Quantitative analysis of somatostatin receptor subtypes (1-5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR.
To determine whether the somatostatin receptor subtype (SSTR) expression profile correlates with hormonal and tumor volume responses to postsurgical octreotide long acting repeatable (OCT LAR) treatment. Quantitative real-time RT-PCR was used to evaluate the absolute mRNA copy numbers for all five SSTR subtypes in 22 somatotropinomas. Response to OCT LAR was studied by hormone levels (GH and IGF-I) and tumor volume (sella turcica magnetic resonance imaging). SSTR5 was present at the highest level followed by SSTR2, SSTR3, SSTR1, and SSTR4 (2327 (1046-5555), 2098 (194-23 954), 97 (0-460), 14 (0-29 480), and 0 (0-652) copies respectively). Positive correlations were found between SSTR2 levels and the percentage decrease of GH and IGF-I after 3 (r=0.49, P<0.027 and r=0.49, P<0.029 respectively) and 6 (r=0.59, P<0.006 and r=0.58, P<0.008 respectively) months of OCT LAR. A negative correlation was found between SSTR5 mRNA levels and the percentage decrease of GH after 3 months of OCT LAR (r=-0.52, P=0.016, n=21). A higher SSTR2/SSTR5 ratio was observed among patients who obtained hormonal control with OCT LAR, when compared with those uncontrolled (2.4 (0.7-10) vs 0.3 (0.1-7.7), P=0.001). A ROC curve analysis showed a SSTR2/SSTR5 ratio of 1.3 as the best predictor of disease control, with a sensitivity of 88% and a specificity of 92% - area under curve, 0.9. A positive correlation was also found between SSTR2 mRNA levels and the percentage decrease in tumor volume after 6 months of OCT LAR (r=0.79, P=0.002, n=12). Somatostatin receptor subtype 2 mRNA expression levels in somatotropinomas correlate positively with in vivo hormonal and tumor volume responses to OCT LAR.


Are videogame training gains specific or general?
Many recent studies using healthy adults document enhancements in perception and cognition from playing commercial action videogames (AVGs). Playing action games (e.g., Call of Duty, Medal of Honor) is associated with improved bottom-up lower-level information processing skills like visual-perceptual and attentional processes. One proposal states a general improvement in the ability to interpret and gather statistical information to predict future actions which then leads to better performance across different perceptual/attentional tasks. Another proposal claims all the tasks are separately trained in the AVGs because the AVGs and laboratory tasks contain similar demands. We review studies of action and non-AVGs to show support for the latter proposal. To explain transfer in AVGs, we argue that the perceptual and attention tasks share common demands with the trained videogames (e.g., multiple object tracking (MOT), rapid attentional switches, and peripheral vision). In non-AVGs, several studies also demonstrate specific, limited transfer. One instance of specific transfer is the specific enhancement to mental rotation after training in games with a spatial emphasis (e.g., Tetris). In contrast, the evidence for transfer is equivocal where the game and task do not share common demands (e.g., executive functioning). Thus, the "common demands" hypothesis of transfer not only characterizes transfer effects in AVGs, but also non-action games. Furthermore, such a theory provides specific predictions, which can help in the selection of games to train human cognition as well as in the design of videogames purposed for human cognitive and perceptual enhancement. Finally this hypothesis is consistent with the cognitive training literature where most post-training gains are for tasks similar to the training rather than general, non-specific improvements.


Characteristics of Electroacupuncture Preconditioning and Treatment on Regulation of the Brain Transcriptome in Rats with Ischemic Stroke.
Accumulating evidence suggests that acupuncture may serve as a potent strategy to mitigate the deleterious effects of ischemic stroke on neural tissue. The present investigation delineated the neuroprotective potential of electroacupuncture (EA) administered pre-and post-stroke, with a focus on determining the commonalities and disparities between these two therapeutic approaches in ameliorating ischemic stroke-induced brain injury. The ultimate objective is to inform optimal timing for acupuncture intervention in the clinical management and prevention of stroke. The extent of cerebral infarction was quantified with 2,3,5-triphenyltetrazolium chloride staining. The integrity of the blood-brain barrier was assessed by evaluating the extravasation of Evans blue (EB) dye, while neurological function was appraised using the Longa neurological scoring system. RNA sequencing was employed to examine the transcriptomic landscape of ischemic brain tissue, with subsequent bioinformatics annotation of the sequencing data facilitated by Metascape. (1) A notable decrease in the ischemic infarct volume was observed in both the EA-preconditioned plus middle cerebral artery occlusion (MCAO), EA-preconditioned plus middle cerebral artery occlusion (EAM) and MCAO plus EA-treated (MEA) groups, compared to the MCAO group. Furthermore, the decreased leakage of EB and reduction in neurological function impairment scores were evident in the EAM and MEA groups compared with the MCAO group. (2) Relative to the Sham group, the MCAO group exhibited a total of 4798 differentially expressed genes (DEGs), with 67.84% demonstrating an expression fold change (FC) greater than 1.5, and 34.16% exceeding a FC of 2. The EAM and MEA groups displayed 4020 and 1956 DEGs, respectively, compared to the MCAO group. In both groups, more than 55% of DEGs showed an expression FC surpassing 1.5, whereas only approximately 10% exhibited a change greater than 2-fold. Remarkably, EA preconditioning and EA treatment resulted in the reversal of 18.72% and 28.91% of DEGs, respectively, in the MCAO group. (3) The DEGs upregulated in response to ischemic stroke were predominantly implicated in immune inflammatory processes and cellular apoptosis, whereas the downregulated DEGs were associated with neurogenesis and neuronal signal transduction. The MEA-induced upregulated DEGs were primarily involved in neural transmission and metabolic processes, whereas the downregulated DEGs were linked to excessive inflammatory responses to physical and chemical stimuli, as well as cell matrix adhesion chemotaxis. In the context of EAM, the upregulated DEGs were chiefly related to protein biosynthesis, and energy and metabolic processes, whereas the downregulated genes were connected to gene transcriptional activity, synaptic function, and neuronal architecture. Both preconditioning and post-event treatment with acupuncture demonstrated efficacy in mitigating pathological damage to brain tissue in a rat model of ischemic stroke, albeit with some divergences in their gene targets. The integration of EA preconditioning and treatment may potentially confer enhanced neuroprotection in the clinical management of stroke patients.


Fingerprinting analysis of fresh ginseng roots of different ages using 1H-NMR spectroscopy and principal components analysis.
Fingerprinting analysis of fresh ginseng according to root age was performed using 1H-NMR spectroscopy and multivariate analysis techniques. Various peaks were detected in the aliphatic (0-3 ppm), sugar (3-6 ppm), and aromatic (6-9 ppm) regions of the 1H-NMR spectra of the water extracts of fresh ginseng root. The use of principal components (PCs) analysis (PCA) for metabolomic profiling allowed the large 1H-NMR data set obtained for various metabolites to be reduced to PC1, PC2, and PC3. Two dimensional score plots showed clear separations with these three components at different roots ages, and explained 89.6% of the total variance. Canonical discriminant analysis identified the ginseng roots at various ages from the NMR results with over 89.9% discrimination accuracy. These results indicate that the combination of 1H-NMR and PCA provides a very promising tool for the authentication and quality control of fresh ginseng roots at different ages.


Serum phosphatidylethanolamine levels distinguish benign from malignant solitary pulmonary nodules and represent a potential diagnostic biomarker for lung cancer.
Recent computed tomography (CT) screening trials showed that it is effective for early detection of lung cancer, but were plagued by high false positive rates. Additional blood biomarker tests designed to complement CT screening and reduce false positive rates are highly desirable. Identify blood-based metabolite biomarkers for diagnosing lung cancer. Serum samples from subjects participating in a CT screening trial were analyzed using untargeted GC-TOFMS and HILIC-qTOFMS-based metabolomics. Samples were acquired prior to diagnosis (pre-diagnostic, n= 17), at-diagnosis (n= 25) and post-diagnosis (n= 19) of lung cancer and from subjects with benign nodules (n= 29). Univariate analysis identified 40, 102 and 30 features which were significantly different between subjects with malignant (pre-, at- and post-diagnosis) solitary pulmonary nodules (SPNs) and benign SPNs, respectively. Ten metabolites were consistently different between subjects presenting malignant (pre- and at-diagnosis) or benign SPNs. Three of these 10 metabolites were phosphatidylethanolamines (PE) suggesting alterations in lipid metabolism. Accuracies of 77%, 83% and 78% in the pre-diagnosis group and 69%, 71% and 67% in the at-diagnosis group were determined for PE(34:2), PE(36:2) and PE(38:4), respectively. This study demonstrates evidence of early metabolic alterations that can possibly distinguish malignant from benign SPNs. Further studies in larger pools of samples are warranted.


Evaluation of tamoxifen doses with and without fluoxymesterone in advanced breast cancer.
From a group of 108 female patients with measurable and/or evaluable metastatic breast carcinoma, 52 were randomized to receive tamoxifen and 56 to receive tamoxifen and fluoxymesterone. The fluoxymesterone dose, given orally twice a day, was 7 mg/m2 body surface area. The tamoxifen dose per patient, also given orally twice a day, ranged from 2 to 100 mg/m2 body surface area. Eighty-five percent of the patients had received previous chemotherapy and 60% previous hormone therapy. The complete and partial remission rate was better with the tamoxifen and fluoxymesterone regimen (p = 0.016), with remission rates of 15% for tamoxifen alone and 38% for the combination. The tamoxifen and fluoxymesterone regimen appeared to have higher remission rates in all subsets of pretreatment variables. Duration of remission with each regimen was similar, but the overall time to treatment failure for tamoxifen and fluoxymesterone was longer than for tamoxifen alone (180 versus 64 days, p = 0.01). Median survival with the combination was 380 days compared to 330 days for tamoxifen. No significant dose-response relationships emerged. Side effects were not different between dose levels or regimens except for the androgen effects in the tamoxifen and fluoxymesterone combination. These results suggest that there is no major dose-response effect for doses ranging from 2 to 100 mg/m2 body surface area given twice daily in this largely (94%) postmenopausal pretreated patient group, and that the tamoxifen and fluoxymesterone regimen is superior to tamoxifen alone.


Analgesic Effects of the GIRK Activator, VU0466551, Alone and in Combination with Morphine in Acute and Persistent Pain Models.
G protein-gated inwardly rectifying potassium (GIRK) channels are potassium-selective ion channels. As their name suggests, GIRK channels are effectors of Gi/o G protein-couple receptors whereby activation of these GPCRs leads to increased GIRK channel activity resulting in decreased cellular excitability. In this way, GIRK channels play diverse roles in physiology as effectors of Gi/o-coupled GPCRs: peacemaking in the heart rate, modulation of hormone secretion in endocrine tissues, as well as numerous CNS functions including learning, memory, and addiction/reward. Notably, GIRK channels are widely expressed along the spinothalamic tract and are positioned to play roles in both ascending and descending pain pathways. More notably, GIRK channel knockout and knock-down studies have found that GIRK channels play a major role in the action of opioid analgesics which act predominantly through Gi/o-coupled, opioid-activated GPCRs (e.g., μ-opioid receptors). Recent advances in GIRK channel pharmacology have led to the development of small molecules that directly and selectively activate GIRK channels. Based on research implicating the involvement of GIRK channels in pain pathways and as effectors of opioid analgesics, we conducted a study to determine whether direct pharmacological activation of GIRK channels could produce analgesic efficacy and/or augment the analgesic efficacy morphine, an opioid receptor agonist capable of activating μ-opioid receptors as well as other opioid receptor subtypes. In the present study, we demonstrate that the small-molecule GIRK activator, VU0466551, has analgesic effects when dosed alone or in combination with submaximally effective doses of morphine.


Effect of the Methylation and N-H Acidic Group on the Physicochemical Properties of Imidazolium-Based Ionic Liquids.
This work presents and highlights the differentiation of the physicochemical properties of the [C1Him][NTf2], [C2Him][NTf2], [(1)C1(2)C1Him][NTf2], and [(1)C4(2)C1(3)C1im][NTf2] that is related with the strong bulk interaction potential, which highlights the differentiation on the physicochemical arising from the presence of the acidic group (N-H) as well as the methylation in position 2, C(2), of the imidazolium ring. Densities, viscosities, refractive indices, and surface tensions in a wide range of temperatures, as well as isobaric heat capacities at 298.15 K, for this IL series are presented and discussed. It was found that the volumetric properties are barely affected by the geometric and structural isomerization, following a quite regular trend. A linear correlation between the glass transition temperature, Tg, and the alkyl chain size was found; however, ILs with the acidic N-H group present a significant higher Tg than the [(1)CN-1(3)C1im][NTf2] and [(1)CN(3)CNim][NTf2] series. It was found that the most viscous ILs, ([(1)C1Him][NTf2], [(1)C2Him][NTf2], and [(1)C1(2)C1Him][NTf2]) have an acidic N-H group in the imidazolium ring in agreement with the observed increase of energy barrier of flow. The methylation in position 2, C(2), as well as the N-H acidic group in the imidazolium ring contribute to a significant variation in the cation-anion interactions and their dynamics, which is reflected in their charge distribution and polarizability leading to a significant differentiation of the refractive indices, surface tension, and heat capacities. The observed differentiation of the physicochemical properties of the [(1)C1Him][NTf2], [(1)C2Him][NTf2], [(1)C1(2)C1Him][NTf2], and [(1)C4(2)C1(3)C1im][NTf2] are an indication of the stronger bulk interaction potential, which highlights the effect that arises from the presence of the acidic group (N-H) as well as the methylation in position 2 of the imidazolium ring.


Fluctuations in Arctic sea-ice extent: comparing observations and climate models.
The fluctuation statistics of the observed sea-ice extent during the satellite era are compared with model output from CMIP5 models using a multifractal time series method. The two robust features of the observations are that on annual to biannual time scales the ice extent exhibits white noise structure, and there is a decadal scale trend associated with the decay of the ice cover. It is shown that (i) there is a large inter-model variability in the time scales extracted from the models, (ii) none of the models exhibits the decadal time scales found in the satellite observations, (iii) five of the 21 models examined exhibit the observed white noise structure, and (iv) the multi-model ensemble mean exhibits neither the observed white noise structure nor the observed decadal trend. It is proposed that the observed fluctuation statistics produced by this method serve as an appropriate test bed for modelling studies.This article is part of the theme issue 'Modelling of sea-ice phenomena'.


Antileukoprotease inhibits stratum corneum chymotryptic enzyme. Evidence for a regulative function in desquamation.
The stratum corneum chymotryptic enzyme (SCCE) has been previously purified from human stratum corneum and resembles a chymotryptic serine endopeptidase involved in physiological detachment of corneocytes from human stratum corneum. From human stratum corneum two inhibitory activities of SCCE could be extracted. These were due to serine protease inhibitors already known to be present in human epidermis, antileukoprotease (secretory leukocyte protease inhibitor) and elafin (skin-derived antileukoprotease). The Inhibition of SCCE by antileukoprotease shows a hyperbolic, mixed type inhibition with an equilibrium dissociation constant of 63 n. Antileukoprotease also inhibits detachment of corneocytes from human plantar callus in vitro almost completely (>96%). In addition, elafin was shown to be a weak inhibitor for SCCE activity, and elafin significantly reduces the shedding of corneocytes. Thus, antileukoprotease, which is known to be produced by human keratinocytes, is likely to be the major physiological inhibitor of SCCE in the epidermis. It seems to be involved in the regulation of desquamation under physiological and pathophysiological conditions.


Vitamin E supplementation for prevention of morbidity and mortality in preterm infants.
Treating very low birth weight (VLBW) infants with pharmacologic doses of vitamin E as an antioxidant agent has been proposed for preventing or limiting retinopathy of prematurity, intracranial hemorrhage, hemolytic anemia, and chronic lung disease. However, excessive doses of vitamin E may result in side effects. The aim of this systematic review was to assess the effects of vitamin E supplementation on morbidity and mortality in preterm infants. We searched MEDLINE (October 2002), EMBASE (March 2002), the Cochrane Controlled Trials Register (CCTR) from the Cochrane Library, 2003, Issue 1, and personal files for clinical trials assessing vitamin E in preterm infants. We selected trials analyzing primary outcomes (mortality or combined long-term morbidity) or secondary outcomes (other morbidity) in infants with gestational age less than 37 weeks or birth weight less than 2500 grams. The intervention was allocation to routine supplementation with vitamin E in the treatment group versus placebo, no treatment or another type, dose or route of administration of vitamin E. We used standard methods of the Cochrane Collaboration and of the Cochrane Neonatal Review Group. Twenty-six randomized clinical trials fulfilled entry criteria. No study assessed combined long-term morbidity. Routine vitamin E supplementation significantly increased hemoglobin concentration by a small amount. Vitamin E significantly reduced the risk of germinal matrix/intraventricular hemorrhage and increased the risk of sepsis; however, heterogeneity limits the strength of these latter two inferences. Vitamin E did not significantly affect other morbidity or mortality. In VLBW infants, vitamin E supplementation significantly increased the risk of sepsis, and reduced the risk of severe retinopathy and blindness among those examined. Subgroup analyses showed (1) an association between intravenous, high-dose vitamin E supplementation and increased risk of sepsis and of parenchymal cerebral hemorrhage; (2) an association between vitamin E supplementation by other than the intravenous route and reduced risk of germinal matrix-intraventricular hemorrhage and of severe intraventricular hemorrhage; and (3) an association between serum tocopherol levels greater than 3.5 mg/dl and increased risk of sepsis and reduced risk for severe retinopathy among those examined. Vitamin E supplementation in preterm infants reduced the risk of intracranial hemorrhage but increased the risk of sepsis. In very low birth weight infants it increased the risk of sepsis, and reduced the risk of severe retinopathy and blindness among those examined. Evidence does not support the routine use of vitamin E supplementation by intravenous route at high doses, or aiming at serum tocopherol levels greater than 3.5 mg/dl.


SGLT-2 Inhibition: A Potential New Treatment for Diabetic Kidney Disease?
Diabetic nephropathy is the leading cause of kidney failure. Treatments with drugs that block the renin-angiotensin system have proven beneficial in slowing kidney disease progression among those with diabetes; their benefit is limited and they do not stop disease progression. Despite multiple clinical trials of various interventions including dual blockade of the renin-angiotensin system over the past 15 years, no new therapies have emerged to slow kidney disease progression in diabetes. SGLT-2 inhibitors are a new class of antiglycemic drugs that have been shown to lower blood glucose by inhibition of the sodium-glucose transporter 2 in the proximal tubule of the kidney. Several of these inhibitors have been marketed for treatment of hyperglycemia in patients with type 2 diabetes mellitus. In a recent double-blind randomized and placebo-controlled trial of cardiovascular outcomes, an SGLT-2 inhibitor-based intervention using empagliflozin was shown to be superior to placebo-based regimen for reducing the risk of major cardiovascular events among people with type 2 diabetes and established cardiovascular disease. In a pre-specified secondary analysis of renal outcomes from this trial, Wanner et al. [N Engl J Med 2016;375:323-334] recently reported that empagliflozin administration was also associated with significant reductions in the progression of kidney disease including the rate of decline in estimated glomerular filtration rate (eGFR), progression of albuminuria and initiation of renal replacement therapy. While the results of this trial are striking and impressive, the majority of those enrolled in the trial did not have evidence of diabetic kidney disease as assessed by eGFR or albuminuria. Thus, whether or not they represent a breakthrough in the treatment of diabetic nephropathy remains to be determined. Several ongoing clinical trials are in the planning stages to evaluate SGLT-2 inhibition in a population of patients with overt kidney disease. These trials will help to substantiate, or not, the potential for this class of drugs to be added to the armamentarium of therapeutic strategies to prevent progression of kidney disease in diabetes.


Incidence and Prevalence of Opportunistic and Other Infections and the Impact of Antiretroviral Therapy Among HIV-infected Children in Low- and Middle-income Countries: A Systematic Review and Meta-analysis.
We conducted a systematic review and meta-analysis to evaluate the incidence and prevalence of 14 opportunistic infections (OIs) and other infections as well as the impact of antiretroviral therapy (ART) among human immunodeficiency virus (HIV)-infected children (aged <18 years) in low- and middle-income countries (LMICs), to understand regional burden of disease, and inform delivery of HIV services. Eligible studies described the incidence of OIs and other infections in ART-naive and -exposed children from January 1990 to November 2013, using Medline, Global Health, Embase, Cumulative Index to Nursing and Allied Health Literature, Web of Knowledge, and Literatura Latino Americana em Ciências da Saúde databases. Summary incident risk (IR) and prevalent risk for each OI in ART-naive and ART-exposed children were calculated, and unadjusted odds ratios calculated for impact of ART. The number of OI cases and associated costs averted were estimated using the AIDS impact model. We identified 4542 citations, and 88 studies were included, comprising 55 679 HIV-infected children. Bacterial pneumonia and tuberculosis were the most common incident and prevalent infections in both ART-naive and ART-exposed children. There was a significant reduction in IR with ART for the majority of OIs. There was a smaller impact on bacterial sepsis and pneumonia, and an increase observed for varicella zoster. ART initiation based on 2010 World Health Organization guidelines criteria for ART initiation in children was estimated to potentially avert >161 000 OIs (2013 UNAIDS data) with estimated cost savings of at least US$17 million per year. There is a decrease in the risk of most OIs with ART use in HIV-infected children in LMICs, and estimated large potential cost savings in OIs averted with ART use, although there are greater uncertainties in pediatric data compared with that of adults.


Creating complete dentures that are stable in function.
Many edentulous people can experience difficulty in carrying out functional activities when wearing complete dentures. This may be due to a number of factors, one of which is the ability to control the dentures effectively during mastication and speech. For this reason, it is critical when constructing complete dentures to incorporate features in their design which will aid stability in function. Usually, the challenges are greater in constructing a prosthesis to replace the missing mandibular teeth. It is recognized that the use of osseointegrated implants offers considerable advantages for people who have to wear complete dentures, and the contribution of implantology to the provision of stable complete dentures will be explored. However, many people will not have the opportunity to experience the benefits of this approach. Furthermore, for people who need to wear conventional dentures, age and other factors may impact on their ability to control the prostheses effectively during oral function. In this paper, the ways in which design features may impact on the stability of complete dentures will be discussed. This paper considers how complete dentures can be designed and constructed so that they are stable in oral function, and can be worn comfortably without causing damage to the intra-oral tissues.


Optical Measurements during Asleep Deep Brain Stimulation Surgery along Vim-Zi Trajectories.
Optics can be used for guidance in deep brain stimulation (DBS) surgery. The aim was to use laser Doppler flowmetry (LDF) to investigate the intraoperative optical trajectory along the ventral intermediate nucleus (VIM) and zona incerta (Zi) regions in patients with essential tremor during asleep DBS surgery, and whether the Zi region could be identified. A forward-looking LDF guide was used for creation of the trajectory for the DBS lead, and the microcirculation and tissue greyness, i.e., total light intensity (TLI) was measured along 13 trajectories. TLI trajectories and the number of high-perfusion spots were investigated at 0.5-mm resolution in the last 25 mm from the targets. All implantations were done without complications and with significant improvement of tremor (p < 0.01). Out of 798 measurements, 12 tissue spots showed high blood flow. The blood flow was significantly higher in VIM than in Zi (p < 0.001). The normalized mean TLI curve showed a significant (p < 0.001) lower TLI in the VIM region than in the Zi region. Zi DBS performed asleep appears to be safe and effective. LDF monitoring provides direct in vivomeasurement of the microvascular blood flow in front of the probe, which can help reduce the risk of hemorrhage. LDF can differentiate between the grey substance in the thalamus and the transmission border entering the posterior subthalamic area where the tissue consists of more white matter tracts.


Placental restriction in multi-fetal pregnancies and between-twin differences in size at birth alter neonatal feeding behaviour in the sheep.
Most individuals whose growth was restricted before birth undergo accelerated or catch-up neonatal growth. This is an independent risk factor for later metabolic disease, but the underlying mechanisms are poorly understood. This study aimed to test the hypothesis that natural and experimentally induced in utero growth restriction increase neonatal appetite and milk intake. Control (CON) and placentally restricted (PR) ewes carrying multiple fetuses delivered naturally at term. Outcomes were compared between CON (n=14) and PR (n=12) progeny and within twin lamb pairs. Lamb milk intake and feeding behaviour and ewe milk composition were determined using a modified weigh-suckle-weigh procedure on days 15 and 23. PR lambs tended to have lower birth weights than CON (-15%, P=0.052). Neonatal growth rates were similar in CON and PR, whilst heavier twins grew faster in absolute but not fractional terms than their co-twins. At day 23, milk protein content was higher in PR than CON ewes (P=0.038). At day 15, PR lambs had fewer suckling bouts than CON lambs and in females light twins had more suckling attempts than their heavier co-twins. Birth weight differences between twins positively predicted differences in milk intakes. Lactational constraint and natural prenatal growth restriction in twins may explain the similar milk intakes in CON and PR. Within twin comparisons support the hypothesis that prenatal constraint increases lamb appetite, although this did not increase milk intake. We suggest that future mechanistic studies of catch-up growth be performed in singletons and be powered to assess effects in each sex.


Acid Ceramidase Depletion Impairs Neuronal Survival and Induces Morphological Defects in Neurites Associated with Altered Gene Transcription and Sphingolipid Content.
The ASAH1 gene encodes acid ceramidase (AC), an enzyme that is implicated in the metabolism of ceramide (Cer). Mutations in the ASAH1 gene cause two different disorders, Farber disease (FD), a rare lysosomal storage disorder, and a rare form of spinal muscular atrophy combined with progressive myoclonic epilepsy (SMA-PME). In the absence of human in vitro neuronal disease models and to gain mechanistic insights into pathological effects of ASAH1 deficiency, we established and characterized a stable ASAH1 knockdown (ASAH1KD) SH-SY5Y cell line. ASAH1KD cells displayed reduced proliferation due to elevated apoptosis and G1/S cell cycle arrest. Distribution of LAMP1-positive lysosomes towards the cell periphery and significantly shortened and less branched neurites upon differentiation, implicate AC for lysosome positioning and neuronal development, respectively. Lipidomic analysis revealed changes in the intracellular levels of distinct sphingolipid species, importantly without Cer accumulation, in line with altered gene transcription within the sphingolipid pathway. Additionally, the transcript levels for Rho GTPases (RhoA, Rac1, and Cdc42), which are key regulators of axonal orientation, neurite branching and lysosome positioning were found to be dysregulated. This study shows the critical role of AC in neurons and suggests how AC depletion leads to defects seen in neuropathology of SMA-PME and FD.


[Intraventricular hemorrhage in full-term neonates].
Intraventricular hemorrhage in full-term neonates is rare; it may develop without any clinical signs. Its cause is not fully understood although some risk factors have been identified. A higher index of suspicion would ensure earlier diagnosis and treatment, which might reduce the rate of severe complications. We describe 2 cases in full-term neonates.


Clinical guidelines for oral appliance therapy in the treatment of snoring and obstructive sleep apnoea.
The purpose of this review is to provide guidelines for the use of oral appliances (OAs) for the treatment of snoring and obstructive sleep apnoea (OSA) in Australia. A review of the scientific literature up to June 2012 regarding the clinical use of OAs in the treatment of snoring and OSA was undertaken by a dental and medical sleep specialists team consisting of respiratory sleep physicians, an otolaryngologist, orthodontist, oral and maxillofacial surgeon and an oral medicine specialist. The recommendations are based on the most recent evidence from studies obtained from peer reviewed literature. Oral appliances can be an effective therapeutic option for the treatment of snoring and OSA across a broad range of disease severity. However, the response to therapy is variable. While a significant proportion of subjects have a near complete control of the apnoea and snoring when using an OA, a significant proportion do not respond, and others show a partial response. Measurements of baseline and treatment success should ideally be undertaken. A coordinated team approach between medical practitioner and dentist should be fostered to enhance treatment outcomes. Ongoing patient follow-up to monitor treatment efficacy, OA comfort and side effects are cardinal to long-term treatment success and OA compliance.


Physiologically-based pharmacokinetic modeling of genistein in rats, Part I: Model development.
Genistein is a phytoestrogen-a plant-derived compound that binds to and activates the estrogen receptor-occurring at high levels in soy beans and food products, leading to widespread human exposure. The numerous scientific publications available describing genistein's dosimetry, mechanisms of action, and identified or putative health effects in both experimental animals and humans make it ideal for examination as an example of endocrine-active compound (EAC). We developed a physiologically-based pharmacokinetic (PBPK) model to quantify the internal, target-tissue dosimetry of genistein in adult rats. Complexities of the model include enterohepatic circulation, binding of both genistein and its conjugates to plasma proteins, and the multiple compartments used to describe transport through the bile duct and gastrointestinal tract. Other aspects of the model are simple perfusion-limited transport to the tissue groups and first-order rates of metabolism, uptake, and excretion. We describe here the model structure and initial calibration of the model by fitting to a large data set for Wistar rats. The model structure can be readily extrapolated to describe genistein dosimetry in humans or modified to describe the dosimetry of other phytoestrogens and phenolic EACs. The model does a fair job of capturing the pharmacokinetics. Although it does not describe the interindividual variability and we have not identified a single set of parameters that provide a good fit to the data for both oral and intravenous exposures, we believe it provides a good initial attempt at PBPK modeling for genistein, which can serve as a template for other phytoestrogens and in the design of future experiments and research that can be used to fill data gaps and better estimate model parameters.


How cognitive engagement fluctuates during a team-based learning session and how it predicts academic achievement.
The objective of the paper is to report findings of two studies that attempted to find answers to the following questions: (1) What are the levels of cognitive engagement in TBL? (2) Are there differences between students who were more exposed to TBL than students who were less exposed to TBL? (3) To which extent does cognitive engagement fluctuate as a function of the different activities involved in TBL? And (4) How do cognitive engagement scores collected over time correlate with each other and with academic achievement? The studies were conducted with Year-1 and -2 medical students enrolled in a TBL curriculum (N = 175, 62 female). In both studies, six measurements of cognitive engagement were taken during the distinct TBL activities (preparation phase, individual/team readiness assurance test, burning questions, and application exercises). Data were analysed by means of one-way repeated-measures ANOVAs and path modelling. The results of the repeated-measures ANOVA revealed that cognitive engagement systematically fluctuated as a function of the distinct TBL activities. In addition, Year-1 students reported significantly higher levels of cognitive engagement compared to Year-2 students. Finally, cognitive engagement was a significant predictor of performance (β = .35). The studies presented in this paper are a first attempt to relate the different activities undertaken in TBL with the extent to which they arouse cognitive engagement with the task at hand. Implications of these findings for TBL are discussed.


Protective mechanisms of mitochondria and heart function in diabetes.
The heart depends on continuous mitochondrial ATP supply and maintained redox balance to properly develop force, particularly under increased workload. During diabetes, however, myocardial energetic-redox balance is perturbed, contributing to the systolic and diastolic dysfunction known as diabetic cardiomyopathy (DC). How these energetic and redox alterations intertwine to influence the DC progression is still poorly understood. Excessive bioavailability of both glucose and fatty acids (FAs) play a central role, leading, among other effects, to mitochondrial dysfunction. However, where and how this nutrient excess affects mitochondrial and cytoplasmic energetic/redox crossroads remains to be defined in greater detail. We review how high glucose alters cellular redox balance and affects mitochondrial DNA. Next, we address how lipid excess, either stored in lipid droplets or utilized by mitochondria, affects performance in diabetic hearts by influencing cardiac energetic and redox assets. Finally, we examine how the reciprocal energetic/redox influence between mitochondrial and cytoplasmic compartments shapes myocardial mechanical activity during the course of DC, focusing especially on the glutathione and thioredoxin systems. Protecting mitochondria from losing their ability to generate energy, and to control their own reactive oxygen species emission is essential to prevent the onset and/or to slow down DC progression. We highlight mechanisms enforced by the diabetic heart to counteract glucose/FAs surplus-induced damage, such as lipid storage, enhanced mitochondria-lipid droplet interaction, and upregulation of key antioxidant enzymes. Learning more on the nature and location of mechanisms sheltering mitochondrial functions would certainly help in further optimizing therapies for human DC.


Prevalence of pulmonary hypertension in obstructive sleep apnea and relation to disease severity.
The purpose of this study is to examine the prevalence of pulmonary hypertension (PHTN) in children with obstructive sleep apnea (OSA) using echocardiographic (ECHO) parameters and to examine ECHO findings as they relate to severity of OSA. A retrospective cohort study of subjects with OSA undergoing polysomnogram (PSG) and ECHO within 30 days of each other, between 01/01/15 - 12/31/20 was performed, excluding cardiac disease. ECHO evidence of PHTN was defined as ≥ 2 of the following: tricuspid regurgitation (TR) velocity > 3.0 m/sec, pulmonary acceleration/ejection time (AT/ET) ratio < 0.3, left ventricular eccentricity index (EI) > 1.5, right ventricular (RV) dysfunction or abnormal geometry. ECHO parameters were compared to OSA severity using obstructive apnea-hypopnea index (AHI), % time with oxygen saturation < 90%, and % time with end-tidal carbon dioxide > 50 mmHg. Odds ratios were calculated for each comorbidity to evaluate for risk factors. Of 509 subjects, 4.3% were found to have echocardiographic evidence of PHTN. Neither oAHI severity, nor worsening hypoxemia or hypercarbia correlated with worsening ECHO parameters. Comorbidities including bronchopulmonary dysplasia (OR 5.22, 2.01 - 13.53), prematurity (OR 3.10, 1.28 - 7.47), and autism (OR 3.69, 1.01 - 13.49) were associated with increased odds of PHTN. Significant echocardiographic evidence of PHTN was seen in 4.3% of children with OSA. ECHO findings of PHTN did not correlate with PSG parameters. Comorbidities, particularly bronchopulmonary dysplasia, prematurity, and autism, appear to be a risk factor for developing PHTN in patients with OSA.


Dimensional changes of resin/ionomer restoratives in aqueous and neutral media.
The aim was to study dimensional time-dependence of resin/ionomer formulations from 5 min age to one month and to separate out the intrinsic setting shrinkage and hygroscopic expansion effects, by using non-aqueous and aqueous storage media, respectively. Materials studied included: A: resin-, B: metal- and C: polyphosphonate-modified glass-ionomer cements [GICs]; and controls of D: poly-acid modified composite [compomer]; and E: resin-composite. Separate specimen groups (n = 5) were stored in different storage-media: (i) silicone fluid; (ii) de-ionized water. Experiments were repeated at 23 and 37 degrees C. Volumetric changes of specimens (4 mm diameter x 6 mm height) were obtained via accurate mass measurements (to 10(-4) g), using Archimedes principle, with silicone or water also used as the Archimedean fluid. These measurements were made periodically over a 30 day period, post fabrication. In silicone at 23 degrees C, all materials underwent further gradual intrinsic shrinkage (after 5 min from mix). This was highly significant (p < 0.05) for the RM-GIC (A). At 37 degrees C, however the RM-GIC expanded, indicating that its cure is temperature-sensitive. In water, at 23 and 37 degrees C, the shrinkage was either partially offset (materials C, D, E), or replaced by appreciable expansions (materials A and B). Differences between RM-GIC (A) and MM-GIC (B) were significant (p < 0.05). The deployment of dual storage media made an important contribution to the separate analysis of the volumetric changes due to the on-going setting chemistry in these systems and the time-dependent effects of an aqueous environment.


Gender differences in limbic responsiveness, by SPECT, following a pharmacologic challenge in healthy subjects.
Limbic system functioning is integral to the control and modulation of affect, motivation, reward, and memory. Neuropsychiatric disturbances involving disruptions in these cognitive and emotional dimensions exhibit different prevalence rates for men and women. Gender-specific differences in this integrated brain area may therefore be important in understanding both normal behavioral functioning and the etiologic underpinnings of neuropsychiatric disorders. To further explore such differences in limbic system function, we assessed regional cerebral blood flow, by SPECT, in men and women following the administration of procaine. Procaine is a local anesthetic that preferentially stimulates limbic structures. Psychiatrically and medically healthy, age-matched women (n = 15, 33.2 +/- 6.9 years) and men (n = 15, 32.8 +/- 6.9 years) were administered 1.38 mg/kg procaine or saline intravenously in two separate sessions. Using voxel-based analyses (P < 0.001), males significantly activated the bilateral insular cortex following procaine, whereas females more strongly activated the bilateral anterior and mesial temporal cortex. Both groups demonstrated significant anterior cingulate activation. Subjective responses to procaine did not significantly differ between the men and women. To our knowledge, this is the first report demonstrating gender-specific responses in limbic activation following a pharmacologic challenge. These findings suggest that men and women can activate different limbic structures following the same provocative pharmacologic stimulus, despite sharing a similar subjective experience. Studies assessing pharmacologic challenges of limbic system structures should consider gender as a critical variable in assessing biologic responsiveness.


Antioxidant Potential of the Polyherbal Formulation "ImmuPlus": A Nutritional Supplement for Horses.
In order to counteract harmful effects of oxidative stress due to pathological conditions or physical exercise, horses are often administered dietary supplements having supposed high antioxidant activities. The aim of the present study was to identify the in vitro antioxidant potential of "ImmuPlus", a polyherbal formulation (Global Herbs LTD, Chichester, West Sussex, Great Britain), containing three medicinal plants (Withania somnifera, Tinospora cordifolia, and Emblica officinalis), known in Ayurveda for their use in human disease treatment. Extracts obtained by different solvents (water, methanol, ethanol, acetone, and hexane) were tested for total antioxidant capacity, total reducing power, scavenging activity against DPPH radical, and total polyphenol and flavonoid contents. Our results showed that, except as regards hexane, all the used solvents are able to extract compounds having high antioxidant activity, even when compared to ascorbic acid. Regression analysis showed significant correlations between antioxidant properties and polyphenol/flavonoid contents, indicating the latter, known for their beneficial effects on health of human and animal beings, as major components responsible for the strong antioxidant capacities. Moreover, obtained results suggest the effective role of the polyherbal mixture as good source of antioxidants in horses.


Interactions of monomeric IgG bearing covalently bound C3b with polymorphonuclear leucocytes.
The interactions of monomeric IgG, monomeric C3b, dimeric C3b, and C3b covalently bound to IgG (C3b-IgG) with neutrophils were examined. C3b-IgG heterodimers exhibited an increased affinity of binding to neutrophils, relative to C3b, both at half normal ionic strength (five-fold enhancement) and at normal ionic strength (six-fold enhancement). Binding of monomeric IgG to neutrophils was barely detectable and did not permit direct measurements of affinity in our assay conditions. The increased affinity of C3b-IgG for neutrophils was the result of divalent interactions with CR1, the C3b receptor, and the Fc gamma receptor of the cells, as could be demonstrated by competition studies using unlabelled IgG in the medium or monoclonal antibodies against the neutrophil Fc gamma receptor. This double receptor-ligand interaction allowed C3b-IgG to bind to the cells not only at normal ionic strength, but also in the presence of a 315-fold excess of IgG (near plasma concentration)--conditions that would preclude the binding of C3b or IgG alone. Furthermore, this interaction leads to the internalization of the C3b-IgG complex by the cells. C3b-IgG is internalized with kinetics similar to those found using dimeric C3b, with resting cells demonstrating a slow initial phase, which is accelerated by phorbol ester activation in both cases. Uptake of the homodimeric C3b was greater at 15 min than that of heterodimeric C3b-IgG, but both were significantly greater than that of monomer C3b, which showed no net internalization. The physiological implications of these findings are discussed.


Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity.
Preadipocyte factor 1 (Pref-1/Dlk1) inhibits in vitro adipocyte differentiation and has been recently reported to be a paternally expressed imprinted gene at human chromosome 14q32. Studies on human chromosome 14 deletions and maternal uniparental disomy (mUPD) 14 suggest that misexpression of a yet-to-be-identified imprinted gene or genes present on chromosome 14 causes congenital disorders. We generated Pref-1 knockout mice to assess the role of Pref-1 in growth and in vivo adipogenesis and to determine the contribution of Pref-1 in mUPD. Pref-1-null mice display growth retardation, obesity, blepharophimosis, skeletal malformation, and increased serum lipid metabolites. Furthermore, the phenotypes observed in Pref-1-null mice are present in heterozygotes that harbor a paternally inherited, but not in those with a maternally inherited pref-1-null allele. Our results demonstrate that Pref-1 is indeed paternally expressed and is important for normal development and for homeostasis of adipose tissue mass. We also suggest that Pref-1 is responsible for most of the symptoms observed in mouse mUPD12 and human mUPD14. Pref-1-null mice may be a model for obesity and other pathologies of human mUPD14.


Elevated chemerin levels in synovial fluid and synovial membrane from patients with knee osteoarthritis.
To test the serum, synovial fluid and synovial membrane levels of the adipokine chemerin in patients with knee osteoarthritis (KOA) and investigate their relationships with the severity of articular cartilage damage and synovitis. According to the American College of Rheumatology criteria for diagnosis of osteoarthritis (OA), 30 cases with OA diagnoses (OA group) were selected from patients who underwent arthroscopic surgery in our hospital from June 2013 to February 2014. Another 30 cases with other knee joint diseases (non-OA group) were included as controls. The synovial fluid and serum levels of chemerin were assayed by ELISA, and the synovial membrane level of chemerin was assayed by the immunohistochemical method. The severity of the knee articular cartilage damage and synovitis-related pathological changes were evaluated by arthroscopy using the Outerbridge and Ayral scores, respectively. The synovial fluid and synovial membrane levels of chemerin in the OA group were higher than those in the non-OA group. Statistically significant differences were found between the two groups in the synovial fluid and synovial membrane levels of chemerin (P < 0.05). The synovial fluid and synovial membrane levels of chemerin were positively correlated with the serum level of high-sensitivity C-reactive protein (HS-CRP), Outerbridge score and Ayral score in the OA group. The synovial fluid and synovial membrane levels of chemerin are increased in KOA patients and are positively correlated with the severity of KOA.


[Effect of surface-active substances on bioluminescence intensity of bacteria].
The study of sensitivity of luminous bacteria isolated from the Black and Azov seas to surfactants from various classes was carried out. It was shown that cationic surfactants had a strong inhibition effect on bacterial luminescence in contrast to anionic and in particular nonionic surfactants. To increase the luminous bacteria sensitivity to the action of OP-10 (nonionic surfactant) and ABS (anionic surfactant), which are widely used in industry, several approaches have been developed. They include modulation of bacterial sensitivity by the additives of cationic substances, use of luminous bacteria at a logarithmic stage of growth, realization of biotesting at low pH = 5.5. The use of these approaches allows to lower effective concentrations of OP-10 and ABS, which caused a decrease of bioluminescence by 50%, 3-200 times and opens perspectives for the use of the bioluminescent method to study these surfactants toxicity on the principle of biosensorics.


Case-mix adjustment, claims data quality, and physician profiling.
On the surface, there are many ways in which case mix may be considered, but the key to any successful system often lies below the surface, in the way in which the available data feed the systems, and in the operational environment in which the output is to be used. This article will review terminology used in case-mix adjustment and profiling techniques, highlight some dangerous (and avoidable) data pitfalls, and emphasize reasonable goals that can be achieved through the use of case-mix adjusted profiling.


[Surgical treatment of Parkinson disease: indications and limitations].
Thalamotomy, a surgical lesion of the ventro-intermediate nucleus of the thalamus, is a well known surgical treatment of tremor in Parkinson's disease. Over the last years, new surgical therapies had been developed. These therapies, instead of making a lesion in the brain, consist in placing electrodes in specific areas of the brain and to inhibit neuronal function by electrical stimulation. Electrical stimulation of the subthalamic nucleus or of the pallidum are effective to treat motor symptoms of Parkinson's disease. The procedure can be done bilaterally, contrary to thalamotomy. A short overview of the indications and contra-indications of this kind of therapy is given.


Analysis of Sex-Specific Prostanoid Production Using a Mouse Model of Selective Cyclooxygenase-2 Inhibition.
Prostanoids are a family of lipid mediators formed from arachidonic acid by cyclooxygenase enzymes and serve as biomarkers of vascular function. Prostanoid production may be different in males and females indicating that different therapeutic approaches may be required during disease. We examined sex-dependent differences in COX-related metabolites in genetically modified mice that produce a cyclooxygenase-2 (COX2) enzyme containing a tyrosine 385 to phenylalanine (Y385F) mutation. This mutation renders the COX2 enzyme unable to form a key intermediate radical required for complete arachidonic acid metabolism and provides a model of selective COX2 inhibition. Mice heterozygous for the Y385F mutation in COX2 were mated to produce cohorts of wild-type, heterozygous, and COX2 mutant mice. We investigated whether the genotype distribution followed Mendelian genetics and studied whether sex-specific differences could be found in certain prostanoid levels measured in peritoneal macrophages and in urinary samples. The inheritance of the COX2 mutation displayed a significant deviation with respect to Mendel's laws of genetics, with a lower-than-expected progeny of weaned COX2 mutant pups. In macrophages, prostaglandin E2 (PGE2) production following lipopolysaccharide (LPS) and interferon gamma (IFNγ) stimulation was COX2-dependent in both males and females, and data indicated that crosstalk between the nitric oxide (NO) and COX2 pathways may be sex specific. We observed significant differences in urinary PGE2 production by male and female COX2 mutant mice, with the loss of COX2 activity in male mice decreasing their ability to produce urinary PGE2. Finally, female mice across all 3 genotypes produced similar levels of urinary thromboxane (measured as 11-dehydro TxB2) at significantly higher levels than males, indicating a sex-related difference that is likely COX1-derived. Our findings clearly demonstrate that sex-related differences in COX-derived metabolites can be observed, and that other pathways (such as the NO pathway) are affected.


Gastrointestinal-associated lymphoid tissue immune reconstitution in a randomized clinical trial of raltegravir versus non-nucleoside reverse transcriptase inhibitor-based regimens.
To examine immune restoration in duodenal tissue and correlates of reduction of immune activation in chronic HIV-infected patients randomized to different treatment regimens. Randomized clinical trial (RCT) comparing raltegravir to a non-nucleoside reverse transcriptase inhibitor-based regimen, both with fixed-dose tenofovir difumerate/emtricitabine. Antiretroviral therapy (ART)-naive volunteers underwent upper endoscopy for duodenal biopsies before and after 9 months of therapy. Tissue was paraffin-embedded for immunohistochemistry or digested into single-cell suspensions for flow cytometry of lymphocyte subsets and activation phenotype. Plasma-soluble CD14 levels were measured as a surrogate for bacterial translocation. Sixteen HIV-positive and seven control individuals completed study procedures. Small increases in duodenal lamina propria CD4 T-cell numbers were observed, especially when viewed relative to populations in control volunteers, with no differences between treatment arms. The increase in CD4 T-cell percentage was due largely to declines in CD8 T-cell numbers, which were disproportionately increased compared to peripheral blood and controls. Patients randomized to the raltegravir arm had consistent declines in both sCD14 levels and CD8 T-cell numbers in the duodenal tissue lamina propria. This first RCT of lymphocyte population restoration in duodenal tissue demonstrates more modest increases in CD4 T-cell numbers during the first 9 months of therapy than when considering CD3/CD4 percentages only. Although reduced after 9 months of ART, disproportional increased CD8 populations persist in duodenal gastrointestinal-associated lymphoid tissue (GALT). Local rather than systemic antigenic stimulation appears to be driving expanded CD8 T lymphocytes in GALT. Factors other than viral-induced CD8 expansion may be contributing to this local immunologic response.


Dual tasking in Parkinson's disease: Cognitive consequences while walking.
Cognitive deficits are common in Parkinson's disease (PD) and exacerbate the functional limitations imposed by PD's hallmark motor symptoms, including impairments in walking. Though much research has addressed the effect of dual cognitive-locomotor tasks on walking, less is known about their effect on cognition. The purpose of this study was to investigate the relation between gait and executive function, with the hypothesis that dual tasking would exacerbate cognitive vulnerabilities in PD as well as being associated with gait disturbances. Nineteen individuals with mild-moderate PD without dementia and 13 age- and education-matched normal control adults (NC) participated. Executive function (set-shifting) and walking were assessed singly and during dual tasking. Dual tasking had a significant effect on cognition (reduced set-shifting) and on walking (speed, stride length) for both PD and NC, and also on stride frequency for PD only. The impact of dual tasking on walking speed and stride frequency was significantly greater for PD than NC. Though the group by condition interaction was not significant, PD had fewer set-shifts than NC on dual task. Further, relative to NC, PD showed significantly greater variability in cognitive performance under dual tasking, whereas variability in motor performance remained unaffected by dual tasking. Dual tasking had a significantly greater effect in PD than in NC on cognition as well as on walking. The results suggest that assessment and treatment of PD should consider the cognitive as well as the gait components of PD-related deficits under dual-task conditions. (PsycINFO Database Record


Male breast cancer: a 24 year experience of a tertiary care hospital in Pakistan.
Male breast cancer accounts for less than 1% of all cancers found in men. It usually presents at a later age and stage as compared to female breast cancer. Treatment strategies are extrapolated from the management of female breast cancer. Our study here looked at 18 patients diagnosed with and treated for male breast cancer at The Aga Khan University Hospital in Pakistan. We compared our findings with the existing data from Asian and Western countries. A retrospective study was conducted looking at patients with male breast cancer between January 1986 and December 2009. Patient and disease characteristics were analyzed and 5 year overall survival was calculated using Microsoft Excel and SPSS. The average age at diagnosis was 52 years (38-67 years). Twelve (66.7%) patients had axillary lymphadenopathy. Stage II disease was the most common stage at presentation (9 patients, 50%). Infiltrating ductal carcinoma was seen in 16 patients (88.8%). Seven lesions were positive for both estrogen and progesterone receptors. Sixteen patients had surgery in the form of either modified radical mastectomy or radical mastectomy. Radiation was used in 7 patients in an adjuvant setting. The five year overall survival for stage I, II, III and IV disease was 100% vs 78% vs 50% vs 0%( p<0.05). Five year overall survival was 61%. None of the other prognostic factors were statistically significant. Median follow up was 15 months (3-202 months). Male breast cancer may be on a slow rise but is still an uncommon disease. Tumor stage and lymph node status are important prognostic markers. Public awareness and screening may help in detecting the disease at an earlier stage. Prospective trials are needed to improve the management of this disease.


Examining the Robustness of the Graded Response and 2-Parameter Logistic Models to Violations of Construct Normality.
When fitting unidimensional item response theory (IRT) models, the population distribution of the latent trait (θ) is often assumed to be normally distributed. However, some psychological theories would suggest a nonnormal θ. For example, some clinical traits (e.g., alcoholism, depression) are believed to follow a positively skewed distribution where the construct is low for most people, medium for some, and high for few. Failure to account for nonnormality may compromise the validity of inferences and conclusions. Although corrections have been developed to account for nonnormality, these methods can be computationally intensive and have not yet been widely adopted. Previous research has recommended implementing nonnormality corrections when θ is not "approximately normal." This research focused on examining how far θ can deviate from normal before the normality assumption becomes untenable. Specifically, our goal was to identify the type(s) and degree(s) of nonnormality that result in unacceptable parameter recovery for the graded response model (GRM) and 2-parameter logistic model (2PLM).


Use of conformal high-dose rate brachytherapy for management of patients with prostate cancer: optimizing dose escalation.
We reviewed our institution's experience treating patients with locally advanced prostate cancer using high-dose rate (HDR) conformal brachytherapy. Treatment technique, interim results, and toxicity are reviewed. From November 1991 to May 1998, 161 patients with locally advanced prostate cancer were treated on a dose escalation trial of external-beam radiation therapy (EBRT) combined with HDR conformal brachytherapy boosts. Patients with any of the following characteristics were acceptable for enrollment: pretreatment prostate-specific antigen (PSA) > or =10 ng/mL, Gleason score > or =7, or clinical stage T2b or higher. All patients received pelvic EBRT to a median dose of 46 Gy. Transperineal ultrasound-guided temporary HDR brachytherapy implant boosts were performed in the first, second, and third week of EBRT. Seventy-two patients were boosted with three implants (boost dose 5.50 to 6.50 Gy), and 89 patients received two implants (boost dose 8.25 to 10.50 Gy). All implants were placed using interactive real-time dosimetry. Biochemical failure was calculated using the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. Median follow-up was 2.8 years (range 0.3-7.2). The 2- and 5-year actuarial biochemical control rates were 86% and 67%, respectively. The 5-year actuarial biochemical control rates for patients with a pretreatment PSA < or =3.9, 4.0-9.9, 10.0-19.9, and > or =20.0 ng/mL were 80%, 87%, 56%, and 54%, respectively. Factors associated with biochemical failure on multivariate analysis included the pretreatment PSA, Gleason score, PSA nadir, and time to PSA nadir. A total of 6 patients (4%) developed grade 3 late toxicity consisting of urethral stricture (5 patients) or incontinence (1 patient). Forty- four patients (27%) developed impotence after radiation therapy. Conformal HDR brachytherapy boosts appear to offer a safe, reproducible, and effective method of dose escalation in patients with locally advanced prostate cancer treated with RT. Interim results with this technology reveal biochemical control rates paralleling those achieved with three-dimensional conformal EBRT and other forms of treatment.


A genetic locus controlling aging-sensitive regression of B lymphopoiesis in an autoimmune-prone MRL/lpr strain of mice.
Aging readily affects immune system under the influence of environmental and/or intrinsic factors while accelerating the development of various immune disorders including autoimmune diseases. Little is known about molecular and cellular mechanisms connecting between immune senescence and development of autoimmune diseases. Here, we first show strain-specific and aging-sensitive onset of B-cell abnormality in a lupus-prone MRL/Mp.Fas(lpr) (MRL/lpr) strain of mice. This abnormality was characterized by the regression of B lymphopoiesis in the bone marrow of this strain. We next examined the association between the B-cell regression and onset of autoimmune diseases in aged (MRL/lpr x C3H/He.Fas(lpr)) F2 mice, in which pathologic phenotypes, such as glomerulonephritis, vasculitis, sialoadenitis and arthritis, variously developed. We also searched whole genome to identify genetic loci linked to the B-cell regression by using the same F2 mice. The B-cell regression manifested in the spleen of F2 mice was retrospectively evaluated by reverse transcriptase-based PCR quantification. The results demonstrated that the onset of autoimmune diseases in the F2 mice was not associated with the aging-sensitive B-cell regression. The genetic study identified a significant locus responsible for the B-cell regression in the vicinity of D5Mit233 (29 cM). This is first evidence for the presence of a genetic locus that affects B lymphopoiesis in an aging-sensitive manner.


Extracellular volume by dual-energy CT, hepatic reserve capacity scoring, CT volumetry, and transient elastography for estimating liver fibrosis.
Our purpose was to compare the efficacy of liver and splenic volumetry (LV and SV), extracellular volume (ECV) on dual-layer spectral-detector CT scoring systems for estimating liver fibrosis (LF) in 45 patients with pathologically staged LF. ECV measured on CT value (HU-ECV), iodine density (ID-ECV), atomic number (Zeff-ECV), and electron density (ED-ECV), LV or SV/body surface area (BSA), albumin bilirubin grade (ALBI), model for end-stage liver disease (MELD) score, aspartate aminotransferase platelet ratio index (APRI), and fibrosis index based on the four factors (FIB-4) were recorded. Transient elastography was measured in 22 patients, and compared to ECV. No correlation was found between transient elastography and all ECVs. Area under the curve (AUC) for estimating F4 on transient elastography was 0.885 (95% CI 0.745-1.000). ALBI was weakly associated with LF (p = 0.451), while MELD (p < 0.001), APRI (p = 0.010), and FIB-4 (p = 0.010) were significantly associated with LF. SV/BSA had a higher AUC than MELD, APRI, and FIB-4 for estimating F4 (AUC = 0.815, 95% CI 0.63-0.999), but MELD (AUC = 0.799, 95% CI 0.634-0.965), APRI (AUC = 0.722, 95% CI 0.561-0.883), and FIB-4 (AUC = 0.741, 95% CI 0.582-0.899) had higher AUCs than ALBI. SV/BSA significantly contributed to differentiation for estimating F4; odds ratio (OR) was 1.304-1.353 (Reader 1-2; R1-R2), whereas MELD significantly contributed to the differentiation between F0-2 and F3-4; OR was 1.528-1.509 (R1-R2). AUC for SV/BSA and MELD combined was 0.877 (95% CI 0.748-1.000). In conclusion, SV/BSA allows for a higher estimation of liver cirrhosis (F4). MELD is more suitable for assessing severe LF (≥ F3-4). The combination of SV/BSA and MELD had a higher AUC than SV/BSA alone for liver cirrhosis (F4).


Superconductivity in topological insulator Sb2Te3 induced by pressure.
Topological superconductivity is one of most fascinating properties of topological quantum matters that was theoretically proposed and can support Majorana Fermions at the edge state. Superconductivity was previously realized in a Cu-intercalated Bi2Se3 topological compound or a Bi2Te3 topological compound at high pressure. Here we report the discovery of superconductivity in the topological compound Sb2Te3 when pressure was applied. The crystal structure analysis results reveal that superconductivity at a low-pressure range occurs at the ambient phase. The Hall coefficient measurements indicate the change of p-type carriers at a low-pressure range within the ambient phase, into n-type at higher pressures, showing intimate relation to superconducting transition temperature. The first principle calculations based on experimental measurements of the crystal lattice show that Sb2Te3 retains its Dirac surface states within the low-pressure ambient phase where superconductivity was observed, which indicates a strong relationship between superconductivity and topology nature.


Plasma concentrations of estradiol and testosterone, gonadal aromatase activity and ultrastructure of the testis in Xenopus laevis exposed to estradiol or atrazine.
The ultrastructure of testicular cells of adult male African clawed frogs (Xenopus laevis) exposed to either estradiol (0.1 microg/L) or 2-chloro-4-ethylamino-6-isopropyl-amino-s-triazine (atrazine; 10 or 100 microg/L) was examined by electron microscopy and compared to plasma concentrations of the steroid hormones, testosterone (T) and estradiol (E2), testicular aromatase activity and gonad growth expressed as the gonado-somatic index (GSI). Exposure to E2 caused significant changes both at the sub-cellular and biochemical levels. Exposure to E2 resulted in significantly fewer sperm cells, inhibition of meiotic division of germ cells, more lipid droplets that are storage compartments for the sex steroid hormone precursor cholesterol, and lesser plasma T concentrations. Although not statistically significant, frogs exposed to E2 had slightly smaller GSI values. These results may be indicative of an inhibition of gonad growth and disrupted germ cell development by E2. Concentrations of E2 in plasma were greater in frogs exposed to E2 in water. Exposure to neither concentration of atrazine caused effects on germ cell development, testicular aromatase activity or plasma hormone concentrations. These results suggest that atrazine does not affect testicular function. In contrast, exposure of male X. laevis to E2 led to sub-cellular events that are indicative of disruption of testicular development, and demasculinization processes (decrease of androgen hormone titers). These results indicate that atrazine does not cause responses that are similar to those caused by exposure to E2.


Escherichia ruysiae sp. nov., a novel Gram-stain-negative bacterium, isolated from a faecal sample of an international traveller.
The genus Escherichia comprises five species and at least five lineages currently not assigned to any species, termed 'Escherichia cryptic clades'. We isolated an Escherichia strain from an international traveller and resolved the complete DNA sequence of the chromosome and an IncI multidrug resistance plasmid using Illumina and Nanopore whole-genome sequencing (WGS). Strain OPT1704T can be differentiated from existing Escherichia species using biochemical (VITEK2) and genomic tests [average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH)]. Phylogenetic analysis based on alignment of 16S rRNA sequences and 682 concatenated core genes showed similar results. Our analysis further revealed that strain OPT1704T falls within Escherichia cryptic clade IV and is closely related to cryptic clade III. Combining our analyses with publicly available WGS data of cryptic clades III and IV from Enterobase confirmed the close relationship between clades III and IV (>96 % interclade ANI), warranting assignment of both clades to the same novel species. We propose Escherichia ruysiae sp. nov. as a novel species, encompassing Escherichia cryptic clades III and IV (type strain OPT1704T=NCCB 100732T=NCTC 14359T).


CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice.
The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.


Sevoflurane activates hippocampal CA3 kainate receptors (Gluk2) to induce hyperactivity during induction and recovery in a mouse model.
In addition to general anaesthetic effects, sevoflurane can also induce hyperactive behaviours during induction and recovery, which may contribute to neurotoxicity; however, the mechanism of such effects is unclear. Volatile anaesthetics including isoflurane have been found to activate the kainate (GluK2) receptor. We developed a novel mouse model and further explored the involvement of kainate (GluK2) receptors in sevoflurane-induced hyperactivity. Maximal speed, mean speed, total movement distance and resting percentage of C57BL/6 mice were quantitatively measured using behavioural tracking software before and after sevoflurane anaesthesia. Age dependence of this model was also analysed and sevoflurane-induced hyperactivity was evaluated after intracerebral injection of the GluK2 receptor blocker NS-102. Neurones from the hippocampal CA3 region were used to undertake in vitro electrophysiological measurement of kainate currents and miniature excitatory postsynaptic potential (mEPSP). Sevoflurane induced significant hyperactivities in mice under sevoflurane 1% anaesthesia and during the recovery period, characterized as increased movement speed and total distance. The hyperactivity was significantly increased in young mice compared with adults (P<0.01) and pre-injection of NS-102 significantly prevented this sevoflurane-induced hyperactivity. In electrophysiological experiments, sevoflurane significantly increased the frequency of mEPSP at low concentrations and evoked kainate currents at high concentrations. We developed a behavioural model in mice that enabled characterization of sevoflurane-induced hyperactivity. The kainate (GluK2) receptor antagonist attenuated these sevoflurane-induced hyperactivities in vivo, suggesting that kainate receptors might be the underlying therapeutic targets for sevoflurane-induced hyperactivities in general anaesthesia.


Ribonucleotide reductases: divergent evolution of an ancient enzyme.
Ribonucleotide reductases (RNRs) are uniquely responsible for converting nucleotides to deoxynucleotides in all dividing cells. The three known classes of RNRs operate through a free radical mechanism but differ in the way in which the protein radical is generated. Class I enzymes depend on oxygen for radical generation, class II uses adenosylcobalamin, and the anaerobic class III requires S-adenosylmethionine and an iron-sulfur cluster. Despite their metabolic prominence, the evolutionary origin and relationships between these enzymes remain elusive. This gap in RNR knowledge can, to a major extent, be attributed to the fact that different RNR classes exhibit greatly diverged polypeptide chains, rendering homology assessments inconclusive. Evolutionary studies of RNRs conducted until now have focused on comparison of the amino acid sequence of the proteins, without considering how they fold into space. The present study is an attempt to understand the evolutionary history of RNRs taking into account their three-dimensional structure. We first infer the structural alignment by superposing the equivalent stretches of the three-dimensional structures of representatives of each family. We then use the structural alignment to guide the alignment of all publicly available RNR sequences. Our results support the hypothesis that the three RNR classes diverged from a common ancestor currently represented by the anaerobic class III. Also, lateral transfer appears to have played a significant role in the evolution of this protein family.


Electron transfer and catalysis with high-valent metal-oxo complexes.
High-valent metal-oxo complexes are produced by reductive activation of dioxygen via reduction of metal complexes with reductants and dioxygen. Photoinduced electron transfer from substrates to metal complexes with dioxygen also leads to the generation of high-valent metal-oxo complexes that can oxygenate substrates. In such a case metal complexes act as a photocatalyst to oxygenate substrates with dioxygen. High-valent metal-oxo complexes are also produced by proton-coupled electron-transfer oxidation of metal complexes by one-electron oxidants with water, oxygenating substrates to regenerate metal complexes. In such a case metal complexes act as a catalyst for electron-transfer oxygenation of substrates by one-electron oxidants with water that acts as an oxygen source. The one-electron oxidants which can oxidize metal complexes can be replaced by much weaker oxidants by a combination of redox photocatalysts and metal complexes. Thus, photocatalytic oxygenation of substrates proceeds via photoinduced electron transfer from a photocatalyst to reductants followed by proton-coupled electron transfer oxidation of metal complexes with the oxidized photocatalyst to produce high-valent metal-oxo complexes that oxygenate substrates. Thermal and photoinduced electron-transfer catalytic reactions of high-valent metal-oxo complexes for oxygenation of substrates using water or dioxygen as an oxygen source are summarized in this perspective.


Dissociation of left ventricular end-ejection from end-systole: scintigraphic evaluation and implication.
We have measured the extent and evaluated afterload dependence of temporal dissociation of left ventricular end-ejection from end-systole using count rate dependent scintigraphic method. Good predictability of the dissociation (y) especially in the lower ranges of afterload (x) has been demonstrated (y = 9.1 x -763: r1 0.72: r2 0.55: r3 0.86). Role of the dissociation as the corrective parameter in count rate dependent scintigraphic method for evaluation of left ventricular contractile function (in contradistinction to the ejection function) has been discussed.


Influencing Change: When "Best Practice" Changes and the Prototypical Good Farmer Turns Bad.
Twenty-nine farmers with a flock prevalence of lameness >5% were visited in 2013. They participated in a facilitated discussion on treatment of footrot, and evidence-based new "best practice." One year later, farmers were revisited and management and motivators for change were discussed. Farmers were asked how they would persuade other farmers to adopt "best practice." Initially, most participants were resigned to having lame sheep. They believed that prototypical "good farmers" (including trusted family) practiced foot trimming, the traditional "best practice" and that the new "best practice" would be expensive and time consuming. Between 2013 and 2014 lameness prevalence reduced from 7.6 to 4.3%. The major behavioral changes were reduction in foot trimming, increased use of antibacterials to treat footrot, and treating sheep within a week of becoming lame. In 2014, participants were re-interviewed. They reported that an increased knowledge of the evidence-base, trust in the facilitator and talking to other trusted farmers who had already adopted the new "best practice" overcame concerns about the prototypical "good farmer" and motivated change. Persistent change occurred because participants observed health benefits for their sheep and that the new "best practice" had saved time and money. Participants stated that other farmers would be convinced to change to the new "best practice" because it saved time and money, ironically, these were among the original barriers to change. This is possibly an example of cognitive dissonance because farmers had become positive about the benefits of saving time and money following a change in their own behaviors.


Vision merges with touch in a purely tactile discrimination.
To construct a coherent percept of the world, the brain continuously combines information across multiple sensory modalities. Simple stimuli from different modalities are usually assumed to be processed in distinct brain areas. However, there is growing evidence that simultaneous stimulation of multiple modalities can influence the activity in unimodal sensory areas and improve or impair performance in unimodal tasks. Do these effects reflect a genuine cross-modal integration of sensory signals, or are they due to changes in the perceiver's ability to locate the stimulus in time and space? We used a behavioral measure to differentiate between these explanations. Our results demonstrate that, under certain circumstances, a noninformative flash of light can have facilitative or detrimental effects on a simple tactile discrimination. The effect of the visual flash mimics that produced by a constant tactile pedestal stimulus. These findings reveal that sensory signals from different modalities can be integrated, even for perceptual judgments within a single modality.


The Impact of Recombinant Human Erythropoietin Administration in Critically ill COVID-19 Patients: A Multicenter Cohort Study.
The use of erythropoietin-stimulating agents (ESAs) as adjunctive therapy in critically ill patients with COVID-19 may have a potential benefit. This study aims to evaluate the effect of ESAs on the clinical outcomes of critically ill COVID-19 patients. A multicenter, retrospective cohort study was conducted from 01-03-2020 to 31-07-2021. We included adult patients who were ≥ 18 years old with a confirmed diagnosis of COVID-19 infection and admitted to intensive care units (ICUs). Patients were categorized depending on ESAs administration during their ICU stay. The primary endpoint was the length of stay; other endpoints were considered secondary. After propensity score matching (1:3), the overall included patients were 120. Among those, 30 patients received ESAs. A longer duration of ICU and hospital stay was observed in the ESA group (beta coefficient: 0.64; 95% CI: 0.31-0.97; P = < .01, beta coefficient: 0.41; 95% CI: 0.12-0.69; P = < .01, respectively). In addition, the ESA group's ventilator-free days (VFDs) were significantly shorter than the control group. Moreover, patients who received ESAs have higher odds of liver injury and infections during ICU stay than the control group. The use of ESAs in COVID-19 critically ill patients was associated with longer hospital and ICU stays, with no survival benefits but linked with lower VFDs.


The Potential Contribution of Chronic Pain and Common Chronic Pain Conditions to Subsequent Cognitive Decline, New Onset Cognitive Impairment, and Incident Dementia: A Systematic Review and Conceptual Model for Future Research.
Growing evidence suggests that chronic pain and certain chronic pain conditions may increase risk for cognitive decline and dementia. In this systematic review, we critically evaluate available evidence regarding the association of chronic pain and specific common chronic pain conditions to subsequent decline in cognitive function, new onset cognitive impairment (CI), and incident Alzheimer's disease and related dementias (ADRD); outline major gaps in the literature; and provide a preliminary conceptual model illustrating potential pathways linking pain to cognitive change. To identify qualifying studies, we searched seven scientific databases and scanned bibliographies of identified articles and relevant review papers. Sixteen studies met our inclusion criteria (2 matched case-control, 10 retrospective cohort, 2 prospective cohort), including 11 regarding the association of osteoarthritis (N = 4), fibromyalgia (N = 1), or headache/migraine (N = 6) to incident ADRD (N = 10) and/or its subtypes (N = 6), and 5 investigating the relation of chronic pain symptoms to subsequent cognitive decline (N = 2), CI (N = 1), and/or ADRD (N = 3). Studies yielded consistent evidence for a positive association of osteoarthritis and migraines/headaches to incident ADRD; however, findings regarding dementia subtypes were mixed. Emerging evidence also suggests chronic pain symptoms may accelerate cognitive decline and increase risk for memory impairment and ADRD, although findings and measures varied considerably across studies. While existing studies support a link between chronic pain and ADRD risk, conclusions are limited by substantial study heterogeneity, limited investigation of certain pain conditions, and methodological and other concerns characterizing most investigations to date. Additional rigorous, long-term prospective studies are needed to elucidate the effects of chronic pain and specific chronic pain conditions on cognitive decline and conversion to ADRD, and to clarify the influence of potential confounding and mediating factors.


Seroprevalence of poliovirus antibodies among children in a Dominican community--Puerto Rico, 2002.
Although the Region of the Americas was certified as polio-free in 1994, an outbreak of paralytic poliomyelitis associated with circulating vaccine-derived poliovirus (cVDPV) occurred during July 2000-July 2001 on the Caribbean island of Hispaniola. A total of 21 cases of paralytic polio associated with type 1 oral poliovirus vaccine (OPV) strain were reported in Haiti and the Dominican Republic (DR). Outbreaks from cVDPV occur among children in communities with low immunity levels to polioviruses and the absence of circulation of wild poliovirus (WPV). The U.S. territory of Puerto Rico (PR), located approximately 72 miles east of DR, has not had a case of paralytic polio since 1974. However, because of its proximity to DR and concerns that visitors and immigrants from DR (who tend to live in a separate community in PR) might not be fully vaccinated against polioviruses, the PR Department of Health (PRDH) and CDC assessed the seroprevalence of poliovirus antibodies among children aged 7-60 months in a predominantly DR community of PR. This report describes the results of that assessment, which indicated high levels of seropositivity for all three poliovirus serotypes. If vaccination rates remain high, the risk for a polio outbreak in this community is low. However, until all threats of poliovirus are eliminated globally, high rates of vaccination among preschool children must be ensured to prevent outbreaks of paralytic polio from any source (e.g., imported WPV, laboratory strains, or cVDPV) in the United States and its territories.


Interaction of gold nanoparticles and nickel(II) sulfate affects dendritic cell maturation.
Despite many investigations have focused on the pristine toxicity of gold nanoparticles (GNPs), little is known about the outcome of co-exposure and interaction of GNPs with heavy metals which can possibly detoxify or potentiate them. Here, the combined exposure of nickel (II) sulfate (NiSO4) and GNPs on the maturation response of dendritic cells (DCs) was explored. Exposure to GNPs or NiSO4 separately induced cell activation. When cells were exposed to a mixture of both, however, the observed cell activation pattern indicated a competitive rather than an additive effect of both inducers with levels similar to those induced by NiSO4 alone. Quantification of the GNP uptake by DCs demonstrated a significant decrease in intracellular gold content during co-incubation with NiSO4. An extensive physiochemical characterization was performed to determine the interaction between GNPs and NiSO4 in the complex physiological media using nanoparticle tracking analyses, disc centrifugation, UV-visible spectroscopy, ICP-MS analyses, zeta potential measurements, electron microscopy, and proteomics. Although GNPs and NiSO4 did not directly interact with each other, the presence of NiSO4 in the physiological media resulted in changes in GNPs' charge and their associated protein corona (content and composition), which may contribute to a decreased cellular uptake of GNPs and sustaining the nickel-induced DC maturation. The presented results provide new insights in the interaction of heavy metals and NPs in complex physiological media. Moreover, this study highlights the necessity of mixture toxicology, since these combined exposures are highly relevant for human subjection to NPs and risk assessment of nanomaterials.


Prolonged nonhydrolytic interaction of nucleotide with CFTR's NH2-terminal nucleotide binding domain and its role in channel gating.
CFTR, the protein defective in cystic fibrosis, functions as a Cl- channel regulated by cAMP-dependent protein kinase (PKA). CFTR is also an ATPase, comprising two nucleotide-binding domains (NBDs) thought to bind and hydrolyze ATP. In hydrolyzable nucleoside triphosphates, PKA-phosphorylated CFTR channels open into bursts, lasting on the order of a second, from closed (interburst) intervals of a second or more. To investigate nucleotide interactions underlying channel gating, we examined photolabeling by [alpha32P]8-N3ATP or [gamma32P]8-N3ATP of intact CFTR channels expressed in HEK293T cells or Xenopus oocytes. We also exploited split CFTR channels to distinguish photolabeling at NBD1 from that at NBD2. To examine simple binding of nucleotide in the absence of hydrolysis and gating reactions, we photolabeled after incubation at 0 degrees C with no washing. Nucleotide interactions under gating conditions were probed by photolabeling after incubation at 30 degrees C, with extensive washing, also at 30 degrees C. Phosphorylation of CFTR by PKA only slightly influenced photolabeling after either protocol. Strikingly, at 30 degrees C nucleotide remained tightly bound at NBD1 for many minutes, in the form of nonhydrolyzed nucleoside triphosphate. As nucleotide-dependent gating of CFTR channels occurred on the time scale of seconds under comparable conditions, this suggests that the nucleotide interactions, including hydrolysis, that time CFTR channel opening and closing occur predominantly at NBD2. Vanadate also appeared to act at NBD2, presumably interrupting its hydrolytic cycle, and markedly delayed termination of channel open bursts. Vanadate somewhat increased the magnitude, but did not alter the rate, of the slow loss of nucleotide tightly bound at NBD1. Kinetic analysis of channel gating in Mg8-N3ATP or MgATP reveals that the rate-limiting step for CFTR channel opening at saturating [nucleotide] follows nucleotide binding to both NBDs. We propose that ATP remains tightly bound or occluded at CFTR's NBD1 for long periods, that binding of ATP at NBD2 leads to channel opening wherupon its hydrolysis prompts channel closing, and that phosphorylation acts like an automobile clutch that engages the NBD events to drive gating of the transmembrane ion pore.


Perioperative outcomes following robot-assisted partial nephrectomy for complex renal masses: A Vattikuti Collective Quality Initiative database study.
Outcomes of robot-assisted partial nephrectomy (RAPN) depend on tumor complexity, surgeon experience and patient profile among other variables. We aimed to study the perioperative outcomes of RAPN for patients with complex renal masses using the Vattikuti Collective Quality Initiative (VCQI) database that allowed evaluation of multinational data. From the VCQI, we extracted data for all the patients who underwent RAPN with preoperative aspects and dimensions used for an anatomical (PADUA) score of ≥10. Multivariate logistic regression was conducted to ascertain predictors of trifecta (absence of complications, negative surgical margins, and warm ischemia times [WIT] <25 min or zero ischemia) outcomes. Of 3,801 patients, 514 with PADUA scores ≥10 were included. The median operative time, WIT, and blood loss were 173 (range 45-546) min, 21 (range 0-55) min, and 150 (range 50-3500) ml, respectively. Intraoperative complications and blood transfusions were reported in 2.1% and 6%, respectively. In 8.8% of the patients, postoperative complications were noted, and surgical margins were positive in 10.3% of the patients. Trifecta could be achieved in 60.7% of patients. Clinical tumor size, duration of surgery, WIT, and complication rates were significantly higher in the group with a high (12 or 13) PADUA score while the trifecta was significantly lower in this group (48.4%). On multivariate analysis, surgical approach (retroperitoneal vs. transperitoneal) and high PADUA score (12/13) were identified as predictors of the trifecta outcomes. RAPN may be a reasonable surgical option for patients with complex renal masses with acceptable perioperative outcomes.


Synthesis, receptor binding affinities and conformational properties of cyclic methylenedithioether analogues of angiotensin II.
Cyclic 12-, 13- and 14-membered ring angiotensin II analogues related to disulfides but encompassing methylene-dithioether bridges have been prepared. The affinity data from these derivatives were compared to those from the disulfides. The methylenedithioether analogues displayed good binding affinities to rat liver AT1 receptors although in most cases somewhat lower than their disulfide counterparts. One of the methylenedithioethers with a 13-membered ring system demonstrated the highest binding affinity among the thioethers. Theoretical conformational analysis of model compounds of the two series were performed suggesting a similarity between the disulfide and the corresponding methylenedithioether analogues and also between the ring size homologues. This analysis also suggested that some of the model compounds were prone to adopt inverse gamma-turn conformations, which was further supported by use of NMR spectroscopy of the 12-membered ring analogue in the series. The easily executed methylenedithioether cyclization should constitute a valuable complement to the common disulfide methodology for fine-tuning and for probing the bioactive conformation of peptides.


Myasthenia Gravis: An Acquired Interferonopathy?
Myasthenia gravis (MG) is a rare autoimmune disease mediated by antibodies against components of the neuromuscular junction, particularly the acetylcholine receptor (AChR). The thymus plays a primary role in AChR-MG patients. In early-onset AChR-MG and thymoma-associated MG, an interferon type I (IFN-I) signature is clearly detected in the thymus. The origin of this chronic IFN-I expression in the thymus is not yet defined. IFN-I subtypes are normally produced in response to viral infection. However, genetic diseases called interferonopathies are associated with an aberrant chronic production of IFN-I defined as sterile inflammation. Some systemic autoimmune diseases also share common features with interferonopathies. This review aims to analyze the pathogenic role of IFN-I in these diseases as compared to AChR-MG in order to determine if AChR-MG could be an acquired interferonopathy.


Osteoradionecrosis of the mandible: scientific basis for clinical staging.
Osteoradionecrosis of the mandible can be a serious complication of radiotherapy for head and neck cancer. The disorder generally presents in one of several distinct clinical variations. This is probably because of a complex interaction of etiologic factors. A clinical staging system for the disorder is described. Such a system is necessary for the conduct of clinical research, and for the development and assessment of treatment regimens.


[Survival of enteric viruses adsorbed on glass microfibers during postal transport].
The survival of enteric viruses (poliovirus type 1, Mahoney strain, and indigenous viruses of waste waters) has been studied after adsorption of the viruses (pH 3.5) on glass microfiber filters. After postal transport, the presence of the viruses was checked on the filters being soaked in a 3% beef extract solution (pH 7.5) either frozen or without protection against heat. Viruses were recovered at a rate of 59 to 65%. For qualitative studies, postal shipment of samples adsorbed on fiberglass may allow extension of a control system for enteroviruses in water.


Cerebral hypometabolism and grey matter density in MAPT intron 10 +3 mutation carriers.
Multiple systems tauopathy with presenile dementia (MSTD), a form of frontotemporal dementia with parkinsonism-17 with tau inclusions (FTDP-17T), is a neurodegenerative disorder caused by an (a) to (g) transition at position +3 of intron 10 of the microtubule associated protein tau (MAPT) gene. The mutation causes overexpression of 4 repeat (4R) tau isoforms with increased 4R/3R ratio leading to neurodegeneration. Clinically, these patients primarily present with behavioral variant FTD (bvFTD) and show disinhibition, disordered social comportment, and impaired executive function, memory, and speech. While altered glucose metabolism has been reported in subjects with sporadic bvFTD, it has yet to be investigated in an FTDP-17 sample of this size. In this study, eleven mutation carriers (5 males; mean age = 48.0 ± 6.9 years) and eight non-carriers (2 males; mean age = 43.7 ± 12.0 years) from a MSTD family were imaged using [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Eight of the MAPT intron 10 +3 mutation carriers met diagnostic criteria for bvFTD at the time of the PET scan, while three MAPT intron 10 +3 carriers were not cognitively impaired at the time of scan. Non-carriers had no clinically-relevant cognitive impairment at the time of the PET scan. Additionally, ten mutation carriers (5 males; mean age = 48.04 ± 2.1 years) and seven non-carriers (2 males; mean age 46.1 ± 4.1 years) underwent magnetic resonance imaging (MRI) which is an expanded sample size from a previous study. Seven MAPT mutation carriers met diagnostic criteria for bvFTD at the time of the MRI scan. Images were assessed on a voxel-wise basis for the effect of mutation carrier status. SPM8 was used for preprocessing and statistical analyses. Compared to non-carriers, MAPT mutation carriers showed lower [(18)F]FDG uptake bilaterally in the medial temporal lobe, and the parietal and frontal cortices. Anatomical changes were predominantly seen bilaterally in the medial temporal lobe areas which substantially overlapped with the hypometabolism findings. These anatomical and metabolic changes overlap previously described patterns of neurodegeneration in MSTD patients and are consistent with the characteristics of their cognitive dysfunction. These results suggest that neuroimaging can describe the neuropathology associated with this MAPT mutation.


Histological response on skeletal muscle to ischemia.
The response of skeletal muscle to ischemia or trauma is similar whatever the mechanism of injury. Muscle has much more inherent ability to regenerate than has been recognized in the past. The extent of muscle damage is proportional to the duration and severity of the ischemic process. Circulation to ischemis muscle must be re-established as soon as possible. Early decompression of the appropriate compartemnts is an essential part of this procedure. No attempt should be made to excise muscle of doubtful or unknown viability during the initial decompression operation.