Mate Preferences and Their Behavioral Manifestations.
Evolved mate preferences comprise a central causal process in Darwin's theory of sexual selection. Their powerful influences have been documented in all sexually reproducing species, including in sexual strategies in humans. This article reviews the science of human mate preferences and their myriad behavioral manifestations. We discuss sex differences and sex similarities in human sexual psychology, which vary according to short-term and long-term mating contexts. We review context-specific shifts in mating strategy depending on individual, social, and ecological qualities such as mate value, life history strategy, sex ratio, gender economic inequality, and cultural norms. We review the empirical evidence for the impact of mate preferences on actual mating decisions. Mate preferences also dramatically influence tactics of mate attraction, tactics of mate retention, patterns of deception, causes of sexual regret, attraction to cues to sexual exploitability, attraction to cues to fertility, attraction to cues to resources and protection, derogation of competitors, causes of breakups, and patterns of remarriage. We conclude by articulating unresolved issues and offer a future agenda for the science of human mating, including how humans invent novel cultural technologies to better implement ancient sexual strategies and how cultural evolution may be dramatically influencing our evolved mating psychology.


Pinusolidic acid: a platelet-activating factor inhibitor from Biota orientalis.
The water extract of Biota orientalis showed a potent inhibitory effect on platelet activating factor (PAF) binding to rabbit platelets using [3H]PAF as a ligand in our previous screening studies for Korean medicinal antagonists by the activity-guided purification studies. Another active compound, compound 1 (IC50 = 2.3 x 10(-5) M, 7.48 +/- 2.11 micrograms/ml, n = 4) was isolated from the title plant. The chemical structure of compound 1 was elucidated as pinusolidic acid by chemical and spectrometric analyses.


Prevalence and clinical correlates of pruritus in patients with systemic sclerosis.
There are no studies of pruritus prevalence or clinical correlates in systemic sclerosis (SSc). The objectives of this study were to document the proportion of SSc patients with pruritus on most days, to determine when in the course of the disease pruritus is most prevalent, and to identify clinical correlates. We performed a cross-sectional, multicenter study of 400 SSc patients from the Canadian Scleroderma Research Group Registry > or =1 year after Registry enrollment. Patients indicated whether they experienced pruritus during the past month on most days and underwent clinical histories and medical examinations. Multiple logistic regression was used to assess the association between sociodemographic and clinical variables and pruritus. A total of 179 patients (45%) reported pruritus on most days, including 69% (11 of 16) among patients 1.0-1.9 years from onset of non-Raynaud's symptoms, 41% (38 of 93) for 2.0-4.9 years, 47% (44 of 94) for 5.0-9.9 years, 43% (60 of 140) for 10.0-19.9 years, and 46% (26 of 57) for > or =20 years. In post hoc analysis, patients 1.0-1.9 years from disease onset were significantly more likely to report pruritus (P = 0.049). Patients with pruritus had significantly more skin involvement (P = 0.029), more gastrointestinal (GI) symptoms (P < 0.001), worse breathing problems (P = 0.001), worse Raynaud's symptoms (P = 0.002), and more severe finger ulcers (P = 0.009). Only the number of GI symptoms predicted pruritus in multiple logistic regression analysis (odds ratio 1.25, 95% confidence interval 1.13-1.37; P < 0.001). Pruritus is common in SSc and is independently associated with GI symptoms. Focused research on sources of pruritus and its management in SSc is needed.


Spontaneous germ cell apoptosis in humans: evidence for ethnic differences in the susceptibility of germ cells to programmed cell death.
Spontaneous death of certain classes of germ cells has been shown to be a constant feature of normal spermatogenesis in a variety of mammalian species, including the human. Recent studies on various animal models have demonstrated that apoptosis is the underlying mechanism of germ cell death during normal spermatogenesis. Withdrawal of gonadotropins and/or testosterone further accelerates the germ cell apoptosis. We examined the involvement of apoptosis in the spontaneous loss of germ cells in men. Testicular samples obtained at autopsy from 5 Chinese and 9 non-Hispanic Caucasian men were analyzed. To identify individual germ cells undergoing apoptosis, we used a modified terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling technique that detects germ cell apoptosis with high sensitivity and specificity. Testicular sections from all 14 subjects exhibited spontaneous occurrence of germ cell apoptosis involving spermatogonia, spermatocytes, and spermatids (apoptotic indexes, 1.6 +/- 0.4 2.5 +/- 0.6, and 5.5 +/- 1.2, respectively). The incidence of spermatogonial (2.8 +/- 0.8 vs. 1.0 +/- 0.2) as well as spermatid (9.3 +/- 2.1 vs. 8.4 +/- 0.9) apoptosis was higher in Chinese than in Caucasian men. A higher incidence of spermatocyte apoptosis was also noted for Chinese (4.4 +/- 1.4) compared to Caucasian (1.9 +/- 0.4) men, but the difference was not statistically significant. These results suggest that germ cell death during normal spermatogenesis in men occurs via apoptosis and provide evidence for ethnic differences in the inherent susceptibility of germ cells to programmed cell death. Our data may also help to explain the greater efficacy of testosterone-induced spermatogenic suppression to azoospermia observed in Asian compared to non-Asian men.


The metastable brain.
Neural ensembles oscillate across a broad range of frequencies and are transiently coupled or "bound" together when people attend to a stimulus, perceive, think, and act. This is a dynamic, self-assembling process, with parts of the brain engaging and disengaging in time. But how is it done? The theory of Coordination Dynamics proposes a mechanism called metastability, a subtle blend of integration and segregation. Tendencies for brain regions to express their individual autonomy and specialized functions (segregation, modularity) coexist with tendencies to couple and coordinate globally for multiple functions (integration). Although metastability has garnered increasing attention, it has yet to be demonstrated and treated within a fully spatiotemporal perspective. Here, we illustrate metastability in continuous neural and behavioral recordings, and we discuss theory and experiments at multiple scales, suggesting that metastable dynamics underlie the real-time coordination necessary for the brain's dynamic cognitive, behavioral, and social functions.


[Hydatid cyst of the right kidney invading into the duodenum. Apropos of a case].
The authors report about one case of hydatid cyst of the right kidney with a fissure opening into the duodenum. They emphasize the exceptional character of this complication, as well as the importance of imaging for its diagnosis.


Potassium-chloride cotransport in cultured chick heart cells.
The polystrand preparation of cultured chick heart cells has a unidirectional transmembrane Cl- efflux that is twice K+ efflux. However, Cl- conductance of this heart cell membrane is low [regardless of extracellular K+ (K+o)], suggesting the existence of electroneutral Cl--dependent transport mechanisms. Furosemide (10(-3) M) decreases the 36Cl tracer efflux rate constant from a control value of 0.67 to 0.33 min-1. Extracellular Na+--free solution, which depletes intracellular Na+ within 1 min, has no significant effect on 36Cl efflux. K+o-free solution plus 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; 10(-4) M) promotes the loss of Cl- against the Cl- electrochemical gradient; Cl- loss is furosemide sensitive in a dose-dependent manner. Incubating polystrands in 133 mM K+o, normal extracellular Cl- (Cl-o) solution causes net K+ and Cl- uptake in a 1:1 stoichiometry as well as a furosemide-sensitive volume increase; 130 mM extracellular choline or Li+ cannot mimic this high-K+o-induced volume increase. Removal of Cl-o from 133 mM K+o solution prevents K+ uptake and causes a Cl- loss as well as a furosemide-sensitive volume decrease. Adjusting Cl-o concentrations in high-K+o solution plus DIDS, so that the Cl- chemical gradient equally opposes the K+ chemical gradient, prevents high-K+o-induced volume changes. These data suggest that the cardiac cell membrane contains a furosemide-sensitive K+-Cl- cotransport mechanism.


Is there any association between overweight, obesity and symptoms of reflux disease?
The present study was aimed to identify the association of overweight and obesity with gastroesophageal reflux disease (GERD). This age- and sex-matched case-control study was carried out in a sample of subjects referred to the specialized clinic of Tabriz University of Medical Sciences from November 2006 to March 2007. Data were collected using a demographic questionnaire and a checklist to determine reflux symptoms. Weight and height were measured and Body Mass Index (BMI) was calculated. Logistic regression was used to examine the association between overweight, obesity and reflux symptoms. The study population included 106 cases (with reflux symptoms) and 111 controls with a mean age of 35.2 +/- 12.9 years. The mean BMI was 2.4 units greater in cases than controls (p = 0.0001). In unadjusted model, overweight (OR = 3.41, CI: 1.8-6.44) and obesity (OR = 2.84, CI: 1.38-5.82) were significantly associated with GERD. Results of multivariate logistic regression revealed significant association between overweight and GERD after adjusting for confounders (OR = 2.87, CI: 1.49-5.53). Given the increasing prevalence of patients with both overweight/obesity and GERD, Serious dietary intervention studies for weight loss as a therapeutic strategy should be carried out in GERD patients complicated with obesity.


Should CYP2C19 Genotyping Be Recommended as a Straight Forward Approach to Optimize Clopidogrel Utilization in Patients with Ischemic Stroke Complicated by Type 2 Diabetes Mellitus?
There have been few studies on CYP2C19 genotypes and clopidogrel response associated with ischemic stroke (IS), especially IS complicated by type 2 diabetes mellitus (T2DM). This study aimed to investigate the possible association between CYP2C19 polymorphisms and high on-treatment platelet reactivity (HTPR) in IS patients with T2DM in China. A total of 426 consecutive IS patients with T2DM were enrolled in this case-control study and they were divided into HTPR group and non-HTPR group according to the ADP-induced platelet inhibition (PIADP) assessed by thromboelastography (TEG). Genotypes were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Various clinical and demographic data were also recorded. The association between CYP2C19 genetic variants and platelet function was assessed. Carriers of CYP2C19*2 heterozygous and mutant homozygous genotypes showed significantly lower PIADP than non-carriers (27.2% vs 38.3%, p < 0.001; 27.41% vs 38.3%, p = 0.012, respectively). Compared with the control group, the CYP2C19*2 A allele was more frequent in the HTPR group (34.51% vs 25.82%, p = 0.002). The carriage of CYP2C19*2 mutant allele was significantly associated with increased risk of HTPR (odds ratio (OR) = 1.94, 95% confidence interval (CI) = 1.32-2.85). There was no significant correlation between CYP2C19*3 or *17 genotypes and HTPR risk. CYP2C19*2 mutant allele was associated with attenuated platelet response to clopidogrel and increased risk of HTPR in IS patients with T2DM, suggesting that CYP2C19*2 polymorphism might be an important predictor of HTPR in this high-risk population.


Studies on the biosynthesis of mitochondrial malate dehydrogenase and the location of its synthesis in the liver cell of the rat.
A method is described for the isolation of mitochondrial malate dehydrogenase from either the whole tissue homogenate or from the microsomal fraction of rat liver. The procedure involves the treatment of the tissue extract with detergent followed by gel filtration and chromatography on Amberlite CG-50 and DEAE-cellulose. The resulting enzyme was homogeneous by the criterion of gel electrophoresis. Incubation of the microsomal fraction from rat liver under the usual conditions for protein synthesis in the presence of [(3)H]leucine resulted in the incorporation of (3)H into the mitochondrial malate dehydrogenase when purified as described. The results are taken to indicate that the mitochondrial enzyme is synthesized by the cytoplasmic ribosomes. Possible ways in which the cytoplasmic and mitochondrial forms of malate dehydrogenase reach their final locations in the cell are discussed.


Neutron diffraction studies of biological membranes and membrane components.
In this paper the methods and techniques of neutron diffraction studies of biological membranes and membrane components have been described and demonstrated. Foremost among these are the methods of deuterium exchange and deuterium labeling, since they can directly provide locations of membrane components. In addition, the methods of contrast variation with H2O-D2O mixtures, swelling, direct scaling of data from deuterium-labeled structures, and magnetic orientation have provided useful information in neutron diffraction analyses of membrane structures. Although this field is only in its infancy, it clearly has very encouraging prospects.


False holes as camouflage.
Long noted by naturalists, leaf mimicry provides some of the most impressive examples of camouflage through masquerade. Many species of leaf-mimicking Lepidoptera also sport wing markings that closely resemble irregularly shaped holes caused by decay or insect damage. Despite proposals that such markings can either enhance resemblance to damaged leaves or act to disrupt surface appearance through false depth cues, to our knowledge, no attempt has been made to establish exactly how these markings function, or even whether they confer a survival benefit to prey. Here, in two field experiments using artificial butterfly-like targets, we show that false hole markings provide significant survival benefits against avian predation. Furthermore, in a computer-based visual search experiment, we demonstrate that detection of such targets by humans is impeded in a similar fashion. Equally contrasting light marks do not have the same effect; indeed, they lead to increased detection. We conclude that the mechanism is the disruption of the otherwise homogeneous wing surface (surface disruptive camouflage) and that, by resembling the holes sometimes found in real leaves, the disruptive benefits are not offset by conspicuousness costs.


Diagnosis and management of diabetes insipidus for the internist: an update.
Diabetes insipidus is a disorder characterized by excretion of large amounts of hypotonic urine. Four entities have to be differentiated: central diabetes insipidus resulting from a deficiency of the hormone arginine vasopressin (AVP) in the pituitary gland or the hypothalamus, nephrogenic diabetes insipidus resulting from resistance to AVP in the kidneys, gestational diabetes insipidus resulting from an increase in placental vasopressinase and finally primary polydipsia, which involves excessive intake of large amounts of water despite normal AVP secretion and action. Distinguishing between the different types of diabetes insipidus can be challenging. A detailed medical history, physical examination and imaging studies are needed to detect the aetiology of diabetes insipidus. Differentiation between the various forms of hypotonic polyuria is then done by the classical water deprivation test or the more recently developed hypertonic saline or arginine stimulation together with copeptin (or AVP) measurement. In patients with idiopathic central DI, a close follow-up is needed since central DI can be the first sign of an underlying pathology. Treatment of diabetes insipidus or primary polydipsia depends on the underlying aetiology and differs in central diabetes insipidus, nephrogenic diabetes insipidus and primary polydipsia. This review will discuss issues and newest developments in diagnosis, differential diagnosis and treatment, with a focus on central diabetes insipidus.


Growth factor release in extra- and intramedullary osteosynthesis following tibial fracture.
Recent studies indicate alterations of local and systemic growth factor level during fracture healing. As a result, osteogenic and angiogenic growth factors allow us to monitor fracture healing on a molecular level. We hypothesised that closed intramedullary (IM) reaming and nail fixation, in contrast to open reduction and internal plate fixation (ORIF), could exert an effect on the cellular elements present in the intramedullary canal, leading to increased release of mediators. The purpose of the study was to investigate whether different osteosynthesis techniques influence the released quantity of cytokines. A total of 34 patients with tibia fractures treated with IM fixation and 19 patients treated with ORIF were included in the study. In addition to clinical and radiological examination, serum concentrations of transforming growth factor beta 1(TGF-β1), macrophage-colony stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF), were analysed at 1, 2, 4, 6, 8, 12, and 24 weeks after surgery. Expression of TGF-β1 and M-CSF was increased during the first 2 weeks of fracture healing in patients treated with the IM fixation technique compared with those treated by ORIF. After 24 weeks, M-CSF levels in patients with IM fixation were clearly higher. Conversely, VEGF levels were higher during the first 2 weeks of fracture healing in patients treated by ORIF compared with IM fixation. However, these results were not significant. Our results show that 1 week after surgery neither reamed IM fixation nor ORIF of the tibia could increase the expression of VEGF, M-CSF and TGF-β1 in its favour.


Regulation of NMDA receptors by dopamine D4 signaling in prefrontal cortex.
Increasing evidence has suggested that the interaction between dopaminergic and glutamatergic systems in prefrontal cortex (PFC) plays an important role in normal mental functions and neuropsychiatric disorders. In this study, we examined the regulation of NMDA-type glutamate receptors by the PFC dopamine D4 receptor (one of the principal targets of antipsychotic drugs). Application of the D4 receptor agonist PD168077 caused a reversible decrease of the NMDA receptor (NMDAR)-mediated current in acutely isolated and cultured PFC pyramidal neurons, an effect that was blocked by selective D4 receptor antagonists. Furthermore, application of PD168077 produced a potent reduction of the amplitude (but not paired-pulse ratio) of evoked NMDAR EPSCs in PFC slices. The D4 modulation of NMDA receptors in PFC involved the inhibition of protein kinase A, activation of protein phosphatase 1 and the ensuing inhibition of active Ca2+-calmodulin-dependent kinase II (CaMKII). Moreover, PD168077 reduced the surface expression of NMDARs and triggered the internalization of NMDARs in a manner dependent on CaMKII activity. These results identify a mechanistic link between D4 and NMDA receptors in PFC pyramidal neurons, suggesting that D4 receptors may play an important role in modulating synaptic plasticity and thus cognitive and emotional processes in PFC circuits.


SCOPE: SCripture Oriented Preventive Education.
Counseling to effect lasting change in health behaviors has proven only moderately effective. The Torah, or Five Books of Moses, conveys many of the key messages regularly promulgated by prevention professionals. The promise of synergy with the behavioral messages of preventive medicine among devout Scripture-based adherents led to the development of a SCripture Oriented Preventive Education (SCOPE) tool. Forty-eight SCOPE articles were written to complement the weekly Torah portion read throughout the year in Orthodox Jewish synagogues. These were disseminated via newsletter within a modern Orthodox Jewish community in Israel. Two articles are included. An age-stratified, 25% random sample (120/471) of community readership was surveyed to ascertain receptivity to SCOPE and to gauge support for future implementation. Response rate was 76% (92/120). Lifestyle behavior-related articles were most popular (77% found them interesting) and injury prevention the least (41%). Knowledge gained was the most common benefit reported (55% of respondents), followed by attitude change (24%). Those aged 30 to 49 years were significantly more likely than others to report behavior change (p=0.002) and health improvement (p=0.005) secondary to SCOPE. Clinical prevention (p=0.007) and environmental health (p=0.03) articles were significantly more popular in people aged > or =30 and 30 to 49, respectively. Between 69% and 84% supported the implementation of SCOPE in secondary schools, by physicians, and/or rabbis. SCOPE was designed to deliver prevention materials to faith communities via a Scripture-based vehicle. A postexposure readership survey in an Israeli Orthodox Jewish community demonstrated its effectiveness. SCOPE's ultimate utility as a counseling adjunct in Scripture-adherent communities awaits broader assessment.


Prognostic significance of CD34 expression in childhood B-precursor acute lymphocytic leukemia: a Pediatric Oncology Group study.
We studied the blasts from 795 children greater than 1 year of age with newly diagnosed, untreated B-precursor acute lymphoblastic leukemia (ALL) for expression of the hematopoietic stem cell-associated antigen CD34. All cases were confirmed as B-lineage lymphoblastic leukemia by virtue of expression of CD19 and/or CD22, lack of T-cell antigens, and lack of surface-membrane immunoglobulin (Ig). The CD34 antigen was present in at least 10% of blast cells in 587 (73.8%) of the patients. There was no significant difference in presenting clinical characteristics between CD34+ and CD34- patients save for an increased incidence of CNS involvement at diagnosis in the latter. Patients with CD34+ leukemia were more likely to have blasts expressing CD22, CD9, and CD13 antigens but were less likely to coexpress CD20. Patients with pre-B (cytoplasmic mu) ALL were significantly more likely to lack CD34 on their blasts, while children with hyperdiploid ALL were more likely to be CD34+. Although remission induction rates were not significantly different between patients with CD34+ and CD34-ALL (P = .23), event-free survival was shorter for patients with CD34- leukemia (P = .0014). Even though CD34 expression was associated with certain other known prognostically favorable variables including hyperdiploidy and lack of cytoplasmic Ig, it had an independent favorable effect on treatment outcome, even after adjusting for competing prognostic factors.


A study of human erythrocyte acetylcholinesterase inhibition by chlorpromazine.
Membrane-bound acetylcholinesterase (AChE) from the human erythrocyte is inhibited by chlorpromazine (CPZ) in a concentration range within this amphiphilic drug has been demonstrated to interact with erythrocyte membranes, causing a large spectrum of physical and structural effects; membrane solubilization with 0.5% Triton X-100 results in a complete loss of CPZ inhibitory potency. Although these observations might suggest a role of membrane lipid environment in mediating human erythrocyte AChE inhibition, we observed that CPZ retains its full inhibitory effect on the fraction of enzyme (5-6% of total) that is solubilized from erythrocytes upon treatment with phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus thuringiensis; furthermore, Triton X-100 is able to reverse the CPZ effect also in the case of PI-PLC-solubilized enzyme. These results demonstrate unequivocally that CPZ inhibits human erythrocyte AChE through direct molecular interaction. The inhibition kinetics displayed by CPZ on human erythrocyte AChE are dependent on drug concentration: evidence is provided that this phenomenon may be related to formation of CPZ micellar aggregates.


[Zinc and parlodel: the treatment potentials for retardation of growth and sexual development in nephropathies in adolescents].
Ten adolescents aged 10-18 years with physical and/or sexual development retardation associated with nephropathy were examined. Eight patients were treated with immunodepressants before and/or at the moment of examination. The difference between the age indicated in the patient's passport and bone age ranged within 0 to 3 years. On spermogram examination 3 of 4 patients manifested pathospermia. The serum prolactin level and the level of gonadotropins appeared normal but the testosterone content and plasma zinc level were lowered. As a result of the treatment with parlodel and/or zinc acetate for 1.5 to 23 months, 9 of 10 patients demonstrated the rise of the height and body weight and developed secondary sexual signs. In 3 of 4 patients examined for that parameter, the spermograms improved. In the whole group, the concentration of blood prolactin decreased, that of testosterone and zinc rose, whereas the content of gonadotropins remained unchanged.


Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review.
Tracheomalacia and tracheobronchomalacia are disorders that are encountered in both pediatric and adult medicine. Despite increasing recognition of these disease processes, there remains some uncertainty regarding their identification, causes, and treatment. This article is intended to be a comprehensive review of both the adult and pediatric forms of the diseases, and includes sections on the historical aspects of the disorders, and their classification, associated conditions, histopathology, and natural history. We also review the various modalities that are used for diagnosis as well as the state of the art of treatment, including airway stent placement and surgical intervention.


Variability of core microbiota in newly diagnosed treatment-naïve paediatric inflammatory bowel disease patients.
Intestinal microbiota is considered to play a crucial role in the aetiology of inflammatory bowel disease (IBD). We aimed to describe faecal microbiota composition and dynamics in a large cohort of children with de novo (naïve) IBD, in comparison to healthy paediatric controls (HC). In this prospective study, performed at two tertiary centres, faecal samples from newly diagnosed, treatment-naïve paediatric IBD patients were collected prior to bowel cleansing for colonoscopy (t0) and 1, 3 and 6 weeks and 3 months after initiation of therapy. The microbial profiles of Crohn's disease (CD) and Ulcerative colitis (UC) patients were compared with HC and linked to therapeutic response. Microbiota composition was analysed by IS-pro technology. Microbial profiles of 104 new IBD-patients (63 CD, 41 UC, median age 14.0 years) were compared to 61 HC (median 7.8 years). IBD was mainly characterised by decreased abundance of Alistipes finegoldii and Alistipes putredinis, which characterize a healthy state microbial core. The classifier including these core species as predictors achieved an AUC of the ROC curve of .87. Core bacteria tended to regain abundance during treatment, but did not reach healthy levels. Faecal microbiota profiles of children with de novo CD and UC can be discriminated from HC with high accuracy, mainly driven by a decreased abundance of species shaping the microbial core in the healthy state. Paediatric IBD can therefore be characterized by decreased abundance of certain bacterial species reflecting the healthy state rather than by the introduction of pathogens.


Acute hyperglycaemia and oxidative stress generation.
Oxidative stress is an acknowledged pathogenic mechanism in diabetic complications. Several studies have demonstrated that acute hyperglycaemia can impair the physiological homeostasis of important systems in living organisms and that it may exert these effects via production of free radicals and associated oxidative stress. Acute increases in plasma glucose concentration may increase free radical production by the following mechanisms: labile glycation; auto-oxidation of glucose; and intracellular activation of the polyol pathway, which produces an imbalance in the NADH/NAD+ ratio and favours the production of free radicals. The hypothesis that free radicals may mediate the effects of acute hyperglycaemia is supported by evidence that antioxidants can counteract some of the effects induced by acute hyperglycaemia, for example, vasoconstriction, activation of coagulation, and the increase in plasma intracellular adhesion molecule-1 concentrations. Direct evidence of an association between oxidative stress and hyperglycaemia has come from studies of induced hyperglycaemia or standardized meal intake. In both diabetic and non-diabetic subjects, hyperglycaemia or meal intake causes a reduction in plasma Total Radical-trapping Antioxidant Parameter (TRAP). This is associated with consumption of protein thiol groups, vitamin C, and uric acid. This may confirm the hypothesis that acute hyperglycaemia provokes oxidative stress, which destroys the natural antioxidant defences found in the plasma.


Relation between intracellular sodium and twitch tension in sheep cardiac Purkinje strands exposed to cardiac glycosides.
Changes in intracellular sodium ion activity (aiNa) produced by several cardiac glycosides were correlated with twitch tension in sheep cardiac Purkinje strands. Simultaneous measurements of aiNa and twitch tension were obtained through the use of Na-sensitive intracellular microelectrodes (ETH 227) in Purkinje preparations stimulated at a frequency of 1 Hz. All concentrations of ouabain, acetylstrophanthidin, and actodigin that were tested caused an increase in aiNa immediately before, or coincident with, a positive inotropic effect. No fall in aiNa was observed at any positive inotropic concentration of digitalis in these beating fibers. In all cases, the onset and washout of the positive inotropic effect were paralleled by the rise and fall in aiNa, respectively. No dissociation between changes in aiNa and twitch tension occurred at any concentration of any of the agents used. The relation between changes in aiNa and twitch tension was linear with 1 mM increase in aiNa producing about a 100% increase in the twitch magnitude. Propranolol did not significantly alter this relationship. The increase in aiNa with digitalis was also associated with a reduction in the maximum depolarization rate of the action potential, presumably as a consequence of a reduction in the transmembrane Na electrochemical gradient. These results indicate that the positive inotropic action of digitalis in sheep Purkinje strands is always associated with a rise in aiNa secondary to inhibition of the Na pump. This increase in aiNa could increase calcium available for contraction via the Na-Ca equilibrium exchange process. In addition, the increase in aiNa reduces Vmax, as a consequence of decreasing the electrochemical gradient for Na.


[Effect of a new fermented soy milk product on serum lipid levels in normocholesterolemic adult men].
This study was undertaken to verify the effect of a daily intake of a new fermented soy milk produced with Enterococcus faecium and Lactobacillus jugurti on the serum lipid levels in normocholesterolemic middle-aged men. The study was randomized, double-blind and placebo-controlled and was performed for a period of 6 weeks. Forty-four normocholesterolemic healthy, male volunteers, aged 40-55 years old were randomly separated in two groups: The F-group received 200 ml of the fermented product daily and the P-group received 200 ml of placebo (chemically fermented). The blood samples were drawn initially and after 3 and 6 weeks and serum values for total cholesterol, HDL-cholesterol and triglyceride were determined. The LDL-cholesterol value was estimated. No significant changes in the fermented group (F) were observed for total cholesterol, LDL-cholesterol or triglyceride levels, while the HDL-cholesterol level was significantly higher (p < or = 0.05) after 6 weeks. The total cholesterol and LDL-cholesterol levels were significantly higher (p < or = 0.05) in the placebo group (P), but no changes were found for the HDL-cholesterol and triglyceride levels during the experimental period. In conclusion, the intake of 200 ml/day of the fermented soy milk, produced with E. faecium and L. jugurti, for 6 weeks, did not affect the serum total cholesterol and LDL-cholesterol, and led an increase of 10% in the HDL-cholesterol level.


Rubella seroprevalence among women of childbearing age residing in a rural region: is there a need for rubella vaccination in Turkey?
It is essential to evaluate the susceptibility of women in the reproductive age group to rubella virus in order to set strategies for the prevention of congenital rubella syndrome (CRS). Turkey began implementing measles-mumps-rubella vaccination as part of the national vaccination schedule for children (12 months, 6 years) and adolescents (14 years) in July, 2006, and there is an ongoing discussion of the need for a policy of vaccinating women of child-bearing age against rubella. The aim of this study was to determine the rubella seroprevalence among women in the reproductive age group in a rural district in Ankara and to provide data about rubella susceptibility for policymakers. Four hundred ninety of the women in the 15- to 49-year-old age group in the region who were targeted were reached (68.2%), and 467 (65.0%) of them who had a convenient serology were included in the study. Rubella IgG antibodies were quantified by the enzyme-linked immunosorbent assay method. Seropositivity was 95.5% for the total group and 96.2% among pregnant women. The seropositivity of this rural group of women was found to be high, but in order to rule out the need for a rubella vaccination program for women of child-bearing age, large-scale studies in different settings and studies that describe the CRS burden in Turkey are required.


Tissue-specific inactivation by cytosine deaminase/uracil phosphoribosyl transferase as a tool to study plant biology.
Recent advances in the study of plant developmental and physiological responses have benefited from tissue-specific approaches, revealing the role of some cell types in these processes. Such approaches have relied on the inactivation of target cells using either toxic compounds or deleterious genes; however, both tissue-specific and truly inducible tools are lacking in order to precisely target a developmental window or specific growth response. We engineered the yeast fluorocytosine deaminase (FCY1) gene by creating a fusion with the bacterial uracil phosphoribosyl transferase (UPP) gene. The recombinant protein converts the precursor 5-fluorocytosine (5-FC) into 5-fluorouracyl, a drug used in the treatment of a range of cancers, which triggers DNA and RNA damage. We expressed the FCY-UPP gene construct in specific cell types using enhancer trap lines and promoters, demonstrating that this marker acts in a cell-autonomous manner. We also showed that it can inactivate slow developmental processes like lateral root formation by targeting pericycle cells. It also revealed a role for the lateral root cap and the epidermis in controlling root growth, a faster response. The 5-FC precursor acts systemically, as demonstrated by its ability to inhibit stomatal movements when supplied to the roots in combination with a guard cell-specific promoter. Finally, we demonstrate that the tissular inactivation is reversible, and can therefore be used to synchronize plant responses or to determine cell type-specific functions during different developmental stages. This tool will greatly enhance our capacity to understand the respective role of each cell type in plant physiology and development.


Animal Models of Autoimmune Liver Diseases: a Comprehensive Review.
Autoimmune liver diseases (AILDs) are potentially life-threatening chronic liver diseases which include autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and recently characterized IgG4-related sclerosing cholangitis. They are caused by immune attack on hepatocytes or bile ducts, with different mechanisms and clinical manifestations. The etiologies of AILDs include a susceptible genetic background, environment insults, infections, and changes of commensal microbiota, but remain complicated. Understanding of the underlying mechanisms of AILDs is mandatory for early diagnosis and intervention, which is of great importance for better prognosis. Thus, animal models are developed to mimic the pathogenesis, find biomarkers for early diagnosis, and for therapeutic attempts of AILDs. However, no animal models can fully recapitulate features of certain AILD, especially the late stages of diseases. Certain limitations include different living condition, cell composition, and time frame of disease development and resolution. Moreover, there is no IgG4 in rodents which exists in human. Nevertheless, the understanding and therapy of AILDs have been greatly advanced by the development and mechanistic investigation of animal models. This review will provide a comprehensive overview of traditional and new animal models that recapitulate different features and etiologies of distinct AILDs.


Loss analysis of laser-fiber coupling and fiber combiner, and its application to wavelength division multiplexing.
The combination of index-guided laser diodes and wavelength-independent multiplexers is shown to be the best choice for wavelength-division-multiplexing (WDM) systems. Such a transmitter end of a four-channel WDM system will only cause an insertion loss of 1.5 dB or less (laser-fiber coupling plus multiplexer), which is hard to obtain with wavelength-selective multiplexing. In the case of gain-guided lasers it will depend on the number of channels and wavelength separation whether or not wavelength-independent multiplexing is preferable. To include all types of laser diode we had to extend laser-fiber coupling theory to astigmatic laser diodes. The surprisingly simple exact relations based on Gaussian beam analysis show that the usual gain-guided lasers (astigmatism of ~20 microm) are not able with symmetric lenses to launch more than ~20% of their power into a single-mode fiber, whereas an index-guided laser with the same far-field divergence couples ~85%.


Inhibiting polo-like kinase 1 enhances radiosensitization via modulating DNA repair proteins in non-small-cell lung cancer.
To assure faithful chromosome segregation, cells make use of the spindle assembly checkpoint, which can be activated in aneuploid cancer cells. In this study, the efficacies of inhibiting polo-like kinase 1 (PLK1) on the radiosensitization of non-small-cell lung cancer (NSCLC) cells were studied. Clonogenic survival assay was performed to identify the effects of the PLK1 inhibitor on radiosensitivity within NSCLC cells. Mitotic catastrophe assessment was used to measure the cell death and histone H2AX protein (γH2AX) foci were utilized to assess the DNA double-strand breaks (DSB). The transcriptome was analyzed via unbiased profiling of microarray expression. The results showed that the postradiation mitotic catastrophe induction and the DSB repair were induced by PLK1 inhibitor BI-6727, leading to an increase in the radiosensitivity of NSCLC cells. BI-6727 in combination with radiation significantly induced the delayed tumor growth. PLK1-silenced NSCLC cells showed an altered mRNA and protein expression related to DNA damaging, replication, and repairing, including the DNA-dependent protein kinase (DNAPK) and topoisomerase II alpha (TOPO2A). Furthermore, inhibition of PLK1 blocked 2 important DNA repair pathways. To summarize, our study showed PLK1 kinase as an option in the therapy of NSCLC.


Infant attachment insecurity and dissociative symptomatology: findings from the NICHD Study of Early Child Care and Youth Development.
Based on data from the NICHD Study of Early Child Care and Youth Development (N = 1,149), the current article provides the first large-sample investigation of associations between different forms of infant attachment insecurity and dissociative symptomatology from childhood through midadolescence as measured by scales based on the mother, teacher, and youth self-report versions of the Achenbach System of Empirically Based Assessments. Findings did not replicate the previously reported and highly cited evidence that infant attachment disorganization is associated with dissociative symptomatology. In contrast, correlations of small magnitude were observed between infant avoidance and dissociative symptomatology, as assessed by teachers and mothers (but not self-report). Results were not moderated by contextual risk. Limitations of the study included the absence of measures of maltreatment and interpersonal trauma, leaving open the possibility that infant attachment disorganization is a diathesis for later dissociation in the context of severe and/or chronic trauma. Nevertheless, the present results strongly indicate the need for additional research exploring the possible role of environmental factors in the development of dissociative symptomatology.


Lifestyle of Asian Indians with coronary heart disease: the Australian context.
This paper aims to report lifestyle factors of Asian Indians in Australia in relation to coronary heart disease. This issue has not been previously explored in the Australian context. This study also seeks to identify factors that could inform health education and rehabilitation programs for migrant Asian Indians in Australia. The qualitative descriptive approach of constructivism was used for this study. Semi-structured, in-depth conversations were conducted with eight patients and five family members. Participants were at risk for coronary heart disease either due to unhealthy diet and/or lack of physical exercise and irregular health checks. Although lifestyle modifications were implemented by participants after the cardiac event; these changes were implemented inconsistently and without continuity. Knowledge of the beneficial effects of a healthy diet did not deter the participants from continuing to follow unhealthy dietary habits. The introduction of any exercise or physical activity by participants in this study lacked consistency. A positive aspect revealed from this study was the influence of culture and religious faith, which helped patients and family members to cope with the illness trajectory. The results of this study suggest that health education and rehabilitation programs need to be designed specifically for this high-risk group would be beneficial when initiated early in life and need to be targeted to the individual.


Pseudomonas aeruginosa transmission is infrequent in New Zealand cystic fibrosis clinics.
Pseudomonas aeruginosa is an important pathogen in cystic fibrosis (CF). Although most patients harbour unique P. aeruginosa isolates, some clinics report patients sharing common strains. The overall importance of person-to-person transmission in P. aeruginosa acquisition and whether routine patient segregation is necessary remains uncertain. The present authors therefore investigated the extent of P. aeruginosa transmission in New Zealand CF clinics. New Zealand's seven major CF centres were assessed, combining epidemiological data with computer-assisted SalI DNA fingerprinting of 496 isolates from 102 patients. One cluster of related isolates was significantly more prevalent in the largest clinic than expected by chance. The seven patients with isolates belonging to this cluster had more contact with each other than the remaining patients attending this centre. No other convincing evidence of transmission was found in any of the other smaller clinics. Three P. aeruginosa strains believed to be transmissible between patients in Australian and British CF clinics are present in New Zealand, but there was no definite evidence they had spread. Pseudomonas aeruginosa transmission is currently infrequent in New Zealand cystic fibrosis clinics. This situation could change rapidly and ongoing surveillance is required. The current results confirm that computer-assisted SalI DNA fingerprinting is ideally suited for such surveillance.


John F. Enders and measles virus vaccine--a reminiscence.
Following their initial isolation in cell culture of the virus in 1954, a succession of investigators under the mentorship of John E Enders conducted the research, development, and initial clinical studies responsible for the licensure in 1963 of a successful live attenuated measles virus vaccine. Propagation of the virus successively in human kidney cells, human amnion cells, embryonated hens' eggs, and finally chick embryo cell cultures had selected virus that when inoculated into susceptible monkeys proved immunogenic without viremia or overt disease, in contrast to the early kidney cell-passaged material, which in similar monkeys produced viremia with illness mimicking human measles. Careful clinical studies in children by the Enders group and then by collaborating investigators in many sites established its safety, immunogenicity, and efficacy. This Edmonston strain measles virus became the progenitor of vaccines prepared, studied, and utilized throughout the United States and many other countries. With appreciation of measles morbidity and mortality, most marked among infants and children in the resource-limited lands, the vaccine was incorporated into the World Health Organization's (WHO) Expanded Programme of Immunization (EPI) in 1974 along with BCG, OPV, and DTP. Successful efforts to further reduce measles' burden were launched in 2001 and are continuing as the Measles Initiative (Partnership) under the leadership of the American Red Cross, International Red Cross, and Red Crescent societies, Centers for Disease Control (CDC), United Nations Children's Fund (UNICEF), WHO, and the United Nations Foundation.


Impact of a warm anomaly in the Pacific Arctic region derived from time-series export fluxes.
Unusually warm conditions recently observed in the Pacific Arctic region included a dramatic loss of sea ice cover and an enhanced inflow of warmer Pacific-derived waters. Moored sediment traps deployed at three biological hotspots of the Distributed Biological Observatory (DBO) during this anomalously warm period collected sinking particles nearly continuously from June 2017 to July 2019 in the northern Bering Sea (DBO2) and in the southern Chukchi Sea (DBO3), and from August 2018 to July 2019 in the northern Chukchi Sea (DBO4). Fluxes of living algal cells, chlorophyll a (chl a), total particulate matter (TPM), particulate organic carbon (POC), and zooplankton fecal pellets, along with zooplankton and meroplankton collected in the traps, were used to evaluate spatial and temporal variations in the development and composition of the phytoplankton and zooplankton communities in relation to sea ice cover and water temperature. The unprecedented sea ice loss of 2018 in the northern Bering Sea led to the export of a large bloom dominated by the exclusively pelagic diatoms Chaetoceros spp. at DBO2. Despite this intense bloom, early sea ice breakup resulted in shorter periods of enhanced chl a and diatom fluxes at all DBO sites, suggesting a weaker biological pump under reduced ice cover in the Pacific Arctic region, while the coincident increase or decrease in TPM and POC fluxes likely reflected variations in resuspension events. Meanwhile, the highest transport of warm Pacific waters during 2017-2018 led to a dominance of the small copepods Pseudocalanus at all sites. Whereas the export of ice-associated diatoms during 2019 suggested a return to more typical conditions in the northern Bering Sea, the impact on copepods persisted under the continuously enhanced transport of warm Pacific waters. Regardless, the biological pump remained strong on the shallow Pacific Arctic shelves.


Nitric oxide-induced apoptosis: p53-dependent and p53-independent signalling pathways.
Nitric oxide (NO) generation initiates apoptotic cell death in different experimental systems. In RAW 264.7 macrophages the appearance of typical apoptotic markers is linked to inducible NO synthase induction. Mechanistically, accumulation of tumour suppressor p53 precedes apoptotic DNA fragmentation. With the use of S-nitroglutathione (GSNO) we correlated a dose-dependent p53 up-regulation to DNA fragmentation measured after 4 h and 8 h, respectively. Our studies revealed a linear correlation between the potency of five different NO donors with respect to apoptosis induction and p53 accumulation. Furthermore, we probed for NO-induced apoptosis after stable transfection of RAW 264.7 macrophages with plasmids encoding p53 antisense RNA. Clones with down-regulated p53 levels in response to GSNO exhibited a marked reduction in DNA fragmentation. Expression of the inducible NO synthase in response to lipopolysaccharide and interferon-gamma caused apoptosis in RAW 264.7 macrophages and neomycin-vector controls within 24 h. In contrast, p53 antisense RNA-expressing clones appeared highly resistant towards endogenous NO, although inducible NO synthase induction with concomitant nitrite production remained unchanged. For RAW 264.7 macrophages our results established a functional role of the tumour suppressor p53 during NO-induced apoptotic cell death. However, p53 antisense experiments and the use of the p53-negative cell line U937 substantiated p53-independent signalling pathways operative during NO-mediated apoptosis.


Circulating cell-free DNA is a predictor of short-term neurological outcome in stroke patients treated with intravenous thrombolysis.
Circulating cell-free DNA (cfDNA) has been described as a prognostic marker for several diseases. Its prognostic value for short-term outcome in stroke patients treated with intravenous thrombolysis remains unexplored. cfDNA was measured on admission in 54 tissue plasminogen activator (tPA)-treated patients and 15 healthy controls using a real-time quantitative polymerase chain reaction assay. Neurological outcome was assessed at 48 h. Predictors of neurological improvement were evaluated by logistic regression analysis, and the additional predictive value of cfDNA over clinical variables was determined by integrated discrimination improvement (IDI). Stroke patients presented higher baseline cfDNA than healthy controls (408.5 (179-700.5) vs. 153.5 (66.9-700.5) kilogenome-equivalents/L, p = 0.123). A trend towards lower cfDNA levels was found in patients who neurologically improved at 48 h (269.5 (143.3-680) vs. 504 (345.9-792.3) kilogenome-equivalents/L, p = 0.130). In logistic regression analysis, recanalization at 1 h and cfDNA < 302.75 kilogenome-equivalents/L was independently associated with neurological improvement after adjustment by age, gender and baseline National Institutes of Health Stroke Scale score. The addition of cfDNA to the clinical predictive model improved its discrimination (IDI = 21.2% (9.2-33.3%), p = 0.009). These data suggest that cfDNA could be a surrogate marker for monitoring tPA efficacy by the prediction of short-term neurological outcome.


A Fatal Case of Opioid Intoxication After Raw Poppy Plant Ingestion.
Papaver somniferum contains many opioids and is frequently used in agriculture. Both the intoxication and the withdrawal of opioids have a wide range of symptoms such as coma, depressed respiration and agitation. Here, a fatal case of opioid intoxication will be presented. A four-year-old female patient was admitted to the pediatric intensive care unit after ingesting raw poppy plants. She had shallow respiration, tachycardia, hypertension and muscle cramps. A high plasma opioid level was measured and bolus intravenous naloxone was administered which resulted in a brief gain of consciousness. She was intubated after a sudden respiratory depression and loss of consciousness 10 hours later. Naloxone infusion was started and continued for two days. She developed disseminated intravascular coagulation and was lost on day twelve. Raw plant ingestion proves difficult to treat since there is less information about the ingredients. Having no consensus on naloxone dosage and intrinsic complications such as hypo- and hypertension, redistribution, rhabdomyolysis and dysmotility disrupts naloxone administration. Ingestion of opioids as plants brings out different complications for the treatment course while deciding on naloxone dosage proves opioid intoxication difficult to treat.


Two-body wear of dental composites under different loads.
Although dental composites are excellent for restoring the appearance of natural tooth tissues, their relatively poor resistance to wear, especially in approximal and occlusal contact areas, is still a major source of concern. The aim of this research was to study a basic wear mechanism, under 2-body wear conditions, that may be integrated into our understanding of the in vitro and in vivo wear behavior of dental composites. An in vitro 2-body wear test was conducted on 2 selected ultrafine compact-filled dental composites under different magnitudes of sinusoidal cyclic load. The wear surfaces and cross sections of the wear layers were assessed using scanning electron microscopy (SEM) to explore the nature of the wear pattern of the dental composites under cyclic loading conditions. The wear losses of both composites increased with load. SEM analysis of wear surfaces and subsurface sections indicated that the composites tested displayed different wear mechanisms from low to high loads. An explanation for the wear pattern is proposed based on the observed wear behavior. The in vitro wear pattern of the ultrafine compact-filled dental composites tested is closely related to the applied load. Although the wear loss increased in a roughly linear relationship with applied load, the underlying wear mechanism involved may experience a significant change from low to high load conditions during wear.


Public health issues in aquaculture.
The authors address the public health issues associated with the consumption of aquacultural products using numerous examples from the United States of America. As with other foods, public health risks exist but these mostly involve open water environments or products which are consumed raw or undercooked. Unlike wild fisheries, inland aquaculture systems can minimise public health risks by proper site evaluation and good aquacultural practices. Responsible use of pesticides and therapeutants can prevent violative residues to assure product safety and wholesomeness. The implementation of hazard analysis and critical control point regulations will further enhance the preventive approach to hazards control. The most challenging public health risks arise from shellfish production in open, surface waters, where both naturally-occurring and trace environmental residue contaminants can bioaccumulate in tissues and may cause disease outbreaks (and, in severe cases, death). Water quality certification programmes and field surveillance efforts including product sampling, testing and monitoring can address critical safety criteria. This paper focuses primarily on public health risks associated with production: however, the fact that consumer risks also occur as a result of the processing of aquacultural products and that foodborne diseases arise additionally from unsanitary handling or preparation and storage at incorrect temperatures (as is the case for food products from other animals) must also be taken into consideration.


Dietary combination effects of conjugated linoleic acid and flaxseed or fish oil on the concentration of linoleic and arachidonic acid in poultry meat.
This study was conducted to determine the effects of the combination of dietary conjugated linoleic acid (CLA) and n-3 fatty acids on the linoleic acid (C18:2n-6) and arachidonic acid (C20:4n-6) concentrations of broiler chicken breast and thigh muscles. One hundred and twenty broilers were raised to 6 wk of age. All chicks were fed a basal corn-soybean meal diet containing 5 different fat sources at an inclusion level of 2% total fat: 1) CLA, 2) flaxseed oil, 3) menhaden fish oil, 4) CLA and flaxseed oil, and 5) CLA and menhaden fish oil. Eight broilers from each treatment were processed at 4 and 6 wk of age. Breast and thigh muscle samples were collected and analyzed for total fat content and fatty acid composition. The results showed that broilers from the CLA and fish oil treatment had lower arachidonic acid concentrations in both breast and thigh muscles than those fed the flaxseed oil diet or the CLA and flaxseed oil diet (P < 0.05). The arachidonic acid concentration and n-6:n-3 ratio of breast and thigh samples from the menhaden fish oil diet were similar to those of the CLA and fish oil diet (P > 0.05), but the inclusion of linoleic acid into chicken thigh muscles of broilers fed the CLA and menhaden fish oil diet improved significantly when compared with that of the diet containing menhaden fish oil only. Thus, the combination of CLA and menhaden fish oil is recommended to reduce the concentrations of linoleic and arachidonic acids in broiler chicken breast and thigh muscles.


Chemistry and microbiology of permeable reactive barriers for in situ groundwater clean up.
Permeable reactive barriers (PRBs) are receiving a great deal of attention as an innovative, cost-effective technology for in situ clean up of groundwater contamination. A wide variety of materials are being proposed for use in PRBs, including zero-valent metals (e.g., iron metal), humic materials, oxides, surfactant-modified zeolites (SMZs), and oxygen- and nitrate-releasing compounds. PRB materials remove dissolved groundwater contaminants by immobilization within the barrier or transformation to less harmful products. The primary removal processes include: (1) sorption and precipitation, (2) chemical reaction, and (3) biologically mediated reactions. This article presents an overview of the mechanisms and factors controlling these individual processes and discusses the implications for the feasibility and long-term effectiveness of PRB technologies.


An innovative method to assess negotiation skills necessary for quality improvement.
Quality improvement (QI) initiatives require leaders who can facilitate change through negotiation. Although a few education programs teach these skills, there is no published literature on methods to assess competency in negotiation. This study's purpose was to determine the psychometric properties of an Objective Structured Clinical Examination (OSCE) to assess negotiation skills. The OSCE uses an actor trained to respond to the learner in a standardized fashion. The negotiation station was part of an 8-station QI OSCE piloted in the Mayo Clinic Endocrinology and Preventive Medicine fellowship programs. External experts judged the content validity to be excellent. Interrater reliability was outstanding for the global competency assessment (0.80) and moderate for checklist scores (0.53). All participating faculty strongly agreed (33.3%) or agreed (66.7%) that the OSCE station was an authentic assessment tool. Further research is needed to study the predictive validity of such an OSCE and its application to assessing other quality improvement competencies.


The significance of the International Normalized Ratio (INR) for oral anticoagulant therapy.
For the laboratory control of oral anticoagulant treatment, the prothrombin time (PT) is used universally as the primary measurement. Important variability of the PT ratio (patient PT: mean health persons' PT) caused by different brands and batches of thromboplastin and instruments exists not only in North America, but throughout the world. To achieve uniformity of reporting, it is recommended that the PT ratio be transformed to the International Normalized Ratio (INR). This is possible if the thromboplastin manufacturer provides calibration data for each batch of thromboplastin. The INR scale facilitates the achievement of consensus on optimal therapeutic ranges for various clinical conditions. The INR will further improve the stability of anticoagulant treatment of travelling patients.


[Knee joint ligament reconstruction--indications, results].
Cruciate ligament injuries have increased in number in the last 10 to 20 years. Nonoperative treatment of ligament injuries about the knee joint has lost some of its popularity; however, there are only very few randomized prospective studies demonstrating that operative reconstructions of knee ligament injuries do have a positive effect on preventing late osteoarthritic changes. In contrast, one of the best studies recently published shows that there may even be some increased rate of osteoarthritis in reconstructed patients. Why this? The concept of the 'Envelope of Load Acceptance' may explain, why some of the patients who opt for a nonoperative treatment of cruciate ligament injuries do very well. They lower the load and frequency to the knee joint and diminish their activity level. Patients with successfully treated ligament lesions about the knee joint may wish to go back to their preinjury level and may want to reach their preinjury 'shell' of load acceptance [Scott Dye, 1995]; however, this may already be too much for their knees [physiological overload] and may eventually lead to the osteoarthritic changes about the knee joint. Careful consultation of each individual patient's case of knee ligament injuries is essential for the successful treatment, a treatment which may reduce the rate of osteoarthritis and reduce costs for the injured and the community.


The effect of recombinant human tsh on the thyroid (123)i uptake in iodide treated normal subjects.
Radioactive iodine therapy is often successful in the treatment of toxic or non-toxic multinodular goiter. However, when the patient has been exposed to iodine in the form of medication or radiocontrast agents prior to therapy, the thyroid radioactive iodine is often too low for successful ablation. Recently, administration of 0.9 mg of recombinant human TSH (rhTSH) has been shown to nearly double the 24-hour thyroid radioactive iodine uptake (RAIU) in euthyroid men living in the United States. In addition, 0.01 to 0.03 mg rhTSH administered 24 hours prior to (131)I in patients with a history of non-toxic multinodular goiter residing in an area of modestly low iodine intake, has also been shown to increase the 24-hour thyroid radioactive iodine uptake. We now have determined whether rhTSH administration prior to (123)I would increase the low thyroid RAIU in subjects treated with sodium iodide. Nine euthyroid men were given 15 mg iodide daily for 7 days. There was a marked increase in serum TSH values 8 and 24 hours after rhTSH administration, which induced elevated serum T4 and T3 concentrations. A 16 hour thyroid RAIU was measured at baseline, after 5 days of iodide administration, and either 8 or 32 hours after intramuscular administration of rhTSH. Administration of rhTSH 8 hours before (123)I to 4 subjects increased the 16 hour thyroid RAIU by 62% above the low post iodide thyroid RAIU. Administration of rhTSH 32 hours before (123)I administration to 5 subjects increased the 16 hour thyroid RAIU by 97% above the low iodide induced RAIU. Thus, the overall increase in the thyroid RAIU was 88% in the 9 subjects. Recombinant TSH moderately increased the thyroid RAIU in subjects with depressed thyroid RAIU's during iodide administration and thus may be useful in preparing patients with non-toxic or toxic goiters and low thyroid RAIU's due to excess iodine for radioactive iodine treatment. Further studies to determine the optimal protocol to enhance the effect of rhTSH will be carried out.


On the specificity of lipid hydroperoxide fragmentation by fatty acid hydroperoxide lyase from Arabidopsis thaliana.
Fatty acid hydroperoxide lyase (HPL) is a membrane associated P450 enzyme that cleaves fatty acid hydroperoxides into aldehydes and omega-oxo fatty acids. One of the major products of this reaction is (3Z)-hexenal. It is a constituent of many fresh smelling fruit aromas. For its biotechnological production and because of the lack of structural data on the HPL enzyme family, we investigated the mechanistic reasons for the substrate specificity of HPL by using various structural analogues of HPL substrates. To approach this 13-HPL from Arabidopsis thaliana was cloned and expressed in E. coli utilising a His-Tag expression vector. The fusion protein was purified by affinity chromatography from the E. coli membrane fractions and its pH optimum was detected to be pH 7.2. Then, HPL activity against the respective (9S)- and (13S)-hydroperoxides derived either from linoleic, alpha-linolenic or gamma-linolenic acid, respectively, as well as that against the corresponding methyl esters was analysed. Highest enzyme activity was observed with the (13S)-hydroperoxide of alpha-linolenic acid (13alpha-HPOT) followed by that with its methyl ester. Most interestingly, when the hydroperoxy isomers of gamma-linolenic acid were tested as substrates, 9gamma-HPOT and not 13gamma-HPOT was found to be a better substrate of the enzyme. Taken together from these studies on the substrate specificity it is concluded that At13HPL may not recognise the absolute position of the hydroperoxy group within the substrate, but shows highest activities against substrates with a (1Z4S,5E,7Z)-4-hydroperoxy-1,5,7-triene motif. Thus, At13HPL may not only be used for the production of C6-derived volatiles, but depending on the substrate may be further used for the production of Cg-derived volatiles as well.


Effects of delta 9-THC on pregnancy and offspring in rats.
Pregnant rats were intubated with increasing doses of delta 9-THC (5-50 mg/kg/day) up to gestation day 5. On gestation day 5, these animals continued to receive either 50 or 150 mg/kg/day of delta 9-THC. Animals receiving the 50 mg/kg/day dose and a control group of vehicle (olive oil) treated animals were pair-fed and pair- watered to animals given the 150 mg/kg/day dose. A second control group served as nontreated, ad lib control animals. Animals were tested postnatally for spontaneous alteration, avoidance learning and rotarod behavior to determine if delta 9-THC was behaviorally teratogenic. Drug treatments produced a dose-related decrease in pregnancies carried to term, weight gain during pregnancy, and birth weight. However, since no viable litters were born to animals in the high dose-group, their data was not included in statistical analyses. Nevertheless, the effects of drug treatment (50 mg/kg/day) were still statistically significant for weight gain during pregnancy and birth weight. Drug treatment (50 mg/kg/day) did not affect litter size or weight at 21 days of age, nor did it affect any of the behavioral tests.


[Multi-component quantitative analysis combined with chromatographic fingerprint for quality assessment of Onosma hookeri].
A method for simultaneous determination of the shikonin, acetyl shikonin and β, β'-dimethylpropene shikonin in Onosma hookeri and the chromatographic fingerprint was estabished by HPLC-DAD on an Agilent Zorbax SB-column with a gradient elution of acetonitrile and water at 0.8 mL x min(-1), 30 degrees C. The quality assessment was conducted by comparing the content difference of three naphthoquinone constituents, in combination with chromatographic fingerprint analysis and systems cluster analysis among 7 batches of radix O. hookeri. The content of the three naphthoquinone constituents showed wide variations in 7 bathces. The similarity value of the fingerprints of sample 5, 6 and 7 was above 0.99, sample 2 and 3 above 0.97, sample 3 and 4 above 0.90, and other samples larger than 0.8, which was in concert with the content of three naphthoquinone constituents. The 7 samples were roughly divided into 4 categories. The results above indicated that the using of this medicine is complex and rather spotty. The established HPLC fingerprints and the quantitative analysis method can be used efficiently for quality assessment of O. hookeri.


Contrasting Roles of the PD-1 Signaling Pathway in Dendritic Cell-Mediated Induction and Regulation of HIV-1-Specific Effector T Cell Functions.
Eliciting highly functional CD8+ cytotoxic T lymphocyte (CTL) responses against a broad range of epitopes will likely be required for immunotherapeutic control of HIV-1 infection. However, the combination of CTL exhaustion and the ability of HIV-1 to rapidly establish CTL escape variants presents major hurdles toward this goal. Our previous work highlighted the use of monocyte-derived, mature, high-interleukin-12 (IL-12)-producing type 1 polarized dendritic cells (MDC1) to selectively induce more potent effector CTLs derived from naive, rather than memory, CD8+ T cell precursors isolated from HIV-1-positive participants in the Multicenter AIDS Cohort Study. In this study, we report that these highly stimulatory antigen-presenting cells also express enhanced levels of the coinhibitory molecule programmed cell death ligand 1 (PD-L1), the ligand for PD-1, which is further upregulated upon subsequent stimulation with the CD4+ T helper cell-derived factor CD40L. Interestingly, blocking the PD-1 signaling pathway during MDC1 induction of HIV-1-specific CTL responses inhibited the priming, activation, and differentiation of naive CD8+ T cells into effector T cells expressing high levels of T-box transcription factor (T-bethi) and eomesodermin (Eomes+). In contrast, PD-1 blockade enhanced the overall magnitude of memory HIV-specific CTL responses and reversed the exhausted memory phenotype from a T-betlow/Eomes+ to a T-bethi/Eomes+ phenotype. These results indicate that the PD-L1/PD-1 signaling pathway has a previously unappreciated dual role in the induction and regulation of HIV-1-specific CTL immunity, which is greatly determined by the context and differentiation stage of the responsive CD8+ T cells.IMPORTANCE Targeting the PD-1/PD-L1 immune checkpoint axis with signaling inhibitors has proven to be a powerful immunotherapeutic strategy to enhance the functional quality and survival of existing antigen-specific effector T cells. However, our study demonstrates that the context and timing of PD-1 signaling in T cells greatly impact the outcome of the effector response. In particular, we show that PD-1 activation plays a positive role during the DC-mediated initiation stage of the primary T cell response, while it serves as an inhibitory mechanism during the effector phase of the response. Therefore, caution should be taken in the design of therapies that include targeting of the PD-1/PD-L1 signaling pathway in order to avoid potential negative impacts on the induction of de novo T cell responses.


Nonlinear directionally selective subunits in complex cells of cat striate cortex.
1. We have analyzed receptive fields (RFs) of directionally selective (DS) complex cells in the striate cortex of the cat. We determined the extent to which the DS of a complex cell depends on spatially identifiable subunits within the RF by studying responses to an optimally oriented, three-luminance-valued, gratinglike stimulus that was spatiotemporally randomized. 2. We identified subunits by testing for nonlinear spatial RF interactions. To do this, we calculated Wiener-like kernels in a spatial superposition test that depended on two RF positions at a time. The spatial and temporal separation of light and dark bars at these two positions varied over a spatial range of 8 degrees and a temporal range of +/- 112 ms in increments of 0.5 degree and 16 ms, respectively. 3. DS responses in complex cells cannot be explained by their responses to single light or dark bars because any linear superposition of responses whose time course is uniform across space shows no directional preference. 4. Nonlinear interactions between a flashed reference bar that is fixed in position and a second bar that is flashed at surrounding positions help explain DS by showing multiplicative-type facilitation for bar pairs that mimic motion in the preferred direction and suppression for bar pairs that mimic motion in the null direction. Interactions in the preferred direction have an optimal space/time ratio (velocity), exhibited by elongated, obliquely oriented positive domains in a space-time coordinate frame. This relationship is inseparable in space-time. The slope of the long axis specifies the preferred speed, and its negative agrees with the most strongly suppressed speed in the opposite direction. 5. When the reference bar position is moved across the RF, the spatiotemporal interaction moves with it. This suggests the existence of a family of nearly uniform subunits distributed across the RF. We call the subunit interaction, as averaged across the RF, the "motion kernel" because its spatial and temporal variables are those necessary to specify the velocity, the only parameter that distinguishes a moving image from a temporally modulated stationary image. The nonlinear interaction shows a spatial periodicity, which suggests a mechanism of velocity selectivity for moving extended images.(ABSTRACT TRUNCATED AT 400 WORDS)


Drosophila oocyte proteome composition covaries with female mating status.
Oocyte composition can directly influence offspring fitness, particularly in oviparous species such as most insects, where it is the primary form of parental investment. Oocyte production is also energetically costly, dependent on female condition and responsive to external cues. Here, we investigated whether mating influences mature oocyte composition in Drosophila melanogaster using a quantitative proteomic approach. Our analyses robustly identified 4,485 oocyte proteins and revealed that stage-14 oocytes from mated females differed significantly in protein composition relative to oocytes from unmated females. Proteins forming a highly interconnected network enriched for translational machinery and transmembrane proteins were increased in oocytes from mated females, including calcium binding and transport proteins. This mating-induced modulation of oocyte maturation was also significantly associated with proteome changes that are known to be triggered by egg activation. We propose that these compositional changes are likely to have fitness consequences and adaptive implications given the importance of oocyte protein composition, rather than active gene expression, to the maternal-to-zygotic transition and early embryogenesis.


To study the mechanism of panax notoginseng in the treatment of aspirin resistance in the secondary prevention of stroke based on TLR4/MyD88/NF-κB signaling pathway: A study protocol.
Aspirin, as an typical antiplatelet therapy for secondary stroke prevention, have been proved that can significantly reduce incidence and recurrence of cerebrovascular ischemic events. However, due to drugs biological characteristics, aspirin resistance (AR) often occurs in clinical practice, which significantly influence secondary prevention in stroke patients. The growing evidence of activating blood and removing stasis herbs medicine (Sanqi) for AR is promising. However, the efficacy and mechanism of Panax notoginseng (Sanqi) for AR in secondary stroke prevention has not been confirmed. This is a prospective 2-center, assessor and statistician blinded, randomized, controlled trial. We will allocate 106 subjects aged between 45 and 65 years old, diagnosed with aspirin semi-resistance after stroke to 2 groups randomly in a ratio of 1:1. Patients in the experimental group will be treated with conventional treatments plus Panax notoginseng (Sanqi) while the others in the control group will be treated with only conventional treatments. All will be given different medications for 30 days. Patients will be measured with the platelet aggregation rate and serum TLR4, MyD88, NF-κB, COX-2, IL-6, CRP, TXB2 level for clinical efficacy and mechanisms at baseline and the 14th, 30th day of treatment. Baseline characteristics of patients will be summarized by groups and compared with Chi-square for categorical variables, and Student's independent t test or nonparametric Mann-Whitney U test for the continuous variables. Primary and secondary outcomes will be analyzed with 2-way repeated measures Anova, and Post Hoc test. The present study aims to investigate short-term add-on efficacy and mechanism of Panax notoginseng (Sanqi) for aspirin resistance in secondary stroke prevention via TLR4/MyD88/NF-κB signaling pathway. With this, we expect to find out an appropriate partial substitute of aspirin for aspirin resistance individuals. The trial was registered on Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx) with the ID ChiCTR2100045773 at April 24, 2021.


Complications of bioabsorbable suture anchors in the shoulder.
The development of the suture anchor has played a pivotal role in the transition from open to arthroscopic techniques of the shoulder. Various suture anchors have been manufactured that help facilitate the ability to create a soft tissue to bone repair. Because of reported complications of loosening, migration, and chondral injury with metallic anchors, bioabsorbable anchors have become increasingly used among orthopaedic surgeons. In this review, the authors sought to evaluate complications associated with bioabsorbable anchors in or about the shoulder and understand these in the context of the total number of bioabsorbable anchors placed. In 2008, 10 bioabsorbable anchor-related complications were reported to the US Food and Drug Administration. The reported literature complications of bioabsorbable anchors implanted about the shoulder include glenoid osteolysis, synovitis, and chondrolysis. These potential complications should be kept in mind when forming a differential diagnosis in a patient in whom a bioabsorbable anchor has been previously used. These literature reports, which amount to but a fraction of the total bioabsorbable anchors implanted in the shoulder on a yearly basis, underscore the relative safety and successful clinical results with use of bioabsorbable suture anchors. Product development continues with newer composites such as PEEK (polyetheretherketone) and calcium ceramics (tricalcium phosphate) in an effort to hypothetically create a mechanically stable construct with and improve biocompatibility of the implant. Bioabsorbable anchors remain a safe, reproducible, and consistent implant to secure soft tissue to bone in and about the shoulder. Meticulous insertion technique must be followed in using bioabsorbable anchors and may obviate many of the reported complications found in the literature. The purpose of this review is to provide an overview of the existing literature as it relates to the rare complications seen with use of bioabsorbable suture anchors in the shoulder.


Influenza virus infection induces the nuclear relocalization of the Hsp90 co-chaperone p23 and inhibits the glucocorticoid receptor response.
The genomic RNAs of influenza A viruses are associated with the viral polymerase subunits (PB1, PB2, PA) and nucleoprotein (NP), forming ribonucleoprotein complexes (RNPs). Transcription/replication of the viral genome occurs in the nucleus of infected cells. A role for Hsp90 in nuclear import and assembly of newly synthetized RNA-polymerase subunits has been proposed. Here we report that the p23 cochaperone of Hsp90, which plays a major role in glucocorticoid receptor folding and function, associates with influenza virus polymerase. We show that p23 is not essential for viral multiplication in cultured cells but relocalizes to the nucleus in influenza virus-infected cells, which may alter some functions of p23 and Hsp90. Moreover, we show that influenza virus infection inhibits glucocorticoid receptor-mediated gene transactivation, and that this negative effect can occur through a p23-independent pathway. Viral-induced inhibition of the glucocorticoid receptor response might be of significant importance regarding the physiopathology of influenza infections in vivo.


Practice patterns in endoscopic skull base surgery: survey of the American Rhinologic Society.
The introduction of advanced endoscopic techniques has facilitated significant growth in the field of endoscopic skull base surgery (SBS). The purpose of this study is to evaluate the impact of endoscopic SBS on the clinical practice patterns of the American Rhinologic Society (ARS) membership. A 23-item survey vetted by the ARS Board of Directors was electronically disseminated to the ARS membership from February 5, 2013, to March 31, 2013. The target group encompassed 982 ARS members. A total of 152 physicians (15.5%) completed the survey. Open and endoscopic skull base procedures were performed by 41% and 94% of the respondents, respectively. During a typical year, the number of endoscopic skull base cases ranged from 0 to 20 in 56%, 21 to 50 in 26%, 51 to 100 in 9%, and >100 in 8%. Endoscopic cerebrospinal fluid (CSF) leak repair (96%) and transsphenoidal pituitary surgery (81%) were the most commonly performed procedures, followed by transcribriform (68.4%), transplanum (54.4%), and transclival (49.6%) approaches. Overall, 69.6% used endoscopy for resections of malignant sinus/skull base lesions. Considerable variation in Current Procedural Terminology (CPT) coding philosophy was observed, with open skull base (32%), unlisted endoscopic (29%), sinus surgery (24%), and unlisted neurosurgical (15%) codes employed by surgeons. Only 29% of physicians reported adequate reimbursement in ≥75% of cases. Eighty-five percent of respondents supported creation of dedicated endoscopic SBS codes. This study illustrates the widespread integration of endoscopic SBS procedures into rhinologic clinical practice among survey respondents. However, current variability in coding strategies and inadequate reimbursement may warrant development of specific guidelines to standardize coding and billing processes in the future.


Canada Should Retain Its Reservation on the United Nation's Convention on the Rights of Persons with Disabilities.
The United Nations adopted the Convention on the Rights of Persons with Disabilities (CRPD) in 2006. When Canada ratified the CRPD, it reserved the right to continue using substitute decision making schemes even if the CRPD was 'interpreted as requiring their elimination'. This was a prescient decision because the CRPD Committee, which is tasked with overseeing the interpretation and implementation of the CRPD, subsequently opined that all legislation supporting substitute decision making schemes contravene the CRPD and must be revoked. The CRPD Committee insists that every person can make decisions with sufficient support and that if a person lacks capacity to make a decision, we must rely on their 'will and preferences'. Many international legal scholars have called this interpretation unrealistic. We agree and, in this article, describe how this unrealistic approach would result in extensive harm and suffering for people with severe cognitive or psychotic disorders. The reader should also be aware that the CRPD Committee also calls for the elimination of all mental health acts and the United Nations Commissioner for Human Rights for the abandonment of the not criminally responsible (NCR) defence.


The training of neural classifiers with condensed datasets.
In this paper we apply a k-nearest-neighbor-based data condensing algorithm to the training set of multilayer perceptron neural networks. By removing the overlapping data and retaining only training exemplars adjacent to the decision boundary we are able to significantly speed the network training time while achieving an undegraded misclassification rate compared to a network trained on the unedited training set. We report results on a range of synthetic and real datasets that indicate that a training speed-up of an order of magnitude is typical.


Improving advanced pharmacy practice experiences with an intention/reflection practice.
Experiential learning in pharmacy has the potential to offer transformative experiences for students. Advanced pharmacy practice experiences (APPEs) can be improved if students are encouraged and able to (1) identify and track individual learning gains and interests, and (2) develop self-awareness and intrinsic motivation. The intention/reflection (I/R) practice was developed to address these educational concepts and help facilitate meaningful experiences during APPEs. The I/R tool is a simple, nontechnical, resource-light activity consisting of a set of three to five questions at the beginning, midpoint, and end of an APPE. The questions were designed to help students identify how they can attain meaningful gains from each APPE. Preceptors across three universities designed, implemented, and evaluated the impact of an I/R practice within the context of a variety of APPEs. The APPEs varied between 4, 5, 6, and 10 weeks and were focused on patient care and academia. Three of the I/R questions were selected for thematic analysis, one at each point of the rotation. These questions were strategically selected because they demonstrate the value resulting from the progressive nature of the I/R tool. The answers to the three questions were descriptively coded to capture the main thought(s) of each student's response. A quarter of students indicated I/R helped them achieve their goals. A retrospective pre-post survey demonstrated statistically significant improvements in all survey items, including (1) ability to identify learning outcomes, (2) focus and motivation, and (3) self-awareness and metacognition.


Molecular characterization of a flagellar/chemotaxis operon in the spirochete Borrelia burgdorferi.
A chemotaxis gene cluster from Borrelia burgdorferi, the spirochete that causes Lyme disease, was cloned, sequenced, and analyzed. This cluster contained three chemotaxis gene homologs (cheA, cheW and cheY) and an open reading frame we identified as cheX. Although the major functional domains for B. burgdorferi CheW and CheY were well conserved, the size of cheW was significantly different from the homolog of other bacteria. Phylogenetic analysis of CheY indicated that B. burgdorferi constitutes a distinct branch with Treponema pallidum and is closely associated with Archea and Gram-positive bacteria. RT-PCR analysis indicated that the chemotaxis genes and the upstream flagellar gene flaA constitute an operon. Western blot analysis using antibody to Escherichia coli CheA resulted in two reactive proteins in the cell lysates of B. burgdorferi that is consistent with two cheA homologs being present in this organism. The results taken together suggest both similarities and differences in the chemotaxis apparatus of B. burgdorferi compared to those of other bacteria.


Assessment of the prognostic utility of the FIT treadmill score in coronary artery disease patients undergoing cardiac rehabilitation.
Introduction: Cardiovascular fitness is an important goal in cardiac rehabilitation (CR) programs and is predictive of outcomes. We sought to determine the utility of a novel clinical treadmill score in determining prognosis of coronary artery disease (CAD) patients after CR. Methods: Demographic, clinical and exercise data of 262 patients (mean age 55.8 ± 10.1 years) who completed an outpatient CR program were analyzed. The FIT treadmill score was determined prior to program initiation and after completion. Patients were classified according to risk category using the FIT scores after CR completion and were followed up for the occurrence of 10 year all cause mortality. Results: On median follow up of 10.3 years, 52 patients died. An improvement of the FIT treadmill score by 18.2 points was associated with a 21% reduction in mortality (multivariate-adjusted Hazard Ratio 0.79, 95% CI 0.56-1.08, P≤0.05). Kaplan-Meier survival curves showed increased occurrence of mortality in the high-risk group. After adjustment for confounders a high-risk FIT score category on exit (HR: 2.7, 95% CI 1.41-5.17, P≤0.05) was predictive of increased mortality. Both an improvement in the FIT score (AUC=0.81) and the FIT score category on exit (AUC=0.92) had good discrimination in predicting mortality. Conclusion: The FIT treadmill score is predictive of all cause mortality in patients with CAD undergoing CR. An improvement in the FIT score after CR is associated with improved survival. The FIT score may be a useful prognostic marker of overall cardiovascular fitness and successful outcome for patients who participate in CR programs.


Antibiotic resistance patterns of bacteria isolated from indwelling Foley catheters following tube cystostomy in goats with obstructive urolithiasis.
Tube cystostomy is a surgical method used for managing obstructive urolithiasis and involves placement of a Foley catheter into the urinary bladder. We identified and evaluated the antibiotic resistance patterns of bacteria isolated from indwelling Foley catheters following tube cystostomy in goats with obstructive urolithiasis. Urine samples collected over a 10-y period from catheter tips at the time of removal were submitted for bacteriologic culture and antibiotic susceptibility testing. Resistance patterns to antibiotics, trends in the resistance patterns over the study period, and the probability of a bacterial isolate being resistant as a function of the identity of the isolate and antibiotic tested were determined. A total of 103 urine samples from 103 male goats with obstructive urolithiasis managed surgically with tube cystostomy were included in the study. Aerococcus (36.9%) and Enterococcus (30.1%) were isolated most frequently. The susceptibility patterns of all bacteria isolated did not change over the study period ( p > 0.05). Proportions of isolates resistant to 1, 2, and ≥3 antibiotics were 36.9%, 18.5%, and 23.3%, respectively. Thus, 41.8% of bacterial isolates were resistant to 2 or more antibiotics tested. The probability of Aerococcus spp., Escherichia coli, and Pseudomonas aeruginosa isolates to be resistant to ampicillin, ceftiofur, erythromycin, penicillin, or tetracycline ranged from 0.59 to 0.76.


An analysis of the sensitivity and specificity of MHC-I and MHC-II immunohistochemical staining in muscle biopsies for the diagnosis of inflammatory myopathies.
Although there have been several previous reports of immunohistochemical staining for MHC antigens in muscle biopsies, there appears to be a lack of consensus about its routine use in the diagnostic evaluation of biopsies from patients with suspected inflammatory myopathy. Positive MHC-I staining is nonspecific but is widely used as a marker for inflammatory myopathy, whilst the role of MHC-II staining is not clearly defined. We investigated the sensitivity and specificity of MHC-I and MHC-II immunostaining for the diagnosis of inflammatory myopathy in a large group of biopsies from a single reference laboratory. Positive staining for MHC-I was found to have a high sensitivity in biopsies from patients with inflammatory myopathy but a very low specificity, as it was also common in other non-inflammatory myopathies and neurogenic disorders. On the other hand, MHC-II positivity had a much higher specificity in all major subgroups of inflammatory myopathy, especially inclusion body myositis. The findings indicate that the combination of MHC-I and MHC-II staining results in a higher degree of specificity for the diagnosis of inflammatory myopathy and that in biopsies with inflammation, positive MHC-II staining strongly supports the diagnosis of an immune-mediated myopathy. We recommend that immunohistochemical staining for both MHC-I and MHC-II should be included routinely in the diagnostic evaluation of muscle biopsies from patients with suspected inflammatory myopathy. However, as the sensitivity and interpretation of MHC staining may depend on the technique used, further studies are needed to compare procedures in different centres and develop standardised protocols.


Inhibition of rotaviruses by selected antiviral substances: mechanisms of viral inhibition and in vivo activity.
Several RNA virus inhibitors were evaluated against simian (SA11) rotavirus infections in vitro and murine rotavirus gastroenteritis in vivo. Test compounds included 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin), 3-deazaguanine (3-DG), 3-deazauridine, and 9-(S)-(2,3-dihydroxypropyl)adenine [(S)-DHPA]. All drugs inhibited total infectious SA11 virus yields in MA-104 cells. Ribavirin, 3-DG, and (S)-DHPA affected [3H]uridine uptake into uninfected MA-104 cells in both the acid-soluble and -insoluble fractions. All drugs reduced the levels of dense (precursor) and light (complete) SA11 particle yields compared with control but did not alter the relative amounts of dense compared with light particles, suggesting that the agents did not interfere with virus assembly. Ribavirin and 3-DG inhibited SA11 polypeptide synthesis, as determined by polyacrylamide gel electrophoresis studies. None of the agents or mono- and triphosphate derivatives of ribavirin inhibited SA11 RNA polymerase activity. In murine rotavirus studies, oral therapy with ribavirin-2',3',5'-triacetate and (S)-DHPA increased mean survival time, but no increase in survivor rate was observed. 3-DG- and (S)-DHPA-treated mice had a more rapid weight gain than controls, suggesting a probable lessening of the severity of the disease.


Electro-oculography in pigment dispersion syndrome.
Clinical data and the common embryological origin of the pigment epithelium of the iris and retinal pigment epithelium suggest that the latter may be involved in the pigment dispersion syndrome (PDS). In our study functional changes of the retinal pigment epithelium were evaluated by electro-oculography in 10 PDS patients, 10 patients with chronic open-angle glaucoma (COAG) and 10 normal subjects. The mean dark-trough latency and Arden ratio for the PDS group were significantly lower than those of the COAG and control groups. Analysis of the Arden ratios based on the Kruskall-Wallis test revealed that 30% of the PDS values were subnormal with respect to the control group mean -1 SD. These results indicate primary involvement of the retinal pigment epithelium in PDS.


Hydrogenosomes of Metopus contortus physiologically resemble mitochondria.
The anaerobic free-living ciliated protozoon Metopus contortus is a grazer in anoxic marine sediments. It does not possess mitochondria, but it does have specialized organelles termed hydrogenosomes which release hydrogen gas. The cationic lipophilic cyanine dye DiOC7(3) is an indicator of transmembrane electrochemical potential. With the aid of confocal laser scanning microscopy (CLSM), the association of this dye with hydrogenosomes in situ was followed. Flow cytometric measurements showed that fluorescence of the membrane potential dye decreased in response to an elevated pH2 in the cell. CLSM also revealed localization of fluorescence of the calcium probe Fluo 3-AM, and of the transmembrane pH gradient probe BCECF-AM, within the lumen of the hydrogenosomes. In addition, hydrogenosomal inclusions were detected. X-ray microanalysis of these electron-dense granules revealed high levels of calcium, phosphate and magnesium. It is concluded that M. contortus hydrogenosomes are calcium stores, have a membrane potential, and an alkaline lumen. These physiological features resemble those of mitochondria in aerobic protozoa.


Recent developments of small molecule γ-secretase modulators for Alzheimer's disease.
Alzheimer's disease (AD) is the most common form of progressive neurodegenerative disorder, marked by memory loss and a decline in cognitive function. The major hallmarks of AD are the presence of intracellular neurofibrillary tau tangles (NFTs) composed of hyperphosphorylated tau proteins and extracellular plaques composed of amyloid beta peptides (Aβ). The amyloid (Aβ) cascade hypothesis proposes that the AD pathogenesis is initiated by the accumulation of Aβ peptides in the parenchyma of the brain. An aspartyl intramembranal protease called γ-secretase is responsible for the production of Aβ by the cleavage of the amyloid precursor protein (APP). Clinical studies of γ-secretase inhibitors (GSIs) for AD failed due to the lack of substrate specificity. Therefore, γ-secretase modulators (GSMs) have been developed as potential disease modifying agents to modulate the γ-secretase cleavage activity towards the production of toxic Aβ42 peptides. Following the first-generation 'nonsteroidal anti-inflammatory drug' (NSAID) based GSMs, second-generation GSMs (carboxylic acid based NSAID derivatives and non-NSAID derived heterocyclic analogues), as well as natural product-based GSMs, have been developed. In this review, we focus on the recent developments of small molecule-based GSMs that show potential improvements in terms of drug-like properties as well as their current status in human clinical trials and the future perspectives of GSM research.


Coxsackievirus and adenovirus receptor (CAR) is modified and shed in membrane vesicles.
Vesicles shed by U87-MG cells contain coxsackievirus and adenovirus receptor (CAR) protein that has been posttranslationally modified. Relative to full-length CAR, migration of the vesicle-associated soluble CAR antigen (CARd6) on SDS-polyacrylamide gels indicated a loss of approximately 6 kDa. HeLa and END-HHV6 cells also shed a similar vesicle-associated CAR protein. Vesicles shed by U87-MG cells following stimulation with calcium and A23187 contained CARd6 similar to that present in vesicles shed constitutively. RD cells transfected to express full-length CAR produced CARd6, but cells that expressed CAR with a truncated cytoplasmic domain produced no equivalent to CARd6. In U87-MG cells, calpain activity was required for release of CARd6 with shed vesicles, and accumulation of CARd6 in cells that rounded up and released from the plastic substrate in response to A23187 treatment was blocked by N-ethylmaleimide. These experiments show that CAR, posttranslationally modified in the cytoplasmic domain, can be released with vesicles shed by cells. Posttranslational modification of the CAR cytoplasmic domain occurs during cell rounding and release from the culture substrate. This modified, vesicle-associated CAR was the principal form of soluble CAR released by the cells.