Natural hydrogels such as collagen offer desirable properties for tissue engineering, including cell adhesion sites, but their low mechanical strength is not suitable for bladder tissue regeneration. In contrast, synthetic hydrogels such as poly (ethylene glycol) allow tuning of mechanical properties, but do not elicit protein adsorption or cell adhesion. For this reason, we explored the use of composite hydrogel blends composed of Tetronic (BASF) 1107-acrylate (T1107A) in combination with extracellular matrix moieties collagen and hyaluronic acid seeded with bladder smooth muscle cells (BSMC). This composite hydrogel supported BSMC growth and distribution throughout the construct. When compared to the control (acellular) hydrogels, mechanical properties (peak stress, peak strain, and elastic modulus) of the cellular hydrogels were significantly greater. When compared to the 7-day time point after BSMC seeding, results of mechanical testing at the 14-day time point indicated a significant increase in both ultimate tensile stress (4.1-11.6 kPa) and elastic modulus (11.8-42.7 kPa) in cellular hydrogels. The time-dependent improvement in stiffness and strength of the cellular constructs can be attributed to the continuous collagen deposition and reconstruction by BSMC seeded in the matrix. The composite hydrogel provided a biocompatible scaffold for BSMC to thrive and strengthen the matrix; further, this trend could lead to strengthening the construct to match the mechanical properties of the bladder.


[Synthesis of acyclic 1,3-polyols and its application to structural study of natural products].
A 1,3-polyhydroxylated chain is often found on the backbone of biologically important natural products. The acyclic nature and the regular array of many hydroxyl groups are main obstacles to structural and synthetic studies, and many efforts have been made to this end. We have developed a new general synthetic method of 1,3-polyols based on the coupling of a chiral dithiane, a four-carbon unit, and an epoxide, followed by 1,3-diastereoselective reduction. We applied the method to the synthesis of polymethoxy-1-alkenes isolated from blue-green algae to establish their absolute stereochemistry. Moreover, a general procedure for assigning the absolute stereochemistry of acyclic 1,3-polyols by the difference circular dichroism (CD) method have been established. Combination of the method and a reiterative degradation enables one to determine the absolute configuration of 1,3-polyols, even if the relative stereochemistry is unknown.


[Use of urine drug screening in the emergency department of a paediatric hospital].
To describe the situations in which urine drug screening is used in a Paediatric Emergency Department (ED). An analysis is also made on its potential usefulness on whether it changes the patient management, and if the results are confirmed by using specific techniques. A retrospective study was conducted on patients under the age of 18 attended in the ED during 2014 and in whom urine drug screening was requested. Depending on the potential capacity of the screening result to change patient management, two groups were defined (potentially useful and not potentially useful). Urine drug screening was performed on a total of 161 patients. The screening was considered not to be potentially useful in 87 (54.0%). This was because the clinical history already explained the symptoms the patient had in 55 (34.1%) patients, in 29 (18.0%) because the patient was asymptomatic, and in 3 (1.9%) because the suspected drug was not detectable in the screening. The drug screening results changed the patient management in 5 (3.1%) cases. A toxic substance was detected in 44 (27.3%). Two out of the 44 that were positive (2.1%) were re-tested by specific techniques, and presence of the toxic substance was ruled out in both of them (false positives). Most of the drug screening tests are not justified, and it is very infrequent that they change patient management. It is very rare that the results are confirmed using more specific methods. Urine drug screening tests should be restricted to particular cases and if the result has legal implications, or if the patient denies using the drug, it should be followed by a specific toxicological study to provide a conclusive result.


Compassionate Care for Parents Experiencing Miscarriage in the Emergency Department: A Situation-Specific Theory.
In many countries, parents experiencing miscarriage seek treatment in the emergency department (ED). Parents frequently report dissatisfaction with ED care, while nurses report not knowing how to provide optimal care. This article describes the development of a situation-specific theory, Compassionate care for parents experiencing miscarriage in the ED , based on 4 concepts (change trigger, transition properties, conditions of change, and interventions). This theory evolved from a comprehensive review of the literature, 2 empirical studies, Transitions Theory, and collaborative efforts of an experienced team. The detailed theory development process facilitates its integration in practice and supports new theory development.


Aquilide A, a new mutagenic compound isolated from bracken fern (Pteridium aquilinum (L.) Kuhn).
A mutagenic compound, designated aquilide A, was isolated and identified from bracken fern (Pteridium aquilinum (L.) Kuhn). Aquilide A was found to be responsible for greater than 50% of the mutagenic activity observed after incubation of the methanol extract at alkaline conditions. This compound was found to be a potent genotoxic compound in mammalian cells in vitro and therefore, may be responsible for at least part of the carcinogenic activity of bracken. The instability of aquilide A under conditions normally encountered during analytical chemical procedures may explain why so many efforts to elucidate the carcinogenic factor(s) present in bracken have been unsuccessful.


Exposure of men and lactating women to environmental phenols, phthalates, and DINCH.
Phthalates and 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH), bisphenols (BPs), parabens (PBs), and triclosan (TCS) are high-production-volume chemicals of pseudo-persistence that are concerning for the environment and human health. This study aims to assess the exposure to 10 phthalates, DINCH, and environmental phenols (3 BPs, 7 PBs, and TCS) of Slovenian men (n = 548) and lactating primiparous women (n = 536). We observed urinary concentrations comparable to studies from other countries and significant differences among the sub-populations. In our study, men had significantly higher levels of phthalates, DINCH, and BPs, whereas the concentrations of PBs in urine were significantly higher in women. The most significant determinant of exposure was the area of residence and the year of sampling (2008-2014) that mirrors trends in the market. Participants from urban or industrialized sampling locations had higher levels of almost all monitored analytes compared to rural locations. In an attempt to assess the risk of the population, hazard quotient (HQ) values were calculated for individual compounds and the chemical mixture. Individual analytes do not seem to pose a risk to the studied population at current exposure levels, whereas the HQ value of the chemical mixture is near the threshold of 1 which would indicate a higher risk. We conclude that greater emphasis on the risk resulting from cumulative exposure to chemical mixtures and additional studies are needed to estimate the exposure of susceptible populations, such as children.


Ulcer simulating gastric carcinoma. I. Diagnostic considerations and treatment.
Small ulcer-simulating carcinomas accounted for 3.9% (48 cases) of the 1324 patients with carcinoma of the stomach treated at the Second Department of Surgery, University Centtive of a malignant ulcer in 52% of the cases whereas gastroscopy combined with exfoliative gastric cytology gave 73% correct results. In spite of preoperative suspicion of malignancy most patients were operated on as for a benign ulcer. Partial distal gastrectomy without splenectomy was performed in 93% of the patients. There was no hospital mortality. The 5-year survival rate by the actuarial method was 63%.


In vitro comparison of the selectivity of electrodes for in vivo electrochemistry.
The properties of 4 types of carbon electrodes designed for use as in vivo sensors of easily oxidized species in the mammalian brain have been evaluated in aqueous solutions at physiological pH. The electrodes are formed from a graphite-epoxy mixture, carbon paste, or carbon fibers, and have the geometries of a disk or a cylinder. The voltammetric properties of several catecholamines, some of their metabolites and precursors, uric acid, and ascorbic acid are reported at unmodified carbon surfaces. The problem of overlap of the voltammetric waves of ascorbate and catechols is addressed, and two different methods which minimize this problem are examined. These are the use of disk-shaped electrodes fabricated from carbon fibers, which facilitate the use of subtracted voltammograms to determine small changes in the concentration of catecholamines in the presence of ascorbic acid, and the use of electrochemically modified, cylindrically-shaped electrodes also fabricated from carbon fibers. Voltammetry at the modified electrodes gives evidence the catechols can be resolved from ascorbate, and that catechols, but not ascorbic acid, adsorb to the electrode surface.


Structure of recombinant Haemophilus influenzae e (P4) acid phosphatase reveals a new member of the haloacid dehalogenase superfamily.
Lipoprotein e (P4) from Haemophilus influenzae belongs to the "DDDD" superfamily of phosphohydrolases and is the prototype of class C nonspecific acid phosphatases. P4 is also a component of a H. influenzae vaccine. We report the crystal structures of recombinant P4 in the ligand-free and tungstate-inhibited forms, which are the first structures of a class C phosphatase. P4 has a two-domain architecture consisting of a core alpha/beta domain and a smaller alpha domain. The core domain features a five-stranded beta-sheet flanked by helices on both sides that is reminiscent of the haloacid dehalogenase superfamily. The alpha domain appears to be unique and plays roles in substrate binding and dimerization. The active site is solvent accessible and located in a cleft between the two domains. The structure shows that P4 is a metalloenzyme and that magnesium is the most likely metal ion in the crystalline recombinant enzyme. The ligands of the metal ion are the carboxyl groups of the first and third Asp residues of the DDDD motif, the backbone carbonyl of the second Asp of the DDDD motif, and two water molecules. The structure of the tungstate-bound enzyme suggests that Asp64 is the nucleophile that attacks the substrate P atom. Dimerization appears to be important for catalysis because intersubunit contacts stabilize the active site. Analysis of the structural context of mutations engineered for vaccine studies shows that the most promising mutations are located in the dimer interface. This observation suggests a structure-based vaccine design strategy in which the dimer interface is disrupted in order to expose epitopes that are buried in dimeric P4.


[Application of quality constant method in evaluation of Ligusticum chuanxiong pieces].
The method of classifying the quality grade of traditional Chinese medicine slices with cross section model quality constant was applied to the grade evaluation of Ligusticum chuanxiong pieces,and a reasonable grade standard of L. chuanxiong pieces was established. The purpose is to classify the 15 batches of L. chuanxiong pieces by combining the advantages of traditional grading with modern quality control indicators. By measuring the natural morphological parameters,processing parameters and the intrinsic content of ferulic acid,an important active ingredient,of the 15 batches of L. chuanxiong pieces collected from different manufacturers and different batches of different medicinal materials markets,we can synthesize the results. The mass constants and percentage mass constants are calculated and analyzed based on the above data. The results showed that the quality constants of 15 batches of L. chuanxiong pieces collected ranged from 0.53-3.00; if the percentage mass constants were more than 80%,50%-80% was second-class pieces,and the rest were third-class pieces,the evaluation results were as follows: the quality constants of first-class L. chuanxiong pieces were more than 2.40,the quality constants of second-class L. chuanxiong pieces should be 1.70-2.40,and the quality constants of third-class L. chuanxiong pieces should be less than 1.70. In this paper,the method of dividing the quality constants of the top blade model into different grades is further applied and practiced,which proves that the method is scientific,reasonable and multi-adaptable. At the same time,it enriches the research data of the grade evaluation of L. chuanxiong pieces,provides a useful reference for the promotion of the grade evaluation of L. chuanxiong pieces,and lays an experimental foundation for the next research of the subject group.


An architect of the golden years.
William H. Morse has played a major role in the experimental analysis of behavior. His view of operant behavior as the outcome of differential reinforcement provides an invaluable lesson in scientific research and theory. He studied schedules of reinforcement to generate an in-depth analysis of the complex interactions existing when contingencies exert their control over behavior. He has been instrumental in showing how behavior is determined by the dynamic interaction of factors brought into play by the imposition of any schedule, and he has a remarkably intuitive understanding of the nature of these determining variables. Some of these causal events are imposed directly by the schedule, but others arise in a more indirect manner through necessary constraints. In Morse's view, schedules can be more fundamental in determining behavior than are the scheduled events themselves. Behavior is the shaped product of an organism's history in combination with present environmental conditions. His impact deserves to be more than historical: A study of his work continues to reward the reader with exciting insights into the nature of behavioral control.


Role of long-acting selective alpha-1 blockers in the treatment of benign prostatic hyperplasia.
Alpha blockers are effective for the treatment of symptomatic BPH, although the long-term response to and compliance with alpha blockers remain critical issues. The ultimate role of alpha blockade for the management of symptomatic BPH is undefined pending their resolution. The effectiveness of nonselective alpha blockers such as phenoxybenzamine is counterbalanced by the incidence and severity of adverse reactions. Selective alpha blockers such as prazosin and terazosin are far better tolerated while providing similar degrees of subjective and objective relief of bladder outlet obstruction. The preliminary experience with alpha blockers demonstrates statistically and clinically significant improvements in the symptoms of prostatism and urinary flow rates, and the majority of patients receiving alpha blockers have been extremely satisfied. The data on alpha blockers are preliminary, and therefore the role of these drugs at present must be decided upon by the individual urologist. There is sufficient evidence to justify the use of alpha blockers for men with moderate symptoms of prostatism, yet urologists may validly interpret the clinical experience with alpha blockers as preliminary. Nevertheless, urologists should at least present this option to patients before performing a prostatectomy. The patients selected for alpha blockade must be advised that the drugs alleviate the symptoms of prostatism rather than permanently reversing the pathophysiology of BPH.(ABSTRACT TRUNCATED AT 250 WORDS)


Individual species and cumulative mixture relationships of 24-hour urine metal concentrations with DNA methylation age variables in older men.
Globally, toxic metal exposures are a well-recognized risk factor for many adverse health outcomes. DNA methylation-based measures of biological aging are predictive of disease, but have poorly understood relationships with metal exposures. We performed a pilot study examining the relationships of 24-h urine metal concentrations with three novel DNA methylation-based measures of biological aging: DNAmAge, GrimAge, and PhenoAge. We utilized a previously established urine panel of five common metals [arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg)] found in a subset of the elderly US Veterans Affairs Normative Aging Study cohort (N = 48). The measures of DNA methylation-based biological age were calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. Bayesian Kernel Machine Regression (BKMR) was used to determine metals most important to the aging outcomes and the relationship of the cumulative metal mixture with the outcomes. Individual relationships of important metals with the biological aging outcomes were modeled using fully-adjusted linear models controlling for chronological age, renal function, and lifestyle/environmental factors. Mn was selected as important to PhenoAge. A 1 ng/mL increase in urine Mn was associated with a 9.93-year increase in PhenoAge (95%CI: 1.24, 18.61, p = 0.03). The cumulative urine metal mixture was associated with increases in PhenoAge. Compared to a model where each metal in the mixture is set to its 50th percentile value, every one-unit increase of the cumulative mixture with each metal at its 70th percentile was associated with a 2.53-year increase in PhenoAge (95%CI: 0.10, 4.96, P<0.05). Our results add novel evidence that metals detected in urine are associated with increases in biological aging and suggest that these DNA methylation-based measures may be useful for identifying individuals at-risk for diseases related to toxic metal exposures. Further research is necessary to confirm these findings more broadly.


Resonant Excitation of the Ferroelectric Soft Mode by a Narrow-Band THz Pulse.
This study investigates the impact of narrow-band terahertz pulses on the ferroelectric order parameter in Ba0.8Sr0.2TiO3 films on various substrates. THz radiation in the range of 1-2 THz with the pulse width of about 0.15 THz was separated from a broadband pulse with the interference technique. The 375 nm thick BST film on a MgO (001) substrate exhibits enhanced THz-induced second harmonic generation when excited by THz pulses with a central frequency of 1.6 THz, due to the resonant excitation of the soft phonon mode. Conversely, the BST film on a Si (001) substrate shows no enhancement, due to its polycrystalline state. The 800 nm thick BST film on a MgO (111) substrate demonstrates the maximum of a second harmonic generation signal when excited by THz pulses at 1.8 THz, which is close to the soft mode frequency for the (111) orientation. Notably, the frequency spectrum of the BST/MgO (111) film reveals peaks at both the fundamental and doubled frequencies, and their intensities depend, respectively, linearly and quadratically on the THz pulse electric field strength.


Macroamylasemia and other immunoglobulin-complexed enzyme disorders.
Macroamylase is a circulating complex of immunoglobulin linked to normal amylase in most cases. Its physical properties are heterogeneous, but its large size impairs renal filtration. Macroamylasemia usually causes hyperamylasemia and an amylase clearance:creatinine clearance (C(AM):C(CR)) ratio of less than 1 percent. Macroamylasemia occurs in 2.5 percent of hyperamylasemic patients, and 1 percent of apparently healthy subjects with normal amylase levels. It often accompanies diseases of aberrant immunity or conditions in which pancreatitis must be ruled out. This disorder should be considered in a patient with asymptomatic hyperamylasemia because its detection can obviate a prolonged diagnostic workup. The condition requires no treatment and may be transient. Macroamylasemia is one of several immunoglobulin-complexed enzyme (ICE) disorders. MacroLDemia, an ICE disorder of lactate dehydrogenase (LD), shares features with macroamylasemia. These and other ICE disorders appear to represent nonspecific dysproteinemic responses to disease.


Comparison of Gold Nanoparticle Conjugated Secondary Antibody with Non-Gold Secondary Antibody in an ELISA Kit Model.
In this study, gold nanoparticles (AuNPs) were used as carriers of the signaling anti-chicken antibody peroxidase in comparison with anti-chicken antibody peroxidase without gold nanoparticle in a commercial avian influenza kit. AuNPs enhanced the absorbance and shortened the assay time. AuNPs act as a carrier of many enzymes and multiply the effect of enzyme when reacting with substrate. They amplify optical signal, while keeping low background signals.


Evaluating the Effects of Rewards and Schedule Length on Response Rates to Ecological Momentary Assessment Surveys: Randomized Controlled Trials.
Ecological momentary assessments (EMAs) are short, repeated surveys designed to collect information on experiences in real-time, real-life contexts. Embedding periodic bursts of EMAs within cohort studies enables the study of experiences on multiple timescales and could greatly enhance the accuracy of self-reported information. However, the burden on participants may be high and should be minimized to optimize EMA response rates. We aimed to evaluate the effects of study design features on EMA response rates. Embedded within an ongoing cohort study (Health@NUS), 3 bursts of EMAs were implemented over a 7-month period (April to October 2021). The response rate (percentage of completed EMA surveys from all sent EMA surveys; 30-42 individual EMA surveys sent/burst) for each burst was examined. Following a low response rate in burst 1, changes were made to the subsequent implementation strategy (SMS text message announcements instead of emails). In addition, 2 consecutive randomized controlled trials were conducted to evaluate the efficacy of 4 different reward structures (with fixed and bonus components) and 2 different schedule lengths (7 or 14 d) on changes to the EMA response rate. Analyses were conducted from 2021 to 2022 using ANOVA and analysis of covariance to examine group differences and mixed models to assess changes across all 3 bursts. Participants (N=384) were university students (n=232, 60.4% female; mean age 23, SD 1.3 y) in Singapore. Changing the reward structure did not significantly change the response rate (F3,380=1.75; P=.16). Changing the schedule length did significantly change the response rate (F1,382=6.23; P=.01); the response rate was higher for the longer schedule (14 d; mean 48.34%, SD 33.17%) than the shorter schedule (7 d; mean 38.52%, SD 33.44%). The average response rate was higher in burst 2 and burst 3 (mean 50.56, SD 33.61 and mean 48.34, SD 33.17, respectively) than in burst 1 (mean 25.78, SD 30.12), and the difference was statistically significant (F2,766=93.83; P<.001). Small changes to the implementation strategy (SMS text messages instead of emails) may have contributed to increasing the response rate over time. Changing the available rewards did not lead to a significant difference in the response rate, whereas changing the schedule length did lead to a significant difference in the response rate. Our study provides novel insights on how to implement EMA surveys in ongoing cohort studies. This knowledge is essential for conducting high-quality studies using EMA surveys. ClinicalTrials.gov NCT05154227; https://clinicaltrials.gov/ct2/show/NCT05154227.


Buried penis: a histological and histochemical study of dartos fascia.
This study aimed to determine whether the abnormal deep layer of dartos fascia plays an important role in buried penis. Forty-nine patients with buried penis were treated with anatomical resection of the deep layer of dartos fascia under a microscope. Penile length was measured before and after completely resecting the deep layer to investigate the role of this layer in penile retraction. The superficial and deep layers of dartos fascia were collected from 49 patients with buried penis, the normal superficial layers were collected from 25 children/adults who underwent circumcision for nonmedical reasons, and the normal deep layers were collected from 20 adult cadavers. The penile fascia samples were stained with hematoxylin-eosin, Masson's trichrome, Sirius red, and Verhoeff's Van Gieson, and subjected to immunohistochemical examination and scanning electron microscopy. The penile shaft (mean ± standard deviation) was found to be significantly elongated after resecting the deep layer compared with that before resection (6.8 ± 1.9 cm vs 6.0 ± 1.6 cm, P < 0.001). An abnormal deep layer of dartos fascia characterized by disordered and fragmented elastic fibers was observed in 87.8% (43/49) of buried penis samples, whereas no abnormal deep layer was observed in normal penises from cadavers (0/20, P < 0.001). Thus, the abnormal deep layer of dartos fascia plays an important role in the buried penis. Its resection is helpful for avoiding recurrence.


A Highly Active Anticomplement Factor from the Venom of Naja kaouthia.
A highly active anticomplement factor (cobra venom factor) from the venom of Naja kaouthia in South Yunnan, China was isolated by sequential column chromatography (SP-Sephadex-C-25, Q Sepharose HP and Sephadex G-150). It displays strong anticomplement activities in vitro and in vivo, and has anticomplement activity of 1 515 u per mg. The purified anticomplement factor was homogeneous on SDS-PAGE with a molecular weight of 149 kD. It is composed of three polypeptide chains which are connected by disulfide bonds. The molecular weights of the three chains were determined to be 65.4 kD (alpha-chain), 52.1 kD (beta-chain), and 35.5 kD (gamma-chain). The gamma-chain displayed size heterogeneity, and two bands could be clearly detected in gels. All polypeptide chains were stained with periodate-Schiff reagent, suggesting the presence of carbohydrate. Neutral sugar and sialicacid were determined to be 1.78% and 0.38%, respectively. The isoelectric point of this anticomplement factor was 6.2. Its amino acid composition was analyzed and N-terminal amino acid sequence of each polypeptide chain was determined.


Genomic and template RNA transcription in a model of persistent enteroviral infection.
Enteroviruses have been implicated in persistent infections of the nervous system and in certain paralytic motor neuron syndromes. Enteroviral persistence may depend on defective transcription, resulting in the abnormal production of equal amounts of genomic and template RNA strands rather than the normal ratio of 60-100:1. An in vitro model of a persistent coxsackie virus in human skeletal muscle cells was investigated using in situ hybridisation and a semiquantitative parallel, complementary, reverse transcriptase polymerase chain reaction. The ratio of genomic to template RNA was found to be approximately 60:1. We conclude that enteroviral persistence in this in vitro model is not dependent on altered transcription. In vivo, other viral and host factors should be considered.


A role of immunotherapy in metastatic malignant melanoma.
Malignant melanoma is a tumor of the melanocytes of the skin with different types, that can metastasize to many organs including the brain at the advanced stages. Metastasis to brain is most dreadful complication, and at times untreatable as it's noted in the late stages. Therefore, tremendous effort has been made in the past decades to treat metastatic melanoma patients more efficiently. Although chemotherapy is one of the treatment options, it also interferes with all rapidly dividing cells including the non-cancerous cells; therefore one should consider the side effects. As there is lot of evidence that melanoma is immunogenic, a concept of immunotherapy has risen. Immunotherapy uses molecules of the body's own immune system and disrupts the growth of cancer cells has gained a lot of attention in the past two decades. Adoptive cell therapies (ACT), vaccines, viruses, and cytokine administration in immunotherapy stimulate T cells to recognize and destroy the cancer cells. This article is a brief review of various molecules and strategies that are currently used in immunotherapy against malignant melanoma. These include the anti-Cytotoxic T-lymphocyte antigen-4 (CTLA4) antibody, cytokine administration, vaccine therapy, oncolytic viruses, adoptive cell therapy, and inhibitor of STAT3 activation.


Automated extraction of BI-RADS final assessment categories from radiology reports with natural language processing.
The objective of this study is to evaluate a natural language processing (NLP) algorithm that determines American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) final assessment categories from radiology reports. This HIPAA-compliant study was granted institutional review board approval with waiver of informed consent. This cross-sectional study involved 1,165 breast imaging reports in the electronic medical record (EMR) from a tertiary care academic breast imaging center from 2009. Reports included screening mammography, diagnostic mammography, breast ultrasound, combined diagnostic mammography and breast ultrasound, and breast magnetic resonance imaging studies. Over 220 reports were included from each study type. The recall (sensitivity) and precision (positive predictive value) of a NLP algorithm to collect BI-RADS final assessment categories stated in the report final text was evaluated against a manual human review standard reference. For all breast imaging reports, the NLP algorithm demonstrated a recall of 100.0 % (95 % confidence interval (CI), 99.7, 100.0 %) and a precision of 96.6 % (95 % CI, 95.4, 97.5 %) for correct identification of BI-RADS final assessment categories. The NLP algorithm demonstrated high recall and precision for extraction of BI-RADS final assessment categories from the free text of breast imaging reports. NLP may provide an accurate, scalable data extraction mechanism from reports within EMRs to create databases to track breast imaging performance measures and facilitate optimal breast cancer population management strategies.


Performance deficits following failure: learned helplessness or self-esteem protection?
We report two laboratory experiments which compare two competing explanations of performance deficits following failure: one based on Seligman's learned helplessness theory (LHT), and the other, on self-esteem protection theory (SEPT). In both studies, participants (Study 1: N = 40 pupils from secondary schools in Walbrzych, Poland; Study 2: N = 45 students from the University of Bielefeld, Germany) were confronted with either success or failure in a first phase of the experiment. Then, in the second phase of the experiment the participants had to work on a set of mathematical problems (Study 1) or a set of tasks taken from Raven's Progressive Matrices (Study 2) either privately or in public. In both studies failure in the first phase causes performance deficits in the second phase only if the participants had to solve the test tasks in public. These results were interpreted in line with SEPT and as incompatible with LHT.


Changes in biodistribution on 68Ga-DOTA-Octreotate PET/CT after long acting somatostatin analogue therapy in neuroendocrine tumour patients may result in pseudoprogression.
To evaluate the effects of long-acting somatostatin analogue (SSA) therapy on 68Ga-DOTA-octreotate (GaTate) uptake at physiological and metastatic sites in neuroendocrine tumour (NET) patients. Twenty-one patients who underwent GaTate PET/CT before and after commencement of SSA therapy were reviewed. Maximum standardized uptake values (SUVmax) were measured in normal organs. Changes in uptake of 49 metastatic lesions in 12 patients with stable disease were also compared. Serum chromogranin-A (CgA) levels were available for correlation between scans in 17/21 patients. Mean thyroid, spleen and liver SUVmax decreased significantly following SSA therapy from a baseline of 5.9 to 3.5, 30.3 to 23.1 and 10.3 to 8.0, respectively (p = < 0.0001 for all). Pituitary SUVmax increased from 10.2 to 11.0 (p = 0.004) whereas adrenal and salivary gland SUVmax did not change. Tumour SUVmax increased in 7 of 12 patients with stable disease; CgA was stable or decreasing in 5 of these patients. 30/49 (61%) metastatic lesions had an increase in SUVmax and lesion-to-liver uptake ratio increased in 40/49 (82%) following SSA therapy. Long-acting SSA therapy decreases GaTate uptake in the thyroid, spleen and liver but in most cases increases intensity of uptake within metastases. This has significant implications for interpretation of GaTate PET/CT following commencement of therapy as increased intensity alone may not represent true progression. Our findings also suggest pre-dosing with SSA prior to PRRT may enable higher doses to be delivered to tumour whilst decreasing dose to normal tissues.


Assessment of Atlanto-Axial and Mandibular Rotation by Cone Beam Computed Tomography.
The cranial portion of the vertebral segment together with the atlanto-occipital joint represents a very complex area. Since this system could be influenced by different atlas and mandibular position, the aim of this work was to assess atlanto-axial and mandibular rotation. Scanora 3-dimensional cone bean computed tomography images from 205 patients without signs or symptoms of temporomandibular disorder were evaluated. Using a digitalized images analyzer, the axial rotations of atlas and mandible rotation were calculated, measuring the angle with respect to the frontal plane. The same direction for the axial rotation of the mandible and for the atlanto-axial rotation (consistent group) was observed in 80.98% of the patients; opposite directions (inconsistent group) were observed in 19.02%. Among the consistent group, the left rotation was observed in 71.08% of the patients and the right rotation in 28.92%. Absolute values showed a more marked rotation for atlas than mandible and higher values for the left rotation were reported for both.Taking together these data represents important starting points for the knowledge of atlas and mandible relationship and its functional and clinical implication.


Development of a Sox2 reporter system modeling cellular heterogeneity in glioma.
Malignant gliomas are complex systems containing a number of factors that drive tumor initiation and progression, including genetic aberrations that lead to extensive cellular heterogeneity within the neoplastic compartment. Mouse models recapitulate these genetic aberrations, but readily observable heterogeneity remains challenging. To interrogate cellular heterogeneity in mouse glioma models, we utilized a replication-competent avian sarcoma-leukosis virus long terminal repeat with splice acceptor/tumor virus A (RCAS-tva) system to generate spontaneous mouse gliomas that contained a Sox2-enhanced green fluorescent protein (EGFP) reporter. Glial fibrillary acidic protein-tva mice were crossed with Sox2-EGFP mice, and tumors were initiated that contained a subpopulation of Sox2-EGFP-high cells enriched for tumor-initiating cell properties such as self-renewal, multilineage differentiation potential, and perivascular localization. Following implantation into recipient mice, Sox2-EGFP-high cells generated tumors containing Sox2-EGFP-high and Sox2-EGFP-low cells. Kinomic analysis of Sox2-EGFP-high cells revealed activation of known glioma signaling pathways that are strongly correlated with patient survival including platelet-derived growth factor receptor beta, phosphoinositide-3 kinase, and vascular endothelial growth factor. Our functional analysis identified active feline sarcoma (Fes) signaling in Sox2-EGFP-high cells. Fes negatively correlated with glioma patient survival and was coexpressed with Sox2-positive cells in glioma xenografts and primary patient-derived tissue. Our RCAS-tva/Sox2-EGFP model will empower closer examination of cellular heterogeneity and will be useful for identifying novel glioma pathways as well as testing preclinical treatment efficacy.


Does cumulative topical antibiotic powder use increase the risk of drug induced acute kidney injury in fracture patients?
There is increasing evidence to support the use of topical antibiotics to prevent surgical site infections. Although previous research suggests a minimal nephrotoxic risk with a single dose of vancomycin powder, fracture patients often require multiple procedures and receive additional doses of topical antibiotics. We aimed to determine if cumulative doses of intrawound vancomycin or tobramycin powder for infection prophylaxis increased the risk of drug-induced acute kidney injury (AKI) among fracture patients. This cohort study was a secondary analysis of single-centre Program of Randomized Trials to Evaluate Pre-operative Antiseptic Skin Solutions in Orthopaedic Trauma (PREP-IT) trial data. We included patients with a surgically treated appendicular fracture. The primary outcome was drug-induced AKI. The odds of AKI per gram of vancomycin or tobramycin powder were calculated using Bayesian regression models, which adjusted for measured confounders and accounted for the interactive effects of vancomycin and tobramycin. Of the 782 included patients (mean age 48 years (SD 20); 59% male), 83% (n = 648) received at least one vancomycin dose (cumulative range 1 to 12 g). Overall, 45% of the sample received at least one tobramycin dose (cumulative range 1.2 to 9.6 g). Drug-induced AKI occurred in ten patients (1.2%). No association was found between the cumulative dose of vancomycin and drug-induced AKI (odds ratio (OR) 1.08 (95% credible interval (CrI) 0.52 to 2.14)). Additional doses of tobramycin were associated with a three-fold increase in the adjusted odds of drug-induced AKI (OR 3.66 (95% CrI 1.71 to 8.49)). Specifically, the risk of drug-induced AKI rose substantially after 4.8 g of tobramycin powder (7.5% (95% CrI 1.0 to 35.3)). Cumulative doses of vancomycin were not associated with an increased risk of drug-induced AKI among fracture patients. While the risk of drug-induced AKI remains less than 4% with three or fewer 1.2 g tobramycin doses, the estimated risk increases substantially to 8% after four cumulative doses. Level of evidence: Therapeutic Level III Cite this article: Bone Jt Open 2022;3(4):284-290.


Blood pressure, cardiac, and renal responses to salt and deoxycorticosterone acetate in mice: role of Renin genes.
Several studies have demonstrated that mice are polymorphic for the number of renin genes, with some inbred strains harboring one gene (Ren-1(c)) and other strains containing two genes (Ren-1(d) and Ren-2). In this study, the effects of 1% salt and deoxycorticosterone acetate (DOCA)/salt were investigated in one- and two-renin gene mice, for elucidation of the role of renin in the modulation of BP, cardiac, and renal responses to salt and DOCA. The results demonstrated that, under baseline conditions, mice with two renin genes exhibited 10-fold higher plasma renin activity, 100-fold higher plasma renin concentrations, elevated BP (which was angiotensin II-dependent), and an increased cardiac weight index, compared with one-renin gene mice (all P < 0.01). The presence of two renin genes markedly increased the BP, cardiac, and renal responses to salt. The number of renin genes also modulated the responses to DOCA/salt. In one-renin gene mice, DOCA/salt induced significant renal and cardiac hypertrophy (P < 0.01) even in the absence of any increase in BP. Treatment with losartan, an angiotensin II AT(1) receptor antagonist, decreased BP in two-renin gene mice but not in one-renin gene mice. However, losartan prevented the development of cardiac hypertrophy in both groups of mice. In conclusion, these data demonstrate that renin genes are important determinants of BP and of the responses to salt and DOCA in mice. The results confirm that the Ren-2 gene, which controls renin production mainly in the submaxillary gland, is physiologically active in mice and is not subject to the usual negative feedback control. Finally, these data provide further evidence that mineralocorticoids promote cardiac hypertrophy even in the absence of BP changes. This hypertrophic process is mediated in part by the activation of angiotensin II AT(1) receptors.


Observations on social organization and behaviour of African and Asiatic wild asses (Equus africanus and E. hemionus).
The social organization of Equss africanus (African Wild Ass) was observed during the breeding season, that of E. hemionus (Asiatic Wild Ass) for a very brief period outside the breeding season. Territoriality could be observed in both species and the systems were found to be basically identical to that of Grevy's zebra. Territories are very large, measuring on the order of 200 km2 in E. africanus and probably even more in E. hemionus. Members of both species live in unstable groups of variable composition, and there was no indication of permanent bonds between any adult individuals.


One Fixed Point Can Hide Another One: Nonperturbative Behavior of the Tetracritical Fixed Point of O(N) Models at Large N.
We show that at N=∞ and below its upper critical dimension, d<d_{up}, the critical and tetracritical behaviors of the O(N) models are associated with the same renormalization group fixed point (FP) potential. Only their derivatives make them different with the subtleties that taking their N→∞ limit and deriving them do not commute and that two relevant eigenperturbations show singularities. This invalidates both the ε-and the 1/N-expansions. We also show how the Bardeen-Moshe-Bander line of tetracritical FPs at N=∞ and d=d_{up} can be understood from a finite-N analysis.


Preparation and evaluation of a Carbopol/HPMC-based in situ gelling ophthalmic system for puerarin.
The purpose of this study was to develop a pH-triggered in situ gelling vehicle for ophthalmic delivery of puerarin. The effect of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the aqueous solubility and in vitro corneal permeation of puerarin was also investigated. The puerarin solubility increased linearly and proportionally to the HP-beta-CD concentrations and 5% (w/v) HP-beta-CD enhanced its ocular permeability significantly. Carbopol 980NF was used as the gelling agent in combination with HPMC (Methocel E4M) which acted as a viscosity-enhancing agent. The optimum concentrations of Carbopol 980NF and HPMC E4M for the in situ gel-forming delivery systems were 0.1% (w/v) and 0.4% (w/v), respectively. When these two vehicles were combined, an in situ gel that had the appropriate gel strength and gelling capacity under physiological condition could be obtained. This combined solution could flow freely under non- physiological condition and showed the character of pseudoplastic fluid under both conditions. Both in vitro release studies and in vivo pharmacokinetics studies indicated that the combined polymer systems performed better in retaining puerarin than puerarin eye drops did. These results demonstrate that the Carbopol 980NF/HPMC E4M can be a viable alternative to conventional puerarin eye drops to enhance ocular bioavailability and patient compliance.


Biscysteine-Bearing Peptide Probes To Reveal Extracellular Thiol-Disulfide Exchange Reactions Promoting Cellular Uptake.
In recent years, delivery systems based on the incorporation of thiols/disulfides have been extensively explored to promote the intracellular delivery of biological cargoes. However, it remains unclear about the detailed processes of thiol-disulfide exchanges taking place on the cell surface and how the exchange reactions promote the cellular uptake of cargoes bearing thiols or disulfide bonds. In this work, we report the rational design of biscysteine motif-containing peptide probes with substantially different ring-closing property and how these peptide probes were employed to explore the thiol-disulfide exchanges on the cell surface. Our results show that extensive thiol-disulfide exchanges between peptides and exofacial protein thiols/disulfides are involved in the cellular uptake of these peptide probes, and importantly glutathione (GSH) exported from the cytosols participates extensively in the exchange reactions. Cysteine-glycine-cysteine (CGC)-containing peptide probes can be more efficiently taken up by cells compared to other probes, and we suggested that the driving force for the superior cellular uptake arises from very likely the unique propensity of the CGC motif in forming doubly bridged disulfide bonds with exofacial proteins. Our probe-based strategy provides firsthand information on the detailed processes of the exchange reactions, which would be of great benefit to the development of delivery systems based on the extracellular thiol-disulfide exchanges for intracellular delivery of biologics.


Analysis of 2167 head and neck cancer patients' management, treatment compliance and outcomes from a regional cancer centre, Delhi, India.
Head and neck cancer care was analysed in 2167 unselected patients for management compliance and outcome. Median age was 55 years, with a male to female ratio of 5.5ratio1. Major sites were oropharynx (32.4 per cent), larynx (19.8 per cent), oral (16.6 per cent) and hypopharynx (12.9 per cent). Stage-wise distribution was I-II=8.9 per cent, III=20.6 per cent and IV=60.3 per cent and unstaged=10.2 per cent. Squamous cell carcinoma was the dominant histology for 90.9 per cent. Clinic-based cancer-directed treatment decisions were made for 1905 patients: curative intent in 53 per cent, palliative in 35 per cent and for the remaining 262 (12 per cent) supportive care. Overall, 1209 (56 per cent) patients complied with the prescribed treatments; 62 per cent, 54 per cent, and 35 per cent of curative, palliative and supportive care intent groups, respectively. Modalities were radiotherapy alone (64.6 per cent), combined surgery with irradiation (17.6 per cent), and chemoradiotherapy (11.2 per cent). Median follow-up periods were 17.5 and three months in curative and palliative groups respectively. Overall, 712 (33 per cent) cases received curative therapy, with three-year disease-specific survival of 49 per cent. Patient compliance was a major obstacle. The comparison of this series with the USA, Canada and Norway showed wide disparities in stage of presentation and survival.


Pain Control in a Pediatric Patient With Sickle Cell Disease Using Regional Nerve Blocks for Laparoscopic Cholecystectomy: A Case Report.
The sickle cell patient population continues to provide challenges in pain control. Current therapies include narcotic usage with adjuvant therapies such as anti-inflammatories and nonpharmacological interventions. Poor pain management in the sickle cell patient population, especially postoperatively, can lead to hypoventilation, escalating opioid requirements, poor recovery, and longer hospital stays. This case report addresses a novel addition of ultrasound-guided paravertebral and rectus sheath blocks postinduction of general anesthesia and before surgical incision to assist with the intravenous postoperative pain management regimen after laparoscopic cholecystectomy in a 10-year-old boy with sickle cell disease.


A Comparison of Substance Use Behaviors of Hispanic Men by Sexual Orientation.
Substance use is a public health concern in the United States. Hispanic men in the United States experience disproportionate rates of substance use when compared to other ethnic groups. Previous research with the general population of Hispanic men has identified factors that are related and may contribute to substance use. In addition, Hispanic men who have sex with men (HMSM) may experience additional social factors that may result in substance use. Despite the body of research on substance use among Hispanic men, no study to date has compared the substance use behaviors of Hispanic men by sexual orientation. The purpose of this study was to compare the substance use behaviors of Hispanic men by sexual orientation. A cross-sectional descriptive design was used to collect data from 164 community-dwelling Hispanic men (i.e., 77 heterosexual men and 87 HMSM) who resided in the South Florida area. Participants completed standardized measures of substance use and demographic characteristics. Findings suggested that heterosexual men had higher rates of substance use when compared to MSM. No differences were found among the two groups of men in terms of alcohol intoxication. Religion, education, and income were not predictors of substance use. When health insurance status was controlled, MSM were less likely to report substance use. As a population, Hispanic men continue to experience health disparities in terms of substance use. Because substance use renders Hispanic men at risk for other health issues, more research is needed to understand the co-occurring health disparities experienced by Hispanic men who reside in the United States.


A shape-recovery polymer coating for the corrosion protection of metallic surfaces.
Self-healing polymer coatings are a type of smart material aimed for advanced corrosion protection of metals. This paper presents the synthesis and characterization of two new UV-cure self-healing coatings based on acrylated polycaprolactone polyurethanes. On a macroscopic scale, the cured films all show outstanding mechanical properties, combining relatively high Young's modulus of up to 270 MPa with a strain at break above 350%. After thermal activation the strained films recover up to 97% of their original length. Optical and electron microscopy reveals the self-healing properties of these coatings on hot dip galvanized steel with scratches and microindentations. The temperature-induced closing of such defects restores the corrosion protection and barrier properties of the coating as shown by electrochemical impedance spectroscopy and scanning vibrating electrode technique. Therefore, such coatings are a complementary option for encapsulation-based autonomous corrosion protection systems.


Connexin43 increases the sensitivity of prostate cancer cells to TNFalpha-induced apoptosis.
To examine the effects of increased expression of connexin43 (Cx43) upon cell viability and response to cytotoxic agents, we expressed Cx43 in LNCaP and PC3 prostate cancer cells by infection with a recombinant adenovirus (Ad-Cx43). Infection with Ad-Cx43 led to the formation of Cx43-containing gap junction plaques at appositional membranes and increased Lucifer Yellow transfer in LNCaP cells, but not in PC3 cells. The increased intercellular communication was blocked by co-infection with an adenovirus containing a dominant-negative Cx43 (Ad-Cx43DN). Infection of LNCaP (but not PC3) cells with Ad-Cx43 greatly increased their sensitivity to killing by tumor necrosis factor alpha (TNFalpha), anti-Fas antibodies, and TRAIL as quantified using an MTS assay. The TNFalpha-induced cell death was dependent on cell density, and it was associated with increased annexin V staining, an increased proportion of sub-G1 cells, and activation of caspase 8. The TNFalpha-induced effects on Ad-Cx43-infected LNCaP cells were blocked by co-infection with Ad-Cx43DN or by pre-incubation with neutralizing antibodies directed against TNFalpha receptor 1. These results demonstrate that TNFalpha induces apoptosis in LNCaP cells by signaling through TNFalpha receptor 1 and that expression of functional Cx43 gap junction channels increases their sensitivity to TNFalpha.


Bovine monocyte TLR2 receptors differentially regulate the intracellular fate of Mycobacterium avium subsp. paratuberculosis and Mycobacterium avium subsp. avium.
Pathogenic mycobacterial organisms have the capacity to inhibit macrophage activation and phagosome maturation. Although the mechanism is complex, several studies have incriminated signaling through TLR2 receptors with subsequent activation of the MAPK pathway p38 (MAPKp38) and overproduction of IL-10 in the survival of pathogenic mycobacterial organisms. In the present study, we compared the response of bovine monocytes with infection by Mycobacterium avium subspecies paratuberculosis (MAP), the cause of paratuberculosis in ruminants, with the closely related organism M. avium subspecies avium (Maa), which usually does not cause disease in ruminants. Both MAP and Maa induced phosphorylation of MAPKp38 by bovine monocytes; however, addition of a blocking anti-TLR2 antibody partially prevented MAPKp38 phosphorylation of MAP-infected monocytes but not Maa-infected monocytes. Addition of anti-TLR2 antibody enhanced phagosome acidification and phagosome-lysosome fusion in MAP-containing phagosomes and enabled monocytes to kill MAP organisms. These changes were not observed in Maa-infected monocytes. The effect on phagosome maturation appears to occur independently from the previously described inhibitory effects of IL-10 on phagosome acidification and organism killing, as IL-10 production was not affected by addition of anti-TLR2 antibody to monocyte cultures. Therefore, signaling through the TLR2 receptor appears to play a role in phagosome trafficking and antimicrobial responses in MAP-infected bovine mononuclear phagocytes.


EFFECTS OF LIRAGLUTIDE 3.0 MG ON WEIGHT AND RISK FACTORS IN HISPANIC VERSUS NON-HIPANIC POPULATIONS: SUBGROUP ANALYSIS FROM SCALE RANDOMIZED TRIALS.
Scarce data exist on pharmacotherapy for obesity in Hispanic individuals. This post hoc analysis of pooled data from 4 phase 3a trials compared the efficacy and safety of liraglutide 3.0 mg versus placebo, as adjunct to a reduced-calorie diet and physical activity, in Hispanic versus non-Hispanic subgroups. We conducted the double-blind randomized, placebo-controlled trials in adults with a minimum body mass index (BMI) of 27 kg/m2 with at least 1 comorbidity, or a minimum BMI of 30 kg/m2, at clinical research sites worldwide. In this analysis, we investigated possible differences in treatment effects between 534 Hispanics (10.4% of the population) and 4,597 non-Hispanics (89.6%) through statistical tests of interaction between subgroups and treatment. Variables examined included mean and categorical weight change, cardiovascular risk markers, and safety data. Both subgroups achieved clinically significant mean weight loss at end-of-treatment with liraglutide 3.0 mg versus placebo: Hispanics 7.0% versus 1.5%, treatment difference -5.1% (95% CI, -6.2 to -4.0); non-Hispanics 7.5% versus 2.3%, -5.2% (95% CI, -5.5 to -4.8). More individuals in both subgroups lost ≥5%, >10%, and >15% of their baseline weight with liraglutide 3.0 mg than with placebo. Efficacy endpoints generally did not vary with ethnicity (P>.05). Adverse events were comparable between ethnic subgroups, with more gastrointestinal disorders reported with liraglutide 3.0 mg than placebo. Efficacy and safety were largely similar between Hispanic and non-Hispanic subgroups. Results support that liraglutide 3.0 mg, used with a reduced-calorie diet and physical activity, can facilitate weight loss in Hispanic individuals. A1c = glycated hemoglobin BMI = body mass index CI = confidence interval FPG = fasting plasma glucose GLP-1 = glucagon-like peptide-1 hsCRP = high-sensitivity C-reactive protein SCALE = Satiety and Clinical Adiposity - Liraglutide Evidence in individuals with and without diabetes T2DM = type 2 diabetes mellitus.


Phenotypic Responses of Some Functional Traits in Four Native Perennial Grass Species Grown on Fly Ash Dump and Native Soil.
Functional response traits of four perennial grass species (Imperata cylindrica, Cenchrus ciliaris, Sporobolus diander, and Cynodon dactylon) growing on the fly ash dump and referral site having native soil were evaluated with the objective of selecting species suitable for rapid development of vegetation cover on the fly ash dumps. All the four species showed spectacular plastic responses in functional traits of plants grown on the fly ash dump and are induced by habitat and hence are adaptive. The traits associated with the root system such as root length, spread, the volume of the substratum occupied by the root system, and root biomass showed greater plasticity than the traits of the shoot system such as shoot biomass, the mean number of tillers per clump, and mean height of tillers. For instance, for all the grass species, the ratio of root/shoot biomass was higher for fly ash grown plants as compared to that of plants grown in native soil. The highest ratio was recorded for C. dactylon (5.61 ± 2.36) and I. cylindrica (5.37 ± 2.36) whereas the lowest ratio was recorded for C. ciliaris (1.87 ± 0.44). This suggests greater allocation of resources to root than to shoot by the species for space exploitative growth that enables them to acquire nutrients from nutritionally poor and unfavorable substratum like fly ash dump. Such a strategy enables species to establish and regenerate on barren areas that include fly ash dumps. The higher root length, spread, biomass, and root/shoot ratio in plants of all the species grown on fly ash as compared to plants grown on the native soil substantiate that plasticity in functional traits enabled the species to adapt to stressed habitats. The plastic responses observed are specific to the trait, specific to the species, and specific to the environment. This is evident by the quantitative differences in the responses between traits within a species, between species, and between habitats. The phenotypic plasticity induced by the fly ash altered the relationships between functional traits of the plants. This is evident by the marked differences in the r-values for different character associations between plants grown on fly ash dump and native soil. The results suggest that all the four grass species evaluated can be used for the rapid development of vegetation cover on the fly ash dumps to mitigate environmental contamination.


An Ultrastructural Study of Vairimorpha necatrix (Microspora, Microsporida) with Particular Reference to Episporontal Inclusions During Octosporogony.
The life cycle of Vairimorpha necatrix was studied by electron microscopy. Disporous development has two distinct stages: 1) diplokaryotic meronts which are actively mitotic, and 2) diplokaryotic sporonts which are distinguished by reduced ribosome density and a thickened plasmalemma. After final division of the sporont, sporoblasts form spores which are ovocylindrical and measure 4.4 ± 0.08 × 2.3 ± 0.05 μm (mean ± SE). Octosporous development results in eight haploid spores being formed in a sporophorous vesicle. The uninucleate octospores were smaller than the binucleate dispores and the exospore was thicker but less crenulate in outline. Early in octosporogony, tubules are produced from the sporont plasmalemma and electron-dense material accumulates in the episporontal space. The latter may be amorphous, vesiculated, or vacuolated in appearance and in later stages may take a stacked, lamellar form. At sporoblast formation, exospore material coats the plasmalemma and attached tubules; all inclusions in the episporontal space gradually disappear as spores are formed. These secretory products may have application to taxonomic distinction at the species level.


Rab4 function in membrane recycling from early endosomes depends on a membrane to cytoplasm cycle.
The monomeric GTPase rab4 is associated with early endosomes and regulates recycling vesicle formation. Because the function of rab proteins in the biosynthetic pathway does not appear to depend on cycling between membranes and cytosol, we were interested to investigate whether or not this holds true for rab function in the endocytic pathway. We created a chimeric rab4 protein (NHrab4cbvn) in which the carboxyl-terminal prenylation motif was replaced by the transmembrane domain of cellubrevin. The chimeric protein was permanently attached to membranes, properly targeted to early endosomes, and bound guanine nucleotide to the same extent as wild type rab4. However, in transport assays we found that basolaterally endocytosed transferrin was less efficiently transported to the apical cell surface in Madin-Darby canine kidney cells transfected with NHrab4cbvn than in cells expressing wild type rab4. Hence, rab4 function requires ongoing cycles of association and dissociation from early endosomes. This cycle is altered during mitosis when rab4 accumulates in the cytoplasm through phosphorylation by a mitotic kinase. We show here, using a rab4 construct that is permanently hooked onto membranes, that the membrane-bound pool of rab4 is targeted by a mitotic kinase.