Pervasive density-dependent recruitment enhances seedling diversity in a tropical forest.
Negative density-dependent recruitment of seedlings, that is, seeds of a given species are less likely to become established seedlings if the density of that species is high, has been proposed to be an important mechanism contributing to the extraordinary diversity of tropical tree communities because it can potentially prevent any particular species from usurping all available space, either in close proximity to seed sources or at relatively larger spatial scales. However, density-dependent recruitment does not necessarily enhance community diversity. Furthermore, although density-dependent effects have been found at some life stages in some species, no study has shown that density-dependent recruitment affects community diversity. Here we report the results of observations in a lowland, moist forest in the Republic of Panamá in which the species identities of 386,027 seeds that arrived at 200 seed traps were compared with the species identities of 13,068 seedlings that recruited into adjacent plots over a 4-year period. Across the 200 sites, recruit seedling diversity was significantly higher than seed diversity. Part of this difference was explained by interspecies differences in average recruitment success. Even after accounting for these differences, however, negative density-dependent recruitment contributes significantly to the increase in diversity from seeds to seedling recruits.


Prevalence of depression and its associations with cardio-metabolic control in Aboriginal and Anglo-Celt patients with type 2 diabetes: the Fremantle Diabetes Study Phase II.
To determine the prevalence and associates of depression in Aboriginal and Anglo-Celt (AC) Australians with type 2 diabetes. Community-based patients were screened using the Patient Health Questionnaire (PHQ-9) as part of detailed assessment. The prevalence of any current depression, major depression and antidepressant use by racial group was compared after adjustment for age, sex, educational attainment and marital status. Multiple logistic regression was used to determine associates of current depression. The 107 Aboriginal participants were younger (mean±SD 54.3±11.8 vs. 67.2±10.6 years), less often male (34.6% vs. 50.9%) and married (39.3% vs. 61.7%), and more likely to smoke (44.6% vs. 8.1%) than the 793 AC subjects (P≤0.002). Fifty-two Aboriginal (48.5%) and 772 AC participants (97.4%) completed the PHQ-9; these Aboriginals had similar socio-demographic, anthropometric and diabetes-related characteristics to those without PHQ-9 data. A quarter of the Aboriginals had current depression vs 10.6% of ACs (P=0.16), 15.4% vs. 4.1% had major depression (P=0.029), and 68.8% vs. 29.7% had untreated depression (P=0.032). Compared with non-depressed participants, patients with current depression were younger and more likely to smoke, to be overweight/obese and to have worse glycaemic control (P≤0.024). Significant independent associates of current depression were educational attainment (inversely), smoking status, body mass index and fasting plasma glucose in the AC group and alcohol use in the Aboriginal group. Although prevalence of depression was not significantly increased in the Aboriginal patients, it was more likely to be major and untreated. Depression complicating type 2 diabetes is associated with adverse cardiovascular risk.


Adipogenic Differentiation of hMSCs is Mediated by Recruitment of IGF-1r Onto the Primary Cilium Associated With Cilia Elongation.
Primary cilia are single non-motile organelles that provide a highly regulated compartment into which specific proteins are trafficked as a critical part of various signaling pathways. The absence of primary cilia has been shown to prevent differentiation of human mesenchymal stem cells (hMSCs). Changes in primary cilia length are crucial for regulating signaling events; however it is not known how alterations in cilia structure relate to differentiation. This study tested the hypothesis that changes in primary cilia structure are required for stem cell differentiation. hMSCs expressed primary cilia that were labeled with acetylated alpha tubulin and visualized by confocal microscopy. Chemically induced differentiation resulted in lineage specific changes in cilia length and prevalence which were independent of cell cycle. In particular, adipogenic differentiation resulted in cilia elongation associated with the presence of dexamethasone, while insulin had an inhibitory effect on cilia length. Over a 7-day time course, adipogenic differentiation media resulted in cilia elongation within 2 days followed by increased nuclear PPARγ levels; an early marker of adipogenesis. Cilia elongation was associated with increased trafficking of insulin-like growth factor-1 receptor β (IGF-1Rβ) into the cilium. This was reversed on inhibition of elongation by IFT-88 siRNA transfection, which also decreased nuclear PPARγ. This is the first study to show that adipogenic differentiation requires primary cilia elongation associated with the recruitment of IGF-1Rβ onto the cilium. This study may lead to the development of cilia-targeted therapies for controlling adipogenic differentiation and associated conditions such as obesity.


In vitro effects of E. coli endotoxin on fatty acid and lactate oxidation in canine myocardium.
We studied the in vitro effect of E. coli endotoxin on the oxidation of palmitate, palmitoyl CoA, and lactate by canine heart homogenate. Heart homogenates were incubated in calcium-free Krebs-Ringer-phosphate buffer in the presence of a 14C-labeled substrate. Oxidation of the individual substrate was calculated from the rate of 14CO2 production. The rate of oxidation of palmitate, palmitoyl CoA, and lactate was proportionally inhibited by increasing amounts (80-800 microgram) of endotoxin. The decrease in substrate oxidation could be mimicked by adding calcium chloride to the tissue preparation, and could be effectively prevented by the chelating agent, EDTA. Ionic calcium was released from tissue stores during incubation of the tissue preparation with endotoxin. These findings demonstrate that E. coli endotoxin inhibits substrate oxidation by heart homogenates when incubated under in vitro conditions. The data also suggest that the inhibition may be mediated by ionic calcium released from the tissue in response to the action of endotoxin.


Adolescents' physical activity is associated with previous and current physical activity practice by their parents.
The purpose of this study was to determine whether parents' current and previous physical activity practice is associated with adolescents' physical activity. The sample was composed of 1231 adolescents (14-17 years), and 1202 mothers and 871 fathers were interviewed. Weight and height of the adolescents were measured. Self-reported parents' weight and height were obtained. The current and previous physical activity levels (Baecke's questionnaire) of parents (during childhood and adolescence) and adolescents' physical activity levels were obtained using a questionnaire. The magnitude of the associations between parent and adolescent physical activity levels was determined by binary logistic regression (adjusted by sex, age, and socioeconomic level of adolescents and education level of parents). The current physical activity practice by parents was associated with adolescents' physical activity (p<0.001). The physical activities reported by parents in their childhood and adolescence were also associated with higher physical activity levels among adolescents. Adolescents whose parents were both physically active in the past and present were six times (OR=6.67 [CI=1.94-22.79]) more likely to be physically active compared to adolescents with no parents who were physically active in the past. The current and previous physical activities of parents were associated with higher levels of physical activity in adolescents, even after controlling for confounding factors.


Role of peroxisome proliferator-activated receptor-α on the synthesis of monounsaturated fatty acids in goat mammary epithelial cells.
A key member of the nuclear receptor superfamily is the peroxisome proliferator-activated receptor alpha (PPARA) isoform, which in nonruminants is closely associated with fatty acid oxidation. Whether PPARA plays a role in milk fatty acid synthesis in ruminants is unknown. The main objective of the present study was to use primary goat mammary epithelial cells (GMEC) to activate PPARA via the agonist WY-14643 (WY) or to silence it via transfection of small-interfering RNA (siRNA). Three copies of the peroxisome proliferator-activated receptor response element (PPRE) contained in a luciferase reporter vector were transfected into GMEC followed by incubation with WY at 0, 10, 20, 30, 50, or 100 µM. A dose of 50 µM WY was most effective at activating PPRE without influencing PPARA mRNA abundance. Transfecting siRNA targeting PPARA decreased its mRNA abundance to 20% and protein level to 50% of basal levels. Use of WY upregulated FASN, SCD1, ACSL1, DGAT1, FABP4, and CD36 (1.1-, 1.5-, 2-, 1.4-, 1.5-, and 5-fold, respectively), but downregulated DGAT2 and PGC1A (-20% and -40%, respectively) abundance. In contrast, triacylglycerol concentration decreased and the content and desaturation index of C16:1 and C18:1 increased. Thus, activation of PPARA via WY appeared to channel fatty acids away from esterification. Knockdown of PPARA via siRNA downregulated ACACA, SCD1, AGPAT6, CD36, HSL, and SREBF1 (-43%, -67%, -16%, -56%, -26%, and -29%, respectively), but upregulated ACSL1, DGAT2, FABP3, and PGC1A (2-, 1.4-, 1.3-, and 2.5-fold, respectively) mRNA abundance. A decrease in the content and desaturation index of C16:1 and C18:1 coupled with an increase in triacylglycerol content accompanied those effects at the mRNA level. Overall, data suggest that PPARA could promote the synthesis of MUFA in GMEC through its effects on mRNA abundance of genes related to fatty acid synthesis, oxidation, transport, and triacylglycerol synthesis.


Destructive intrahepatic bile duct diseases.
This paper reviews cholestatic liver diseases which are characterized by disappearance of the intrahepatic bile ducts ("vanishing bile duct" diseases). In neonates and children, the most important entities are extrahepatic bile duct atresia and paucity of intrahepatic bile ducts, including syndromatic and nonsyndromatic varieties. Immunological mechanisms play a role in the bile duct obstruction observed in primary biliary cirrhosis, graft-versus-host disease and chronic liver transplant rejection, and possibly also in primary sclerosing cholangitis and sarcoidosis with chronic intrahepatic cholestasis. Idiopathic adulthood ductopenia represents a newly defined entity, the nature of which remains unclear. Mention is made of recently reported forms of intrahepatic bile duct destruction due to toxins and drugs (iatrogenic cholangiopathies). New insight into the pathogenesis of these diseases has been brought about by progress in immunology, imaging techniques of the liver and hepatobiliary surgery.


'Real time' genetic manipulation: a new tool for ecological field studies.
Field experiments with transgenic plants often reveal the functional significance of genetic traits that are important for the performance of the plants in their natural environments. Until now, only constitutive overexpression, ectopic expression and gene silencing methods have been used to analyze gene-related phenotypes in natural habitats. These methods do not allow sufficient control over gene expression for the study of ecological interactions in real time, of genetic traits that play essential roles in development, or of dose-dependent effects. We applied the sensitive dexamethasone (DEX)-inducible pOp6/LhGR expression system to the ecological model plant Nicotiana attenuata and established a lanolin-based DEX application method to facilitate ectopic gene expression and RNA interference-mediated gene silencing in the field and under challenging conditions (e.g. high temperature, wind and UV radiation). Fully established field-grown plants were used to silence phytoene desaturase and thereby cause photobleaching only in specific plant sectors, and to activate expression of the cytokinin (CK) biosynthesis gene isopentenyl transferase (ipt). We used ipt expression to analyze the role of CKs in both the glasshouse and the field to understand resistance to the native herbivore Tupiocoris notatus, which attacks plants at small spatial scales. By spatially restricting ipt expression and elevating CK levels in single leaves, damage by T. notatus increased, demonstrating the role of CKs in this plant-herbivore interaction at a small scale. As the arena of most ecological interactions is highly constrained in time and space, these tools will advance the genetic analysis of dynamic traits that matter for plant performance in nature.


Spontaneous rupture of spleen due to Q fever.
Spontaneous rupture of the spleen is a rare complication of acute Q fever infection. Only two cases have been reported, both in Europe. This is the first reported case of spontaneous rupture of the spleen caused by acute Q fever in the United States.


My best case: homeopathic management of adverse effects of tamoxifen.
Nearly half of patients discontinue tamoxifen hormone therapy early because of side effects, thus increasing the risk of breast cancer recurrence. Could a homeopathic treatment improve compliance? A patient suffering from side effects of tamoxifen was seen in consultation every 2 months for 10 months by a senior homeopathic doctor and a registrar. Case analysis and repertorisation led to the identification of Pulsatilla as the simillimum drug and tamoxifen 7c as the etiological treatment. This treatment resulted in a rapid and lasting improvement of all the symptoms. The combination of a homeopathic medicine and a hetero-isotherapic illustrates both the principles of "similarity" and "the identical". It has proved to be an excellent response to the side effects of tamoxifen. By enhancing the patient's quality of life, this combined approach also improved adherence to treatment.


Focus on an infrequently used quantity in the context of competing risks: The conditional probability function.
In clinical studies of hematologic and oncologic diseases, the outcomes of interest are generally composite time to event endpoints which are usually defined by occurrence of different event types. Nonetheless, clinicians are interested in studying only one event type, which leads to a competing risks situation. In this context, Pepe and Mori presented a quantity directly derived from the cumulative incidence: the conditional probability. This function defines the probability that a given event occurs, conditionally on not having had a competing event by that time. The objective of this paper is to present this conditional cumulative incidence function and to compare its use to the cumulative incidence in different data sets. Different scenarios highlight the importance of the competing event on the interpretation of the conditional probability. Conditional probability needs to be interpreted jointly with the cumulative incidence. This quantity can be of interest especially when the risk of the competing event is large, strongly precludes the risk of the event of interest and provides useful additional information.


Schwartz-Jampel syndrome: three pediatric case reports.
Schwartz-Jampel syndrome is a heterogeneous autosomal recessive syndrome defined by myotonia, short stature, bone dysplasia and growth retardation. Three types have been described: type 1A, usually recognized in childhood, with moderate bone dysplasia; type 1B similar to type 1A but recognizable at birth, with more prominent bone dysplasia and type 2, a rare, more severe form with increased mortality in the neonatal period. In this paper we report three pediatric cases, one with neonatal manifestation.


Characterization and transplantation of agarose microencapsulated canine islets of Langerhans.
The bioartificial pancreas was designed to incorporate islet tissues and a selectively permiable membrane that isolates islets from the immune system of the recipient. The efficacy of agarose, a nontoxic polysaccharide, has been evaluated as a material of microcapsules to prevent allo- and xenograft rejection in rodents. The aim of this study is to demonstrate the possibility of the agarose microcapsule containing allo-islets as a bioartificial pancreas in canine model. In vitro viability of islets was determined by glucose challenge during perifusion experiments (n = 4). Insulin secretion from both encapsulated (enc.) and non-encapsulated (non-enc.) canine islets rose from initial basal levels of 0.09 (encap.), 0.07 (non-encap.) to the peak of 0.2 (encap.), 0.1 (non-encap.) in microU/islet/min after 5 minutes, then decreased to the basal level when the glucose challenge was discontinued. Auto-transplantation was performed in two dogs to evaluated in vivo viability and biocompatibility of encapsulated islets implanted into the splenic sinus by venouse reflux. Two weeks after auto-transplantation, the plasma insulin levels in the splenic vein and artery of two dogs were assayed. In the first dog, serum insulin level was 1 microU/ml both in the vein and the artery and increased, after glucagon (1.0 mg) injection, to levels of 9 microU/ml in the vein, but still kept 1 microU/ml in artery, as well as in the second one. Histological and electron-microscopical examination of the spleen revealed that encapsulated islets remained morphologically intact and the surface of agarose capsules showed no significant adherence of fibroblasts and inflammatory cells. Functional efficacy of the microencapsulated islets was determined using five totally-pancreatectomized diabetic dogs as recipients without immunosuppression. Defined quantity of microencapsulated islets from outbred mongrel donors were grafted through the catheter into omental tissue of the pancreatectomized recipients. All dogs had various degrees of reduced insulin requirements. In three of five recipients, the average fasting glucose values were controlled under 120 mg/dl for 28, 42, 49 days without exogenous insulin, which received totally 4.3 x 10(3), 7.3 x 10(3) and 1.0 x 10(4) (IE/kg) of microencapsulated islets, respectively. In conclusion, the present study indicates that the agarose-based microencapsulated islets can function in large diabetic animals, resulting in the independence of exogenous insulin therapy for prolonged periods without the need for immunosuppression.


Bioacoustic signal analysis through complex network features.
The paper proposes a graph-theoretical approach to auscultation, bringing out the potential of graph features in classifying the bioacoustics signals. The complex network analysis of the bioacoustics signals - vesicular (VE) and bronchial (BR) breath sound - of 48 healthy persons are carried out for understanding the airflow dynamics during respiration. The VE and BR are classified by the machine learning techniques extracting the graph features - the number of edges (E), graph density (D), transitivity (T), degree centrality (Dcg) and eigenvector centrality (Ecg). The higher value of E, D, and T in BR indicates the temporally correlated airflow through the wider tracheobronchial tract resulting in sustained high-intense low-frequencies. The frequency spread and high-frequencies in VE, arising due to the less correlated airflow through the narrow segmental bronchi and lobar, appears as a lower value for E, D, and T. The lower values of Dcg and Ecg justify the inferences from the spectral and other graph parameters. The study proposes a methodology in remote auscultation that can be employed in the current scenario of COVID-19.


Venous Thromboembolism Risk in Asian Patients with Inflammatory Bowel Disease: A Population-Based Nationwide Inception Cohort Study.
Inflammatory bowel disease (IBD) is associated with the occurrence of venous thromboembolism (VTE). However, to date, there have been few studies on the risk of VTE in Asian IBD patients. We aimed to estimate the incidence of VTE in Asian IBD patients and to determine if IBD is related to increased VTE risk. We performed a population-based cohort study between 2004 and 2015 using Korean National Health Insurance data. IBD and VTE were defined by ICD-10 codes. Incidence rates of VTE were calculated among patients with IBD and among age- and sex-matched controls. Hazard ratios were estimated using Cox regression with adjustment for multiple variables. We performed additional analyses stratifying by age, sex, Charlson comorbidity index (CCI) score, and disease type. Among the 45,037 patients with IBD (IBD cohort) and 133,019 matched controls (non-IBD cohort) included in our analysis, 411 IBD patients and 641 controls developed VTE. The IBD cohort had a higher incidence rate ratio and risk of VTE than the non-IBD cohort (incidence rate ratio: 1.92 and hazard ratio: 1.93). Older age, female sex, higher CCI scores, cardiovascular disease, chronic kidney disease, use of steroids, and hospitalization were significant risk factors for VTE in patients with IBD. The IBD patients in this study were approximately two times more likely to develop VTE than the non-IBD individuals. Our findings support the need for thromboprophylaxis in Asian IBD patients with various factors that further increase the risk of VTE.


Prevalence of substance misuse among US veterans in the general population.
Epidemiologic data on substance misuse prevalence among US Veterans are crucial to plan for Veterans' future healthcare needs. We estimated US Veterans' age-specific, overall, and age-adjusted prevalence of substance misuse, assessed whether prevalence differed between Veterans and civilians, and examined temporal trends in prevalence. Substance-related measures were obtained from the National Surveys on Drug Use and Health, 2002-2012 (N = 24,210 Veterans; 338,556 civilians). Among women and men Veterans overall, past-month heavy episodic drinking and daily cigarette smoking were the most prevalent types of substance misuse. For Veteran women and men ages 18-25, the prevalence of past-year illicit drug use was 29% and 38%, which was comparable to the prevalence of past-month daily cigarette smoking, and the prevalence of past-year prescription drug misuse was 14% and 18%. For men ages 18-25, heavy episodic drinking, daily cigarette smoking, alcohol use disorder (AUD), and substance use disorder were more prevalent among Veterans than civilians. For women, the age-specific, overall, and age-adjusted prevalence of daily cigarette smoking was generally greater among Veterans than civilians. There was a decreasing temporal trend in overall AUD prevalence among Veteran men, reflecting a decreasing trend in age-specific prevalence among Veteran men ages 35-49. Young Veterans' high prevalence of substance misuse, and the generally high prevalence of daily smoking among Veterans, underscore the need for evidence-based assessments and treatment options that are accessible and effective for Veterans. This study provides foundational information on the epidemiology of substance misuse among Veterans. (Am J Addict 2017;26:357-365).


Prolactin: a pleiotropic neuroendocrine hormone.
The neuroendocrine control of prolactin secretion is unlike that of any other pituitary hormone. It is predominantly inhibited by the hypothalamus and, in the absence of a regulatory feedback hormone, it acts directly in the brain to suppress its own secretion. In addition to this short-loop feedback action in the brain, prolactin has been reported to influence a wide range of other brain functions. There have been few attempts to rationalise why a single hormone might exert such a range of distinct and seemingly unrelated neuroendocrine functions. In this review, we highlight some of the original studies that first characterised the unusual features of prolactin neuroendocrinology, and then attempt to identify areas of new progress and/or controversy. Finally, we discuss a hypothesis that provides a unifying explanation for the pleiotrophic actions of prolactin in the brain.


The dopamine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavenging free radicals.
Free radicals are involved in the pathogenesis and/or progression of Parkinson's disease (PD). Several ergot derivative dopamine (DA) agonists have been reported to scavenge free radicals in vitro and to show a neuroprotective effect in vivo. We investigated the in vitro free radical scavenging and antioxidant activities of cabergoline, a long-acting ergot DA agonist, as well as its ability to activate glutathione (GSH), catalase (Cat) and superoxide dismutase (SOD) activating effects and its in vivo neuroprotective properties against 6-hydroxydopamine (6-OHDA) intracerebroventricularly (i.c.v.) in mice. The striatal DA turnover induced by i.c.v. injection of 6-OHDA was completely normalized by pretreatment with cabergoline. Moreover, cabergoline scavenged free radicals in vitro and significantly reduced lipid peroxidation in vitro and in vivo. Furthermore, daily administration of cabergoline to mice significantly increased striatal GSH levels by activation of RNA expressions of GSH-related enzymes, although striatal Cat and SOD activities did not change. In addition, our present results suggest that repeated administration of cabergoline attenuates both 6-OHDA-induced nigrostriatal DAergic dysfunction and DA neuronal cell death, since cabergoline also had a neuroprotective effect in the immunohistochemical experiment. In conclusion, our findings indicate that the multiple antioxidant mechanisms of cabergoline, such as activation of the GSH system and the direct free radical scavenging activity, may explain the neuroprotective effect of this ergot DA agonist.


Self-assembling amyloid-like nanostructures from SARS-CoV-2 S1, S2, RBD and N recombinant proteins.
Self-assembling nanoparticles (saNP) and nanofibers were found in the recombinant coronavirus SARS-CoV-2 S1, S2, RBD and N proteins purified by affinity chromatography using Ni Sepharose. Scanning electron (SEM), atomic force (AFM) microscopy on mica or graphite surface and in liquid as well as dynamic light scattering (DLS) revealed nanostructures of various sizes. AFM in liquid cell without drying on the surface showed mean sizes of S1 saNP 80.03 nm, polydispersity index (PDI) 0.078; for S2 saNP mean size 93.32 nm, PDI = 0.086. Ratios between the height and radius of each saNP in the range 0.1-0.5 suggested solid protein NP but not vesicles with internal empty spaces. The solid but not empty structures of the protein saNP were also confirmed by STEM after treatment of saNP with the standard contrasting agent uranyl acetate. The saNP remained stable after multiple freeze-thaw cycles in water and hyperosmotic solutions for 2 years at -20 °C. Receptor-mediated penetration of the SARS-CoV-2 S1 and RBD saNP in the African green mokey kidney Vero cells with the specific receptors for β-coronavirus reproduction was more efficient compared to unspecific endocytosis into MDCK cells without the specific receptors. Amyloid-like structures were revealed in the SARS-CoV-2 S1, S2, RBD and N saNP by means of their interaction with Thioflavin T and Congo Red dyes. Taken together, spontaneous formation of the amyloid-like self-assembling nanostructures due to the internal affinity of the SARS-CoV-2 virion proteins might induce proteinopathy in patients, including conformational neurodegenerative diseases, change stability of vaccines and diagnostic systems.


The association of atherosclerosis, vascular risk factors, and retinopathy in adults with diabetes : the atherosclerosis risk in communities study.
The aim of this report is to describe the prevalence of retinopathy and its associations with atherosclerosis and vascular risk factors in people with diabetes. Cross-sectional study. Persons with diabetes, having gradable fundus photographs, from a biracial population-based cohort of adults (ages 51-72 years), and living in four United States communities (Forsyth County, North Carolina; the city of Jackson, Mississippi; suburbs of Minneapolis, Minnesota; and Washington County, Maryland) were studied from 1993 to 1995. Lesions typical of diabetic retinopathy were detected by grading a 45 degrees color fundus photograph of one eye of each participant, using a modification of the Airlie House classification system. Severity of diabetic retinopathy (none, minimal nonproliferative, moderate nonproliferative, severe nonproliferative, and proliferative) and macular edema. Retinopathy was detected in 328/1600 (20.5%) of those with diabetes; 114/1724 (6.6%) had hard exudate, 28/1600 (1.8%) had proliferative diabetic retinopathy, and 27/1662 (1.6%) had macular edema. The prevalence of diabetic retinopathy was higher in blacks (27.7%) compared with whites (16.7%). Controlling for duration of diabetes, serum glucose, systolic blood pressure, and type of diabetes medications taken, severity of retinopathy was associated with carotid artery intima-media wall thickness (odds ratio [OR]/0.1-mm thickness 1.09; 95% confidence interval [CI], 1.01, 1.17; P = 0.01), serum albumin (OR/0.1 g/dl 0.94; 95% CI, 0.88, 0.99; P = 0.02), but not race (OR blacks versus whites,1.24; 95% CI, 0.88, 1.75; P = 0.21). Severity of diabetic retinopathy was not associated with coronary artery disease or stroke history or any of the plasma lipids studied. Controlling for age, gender, duration of diabetes, serum glucose, and type of diabetes medications taken, the presence of retinal hard exudates was associated with plasma low-density lipoprotein cholesterol (OR/10 mg/dl 1.18; 95% CI, 1.09, 1.29; P < 0.001), and plasma Lp(a) (OR/10 mg/dl 1.02; 95% CI, 1.00, 1.05; P = 0.04) but not race or blood pressure. These data suggest that plasma lipids are associated with the presence of hard exudate and that carotid artery intima-media wall thickness is associated with retinopathy, but other manifestations of atherosclerosis and most of its risk factors are not associated with severity of diabetic retinopathy.


The disposition of primaquine in the isolated perfused rat liver. Effect of dose size.
The disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation was investigated after the administration of 0.5-, 1.5-, and 5.0-mg doses of the drug. The pharmacokinetics of primaquine in this experimental model were dependent on dose size. Increasing the dose from 0.5 to 5.0 mg produced a significant reduction in clearance from 11.6 +/- 2.5 to 2.9 +/- 1.0 ml X min-1. This decrease was accompanied by a disproportionate increase in the value of AUC from 25.4 +/- 5.9 to 1128.6 +/- 575.7 micrograms X min X ml-1, elimination half-life from 33.2 +/- 10.7 to 413.0 +/- 239.3 min, and volume of distribution from 547.7 +/- 153.1 to 1489.0 +/- 249.0 ml. Furthermore, primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected in perfusate after the 0.5-mg dose, it was the principal perfusate metabolite after the 5.0-mg dose. Primaquine was subject to extensive biliary excretion at all doses; the total amount of 14C radioactivity excreted in the bile decreased from 60 to 30% as the dose of primaquine was increased from 0.5 to 5.0 mg. The metabolite composition of radioactivity excreted in the bile was also examined. Total recovery of the administered radioactivity from bile, perfusate, and liver was essentially complete at all doses. The perfusate concentrations at the conclusion of each experiment (i.e. 5 hr) did not differ among dosage groups. By contrast, increased dose size produced a reduction in the amount of 14C radioactivity recovered in bile which was associated with increased levels of 14C in the liver.


Impact of induction therapy on postoperative outcome after extrapleural pneumonectomy for malignant pleural mesothelioma: does induction-accelerated hemithoracic radiation increase the surgical risk?
Patients with malignant pleural mesothelioma (MPM) eligible for extrapleural pneumonectomy (EPP) may benefit from induction chemotherapy (CT) as historically described, or from induction-accelerated hemithoracic intensity-modulated radiation therapy (IMRT) as a potential alternative. However, the impact of the type of induction therapy on postoperative morbidity and mortality remains unknown. We performed a retrospective study including every patient who underwent EPP for MPM in our institution between January 2001 and December 2014. Patients without induction treatment (n = 7) or undergoing both induction CT and IMRT (n = 2) were then excluded. The remaining patients (study group) were divided according to the type of induction treatment in Group 1-CT and Group 2-IMRT. Major complications were defined by complications of Grade 3 or higher according to the National Cancer Institute Common Terminology Criteria for Adverse Events 4.0 guidelines. Red blood cell (RBC) transfusion was analysed as a number of packs, and dichotomized as <3 vs ≥3 packs. Plasma and platelet transfusion were analysed as a number of units, and dichotomized as no transfusion versus any plasma or platelet transfusion. Altogether, 126 patients (mean age 61.3 ± 8.1 years, males 82.5%, right side 60.3%, 90-day mortality rate 4.8%) accounted for the study group. Sixty-four patients were included in Group 1-CT and 62 patients were included in Group 2-IMRT. When compared with Group 1-CT, Group 2-IMRT was characterized by older patients (59.3 ± 9.2 vs 63.3 ± 8.3 years, P = 0.012), more right-sided resections (46.8 vs 74.1%, P = 0.003), more advanced disease (pathological stage IV: 28.1 vs 53.2%, P = 0.007), less RBC transfusions (5.1 ± 3.0 vs 3.0 ± 2.4 packs, P < 0.001), less plasma or platelet transfusions (31.2 vs 9.6%, P = 0.005) and similar rate of major complications (29.6 vs 35.4%, P = 0.614). The 90-day mortality rate was 6.2% in Group 1-CT (n = 4) and 3.2% in Group 2-RT (n = 2, P = 0.680). Induction with IMRT was significantly associated with a decreased risk of transfusion with RBCs [odds ratio (OR) = 0.10, 95% confidence interval (CI) 0.04-0.23, P < 0.001] as well as plasma and platelets (OR = 0.25, 95% CI 0.086-0.67, P = 0.008). In this large single-centre series of EPP for MPM, the implementation of induction IMRT was not associated with any significant increase in the surgical risks above and beyond induction CT. The switch from induction CT to induction IMRT was associated with resection in older patients with more advanced tumours, less transfusion requirements, comparable postoperative morbidity and 90-day mortality.


Biological properties of the deer papillomavirus E5 gene in mouse C127 cells: growth transformation, induction of DNA synthesis, and activation of the platelet-derived growth factor receptor.
We determined the biological activities of the 44-amino-acid deer papillomavirus (DPV) E5 protein in mouse C127 cells. The DPV E5 gene can induce focus formation, stable and acute morphologic transformation, and DNA synthesis, and it activates the platelet-derived growth factor (PDGF) beta receptor as assessed by increased constitutive tyrosine phosphorylation of mature and precursor receptor forms. Thus, the DPV E5 protein has biological activities similar to those of the closely related E5 protein from bovine papillomavirus type 1. Moreover, like the bovine papillomavirus type 1 E5 protein, the DPV E5 protein shares a short region of sequence similarity with the B chain of PDGF. These results show that activation of the PDGF receptor is a general property of fibropapillomavirus E5 proteins, lending support to our previous proposal (L. Petti, L. Nilson, and D. DiMaio, EMBO J. 10:845-855, 1991) that activation of the PDGF receptor may play a central role in transformation of fibroblasts by E5 proteins.


The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone.
The extracellular calcium-sensing receptor (CaR; alternate gene names, CaR or Casr) is a membrane-spanning G protein-coupled receptor. CaR is highly expressed in the parathyroid gland, and is activated by extracellular calcium (Ca(2+)(o)). Mice homozygous for null mutations in the CaR gene (CaR(-/-)) die shortly after birth because of the effects of severe hyperparathyroidism and hypercalcemia. A wide variety of functions have been attributed to CaR. However, the lethal CaR-deficient phenotype has made it difficult to dissect the direct effect of CaR deficiency from the secondary effects of hyperparathyroidism and hypercalcemia. We therefore generated parathyroid hormone-deficient (PTH-deficient) CaR(-/-) mice (Pth(-/-)CaR(-/-)) by intercrossing mice heterozygous for the null CaR allele with mice heterozygous for a null Pth allele. We show that genetic ablation of PTH is sufficient to rescue the lethal CaR(-/-) phenotype. Pth(-/-)CaR(-/-) mice survive to adulthood with no obvious difference in size or appearance relative to control Pth(-/-) littermates. Histologic examination of most organs did not reveal abnormalities. These Pth(-/-)CaR(-/-) mice exhibit a much wider range of values for serum calcium and renal excretion of calcium than we observe in control littermates, despite the absence of any circulating PTH. Thus, CaR is necessary for the fine regulation of serum calcium levels and renal calcium excretion independent of its effect on PTH secretion.


Molecular characterization of wild-type measles viruses in Tamil Nadu, India, during 2005-2006: relationship of genotype D8 strains from Tamil Nadu to global strains.
Molecular characterization of measles viruses is a valuable tool for measuring the effectiveness of measles control and elimination programmes. WHO recommends that virological surveillance be conducted during all phases of measles control to document circulation of indigenous strains and trace future importation. This report describes the genetic characterization of wild type measles viruses from Tamil Nadu, India isolated between January 2005 and January 2006. In the study, 304 suspected measles cases (292 from 56 outbreaks and 12 sporadic cases) were investigated. Blood samples were collected from suspected measles outbreaks and 11 suspected sporadic cases and tested for the presence of measles and rubella specific IgM. Based on serological results, 53 outbreaks were confirmed as measles, 2 as a combination of measles and rubella, and 1 negative for both. Eight sporadic cases were confirmed as measles and one as rubella. Throat swab and urine samples were collected for virus isolation and 28 isolates were obtained. Sequencing and analysis showed that 3 isolates belonged to genotype D4 and 25 to genotype D8. Comparison of the genotype D8 sequences from Tamil Nadu with previously reported genotype D8 sequences from India and abroad showed six distinct clusters with Tamil Nadu strains forming two clusters. This study has established baseline molecular data and is the first report that describes genetic diversity of circulating measles strains in Tamil Nadu, a state in India. D8 has multiple lineages and this has been linked with importation of measles into the USA and UK.


Pain Treatment Services; A National Survey Of Tertiary Care Hospitals In Pakistan.
To quantify pain services in Pakistan and classify them according to the International Association for the Study of Pain guidelines. The study was conducted at the Aga Khan University, Karachi, from January to June 2022, and comprised data of all public and private tertiary care hospitals anywhere in Pakistan that were registered with the Pakistan Medical Council till November 25, 2021. Data was collected using a predesigned Google form. Data was obtained primarily via email and secondarily by a phone call in a structured format. The facilities providing dedicated pain management services were classified according to the International Association for the Study of Pain guidelines. Of 118 hospitals, 45(38.1%) were in the public sector and 73(61.8%) were in the private sector. Overall, 78(65.2%) had no pain treatment services, while 40(34.2%) had such services. Of these 40(34.2%) facilities, 25(62.5%) were classified as pain centres, 11(27.5%) were pain clinics and 4(10%) were pain practices. In terms of per 100,000 population, there were 0.0193 pain services, 0.0351 pain physicians, 0.025 nursing staff and 0.02 administrative staff in the country. Physiotherapy was present in 37(92.5%) hospitals, psychiatry and psychology as allied services were used in 38(95%), acupuncture was integrated into the practice in 25(62.5%), while 39(97.5%) hospitals offered interventional procedures. Also, 9(22.5%) hospitals offered advanced training in pain medicine. A severe shortage of chronic pain services in Pakistan was found.


Neuropathic pain modeling: Focus on synaptic and ion channel mechanisms.
Animal models of pain consist of modeling a pain-like state and measuring the consequent behavior. The first animal models of neuropathic pain (NP) were developed in rodents with a total lesion of the sciatic nerve. Later, other models targeting central or peripheral branches of nerves were developed to identify novel mechanisms that contribute to persistent pain conditions in NP. Objective assessment of pain in these different animal models represents a significant challenge for pre-clinical research. Multiple behavioral approaches are used to investigate and to validate pain phenotypes including withdrawal reflex to evoked stimuli, vocalizations, spontaneous pain, but also emotional and affective behaviors. Furthermore, animal models were very useful in investigating the mechanisms of NP. This review will focus on a detailed description of rodent models of NP and provide an overview of the assessment of the sensory and emotional components of pain. A detailed inventory will be made to examine spinal mechanisms involved in NP-induced hyperexcitability and underlying the current pharmacological approaches used in clinics with the possibility to present new avenues for future treatment. The success of pre-clinical studies in this area of research depends on the choice of the relevant model and the appropriate test based on the objectives of the study.


Viral infection and smell loss: The case of COVID-19.
Olfactory disorders have been increasingly reported in individuals infected with SARS-CoV-2, the virus causing the coronavirus disease 2019 (COVID-19). Losing the sense of smell has a strong impact on the quality of life, since it may lead to malnutrition, weight loss, food poisoning, depression, and exposure to dangerous chemicals. Individuals who suffer from anosmia (inability to smell) also cannot sense the flavor of food, which is a combination of taste and smell. Interestingly, infected individuals have reported sudden loss of smell with no congested nose, as is frequently observed in common colds or other upper respiratory tract infections. These observations suggest that SARS-CoV-2 infection leads to olfactory loss through a distinct mechanism, which is still unclear. This article provides an overview of olfactory loss and the recent findings relating to COVID-19. Possible mechanisms of SARS-CoV-2-induced olfactory loss are also discussed.


Uptake of health insurance and the productive safety net program in rural Ethiopia.
Due to lack of well-developed insurance and credit markets, rural families in Ethiopia are exposed to a range of covariate and idiosyncratic risks. In 2005, to deal with the consequences of covariate risks, the government implemented the Productive Safety Net Program (PSNP), and in 2011, to mitigate the financial consequences of ill-health, the government introduced a pilot Community Based Health Insurance (CBHI) Scheme. This paper explores whether scheme uptake and retention is affected by access to the PSNP. Based on household panel data and qualitative information, the analysis shows that participating in the PSNP increases the probability of CBHI uptake by 24 percentage points and enhances scheme retention by 10 percentage points. A large proportion of this effect may be attributed to explicit and implicit pressure applied by government officials on PSNP beneficiaries. Whether this is a desirable approach is debatable. Nevertheless, the results suggest that membership in existing social protection programs may be leveraged to spread new schemes and potentially accelerate poverty reduction efforts.


Alpha-1 Antitrypsin Deficiency and Pregnancy.
Alpha-1 Antitrypsin Deficiency (A1AD) is a hereditary condition characterized by low levels of circulating alpha-antitrypsin (AAT) in plasma. It is the best understood genetic risk factor for the development of chronic obstructive pulmonary disease (COPD). The diagnosis of A1AD is under-recognized. While there is a significant heterogeneity in disease presentation in relation to the severity of symptoms and prognosis, it is not uncommon for young individuals, including pregnant women to already have moderate to advanced lung disease at the time of diagnosis. Reductions in AAT levels may have unique implications for a gravid patient beyond that of lung disease. Care of the pregnant A1AD patient with chronic lung disease follows the principles of care for the management of airways disease in general with control of symptoms and reduction in exacerbation risk the main tenets of treatment. The effect of A1AD and augmentation in pregnancy has not been studied and thus care is reliant on expert opinion and clinical experience. Providers caring for pregnant patients with A1AD should consider referral to health care systems and providers with specific expertise in A1AD. Ultimately the decision is left to the individual patient and their physician to weigh the risk benefit of cessation or continuation of therapies. In this review, we present the perinatal course of a woman with A1AD and review the available literature pertaining to AAT and pregnancy and discuss the clinical implications.


Serotonin type 1D receptors (5HTR) are differentially distributed in nerve fibres innervating craniofacial tissues.
We tested the hypothesis that the 5HT(1D)R, the primary antinociceptive target of triptans, is differentially distributed in tissues responsible for migraine pain. The density of 5HT(1D)R was quantified in tissues obtained from adult female rats with Western blot analysis. Receptor location was assessed with immunohistochemistry. The density of 5HT(1D)R was significantly greater in tissues known to produce migraine-like pain (i.e. circle of Willis and dura) than in structures in which triptans have no antinociceptive efficacy (i.e. temporalis muscle). 5HT(1D)R-like immunoreactivity was restricted to neuronal fibres, where it colocalized with calcitonin gene-related peptide and tyrosine hydroxylase immunoreactive fibres. These results are consistent with our hypothesis that the limited therapeutic profile of triptans could reflect its differential peripheral distribution and that the antinociceptive efficacy reflects inhibition of neuropeptide release from sensory afferents. An additional site of action at sympathetic efferents is also suggested.


Fast 3D-lithium-ion diffusion and high electronic conductivity of Li2MnSiO4 surfaces for rechargeable lithium-ion batteries.
High theoretical capacity, high thermal stability, the low cost of production, abundance, and environmental friendliness are among the potential attractiveness of Li2MnSiO4 as a positive electrode (cathode) material for rechargeable lithium-ion batteries. However, the experimental results indicated poor electrochemical performance in its bulk phase due to high intrinsic charge transfer resistance and capacity fading during cycling, which limit its large-scale commercial applications. Herein, we explore the surface stability and various lithium-ion diffusion pathways of Li2MnSiO4 surfaces using the density functional theory (DFT) framework. Results revealed that the stability of selected surfaces is in the following order: (210) > (001) > (010) > (100). Moreover, the Wulff-constructed equilibrium shape revealed that the Li2MnSiO4 (001) surface is the most predominant facet, and thus, preferentially exposed to electrochemical activities. The Hubbard-corrected DFT (DFT + U, with U = 3 eV) results indicated that the bulk insulator with a wide band gap (E g = 3.42 eV) changed into narrow electronic (E g = 0.6 eV) when it comes to the Li2MnSiO4 (001) surface. Moreover, the nudged elastic band analysis shows that surface diffusion along the (001) channel was found to be unlimited and fast in all three dimensions with more than 12-order-of-magnitude enhancements compared with the bulk system. These findings suggest that the capacity limitation and poor electrochemical performance that arise from limited electronic and ionic conductivity in the bulk system could be remarkably improved on the surfaces of the Li2MnSiO4 cathode material for rechargeable lithium-ion batteries.


Interaction between Maternal and Paternal SHMT1 C1420T Predisposes to Neural Tube Defects in the Fetus: Evidence from Case-Control and Family-Based Triad Approaches.
Neural tube defects (NTDs) are caused by the failure of neural tube formation which occurs during early embryonic development. NTDs are the most severe and leading cause of fetal mortality. Serine hydroxymethyl transferase (SHMT1) provides one-carbon units necessary for embryogenesis and defects in one-carbon production result in specific pathological conditions during pregnancy. The present study is aimed to evaluate the association of SHMT1 C1420T with NTD risk in the fetus using fetal, maternal and paternal groups by applying both case-control and family-based triad approaches. A total of 924 subjects including 124 NTD case-parent trios (n = 124 × 3 = 372) and 184 healthy control-parent trios (n = 184 × 3 = 552) from Telangana State, South India were analyzed. DNA from umbilical cord tissues and parental blood samples were extracted, and genotyped by polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis used were SPSS, parent-of-origin effect (POE) analysis. Case-control study design demonstrated fetuses with homozygous variant genotype (TT) to be at risk toward spina bifida subtype (p = 0.022). Among parents, fathers with TT genotype were associated with anencephaly (p = 0.018) and spina bifida subtypes (p = 0.027) in the offspring. Of interest, maternal-paternal-offspring genotype incompatibility revealed maternal CT genotype in combination with paternal TT genotype increased risk for NTDs in the fetus (CTxTT = TT; p = 0.021). Family-based parent-of-origin effect linkage analysis revealed significant maternal over-transmission of variant allele to NTD fetuses (p < 0.01). The present study, using both case-control and family-based triad approach is the first report to demonstrate parental association of SHMT1 C1420T variant in conferring NTD risk in the fetus. Birth Defects Research 109:1020-1029, 2017. © 2017 Wiley Periodicals, Inc.


Time-dependent pretreatment with bevacuzimab increases tumor specific uptake of cetuximab in preclinical oral cavity cancer studies.
Inadequate delivery of therapeutics into tumors has been suggested as a reason for poor response. We hypothesize that bevacizumab, an antibody to vascular endothelial growth factor (VEGF), can improve cetuximab uptake in squamous cell carcinoma tumors. Athymic nude mice were implanted with OSC19 and SCC1 human cancer lines in a subcutaneous flank model. Mice were imaged daily for 14 days after intravenous tail vein injections of the following groups: IgG-IRDye800 (Control), cetuximab-IRDye800 (CTX800 Only), bevacizumab-IRDye800 (BVZ800 Only), cetuximab-IRDye800 + bevacuzimuab-IRDye800 (Simultaneous), and unlabeled bevacizumab followed by cetuximab-IRDye800 3 days later (Neoadjuvant). Within single-agent groups, the CTX800 Only tumor-specific uptake (TSU) was significantly higher than BVZ800 Only at Day 13 (TSU 8.6 vs 2.8, P < 0.001). The Simultaneous treatment with BVZ800 and CTX800 demonstrated no increase in antibody delivery. However, administration of unlabeled bevacizumab 3 days prior to CTX800 (Neoadjuvant group) resulted in significantly higher tumor specific delivery than administration of both antibodies at the same time (11.8 vs Simultaneous 5.0, P < 0.001). This difference can be attributed to a slower decline in tumor fluorescence intensity (-6.8% vs. Simultaneous -11.5% per day, respectively). Structural changes in pericyte coverage and functional vessel changes demonstrating decreased proliferation and tumor growth corroborate these fluorescence results. Although simultaneous administration of bevacizumab with cetuximab failed to increase antibody delivery to the tumor, pretreatment with bevacizumab improved TSU reflecting an increase in tumor-specific uptake of cetuximab as a result of vessel normalization.


Do unfavourable alcohol, smoking, nutrition and physical activity predict sustained leisure time sedentary behaviour? A population-based cohort study.
Comparing lifestyle of people remaining sedentary during longer periods of their life with those favourably changing their behaviour can provide cues to optimize interventions targeting sedentary behaviour. The objective of this study was to determine lifestyle predictors of sustained leisure time sedentary behaviour and assess whether these predictors were dependent on gender, age, socioeconomic position and occupational sedentary behaviour. Data from a large longitudinal population-based cohort of adults (aged 18-97years) in Stockholm responding to public health surveys in 2010 and 2014 were analysed (n=49,133). Leisure time sedentary behaviour was defined as >3h per day of leisure sitting time e.g. watching TV, reading or using tablet. Individuals classified as sedentary at baseline (n=9562) were subsequently categorized as remaining sedentary (n=6357) or reduced sedentary behaviour (n=3205) at follow-up. Lifestyle predictors were unfavourable alcohol consumption, smoking, nutrition, and physical activity. Odds ratios (OR) and corresponding 95% Confidence Intervals (CI) were calculated, adjusting for potential confounders. Unfavourable alcohol consumption (OR=1.22, CI:1.11-1.34), unfavourable candy- or cake consumption (OR=1.15, CI:1.05-1.25), and unfavourable physical activity in different contexts were found to predict sustained sedentary behaviour, with negligible differences according to gender, age, socioeconomic position and occupational sedentary behaviour. People with unfavourable lifestyle profiles regarding alcohol, sweets, or physical activity are more likely to remain sedentary compared to sedentary persons with healthier lifestyle. The impact of combining interventions to reduce leisure time sedentary behaviour with reducing alcohol drinking, sweet consumption and increasing physical activity should be tested as a promising strategy for behavioural modification.


Network-based modeling of the human gut microbiome.
In this article, we used a network-based approach to characterize the microflora abundance in colonic mucosal samples and correlate potential interactions between the identified species with respect to the healthy and diseased states. We analyzed the modelled network by computing several local and global network statistics, identified recurring patterns or motifs, fit the network models to a family of well-studied graph models. This study has demonstrated, for the first time, an approach that differentiated the gut microbiota in alcoholic subjects and healthy subjects using topological network analysis of the gut microbiome.


Medication safety risks to be managed in national implementation of automatic substitution of biological medicines: a qualitative study.
To explore relevant Finnish stakeholders' perceptions on the automatic substitution of biological medicines with particular focus on medication safety and issues that need to be considered to create an appropriate model for automatic biological product substitution. Qualitative interview study. Data were collected in semistructured individual (n=17), pair (n=7) and group (n=8) interviews (32 interviews, 62 participants) in 2018. Participants represented a wide range of stakeholders involved in the pharmacotherapy process: community pharmacists (n=8 interviews), authorities (n=7), prescribers (n=7), pharmaceutical industry and wholesalers (n=6), patients/customers (n=2), hospital pharmacists (n=1) and nurses (n=1). Inductive content analysis was performed. Benefits of automatic substitution were identified as cost savings, more patients receiving biological treatments and enhanced continuity of treatment. Six major risk categories were identified: (1) the patient's medication is interrupted or complicated temporarily or permanently, (2) the patient uses two products with the same active substance, (3) the traceability of the product is compromised, (4) the patient cannot get into healthcare in case of problems, (5) the patient does not receive substitution-related advice from a pharmacy and (6) the patient is distracted by the support material he/she receives. Several risk mitigation measures were commonly mentioned: medication and device counselling by pharmacists (n=23), infrequent substitution interval (n=15) and better knowledge on biosimilars among healthcare providers (n=13). Automatic substitution of biologics is associated with risks that should be prospectively managed before implementing the procedure. The substitution also introduces new tasks and communication needs to those involved in actual medication use process, particularly to community pharmacists who will be responsible for substitution and counselling the patients.


Progress toward improving medical school graduates' skills via a "boot camp" curriculum.
Medical school graduates are expected to possess a broad array of clinical skills. However, concerns have been raised regarding the preparation of medical students to enter graduate medical education. We designed a simulation-based "boot camp" experience for students entering internal medicine residency and compared medical student performance with the performance of historical controls who did not complete boot camp. This was a cohort study of a simulation-based boot camp educational intervention. Twenty medical students completed 2 days (16 hours) of small group simulation-based education and individualized feedback and skills assessment. Skills included (a) physical examination techniques (cardiac auscultation); technical procedures including (b) paracentesis and (c) lumbar puncture; (d) recognition and management of patients with life-threatening conditions (intensive care unit clinical skills/mechanical ventilation); and (e) communication with patients and families (code status discussion). Student posttest scores were compared with baseline scores of postgraduate year 1 (PGY-1) historical controls to assess the effectiveness of the intervention. Boot camp-trained medical students performed significantly better than PGY-1 historical controls on each simulated skill (P<0.01). Results remained significant after controlling for age, sex, and US Medical Licensing Examination step 1 and 2 scores (P<0.001). A 2-day simulation-based boot camp for graduating medical students boosted a variety of clinical skills to levels significantly higher than PGY-1 historical controls. Simulation-based education shows promise to help ensure that medical school graduates are prepared to begin postgraduate training.


Do fish perceive anaesthetics as aversive?
This study addresses a fundamental question in fish welfare: are the anaesthetics used for fish aversive? Despite years of routine general use of many agents, within both scientific research and aquaculture, there is a paucity of information regarding their tolerance and associated behavioural responses by fish. This study examined nine of the most commonly used fish anaesthetic agents, and performed preference tests using adult mixed sex zebrafish (Danio rerio), the most commonly held laboratory fish. Video tracking software quantified swimming behaviour related to aversion for each anaesthetic at 50% of its standard recommended dose compared with clean water in a flow-through chemotaxic choice chamber. Results suggest that several commonly used anaesthetics were aversive, including two of the most commonly recommended and used: MS222 (ethyl 3-aminobenzoate methanesulphate) and benzocaine. For ethical best practice, it is recommended that compounds that are aversive, even at low concentration, should no longer be used routinely for anaesthesia or indeed the first step of humane euthanasia of adult zebrafish. Two agents were found not to induce aversive behavioural responses: etomidate and 2,2,2 tribromoethanol. For the millions of adult zebrafish used in laboratories and breeding worldwide, etomidate appears best suited for future routine humane use.


Parkinson's disease in a Scottish city.
In a detailed community study the total prevalence of idiopathic Parkinson's disease in Aberdeen was 164.2/10(5) of the population. The age and sex specific prevalence rose to 2657.8/10(5) (2.7%) of men and 2071.0/10(5) (2.0%) of women aged over 84. The mean age at onset, irrespective of sex, was 65.3 years (SD 12.6) and varied little compared with similar studies over the past 25 years. Half of patients were independent but 78/225 (34.7%) were considerably disabled and 23/225 (10.2%) were confined to bed or a wheelchair. Disability increased with age and also with a low minimental state questionnaire score. The score was less than or equal to 7/10 (graded 0-10) in 93/252 (37%) of patients and less than 5/10 in 28/252 (11%). Parkinson's disease remains a common and disabling condition in the community.


Platelet-activating factor receptor and signal transduction mechanisms.
Platelet-activating factor (PAF) is the most potent phospholipid agonist known to date. Radioligand binding studies using [3H]PAF and structurally different PAF antagonists have provided the characteristics of PAF receptor(s) and its heterogeneity. Although efforts have been made to isolate the receptor, it was not until the recent cloning of the PAF receptor that the molecular architecture of the receptor can be visualized. The receptor shows homology to the G protein-coupled receptors with seven transmembrane spanning segments. Several serine, threonine, and tyrosine residues are present at the cytoplasmic side, which could serve as sites for phosphorylation. PAF activates GTPase, causes phospholipid turnover via phospholipases C, D, and A2 pathways and also activates protein kinase C and tyrosine kinase. Further, PAF stimulates Ca2+ mobilization some of which may occur via receptor operated channel. Second messengers generated by these multiple signalling pathways play role (or roles) in PAF responses and in the PAF induced expression of primary response genes. These recent developments throw light on the PAF receptor and its signal transduction mechanisms.


Identification of Diosmin and Flavin Adenine Dinucleotide as Repurposing Treatments for Monkeypox Virus: A Computational Study.
The World Health Organization declared monkeypox a global public health emergency on 23 July 2022. This disease was caused by the monkeypox virus (MPXV), which was first identified in 1958 in Denmark. The MPXV is a member of the Poxviridae family, the Chordopoxvirinae subfamily, and the genus Orthopoxvirus, which share high similarities with the vaccinia virus (the virus used to produce the smallpox vaccine). For the initial stage of infection, the MPXV needs to attach to the human cell surface glycosaminoglycan (GAG) adhesion molecules using its E8 protein. However, up until now, neither a structure for the MPXV E8 protein nor a specific cure for the MPXV exists. This study aimed to search for small molecules that inhibit the MPXV E8 protein, using computational approaches. In this study, a high-quality three-dimensional structure of the MPXV E8 protein was retrieved by homology modeling using the AlphaFold deep learning server. Subsequent molecular docking and molecular dynamics simulations (MDs) for a cumulative duration of 2.1 microseconds revealed that ZINC003977803 (Diosmin) and ZINC008215434 (Flavin adenine dinucleotide-FAD) could be potential inhibitors against the E8 protein with the MM/GBSA binding free energies of -38.19 ± 9.69 and -35.59 ± 7.65 kcal·mol-1, respectively.


Does β-catenin have a role in pathogenesis of sebaceous cell carcinoma of the eyelid?
Expression of β-catenin in sebaceous cell carcinoma (SbCC) of the eyelid and its correlation with histopathological features. 48 cases of SbCC were analysed immunohistochemically using monoclonal β-catenin antibody and the results correlated with tumour size, histopathological differentiation, orbital invasion and pagetoid spread. Cytoplasmic overexpression of β-catenin was seen in 66% cases of SbCC which correlated positively with tumour size, orbital invasion and pagetoid spread. This correlation was found to be significant in tumour size > 2 cm (p = 0.242). Nuclear staining was not observed in any of the cases. Cytoplasmic overexpression of β-catenin was observed in the majority of the cases of SbCC of eyelid, and this correlated significantly with tumour size. The authors therefore hypothesise that β-catenin overexpression in SbCC of eyelid may be a result of Wnt/β-catenin pathway dysregulation. However, its role both in the development of sebaceous cell carcinoma of the eyelid as well as its prognosis needs to be explored further.


[Isolation of Mycobacterium avium-intracellulare from a hepatic biopsy].
A 64 years-old patient, who was a farmer suffering from chronic fever for two years, loss of weight and acute asthenia, was studied. He was admitted to "Pedro Kourí" Tropical Medicine Institute where the studies were conducted and revealed a globular sedimentation rate of 116 mm in 2 hours, and anemia of 9,8g% hemoglobin. The laparoscopic study indicated hepatic granulomatosis that was confirmed by hepatic biopsy in which a sample was taken from the liver to be microbiologically and cytologically examined. By microbiological methods, a non-pigmented slowly-growing strain was isolated, which was classified by conventional diagnostic techniques for the non-tuberculous mycobacteria classification and the alternative diagnosing technique known as bidimensional thin layer chromatography to confirm the previous classification and set the mycolic acid patterns. The isolated strain belonged to group III of Rynyon and was identified as Mycobacterium avium-intracellulare.


DSM-III in the training of British psychiatrists: a national survey.
All 223 psychiatric clinical tutors in the UK were surveyed on their use of DSM-III in their postgraduate training programmes. Results indicate that DSM-III is widely used in clinical training to some extent in the majority of schemes (73%) and in the schemes where it is used it is rated as moderately useful by nearly everyone (93%). DSM-III is generally perceived to have positive effects on learning basic elements of psychopathology and in offering a common language for diagnostic discussion. Interestingly only 16% of users felt that DSM-III was so complicated that it impeded rather than facilitated the teaching of diagnosis. Few schemes provide specific teaching courses and case conferences provide the major forum for teaching DSM-III.


The multidisciplinary approach to develop artificial organs.
This paper presents the author's perspective of how artificial organ development has evolved in the past 35 years into a multidisciplinary effort. Examples are taken from the fields of hemodialysis, oxygenators, and affinity immunoadsorption devices. Development of the multidisciplinary approach to develop dialysis and oxygenation membranes has been significantly advanced by private and governmental collaboration and conferences that gathered together chemists, physicians, engineers, and fluid dynamics experts. Lengthy delays occurred in artificial organ development when such interdisciplinary collaborations did not take place.


Glomerular filtration rate in children following renal transplantation.
Most studies evaluating renal function post-renal transplantation in children have used serum creatinine (S(Cr)) or estimates of its clearance (C(SCH)). When renal function is impaired both S(Cr) and the C(SCH) overestimate glomerular filtration rate (GFR), especially during cyclosporine therapy. This study measured GFR in 64 children (age range: 4-19 years) with stable renal function who received renal allografts at the Childrens Medical Center of Dallas, 31 from live related donors (LRD) and 33 from cadaveric donors (CAD). 125I-iothalamate clearance (C(IO)) was used as the reference standard for measuring GFR. Data from 100 C(IO) studies, were analyzed and results reported as mean +/- S.E.M. C(IO) performed during the first year after renal transplantation in 23 children who received allografts from LRD was 72.4+/-5.5 ml/min per 1.73 m2 compared to 50.4+/-7.4 ml/min per 1.73 m2 in 18 children who received allografts from CAD (p<0.05). Beyond the first year post-renal transplantation there was no difference in C(IO) between LRD and CAD allografts. When S(Cr) was compared to C(IO), the relationship was nonlinear. C(IO) was also compared to the simultaneous estimation of creatinine clearance by C(SCH). The overestimation of GFR by C(SCH) was inversely proportional to the level of renal function. When renal function was normal or mildly reduced (C(IO) > 50 ml/min per 1.73 m2), C(SCH) closely approximated C(IO). When renal function was moderately to severely curtailed (C(IO) < or = 50 ml/min per 1.73 m2), C(SCH) overestimated C(IO) by 43.6+/-5.6%. The study concludes that in children with renal transplant: 1) C(IO) is higher in allografts from LRD compared to CAD kidneys only in the first 12 months following renal transplantation; 2) S(Cr) is a poor predictor of C(IO); and 3) C(SCH) consistently overestimates GFR children following renal transplantation unless renal function is normal or only mildly decreased.


[Anatomo-clinical correlations of carotid plaques].
Recently, much attention has been focused on pathologic plaque characteristics and their importance in producing cerebrovascular symptoms. There remains much controversy on the significance of plaque ulceration, mural thrombi, and intraplaque hemorrhage in symptomatic and asymptomatic patients. We investigated 110 plaques, and the only significant correlation with preoperative symptoms was the presence of fresh mural thrombus, mostly intraluminal, associated with stenosis. Exulceration without fresh thrombus, intraplaque hemorrhage with intact endothelium and recanalized thrombus were also found in a considerable number of asymptomatic patients.


Effects of beta-carotene and other factors on outcome of cervical dysplasia and human papillomavirus infection.
Women with histopathologically confirmed cervical intraepithelial neoplasia (CIN) were followed at 3-month intervals in a randomized double-blinded trial to evaluate the efficacy of beta-carotene to cause regression of CIN. Questionnaire data, plasma levels of micronutrients, and a cervicovaginal lavage for human papillomavirus (HPV) detection were obtained at each visit, and an endpoint biopsy was performed at 9 months. Sixty-nine subjects had a biopsy endpoint evaluation; 9 of 39 (23%) subjects in the beta-carotene group versus 14 of 30 (47%) in the placebo group had regression of CIN (P = 0.039). Independent risk factors for persistent CIN at 9 months included type-specific persistent HPV infection (OR = 11.38, P = 0.006) and continual HPV infection with a high viral load (OR = 14.25, P = 0.007) at baseline and 9 months, an initial diagnosis of > or =CIN II (OR = 6.74, P = 0.016), and older age (OR for > or =25 years = 4.10, P = 0.072). After controlling for these factors, the beta-carotene and placebo groups did not differ in risk for having CIN at 9 months (OR = 1.53, P = 0.550). Resolution of baseline HPV infection was significantly correlated with non-high-risk HPV types (RR = 2.94, P = 0.015), age <25 years (RR = 2.62, P = 0.014), and douching after sexual intercourse (RR = 3.02, P = 0.012), but not with randomization group. Our data indicate that a large proportion of mild CIN lesions regress; age and HPV infection play an important role in the natural course of CIN; and repeated HPV testing may have a value in distinguishing women who need aggressive treatment for CIN versus those who do not. Supplementation of beta-carotene does not appear to have a detectable benefit in treatment of CIN.


Effects of delta-9-tetrahydrocannabinol on cultured HeLa cell growth and development.
Monolayer cultures of HeLa cells were used to monitor the effects of non-lethal concentrations of delta-9-tetrahydrocannabinol (delta-9-THC) on the pool sizes of the acid-soluble and acid-insoluble DNA moieties and cytoplasmic RNA pool sizes. The DNA fractions were separated using acid precipitation and low speed centrifugation, while the RNA was examined through the use of sucrose gradients and high speed ultracentrifugation. The ratio of acid-insoluble to acid-soluble DNA per cell in untreated HeLa cells is 16:1, which did not change appreciably following delta-9-THC treatment. However, cell division was retarded as much as 25% in the 24 hours treatment period indicating that nucleic acid synthesis, while not inhibited, is depressed by delta-9-THC. This is not related to cell death as indicated by cell viability (> 95%). At both 1.0 x 10(-5)M and 3.2 x 10(-7)M, delta-9-THC caused a marked change in the free ribosomal RNA (an increase with 3.2 x 10(-7)M and a decrease with the 10(-5)M), total ribosomal RNA (a decrease with both observed delta-9-THC concentrations) and non-sedimental RNA (an increase with both observed delta-9-THC concentrations).


Thyrotropin (TSH) beta-subunit gene expression--an example for the complex regulation of pituitary hormone genes.
Synthesis of pituitary hormones was shown to be efficiently regulated at the transcriptional level. The specialized function of the five cell types in the anterior pituitary is controlled by ubiquitous as well as cell-specific transcription factors. Pit-1 is such a cell-specific regulator found only in lacto-, somato- and thyrotropes which could be shown to be essential for basal expression of growth hormone (GH) and prolactin (Prl) genes and the regulated expression of Prl and thyrotropin (TSH) beta-subunit genes. Identification of distinct binding sites for transcription factors and some of the mechanisms of transcriptional control shed light on the complex regulation of pituitary hormone gene expression which is exemplified for the TSH beta gene. The control of basal as well as positively and negatively regulated expression of some pituitary hormone genes becomes fairly well understood by the investigation of the role of Pit-1. Identification of different mutations in the human pit-1 gene supported the role of this protein for combined pituitary hormone deficiency (CPHD) characterized by the deficiency of GH, prolactin and TSH.


Degradation of a mixture of pollutants in water using the UV/H2O2 process.
The degradation reaction of a simple mixture of pollutants (dichloroacetic acid + formic acid) employing H2O2 and UVC radiation (253.7 nm) has been studied in a well-mixed reactor which operates inside a recycling system. The aim of this work is to develop a systematic methodology for treating degradation of mixtures of pollutants, starting from a rather manageable system to more complex aggregates. In this contribution, the effects of different variables such as hydrogen peroxide/pollutant mixture initial concentration ratio, pH and incident radiation at the reactor wall were studied. The results show that the best degrading conditions are: pH = 3.5 and hydrogen peroxide concentrations from 3.9 to 11.8 mM (134-400 mg/L), for initial concentrations of 1.10 and 0.39 mM for formic acid and dichoroacetic acid respectively (50 mg/L for both pollutants). The influence of the incident radiation at the reactor wall on the degradation rates of the mixture is significant. In addition to this, it has been shown that in the employed aqueous solution no stable reaction intermediates are formed. On this basis, a complete reaction scheme for the mixture is proposed that is suitable for a reaction kinetics mathematical modeling of the mixture and further studies of increasing complexity.


Co-instillation of nano-solid magnesium hydroxide enhances corneal permeability of dissolved timolol.
We prepared magnesium hydroxide (MH) nanoparticles by a bead mill method, and investigated whether the co-instillation of MH nanoparticles improves the low transcorneal penetration of water-soluble drugs, such as the anti-glaucoma eye drug timolol maleate (TM). MH particle size was decreased by the bead mill treatment to a mean particle size of 71 nm. In addition, the MH nanoparticles were highly stable. Next, we demonstrated the effect of MH nanoparticles on the corneal surface. MH shows only slight solubility in lacrimal fluid, and the instillation of MH nanoparticles for 14 days did not affect the behavior (balance of secretion and excretion) of the lacrimal fluid in rabbit corneas. Moreover, there was no observable corneal toxicity of MH nanoparticles, and treatment with MH nanoparticles enhanced the intercellular space ratio in the eyes of rats. MH alone did not permeate into the cornea; however, the co-instillation of MH nanoparticles and dissolved TM (nMTFC) enhanced the corneal penetration of TM. In addition, the intraocular pressure (IOP)-reducing effect of nMTFC was significantly higher than those of the TM solution or the co-instillation of MH microparticles and TM. In conclusion, we found that MH nanoparticles enhance the corneal penetration of dissolved TM with no observable corneal stimulation or obstruction of the nasolacrimal duct by the MH nanoparticles. It is possible that the co-instillation of MH nanoparticles may provide a useful way to improve the bioavailability of water-soluble drugs in the ophthalmic field. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs.


The management of hypertension in older patients.
Hypertension need not be a natural consequence of aging; nevertheless, as many as 70% of individuals aged 70 years or more have diastolic blood pressures greater than or equal to 90 mm Hg and/or systolic blood pressures greater than 160 mm Hg. Well-controlled trials have documented significant reductions in cardiovascular mortality with treatment of diastolic elevation. Double-blind, long-term, open-label studies have been conducted of quinapril, a new angiotensin-converting enzyme (ACE) inhibitor, in 451 older patients compared with 1,887 younger patients. Results of these studies showed that quinapril is equally effective in older and younger patients. The studies also demonstrated that the safety of quinapril in the treatment of older patients is comparable with that in younger patients, in terms of both the incidence of adverse events and the types of adverse events reported. However, because many older patients have impaired renal function, which can prolong the half-life of renally excreted ACE inhibitors such as quinaprilat (the active metabolite of quinapril), they should be started on lower doses of quinapril (5 mg) than are used in younger patients. The shorter half-life and duration of action of quinaprilat compared with other once-daily ACE inhibitors may make quinapril better suited than these other agents for use in older patients.


Latency and tumorigenesis in Marek's disease.
Despite the remarkable progress in our understanding of Marek's disease (MD) and the causative Marek's disease virus (MDV) biology, a number of major features of this complex viral disease remain unknown. Significant information on critical aspects of virus latency in lymphoid cells, and the virus-host interaction in MDV-induced lymphoma, remains to be identified. Moreover, the nature of the unique milieu of the feather follicle epithelial cell that allows cytolytic infection to continue, despite maintaining the latent infection in the lymphoid cells, is not fully understood. Although there has been significant progress in our understanding of the functions of a number of viral genes in the pathogenesis of the disease, the characteristics of the latent infection, how it differs from tumor phase, and whether latency is a prerequisite for the tumor phase are all important questions still to be answered. Reticuloendotheliosis virus-transformed cell lines have been shown to support MDV latency in a manner almost identical to that seen in MDV-transformed cell lines. There are increasing data on the role of epigenetic regulation, including DNA methylation and histone modifications, in maintaining viral latency. Onset of MD tumor is relatively rapid, and recent studies based on chromosomal integration and T-cell repertoire analysis demonstrated the clonal nature of MD lymphomas. Among the viral determinants of oncogenicity, the basic leucine zipper protein Meq is considered to be the most important and the most extensively studied. Deleting the Meq proteins or abolishing some of the important interactions does affect the oncogenicity of the virus. In addition, the noncoding sequences in the viral genome, such as the viral telomerase RNA and the virus-encoded microRNAs, also have significant influence on MDV-encoded oncogenesis.


A position-sensitive superheated emulsion chamber for three-dimensional photon dosimetry.
A position-sensitive detector chamber is introduced for the three-dimensional (3D) dosimetry of photon-emitting brachytherapy sources. The detector is based on an extremely fine suspension of monochloropentafluoroethane droplets emulsified in a gel. The droplets are highly superheated at room temperature and their evaporation can be triggered by photon interactions, leading to the formation of microscopic bubbles. Thus, when photon-emitting brachytherapy sources are inserted into the detector, bubble distributions form around them, enabling visualization of the radiation field. The tissue-equivalent emulsifier gel is highly viscous and keeps the bubbles immobilized at the location of their formation. Bubbles can then be imaged by nuclear magnetic resonance or optical scanning techniques. After the imaging, the detector can be pressurized in order to recondense the bubbles to the liquid phase. In a few minutes, the device is annealed and ready to be used again for repeated measurements improving the counting statistics. The photon sensitivity of the monochloropentafluoroethane droplets was determined with highly filtered, quasi-monochromatic x-ray beams and radionuclide gamma sources. The air-kerma response presents a broad maximum at low energies, due to the relatively high effective atomic number of the halocarbon molecule. A prototype chamber was built and successfully tested: bubble distributions deriving from the insertion of a 125I source were imaged by means of a slice-selective 3D gradient-echo technique. These experiments confirm the potential and viability of this new approach to 3D photon dosimetry.


DNA-binding proteins induced by the cottontail rabbit herpesvirus CTHV.
Several new polypeptides were detected in cells infected with CTHV, a cottontail rabbit herpesvirus. All of them (Mr 150K, 110K, 93K, 83K, 75K and 35K) accumulated in the nucleus during the infectious cycle, and all except the 150K species bound to DNA-cellulose affinity columns in low-salt buffers. Polyclonal antisera prepared against the 35K DNA-binding protein also recognized the 75K species. Although the 75K protein could be detected earlier in infection than the 35K protein, late in the infectious cycle the latter increased to an abundance approaching that of cellular histones. Treatment of partially purified virions with a non-ionic detergent indicated that the 35K protein, but not the 75K protein, is a component of capsid/tegument structures. The anti-35K/75K serum did not cross-react with herpesvirus sylvilagus virion proteins, which, in an electrophoretic comparison, exhibited both similarities to and differences from the virion proteins of CTHV. Labelling of CTHV-infected cells with [32P]orthophosphate revealed the presence of phosphoproteins electrophoretically comigrating with the 93K, 83K, 75K and 35K proteins.


O-GlcNAcylation: the sweet side of epigenetics.
Histones display a wide variety of post-translational modifications, including acetylation, methylation, and phosphorylation. These epigenetic modifications can influence chromatin structure and function without altering the DNA sequence. Histones can also undergo post-translational O-GlcNAcylation, a rather understudied modification that plays critical roles in almost all biological processes and is added and removed by O-linked N-acetylglucosamine transferase and O-GlcNAcase, respectively. This review provides a current overview of our knowledge of how O-GlcNAcylation impacts the histone code both directly and by regulating other chromatin modifying enzymes. This highlights the pivotal emerging role of O-GlcNAcylation as an essential epigenetic marker.


Estimating Sizes of Key Populations at the National Level: Considerations for Study Design and Analysis.
National estimates of the sizes of key populations, including female sex workers, men who have sex with men, and transgender women are critical to inform national and international responses to the HIV pandemic. However, epidemiologic studies typically provide size estimates for only limited high priority geographic areas. This article illustrates a two-stage approach to obtain a national key population size estimate in the Dominican Republic using available estimates and publicly available contextual information. Available estimates of key population size in priority areas were augmented with targeted additional data collection in other areas. To combine information from data collected at each stage, we used statistical methods for handling missing data, including inverse probability weights, multiple imputation, and augmented inverse probability weights. Using the augmented inverse probability weighting approach, which provides some protection against parametric model misspecification, we estimated that 3.7% (95% CI = 2.9, 4.7) of the total population of women in the Dominican Republic between the ages of 15 and 49 years were engaged in sex work, 1.2% (95% CI = 1.1, 1.3) of men aged 15-49 had sex with other men, and 0.19% (95% CI = 0.17, 0.21) of people assigned the male sex at birth were transgender. Viewing the size estimation of key populations as a missing data problem provides a framework for articulating and evaluating the assumptions necessary to obtain a national size estimate. In addition, this paradigm allows use of methods for missing data familiar to epidemiologists.


Developmental intervention for low birth weight infants: improved early development outcome.
This prospective longitudinal study was designed to evaluate the effects of a multidisciplinary infant development program (IDP) on the mental and physical development of low birth weight infants (less than 1,800 g). Infants in the neonatal intensive care were randomly assigned to the IDP or to traditional care (control group). IDP infants received developmental interventions in the hospital and at home through the first 2 years of life. Counseling and parenting education were provided to their parents during this same period. The control group received all the postnatal care and referrals customarily given in traditional care. Both IDP and control infants were enrolled in an independent follow-up program, which used the Bayley Scales of Infant Development in a blind evaluation design. The IDP group had a significantly lower incidence of developmental delay (P less than .05) and scored significantly higher than the control group (P less than .05) on mean mental and physical indices at 12 and 24 months of adjusted age.


Medical Marijuana Use for Cancer-Related Symptoms among Floridians: A Descriptive Study.
Background: Thirty-six states, including Florida, have legalized marijuana for medical and/or recreational use, yet how it is used and perceived by persons with cancer is not well understood. Objectives: The purpose of this study was to identify patterns of use, perceived benefits, and side effects of medical marijuana (MMJ) among cancer patients in Florida. Methods: For this descriptive, cross-sectional study, anyone residing within the state of Florida who was diagnosed or treated for a malignancy within the last five years and had used MMJ was eligible. An online survey containing questions about dosing, side effects, perceived benefits, and barriers to use was used. Descriptive statistics including frequencies, percentages, means, and standard deviations were used to analyze quantitative data. Responses to open-ended questions were coded and categorized. Results: Sleep (n = 112), pain (n = 96), and anxiety (n = 82) were the most common symptoms participants used MMJ to relieve and overall felt it was highly effective. MMJ was well tolerated with a minority (10.3%) reporting any adverse effects. Cost was the most frequent barrier reported by participants (42.8%). A variety of legal, bureaucratic, and system-related barriers were described. Conclusion: Participants perceived MMJ to be helpful in alleviating cancer symptoms. They held negative perceptions of the way MMJ is implemented and integrated into their oncology treatment plan. Enhanced communication and patient/provider education on MMJ are needed to inform patient decision making.


Mutational analysis of essential interactions involved in the assembly of hepatitis E virus capsid.
The hepatitis E virus (HEV) capsid consists of a single structural protein, a portion of which is engaged in isosahedral contact to form a basal shell, and another portion in dimeric contact to form the homodimers protruding from the shell. Previous studies revealed that homodimers of the truncated HEV capsid proteins, E2 (amino acids 394-606) and p239 (amino acids 368-606), model dominant antigenic determinants of HEV. Immunization with these proteins protected rhesus monkeys against the virus, and three monoclonal antibodies against the homodimers could neutralize HEV infectivity and/or immune-capture of the virus. Furthermore, homodimers of p239 further interact to form particles of 23 nm diameter, rendering it an efficacious candidate vaccine. In light of this we postulate that the interactions involved in the formation of the homodimers and particles might be similar to those involved in assembly of the virus capsid. Presently, mutational analysis was carried out to identify these sites of interactions. The site of dimeric interactions was located to a cluster of six hydrophobic amino acids residues, Ala597, Val598, Ala599, Leu601, and Ala602; furthermore, the site involved in particle formation was located at amino acids 368-394. The possibility that these sites are also involved in assembly of the virus capsid is supported by the fact that they are located at two major and highly conserved hydrophobic regions of the HEV structural protein.


The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease.
The heterogeneity of Alzheimer disease requires the development of multitarget drugs for treating the symptoms of the disease and its progression. Both cholinergic and monoamine oxidase dysfunctions are involved in the pathological process. Thus, we hypothesized that the development of therapies focused on these targets might be effective. We have developed and assessed a new product, coded ASS234, a multipotent acetyl and butyrylcholinesterase/monoamine oxidase A-B inhibitor with a potent inhibitory effect on amyloid-β aggregation as well as antioxidant and antiapoptotic properties. But there is a need to reliably correlate in vitro and in vivo drug release data. We examined the effect of ASS234 on cognition in healthy adult C57BL/6J mice in a model of scopolamine-induced cognitive impairment that often accompanies normal and pathological aging. Also, in a characterized transgenic APPswe/PS1ΔE9 mouse model of Alzheimer disease, we examined the effects of short-term ASS234 treatment on plaque deposition and gliosis using immunohistochemistry. Toxicology of ASS234 was assessed using a quantitative high-throughput in vitro cytotoxicity screening assay following the MTT assay method in HepG2 liver cells. In vivo, ASS234 significantly decreased scopolamine-induced learning deficits in C57BL/6J mice. Also, reduction of amyloid plaque burden and gliosis in the cortex and hippocampus was assessed. In vitro, ASS234 exhibited lesser toxicity than donepezil and tacrine. The study was conducted in male mice only. Although the Alzheimer disease model does not recapitulate all features of the human disease, it exhibits progressive monoaminergic neurodegeneration. ASS234 is a promising alternative drug of choice to treat the cognitive decline and neurodegeneration underlying Alzheimer disease.


The meaning of guilt and shame: a qualitative study of mothers who suffer from eating difficulties.
The aim of this study was to illuminate and interpret guilt and shame expressed by mothers with eating difficulties (ED). The research question was: What is the meaning of guilt and shame experienced by mothers with ED? Experiences of guilt and shame in mothers with ED may be strong, yet concealed, and should be addressed when promoting women's mental health. The study design was explorative, and in-depth interviews were conducted with eight mothers suffering from ED. The data were analysed by means of qualitative content analysis and interpreted according to a hermeneutic approach. The main theme 'Struggling in silence with guilt and shame as a mother living with ED and trying to keep it secret' was interpreted on two levels: emotional, 'Feeling worried about failure and wanting to be successful', and cognitive, 'Having condemning thoughts about one's own sense of responsibility'. In addition, each theme contained two subthemes. Feelings and awareness of guilt and shame are strong; they vary between individuals and are intensified in mothers who suffer from ED. It is important for mental health nurses to help mothers with ED articulate such feelings in order to promote health.


Clinical utility of preoperative evaluation of bronchial arteries by three-dimensional computed tomographic angiography for esophageal cancer surgery.
An identification of bronchial arteries (BAs) is critical in esophageal cancer surgery to avoid tracheobronchial ischemia and unexpected massive bleeding during surgical procedure particularly in thoracoscopic video-assisted esophagectomy. We describe the efficacy of three-dimensional computed tomographic angiography (3D-CTA) of BAs for preoperative evaluation in esophageal cancer surgery. Sixty-four patients with esophageal cancer who preoperatively underwent multidetector computed tomography examination were included in this study. We evaluated the number, origin, and intraoperative preservation rate of BAs, and we compared the number of thoracic paratracheal lymph nodes harvested between two groups comprising patients who either underwent preoperative 3D-CTA of BAs (3D-CTA group) or did not (non-3D-CTA group). The right and left BAs were preoperatively identified in 62 patients (97%) and 55 patients (86%), respectively, using 3D-CTA. In 34 patients (53%), the right BA originated as a common trunk with the right intercostal artery. In 48 patients (75%), the left BA originated from the descending aorta as a single or double branch. Some anomalies such as the right BA originated from the left subclavian artery were observed. In all patients, either the right or the left BA was preserved. The number of harvested lymph nodes in left side of paratrachea was significantly increased in 3D-CTA group, than those in non-3D-CTA group. 3D-CTA clearly revealed BA anatomy, contributing to BA preservation and safe and precise lymphadenectomy in esophageal cancer surgery. 3D-CTA of BAs is useful for preoperative evaluation in esophageal cancer surgery.


Basaloid squamous cell carcinoma of the sinonasal tract with metastasis to the liver: a case report and literature review.
Basaloid squamous cell carcinoma (BSCC) is a rare subtype of squamous cell carcinoma. To date, only 95 cases of sinonasal BSCC have been reported in the English-language literature, and they account for 5% of all cases of head and neck BSCC. We describe what we believe is only the second reported case of a sinonasal tract BSCC that metastasized to the liver. The patient was a 36-year-old woman who presented with right-sided nasal obstruction and a foul-smelling discharge. Clinical examination and imaging identified a large, lobulated, enhancing mass in the right nasal cavity. Following excision of the mass, the patient was scheduled for radiotherapy. However, before it could be administered, follow-up imaging detected a metastasis to the liver and lung, and the patient was switched to chemotherapy. Initially, she responded well clinically, but at 5 months postoperatively, a follow-up CT showed an increasing metastatic presence in the liver and bone. The patient died of her disease 1 year after surgery.


Quality measures and credentialing in gastrointestinal endoscopy.
Quality assessment and improvement are now mainstream activities in medicine. This review presents recent publications pertaining to quality, proposed quality measures, and associated topics in credentialing and delivery of endoscopic services. The literature continues to focus primarily on colonoscopy services. Surveillance colonoscopy continues to suffer from underuse in high-risk patients and overuse in average to moderate-risk patients, based upon current guidelines for application. Several series update and add to our understanding of adenoma detection rates as measures of quality. One study confirmed an inverse association between adenoma detection rates at screening endoscopy and the risk for identification of colorectal cancer at a subsequent diagnostic or surveillance procedure. Credentialing guidelines proposed for worldwide application are becoming uniform and similar to those from several national societies. Quality measures for use in endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography are just beginning to be assessed in large series. Proposed quality measures for colonoscopy are maturing, with increasing emphasis on adenoma detection rates rather than indirect proxies for neoplasia detection. Personal and unit-based benchmarking appears to be gaining favor and is facilitated by use of automated reporting systems. Greater attention is being focused on individual performance and assuring competence of the endoscopy workforce.