Cellular changes in wheat seedlings during orbital flight.
Wheat seedlings in weightlessness aboard NASA Biosatellite 2 differ from ground control seedlings in mitotic count, cell length and nuclear volume as well as in orientation, starch grain distribution, organ length and malformations previously reported to COSPAR. Dividing cells are fewer in roots of orbited seedlings than in erect or clinostat ground controls. The greatest difference is among cells in early prophase. Root cells, proximal to the zone of cell division are longer in flight seedlings than erect or clinostat ground controls. As the roots are the same length, greater elongation compensates for the reduced rate of cell division. Volume of interphase nuclei in all seedling organs is increased by orbital flight. In clinostat controls, only nuclei of primary roots increase in size. Between 58 and 65 hours of age, nuclear volume in erect 1 g coleoptiles decreases; in flight seedlings it increases. Simulated launch vibration, alone or followed by growth on the clinostat, increases nuclear volume in some roots, but coleoptile nuclei do not respond as in flight seedlings. Thus, at the cellular level, orbital flight cannot be exactly duplicated by the clinostat whether preceded by vibration or not.


Acute effects of ingestion of black and green tea on lipoprotein oxidation.
Tea has been associated with a reduced risk of cardiovascular disease. One proposed mechanism of this risk reduction involves inhibition of lipoprotein oxidation in vivo by antioxidant polyphenolic compounds derived from tea. However, controlled interventions uniformly failed to show that ingestion of tea can inhibit LDL oxidation ex vivo. The absence of effects in previous studies may be due to the isolation of LDL particles from polyphenolic compounds that are present in the aqueous phase of serum. The objective of this study was to examine the acute effects of ingestion of black and green tea on ex vivo Cu(2+)-induced lipoprotein oxidation without prior isolation of lipoproteins from serum. The acute effects of 4 hot drinks-green tea and black tea (each at a dose equivalent to 4 standard cups), water matched to the teas for caffeine content, and water-were assessed in 20 healthy men by using a Latin-square design. The lag time to lipoprotein diene formation, slope of the propagation phase of the oxidation curve, and area under the oxidation curve were calculated. Urinary concentrations of 4-O-methylgallic acid were used as a marker of uptake and metabolism of polyphenolic compounds from tea. Significant increases in urinary 4-O-methylgallic acid for black and green tea (P < 0. 0001) were observed. Caffeine did not significantly influence lipoprotein oxidation. Compared with the water control, there was a greater lag time for black tea (5.4 +/- 2.9 min; P = 0.05) that was of borderline significance and a similar trend for green tea (4.4 +/- 2.8 min; P = 0.17). Slope and area under the oxidation curve were not altered. Black tea has a mild acute effect on ex vivo lipoprotein oxidation in human serum. 2000;71:-7.


Future of Days Past: Neurodevelopment and Schizophrenia.
Since a proposal in 1986 that schizophrenia involved early neurodevelopmental deviations beginning in intrauterine life that showed varying expressivity as relevant neural systems matured, our understanding of the developmental components of the pathogenesis of schizophrenia has substantially evolved. This commentary highlights recent genetic and epigenetic evidence that prenatal development is a critical period for the expression of schizophrenia risk. Studies of gene expression have been fairly consistent in showing that genes implicated in schizophrenia show relatively greater expression during fetal than postnatal life. Consistent molecular evidence of early environmental perturbations contributing to risk has emerged from studies of epigenetic marks in the brain genome as potential environmental footprints and these also highlight the prenatal period. Analyses of gene expression in placenta dramatically identify the intrauterine environment as a direct point of impact of a component of schizophrenia genetic risk. Together, the enrichment of transcriptional and epigenetic associations with schizophrenia during fetal life suggest that both genetic and environmental risk for schizophrenia have a particular molecular impact on early development, possibly because of genetic biases in environmental sensitivity.


The effects of ghrelin antagonists [D-Lys(3) ]-GHRP-6 or JMV2959 on ethanol, water, and food intake in C57BL/6J mice.
Alcohol use and abuse patterns have created a need for novel treatment models. Current research has turned its focus on reward pathways associated with intrinsic necessities, such as feeding. Theories suggest that drugs of abuse seize control of natural reward pathways and dysregulate normal function, leading to chronic addiction. One such pathway involving the hunger stimulating peptide, ghrelin, is the focus of our study. Male C57BL/6J mice were randomly assigned to groups and treated with vehicle or a ghrelin antagonist, either [D-Lys(3) ]-GHRP-6 (DLys) or JMV2959. Three experiments tested ghrelin antagonism using different doses; experiment 1 tested 12 mg/kg JMV2959; experiment 2 tested 15 mg/kg DLys; experiment 3 tested 9 mg/kg JMV2959. Using a 2-bottle choice 24-hour access paradigm, data were collected for ethanol intake, preference, water intake, and food intake at 4 and 24 hours after injection. Experiment 1 showed that 12 mg/kg of JMV2959 decreased ethanol, water, and food intake, without affecting preference. Experiment 2 showed that 15 mg/kg of DLys decreased ethanol intake, preference, and water intake only on the first day of treatment. Experiment 3 showed that 9 mg/kg of JMV2959 decreased only ethanol and food intake. No change was seen during deprivation, and JMV2959 was still effective at reducing ethanol intake upon reintroduction. Despite the change in food intake, there were no differences in body weight throughout the experiments. It should be noted that the majority of significant effects were only found 4 hours postinjection. The results show that compounds that block ghrelin receptor activity are effective at decreasing ethanol intake. However, DLys was only effective at reducing intake and preference on the first day, suggesting a quick tolerance and selectivity for ethanol. JMV2959 consistently reduced ethanol intake, but at the higher dose also reduced all other consummatory behaviors. Thus, ghrelin antagonists provide a viable potential for treatment of alcohol abuse disorders, but further research is needed to determine an appropriate dose and administration paradigm.


Effect of positive well-being on incidence of symptomatic coronary artery disease.
Although negative emotions and psychiatric morbidity have often been found to increase incident coronary artery disease (CAD) risk, fewer studies have shown positive emotions to be protective against CAD; none have been performed in high-risk healthy populations, taking risk factors into account. Thus, we examined the effect of positive well-being on incident CAD in both a high-risk initially healthy population and a national probability sample. We screened healthy siblings of probands with documented early-onset CAD from 1985 to 2007 in the GeneSTAR (Genetic Study of Atherosclerosis Risk) population and examined sociodemographic data, risk factors, and positive well-being using the General Well-Being Schedule. We further classified siblings into high-, intermediate-, and low-risk strata according to the Framingham risk score and followed them for 5 to 25 years. Siblings (n = 1,483) with greater baseline General Well-Being Schedule total scores were significantly less likely to develop CAD (hazard ratio 0.67, 95% confidence interval 0.58 to 0.79), independent of age, gender, race, and traditional risk factors. Protection was strongest in the high Framingham risk score stratum (hazard ratio 0.52, 95% confidence interval 0.30 to 0.90). The findings were replicated in the first National Health and Nutrition Examination Survey and Epidemiologic Follow-up Study (n = 5,992; hazard ratio 0.87, 95% confidence interval 0.83 to 0.93). In conclusion, positive well-being was associated with nearly a 1/3 reduction in CAD in a high-risk population with a positive family history, a nearly 50% reduction in incident CAD in the highest risk stratum in those with a positive family history, and a 13% reduction in incident CAD in a national probability sample, independent of the traditional CAD risk factors.


Ependyma-Lined Canal with Surrounding Neuroglial Tissues in Lumbosacral Lipomatous Malformations: Relationship with Retained Medullary Cord.
An ependyma-lined canal with surrounding neuroglial tissues can be present in lumbosacral lipomatous malformations; however, the precise embryological significance is still unclear. Six out of 50 patients with lipomatous malformations had ependymal structures. We retrospectively analyzed the clinical, neuroradiological, and histological findings of these patients to demonstrate the relationship with the embryological background of the retained medullary cord (RMC), which normally regresses, but was retained here because of late arrest of secondary neurulation. Five (13.9%) of 36 patients with filar and caudal types and 1 of 3 lipomyelomeningoceles had ependymal structures, while none with dorsal and transitional types had these tissues. Histologically, the ependymal structures surrounded by neuroglial tissue and containing various amounts of adipose tissue bear a striking resemblance to the ependymal structures in RMC. The 13.9% incidence of association between the ependymal structures and filar and caudal types is thought to be because of second ary neurulation failure with the same embryological background as that of RMC. Dorsal and transitional types, resulting from primary neurulation failure, therefore, did not have ependymal structures.


The effects of sevoflurane and isoflurane on intracranial pressure and cerebral perfusion pressure after diffuse brain injury in rats.
Twenty-four adult male Wistar rats, weighing 220 to 290 g, were anesthetized with 30 mg/kg intraperitoneal sodium thiopental, then underwent a tracheostomy. After diffuse impact-acceleration brain injury (BI) was induced, each rat was paralyzed and mechanically ventilated with 30% O2 in nitrous oxide (N2O). The rats were assigned randomly to two groups, each of which received one of the two volatile anesthetic agents, sevoflurane or isoflurane. The anesthetics were administered at 0.5, 0.75, 1.0, and 1.25 minimal alveolar concentration (MAC) for 30 minutes each, respectively, and anesthesia was maintained at 0.75 MAC during the last hour of the study period. Intracranial pressure (ICP), mean arterial pressure (MAP), rectal and intrahemispheric temperatures, and end-tidal volatile anesthetic concentrations were monitored continuously throughout the 3 hours, with measurements recorded every 15 minutes. At baseline, there were no significant differences between the two groups regarding the monitored physiologic values. In the sevoflurane group, MAP fell significantly after 45 minutes, and a similar change was observed in the isoflurane group after 30 minutes (P < .05, P < .01, and P < .001, respectively). Intracranial pressure increased significantly at 45 minutes in the sevoflurane group (P < .01) and remained elevated from 60 minutes until the end of the study period (P < .01, P < .001). Although ICP increased in the isoflurane group, the change was not significant. Cerebral perfusion pressure (CPP) decreased in parallel with MAP, with the reduction in the sevoflurane group being more pronounced than that in the isoflurane group. The results demonstrated that, under the conditions of diffuse BI, animals that were anesthetized with sevoflurane had higher ICP and lower CPP levels than those anesthetized with isoflurane.


Longitudinal changes in risk variables of insulin resistance syndrome from childhood to young adulthood in offspring of parents with type 2 diabetes: the Bogalusa Heart Study.
The occurrence of metabolic abnormalities related to insulin resistance syndrome in nondiabetic offspring of type 2 diabetic parents is known. However, information is lacking on the timing and the course of development of the components of this syndrome from childhood to adulthood in the offspring of parents with diabetes. This aspect was examined in a community-based cohort with (n = 303) and without (n = 1,136) a parental history of type 2 diabetes followed longitudinally since childhood (ages 4 to 17 years; mean follow-up period, 15 years) by repeated surveys. Offspring with parental diabetes versus those without such history had significantly excess generalized and truncal adiposity as measured by body mass index (BMI) and subscapular skinfold beginning in childhood, higher levels of fasting insulin and glucose and homeostasis model assessment index of insulin resistance (HOMA-IR) from adolescence, and higher levels of low-density lipoprotein (LDL) cholesterol and triglycerides and lower levels of high-density lipoprotein (HDL) cholesterol in adulthood. Many of these risk variables changed adversely at an increased rate in offspring of diabetic parents. In a multivariate analysis, parental diabetes was an independent predictor of longitudinal changes in adiposity, glucose, insulin, HOM-IR, systolic and diastolic blood pressure, and LDL cholesterol in the offspring, regardless of race and gender. As young adults, the offspring of diabetic parents had a higher prevalence of generalized (BMI > 30, 36% v 16%, P =.0001) and visceral (waist > 100 cm, 15% v 6%, P =.0001) obesity, hyperinsulinemia indicative of insulin resistance (insulin > 18 microU/mL, 15% v 8%, P =.0001), hyperglycemia (>or=110 mg/dL, 2% v 0.5%, P =.02), high LDL cholesterol (>or=160 mg/dL, 11% v 7%, P =.02), low HDL cholesterol (<40 mg/dL for males and <50 mg/dL for females, 40% v 31%, P =.004), high triglycerides (>or=150 mg/dL, 23% v 15%, P =.0001), and hypertension (>140/90 mm Hg, 11% v 6%, P =.004). Thus, the offspring of diabetic parents displayed excess body fatness beginning in childhood and accelerated progression of adverse risk profile characteristics of insulin resistance syndrome from childhood to young adulthood. These observations have important implications for early prevention and intervention.


[lymphatic Mapping and Sentinel Lymph Node Biopsy in patients with Breast Cancer ].
Axillary lymphadenectomy is the standard of care in breast cancer patients. Lymphatic mapping has arisen as an alternative offering less morbidity. To determine the success rate of subareolar blue dye injection (SM) in sentinel node (SN) biopsy and its value in axillary staging. 62 stages I and II breast cancer patients without palpable axillary nodes received subareolar injection of blue dye; an intraoperative study of the SN was carried out. Axillary lymphadenectomy was carried out in all patients. Sensitivity, specificity, positive predictive value, and negative predictive value were measured. In 58/62 patients (93.5%), SN was identified; 19/58(32%) patients had nodal metastases, 18 were identified in intraoperative study, and only one false negative; 12/18 patients showed metastasis in other axillary nodes (66%), in 6 (27%) the only metastasis site was SN. Sensitivity/specificity of the SN was 92.8 and 88.6%, respectively. Positive predictive value is 72.2% and negative predictive value is 97.5% SAI of blue dye allows identification of SN in 93.5%; with high sensitivity. SN negative predictive value is 97.5% in this study.


Synergy of tellurium and defects in control of activity of phosphorene for oxygen evolution and reduction reactions.
Developing low-cost and metal-free electrocatalysts for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is desirable for renewable energy technologies. Recent experiments show that tellurium (Te) atoms can be effectively doped into black phosphorus (BP) nanosheets, and they greatly improve its OER catalytic performance. However, the specific active sites and microscopic configurations in the atomic-scale are still ambiguous. Here, we show that the doped Te atoms prefer to bond with each other to form clusters in phosphorene and they can be further stabilized by various intrinsic defects (Stone-Wales, single vacancy defects and zigzag nanoribbon). Benefiting from the reduced binding strength of O*, Te dopants and intrinsic defects synergistically boost the catalytic activity of phosphorene. The best OER catalytic activity could be realized in the cluster SW2-Te1p (Stone-Wales defect decorated by one Te atom). For ORR, the cluster Pri-Te3p (pristine phosphorene decorated by three Te atoms) exhibits optimal catalytic activity. Calculated ORR/OER potential gaps indicate that the SW2-Te3p cluster most likely acts as the efficient bifunctional catalytic site for both ORR and OER.


Omega-3 polyunsaturated fatty acids alleviate hepatic steatosis-induced inflammation through Sirt1-mediated nuclear translocation of NF-κB p65 subunit in hepatocytes of large yellow croaker (Larmichthys crocea).
Hepatic steatosis induced inflammation is becoming increasingly prevalent in farmed fish. This study was conducted to investigate the protective effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) against hepatic steatosis-induced inflammation and its potential molecular mechanisms in hepatocyte of large yellow croaker (Larmichthys crocea). We found that the hepatic steatosis-induced inflammation was relieved by ω-3 PUFAs, meanwhile, the Sirt1 activity and transcript expression was increased by ω-3 PUFAs. The increased Sirt1 activity can decrease the hepatic steatosis-induced inflammation. The protective effects of ω-3 PUFAs against hepatic steatosis-induced inflammation was reversed by the treatment with Sirt1 inhibitor EX-527. The nuclear translocation of nuclear transcription factor kappa-B (NF-κB) p65 was significantly decreased after ω-3 PUFAs treatments compared to the palmitic acid stimulation group. The ω-3 PUFAs induced cytoplasm translocation of NF-κB p65 was reversed by EX-527. Together, ω-3 PUFAs alleviate hepatic steatosis-induced inflammation through Sirt1-mediated nuclear translocation of NF-κB p65 subunit in hepatocytes of large yellow croaker. The present study provides important insight into the mechanisms of the protective effects of ω-3 PUFAs, providing theory bases for alleviating the hepatic steatosis induced inflammation of farmed fish, thereby offering great benefits to the aquaculture industry and fish consumers.


Cytotoxic, antioxidant, and cytoprotective properties of polyphenol-enriched extracts from pecan nutshells in MDA-MB-231 breast cancer cells.
Phenolic compounds present in plants have demonstrated several biological properties such as antioxidant, antitumor, cardioprotective, and antiproliferative. On the other hand, doxorubicin, a chemotherapeutic widely used to treat breast cancer, usually exhibits chronic cardiotoxicity associated with oxidative stress. Therefore, we aimed to study the effects of phenolic compound-enriched extract (PCEE) with doxorubicin in breast cancer. To achieve this, after an SPE-C18 -column purification process of crude extracts obtained from pecan nutshells (Carya illinoinensis), the resulting PCEE was used to evaluate the cytotoxicity and antioxidant properties against the human breast cancer cell line MDA-MB-231 and the normal-hamster ovary cell line CHO-K1. PCEE was selectively cytotoxic against both cell lines, with an IC50 value (≈26.34 mg/L) for MDA-MB-231 lower than that obtained for CHO-K1 (≈55.63 mg/L). As a cytotoxic mechanism, PCEE inhibited cell growth by G2/M cell cycle arrest in MDA-MB-231 cells. Simultaneously, the study of the antioxidant activity showed that PCEE had a cytoprotective effect, evidenced by reduced ROS production in cells with oxidative stress caused by doxorubicin. The results highlight PCEE as a potential antitumor agent, thus revaluing it as an agro-industrial residue.


Evolving concepts related to achieving benefit sharing for custodians of traditional knowledge.
In the context of evolving intellectual property law, defining ownership of traditional knowledge can be challenging when claims of origin are conflicting and requires accepting parameters of how uniqueness is defined and patent law is applied to protect this information. For purposes of this paper, the complexities of evolving benefit sharing for custodians of traditional knowledge are discussed in relationship to the use of medicinal plants. Parameters of ownership can vary not only by the perception of individuals that lay claim to the information but also by international, regional and national laws that govern how benefits should be fairly appropriated. Examples are provided to exemplify the wide variation that presently exists in this evolving process with illustrations of how this information, novel or otherwise, can be utilized to optimize its commercial worth.


A Social Media Group Cognitive Behavioral Therapy Intervention to Prevent Depression in Perinatal Youth: Stakeholder Interviews and Intervention Design.
Adolescents and young adults aged <25 years (youth) are at a higher risk of perinatal depression than older adults, and they experience elevated barriers to in-person care. Digital platforms such as social media offer an accessible avenue to deliver group cognitive behavioral therapy (CBT) to perinatal youth. We aim to develop the Interactive Maternal Group for Information and Emotional Support (IMAGINE) intervention, a facilitated social media group CBT intervention to prevent perinatal depression in youth in the United States, by adapting the Mothers and Babies (MB) course, an evidence-based in-person group CBT intervention. In this study, we report perspectives of youth and health care providers on perinatal youths' mental health needs and document how they informed IMAGINE design. We conducted 21 semistructured in-depth individual interviews with 10 pregnant or postpartum youths aged 14-24 years and 6 health care workers. All interviews were recorded, transcribed, and analyzed using deductive and inductive approaches to characterize perceptions of challenges and facilitators of youth perinatal mental health. Using a human-centered design approach, stakeholder perspectives were incorporated into the IMAGINE design. We classified MB adaptations to develop IMAGINE according to the Framework for Modification and Adaptation, reporting the nature, timing, reason, and goal of the adaptations. Youth and health care workers described stigma associated with young pregnancy and parenting, social isolation, and lack of material resources as significant challenges to youth mental wellness. They identified nonjudgmental support, peer companionship, and access to step-by-step guidance as facilitators of youth mental wellness. They endorsed the use of a social media group to prevent perinatal depression and recommended that IMAGINE facilitate peer support, deliver content asynchronously to accommodate varied schedules, use a confidential platform, and facilitate the discussion of topics beyond the MB curriculum, such as navigating support resources or asking medical questions. IMAGINE was adapted from MB to accommodate stakeholder recommendations and facilitate the transition to web-based delivery. Content was tailored to be multimodal (text, images, and video), and the language was shortened and simplified. All content was designed for asynchronous engagement, and redundancy was added to accommodate intermittent access. The structure was loosened to allow the intervention facilitator to respond in real time to topics of interest for youth. A social media platform was selected that allows multiple conversation channels and conceals group member identity. All adaptations sought to preserve the fidelity of the MB core components. Our findings highlight the effect of stigmatization of young pregnancy and social determinants of health on youth perinatal mental health. Stakeholders supported the use of a social media group to create a supportive community and improve access to evidence-based depression prevention. This study demonstrates how a validated intervention can be tailored to this unique group.


Lymphadenopathy in a Series of Egyptian Pediatric Patients and the Role of Pathology in the Diagnostic Workup.
Assessment of lymphadenopathy in children represents a diagnostic challenge because of the extensive differential diagnoses including reactive and malignant conditions. Knowledge of the etiologic pattern of lymphadenopathy in a given geographical region is essential for making a confident diagnosis or suspecting a disease. Hence, the present study was carried out to identify different etiologies of lymphadenopathy in children in our region, and assess parameters commonly associated with malignancy, with an emphasis on the role of pathology in the diagnostic workup. One hundred and twenty patients aged one month to 18 years were included in the study. They were sorted into neoplastic and non-neoplastic (Infectious and non-infectious). In only 56 patients, biopsy, whether fine needle aspiration cytology (FNAC), core needle or excision biopsy, was essential to reach the final diagnosis. Sensitivity of FNAC in the differentiation between neoplastic and non-neoplastic lymphadenopathy was 92.3%, specificity 90.0%, with a diagnostic accuracy of 91.3%. We concluded that malignancy should be suspected in the following conditions: presence of abdominal or multiple symptoms, symptoms duration of 1-6 months, generalized lymphadenopathy, multiple groups of lymph node (LN) involved, LN size > 2 cm, amalgamated, hard, fixed and non-tender LNs, certain abnormal CBC findings, blast cells in blood film and elevated LDH level. In such cases, LN biopsy is highly recommended. A final diagnosis was achieved after integrating information from history and clinical findings with those of the laboratory, radiological, pathological and microbiological findings. Accordingly, an algorithm for primary diagnostic evaluation of children with lymphadenopathy is suggested.


The intestinal phase of gastric secretion.
The intestinal phase hormone, elaborated by the jejunum in response to an intestinal meal or simple distension, produces profound gastric hypersecretion when it escapes hepatic degradation through a portacaval anastomosis. The hormone is released within 30 min of the application of the stimulus and rapidly reaches peak concentration in the portal blood. Intravenous infusion into a donor dog of active portal plasma from a shunted, intestinally fed dog stimulates gastric acid secretion after a delay of approximately 1 h, and requires a mean 1 1/2 h to stimulate peak secretion, which suggests that intermediate steps may be necessary before the hormone can effectively stimulate the parietal cell mass. The pig develops portacaval-shunt-related gastric acid hypersecretion in response to food comparable to that observed in the dog and in man. Porcine jejunal mucosa is thus an appropriate source for isolation of the intestinal phase hormone. Pig intestinal mucosal extract contains a heat-stable acidic peptide which is a potent stimulator of gastric acid secretion. Administration of crude intestinal mucosal extract elicits gastric acid secretion after a brief delay, again indicating that some intermediate reactions occur before the target organ--the parietal cell mass--is stimulated.


[Lacrimal sac hydrops: etiology, pathogenesis, clinical aspects, treatment].
Thirty-three patients (35 observations) with lacrimal sac hydrops, aged 16 to 84, 31 females and 2 male ones, were examined and operated on. The condition was bilateral in 2 patients. The studies have revealed that lacrimal sac hydrops may develop in chronic dacryocystitis in various periods of this conditions, starting from 2-3 months up to 5-7 years. In 25 cases the condition developed because of lacrimal canaliculi orifice blocking, in 10 because of canalicular orifice obliteration. In 30 patients yellowish-white viscous stinking purulent discharge was found in the lacrimal sac closed cavity, in 5 mucous-serous fluid. Present-day surgical methods have proved to be highly effective in the management of hydrops. In 10 patients with canalicular orifice obliteration canaliculodacryocystorhinostomy was carried out with temporary silicone tube intubation of the canaliculus; remote results were completely successful in 8 patients and partially effective in 2. In the rest 25 cases dacryocystorhinostomy was carried out with completely effective remote results in all the patients.


Effect of body position on electrocardiographic recordings in dogs.
To determine whether body position (standing vs right lateral recumbency) altered the quality of the electrocardiogram (ECG) and value of ECG variables in dogs when the ECG was recorded using American Heart Association guidelines for frequency response. Crossover study using a convenience sample. ECGs were recorded twice in 65 sled dogs in random order with each dog standing or placed in right lateral recumbency. Lead II and three semi-orthogonal leads (I, aVF, and V10 ) were recorded and muscle tremor artefact was assessed. Lead II ECGs obtained from dogs in right lateral recumbency had less muscle tremor artefact and consequently a shorter QRS duration than ECGs obtained with the dogs standing. The P, Q, R and S wave amplitudes differed in selected leads and the mean electrical axis was shifted 20° to the right when dogs were in right lateral recumbency. Right lateral recumbency improves the quality of ECG recording in dogs by decreasing muscle tremor artefact, alters the amplitude of P, R and S waves in specific leads and results in a rightward shift in the mean electrical axis, relative to standing.


Mixed squamous cell carcinoma and follicular carcinoma of the thyroid gland.
Primary squamous cell carcinoma of the thyroid gland (PSCCT) is rare and its aetiology is debated. A 67-year-old man presented with neck mass. Fine-needle-aspiration (FNA) cytology and through-cut biopsy were suggestive of poorly differentiated or anaplastic carcinoma. The patient was offered tracheostomy and palliative cure for unresectable tumor of the thyroid; he refused and decided for other opinion. Lobe-isthmusectomy was performed with diagnostic and debulking intent. Final pathology report was of mixed squamous cell and follicular carcinoma of the thyroid. The tumor was a PSCCT. The patient underwent adjuvant chemoradiotherapy. After 2 years, an iliac crest metastasis of follicular carcinoma was diagnosed. The patient is disease free, after surgery and radio-active-iodine treatment. The hypothesis of squamous cell carcinoma transformation from well differentiated thyroid cancer has to be considered in case of PSCCT. Primary squamous cell carcinoma of the thyroid gland (PSCCT) is rare [1-3]; different theories on its aetiology do exist [4-6]. Mixed squamous cell and follicular carcinoma is even more rare than pure squamous cell of the thyroid gland and only few cases are reported in literature [7]. Preoperative diagnosis can be very challenging and the differential diagnosis with secondary squamous cell carcinoma of the thyroid (SSCCT) is manadatory in order to plan a correct management of the disease. The presence of PSCCT with distant metastasis of follicular carcinoma supports the histogenesis of squamous cell carcinomas arising from follicular epithelial cells.


Methodological approaches in developmental neuroimaging studies.
Pediatric neuroimaging is increasingly providing insights into the neural basis of cognitive development. Indeed, we have now arrived at a stage where we can begin to identify optimal methodological and statistical approaches to the acquisition and analysis of developmental imaging data. In this article, we describe a number of these approaches and how their selection impacts the ability to examine and interpret developmental effects. We describe preferred approaches to task selection, definition of age groups, selection of fMRI designs, definition of regions of interest (ROI), optimal baseline measures, and treatment of timecourse data. Consideration of these aspects of developmental neuroimaging reveals that unlike single-group neuroimaging studies, developmental studies pose unique challenges that impact study planning, task design, data analysis, and the interpretation of findings.


Knowledge, Attitudes, and Acceptance of COVID-19 Vaccines among Secondary School Pupils in Zambia: Implications for Future Educational and Sensitisation Programmes.
The coronavirus disease 2019 (COVID-19) pandemic resulted in the closure of schools to slow the spread of the virus across populations, and the administration of vaccines to protect people from severe disease, including school children and adolescents. In Zambia, there is currently little information on the acceptance of COVID-19 vaccines among school-going children and adolescents despite their inclusion in the vaccination programme. This study assessed the knowledge, attitudes, and acceptance of COVID-19 vaccines among secondary school pupils in Lusaka, Zambia. A cross-sectional study was conducted from August 2022 to October 2022. Of the 998 participants, 646 (64.7%) were female, and 127 (12.7%) would accept to be vaccinated. Those who were willing to be vaccinated had better knowledge (68.5% vs. 56.3%) and a positive attitude (79.1% vs. 33.7%) compared to those who were hesitant. Overall, the odds of vaccine acceptance were higher among pupils who had higher knowledge scores (AOR = 11.75, 95% CI: 6.51-21.2), positive attitude scores (AOR = 9.85, 95% CI: 4.35-22.2), and those who knew a friend or relative who had died from COVID-19 (AOR = 3.27, 95% CI: 2.14-5.09). The low vaccine acceptance among pupils is of public health concern, emphasising the need for heightened sensitisation programmes that promote vaccine acceptance among pupils in Zambia.


Preoperative hormone stimulation; does it increase hypospadias postoperative complications?
To assess the effect of Preoperative Hormone Stimulation (PHS) on glans size in proximal hypospadias with chordee and small glans, and to determine if PHS is associated with increased postoperative complications. Between 2014 and 2021, 101 cases of proximal hypospadias with small glans (12 mm or less) were operated upon in our hospital and are the basis of this cohort. All patients underwent a standard two-stage surgical repair, undergoing a correction of the chordee in the first operation and urethroplasty in the second operation. All patients included were operated by the same surgeon. They were classified into two groups; Group A: 50 children were operated upon between 2014 and 2017 and did not receive PHS and Group B: 51 children operated between 2018 and 2021 and received PHS. Glans dimensions including Dorsal Longitudinal Length (DLL) and Glans Width (GW) were measured during the first operation. PHS was given 1-2 months before the second operation in Group B. The glans dimensions were measured again during the second operation after PHS. Follow up period ranged from 2 to 9 years (mean 5 years). Following PHS a statistically significant increase in glans length (p = 0.042) and glans width (p = 0.011) was observed at the second operation, with 36 patients (70%) showing a mean glans width increase of 2.78 mm (range 2-8 mm) after receiving PHS. There was no statistically significant difference in the complication rates between the two groups (p = 0.556) with a fragility index of zero (FI = 0). The present study separates itself from most other studies in the literature, in the fact that it has included only a specific group of proximal and perineal hypospadias with severe chordee and glans width of 12 mm or less and that glans dimensions were always objectively and accurately measured under general anesthesia. The other major difference is that PHS in our study was given after and not before the first operation. Furthermore, the fact that all patients prior to 2018 did not receive PHS and all patients after 2018 received PHS, indicates that there was no selection bias. This study shows that PHS results in an increase the size of the glans in 70% of patients with hypospadias and a small glans without an increase in postoperative complications.


Phylogeography of Sophora moorcroftiana Supports Wu's Hypothesis on the Origin of Tibetan Alpine Flora.
Wu hypothesized that the Tibetan flora originated mostly from the paleotropical Tertiary flora in the Hengduan Mountains by adapting to the cold and arid environments associated with the strong uplift of the Qinghai-Tibet Plateau (QTP). Here, we combine the phylogeographic history of Sophora moorcroftiana with that of Sophora davidii to explore the speciation of S. moorcroftiana to test this hypothesis. We collected 151 individuals from 17 populations and sequenced 2 chloroplast fragments and the internal transcribed spacer of rDNA. Five chlorotypes and 9 ribotypes were detected but no significant phylogeographic structure was revealed. The integrated results of phylogeographic studies of these 2 species clearly support the progenitor-derivative relationship between them. We infer that the western peripheral population of S. davidii migrated westwards from the Hengduan Mountains to the middle reaches of the Yarlung Zangbo River and differentiated from its ancestor in the process of adaptation to increasingly cold and arid environments with the uplift of the QTP and finally evolved into S. moorcroftiana during the Late Pliocene. In addition, our findings shed light on the idea that natural selection, as imposed by climate differentiation (especially mean diurnal range and precipitation seasonality), directly drove this peripatric speciation event after geographic isolation. The speciation of S. moorcroftiana is a strong case supporting Wu's hypothesis about the origin of Tibet's flora.


Gene expression profiling of rat spermatogonia and Sertoli cells reveals signaling pathways from stem cells to niche and testicular cancer cells to surrounding stroma.
Stem cells and their niches are studied in many systems, but mammalian germ stem cells (GSC) and their niches are still poorly understood. In rat testis, spermatogonia and undifferentiated Sertoli cells proliferate before puberty, but at puberty most spermatogonia enter spermatogenesis, and Sertoli cells differentiate to support this program. Thus, pre-pubertal spermatogonia might possess GSC potential and pre-pubertal Sertoli cells niche functions. We hypothesized that the different stem cell pools at pre-puberty and maturity provide a model for the identification of stem cell and niche-specific genes. We compared the transcript profiles of spermatogonia and Sertoli cells from pre-pubertal and pubertal rats and examined how these related to genes expressed in testicular cancers, which might originate from inappropriate communication between GSCs and Sertoli cells. The pre-pubertal spermatogonia-specific gene set comprised known stem cell and spermatogonial stem cell (SSC) markers. Similarly, the pre-pubertal Sertoli cell-specific gene set comprised known niche gene transcripts. A large fraction of these specifically enriched transcripts encoded trans-membrane, extra-cellular, and secreted proteins highlighting stem cell to niche communication. Comparing selective gene sets established in this study with published gene expression data of testicular cancers and their stroma, we identified sets expressed genes shared between testicular tumors and pre-pubertal spermatogonia, and tumor stroma and pre-pubertal Sertoli cells with statistic significance. Our data suggest that SSC and their niche specifically express complementary factors for cell communication and that the same factors might be implicated in the communication between tumor cells and their micro-environment in testicular cancer.


Patient and graft survival of kidney allograft recipients with minimal hepatitis C virus infection: a case-control study.
The impact of pretransplant hepatitis C virus (HCV) infection on the outcome of kidney transplantation is controversial. This study was designed to determine the impact of pretransplant minimal HCV infection on the patient and graft survival at a single center in southwest of Iran. We designed a historical cohort study on 337 kidney transplant recipients and selected 35 patients with HCV infection and a histological activity index score less than 4 (minimal HCV infection). A group of kidney recipients with negative anti-HCV antibody were compared with the anti-HCV-positive patients in terms of acute allograft rejection, graft loss, mortality, causes of death, and patient and graft survival. The controls were matched for age, sex, donor source, pretransplant dialysis duration, and panel reactive antibodies test. All of the participants had a follow-up period of at least 5 years. There were no significant differences in terms of early and late acute allograft rejection episodes between the groups. Although patient and graft survival rates were lower in HCV-positive patients at 2 and 5 years, the differences between the two groups were not significant. The main causes of death among patients with and without HCV infection were sepsis and cardiovascular events, respectively. Our findings suggest that pretransplant minimal HCV infection had no detrimental effect on the short-term patient and graft survival. However, we suggest that kidney transplant recipients with minimal HCV infection be monitored for severe systemic bacterial infections.


[Study on UHPLC fingerprint and determination of eight phenolic components of Tetrastigma hemsleyanum leaves].
A novel method combining ultra-high performance liquid chromatography (UHPLC) fingerprint and simultaneous quantitative analysis of eight phenolic components was developed and validated for quality evaluation of Tetrastigma hemsleyanum leaves. For fingerprint analysis, 15 peaks were selected as the common peaks to evaluate the similarities among 41 batches of T. hemsleyanum leaves collected from different regions. Additionally, simultaneous quantification of eight markers, including neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, isoorientin, orientin, vitexin-2-O-rhamnoside,vitexin and isovitexin, was performed and the obtained data demonstrated that our method has achieved desired linearity, precision and accuracy. Clustering statistical analysis was further application in T. hemsleyanum leaves from different regions. The results indicated that new approach conbine ultra-high performance liquid chromatography (UHPLC) fingerprint and simultaneous quantitative analysis of eight phenolic components was applicable in quality control of T. hemsleyanum leaves.


Phytoestrogens and cardiovascular health.
Coronary artery disease is the leading overall cause of mortality for women and increases dramatically after menopause. Estrogen has many beneficial cardiovascular actions although concerns have been raised about its effects on the progression of breast and uterine neoplasms and its tendency to increase coagulability. Selective estrogen agonists may be superior to conventional estrogens. A dietary source of a partial estrogen agonist is the plant-based group of phytoestrogens, which include isoflavones, lignans and coumestans. Phytoestrogens have a similar structure to estradiol and have weak affinity for the estrogen receptor. Epidemiologic data indicate that women ingesting high amounts of phytoestrogens, particularly as isoflavones in soy products, have less cardiovascular disease, breast and uterine cancer and menopausal symptoms than those eating Western diets. Preclinical and clinical studies have found that isoflavones have lipid-lowering effects as well as the ability to inhibit low-density lipoprotein oxidation. They have been shown to normalize vascular reactivity in estrogen-deprived primates. Furthermore, phytoestrogens have antineoplastic effects with inhibition of cellular proliferation as well as angiogenesis, properties that could be protective against cancer development. Finally, menopausal symptoms and bone density may be favorably influenced by phytoestrogens. In summary, phytoestrogens, in the form of dietary isoflavones, represent a new area to explore in pursuit of nutritional approaches to cardiovascular protection.


Evaluation of flexural strength and antibacterial effect of orthodontic acrylic resins containing Galla chinensis extract.
To evaluate different concentrations of Galla chinensis extract (GCE) added to poly(methyl methacrylate) (PMMA), which is widely used for fabrication of removable orthodontic appliances, regarding the effectiveness of this herbal extract on antimicrobial effect and flexural strength of PMMA. Acrylic resin samples containing 0.4%, 0.8% and 1.6% GCE were prepared. Flexural strength was investigated via three-point flexural strength test for the 15 acrylic resin blocks of each concentration. Disk diffusion test was used to evaluate antibacterial effects of incorporating the same concentrations of GCE into acrylic resin. All these three groups were compared with the control group, with no added GCE, regarding flexural strength and antibacterial properties. Comparison of flexural strength between the three study groups and the control group showed significant differences between the groups (P=0.018). However, there was no significant difference between the groups containing GCE. There were significant differences in antimicrobial activity between the four groups (P=0.026). Within the limitations of this study, it is suggested that incorporation of GCE into PMMA would be beneficial for antimicrobial activity and flexural strength of PMMA, but further studies on other physical properties and antimicrobial effects on other bacterial strain would be beneficial prior to clinical investigations.


Effect of expanding evidence and evolving clinical guidelines on the prevalence of indication for cardiac resynchronization therapy in patients with heart failure.
To assess the prevalence of indication for cardiac resynchronization therapy (CRT) in patients with heart failure (HF) and reduced ejection fraction (EF) when recommendations from evolving European Society of Cardiology (ESC) guidelines are considered. Unique patients (n=17 193) with EF ≤39% and key data available for evaluation of CRT indication from the Swedish HF Registry were included. Indication for CRT was defined as either CRT implanted or CRT device absent but fulfilling criteria for class I-IIa recommendations in ESC guidelines published between 2005/2007 and 2016. Prevalence was calculated as the ratio of patients with CRT indication to the study population. The prevalence of CRT indication increased from 24.5% when the 2005/2007 ESC guidelines were considered to a peak of 30.0% when the 2013 ESC guidelines were considered (P<0.001, 22.4% relative increase). Compared to the 2013 ESC guidelines, the prevalence declined significantly when the 2016 ESC guidelines were used as determinant for CRT indication (26.8%, 10.7% relative reduction, P<0.001). Actual CRT utilization was 6.8%. Among patients with HF and reduced EF, the prevalence of CRT indication increased significantly comparing recommendations from ESC guidelines published between 2005/2007 and 2013, but then declined when the 2016 ESC guidelines were considered. The 2005-2013 increase may reflect the expansion of documented CRT efficacy to New York Heart Association class II, whereas the subsequent drop likely results from the more stringent criteria for QRS duration in the 2016 ESC guidelines. Actual CRT utilization is lower than indicated, regardless of which guidelines are considered.


Structure distribution in an elastin-mimetic peptide (VPGVG)3 investigated by solid-state NMR.
Elastin is an extracellular-matrix protein that imparts elasticity to tissues. We have used solid-state NMR to determine a number of distances and torsion angles in an elastin-mimetic peptide, (VPGVG)3, to understand the structural basis of elasticity. C-H and C-N distances between the V6 carbonyl and the V9 amide segment were measured using 13C-15N and 13C-1H rotational-echo double-resonance experiments. The results indicate the coexistence of two types of intramolecular distances: a third of the molecules have short C-H and C-N distances of 3.3 +/- 0.2 and 4.3 +/- 0.2 A, respectively, while the rest have longer distances of about 7 A. Complementing the distance constraints, we measured the (phi, psi ) torsion angles of the central pentameric unit using dipolar correlation NMR. The -angles of P7 and G8 are predominantly ~150, thus restricting the majority of the peptide to be extended. Combining all torsion angles measured for the five residues, the G8 C chemical shift, and the V6-V9 distances, we obtained a bimodal structure distribution for the PG residues in VPGVG. The minor form is a compact structure with a V6-V9 C=O-HN hydrogen bond and can be either a type II -turn or a previously unidentified turn with Pro (phi = -70, psi= 20 +/- 20) and Gly ( phi= -100 +/- 20, psi = -20 +/- 20). The major form is an extended and distorted beta-strand without a V6-V9 hydrogen bond and differs from the ideal parallel and antiparallel beta-strands. The other three residues in the VPGVG unit mainly adopt antiparallel beta-sheet torsion angles. Since (VPGVG)3 has the same 13C and 15N isotropic and anisotropic chemical shifts as the elastin-mimetic protein (VPGXG)n (X = V and K, n = 195), the observed conformational distribution around Pro and Gly sheds light on the molecular mechanism of elastin elasticity.


Use of the Objective Grading System of the American Board of Orthodontics to evaluate treatment at the Orthodontic Graduate Program Clinic, University of Puerto Rico, 2007-2008.
The Objective Grading System (OGS) was introduced in 1999 by the American Board of Orthodontics (ABO) as an instrument to reduce subjectivity when evaluating cases submitted to the ABO for examination. The objectives of this study were (1) to employ the OGS to determine the percentage of treated and completed cases from the University of Puerto Rico's (UPR) Orthodontic Graduate Program Clinic that would have earned a passing OGS score (according to the ABO standards) and (2) to assess the contribution of various patient characteristics and factors to this score. A total of 64 cases completed during 2007 and 2008 met the inclusion criteria and were evaluated by a calibrated examiner using the OGS. Logistic regression and multiple regression analyses were performed to assess the association between the explanatory variables and the overall OGS score. Of the cases evaluated, 18.8% received a passing OGS score of <20, 34.4% received a borderline score of 20-30, and 46.9% received a failing score of >30. The mean OGS score was 32.17 +/- 13.03 points, similar to the mean OGS score of 34.36 +/- 10.39 reported in 2004 by a similar study. This study demonstrate that 53% of the completed cases at the university clinic obtained a potential passing score as per the ABO (OGS <30 points). Multiple and logistic regression analyses could neither explain the relationship between the explanatory variables and the OGS scores nor predict the probability of a particular case's passing when all variables were considered.


Chemical transformation of 3-bromo-2,2-bis(bromomethyl)-propanol under basic conditions.
The mechanism of the spontaneous decomposition of 3-bromo-2,2-bis(bromomethyl)propanol (TBNPA) and the kinetics of the reaction of the parent compound and two subsequent products were determined in aqueous solution at temperatures from 30 to 70 degrees C and pH from 7.0 to 9.5. TBNPA is decomposed by a sequence of reactions that form 3,3-bis(bromomethyl)oxetane (BBMO), 3-bromomethyl-3-hydroxymethyloxetane (BMHMO), and 2,6-dioxaspiro[3.3]-heptane (DOH), releasing one bromide ion at each stage. The pseudo-first-order rate constant of the decomposition of TBNPA increases linearlywith the pH. The apparent activation energy of this transformation (98+/-2 KJ/mol) was calculated from the change of the effective second-order rate constant with temperature. The pseudoactivation energies of BBMO and BMHMO were estimated to be 109 and 151 KJ/mol, respectively. Good agreement was found between the rate coefficients derived from changes in the organic molecules concentrations and those determined from the changes in the Br- concentrations. TBNPA is the most abundant semivolatile organic pollutant in the aquitard studied, and together with its byproducts they posess an environmental hazard. TBNPA half-life is estimated to be about 100 years. This implies that high concentrations of TBNPA will persist in the aquifer long after the elimination of all its sources.


Identification of a suitable promoter for the sigma factor of Mycobacterium tuberculosis.
Promoter binding specificity is one of the important characteristics of transcription by Mycobacterium tuberculosis (Mtb) sigma (σ) factors, which remains unexplored due to limited structural evidence. Our previous study on the structural features of Mtb-SigH, consisting of three alpha helices, and its interaction with core RNA polymerase has been extended herein to determine the little known DNA sequence recognition pattern involving its cognate promoters. Herein, high resolution X-ray crystallographic structures of the protein-DNA complexes were inspected to determine the tentative DNA-binding helix of the σ factor. The binding interface in the available crystal structures is found to be populated mainly with specific residues such as Arg, Asn, Lys, Gln, and Ser. We uncovered the helix 3 of Mtb-SigH containing most of these amino acids, which ranged from Arg 64 to Arg 75, forming the predicted active site. The complex of Mtb-SigH:DNA is modelled with 20 promoter sequences. The binding affinity is predicted by scoring these protein-DNA complexes through proximity and interaction parameters obtained by molecular dynamics simulations. The promoters are ranked considering hydrogen bonding, energy of interaction, buried surface area, and distance between centers of masses in interaction with the protein. The ranking is validated through in vitro transcription assays. The trends of these selected promoter interactions have shown variations parallel to the experimental evaluation, emphasizing the success of the active site determination along with screening of the promoter strength. The promoter interaction of Mtb-SigH can be highly beneficial for understanding the regulation of gene expression of a pathogen and also extends a solid platform to predict promoters for other bacterial σ factors.


N-cadherin is developmentally regulated and functionally involved in early hematopoietic cell differentiation.
The cadherins, an important family of cell adhesion molecules, are known to play major roles during embryonic development and in the maintenance of solid tissue architecture. In the hematopoietic system, however, little is known of the role of this cell adhesion family. By RT-PCR, western blot analysis and immunofluorescence staining we show that N-cadherin, a classical type I cadherin mainly expressed on neuronal, endothelial and muscle cells, is expressed on the cell surface of resident bone marrow stromal cells. FACS analysis of bone marrow mononuclear cells revealed that N-cadherin is also expressed on a subpopulation of early hematopoietic progenitor cells. Triple-color FACS analysis defined a new CD34(+) CD19(+) N-cadherin(+) progenitor cell population. During further differentiation, however, N-cadherin expression is lost. Treatment of CD34(+) progenitor cells with function-perturbing N-cadherin antibodies drastically diminished colony formation, indicating a direct involvement of N-cadherin in the differentiation program of early hematopoietic progenitors. N-cadherin can also mediate adhesive interactions within the bone marrow as demonstrated by inhibition of homotypic interactions of bone-marrow-derived cells with N-cadherin antibodies. Together, these data strongly suggest that N-cadherin is involved in the development and retention of early hematopoietic progenitors within the bone marrow microenvironment.


Distinct Pathogenic Patterns of Burkholderia pseudomallei Isolates Selected from Caenorhabditis elegans and Dictyostelium discoideum Models.
Burkholderia pseudomallei is a selective agent that causes septic melioidosis and exhibits a broad range of lethal doses in animals. Host cellular virulence and phagocytic resistance are pathologic keys of B. pseudomallei. We first proposed Caenorhabditis elegans as the host cellular virulence model to mimic bacterial virulence against mammals and second established the resistance of B. pseudomallei to predation by Dictyostelium discoideum as the phagocytosis model. The saprophytic sepsis-causing Burkholderia sp. (B. pseudomallei, Burkholderia thailandensis, Burkholderia cenocepacia, and Burkholderia multivorans) exhibited different virulence patterns in both simple models, but B. pseudomallei was the most toxic. Using both models, attenuated isolates of B. pseudomallei were selected from a transposon-mutant library and a panel of environmental isolates and reconfirmed by in vitro mouse peritoneal exudate cell association and invasion assays. The distinct pathological patterns of melioidosis were inducted by different selected B. pseudomallei isolates. Fatal melioidosis was induced by the isolates with high virulence in both simple models within 4-5 day, whereas the low-virulence isolates resulted in prolonged survival greater than 30 day. Infection with the isolates having high resistance to D. discoideum predation but a low C. elegans killing effect led to 83% of mice with neurologic melioidosis. By contrast, infection with the isolates having low resistance to D. discoideum predation but high C. elegans killing effect led to 20% cases with inflammation in the salivary glands. Our results indicated that individual B. pseudomallei isolates selected from simple biological models contribute differently to disease progression and/or tissue tropism.


Influence of comorbid drug use disorder on receipt of evidence-based treatment for alcohol use disorder among VA patients with alcohol use disorder and Hepatitis C and/or HIV.
Alcohol use is risky for patients with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) infection, but alcohol use disorder (AUD) treatment is underutilized in these populations. Comorbid drug use disorders (DUD) are common, but their influence on AUD treatment receipt is understudied. We evaluated the association between DUD and AUD treatment receipt in two national samples of patients with AUD, those with HIV and those with HCV, in the U.S. Veterans Health Administration. Samples included patients with AUD and HCV and/or HIV among positive alcohol screens (AUDIT-C≥5) documented 10/01/09-5/30/13 in the national electronic health record. Poisson regression models estimated incidence rate ratios for receiving specialty treatment (stop codes) and pharmacotherapy (filled prescription for naltrexone, disulfiram, acamprosate, or topiramate) within 365 days of positive alcohol screening for patients with DUD versus those without. Models were clustered on patient and adjusted for potential confounders. Among 22,039 patients with HCV/AUD, 45.2% (N = 9,964) had DUD, which was associated with receiving specialty treatment [adjusted incidence rate ratio: 1.89 (95% confidence interval 1.82-1.96)] and pharmacotherapy [aIRR: 1.50 (1.37-1.65)]. Among 1,834 patients with HIV/AUD, 56.9% (N = 1,043) had DUD, which was associated with receiving specialty treatment [aIRR: 1.94 (1.68-2.24)], but not pharmacotherapy. Rates of AUD treatment receipt among patients with AUD and HCV and/or HIV were low overall, but likelihood of treatment receipt was generally higher among those with comorbid DUD. Future research should investigate mechanisms underlying these associations, such as enhanced readiness for treatment or differential provider prescribing or referral practices.


Impact of age, body weight and metabolic risk factors on steroid reference intervals in men.
To evaluate the independent impact of age, obesity and metabolic risk factors on 13 circulating steroid levels; to generate reference intervals for adult men. Cross-sectional study. Three hundred and fifteen adults, drug-free and apparently healthy men underwent clinical and biochemical evaluation. Thirteen steroids were measured by LC-MS/MS and compared among men with increasing BMI. Moreover, the independent impact of age, BMI and metabolic parameters on steroid levels was estimated. Upper and lower reference limits were generated in steroid-specific reference sub-cohorts and compared with dysmetabolic sub-cohorts. We observed lower steroid precursors and testosterone and increase in estrone levels in men with higher BMI ranges. By multivariate analysis, 17-hydroxyprogesterone and dihydrotestosterone decreased with BMI, while cortisol decreased with waist circumference. Estrone increased with BMI and systolic blood pressure. Testosterone decreased with worsening insulin resistance. 17-hydroxypregnenolone and corticosterone decreased with increasing total/HDL-cholesterol ratio. Age-related reference intervals were estimated for 17-hydroxypregnenolone, DHEA, 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol, cortisol and androstenedione, while age-independent reference intervals were estimated for progesterone, 11-deoxycorticosterone, testosterone, dihydrotestosterone, estrone and estradiol. Testosterone lower limit was 2.29 nmol/L lower (P = 0.007) in insulin resistant vs insulin sensitive men. Furthermore, the upper limits for dihydrotestosterone (-0.34 nmol/L, P = 0.045), cortisol (-87 nmol/L, P = 0.045-0.002) and corticosterone (-10.1 nmol/L, P = 0.048-0.016) were lower in overweight/obese, in abdominal obese and in dyslipidaemic subjects compared to reference sub-cohorts, respectively. Obesity and mild unmedicated metabolic risk factors alter the circulating steroid profile and bias the estimation of reference limits for testosterone, dihydrotestosterone, cortisol and corticosterone. Applying age-dependent reference intervals is mandatory for steroid precursors and corticosteroids.


In vitro and in vivo anti-tumor activity of alectinib in tumor cells with NCOA4-RET.
Rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) accounts for approximately 1-2% of all NSCLCs. To date, RET fusions that involve at least six fusion partners in NSCLC, such as KIF5B, CCDC6, NCOA4, TRIM33, CLIP1, and ERC1, have been identified. Recent clinical trials for RET fusion-positive NSCLC using vandetanib or cabozantinib demonstrated positive clinical response and considerable differential activities for RET inhibitors among fusion partners. Alectinib, an approved ALK inhibitor, is reported to inhibit KIF5B-RET and CCDC6-RET. However, the activity of alectinib with respect to RET with other fusion partners is unknown. In the present study, we investigated the effects of alectinib on NCOA4-RET fusion-positive tumor cells in vitro and in vivo. Alectinib inhibited the viability of NCOA4-RET-positive EHMES-10 cells, as well as CCDC6-RET-positive LC-2/ad and TPC-1 cells. This was achieved via inhibition of the phosphorylation of RET and induction of apoptosis. Moreover, alectinib suppressed the production of thoracic tumors and pleural effusions in an orthotopic intrathoracic inoculation model of EHMES-10 cells. In vivo imaging of an orthotopically inoculated EHMES-10 cell model also revealed that alectinib could rescue pleural carcinomatosis. These results suggest that alectinib may be a promising RET inhibitor against tumors positive for not only KIF5B-RET and CCDC6-RET, but also NCOA4-RET.


Effect of substrate temperature on pattern formation of nanoparticles from volatile drops.
This study investigates pattern formation during evaporation of water-based nanofluid sessile droplets placed on a smooth silicon surface at various temperatures. An infrared thermography technique was employed to observe the temperature distribution along the air-liquid interface of evaporating droplets. In addition, an optical interferometry technique is used to quantify and characterize the deposited patterns. Depending on the substrate temperature, three distinctive deposition patterns are observed: a nearly uniform coverage pattern, a "dual-ring" pattern, and multiple rings corresponding to "stick-slip" pattern. At all substrate temperatures, the internal flow within the drop builds a ringlike cluster of the solute on the top region of drying droplets, which is found essential for the formation of the secondary ring deposition onto the substrate for the deposits with the "dual-ring" pattern. The size of the secondary ring is found to be dependent on the substrate temperature. For the deposits with the rather uniform coverage pattern, the ringlike cluster of the solute does not deposit as a distinct secondary ring; instead, it is deformed by the contact line depinning. In the case of the "stick-slip" pattern, the internal flow behavior is complex and found to be vigorous with rapid circulating flow which appears near the edge of the drop.


The effectiveness of interventions to treat hypothalamic obesity in survivors of childhood brain tumours: a systematic review.
Survivors of childhood brain tumours (SCBT) are at risk of type 2 diabetes and cardiovascular diseases. Obesity is a major driver of cardiometabolic diseases in the general population, and interventions that tackle obesity may lower the risk of these chronic diseases. The goal of this systematic review was to summarize current evidence for the presence of interventions to manage obesity, including hypothalamic obesity, in SCBT. The primary outcome of this review was the body mass index z-score change from baseline to the end of the intervention and/or follow-up. Literature searches were conducted in PsycINFO, CINAHL, the Cochrane Library, Medline, SPORTDiscus, EMBASE and PubMed. Two reviewers completed study evaluations independently. Eleven publications were included in this systematic review (lifestyle intervention n = 2, pharmacotherapy n = 6 and bariatric surgery n = 3). While some studies demonstrated effectiveness of interventions to manage obesity in SCBT and alter markers of obesity and cardiometabolic risk, the evidence base was limited and of low quality, and studies focused on hypothalamic obesity. We conclude that there is urgent need to conduct adequately powered trials of sufficient duration, using existing and novel therapies to manage obesity, reduce the burden of cardiometabolic disorders and improve outcomes in SCBT.


Is autophagy an elective strategy to protect neurons from dysregulated cholesterol metabolism?
The balance of autophagy, apoptosis and necroptosis is crucial to determine the outcome of the cellular response to cholesterol dysregulation. Cholesterol plays a major role in regulating the properties of cell membranes, especially as regards their fluidity, and the regulation of its biosynthesis influences the shape and functions of these membranes. Whilst dietary cholesterol can easily be distributed to most organs, the central nervous system, whose membranes are particularly rich in cholesterol, mainly relies on de novo synthesis. For this reason, defects in the biosynthesis of cholesterol can variably affect the development of central nervous system. Moreover, defective synthesis of cholesterol and its intermediates may reflect both on structural cell anomalies and on the response to inflammatory stimuli. Examples of such disorders include mevalonate kinase deficiency, and Smith-Lemli-Opitz syndrome, due to deficiency in biosynthetic enzymes, and type C Niemann-Pick syndrome, due to altered cholesterol trafficking across cell compartments. Autophagy, as a crucial pathway dedicated to the degradation of cytosolic proteins and organelles, plays an essential role in the maintenance of homeostasis and in the turnover of the cytoplasmic material especially in the presence of imbalances such as those resulting from alteration of cholesterol metabolism. Manipulating the process of autophagy can offer possible strategies for improving neuronal cell viability and function in these genetic disorders.


[Brainstem auditory evoked potentials latencies, by age and sex, among Mexican adult population].
Brainstem auditory evoked potentials (BAEP) evaluate the auditory pathway, and are a complementary test for tone audiometry in evaluating auditory diseases. The aim of the study was to determine BAEP mean latencies of waves and intervals, among healthy adults. Cross-sectional study, comprising 196 subjects, aged 16 to 65 years, without auditory diseases, to whom family and personal history were asked, physical examination and laboratory studies were made, as well as tonal audiometry, impedanciometry and BAEP. A total of 107 men and 89 women were studied. The mean latency periods of waves I, III and V, and intervals I-III, III-V and I-V from both ears were similar. An increase in the latency periods for each age category was observed. Latency periods were significantly shorter in women compared to men. The predictors that increased the latency periods in the multiple linear regression models for waves and intervals were male gender and age ≥45 years. Age and sex were the variables that showed more statistical power to explain the latencies' differences.


Associations of Chronic Burden, Sleep Characteristics, and Metabolic Syndrome in the Coronary Artery Risk Development in Young Adults Study.
Chronic exposure to stress is associated with metabolic syndrome (MetS), but the mechanism is unclear. We investigated the associations between chronic burden, sleep, and MetS in the Coronary Artery Risk Development in Young Adults Study. Chronic burden was self-reported (2000-2001) according to experiences with stressors for longer than 6 months. Wrist actigraphy-measured sleep duration and sleep efficiency were collected for 6 days; sleep duration, sleep quality, and daytime sleepiness were self-reported (2003-2004). MetS was measured during the clinic visit, from 2005 to 2006. Multivariable logistic and Cox proportional hazard models were fit to determine the associations of interest. Mediation by sleep was assessed using the product of coefficients approach. Among participants ( n = 606), the average (standard deviation) age was 40 (3.6) years, 58% were female, and 43% were Black. The prevalences of chronic burden, short sleep (≤6 hours), and MetS were 35%, 43% and 20.5%, respectively. High versus low chronic burden was associated with shorter self-reported sleep duration and higher daytime sleepiness. Chronic burden was associated with 1.85 higher odds (95% confidence interval = 1.11-3.09) of MetS. Sleep characteristics were not associated with MetS. There was no evidence that sleep mediated the chronic burden-MetS relation. Burden of chronic stress may be an emerging novel risk factor for both poor sleep and MetS.


Benzodiazepine Prescribing in People with Chronic Obstructive Pulmonary Disease: Clinical Considerations.
Benzodiazepines, available clinically for almost six decades, are still one of the most widely prescribed classes of medication. The proportion of the population prescribed benzodiazepines increases with age, and harms also increase with age. The prevalence of prescribing in people > 85 years of age is as high as one in three, including in people with chronic obstructive pulmonary disease (COPD). The prevalence of COPD also increases with age. In COPD, indications cited for prescribing a benzodiazepine include anxiety, sleep disorders, or chronic breathlessness. Each of these symptoms is prevalent in the population with COPD, especially later in the course of the illness. For anxiety and insomnia, there is evidence to support short-term use, with little robust evidence to support prescribing for the symptomatic reduction of chronic breathlessness. People prescribed benzodiazepines are more likely to experience drowsiness or somnolence, exacerbations of their COPD, and respiratory tract infections. Furthermore, the longer people take benzodiazepines, the more likely they will become dependent on them. Prescribing patterns vary internationally but prescriptions of longer-acting benzodiazepines are declining in favour of shorter-acting compounds. Other evidence-based therapies that can more safely treat these problematic symptoms are available. For people already taking benzodiazepines, there are a number of interventions that have been shown to reduce the rate of prescribing. For people with COPD and not taking a benzodiazepine, but with symptoms where there is evidence of benefit, clinicians should weigh carefully the potential net benefit and prescribe at the lowest dose for the briefest time possible.


[Ultrastructural basis of interactions between prokaryotes and eukaryotes in different symbiotic models].
This paper reviews the Author's contribution to the knowledge of the ultrastructural basis of the prokaryote-eukaryote interactions in different models assessed by an ultrastructural approach. In agreement with the hypothesis of the origin of eukaryotic cells, which are chimeras of several prokaryotes with different morpho-functional specializations, symbiosis had major consequence for evolution of life. In Arthropods, one of the most successful lifestyles, the presence of endosymbiotic prokaryotes, plays an important role in their metabolism. In some cases, genome integration has occurred in the endosymbiotic relationships with the host, proving that intracellular symbiosis is not merely a nutritional supplement. Intracellular symbiotic bacteria are also described in nematodes. In particular, the presence of intracellular Wolbachia in filariae, even if its function is not yet completely known, influences positively the reproductive biology and the survival of the host, as proved by antibiotic treatment against this bacterium. The ultrastructural images reported in this review were obtained using different species of cockroaches, termites, ticks and filarial nematodes. The traditional methods of transmission (TEM), scansion (SEM) and immuno electron microscopy were used. In addition, also freeze-fracture and deep-etching techniques were employed. The cockroaches and the primitive termite Mastotermes darwiniensis host symbiotic bacteria in the ovary and in specialized cells (bacteriocytes) of the fat body. These bacteria have the typical cell boundary profile of gram-negative bacteria and are enveloped in a vacuolar membrane produced by the host cell. Molecular sequence data of 16S rDNA of endosymbionts of five species of cockroaches and M. darwiniensis indicate that they are members of the Flavobacteria-bacteroides group and that the infection occurred in an ancestor common to cockroaches and termites probably after the end of the Paleozoic (250 Ma BP). The symbiotic bacteria are transmitted transovarially and, during embryogenesis, they are integrated into the morphogenetic processes. In particular, we were able to demonstrate that the origin of the bacteriocyte should be looked for in the cells of the haemocyte line (embryonic plasmatocytes). The eggs are infected by the bacteria emerging from the bacteriocytes of the ovaric fat body and, at the end of the vitellogenesis, they are actively phagocytized by the egg membrane. In filarial nematodes, intracellular bacteria belonging to the genus Wolbachia have been described: they have evolved an obligatory mutualistic association with their host. In fact, antibiotic treatments lead to the clearance of bacteria and this loss produces a negative impact on reproduction and survival of the filarial host. We evidenced, by TEM, the degenerative events occurring during the embriogenesis of Brugia pahangi and Dirofilaria immitis after tetracycline treatment. The data suggest that the Wolbachia play a direct role in worm metabolism. Finally, a new additional model of the prokaryote-eukaryote interaction has been described: we have recently discovered a new intracellular alpha-proteobacterium, named Iric ES1, which resides in the ovarian tissues of the tick Ixodes ricinus. The intriguing characteristic of this bacterium is its ability to invade and consume the ovaric mitochondria. From an evolutionary perspective, it is interesting to note that Iric ES1 enters mitochondria in a similar way to that employed by the "predatory" bacterium Bdellovibrio bacteriovorus.


Neurocognitive impairment and survival in a cohort of HIV-infected patients treated with HAART.
Before the introduction of HAART, HIV-associated neurocognitive impairment (NCI) was recognized as an independent risk factor for death. Since 1996, we conducted a prospective study to assess whether NCI still represents a negative prognostic factor for mortality. Patients were administered measures of neurocognitive function (a battery of 17 neuropsychological tests), clinical and neurological evaluation, laboratory testing, and brain imaging studies. Among the 412 enrolled patients, 224 (54.4%) were neurocognitively impaired and 188 (45.6%) were neurocognitively unimpaired. A durable virological suppression under highly active antiretroviral therapy (HAART) was achieved by 63.3% of unimpaired patients and by 49.6% of impaired patients (p = 0.007). Overall, 47 deaths were recorded, 38 among impaired and 9 among unimpaired patients. At 84 months, the estimated survival proportions in impaired and unimpaired patients were 68.5% and 84.9%, respectively (p < 0.001). At univariate analysis the virological response to HAART was the variable most strongly associated with survival, since patients with virological failure had a nearly 10-fold increased risk of death than those with durable virological suppression (HR = 9.9, 95% CI: 3.9-25.0). After stratification for virological response to HAART, an increased risk of death for neurocognitively impaired patients was seen only among the 182 patients with virological failure (HR: 2.9, 95% CI: 1.2-7.1), while the survival probability of the 230 patients with durable virological suppression was not affected by neurocognitive impairment (p = 0.89). Our results highlight the clinical relevance of HIV-related central nervous system (CNS) involvement in the HAART era, and raise concerns regarding the clinical relevance of CNS involvement as potent antiretroviral therapies become less effective.


Acetabular changes in coxa vara.
The purpose of this study was to define the acetabular changes associated with coxa vara and determine how these acetabuli differ from those of a normal hip. Charts and radiographs of 33 patients with coxa vara with a mean age of 6 years (range, 2-15 years) were retrospectively reviewed. The diagnosis was developmental coxa vara in 21 patients and congenital femoral deficiency in 12. Radiographic measurements, including acetabular index, sourcil slope, center edge angle, migration index, and medial joint space, were compared with those of 29 hips in the control group. The inclination of the acetabulum or acetabular slope (as measured by the acetabular index and sourcil slope) was significantly increased in the hips with coxa vara as compared with those in the control group. Both parameters have a statistically significant inverse correlation with the degree of varus, ie, the greater the varus of the proximal femur, the greater the upsloping of the acetabulum. Joint subluxation, as measured by the center edge angle, migration index, and medial joint space, showed little difference from that of control subjects. Level III, diagnostic study.


Evaluation of an oral joint supplement on gait kinematics and biomarkers of cartilage metabolism and inflammation in mature riding horses.
Twenty stock-type horses (589 ± 126 kg BW; 13 ± 8 yr) were used in a completely randomized design for 28-d to evaluate the impact of a joint supplement on gait kinematics, inflammation, and cartilage metabolism. Horses were stratified by age, sex, body weight (BW), and initial lameness scores and were randomly assigned to one of two dietary treatments consisting of either a 100-g placebo top-dressed daily to 0.6% BW (as-fed) commercial concentrate (CON; n = 10; SafeChoice Original, Cargill, Inc.), or an oral joint supplement (SmartPak Equine LLC) containing glucosamine, chondroitin sulfate, hyaluronic acid, methylsulfonylmethane, turmeric, resveratrol, collagen, silica, and boron (TRT; n = 10). Horses were group-housed with ad libitum access to coastal bermudagrass hay (Cynodon dactylon) and allowed to graze pasture 2 h/d. Horses were exercised progressively 4 d/wk at 45 min each. On days 13 and 27, blood was harvested followed by a 19.3-km exercise stressor on concrete. Horses traveled at the walk, with no more than 15 min at the trot. Every 14 d, BW and BCS were recorded, and blood was collected for plasma prostaglandin E2 (PGE2), serum collagenase cleavage neopeptide (C2C), carboxypropeptide of type II collagen (CPII), and chondroitin sulfate 846 epitope (CS846) analysis. Kinematic gait analysis was performed every 14 d (Kinovea v.0.8.15) to determine stride length (SL) and range of motion (ROM) of the knee and hock at the walk and trot. Data were analyzed using PROC MIXED of SAS. All horses increased BW and BCS over time (P ≤ 0.01). Hock ROM increased in TRT horses (P ≤ 0.02) at the walk and tended to increase at the trot compared to CON (P = 0.09). At the walk, SL and knee ROM increased over time, independent of dietary treatment (P ≤ 0.01); no time effect was observed at the trot (P > 0.15). Regardless of treatment, C2C and CPII increased over time (P ≤ 0.05) and no effect was observed for CS846 or PGE2 (P > 0.12). In response to the exercise stressor, CPII and PGE2 decreased (P ≤ 0.05) from day 13 to 14, and CS846 and PGE2 tended to decrease (P ≤ 0.10) from day 27 to 28, independent of dietary treatment. In conclusion, hock ROM at the walk and trot was most sensitive to dietary treatment. Supplementation did not alter biomarker concentration of collagen metabolites or systemic inflammation in the 28-d period, but a future study utilizing arthrocentesis may be warranted to specifically evaluate intra-articular response to dietary treatment.


Characterization of a novel binding protein for Fortilin/TCTP--component of a defense mechanism against viral infection in Penaeus monodon.
The Fortilin (also known as TCTP) in Penaeus monodon (PmFortilin) and Fortilin Binding Protein 1 (FBP1) have recently been shown to interact and to offer protection against the widespread White Spot Syndrome Virus infection. However, the mechanism is yet unknown. We investigated this interaction in detail by a number of in silico and in vitro analyses, including prediction of a binding site between PmFortilin/FBP1 and docking simulations. The basis of the modeling analyses was well-conserved PmFortilin orthologs, containing a Ca(2+)-binding domain at residues 76-110 representing a section of the helical domain, the translationally controlled tumor protein signature 1 and 2 (TCTP_1, TCTP_2) at residues 45-55 and 123-145, respectively. We found the pairs Cys59 and Cys76 formed a disulfide bond in the C-terminus of FBP1, which is a common structural feature in many exported proteins and the "x-G-K-K" pattern of the amidation site at the end of the C-terminus. This coincided with our previous work, where we found the "x-P-P-x" patterns of an antiviral peptide also to be located in the C-terminus of FBP1. The combined bioinformatics and in vitro results indicate that FBP1 is a transmembrane protein and FBP1 interact with N-terminal region of PmFortilin.


Repercussions of adjuvant-induced arthritis on body composition, soleus muscle, and heart muscle of rats.
This study investigated the repercussions of adjuvant-induced arthritis (AIA) on body composition and the structural organization of the soleus and cardiac muscles, including their vascularization, at different times of disease manifestation. Male rats were submitted to AIA induction by intradermal administration of 100 μL of Mycobacterium tuberculosis (50 mg/mL), in the right hind paw. Animals submitted to AIA were studied 4 (AIA4), 15 (AIA15), and 40 (AIA40) days after AIA induction as well as a control group of animals not submitted to AIA. Unlike the control animals, AIA animals did not gain body mass throughout the evolution of the disease. AIA reduced food consumption, but only on the 40th day after induction. In the soleus muscle, AIA reduced the wet mass in a time-dependent manner but increased the capillary density by the 15th day and the fiber density by both 15 and 40 days after induction. The diameter of the soleus fiber decreased from the 4th day after AIA induction as well as the capillary/fiber ratio, which was most evident on the 40th day. Moreover, AIA induced slight histopathological changes in the cardiac muscle that were more evident on the 15th day after induction. In conclusion, AIA-induced changes in body composition as well as in the soleus muscle fibers and vasculature have early onset but are more evident by the 15th day after induction. Moreover, the heart may be a target organ of AIA, although less sensitive than skeletal muscles.


The position of transarterial chemoembolization with drug-eluting beads and yttrium-90 transarterial radioembolization in patients with hepatocellular carcinoma: Consensus statements from a Delphi-method expert panel in Turkey.
Clinical studies conducted in different geographic regions using different methods to compare transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) have demonstrated discordant results. Meta-analyses in this field indicate comparable overall survival (OS) with TACE and TARE, while reporting a longer time to progression and a higher downstaging effect with TARE treatment. In terms of isolated procedure costs, treatment with TARE is 2 to 3 times more, and in some countries even more, expensive than TACE. However, relevant literature indicates that TARE is more advantageous compared to TACE regarding the need for repeat procedures, costs of complication management, total hospital stay and quality of life. Heterogeneity of hepatocellular carcinoma (HCC) patients as well as the shortcomings of clinical classifications, randomized clinical trials and cost-effectiveness studies make it difficult to choose between treatment alternatives in this field. As in other countries, these challenges lead to differences in treatment choice across different centers in Turkey. The present expert panel used two round modified Delphi method to investigate the resources and clinical parameters referenced while selecting patients for drug-eluting beads (DEB)-TACE and TARE treatment modalities in Turkish clinical practice. The cost-effectiveness parameters and comparisons of these treatments have also been evaluated at a prediction level. The panelists stated that they most commonly use the BCLC staging system for the management of HCC patients in Turkey. However, they did not find any of the staging systems or treatment guidelines sufficient enough for their clinical practice in terms of covering the down-staging intent of treatments. Since living donor transplant preference is higher in Turkey than the rest of the Western countries, down-staging treatments are thought to be more prioritized in Turkey than that in other Western countries. The panelists reached a consensus that TARE may provide improved OS and reduce the number of repeat procedures compared to DEB-TACE in intermediate-stage patients with a single tumor spanning a diameter above 5 cm who experience recurrence after previous treatment with TACE and most TACE-naïve patient groups in intermediate stage. Based on the consensus on OS and the number of procedures, the panelists assumed that TARE would be more cost-effective than DEB-TACE in most groups of TACE-naïve patients in intermediate stage and in those with a single tumor spanning a diameter above 5 cm. It was also stated that the predicted cost-effectiveness advantage of TARE could be more pronounced in patients with a tumor diameter greater than 7 cm.


Tumor-specific immunity in MUC1.Tg mice induced by immunization with peptide vaccines from the cytoplasmic tail of CD227 (MUC1).
CD227 (MUC1), a membrane-associated glycoprotein expressed by many types of ductal epithelia, including pancreas, breast, lung, and gastrointestinal tract, is overexpressed and aberrantly glycosylated by malignant cells. We sought to define epitopes on MUC1 recognized by the different cell-mediated immune responses by an in vivo assay. Epitopes identified by this assay were evaluated for efficacy to protect mice transgenic for human MUC1 (MUC1.Tg) against MUC1-expressing tumor growth. We investigated contributions of the tandem repeat (TR) and the cytoplasmic tail (CT) of MUC1 to the MUC1-specific immunological rejection of tumor cells. MUC1 cDNA constructs, in which the TR region was deleted or the CT was truncated, were transfected into two different murine tumor cell lines (B16 and Panc02), which were used to challenge mice and evaluate immunological rejection of the tumors. We used tumor rejection in vivo to define epitopes on the TR and CT of MUC1 recognized by T cell-mediated immune responses in a preclinical murine model. Our findings demonstrated that the TR and a portion of the MUC1 CT contributed to CD4+ T cell rejection of MUC1-expressing B16 tumor cells, but not rejection of MUC1-expressing Panc02 tumor cells. A separate epitope in the CT of MUC1 was necessary for CD8+ T cell rejection of Panc02 tumor cells. Based on these studies, we sought to evaluate the efficacy of immunizing mice transgenic for (and immunologically tolerant to) human MUC1 with peptides derived from the amino acid sequence of the CT of MUC1. Results showed that survival can be significantly prolonged in vaccinated MUC1.Tg mice challenged with MUC1-expressing tumor cells, without induction of autoimmune responses. These studies demonstrated that MUC1 peptides may be utilized as an effective anticancer immunotherapeutic, and confirmed the importance of immunogenic epitopes outside of the TR.


Cyberbullying perpetration and victimisation amongst adolescent psychiatric patients at Lentegeur Hospital, South Africa.
Cyberbullying is a type of harassment that is perpetrated or experienced by a person or groups of persons via the use of electronic devices, and it frequently occurs amongst young people. Research has shown that cyberbullying is associated with psychiatric comorbidity, which could indicate a need for screening adolescents who present for mental health services. This study aimed to determine the prevalence of cyberbullying amongst adolescents. The secondary aim was to determine the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 psychiatric diagnoses associated with cyberbullying. Lentegeur Hospital Child and Adolescent Mental Health Service in the Western Cape, South Africa. This cross-sectional study included a convenience sample of 97 participants (sampled from both inpatient and outpatient services) between the ages of 13 years and 18 years. Adolescent assent and parental consent were obtained. Demographic and clinical data were collected from patient folders, and the Revised Cyber Bullying Inventory II was used to assess cyberbullying behaviours. The overall prevalence rate of some form of cyberbullying in this sample was 56.7%, of which 6.2% were cyberbullies, 20.6% were cyber-victims and 29.9% were cyberbullies and cyber-victims. Female participants were more likely to be involved in cyberbullying than males. The most prevalent primary psychiatric diagnoses in adolescents involved in cyberbullying included major depressive disorder (72.4%), schizophrenia (57.1%) and attention deficit hyperactivity disorder (22%). There was no significant association between cyberbullying and any psychiatric diagnoses. The high prevalence rate of adolescents involved in cyberbullying suggests that this behaviour is a cause for concern in the South African population. More screening and treatment programmes should be implemented to address this issue.


Prostaglandin E2 induces vascular endothelial growth factor and basic fibroblast growth factor mRNA expression in cultured rat Müller cells.
To investigate the induction of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) gene expression by prostaglandin E2 (PGE2) in cultured rat Müller cells and to study the mechanism of the induction. Müller cells were obtained from neonatal Sprague-Dawley rat retinas and cultured in essential modified Eagle's medium supplemented with 10% fetal calf serum for up to four passages. Cells were treated with PGE2, protein kinase A (PKA) inhibitors H-89 or SQ 22536, protein kinase C (PKC) inhibitors calphostin C or GF 109203X, PKC activator phorbol 12-myristate 13-acetate (PMA), or the PKA activator forskolin. Northern blot analysis was performed to determine the levels of VEGF and bFGF mRNA. PGE2 induced VEGF and bFGF mRNA expression in a dose- and time-dependent manner. VEGF and bFGF mRNA reached peaks of 2- and 3.5-fold at 10 microM PGE2. No further increases were observed at 100 microM PGE2. When treated with 10 microM PGE2, the increases in VEGF and bFGF mRNA reached maximum by 2 hours, then slowly declined toward the control level within 24 hours of PGE2 treatment. The inductions of VEGF and bFGF mRNA expression by PGE2 were blocked by the specific PKA inhibitors H-89 (30 microM) or SQ 22536 (500 microM, 1000 microM). Forskolin (10 microM), a cyclic adenosine monophosphate activator, also stimulated VEGF and bFGF mRNA expression. However, the effects of forskolin and PGE2 on VEGF gene expression were not additive, whereas forskolin enhanced the effect of PGE2 on bFGF mRNA expression. The specific PKC inhibitors, GF 109203X (2 microM) and calphostin C (1 microM), did not inhibit PGE2-induced VEGF gene expression, whereas PGE2-induced bFGF expression was blocked by the PKC inhibitor GF 109203X. In addition, downregulation of PKC by PMA (0.8 microM) treatment did not block the induction of VEGF gene expression, whereas it did inhibit the induction of bFGF mRNA expression. These results indicate that PGE2 stimulates VEGF and bFGF mRNA expression in cultured rat Müller cells. The induction of VEGF seems to occur through activation of the PKA pathway, whereas that of bFGF occurs through PKA and PKC activation. These findings raise the possibility that endogenous PGE2 stimulates VEGF and bFGF mRNA expression in Müller cells in vivo under conditions in which PGE2 production is increased, such as in injury.


Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions.
The identification of a hexanucleotide repeat expansion in a non-coding region of C9orf72 as a major cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) drastically changed the field of research on both of these conditions. Yet, despite the vast amount of work aimed at elucidating the molecular mechanisms underlying the role of this repeat in disease, the exact pathomechanisms are still unclear. A reduction in the expression of the C9orf72 gene is observed in patients, but a gain-of-function model is now preferred. The hexanucleotide repeat expansion forms RNA foci in the central nervous system (CNS) of repeat-positive FTD and ALS patients, and these foci are believed to sequester RNA-binding proteins (RBPs) and impair their function in RNA processing. At the same time, the repeat undergoes repeat-associated non-ATG translation to produce dipeptide repeat proteins that also form inclusions in the patient CNS. Studies from cells and flies suggest that these proteins may also be an important factor in the disease. Finally, the hexanucleotide repeat also induces the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43) through an as yet unknown mechanism. This review covers the different potential pathogenic factors that have been put forth for C9orf72-repeat-associated FTD and ALS (C9-FTD/ALS), while highlighting some remaining questions. A repeat expansion in C9orf72 is a common cause of both frontal temporal dementia and amyotrophic lateral sclerosis. Although there is a decrease in C9orf72 expression in patients, this repeat is believed to induce disease primarily through an unknown gain-of-function mechanism involving the RNA, repeat-associated non-AUG translation, or both. This review summarizes and discusses current knowledge on C9orf72 repeat-associated pathophysiology. This article is part of the Frontotemporal Dementia special issue.


Nursing homes and assisted living facilities as places for dying.
This chapter reviews the state of knowledge about nursing homes and assisted living facilities as places for dying. Reviewed are 25 published and unpublished research reports by nurse researchers and researchers from other disciplines that address the following questions: (a) What is known about how communication and shared decision-making about end-of-life care preferences occur? (b) How are symptoms assessed and managed at end-of-life? and (c) What are facility characteristics that influence end-of-life care services delivery? Reports were identified through searches of the following databases: MEDLINE, CINAHL, Health Star, PsychLit, Ageline, Ebsco, and PubMed. The following terms guided the search: advance directives, geriatric assessment or nursing, health services for the aged, hospice, residential facilities, palliative care, symptom management, and terminal care. Reports were included if published between 1990 and 2000, if relevant to nursing research on end-of-life care, if conducted on samples age 65 or older and living in nursing home or residential care settings, and if published in English. The studies reviewed were primarily descriptive. The findings indicate that little is known about end-of-life care in these settings, and that family and staff perspectives differ on the nature and quality of the services provided. Both external and internal factors influence the ability of facilities to provide end-of-life care. Recommendations are provided for further research related to nursing homes and assisted living facilities as places for dying.