Robotic-Assisted Live Donor Ileal Segmentectomy for Intestinal Transplantation.
Every effort should be made to optimize surgical techniques and to minimize potential morbidity rates associated with live donor operations. Advances in a minimally invasive approach by robotic surgery to donor nephrectomy have raised the possibility of applying this technique to live donor bowel resections for intestinal transplantation. We report the first 5 consecutive cases of a robotic-assisted live donor ileal segmentectomy. We describe the technical aspects of the procedure, discuss the rationale for considering this option, and evaluate potential advantages of this approach. We found that this new approach is associated with less postoperative discomfort, a shorter hospital length of stay, and a faster recovery of bowel function compared to our previous open surgery. Our initial experience suggests that robotic surgery is a safe and feasible procedure for live donor ileal resection for intestinal transplantation and is a useful alternative to conventional open surgery.


Benign hepatocellular tumors: a regional survey.
A survey of benign hepatocellular tumors in a metropolitan area included six cases of hepatocellular adenoma, eight of focal nodular hyperplasia, and two of nodular transformation. Two thirds of the adenomas occurred in women using oral contraceptives; two had life-threatening complications. The focal nodular hyperplasias were generally asymptomatic tumors occurring in patients over a wide age range and apparently not related to oral contraceptive use. The two cases of nodular transformation were incidental findings in patients having abdominal surgery. One of them had used oral contraceptives.


miR-195-5p as Regulator of γ-Catenin and Desmosome Junctions in Colorectal Cancer.
Desmosomes play a key role in the regulation of cell adhesion and signaling. Dysregulation of the desmosome complex is associated with the loss of epithelial cell polarity and disorganized tissue architecture typical of colorectal cancer (CRC). The aim of this study was to investigate and characterize the effect of miR-195-5p on desmosomal junction regulation in CRC. In detail, we proposed to investigate the deregulation of miR-195-5p and JUP, a gene target that encodes a desmosome component in CRC patients. JUP closely interacts with desmosomal cadherins, and downstream, it regulates several intracellular transduction factors. We restored the miR-195-5p levels by transient transfection in colonic epithelial cells to examine the effects of miR-195-5p on JUP mRNA and protein expression. The JUP regulation by miR-195-5p, in turn, determined a modulation of desmosome cadherins (Desmoglein 2 and Desmocollin 2). Furthermore, we focused on whether the miR-195-5p gain of function was also able to modulate the expression of key components of Wnt signaling, such as NLK, LEF1 and Cyclin D1. In conclusion, we have identified a novel mechanism controlled by miR-195-5p in the regulation of adhesive junctions, suggesting its potential clinical relevance for future miRNA-based therapy in CRC.


Glycemic control and cardiovascular events in diabetic hemodialysis patients.
Patients on maintenance dialysis treatment experience an excess mortality, predominantly of sudden cardiac death. Poor glycemic control is associated with cardiovascular comorbidities in the general population. This study investigated the impact of glycemic control on cardiac and vascular outcomes in diabetic hemodialysis patients. Glycohemoglobin A1c (HbA(1c)) was measured in 1255 hemodialysis patients with type 2 diabetes mellitus who participated in the German Diabetes and Dialysis Study (4D Study) and were followed up for a median of 4 years. Using Cox regression analyses, we determined hazard ratios to reach prespecified, adjudicated end points according to HbA(1c) levels at baseline: sudden cardiac death (n=160), myocardial infarction (n=200), stroke (n=103), cardiovascular events (n=469), death caused by heart failure (n=41), and all-cause mortality (n=617). Patients had a mean age of 66+/-8 years (54% male) and mean HbA(1c) of 6.7+/-1.3%. Patients with an HbA(1c) >8% had a >2-fold higher risk of sudden death compared with those with an HbA(1c) < or =6% (hazard ratio, 2.14; 95% confidence interval, 1.33 to 3.44), persisting in multivariate models. With each 1% increase in HbA(1c), the risk of sudden death rose significantly by 18%; similarly, cardiovascular events and mortality increased by 8%. There was a trend for higher risks of stroke and deaths resulting from heart failure, whereas myocardial infarction was not affected. The increased risks of both cardiovascular events and mortality were explained mainly by the impact of HbA(1c) on sudden death. Poor glycemic control was strongly associated with sudden cardiac death in diabetic hemodialysis patients, which accounted for increased cardiovascular events and mortality. In contrast, myocardial infarction was not affected. Whether interventions achieving tight glycemic control decrease sudden death requires further evaluation. Clinical Trial Registration- URL: http://www.clinicalstudyresults.org. Unique identifier: CT-981-423-239.


Aberrant expression of tenascin-c and neuronatin in malignant peripheral nerve sheath tumors.
Development of neurofibroma (NF) and its malignant counterpart, malignant peripheral nerve sheath tumor (MPNST), is a hallmark of type I neurofibromatosis (NF1). Newly identified glycoprotein neuronatin (Nnat) is predominantly expressed in the fetal central and peripheral nervous systems and is gradually diminished according to the neural maturation. However, its expression in NFs and MPNSTs is unknown. Since an overexpression of tenascin-C (Tn-C), an extracellular matrix component, has been observed in neural malignancies, we investigated the immunohistological expressions of Nnat and Tn-C in NFs and MPNSTs, and compared their expression with that of the proliferation marker Ki-67 to possibly distinguish MPNSTs from ordinal NFs. Standard immunohistological procedure was performed for Nnat, Tn-C and Ki-67 in 9 sporadic NFs, 15 diffuse NFs (NF1), 15 plexiform NFs (NF1) and 6 MPNSTs (NF1), as well as 5 normal skins. All of the MPNSTs showed positive staining for Nnat, Tn-C and Ki-67, in sharp contrast to completely negative staining in all sporadic or NF-1-derived NFs. The aberrant expression of Nnat and Tn-C was a useful marker for distinguishing MPNSTs from benign NFs.


Effect of two Howard Hughes Medical Institute research training programs for medical students on the likelihood of pursuing research careers.
To assess the effect of Howard Hughes Medical Institute's (HHMI) two one-year research training programs for medical students on the awardees' research careers. Awardees of the HHMI Cloister Program who graduated between 1987 and 1995 and awardees of the HHMI Medical Fellows Program who graduated between 1991 and 1995 were compared with unsuccessful applicants to the programs and MD-PhD students who graduated during the same periods. Logistic regression analyses were conducted to assess research career outcomes while controlling for academic and demographic variables that could affect selection to the programs. Participation in both HHMI programs increased the likelihood of receiving National Institutes of Health postdoctoral support. Participation in the Cloister Program also increased the likelihood of receiving a faculty appointment with research responsibility at a medical school. In addition, awardees of the Medical Fellows Program were not significantly less likely than Medical Scientist Training Program (MSTP) and non-MSTP MD-PhD program participants to receive a National Institutes of Health postdoctoral award, and awardees of the Cloister Program were not significantly less likely than non-MSTP MD-PhD students to receive a faculty appointment with research responsibility. Women and underrepresented minority students were proportionally represented among awardees of the two HHMI programs whereas they were relatively underrepresented in MD-PhD programs. The one-year intensive research training supported by the HHMI training programs appears to provide an effective imprinting experience on medical students' research careers and to be an attractive strategy for training physician-scientists.


Functional TCR T cell screening using single-cell droplet microfluidics.
Adoptive T cell transfer, in particular TCR T cell therapy, holds great promise for cancer immunotherapy with encouraging clinical results. However, finding the right TCR T cell clone is a tedious, time-consuming, and costly process. Thus, there is a critical need for single cell technologies to conduct fast and multiplexed functional analyses followed by recovery of the clone of interest. Here, we use droplet microfluidics for functional screening and real-time monitoring of single TCR T cell activation upon recognition of target tumor cells. Notably, our platform includes a tracking system for each clone as well as a sorting procedure with 100% specificity validated by downstream single cell reverse-transcription PCR and sequencing of TCR chains. Our TCR screening prototype will facilitate immunotherapeutic screening and development of T cell therapies.


Skeletal muscle functional and structural adaptations after eccentric overload flywheel resistance training: a systematic review and meta-analysis.
The purpose of this meta-analysis was to examine the effect of flywheel (FW) resistance training with Eccentric Overload (FW-EOT) on muscle size and functional capacities (i.e. strength and power) in athletes and healthy subjects, and to compare FW-induced adaptations with those triggered by traditional resistance exercise interventions. A systematic review and meta-analysis of randomised controlled trials. A search of electronic databases [PubMed, MEDLINE (SportDiscus), Web of Science, Scopus and PEDro] was conducted to identify all publications employing FW-EOT up to April 30, 2016. Outcomes were analyzed as continuous outcomes using a random effects model to calculate a standardized mean difference (SMD) and 95% CI. A total of 9 studies with 276 subjects and 92 effect sizes met the inclusion criteria and were included in the statistical analyses. The overall pooled estimate from the main effects analysis was 0.63 (95% CI 0.49-0.76) with a significant (p<0.001) Z overall effect of 9.17. No significant heterogeneity (p value=0.78) was found. The meta-analysis showed significant differences between FW-EOT vs. conventional resistance training in concentric and eccentric strength, muscle power, muscle hypertrophy, vertical jump height and running speed, favoring FW-EOT. This meta-analysis provides evidence supporting the superiority of FW-EOT, compared with traditional weight-stack exercise, to promote skeletal muscle adaptations in terms of strength, power and size in healthy subjects and athletes.


Dysregulation of the leukocyte signaling landscape during acute COVID-19.
The global COVID-19 pandemic has claimed the lives of more than 750,000 US citizens. Dysregulation of the immune system underlies the pathogenesis of COVID-19, with inflammation mediated tissue injury to the lung in the setting of suppressed systemic immune function. To define the molecular mechanisms of immune dysfunction in COVID-19 we utilized a systems immunology approach centered on the circulating leukocyte phosphoproteome measured by mass cytometry. We find that although COVID-19 is associated with wholesale activation of a broad set of signaling pathways across myeloid and lymphoid cell populations, STAT3 phosphorylation predominated in both monocytes and T cells. STAT3 phosphorylation was tightly correlated with circulating IL-6 levels and high levels of phospho-STAT3 was associated with decreased markers of myeloid cell maturation/activation and decreased ex-vivo T cell IFN-γ production, demonstrating that during COVID-19 dysregulated cellular activation is associated with suppression of immune effector cell function. Collectively, these data reconcile the systemic inflammatory response and functional immunosuppression induced by COVID-19 and suggest STAT3 signaling may be the central pathophysiologic mechanism driving immune dysfunction in COVID-19.


Desensitization of GSTF8 induction by a prior chemical treatment is long lasting and operates in a tissue-dependent manner.
The Arabidopsis (Arabidopsis thaliana) GSTF8 gene is a member of the glutathione S-transferase (GST) family whose expression is induced by defense signals, certain chemical stresses, and some pathogens. Here, we have used transgenic plants and an in vivo imaging system to demonstrate that GSTF8 expression is subject to a distinct desensitization phenomenon because prior chemical treatment significantly reduces reactivation of the GSTF8 promoter by hydrogen peroxide, auxin, and salicylic acid. A GSTF8 null line had similar desensitization properties to wild type, demonstrating that GSTF8 protein levels are not responsible for desensitization. The resulting refractory period is unusually long lasting, with full recovery taking 4 d. Expression of the GSTF8 promoter following a second treatment occurred predominantly in newly formed tissue at the root tip, suggesting that desensitization is lost upon cell division. Expression of the endogenous GSTF8 gene and another GST gene, GSTF6, is also desensitized following treatment with hydrogen peroxide. The desensitization phenomenon can be activated by a very low concentration of inducer that is not sufficient to activate the GSTF8 promoter. These results demonstrate that activation of the GSTF8 promoter is not essential for eliciting desensitization. A key promoter sequence within the GSTF8 gene, the ocs element, is also affected by desensitization. Treatment with a phosphatase inhibitor prevents desensitization of GSTF8 expression and ocs element activity, suggesting that dephosphorylation of one or more proteins is required for desensitization to occur.


Role of Interventional Radiology in the Management of Venous Trauma.
Traumatic injury to the large, central venous vasculature, although rare, is associated with high morbidity and mortality rates. Conventional open surgical treatment by repair or ligation can be technically challenging in anatomically difficult areas to expose. Furthermore, open surgical approach can release tension on the venous injury and result in uncontrollable bleeding. Endovascular techniques such as stenting and embolization can be used effectively for the treatment of traumatic venous injury. This article will discuss the morbidity and mortality associated with traumatic venous injuries, venous anatomy, endovascular treatment options, and management of traumatic venous injury.


Microphthalmia, retinal dysplasia, and anterior segment dysgenesis in a litter of Doberman Pinschers.
Blindness was found in 5 of 11 7-week-old Doberman Pinscher littermates. Each eye in the affected pups had moderate to marked corneal opacification, and there was variable microphthalmia. Gross and microscopic examination of the globes revealed multiple ocular defects highlighted by anterior segment and lenticular dysgenesis, hyperplastic primary vitreous, and retinal dysplasia. The cause of the ocular malformations was undetermined.


Differential involvement of protein kinase C in human promyelocytic leukemia cell differentiation enhanced by artemisinin.
Artemisinin, a sesquiterpene lactone endoperoxide that exists in several medicinal plants, is a well-known anti-malarial agent. In this report, we investigated the effect of artemisinin on cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system. Artemisinin markedly increased the degree of HL-60 leukemia cell differentiation when simultaneously combined with low doses of 1 alpha,25-dihydoxyvitamin D(3) [1,25-(OH)(2)D(3)] or all-trans retinoic acid (all-trans RA). Artemisinin by itself had very weak effects on the differentiation of HL-60 cells. Cytofluorometric analysis and cell morphologic studies indicated that artemisinin potentiated 1,25-(OH)(2)D(3)-induced cell differentiation predominantly into monocytes and all-trans RA-induced cell differentiation into granulocytes, respectively. Extracellular-regulated kinase (ERK) inhibitors markedly inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH)(2)D(3) or all-trans RA, whereas phosphatidylinositol 3-kinase (PI3-K) inhibitors did not. Particularly, protein kinase C (PKC) inhibitors inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH)(2)D(3) but not with all-trans RA. Artemisinin enhanced PKC activity and protein level of PKC beta I isoform in only 1,25-(OH)(2)D(3)-treated HL-60 cells. Taken together, these results indicate that artemisinin strongly enhanced 1,25-(OH)(2)D(3)- and all-trans RA-induced cell differentiation in which PKC is differentially involved in arteminisin-mediated enhancement of leukemia cell differentiation.


Weight loss practices and eating behaviours among female physique athletes: Acquiring the optimal body composition for competition.
Little is known about weight loss practices and eating behaviours in female physique athletes. This study investigated the weight loss history, practices, and key influences during the pre-competition period in a large cohort of female physique athletes stratified by division and experience level. Eating attitudes and behaviours were assessed to identify whether athletes were at risk of developing an eating disorder. Using a cross-sectional research design, female physique athletes (n = 158) were recruited and completed an anonymous online self-reported survey consisting of two validated questionnaires: Rapid Weight Loss Questionnaire and Eating Attitudes Test-26. Irrespective of division or experience, female physique athletes used a combination of weight loss practices during the pre-competition phase. Gradual dieting (94%), food restriction (64%) and excessive exercise (84%), followed by body water manipulation via water loading (73%) were the most commonly used methods. Overall, 37% of female physique athletes were considered at risk of developing an eating disorder. Additionally, 42% of female physique athletes used two pathogenic weight control methods with 34% of Figure novice athletes indicating binge eating once a week or more. The coach (89%) and another athlete (73%) were identified as key influences on athletes' dieting practices and weight loss. The prevalence of athletes identified with disordered eating symptoms and engaging in pathogenic weight control methods is concerning. In future, female physique athletes should seek advice from registered nutritionists to optimise weight management practices and minimise the risk of developing an eating disorder.


Bacteriological examination of milk and milk products sold in Harare.
A study to assess the bacteriological quality of milk and ice cream was conducted using the direct plate count method and the methylene blue dye reduction test. A total of 105 milk and 95 ice cream samples were obtained form two factories (depots) and distributing supermarkets (outlets) in Harare. Under the methylene blue test, all milk and ice cream samples passed the hour and 2 hour tests respectively. However, 99% of the milk and 69% of the ice cream samples reduced the dye after 5.5 and 4 hrs respectively. The results from the direct plate counts revealed the presence of both pathogens and non-pathogens. The median plate counts in the milk and ice cream were found 400 cfu / ml and 100 cfu / ml respectively. Organisms isolated in both samples and in all outlets were similar, these included Bacillus spp. Coagulase Staphlococcus spp., microcuccus spp., Steptococcus spp., Diphthroids, Fusiform bacterial Klebsiella spp., and Citrobacter spp. No significant differences were found in the plate counts of the samples obtained from the depots and outlets for the milk (P = 0.542, df = 1)) and ice cream samples (P = 0.377, df = 1). Results further revealed that there was no significant difference in isolates obtained form strawberry ice cream (0.0096). The study has therefore, revealed that milk and milk product sold in various outlets in Harare contained a variety of bacteria of public health importance and also that the methylene blue dye reduction test is not reliable for the detection of bacterial contaminants in dairy products. It is thus suggested that the use of methylene blue dyes be adapted in combination with other tests such as the plate count in assessing bacterial contaminants in milk products.


Are male and female smokers at equal risk of smoking-related cancer: evidence from a Swedish prospective study.
This study examines sex differences in the relative risks of lung cancer and other smoking-related cancers (i.e. cancers of the upper respiratory tract, oesophagus, pancreas, bladder, and renal pelvis). Data on smoking habits in 1963 from a random sample of 56,000 men and women were linked with information on new cases of cancer for 1964-89. Compared with people who have never smoked, the relative risks of lung cancer at different levels of pack-years completed in 1963 (>5, 6-15, 16-25 and 25 + pack-years) were 1.6, 4.4, 14.2, and 17.9 for men, and 2.1, 6.3, 10.3, and 16.5 for women. The corresponding relative risks of other smoking-related cancers were 1.8, 3.0 5.4, and 6.4 for men, and 2.0, 3.1, 5.0, and 6.5 for women. These results suggest that men and women have similar relative risks of smoking-related cancers at different levels of smoking.


[Effect of temperature and binding with copper ions on the motility of spin-labeled oxy- and methemoglobin subunits].
Using the method for separate determination of correlation times of spin-labeled proteins (tau M) and labels (tau R) it has been shown that at temperatures below and about 25 degrees the mobility of oxy Hb subunits is higher than that of met Hb. From 30 degrees on oxy and met Hb show identical flexibility (tau M = 40 ns) in 0.01 M phosphate buffer (pH 7.3) containing 0.15 M NaCl. With a decline in pH from 7.3 to 6.4 the intramolecular mobility of met Hb subunits decreases. In the absence of 0.15 M NaCl at pH 7.3 (5 degrees C) met Hb becomes more flexible (tau M drops from 25 to 16 ns). Complex formation of beta-chains of oxy Hb with one Cu+2 ion at 20 degrees has a negligible bearing on the flexibility of the protein, whereas addition of second ion considerably enhances interaction between the subunits of the tetramer and decreases its flexibility (tau M rises from 17 to 30 ns).


Motor planning in bimanual object manipulation: two plans for two hands?
We examined anticipatory motor planning and the interaction among both hands in a discrete bimanual task. To this end, participants had to grasp and manipulate two cylindrical objects simultaneously under varying conditions in which (a) the grip selection requirements, i.e., orientation of the to-be-grasped objects, differed between the two hands and (b) the type of grip for one hand was preinstructed, while the grip for the other hand was free choice. Results showed that participants, when grasping for two bars with a free grip choice, prioritized planning for comfortable end postures over symmetry of movement execution. Furthermore, when participants were free to choose a grip for their left hand, but were instructed on how to grasp an object with their right hand, we found no interaction between the grip selections of both hands, suggesting that motor planning proceeds independently for both hands.


Cholinergic mechanisms in affective disorders. Future directions for investigation.
Advances in clinical and basic research methodology combined with clearly articulated concepts create new opportunities for researching the roles of cholinergic mechanisms in the pathophysiology of affective disorders. Areas for study include: roles of cholinergic mechanisms in mediating effects of stress and cholinergic mechanisms linking the pathophysiologies of affective and panic disorders, use of pharmacologic agents to produce cholinergic system supersensitivity in modeling biologic aspects of affective illness, use of multigenerational intrapedigree studies of cholinergic markers associated with affective disease, research into the neurobiology of lithium and ECT as they pertain to muscarinic cholinergic mechanisms, study of the interrelationship of sodium, calcium and lithium ion metabolism and their relationship to cholinergic-monoaminergic interaction, the development of brain imaging strategies and techniques, e.g., positron emission tomography (PET), to measure changes in cholinergic receptor density and affinity as a function of clinical state, identification and validation of a peripheral model of the central muscarinic receptor, study of the pharmacology of abusable substances and its relationship to mechanisms regulating mood, affect, psychomotor function and other variables related to the affective disorders, and development of in vitro and in vivo models useful in studying the physiology and biochemistry of the interaction of cholinergic and monoaminergic neurons. These models may allow us to bridge the traditional cholinergic and monoamine hypotheses of affective disorders.


Effect of protective filters on fire fighter respiratory health during simulated bushfire smoke exposure.
Bushfire fighters are potentially subject to risks from bushfire smoke. Although many different protective masks and filters are available, it is not clear which is the most effective from a health and safety perspective. The effect of protective filters on the respiratory health of Western Australian urban career fire fighters under controlled simulated conditions is investigated. Sixty-four healthy Fire and Emergency Services Authority of Western Australia (FESA) urban career fire fighters were subjected to controlled simulated bushfire smoke in an open smoke chamber for 15 min. The fire fighters were allocated one of the three types of protective filters: particulate only (P), particulate/organic vapor (POV), and a particulate/organic vapor/formaldehyde (POVF) filter using a double-blind randomized procedure. Personal air sampling inside the fire fighters' masks, spirometry, oximetry, and self-reported symptom data were collected at baseline and at two time intervals after the smoke exposure. A significant decline in oxygen saturation was seen immediately after exposure, however, the decline was small and no significant relationships could be established between this and the type of filter used. A significantly higher number of participants in the P and POV filter groups self-reported an increase in coughing, wheezing, and shortness of breath compared to the POVF group. Air sampling demonstrated a significantly higher level of formaldehyde and acrolein inside the masks fitted with P filters compared to POV and POVF filters. Testing the effectiveness of P, POV, and POVF filters under controlled conditions has demonstrated that the POVF filter provides statistically significant better protection for the fire fighters' airways in a simulated bushfire exposure chamber.


Amphetamine withdrawal: a behavioral evaluation.
The effects of withdrawal from long-term amphetamine treatment of intracranial self-stimulation, forced swim-induced immobility, shuttle escape performance, acoustic startle and locomotor activity were evaluated. Mice implanted with stimulating electrodes in the lateral hypothalamus demonstrated stable and reliable rates of self-stimulation responding. After exposure to a chronic schedule of amphetamine treatment response rates were severely depressed. In addition to modifying intracranial self-stimulation responding, amphetamine withdrawal increased the duration of immobility in a forced-swim situation. Although chronic amphetamine exposure induced pronounced behavioral changes in the intracranial self-stimulation and forced swim tasks, drug withdrawal had little effect on shuttle escape performance, acoustic startle and locomotor activity. Based on these findings it was suggested that the development of post-amphetamine depression in the self-stimulation and forced swim paradigms was not related to variations in motoric or arousal mechanisms resulting from amphetamine withdrawal, but rather involved drug-induced changes in motivational processes.


A compact from of methylated DNA is solutions containing poly (ethylene glycol).
Some peculiarities of compactization of double-stranded DNA molecules containing methylated nitrogen bases have been studied in water-salt solutions of PEG. It is shown that the methylation of N7-atoms of guanyl residues in original DNA molecules does not prevent the formation of DNA compact particles, but results in a decrease of the amplitude of the negative band in the CD spectrum of compact particles. The influence of N7-guanine methylation on the shape of the CD spectrum being the greater, the lower is the concentration of PEG. The dependence of the negative band amplitude in the CD spectrum on the content of methylated guanyl residues is practically the same for low-molecular weight DNA's from different sources. The observed decrease in the negative band amplitude is interpreted as a result of alterration of guanyl residue orientation relative to the helix axis which leads to diminished optical activity of the "microcrystalline" domains of compact particles. The evidence obtained suggests that changes in the secondary structure of DNA lead to considerable difference between CD spectra of compact particles of methlated DNA and psi-form of DNA. (The changes in the CD spectrum of the DNA compact particles occur also as a result of methylation of C5-atoms of cytosine residues). It is suggested that the negative band in the CD spectrum can be used a criterion for detection of negligible alterations in the DNA secondary structure.


Pregnane X receptor (PXR) at the crossroads of human metabolism and disease.
Pregnane X Receptor (PXR), a member of the nuclear receptor (NR) superfamily, is expressed in liver and intestine, as also in other tissues and cells. PXR is activated by a wide variety of endobiotics, dietary compounds and pharmaceuticals. This nuclear receptor serves as a master transcriptional regulator of CYP3A isozymes, and also regulates a large number of enzymes and transporters involved in the pharmacokinetics of both endobiotics and xenobiotics. PXR has an impact on energy homeostasis through glucose and lipid metabolism regulation. PXR activation is also hepatoprotective against toxic bile acids. New roles for PXR have been identified in bone homeostasis, inflammatory bowel disease, liver steatosis and fibrogenesis. PXR directly regulates the expression of multidrug resistance protein 1 (MDR1) and other important proteins involved in drug metabolism. Drug-drug interactions can affect patients with cardiovascular disease, tuberculosis, HIV and cancer. Especially cancer patients are at high risk of such interactions, as treated with multi-drug combinations. PXR activation can affect the efficacy of chemotherapeutics, thus targeting PXR may represent a novel strategy for the improvement of the pharmacokinetics of chemotherapeutic agents, thereby providing safer and more effective therapies for cancer patients.


The Effects of COVID-19 Lockdown on Health and Psychosocial Functioning in Older Adults Aged 70 and Over.
The COVID-19 pandemic led to a state-imposed lockdown in the UK; there are many psychosocial consequences of pandemics, with older adults potentially at an increased risk. The current study assessed psychosocial functioning in a sample of older adults in the UK with baseline data collected pre-lockdown and follow-up 12 weeks later during lockdown. Thus, allowing investigation of the effect of COVID-19 and associated lockdown on psychosocial well-being. Thirty-five older adults (Mean age = 76.06, sex = 12 males) participated in this repeated measures study. A final follow-up was then conducted post-lockdown to capture any factors that were viewed as helpful to well-being during lockdown. From pre- to during lockdown, perceived stress, well-being, depressive symptoms, mood disturbance and memory were all significantly worsened. There were significant improvements in self-reported physical health symptoms, social interaction, time spent engaging in physical activity and certain aspects of relationship quality. Follow-up showed that well-being, depression and mood were still negatively affected post-lockdown. Given the sample were all 'healthy' at baseline in comparison to established norms, there may be greater impairment in more vulnerable populations. Support for older populations is needed to mitigate the negative effects shown, particularly in light of the endurance of some of these effects post-lockdown.


Strong associations of telomere length and mitochondrial copy number with suicidality and abuse history in adolescent depressed individuals.
Major depressive disorder (MDD) is highly prevalent in adolescents and is a major risk factor for suicidality. Recent evidence shows that accelerated cellular senescence/aging is associated with psychiatric illness, including depression, in adults. The present study examined if the relationships of telomere length (TL) and mitochondrial DNA copy number (mtDNAcn), two critical indicators of cellular senescence/aging, are altered in depressed adolescents and whether these alterations are associated with suicidality, early-life adversities, and other co-occuring factors. In genomic DNA isolated from 53 adolescents (ages 16-19, 19 MDD with suicide attempt/suicidal ideation [MDD + SI/SA], 14 MDD without SA/SI [MDD-SI/SA], and 20 healthy controls [HC]), TL and mtDNAcn were measured as the ratio between the number of telomere repeats and that of a single-copy nuclear-hemoglobin [HBG] gene or the amount of mtDNA (NADH dehydrogenase, subunit 1) relative to HBG. Our data show that TL was significantly lower, and mtDNAcn was significantly higher in the total MDD group than HC. TL was significantly lower and mtDNAcn was significantly higher in the MDD + SA/SI group than in the HC, whereas there were no differences in the MDD-SI/SA group. TL was positively correlated with mtDNAcn in both HC and MDD-SA/SI groups; however, TL was negatively correlated with mtDNAcn in MDD + SA/SI. Furthermore, TL was negatively correlated with the severity of both depression and anxiety, while mtDNAcn was positively correlated with the severity of prior emotional abuse. Our study indicates that cellular senescence is more advanced in depressed adolescents with suicidal ideation and that childhood emotional abuse may participate in such a process.


Accessing community health services: challenges faced by poor people with disabilities in a rural community in South Africa.
Poor people with disabilities who live in poor rural societies experience unique problems in accessing health services. Their situation is influenced by multiple factors which unfold and interplay throughout the person's life course. The difficulties do not only affect the person with a disability and his or her family, but also impact on the relevant care unit. The barriers are rooted in a life in poverty, upheld and maintained by poverty-reinforcing social forces of the past and the present, and reinforced by the lack of the person's perspective of the health services. This article explores how difficulties may interact and influence access to and utilisation of health services, and how this may render health services out of reach even when they are available. The study reveals that non-compliance is not necessarily about neglect but could as well be a matter of lived poverty. The study was based on in-depth interviews with people with disabilities and family members, and semi-structured interviews with health personnel. The data analysis is contextual and interpretive. When offering health services to people with disabilities living in resource-poor settings, services should take into consideration the person's history, the needs, and the resources and abilities of the family group. Rethinking access to health services should transcend a narrow medical institutionalisation of health professional's training, and include a patient's perspective and a social vision in understanding and practice. Such rethinking requires health service models that integrate the skills of health professionals with the skills of disabled people and their family members. Such skills lie dormant at community level, and need to be recognised and utilised.


In vivo biosafety model to assess the risk of adverse events from retroviral and lentiviral vectors.
Serious adverse events in some human gene therapy clinical trials have raised safety concerns when retroviral or lentiviral vectors are used for gene transfer. We evaluated the potential for generating replication-competent retrovirus (RCR) and assessed the risk of occurrence of adverse events in an in vivo system. Human hematopoietic stem and progenitor cells (HSCs) and mesenchymal stem cells (MSCs) transduced with two different Moloney murine leukemia virus (MoMuLV)-based vectors were cotransplanted into a total of 481 immune-deficient mice (that are unable to reject cells that become transformed), and the animals were monitored for 18 months. Animals with any signs of illness were immediately killed, autopsied, and subjected to a range of biosafety studies. There was no detectable evidence of insertional mutagenesis leading to human leukemias or solid tumors in the 18 months during which the animals were studied. In 117 serum samples analyzed by vector rescue assay there was no detectable RCR. An additional 149 mice received HSCs transduced with lentiviral vectors, and were followed for 2-6 months. No vector-associated adverse events were observed, and none of the mice had detectable human immunodeficiency virus (HIV) p24 antigen in their sera. Our in vivo system, therefore, helps to provide an assessment of the risks involved when retroviral or lentiviral vectors are considered for use in clinical gene therapy applications.


Batch Blast Extractor: an automated blastx parser application.
BLAST programs are very efficient in finding similarities for sequences. However for large datasets such as ESTs, manual extraction of the information from the batch BLAST output is needed. This can be time consuming, insufficient, and inaccurate. Therefore implementation of a parser application would be extremely useful in extracting information from BLAST outputs. We have developed a java application, Batch Blast Extractor, with a user friendly graphical interface to extract information from BLAST output. The application generates a tab delimited text file that can be easily imported into any statistical package such as Excel or SPSS for further analysis. For each BLAST hit, the program obtains and saves the essential features from the BLAST output file that would allow further analysis. The program was written in Java and therefore is OS independent. It works on both Windows and Linux OS with java 1.4 and higher. It is freely available from: http://mcbc.usm.edu/BatchBlastExtractor/


Potential retroviruses in plants: Tat1 is related to a group of Arabidopsis thaliana Ty3/gypsy retrotransposons that encode envelope-like proteins.
Tat1 was originally identified as an insertion near the Arabidopsis thaliana SAM1 gene. We provide evidence that Tat1 is a retrotransposon and that previously described insertions are solo long terminal repeats (LTRs) left behind after the deletion of coding regions of full-length elements. Three Tat1 insertions were characterized that have retrotransposon features, including a primer binding site complementary to an A. thaliana asparagine tRNA and an open reading frame (ORF) with approximately 44% amino acid sequence similarity to the gag protein of the Zea mays retrotransposon Zeon-1. Tat1 elements have large, polymorphic 3' noncoding regions that may contain transduced DNA sequences; a 477-base insertion in the 3' noncoding region of the Tat1-3 element contains part of a related retrotransposon and sequences similar to the nontranslated leader sequence of AT-P5C1, a gene for pyrroline-5-carboxylate reductase. Analysis of DNA sequences generated by the A. thaliana genome project identified 10 families of Ty3/gypsy retrotransposons, which share up to 51 and 62% amino-acid similarity to the ORFs of Tat1 and the A. thaliana Athila element, respectively. Phylogenetic analyses resolved the plant Ty3/gypsy elements into two lineages, one of which includes homologs of Tat1 and Athila. Four families of A. thaliana elements within the Tat/Athila lineage encode a conserved ORF after integrase at a position occupied by the envelope gene in retroviruses and in some insect Ty3/gypsy retrotransposons. Like retroviral envelope genes, this ORF encodes a transmembrane domain and, in some insertions, a putative secretory signal sequence. This suggests that Tat/Athila retrotransposons may produce enveloped virions and may be infectious.


Psychometric evaluation of the post-discharge surgical recovery scale.
RATIONALE, AIM AND OBJECTIVES: Day surgery patients are discharged after a short period of postoperative surveillance, and reliable and valid instruments for assessment at home are needed. The aim of this study was to evaluate the psychometric properties of a Swedish version of the post-discharge surgical recovery (PSR) scale, an instrument to monitor the patient's recovery after day surgery, in terms of data quality, internal consistency, dimensionality and responsiveness. Data were collected on postoperative days 1 and 14 and included 525 patients. Data quality and internal consistency were evaluated using descriptive statistics, correlation analyses and Cronbach's alpha. The dimensionality of the scale was determined through an exploratory factor analysis. Responsiveness was evaluated using the standardized response mean and the area under the receiver operating characteristics curve (AUC). The correlation between change score in PSR and change score in self-rated health was assessed using Pearson's correlation coefficient. Patients' ability to work and their self-rated health on postoperative day 14 were used as external indicators of change. Six items showed floor or ceiling effects. Cronbach's coefficient alpha was 0.90 and the average inter-item correlation coefficient was 0.44 after the deletion of two items. The items were closely related to each other, and a one-factor solution was decided on. A robust ability to detect changes in recovery (standardized response mean = 1.14) was shown. The AUC for the entire scale was 0.60. When initial PSR scores were categorized into three intervals, the ability to detect improved and non-improved patients varied (AUC 0.58-0.81). There was a strong correlation between change scores in PSR and health (0.63). The Swedish version of the PSR scale demonstrates acceptable psychometric properties of data quality, internal consistency, dimensionality and responsiveness. In addition to previous findings, these results strengthen the PSR scale as a potential instrument of recovery at home.


Genome Typing and Epidemiology of Human Listeriosis in New Zealand, 1999 to 2018.
This study describes the epidemiology of listeriosis in New Zealand between 1999 and 2018 as well as the retrospective whole-genome sequencing (WGS) of 453 Listeria monocytogenes isolates corresponding to 95% of the human cases within this period. The average notified rate of listeriosis was 0.5 cases per 100,000 population, and non-pregnancy-associated cases were more prevalent than pregnancy-associated cases (averages of 19 and 5 cases per annum, respectively). WGS data was assessed using multilocus sequencing typing (MLST), including core-genome and whole-genome MLST (cgMLST and wgMLST, respectively) and single-nucleotide polymorphism (SNP) analysis. Thirty-nine sequence types (STs) were identified, with the most common being ST1 (21.9%), ST4 (13.2%), ST2 (11.3%), ST120 (6.1%), and ST155 (6.4%). A total of 291 different cgMLST types were identified, with the majority (n = 243) of types observed as a single isolate, consistent with the observation that listeriosis is predominately sporadic. Among the 49 cgMLST types containing two or more isolates, 18 cgMLST types were found with 2 to 4 isolates each (50 isolates in total, including three outbreak-associated isolates) that shared low genetic diversity (0 to 2 whole-genome alleles), some of which were dispersed in time or geographical regions. SNP analysis also produced results comparable to those from wgMLST. The low genetic diversity within these clusters suggests a potential common source, but incomplete epidemiological data impaired retrospective epidemiological investigations. Prospective use of WGS analysis together with thorough exposure information from cases could potentially identify future outbreaks more rapidly, including those that may have been undetected for some time over different geographical regions.


In vivo and in vitro cell-based model of lung adenocarcinoma from patients with pleural effusion.
Lung adenocarcinoma (LAC) is a common and aggressive form of lung cancer that is increasing in incidence among never smokers at a younger age. Current treatment of patients with LAC is insufficient and there is a need for identification of effective biomarkers and development of therapeutic targets. These demands require also improved models for in vivo and in vitro experimentation. In this study, we describe the establishment of two LAC cell lines, named LuCa-3 and LuCa-6. Both were derived from pleural effusion (PE) cells of LAC patients (L3 and L6) and readily propagated as tumor xenografts in immunodeficient mice. PE cells from the patient L6 exhibited also the capacity for in vitro growth and were cultured in two forms: (i) as a suspension growing cell population, labeled LuCa-6S, composed of non-clumping single cells; and (ii) as a monolayer-like culture, labeled LuCa-6A, exhibiting tight cell-to-cell and to culture surface adherence. Unique features of these two sublines and their cell clones are the capacity to convert from a non-clumping single-cell suspension into the adherent growth pattern and vice versa. Immunostaining of patients' tumor tissue xenografts and cultured subline cells displayed markers specific for the phenotype of human LAC. LuCa-6S and LuCa-6A cells did not reveal a noticeable disparity in quantitative growth characteristics. However, a number of differences were detected between these two cell populations manifested in detection or intensities of antigen expressions on the cell surface (CD133, SFTPC) and in the nucleus (TTF-1) including pluripotent (OCT-4, SOX-2, NANOG) genes in cancer stem-like cells (CSCs). Dissimilarities between these two sublines were also detected in N-glycan profiles and in the sensitivity to natural killer cells. Salient features of these subline cell populations are responsiveness to selective upregulation of the pluripotent genes in subsets of CSCs via conversion of their growth patterns and/or by using culture stem media with growth factors. The described in vivo/in vitro model enables broader experimental approaches in studies of lung adenocarcinoma.


A pharmacologically immunosuppressed mouse model for assessing influenza B virus pathogenicity and oseltamivir treatment.
Immunocompromised patients are highly susceptible to influenza virus infections. Although neuraminidase inhibitor (NAI) therapy has proved effective in these patients, the treatment regimens require optimization, which can be partly addressed via animal models. Here, we describe a pharmacologically immunosuppressed mouse model for studying the pathogenesis of influenza B viruses and evaluating the efficacy of antiviral treatment. We modeled clinical regimens for dexamethasone and cyclophosphamide to immunosuppress BALB/c mice that were then inoculated with B/Phuket/3073/2013 (Yamagata lineage) or B/Brisbane/60/2008 (BR/08, Victoria lineage) virus. Although both viruses caused morbidity and mortality in immunosuppressed mice, BR/08 was more virulent, consistently inducing greater morbidity and 100% lethality in mice inoculated with at least 103 TCID50/mouse. The replication of both viruses was prolonged in the lungs of immunosuppressed mice, but the extent of pulmonary inflammation in these mice was markedly less than that in immunocompetent animals. Most of the examined cytokines, including IFN-γ, IL-1β, and RANTES, were significantly decreased in the lungs of immunosuppressed mice, as compared to immunocompetent animals, until at least 10 days post-infection. Treatment with the NAI oseltamivir for 8 or 16 days increased the mean survival time and reduced virus spread in the lungs of immunosuppressed mice challenged with a lethal dose of BR/08 but did not completely provide protection or decrease the virus titers. Our data suggests that the synergy of the viral load and aberrant immune responses is a key contributor to the severity of infection, as well as the limited efficacy of oseltamivir, which in immunosuppressed mice curtails virus release without clearing infected cells.


Causes of mortality in neurofibromatosis type 2.
The causes of mortality in neurofibromatosis type 2 (NF2) patients are poorly studied in the literature. Our study aimed to fit this gap by analyzing the main causes of death in this population. This study is the retrospective review of prospectively collected data of 80 patients with NF2 disease followed in Lille University Hospital between 1987 and 2011. Demographical data, diagnosis criteria, and cause of death were recorded. There were 45 men and 35 women, with a mean age at diagnosis of 27.2 years (range: 6-73 years; SD: ± 15.4). Sixty-eight patients met Manchester criteria and the others had an identified mutation in the NF2 gene which confirmed the diagnosis. Of all patients, we noted 7 deaths. The mean age at diagnosis of dead patients was 26 years. The mean age of death was 38.9 years. The causes of death were suicide in 1 patient, hematoma after surgical removal of grade IV vestibular schwannoma in 1 patient, aspiration pneumonia after swallowing disturbances in 3 patients, intracranial hypertension related to growth of multiple meningiomas in 1 patient, and brachial plexus sarcoma grade 3 in the last patient. NF2 is a serious disease that can quickly be life-threatening. The presence of lower cranial nerves schwannomas is a poor prognostic factor, and radiosurgery should be considered for their treatment, as surgical removal often worsens the swallowing disturbances. A psychological support should also be provided.


Magnetic Technique for Sentinel Lymph Node Biopsy in Melanoma: The MELAMAG Trial.
Sentinel lymph node biopsy (SLNB) in melanoma is currently performed using the standard dual technique (radioisotope and blue dye). The magnetic technique is non-radioactive and provides a brown color change in the sentinel lymph node (SLN) through an intradermal injection of a magnetic tracer, and utilizes a handheld magnetometer. The MELAMAG Trial compared the magnetic technique with the standard technique for SLNB in melanoma. Clinically node-negative patients with primary cutaneous melanoma were recruited from four centers. SLNB was undertaken after intradermal administration of both the standard (blue dye and radioisotope) and magnetic tracers. The SLN identification rate per patient, with the two techniques, was compared. A total of 133 patients were recruited, 129 of which were available for final analysis. The sentinel node identification rate was 97.7 % (126/129) with the standard technique and 95.3 % (123/129) with the magnetic technique [2.3 % difference; 95 % upper confidence limit (CL) 6.4; 5.4 % discordance]. With radioisotope alone, the SLN identification rate was 95.3 % (123/129), as with the magnetic technique (0 % difference; 95 % upper CL 4.5; 7.8 % discordance). The lymph node retrieval rate was 1.99 nodes per patient overall, 1.78 with the standard technique and 1.87 with the magnetic technique. The magnetic technique is feasible for SLNB in melanoma with a high SLN identification rate, but is associated with skin staining. When compared with the standard dual technique, it did not reach our predefined non-inferiority margin.


The effect of a creative art program on self-esteem, hope, perceived social support, and self-efficacy in individuals with multiple sclerosis: a pilot study.
Creative art has been found to be beneficial to some patients with chronic illness. Little is understood about how creative art can benefit individuals living with multiple sclerosis (MS). The purpose of the pilot study was to determine if there was a difference in self-esteem, hope, perceived social support, and self-efficacy in individuals with MS after a 4-week creative art program. A one-group, pretest/posttest design was used. The convenience sample of 14 individuals was recruited from MS Centers and the National MS Society. They ranged in age from 29 to 70 years (M = 51.3 years, SD = 12.5 years). Participants included 14 women. The creative art program included week 1-watercolor, week 2-collage making, week 3-beading, and week 4-knitting. Each of the four weekly sessions was facilitated by a registered nurse with expertise in MS and lasted 2 hours. Creative artists instructed participants and provided a hands-on experience for each of the creative projects. Participants were free to share thoughts, experiences, and words of support and encouragement during each session. The variables were measured before starting the creative art program and after the final session. The instruments included the Rosenberg Self-Esteem Scale, the Herth Hope Index, the Modified Social Support Survey, the MS Self-Efficacy Scale, and a sociodemographic questionnaire. The Statistical Package for the Social Sciences Version 16.0 was used to analyze the data. There was a significant increase in all variables after the creative art program as follows: self-esteem (t = -3.05, p = 009), hope (t = -3.96, p = .002), social support (t = -2.21, p = .046), self-efficacy to function with MS (t = -2.68, p = .019), and self-efficacy to control MS (t = 3.22, p = .007). The power analysis revealed a large effect size for hope (d = 1.06), self-esteem (d = 0.82), and self-efficacy (control; d = 0.86). A medium effect size was found for self-efficacy (function; d = 0.72) and social support (d = 0.59). The creative art program was found to be effective and had a positive influence on self-esteem, hope, social support, and self-efficacy to function and control MS. Creative art has the potential to enhance the lives of those living with MS and should be investigated with a larger sample of participants.


Promising Cytomegalovirus-Based Vaccine Vector Induces Robust CD8+ T-Cell Response.
Vaccination has had great success in combating diseases, especially infectious diseases. However, traditional vaccination strategies are ineffective for several life-threatening diseases, including acquired immunodeficiency syndrome (AIDS), tuberculosis, malaria, and cancer. Viral vaccine vectors represent a promising strategy because they can efficiently deliver foreign genes and enhance antigen presentation in vivo. However, several limitations, including pre-existing immunity and packaging capacity, block the application of viral vectors. Cytomegalovirus (CMV) has been demonstrated as a new type of viral vector with additional advantages. CMV could systematically elicit and maintain high frequencies of effector memory T cells through the "memory inflation" mechanism. Studies have shown that CMV can be genetically modified to induce distinct patterns of CD8+ T-cell responses, while some unconventional CD8+ T-cell responses are rarely induced through conventional vaccine strategies. CMV has been used as a vaccine vector to deliver many disease-specific antigens, and the efficacy of these vaccines was tested in different animal models. Promising results demonstrated that the robust and unconventional T-cell responses elicited by the CMV-based vaccine vector are essential to control these diseases. These accumulated data and evidence strongly suggest that a CMV-based vaccine vector represents a promising approach to develop novel prophylactic and therapeutic vaccines against some epidemic pathogens and tumors.


Bordetella pertussis-specific Th1/Th2 cells generated following respiratory infection or immunization with an acellular vaccine: comparison of the T cell cytokine profiles in infants and mice.
In an investigation of cell-mediated immunity against Bordetella pertussis, we found that B. pertussis infection in infants and in mice was associated with the induction of antigen-specific T cells that secrete IFN-g and IL-2, but not IL-4 or IL-5. This cytokine profile is characteristic of Th1 cells that mediate cellular immune responses against a range of intracellular pathogens. An examination of cytokine production following immunization with a three-component acellular vaccine, comprising inactive PT, FHA and pertactin adsorbed to alum, demonstrated that spleen cells from vaccinated mice produced high levels of IL-5, but no detectable IFN-g and low levels of IL-2. In contrast, peripheral blood mononuclear cells from vaccinated infants produced IL-2, IL-5 and IFN-g. These findings highlight significant differences in the immune responses generated by vaccination and natural infection with B. pertussis and demonstrate that the T-cell response induced with an acellular vaccine, although dominated by type 2 cytokines in mice, is more heterogeneous in infants with a Th0 or mixed Th1/Th2 cytokine profile.


Endogenous recoveries and true ileal digestibilities of amino acids in newly weaned pigs fed diets with protease-treated soybean meal.
Endogenous recoveries and true ileal digestibilities of amino acids were determined in pigs fed cornstarch-based diets with untreated or protease-treated soybean meal as protein sources. Twelve pigs, fitted with a modified post valve T-cecum cannula on d 14, 15, and 16 after birth, were weaned on d 20 and assigned to one of four diets according to a two-period balanced change-over design. Diets consisted of soybean meal 1) untreated (SBM), 2) incubated (1:2 wt/vol in distilled water adjusted to pH 4.5, for 16 h at 50 degrees C; CI-SBM), 3) sprayed with protease (1 microL/g of soybean meal; PS-SBM), and 4) incubated, as for CI-SBM, with protease in the water (PI-SBM) at the same application rate as that for PS-SBM. Each period consisted of 5 d of adaptation to diets followed by collection of ileal digesta on d 6 and 7 to determine the apparent ileal amino acid digestibilities of the diets. On d 9, guanidinated meals were fed, followed by a 24-h continuous collection of digesta. Recoveries of chromic oxide and dysprosium from the guanidinated meals were 96.0 +/- .5 and 94.5 +/- 1.1%, respectively. Endogenous amino acid recoveries were similar (P > .05) for SBM, CI-SBM, and PS-SBM but less (P < .05) for PI-SBM. True digestibilities were also less (P < .05) for PI-SBM than for the other meals. Recoveries of endogenous branched-chain and aromatic amino acids were less (P < .05) during Period 2 than during Period 1, suggesting dietary change- and(or) age-dependent adaptive increases in the secretions of pepsin and pancreatic proteases. In conclusion, protease treatment did not improve the true digestibilities of amino acids in soybean meal fed to newly weaned pigs.


Comparison of Histogram-Based Gaussian Analysis With and Without Noise Correction for the Characterization of Indeterminate Adrenal Nodules.
OBJECTIVE. The purpose of this study is to determine whether gaussian-based histogram analysis without and with noise correction can characterize indeterminate adrenal nodules (those with attenuation greater than 10 HU on unenhanced CT) as lipid-poor adenomas. MATERIALS AND METHODS. This retrospective study evaluated adrenal nodules larger than 1 cm on unenhanced CT using gaussian analysis without and with noise correction on intralesional ROIs. Two independent readers who were blinded to the final diagnoses evaluated the nodules. The final diagnosis for each nodule was determined on the basis of pathologic findings or accepted imaging criteria. Interreader agreement was assessed using the intraclass correlation coefficient. Algorithm performance was summarized using sensitivity, specificity, and the AUC. RESULTS. Ninety-four adrenal nodules in 85 patients were analyzed; 36 of these were metastases (34 of which were pathologically confirmed), and 58 were presumed adenomas. Interreader agreement was excellent for nodule size, mean attenuation, SD of attenuation, and the gaussian index. Noise-corrected gaussian analysis had significantly higher specificity (81.9% vs 55.6%; p < 0.001) and lower sensitivity (36.2% vs 56.9%; p < 0.001) for identifying adenomas than did the uncorrected gaussian analysis. The AUC of corrected gaussian analysis was 0.72, which is significantly greater than that of uncorrected gaussian analysis (0.51; p ≤ 0.001) and similar to that of mean attenuation (0.77). CONCLUSION. Noise correction is necessary when using a gaussian analysis characterization of indeterminate adrenal nodules on modern unenhanced CT examinations. This method may be able to discriminate between adenomas and nonadenomas.


Induction of cytokines and adhesion molecules in stable hemodialysis patients: is there an effect of membrane material?
The aim of this study was to examine the effects of a biocompatible and a nonbiocompatible hemodialysis membrane on the secretion of cytokines and their specific antagonists as well as on the expression of adhesion molecules. A crossover study using cuprophane (CU) and polysulfone (PS) dialyzers and measurements of serum tumor necrosis factor (TNF)-alpha, soluble TNF receptors, interleukin (IL)-6, IL-6 receptor, IL-2 receptor, IL-1 receptor antagonist and the adhesion molecules intercellular adhesion molecule 1, endothelial leukocyte adhesion molecule and vascular cell adhesion molecule was performed in 19 hemodialysis patients. 44 healthy volunteers served as controls. All of the measured cytokines and cytokine antagonists as well as all adhesion molecules were significantly elevated in hemodialysis patients compared to controls. There was a significant increase in TNF-alpha during a dialysis session with a CU dialyzer, but only a moderate increase using a PS dialyzer. None of the other cytokines and adhesion molecules were changed during a dialysis session. We were also able to show an upregulation of adhesion molecules in dialysis patients. Our study clearly demonstrates that levels of inflammatory cytokines as well as their antagonists and adhesion molecules are elevated in patients on hemodialysis therapy. Baseline values before the start of a dialysis session did not show any differences with regard to the usage of CU or PS dialysis membranes. However, CU dialyzers led to a significantly greater stimulation of TNF-alpha during the dialysis session in comparison to PS membranes, suggesting a higher degree of bioincompatibility.


Industry Television Ratings for Violence, Sex, and Substance Use.
To examine whether the industry-run television (TV) Parental Guidelines discriminate on violence, sexual behavior, alcohol use, and smoking in TV shows, to assess their usefulness for parents. Seventeen TV shows (323 episodes and 9214 episode minutes) across several TV show rating categories (TVY7, TVPG, TV14, and TVMA) were evaluated. We content-coded the episodes, recording seconds of each risk behavior, and we rated the salience of violence in each one. Multilevel models were used to test for associations between TV rating categories and prevalence of risk behaviors across and within episodes or salience of violence. Every show had at least 1 risk behavior. Violence was pervasive, occurring in 70% of episodes overall and for 2.3 seconds per episode minute. Alcohol was also common (58% of shows, 2.3 seconds per minute), followed by sex (53% of episodes, 0.26 seconds per minute), and smoking (31% of shows, 0.54 seconds per minute). TV Parental Guidelines did not discriminate prevalence estimates of TV episode violence. Although TV-Y7 shows had significantly less substance use, other categories were poor at discriminating substance use, which was as common in TV-14 as TV-MA shows. Sex and gory violence were the only behaviors demonstrating a graded increase in prevalence and salience for older-child rating categories. TV Parental Guidelines ratings were ineffective in discriminating shows for 3 out of 4 behaviors studied. Even in shows rated for children as young as 7 years, violence was prevalent, prominent, and salient. TV ratings were most effective for identification of sexual behavior and gory violence.


Ferromagnetic coupling in hexanuclear gadolinium clusters.
The magnetic susceptibilities of hexanuclear gadolinium clusters in the compounds Gd(Gd6ZI12) (Z = Co, Fe, or Mn) and CsGd(Gd6CoI12)2 are reported and subjected to theoretical analysis with the help of density functional theory (DFT) computations. The single-crystal structure of Gd(Gd6CoI12) is reported here as well. We find that the compound with a closed shell of cluster bonding electrons, Gd(Gd6CoI12), exhibits the effects of antiferromagnetic coupling over the entire range of temperatures measured (4-300 K). Clusters with unpaired, delocalized cluster bonding electrons (CBEs) exhibit enhanced susceptibilities consistent with strong ferromagnetic coupling, except at lower temperatures (less than 30 K) where intercluster antiferromagnetic coupling suppresses the susceptibilities. The presence of two unpaired CBEs, as in [Gd6MnI12]3-, yields stronger coupling than when just one unpaired CBE is present, as in [Gd6FeI12]3- or [Gd6CoI12]2-. DFT calculations on model molecular systems, [Gd6CoI12](OPH3)6 and [Gd6CoI12]2(OPH3)10, indicate that the delocalized cluster bonding electrons are highly effective at mediating intracluster ferromagnetic exchange coupling between the Gd atom 4f7 moments and that intercluster coupling is expected to be antiferromagnetic. The DFT calculations were used to calculate the relative energies of various 4f7 spin patterns and form the basis for construction of a simple spin Hamiltonian describing the coupling within the [Gd6CoI12] cluster.


Characterization of the state of body fluids in anuric hyperglycemic humans.
Based on mathematical analysis, a method computing deviations from normal in body weight, water and sodium, and requiring only presenting body weight and hyperglycemic and euglycemic plasma glucose and sodium concentrations in anuria was developed. Data from 18 hyperglycemic episodes (12 anuric patients) treated with insulin alone were analyzed by this method and were compared to clinical estimates. When normal body water and extracellular volume were assumed to be 0.579 and 0.213 of dry weight, respectively, deviations of presenting weight from dry weight (in kg) were as follows (x = clinical estimate, y = new method estimate): x: -2.5 to +17.2 (+4.6 +/- 5.1, SD); y: -4.1 to +16.7 (+4.2 +/- 5.4, NS); y = -0.4 + 1.0008x, r = 0.96 (p less than 0.01). Similar comparisons were obtained for deviation of body sodium from normal and for euglycemic extracellular volume. Estimates by the two methods agreed when normal body water was assumed to vary between 0.525 and 0.625 of dry weight and when normal extracellular volume was assumed to vary between 0.31 and 0.40 of normal body water.


Psychological adjustment of women to gynecologic cancers.
Successful physical and psychological adjustment for the woman with gynecologic cancer is an involved and often lengthy process. Nurses can provide comprehensive therapeutic interactions that maximize the woman's own adaptive style and strengths. A recognizable pattern of adaptation is exhibited by the woman, providing the nurse with opportunities to assess, plan, and implement a variety of supportive and therapeutic approaches for individuals, families, or groups of patients. The psychological component in the recovery of women with gynecologic cancers plays an essential role in the total rehabilitative process.


The fatty acid amide hydrolase inhibitor PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury.
Traumatic brain injury (TBI) is the leading cause of death in young adults in the United States, but there is still no effective agent for treatment. N-arachidonoylethanolamine (anandamide, AEA) is a major endocannabinoid in the brain. Its increase after brain injury is believed to be protective. However, the compensatory role of AEA is transient due to its rapid hydrolysis by the fatty acid amide hydrolase (FAAH). Thus, inhibition of FAAH can boost the endogenous levels of AEA and prolong its protective effect. Using a TBI mouse model, we found that post-injury chronic treatment with PF3845, a selective and potent FAAH inhibitor, reversed TBI-induced impairments in fine motor movement, hippocampus dependent working memory and anxiety-like behavior. Treatment with PF3845 inactivated FAAH activity and enhanced the AEA levels in the brain. It reduced neurodegeneration in the dentate gyrus, and up-regulated the expression of Bcl-2 and Hsp70/72 in both cortex and hippocampus. PF3845 also suppressed the increased production of amyloid precursor protein, prevented dendritic loss and restored the levels of synaptophysin in the ipsilateral dentate gyrus. Furthermore, PF3845 suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 and enhanced the expression of arginase-1 post-TBI, suggesting a shift of microglia/macrophages from M1 to M2 phenotype. The effects of PF3845 on TBI-induced behavioral deficits and neurodegeneration were mediated by activation of cannabinoid type 1 and 2 receptors and might be attributable to the phosphorylation of ERK1/2 and AKT. These results suggest that selective inhibition of FAAH is likely to be beneficial for TBI treatment.


Attending to the Emotional Well-Being of the Health Care Workforce in a New York City Health System During the COVID-19 Pandemic.
The COVID-19 pandemic has placed an enormous strain on health care workers, and its potential impact has implications for the physical and emotional well-being of the workforce. As hospital systems run well over capacity, facing possible shortages of critical care medical resources and personal protective equipment as well as clinician deaths, the psychological stressors necessitate a strong well-being support model for staff. At the Mount Sinai Health System (MSHS) in New York City, health care workers have been heroically providing frontline care to COVID-19 patients while facing their own appropriate fears for their personal safety in the setting of contagion. This moral obligation cannot be burdened by unacceptable risks; the health system's full support is required to address the needs of its workforce.In this Invited Commentary, the authors describe how an MSHS Employee, Faculty, and Trainee Crisis Support Task Force-created in early March 2020 and composed of behavioral health, human resources, and well-being leaders from across the health system-used a rapid needs assessment model to capture the concerns of the workforce related to the COVID-19 pandemic. The task force identified 3 priority areas central to promoting and maintaining the well-being of the entire MSHS workforce during the pandemic: meeting basic daily needs; enhancing communications for delivery of current, reliable, and reassuring messages; and developing robust psychosocial and mental health support options. Using a work group strategy, the task force operationalized the rollout of support initiatives for each priority area. Attending to the emotional well-being of health care workers has emerged as a central element in the MSHS COVID-19 response, which continues to be committed to the physical and emotional needs of a workforce that courageously faces this crisis.


Risk factors and the prevalence of neurosis and psychosis in ethnic groups in Great Britain.
Our aim was to examine whether variations in the prevalence of neurosis and psychosis between ethnic minorities throughout Great Britain are explained by social disadvantage. A total of 10,108 adult householders throughout Great Britain were assessed in a two-stage survey with the Revised Clinical Interview Schedule (CIS-R) and Psychosis Screening Questionnaire (PSQ). Respondents with a positive PSQ or who received a diagnosis of, or treatment for, psychosis were examined by a psychiatrist using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). Data on respondents' preferred ethnic group were collapsed into four groups: Whites, African-Caribbean or Africans, south Asians and other. Ethnic grouping was strongly associated with: unemployment; lone parent status; lower social class; low perceived social support; poverty (indicated by lack of car ownership) and having a primary social support group of less than three close others. All these associations applied to the group Africans and Afro-Caribbeans, but only some applied to the other groups. No ethnic group had significantly increased rates of neurosis. Only the African-Caribbean group were at significantly increased risk of a psychotic disorder (odds ratio 4.55; 95% CI: 1.13, 18.30). After adjustment for risk factors, the odds of psychosis were lower (odds ratio 2.97; 95% CI: 0.66, 13.36). The excess of psychosis in Africans and Afro-Caribbeans in Great Britain appears to be partly explained by socio-economic disadvantage, but larger studies are needed to confirm this.


A matching-adjusted indirect comparison of the efficacy of elranatamab versus physician's choice of treatment in patients with triple-class exposed/refractory multiple myeloma.
For patients with triple-class exposed/refractory multiple myeloma (TCE/R MM), prognosis is poor and effective treatment options are limited. Elranatamab is a novel B-cell maturation antigen (BCMA)- and CD3-directed bispecific antibody which was approved by the US Food and Drug Administration in August 2023 and demonstrated safety and efficacy in patients with TCE/R MM in the phase 2, single-arm MagnetisMM-3 trial (NCT04649359). To compare the effectiveness of elranatamab vs physician's choice of treatment (PCT) in the absence of head-to-head comparative data, a matching-adjusted indirect comparison (MAIC) was conducted. Individual patient data from MagnetisMM-3 (Cohort A [BCMA-naïve] N = 123, 14.7 months of follow-up) were reweighted to match published summary data from two real-world studies of PCT in patients with TCE/R MM (LocoMMotion and MAMMOTH) using a propensity score-type logistic regression. Unanchored MAIC analyses were conducted according to National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) 18 guidance. Compared with PCT in LocoMMotion, elranatamab was associated with a significantly higher objective response rate (ORR rate difference: 37.52; 95% CI 26.20-48.83; odds ratio: 4.85; 95% CI 2.85-8.23) and complete or stringent complete response rate (≥CR rate difference: 42.29; 95% CI 31.84-52.74; odds ratio: 184.01; 95% CI 24.66-1372.86), longer progression-free survival (PFS HR 0.32; 95% CI 0.20-0.49), and overall survival (OS HR 0.62; 95% CI 0.40-0.94). Compared with PCT in MAMMOTH, elranatamab was associated with significantly higher ORR (rate difference: 28.14; 95% CI 16.77-39.52; odds ratio: 3.24; 95% CI 1.98-5.32) and ≥ CR (rate difference: 26.22; 95% CI 16.40-36.05; odds ratio: 5.48; 95% CI 2.88-10.44), as well as longer PFS (HR 0.25; 95% CI 0.17-0.37) and OS (HR 0.49; 95% CI 0.33-0.71) (Table 2). Sensitivity analysis results were consistent with the base case.[Table: see text]. In the MAIC, elranatamab was consistently associated with improved rates and depth of response and significantly longer PFS and OS versus PCT in LocoMMotion and MAMMOTH.


Treatment, prevention and public health management of impetigo, scabies, crusted scabies and fungal skin infections in endemic populations: a systematic review.
We conducted a systematic review of the treatment, prevention and public health control of skin infections including impetigo, scabies, crusted scabies and tinea in resource-limited settings where skin infections are endemic. The aim is to inform strategies, guidelines and research to improve skin health in populations that are inequitably affected by infections of the skin and the downstream consequences of these. The systematic review is reported according to the PRISMA statement. From 1759 titles identified, 81 full text studies were reviewed and key findings outlined for impetigo, scabies, crusted scabies and tinea. Improvements in primary care and public health management of skin infections will have broad and lasting impacts on overall quality of life including reductions in morbidity and mortality from sepsis, skeletal infections, kidney and heart disease.


Transcranial magnetic stimulation in basic and clinical neuroscience: A comprehensive review of fundamental principles and novel insights.
Non-invasive brain stimulation methods, such as Transcranial Magnetic Stimulation (TMS), are widely used worldwide to make causality-based inferences about brain-behavior interactions. TMS-based clinical applications have been shown promising to treat neurological or psychiatric diseases. TMS works by inducing non-invasively electric currents in localized cortical regions thus modulating their excitability levels and ongoing activity patterns depending on stimulation settings: frequency, number of pulses, train duration and intertrain intervals. Proper use of TMS in the fundamental and clinical neuroscience research requires a deep understanding of its operational principles, risks, potential and limitations. In this article we present the principles through which TMS is thought to operate. Readers will be provided with the bases to be able to understand and critically discuss TMS studies and design hypothesis driven TMS applications for basic and clinical neuroscience. Moreover, some recently identified physiological phenomena which that can dramatically influence the efficacy and magnitude of TMS impact and technological and methodological developments to guide TMS interventions that are becoming mainstream in the field will be also reviewed.


Inhibition of Helicobacter pylori-induced inflammation in human gastric epithelial AGS cells by Phyllanthus urinaria extracts.
Helicobacter pylori is linked to a majority of peptic ulcers and to some types of gastric cancer, and its resistance to antibiotic treatment is now found worldwide. This study is aimed at evaluating the antimicrobial activity of Phyllanthus urinaria Linnea (Euphorbiaceae), chloroform (PUC) and methanol (PUM) extracts, and its eight isolates on H. pylori-infected human gastric epithelial AGS cells. The in vitro anti-bacterial activity of P. urinaria chloroform (PUC) and methanol (PUM) extracts, and its eight isolates were determined. Additional experiments were also performed to know the PUC and PUM ability to inhibit the H. pylori adhesion to and invasion of AGS cells, in addition to the effect of PUC on NF-kappaB activity as well as IL-8 synthesis during H. pylori infection of AGS cells. The results revealed that crude extracts PUC and PUM showed potent antimicrobial activity against H. pylori than pure isolates. On the other hand, in vitroH. pylori-infection model revealed that the inhibition of bacterial adhesion and invasion to AGS cells has dramatically reduced by treatment of extract PUC, while PUM has the same moderate effect. Furthermore, H. pylori-induced nuclear factor (NF)-kappaB activation, and the subsequent release of interleukin (IL)-8 in AGS cells were also inhibited by the extract PUC. These results open the possibility of considering P. urinaria a chemopreventive agent for peptic ulcer or gastric cancer, but this bioactivity should be confirmed in vivo in the future.


Evolutionary divergence of enzymatic mechanisms for posttranslational polyglycylation.
Polyglycylation is a posttranslational modification that generates glycine side chains on proteins. Here we identify a family of evolutionarily conserved glycine ligases that modify tubulin using different enzymatic mechanisms. In mammals, two distinct enzyme types catalyze the initiation and elongation steps of polyglycylation, whereas Drosophila glycylases are bifunctional. We further show that the human elongating glycylase has lost enzymatic activity due to two amino acid changes, suggesting that the functions of protein glycylation could be sufficiently fulfilled by monoglycylation. Depletion of a glycylase in Drosophila using RNA interference results in adult flies with strongly decreased total glycylation levels and male sterility associated with defects in sperm individualization and axonemal maintenance. A more severe RNAi depletion is lethal at early developmental stages, indicating that protein glycylation is essential. Together with the observation that multiple proteins are glycylated, our functional data point towards a general role of glycylation in protein functions.


[Ru(bpy)3]2+-doped silica nanoparticles within layer-by-layer biomolecular coatings and their application as a biocompatible electrochemiluminescent tag material.
[Ru(bpy)3]2+-doped silica (RuSi) nanoparticles were synthesized by using a water/oil microemulsion method. Stable electrochemiluminescence (ECL) was obtained when the RuSi nanoparticles were immobilized on a glassy carbon electrode by using tripropylamine (TPA) as a coreactant. Furthermore, the ECL of the RuSi nanoparticles with layer-by-layer biomolecular coatings was investigated. Squential self-assembly of the polyelectrolytes and biomolecules on the RuSi nanoparticles gave nanocomposite suspensions, the ECL of which decreased on increasing the number of bilayers. Moreover, factors that affected the assembly and ECL signals were investigated. The decrease in ECL could be assigned to steric hindrance and limited diffusion of the coreactant molecules in the silica matrix after they were attached to the biomolecules. Since surface modification of the RuSi nanoparticles can improve their biocompatibility and prevent leaking of the [Ru(bpy)3]2+ ions, the RuSi nanoparticles can be readily used as efficient and stable ECL tag materials in immunoassay and DNA detection.


Piezo-phototronic effect-modulated carrier transport behavior in different regions of a Si/CdS heterojunction photodetector under a Vis-NIR waveband.
The piezo-phototronic effect, as a three-way coupling effect of piezoelectricity, semiconductor and optical excitation in piezoelectric semiconductors to improve the performance of optoelectronic devices, has a wide range of applications in various fields. However, under different light illumination conditions, the piezo-phototronic effect would have different effects on the optoelectronic performance due to the different photo-generated carrier excitation regions. Here, the piezo-phototronic effect is utilized to modulate the carrier transport behavior of a p-Si/n-CdS heterojunction PD during the optoelectronic process in a broadband range from visible to near-infrared light. The strain-induced piezo-charges significantly improve the photoresponse performance of the heterojunction PD. The photoresponsivity increases by 1867% under -0.35‰ strain under 808 nm light illumination, with a remarkable reduction in the rise and fall times to ∼2.1 ms (reduced by 83.3% and 50.0%, respectively). However, since the photo-generated carriers are produced only at the n-CdS side under 442 nm light illumination, the photoresponse performance is greatly weakened by the piezo-phototronic effect. The corresponding working mechanism of the piezo-phototronic effect on the heterojunction photodiode under different light illumination conditions is proposed in detail. These results provide an in-depth understanding about the piezo-phototronic effect, which would enable more efficient utilization of the piezo-phototronic effect in optoelectronic devices.


Hyperhomocysteinemia, pteridines and oxidative stress.
Tetrahydrofolate is an essential cofactor for the conversion of homocysteine to methionine, and hyperhomocysteinemia is considered as a risk factor for cardiovascular and cerebrovascular diseases. In subjects with hyperhomocysteinemia usually an inverse relationship exists to folic acid levels, and supplementation with folic acid is able to lower homocysteine concentrations. The pathogenesis of most if not all diseases which are accompanied with moderate hyperhomocysteinemia involves cellular immune activation and therefore in patients very often exists also a positive correlation between homocysteine concentrations and the degree of immune activation which is indicated, e.g. by increased neopterin concentrations. Since neopterin concentrations also serves as an estimate of oxidative stress merging from immune system activation, this association suggests that cellular immune activation and oxidative stress could be involved in the development of hyperhomocysteinemia. Because tetrahydrofolate is very susceptible to oxidation, an increased oxidative degradation of tetrahydrofolates may become relevant under oxidative stress conditions. In this way folate deficiency may develop despite normal dietary intake of the vitamin. In our patients, hyperhomocysteinemia is considered as an indirect consequence of hyperconsumption of antioxidant vitamins during prolonged states of immune activation.


Stimulation-produced spinal inhibition from the midbrain in the rat is mediated by an excitatory amino acid neurotransmitter in the medial medulla.
It has been previously established that a bulbar relay plays an important role in descending inhibition of spinal dorsal horn nociceptive neurons and nociceptive reflexes produced by stimulation in the midbrain periaqueductal gray (PAG). In the present study, selected receptor antagonists were microinjected into the medial medullary nucleus raphe magnus (NRM) to determine whether descending inhibition of the tail flick (TF) reflex in the rat produced by focal electrical stimulation in the midbrain PAG was mediated by serotonin, opioid, or glutamate receptors on bulbospinal neurons in the NRM. It was determined in initial experiments that the serotonin receptor antagonist methysergide, the opioid receptor antagonist naloxone, the local anesthetic lidocaine, and the glutamate receptor antagonists gamma-D-glutamylglycine (DGG) and DL-2-amino-5-phosphonovalerate (APV) microinjected into the medulla all significantly increased the threshold of focal electrical stimulation in the medulla required to inhibit the TF reflex. The antinociceptive efficacy of agonists at opioid, serotonin, and glutamate receptors was also tested in other experiments. The microinjection of morphine (2.5-10 micrograms) into the NRM increased significantly TF latencies in a dose-dependent manner in rats in the awake or lightly anesthetized state; morphine was more potent in awake rats. Inhibition of the TF reflex produced by the microinjection of morphine was reversed by a subsequent microinjection of naloxone into the same site in the medulla. The microinjection of serotonin (5 and 10 micrograms), however, did not affect the latency of the TF reflex in either awake or lightly anesthetized rats. Glutamate (100 microM, 0.5 microliter) microinjected into the rostral ventral medulla produced an inhibition of the TF reflex of short duration that could be blocked or attenuated significantly by the glutamate receptor antagonists DGG or APV microinjected into the same site. In subsequent experiments, a nonspecific functional block was introduced adjacent to the NRM bilaterally in the medullary reticular formations (MRFs) by the microinjection of the local anesthetic lidocaine; receptor antagonists were then microinjected into the NRM and their effect on the threshold of focal electrical stimulation in the PAG to inhibit the TF reflex determined. No increase was seen in stimulation thresholds in the PAG following the microinjection of either methysergide or naloxone into the NRM. Following the microinjection of lidocaine, DGG or APV into the NRM, the stimulation threshold in the PAG for inhibition of the TF reflex was increased significantly.(ABSTRACT TRUNCATED AT 400 WORDS)


Paroxetine alters KCl- or ATP-induced contractile responses of isolated vas deferens in rats chronically treated with ethanol.
Chronic ethanol administration affects many organ systems, including sexual organs. One of these organs is the vas deferens whose contractility can also be altered by selective serotonin re-uptake inhibitors (SSRIs). The aim of the present study, is to evaluate whether paroxetine (PX), a SSRI, can modify the contractile responses of isolated vas deferens obtained from rats chronically treated with ethanol to the contractile agents, potassium chloride (KCl) and adenosine triphosphate (ATP). For 21 days, alcohol was applied with a modified liquid diet to sexually mature male Sprague-Dawley rats (200-240 g). The vas deferens of the rats were excised at the end of day 21 and suspended in the organ baths by classical pharmacological methods. The responses to contractile agents tested were decreased by chronic ethanol treatment in all groups compared to their untreated matches. PX (10(-7) and 10(-6)M) potentiated the contractions to KCl (20-180 mM) and ATP (10(-6) to 10(-3)M) in epididymal portion but its higher concentrations (10(-5) and 10(-4)M) inhibited the responses, both in the control and chronically ethanol treated rat groups. Prazosin (PR), an alpha adrenergic receptor blocker, could not inhibit PX-induced potentiation in lower concentrations of KCl but could inhibit the potentiation occurred at higher concentrations of KCl in epididymal portion both in the control and chronically ethanol treated rat groups. PR also inhibited PX-induced potentiation on the responses to ATP in epididymal portion both in the control and chronically ethanol treated rat groups. In conclusion, all the results obtained in this study, suggest that chronic ethanol treatment decreased the contractility of vas deferens but did not alter the action pattern of PX on responses to KCl and ATP in rat vas deferens. On the other hand, the potentiation of responses to contractile agents induced by PX can be partially considered as the result of inhibition of noradrenaline re-uptake.


How often can an embolic stroke be diagnosed clinically? A clinicopathological correlation.
A retrospective case note survey of 103 autopsy proven cases of cerebral infarction was carried out to assess how often a cardiac source for embolism had been correctly suspected on clinical grounds. Only 61% of 46 patients with cardiac embolic sources were so identified. Cases of rheumatic heart disease and bacterial endocarditis were more frequently identified than cases of mural thromboembolism from ischaemic heart disease. This relative failure of unaided clinical diagnostic criteria probably accounts for the discrepancy between the autopsy evidence of cardiac embolism as a cause of stroke (about 40%), and clinical studies (about 20%).


Is procalcitonin-guided antimicrobial use cost-effective in adult patients with suspected bacterial infection and sepsis?
Procalcitonin has emerged as a promising biomarker of bacterial infection. Published literature demonstrates that use of procalcitonin testing and an associated treatment pathway reduces duration of antibiotic therapy without impacting mortality. The objective of this study was to determine the financial impact of utilizing a procalcitonin-guided treatment algorithm in hospitalized patients with sepsis. Cost-minimization and cost-utility analysis. Hypothetical cohort of adult ICU patients with suspected bacterial infection and sepsis. Utilizing published clinical and economic data, a decision analytic model was developed from the U.S. hospital perspective. Effectiveness and utility measures were defined using cost-per-clinical episode and cost per quality-adjusted life years (QALYs). Upper and lower sensitivity ranges were determined for all inputs. Univariate and probabilistic sensitivity analyses assessed the robustness of our model and variables. Incremental cost-effectiveness ratios (ICERs) were calculated and compared to predetermined willingness-to-pay thresholds. Base-case results predicted the use of a procalcitonin-guided treatment algorithm dominated standard care with improved quality (0.0002 QALYs) and decreased overall treatment costs ($65). The model was sensitive to a number of key variables that had the potential to impact results, including algorithm adherence (<42.3%), number and cost of procalcitonin tests ordered (≥9 and >$46), days of antimicrobial reduction (<1.6 d), incidence of nephrotoxicity and rate of nephrotoxicity reduction. The combination of procalcitonin testing with an evidence-based treatment algorithm may improve patients' quality of life while decreasing costs in ICU patients with suspected bacterial infection and sepsis; however, results were highly dependent on a number of variables and assumptions.


Synthesis and identification of novel pyridazinylpyrazolone based diazo compounds as inhibitors of human islet amyloid polypeptide aggregation.
We have carried out a docking inspired synthesis and screening of a library of diazenyl-derivatives of pyridazinylpyrazolone molecules for their ability to modulate the amyloidogenic self-assembly of human islet amyloid polypeptide (hIAPP). hIAPP is a 37-residue peptide which is involved in glycemic control along with insulin. Its extracellular fibrillar assemblies in pancreatic β-cells are responsible for type 2 diabetes. A three-step synthetic scheme was used to prepare these novel compounds using 2-(6-chloropyridazin-3-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one as a key intermediate that was reacted with various diazo electrophiles to generate a library of compounds with yields ranging from 64 to 85%. The effect of the compounds on hIAPP amyloid fibril formation was evaluated with a thioflavin T (ThT) fluorescence-based kinetic assay. Furthermore, TEM imaging was carried out to corroborate the interactions of the compounds with hIAPP and subsequent hIAPP inhibition at the different level of fibrillization. The CD spectroscopy showed that upon incubation with SSE15314 for 12 h, the percentage of α-helices was maintained to a level of hIAPP at 0 h. The current study presents identification and characterization of SSE15314 as the hit, which completely inhibited the fibril formation and can be further optimized into a lead compound.


PDE4 Phosphodiesterases in Cardiovascular Diseases: Key Pathophysiological Players and Potential Therapeutic Targets.
3',5'-cyclic adenosine monophosphate (cAMP) is a second messenger critically involved in the control of a myriad of processes with significant implications for vascular and cardiac cell function. The temporal and spatial compartmentalization of cAMP is governed by the activity of phosphodiesterases (PDEs), a superfamily of enzymes responsible for the hydrolysis of cyclic nucleotides. Through the fine-tuning of cAMP signaling, PDE4 enzymes could play an important role in cardiac hypertrophy and arrhythmogenesis, while it decisively influences vascular homeostasis through the control of vascular smooth muscle cell proliferation, migration, differentiation and contraction, as well as regulating endothelial permeability, angiogenesis, monocyte/macrophage activation and cardiomyocyte function. This review summarizes the current knowledge and recent advances in understanding the contribution of the PDE4 subfamily to cardiovascular function and underscores the intricate challenges associated with targeting PDE4 enzymes as a therapeutic strategy for the management of cardiovascular diseases.


Non-visualization of sentinel lymph node in patients with breast cancer.
Histological evaluation of the first draining lymph node (sentinel node) in the axilla of patients with breast cancer has dramatically altered the surgical approach to these patients, with sparing of the axilla if no tumour cells are identified. In a fraction of patients imaged after peri-tumoural injection of the breast, there is no visualization of the sentinel node. We retrospectively analysed the status of patients whose nodes were visualized and of patients whose nodes failed to visualize, to define the variables associated with non-visualization of the sentinel node. Seventy-four breast cancer patients were imaged following peri-tumoural injection of filtered 99Tc(m)-sulfur colloid, immediately and up to 5.5 h post-injection. The scintigraphic data were analysed with reference to the patient's age, histology, grade, site and size of tumour, previous diagnostic procedure and time interval to scan, using univariate analysis and a logistic regression model. A sentinel node was visualized in 53 of 74 women (72%). Comparison of patients with non-visualized versus visualized sentinel nodes disclosed no statistically significant univariate relation to age of the patients (P = 0.10), size of tumour (P = 0.46), site (P = 0.26), histology [invasive ductal carcinoma in 16 of 20 (80%) non-visualized cases, and in 43 of 53 (81%) visualized patients], prior excision biopsy (P = 0.36) and time interval to surgery (P = 0.29). Tumour grade was the only significant variable on univariate analysis (P = 0.03), though multivariate analysis showed that none of the independent parameters were statistically significant. In 39 patients with an upper outer quadrant tumour, the location of the sentinel node was not limited to the axilla and even crossed the midline of the breast. Our results show that none of the independent variables is associated with non-visualization of sentinel lymph node on preoperative lymphoscintigraphy of patients with breast cancer, though the tumour grade may have contributed to non-visualization of this node. The non-axillary drainage from upper outer quadrant tumours suggests the routine use of lymphoscintigraphy prior to axillary dissection.