Processing speed and memory mediate age-related differences in decision making.
Decision making under risk changes with age. Increases in risk aversion with age have been most commonly characterized, although older adults may be risk seeking in some decision contexts. An important, and unanswered, question is whether these changes in decision making reflect a direct effect of aging or, alternatively, an indirect effect caused by age-related changes in specific cognitive processes. In the current study, older adults (M = 71 years) and younger adults (M = 24 years) completed a battery of tests of cognitive capacities and decision-making preferences. The results indicated systematic effects of age upon decision quality-with both increased risk seeking and increased risk aversion observed in different tasks-consistent with prior studies. Path analyses, however, revealed that age-related effects were mediated by individual differences in processing speed and memory. When those variables were included in the model, age was no longer a significant predictor of decision quality. The authors conclude that the reduction in decision quality and associated changes in risk preferences commonly ascribed to aging are instead mediated by age-related changes in underlying cognitive capacities.


Atypical lobular hyperplasia and lobular carcinoma in situ at core breast biopsy: use of careful radiologic-pathologic correlation to recommend excision or observation.
To assess the utility of precise radiologic and pathologic correlation for establishing imaging-histologic concordance or discordance as a method to limit the number of patients requiring surgical excision when atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS) is diagnosed at core biopsy. This study was approved by the institutional review board, and the requirement to obtain informed consent was waived. The pathology database was searched from 2000 to 2010 for core biopsies yielding ALH or LCIS devoid of any additional lesion that independently necessitated excision. All cases had to have either subsequent surgical excision or a minimum of 2 years of imaging follow-up. This yielded 50 cases from 49 women aged 40-73 years (mean age, 59 years). The authors performed detailed radiologic-pathologic analysis while blinded to subsequent follow-up information, comparing all biopsy-related images with the histologic findings at core biopsy and then designating each core biopsy finding as concordant or discordant. Then, results of subsequent surgery or extended follow-up for each case were unblinded and compared with original concordant or discordant designations. Outcomes and confidence intervals (CIs) were calculated. Of the 43 benign concordant core biopsy findings, none were upgraded at surgery (n = 38) or extended follow-up (n = 5) (95% CI: 0%, 8%). Of the seven discordant biopsy findings, two were upgraded to ductal carcinoma in situ at surgery (n = 5); none of the cases were upgraded at follow-up (n = 2). When careful radiologic-pathologic correlation is performed and concordance is achieved, women with ALH or LCIS at core biopsy can be observed.


A medical student scholarly concentrations program: scholarly self-efficacy and impact on future research activities.
The Scholarly Concentrations program was established at Johns Hopkins University School of Medicine in 2009 with the aim of instilling passion for scholarship. Our study aimed to determine whether the Scholarly Concentrations program achieves positive changes in medical student self-efficacy in conducting research and, if so, whether this results in future career aspirations toward scholarship. We used the Clinical Research Appraisal Inventory-Short Form (CRAI-SF) to assess changes in self-efficacy among students completing the Scholarly Concentrations program between 2014 and 2017. We calculated composite mean scores of six domains. We included outcomes on whether students published a manuscript, overall program perceptions, and likelihood of future research careers. We analyzed relationships between CRAI-SF scores and outcomes using paired t-tests and multivariable-adjusted logistic regression. A total of 419 students completed the Scholarly Concentrations program. All 6 CRAI domain scores showed significant improvements in self-efficacy between the pre-Scholarly Concentrations and post-Scholarly Concentrations ratings (range of changes 0.76-1.39, p < 0.05 for all). We found significant associations between post-Scholarly Concentrations self-efficacy ratings and course satisfaction (adjusted OR 1.57 [95% CI 1.20, 2.07]) and mentor satisfaction (OR 1.46 [1.15, 1.86]), as well as students' intent to conduct future research (OR 1.46 [1.15, 1.86]). These results were robust to sensitivity analyses, and pronounced in the group of students without prior research experience. Our findings suggest that a Scholarly Concentrations program is associated with an increased self-efficacy for research, and these changes in self-efficacy are associated with higher satisfaction in the scholarly experience and increased likelihood of pursuing scholarly work. Other medical schools could use such a tool of self-efficacy to both investigate the overall Scholarly Concentrations experience and understand factors that may increase interest in future physician-scientist pathways.


Synthesis of 1,1'-binaphthyl-based enantiopure C(60) dimers.
The first enantiomerically pure and soluble C(60) dimers have been synthesized from suitably functionalized 1,1'-binaphthyl derivatives by 1,3-dipolar cycloaddition of the respective in situ generated diazo compounds to C(60). These systems exhibit optical and electrochemical activity.


Cardiovascular-reflex testing and single-fiber electromyography in botulism. A longitudinal study.
Four patients with botulism were studied on admission and at different times after intoxication, using a battery of cardiovascular autonomic tests. The results were compared with clinical status and single-fiber electromyographic findings. In the early stage of intoxication, the control of heart-rate and blood-pressure responsivity was markedly impaired, as was the neuromuscular transmission. At follow-up, results of sympathetic tests normalized earlier than those of parasympathetic tests. The recovery of autonomic function was slower than that of neuromuscular transmission in three patients. Monitoring autonomic derangement in botulism adds further information on the course of the disease and may identify patients at risk for cardiac or respiratory arrest. Further clinical investigation can help in determining more precisely the autonomic sites where the toxin acts.


Craniodental variation among Macaques (Macaca), nonhuman primates.
In terms of structure and function, the skull is one of the most complicated organs in the body. It is also one of the most important parts in terms of developmental and evolutionary origins. This complexity makes it difficult to obtain evolutionary assessments if, as is usually the case with fossils, only part of the skull is available. For this reason this study involves a set of comparisons whereby the smallest functional units are studied first, and these built up, through a triple-nested hierarchical design, into more complex anatomical regions and eventually into the skull-as-a-whole. This design has been applied to macaques (Macaca) in order to reveal patterns of variation at the different levels. The profiles of such variation have been obtained both within and between species. This has lead to a search for the skull parts that have undergone similar selection pressures during evolution and comparable development patterns in both ontogeny and phylogeny. Morphometric analysis (Principal Components) was used to obtain these profiles of species and sex separations based on 77 cranial variables from 11 species of macaques. The results showed that 7 functional units could be aggregated into three functionally reasonable anatomical regions on the basis of similarities in profiles. These were: the masticatory apparatus containing mandible, lower teeth and upper teeth, the face as a whole combining maxilla (actually lower face) and upper face, and the cranium as a whole involving cranium and calvaria. Twenty-six variables were finally selected for analyzing the morphology of the whole skull. This last showed an overall profile similar to that revealed in the masticatory apparatus but also contained additional information pertaining to individual species and species-groups separations. The study provides a model for carrying out analysis of species separations and sex variation simultaneously. Through this design it seems possible to see cranio-dental elements that may result from similar developmental processes, have similar functional adaptations, and show an appropriately integrated structure morphologically. This study also implies that the biological information drawn from part of skull alone, e.g. as in studies of incomplete fossils may provide misleading information.


Mortality of treated alcoholics after eight years in relation to short-term outcome.
This study concerns the relation between mortality and the short-term outcome of inpatient treatment for alcoholism. A total of 121 patients (87 men, 34 women) were included, of whom 89 were voluntary and 32 compulsorily committed. They had a mean age of 41 +/- 7 (SD) years and attended a 5-week programme at Runnagården, Orebro, Sweden. Most patients were socially unstable and severely alcohol-dependent. Ten months (mean) after discharge, 96% of the patients and their referring social workers were contacted with mail questionnaires. Of these patients, 13% had been totally abstinent and a further 42% improved but had had relapses. After a mean of 8.5 +/- 0.27 years, 27 patients (24%) had died. All abstainers survived, but non-abstainers had nine-fold higher mortality than expected. Non-abstinent improved women tended to survive longer than non-improved women, but among non-abstinent improved men no such tendency was found. In conclusion, a reduction in the frequency and quantity of abusive drinking was not enough to reduce the higher risk of death. Only abstinence seemed to be preventive.


Platinum-RNA modifications following drug treatment in S. cerevisiae identified by click chemistry and enzymatic mapping.
With the importance of RNA-based regulatory pathways, the potential for targeting noncoding and coding RNAs by small molecule therapeutics is of great interest. Platinum(II) complexes including cisplatin (cis-diamminedichloroplatinum(II)) are widely prescribed anticancer compounds that form stable adducts on nucleic acids. In tumors, DNA damage from Pt(II) initiates apoptotic signaling, but this activity is not necessary for cytotoxicity (e.g., Yu et al., 2008), suggesting accumulation and consequences of Pt(II) lesions on non-DNA targets. We previously reported an azide-functionalized compound, picazoplatin, designed for post-treatment click labeling that enables detection of Pt complexes (White et al., 2013). Here, we report in-gel fluorescent detection of Pt-bound rRNA and tRNA extracted from picazoplatin-treated S. cerevisiae and labeled using Cu-free click chemistry. These data provide the first evidence that cellular tRNA is a platinum drug substrate. We assess Pt(II) binding sites within rRNA from cisplatin-treated S. cerevisiae, in regions where damage is linked to significant downstream consequences including the sarcin-ricin loop (SRL) Helix 95. Pt-RNA adducts occur on the nucleotide substrates of ribosome-inactivating proteins, as well as on the bulged-G motif critical for elongation factor recognition of the loop. At therapeutically relevant concentrations, Pt(II) also binds robustly within conserved cation-binding pockets in Domains V and VI rRNA at the peptidyl transferase center. Taken together, these results demonstrate a convenient click chemistry methodology that can be applied to identify other metal or covalent modification-based drug targets and suggest a ribotoxic mechanism for cisplatin cytotoxicity.


Translating effects of inbreeding depression on component vital rates to overall population growth in endangered bighorn sheep.
Evidence of inbreeding depression is commonly detected from the fitness traits of animals, yet its effects on population growth rates of endangered species are rarely assessed. We examined whether inbreeding depression was affecting Sierra Nevada bighorn sheep (Ovis canadensis sierrae), a subspecies listed as endangered under the U.S. Endangered Species Act. Our objectives were to characterize genetic variation in this subspecies; test whether inbreeding depression affects bighorn sheep vital rates (adult survival and female fecundity); evaluate whether inbreeding depression may limit subspecies recovery; and examine the potential for genetic management to increase population growth rates. Genetic variation in 4 populations of Sierra Nevada bighorn sheep was among the lowest reported for any wild bighorn sheep population, and our results suggest that inbreeding depression has reduced adult female fecundity. Despite this population sizes and growth rates predicted from matrix-based projection models demonstrated that inbreeding depression would not substantially inhibit the recovery of Sierra Nevada bighorn sheep populations in the next approximately 8 bighorn sheep generations (48 years). Furthermore, simulations of genetic rescue within the subspecies did not suggest that such activities would appreciably increase population sizes or growth rates during the period we modeled (10 bighorn sheep generations, 60 years). Only simulations that augmented the Mono Basin population with genetic variation from other subspecies, which is not currently a management option, predicted significant increases in population size. Although we recommend that recovery activities should minimize future losses of genetic variation, genetic effects within these endangered populations-either negative (inbreeding depression) or positive (within subspecies genetic rescue)-appear unlikely to dramatically compromise or stimulate short-term conservation efforts. The distinction between detecting the effects of inbreeding depression on a component vital rate (e.g., fecundity) and the effects of inbreeding depression on population growth underscores the importance of quantifying inbreeding costs relative to population dynamics to effectively manage endangered populations.


Randomized Controlled Trial of Storytelling vs Didactic Education Effects on Dietary Colorectal Cancer Risk Behaviors among Latinxs.
Dietary patterns associated with risk for colorectal cancer (CRC) may contribute to continuing health disparities in Latinx populations. Latinx from low-income communities, aged 25-65, were randomized to a 12-week storytelling-based intervention (ST) (n = 300) or didactic learning (DL)(n = 285) classes on cancer screening and dietary changes related to CRC risk facilitated by Latinx lay health workers (promotora/es de salud). Dietary intake was assessed pre-and post-intervention (24-hour dietary recall) with no significant differences found between ST and DL groups. Specific dietary changes in both groups included increases (p<.05) in dietary fiber (ST from 17.0 to 18.2; DL from 16.38 to 17.8 gms), calcium (ST from 715.7 to 781.9; DL 666.4 to 748.7 mgs), and vegetables (ST 2.5 to 2.8; DL 2.4 to 2.6 servings/day). Although between-intervention group effects were not significant, both culturally-adapted interventions were found to change a selection of key CRC-preventive dietary behaviors.


Morphology of yeast cell wall as affected by genetic manipulation of beta(1 --> 6) glycosidic linkage.
The morphology of yeast cells as it is affected by the glycosidic linkages of constituent glucan was studied. Four different strains of Saccharomyces cerevisiae were studied. A cell wall matrix particle representing the intact original morphology and composed entirely of beta-glucan was prepared. Using prepared cell wall glucan particles, the morphology and cell wall matrix structure were examined. Genetic modification of the cell wall structure during growth results in the alteration of the shape and hydrodnamic volume of the intact cell wall particles. The shape and hydrodynamic volume of the cell wall particles can also be modified by in vitro chemical and enzymatic treatment. The shape factor and hydrodynamic volume of the whole glucan cell wall matrix particles were evaluated quantitatively using a rheological analysis. An increased degree of beta(1 --> 6) cross-linking in the cell wall matrix induces a nearly 2-fold increase in the shape factor and a 10-fold increase in the compression modulus of the glucan particles. The disruption of beta(1 --> 6) glycosidic cross-linking causes the particles to swell by up to 18% of their original volume. This was used as a strategy to isolate a yeast mutant with a high beta(1 --> 6) glycosidic content in the cell wall glucan.


Neurofibromatosis Type 1 Vasculopathy Presenting as Branch Retinal Vein Occlusion: Case Report and Review of the Literature.
Systemic vascular occlusive disease associated with neurofibromatosis type 1 (NF1) has been reported in the aortic, cerebral, renal, celiac, and mesenteric vessels and is referred to as NF1 vasculopathy. Although retinal vascular involvement in patients with NF1 usually manifests as retinal capillary hemangiomatosis, a few cases of NF1 with retinal vascular occlusive disease have also been described. Here, we report a 2-year-old girl with NF1 who presented with branch retinal vein occlusion and peripheral retinal ischemia secondary to NF1. This case demonstrates that NF1-related retinal occlusive vasculopathy may occur in very young patients and that detailed fundus examination with fluorescein angiography is necessary in all patients with NF1.


Incidence and risk factors for failed medical management of spinal epidural abscess: a systematic review and meta-analysis.
OBJECTIVE Spinal epidural abscess (SEA) is a life-threatening infection. It is uncertain whether medical versus surgical treatment is the ideal initial approach for neurologically intact patients with SEA. Recent evidence demonstrates that initial medical management is increasingly common; however, patients who ultimately require surgery after failed medical management may have a worse prognosis than those whose treatment was initially surgical. The primary objective of this study was to establish the current incidence of failed medical management for SEA. The secondary aim was to identify risk factors associated with the failure of medical management. METHODS The authors conducted a systematic review and meta-analysis by searching electronic databases (MEDLINE, Embase, CINAHL, and PubMed), recent conference proceedings, and reference lists of relevant articles. Studies that reported original data on consecutive adult patients with SEA treated medically were eligible for inclusion. RESULTS Twelve studies met the inclusion criteria, which included a total of 489 medically treated patients with SEA. Agreement on articles for study inclusion was very high between the reviewers (kappa 0.86). In a meta-analysis, the overall pooled risk of failed medical management was 29.3% (95% CI 21.4%-37.2%) and when medical to surgical crossover was used to define failure the rate was 26.3% (95% CI 13.0%-39.7%). Only 6 studies provided data for analysis by intended treatment, with a pooled estimate of 35.1% (95% CI 15.7%-54.4%) of failed medical management. Two studies reported predictors of the failure of medical management. CONCLUSIONS Although the incidence of failed medical management of SEA was relatively common in published reports, estimates were highly heterogeneous between studies, thus introducing uncertainty about the frequency of this risk. A consensus definition of failure is required to facilitate comparison of failure rates across studies.


Effectiveness of the trivalent influenza vaccine in Navarre, Spain, 2010-2011: a population-based test-negative case-control study.
Some studies have evaluated vaccine effectiveness in preventing outpatient influenza while others have analysed its effectiveness in preventing hospitalizations. This study evaluates the effectiveness of the trivalent influenza vaccine in preventing outpatient illness and hospitalizations from laboratory-confirmed influenza in the 2010-2011 season. We conducted a nested case-control study in the population covered by the general practitioner sentinel network for influenza surveillance in Navarre, Spain. Patients with influenza-like illness in hospitals and primary health care were swabbed for influenza testing. Influenza vaccination status and other covariates were obtained from health care databases. Using logistic regression, the vaccination status of laboratory-confirmed influenza cases was compared with that of test-negative controls, adjusting for age, sex, comorbidity, outpatient visits in the previous 12 months, health care setting, time between symptom onset and swabbing, period and A(H1N1)pdm09 vaccination. Effectiveness was calculated as (1-odds ratio)x100. The 303 confirmed influenza cases (88% for A(H1N1)pdm09 influenza) were compared with the 286 influenza test-negative controls. The percentage of persons vaccinated against influenza was 4.3% and 15.7%, respectively (p<0.001). The adjusted estimate of effectiveness was 67% (95% CI: 24%, 86%) for all patients and 64% (95% CI: 8%, 86%) in those with an indication for vaccination (persons age 60 or older or with major chronic conditions). Having received both the 2010-2011 seasonal influenza vaccine and the 2009-2010 pandemic influenza vaccine provided 87% protection (95% CI: 30%, 98%) as compared to those not vaccinated. The 2010-2011 seasonal influenza vaccine had a moderate protective effect in preventing laboratory-confirmed influenza.


A contractile actomyosin network linked to adherens junctions by Canoe/afadin helps drive convergent extension.
Integrating individual cell movements to create tissue-level shape change is essential to building an animal. We explored mechanisms of adherens junction (AJ):cytoskeleton linkage and roles of the linkage regulator Canoe/afadin during Drosophila germband extension (GBE), a convergent-extension process elongating the body axis. We found surprising parallels between GBE and a quite different morphogenetic movement, mesoderm apical constriction. Germband cells have an apical actomyosin network undergoing cyclical contractions. These coincide with a novel cell shape change--cell extension along the anterior-posterior (AP) axis. In Canoe's absence, GBE is disrupted. The apical actomyosin network detaches from AJs at AP cell borders, reducing coordination of actomyosin contractility and cell shape change. Normal GBE requires planar polarization of AJs and the cytoskeleton. Canoe loss subtly enhances AJ planar polarity and dramatically increases planar polarity of the apical polarity proteins Bazooka/Par3 and atypical protein kinase C. Changes in Bazooka localization parallel retraction of the actomyosin network. Globally reducing AJ function does not mimic Canoe loss, but many effects are replicated by global actin disruption. Strong dose-sensitive genetic interactions between canoe and bazooka are consistent with them affecting a common process. We propose a model in which an actomyosin network linked at AP AJs by Canoe and coupled to apical polarity proteins regulates convergent extension.


Calcium channel blockers for neuroleptic-induced tardive dyskinesia.
Schizophrenia and related disorders affect a sizable proportion of any population. Neuroleptic (antipsychotic) medications are the primary treatment for these disorders. Neuroleptic medications are associated with a variety of side effects including tardive dyskinesia. Dyskinesia is a disfiguring movement disorder of the orofacial region that can be tardive (having a slow or belated onset). Tardive dyskinesia is difficult to treat, despite experimentation with several treatments. Calcium channel blockers (diltiazem, nifedipine, nimodipine, verapamil) have been among these experimental treatments. To determine the effects of calcium-channel blocker drugs (diltiazem, nifedipine, nimodipine, verapamil) for treatment of neuroleptic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses. We updated previous searches in May 2010 by searching the Cochrane Schizophrenia Group Register using the Cochrane Schizophrenia Group search strategy. Randomised clinical trials comparing calcium-channel blockers with placebo, no intervention or any other intervention for people with both tardive dyskinesia and schizophrenia or serious mental illness. We planned to extract and analyse data on an intention-to-treat (ITT) basis. We intended to calculate the relative risk (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data using a random-effects model, and, where possible, calculate the number needed to treat. We planned to calculate mean differences (MD) for continuous data. We did not include any trials in this review. We excluded 15 studies; eight were not randomised, one did not use calcium channel blockers, five small, randomised, studies reported no usable data and one did not include people with both tardive dyskinesia and schizophrenia. The effects of calcium-channel blockers for antipsychotic induced tardive dyskinesia are unknown. Their use is experimental and should only be given in the context of well designed randomised clinical trials.


Idiosyncratic drug reactions and membranous glomerulopathy.
An infant boy with steroid-resistant nephrotic syndrome (idiopathic membranous glomerulonephropathy) achieved remission with ciclosporin but developed eosinophilia and high IgE levels (max 19 000 iU/mL). Conversion to tacrolimus resulted in chronic diarrhoea (eosinophilic gastroenteritis), muscle weakness, polyserositis and failure-to-thrive. In contrast, a trial without tacrolimus resulted in a ciclosporin-responsive relapse, therapy-resistant focal seizures with generalised spikes, worsening muscle weakness and diarrhoea. The patient was weaned off of ciclosporin and completely normalised. In vitro testing demonstrated decreased viability of the patient's cells when incubated with calcineurin inhibitors (ciclosporin, 70%; tacrolimus, 80% compared to control cells), supporting their role in this adverse drug reaction.


A comparison of hospital readmission rates between two general physicians with different outpatient review practices.
There has been a relentless increase in emergency medical admissions in the UK over recent years. Many of these patients suffer with chronic conditions requiring continuing medical attention. We wished to determine whether conventional outpatient clinic follow up after discharge has any impact on the rate of readmission to hospital. Two consultant general physicians with the same patient case-mix but markedly different outpatient follow-up practice were chosen. Of 1203 patients discharged, one consultant saw twice as many patients in the follow-up clinic than the other (Dr A 9.8% v Dr B 19.6%). The readmission rate in the twelve months following discharge was compared in a retrospective analysis of hospital activity data. Due to the specialisation of the admitting system, patients mainly had cardiovascular or cerebrovascular disease or had taken an overdose. Few had respiratory or infectious diseases. Outpatient follow-up was focussed on patients with cardiac disease. Risk of readmission increased significantly with age and length of stay of the original episode and was less for digestive system and musculo-skeletal disorders. 28.7% of patients discharged by Dr A and 31.5 % of those discharged by Dr B were readmitted at least once. Relative readmission risk was not significantly different between the consultants and there was no difference in the length of stay of readmissions. Increasing the proportion of patients with this age- and case-mix who are followed up in a hospital general medical outpatient clinic is unlikely to reduce the demand for acute hospital beds.


Isolation and characterisation of novel phages infecting Lactobacillus plantarum and proposal of a new genus, "Silenusvirus".
Bacteria of Lactobacillus sp. are very useful to humans. However, the biology and genomic diversity of their (bacterio)phage enemies remains understudied. Knowledge on Lactobacillus phage diversity should broaden to develop efficient phage control strategies. To this end, organic waste samples were screened for phages against two wine-related Lactobacillus plantarum strains. Isolates were shotgun sequenced and compared against the phage database and each other by phylogenetics and comparative genomics. The new isolates had only three distant relatives from the database, but displayed a high overall degree of genomic similarity amongst them. The latter allowed for the use of one isolate as a representative to conduct transmission electron microscopy and structural protein sequencing, and to study phage adsorption and growth kinetics. The microscopy and proteomics tests confirmed the observed diversity of the new isolates and supported their classification to the family Siphoviridae and the proposal of the new phage genus "Silenusvirus".


Automated External Defibrillator Geolocalization with a Mobile Application, Verbal Assistance or No Assistance: A Pilot Randomized Simulation (AED G-MAP).
Shockable rythms are common among victims of witnessed public out-of-hospital cardiac arrest (OHCA), but bystander defibrillation with a public automated external defibrillator (PAED) is rare. Instructions from the emergency medical dispatcher and mobile applications were developed to expedite the localization of PAEDs, but their effectiveness has not been compared. Participants were enrolled in a three-armed randomized simulation where they witnessed a simulated OHCA on a university campus, were instructed to locate a PAED and provide defibrillation. Participants were stratified and randomized to: (1) no assistance in finding the PAED, (2) assistance from a geolocalization mobile application (AED-Quebec), or (3) verbal assistance. Data collectors tracked each participant's time elapsed and distance traveled to shock. Of the 52 volunteers participating in the study (46% male, mean age 37), 17 were randomized to the no assistance group, 18 to the mobile application group and 17 to the verbal group. Median (IQR) time to shock was, respectively, 10:00 min (7:49-10:00), 9:44 (6:30-10:00), and 5:23 (4:11-9:08), with statistically significant differences between the verbal group and the other groups (p ≤ 0.01). The success rate for defibrillation in <10 minutes was 35%, 56% and 76%. Multivariate regression of all participants pooled showed that knowledge of campus geography was the strongest predictor of shock in <10 minutes (aOR =14.3, 95% CI 1.85-99.9). Among participants without prior geographical knowledge, verbal assistance provided a trend towards decreased time to shock, but the differences over no assistance (7:28 vs. 10:00, p = 0.10) and over the mobile app (7:28 vs. 10:00, p = 0.11) were not statistically significant. In a simulated environment, verbally providing OHCA bystanders with the nearest PAED's location appeared to be effective in reducing the time to defibrillation in comparison to no assistance and to an AED geolocalizing mobile app, but further research is required to confirm this hypothesis, ascertain the external validity of these results, and evaluate the real-life implications of these strategies.


Rotations in a vertebrate setting: evaluation of the symmetry group of the disynaptic canal-neck projection.
Organizational structures intrinsic to nervous systems can be more precisely analyzed and compared with other logical structures once they are expressed in mathematical languages. A standard mathematical language for expressing organizational structure is that of groups. Groups are especially well suited to organizational structures involving multiple symmetries such as spatial structures. The vestibular system is widely believed to mediate many neural functions involving spatial structure. The vestibular nuclei receive direct projections from the vestibular endorgans, the semicircular canals and the otolith organs. The near-orthogonal directions of the semicircular canals are embedded in the bone. However, those canal directions are external to the nervous system. This study addresses the way the three-dimensional space of rotations is also embedded in the group structure of neural connectivity. Although we know a great deal about physical rotation, it is not clear that nervous systems organize rotations in the same way as physicists do. It would make sense for nervous systems to organize rotations in such a way as to provide physiologically relevant information about performing or compensating for rotations. The vestibular nuclei, which might be expected to display an organization that binds rotations into a rotation space, do not give a clear organization. This may be because of the multiplicity of spatial functions performed by the vestibular nuclei; rather than one spatial organization, the vestibular nuclei are likely to accommodate multiple, related spatial organizations. This study evaluates one particular data set from the literature that specifies the organization of the disynaptic canal-neck projection; other projections and neuronal populations may have other intrinsic organizations. The data are evaluated directly for their symmetry group. In the symmetry group, the vertebrate requirement that physiology have a right and left is found to be satisfied in two ways: (i) by a hexagonal symmetry arising from the right-left doubling of front and back, (ii) along with separate organizations on the two sides that may be required to operate independently to some extent. The eight observed muscle innervation patterns from the data are the complete set of possible combinations of inhibitory/excitatory polarities from three canal pairs. These eight innervation patterns are organized as the vertices of a cube. The two types of side muscles provide the vertical direction. As the head rotates in physical space, the cube rotates in sensorimotor space. Like the canal-neck projection, otolith projections and proprioceptive afferents contact both the vestibular nuclei and neck motoneurons. They may have a similar organization, perhaps with extensions of the same pattern. Otherwise, like a checkerboard superimposed over a paisley, they will form an overlapping organization with the disynaptic canal-neck projection. Further research is required to determine whether the sensorimotor spatial structure of the canal-neck projection is widespread in nervous systems or whether there are several complete structures that are fragmented and reintegrated.


The Sodium Paradox: Dysnatremia and Mortality in Patients Implanted With Extracorporeal Mechanical Circulatory Support Devices.
Dysnatremia, abnormal serum sodium levels, has long been used as a marker for disease progression in heart failure patients. Classically, hyponatremia is associated with increased fluid volume in heart failure and is often a result of neuroendocrine dysfunction and poor cardiac output. Recent studies have noted that dysnatremia and hypernatremia are predictive of worsened outcomes in critical care and renal disease populations. We investigated the relationship between dysnatremia and postoperative outcomes in patients implanted with extracorporeal mechanical circulatory devices. A total of 97 patients who underwent implantation with the CentriMag mechanical circulatory assist system were included in this retrospective study. Patients were divided into 2 groups based on preoperative serum sodium level cutoff of 135 mEq/L. Outcomes and mortality were compared between groups. The mean age for the study population was 56.21 ± 15.13 years, and 57 patients (58.8%) were male. The mean time on CentriMag support was 22.7 days. Patients with serum sodium levels ≤135 mEq/L were noted to have significantly worsened indicators of preoperative cardiac function. However, patients with serum sodium levels >135 mEq/L had significantly shorter postoperative survival ( P = .006). When entered into a multivariate Cox proportional hazards model, sodium was an independent predictor for increased risk of mortality (hazard ratio: 1.224; 95% confidence interval: 1.009-1.485; P = .040). Our results indicate that elevated preoperative sodium in patients undergoing implantation of a temporary mechanical circulatory support system is predictive of worsened postoperative survival.


Localized eosinophilic granuloma (Langerhans' cell histiocytosis) of the orbital frontal bone.
Four patients (aged 5, 8, 14, and 51 years at initial manifestation) with isolated eosinophilic granulomas of the orbital frontal bone displayed short symptomatic periods (two weeks to three months) and some combination of erythema of the lids, a soft, palpable anterior orbital mass, periorbital pain, and osteolytic bone lesions on roentgenography. The bone lesions roentgenographically exhibited irregular, serrated, and sclerotic margins, distinguishing them from the more oval appearance of dermoid cysts. Electron microscopy performed in one case disclosed the presence of Langerhans' granules in the cytoplasm of the histiocytes, indicating that the orbital disease is a mild form of "histiocytosis X" and a benign proliferation of a specific kind of histiocyte--the Langerhans' cell. On follow-up (two to 20 years), after incomplete curettage of two lesions coupled with low doses of postoperative radiotherapy, there was reconstitution of the bone defects, whereas more extensive surgery performed on the other two patients resulted in permanent but subclinical bone defects.


Statistically and biomechanically based criterion for impact-induced skull fracture.
This work developed a skull fracture criterion for impact-induced head injury, using post mortem human subject tests, anatomical test device measurements, statistical analyses, and finite element modeling. It is shown that skull fracture correlates with the tensile strain in the outer table of the cranial bone, and an index termed the Skull Fracture Correlate (SFC) predicts injury. SFC offers several advantages as a protection criterion. It accounts for compliance of the impact site; it is extensible to varying head mass; and it is easily implemented using current software. For a 15% or less probability of skull fracture the criterion is SFC < 120 g, with a 95% confidence band of 88 < SFC < 135 g.


[Rotator cuff tear athropathy prevalence].
Glenohumeral arthritis secondary to massive rotator cuff tear presents with a superior displacement and femoralization of the humeral head with coracoacromial arch acetabularization. The purpose of this study was to establish prevalence of rotator cuff tear artropathy (CTA) at our institution. Four hundred electronic records were reviewed from which we identified 136 patients with rotator cuff tears. A second group was composed with patients with massive cuff tears that were analized and staged by the Seebauer cuff tear arthropathy classification. Thirty four patients with massive rotator cuff tears were identified, 8 male and 26 female (age 60.1 ± 10.26 years). Massive rotator cuff tear prevalence was 25%. CTA prevalence found in the rotator cuff group was 19 and 76% in the massive cuff tears group. Patients were staged according to the classification with 32% in stage 1a, 11% 1b, 32% 2a and 0% 2b. CTA prevalence in patients with rotator cuff tears and massive cuff tears is higher than the one reported in American population. We consider that a revision of the Seebauer classification to be appropriate to determine its reliability.


Highly selective and compact tunable MOEMS photonic crystal Fabry-Perot filter.
The authors report a compact and highly selective tunable filter using a Fabry-Perot resonator combining a bottom micromachined 3-pair-InP/air-gap Bragg reflector with a top photonic crystal slab mirror. It is based on the coupling between radiated vertical cavity modes and waveguided modes of the photonic crystal. The full-width at half maximum (FWHM) of the resonance, as measured by microreflectivity experiments, is close to 1.5nm (around 1.55 microm). The presence of the photonic crystal slab mirror results in a very compact resonator, with a limited number of layers. The demonstrator was tuned over a 20nm range for a 4V tuning voltage, the FWHM being kept below 2.5nm. Bending of membranes is a critical issue, and better results (FWHM=0.5nm) should be obtained on the same structure if this technological point is fixed.


Amphibian Mauthner cells.
Presently available data on anatomical, electrophysiological, and behavioral aspects of the Mauthner cell in amphibians are reviewed. Urodelian Mauthner cells appear morphologically distinct from those in anurans with respect to their abundant somatic dendrites, axon cap structures, lack of nodes of Ranvier, and size of axon collaterals. The presence of Mauthner cells does not seem to correlate with the presence of a tail or with an aquatic life-style in either larvae or adults, as they are also found in terrestrial adults, as well as in species without an aquatic larval stage. Electrophysiological data on Mauthner cell circuits are available for only two anuran species and indicate some interspecific differences. Special attention is given to a comparison of startle responses in larval and adult anurans and their possible relationship to Mauthner cell activities. Because of specific differences in Mauthner cell activities, as well as in startle response performance, it is argued that amongst the various ichthyopsid species Mauthner cells may have been adapted to modified functions due to the diverse morphoecological situations in which they are found.


Effect of angiotensin II antagonist eprosartan on hyperglycemia-induced activation of intrarenal renin-angiotensin system in healthy humans.
We have previously reported that hyperglycemia in healthy human subjects increased the renal vasodilator response to the angiotensin-converting enzyme inhibitor captopril. This observation raised intriguing possibilities relevant to the pathogenesis of nephropathy in patients with diabetes mellitus. To ascertain whether the effect of captopril was indeed mediated by a reduction in angiotensin II (Ang II) formation, we performed another study in which an Ang II antagonist, eprosartan, was used in place of captopril. Nine healthy subjects were studied in high sodium balance (ie, sodium intake 200 mmol/d). On the first day, the subjects received 600 mg eprosartan orally, and renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured. Glucose was infused intravenously on the second and third study days to increase plasma glucose to a level below the threshold for glycosuria ( approximately 8.8 mmol/L). Eprosartan at a dose of 600 mg or placebo was administered randomly on the second or third study day 1 hour after initiation of glucose infusion. RPF increased (by 76+/-7 mL. min(-1). 1.73 m(-2), P<0.01) in response to sustained moderate hyperglycemia and then increased further (by 147+/-15 mL. min(-1). 1. 73 m(-2), P<0.01) when eprosartan was administered during hyperglycemia. Eprosartan, conversely, did not affect RPF and GFR in normoglycemic subjects. GFR was not affected by either hyperglycemia or eprosartan. Neither plasma renin activity nor plasma Ang II concentration changed during hyperglycemia, suggesting that the hormonal responses responsible for the enhanced renal vasodilator response to eprosartan occurred within the kidney. The enhancement of the renal vasodilator effect of eprosartan during hyperglycemia is consistent with activation of the intrarenal renin-angiotensin system.


The TEL-Jak2 oncoprotein induces Socs1 expression and altered cytokine response in Ba/F3 cells.
The leukemia-associated TEL-Jak2 fusion protein possesses a constitutive tyrosine kinase activity and transforming properties in hematopoietic cell lines and animal models. In the murine pro-B Ba/F3 cell line, this fusion constitutively activates the Signal Transducer and Activator of Transcription 5 (Stat5) factors and, as a consequence, induces the sustained expression of various Stat5-target genes including the Cytokine Inducible SH2-containing protein (Cis) gene, which codes for a member of the Suppressor of Cytokine Signaling (Socs) protein family. In TEL-Jak2-transformed Ba/F3 cells, we also observed the upregulation of the Socs1 gene, whose product has been reported to negatively regulate the Jak kinase activity. In transient transfection experiments, Socs1 physically interacts with TEL-Jak2 and interferes with the TEL-Jak2-induced phosphorylation and activation of Stat5 factors, probably through the Socs1-induced proteasome-mediated degradation of the fusion protein. Interestingly, TEL-Jak2-expressing Ba/F3 cells were found to be resistant to the anti-proliferative activities of gamma interferon (IFN-gamma) seemingly as a consequence of Socs1 constitutive expression. These results indicate that the Socs1-dependent cytokine feedback loop, although active, is bypassed by the TEL-Jak2 fusion, but may play a role in the leukemogenic process by altering the cytokine responses of the leukemic cells. Our results also suggest that Socs1 plays a role in shutting down the signaling from the normally activated Jak2 kinase by inducing its proteasome-dependent degradation.


Delays in initiating rabies post-exposure prophylaxis among dog bite victims in Wakiso and Kampala districts, Uganda.
Background Although rabies in dog bite patients is preventable through timely initiation of post-exposure prophylaxis (PEP), a number of barriers to achieving PEP exist. This study investigated the delays to initiation of PEP among dog bite patients in the emergency departments of two PEP centers in Uganda. Methods A cross-sectional study was conducted among dog-bite patients that presented to two selected rabies PEP centers. A semi-structured questionnaire was used to collect data. Delay to receive PEP was defined as reporting for PEP beyond 24 hours after the bite event. Generalized linear models were used to calculate prevalence ratios and the 95% confidence intervals as a measure of association between delay and patient factors. Results Out of 376 participants, just over half (53.5%) were males. The majority of participants (54.0%) were 15 years or older and 28.5% had no formal education. Just over three-quarters (77.9%) had category II dog bite wounds. Nearly 40% delayed to receive PEP, and median (inter quartile range) lag time between bite event and seeking medical care of 18 (41) hours. Compared to education level of secondary or above, patients with no formal education (adj. PR=4.06, 95% CI: 2.69 - 6.10) or primary education (adj.PR=2.15, 95% CI: 1.37 - 3.35), belonging to the lowest socio-economic tertile as compared to the highest (adj.PR=1.58, 95% CI: 1.10 - 2.28), knowing the owner of the biting dog (adj.PR=1.30, 95% CI: 1.02 - 1.65) and having category II wounds (adj.PR=2.31, 95% CI: 1.43 - 3.71) were all associated with delayed presentation for PEP. Conclusions and recommendations Delays to receive PEP are common and are associated with poor level of education or low socio-economic status, knowledge of who the dog owner is and less severity of bite wounds. Seeking care irrespective of wound severity or knowledge of dog owner should be promoted.


Pharmacophore based approach to design inhibitors in crustaceans: an insight into the molt inhibition response to the receptor guanylyl cyclase.
The first set of competitive inhibitors of molt inhibiting hormone (MIH) has been developed using the effective approaches such as Hip-Hop, virtual screening and manual alterations. Moreover, the conserved residues at 71 and 72 positions in the molt inhibiting hormone is known to be significant for selective inhibition of ecdysteroidogenesis; thus, the information from mutation and solution structure were used to generate common pharmacophore features. The geometry of the final six-feature pharmacophore was also found to be consistent with the homology-modeled MIH structures from various other decapod crustaceans. The Hypo-1, comprising six features hypothesis was carefully selected as a best pharmacophore model for virtual screening created on the basis of rank score and cluster processes. The hypothesis was validated and the database was virtually screened using this 3D query and the compounds were then manually altered to enhance the fit value. The hits obtained were further filtered for drug-likeness, which is expressed as physicochemical properties that contribute to favorable ADME/Tox profiles to eliminate the molecules exhibit toxicity and poor pharmacokinetics. In conclusion, the higher fit values of CI-1 (4.6), CI-4 (4.9) and CI-7 (4.2) in conjunction with better pharmacokinetic profile made these molecules practically helpful tool to increase production by accelerating molt in crustaceans. The use of feeding sub-therapeutic dosages of these growth enhancers can be very effectively implemented and certainly turn out to be a vital part of emerging nutritional strategies for economically important crustacean livestock.


Non-steroidal anti-inflammatory drugs and cyclooxygenase in Alzheimer's disease.
Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference in the chronic inflammatory reaction, that takes place in AD. The best-characterized action of NSAIDs is the inhibition of cyclooxygenase (COX). There is special interest for anti-inflammatory treatment of AD using selective COX-2 inhibitors. These inhibitors reduce the inflammatory reaction but lack the side effects observed with non-selective NSAIDs. So far, clinical trials designed to inhibit inflammation or COX-2 activity have failed in the treatment of AD patients. Several lines of evidence can explain the failures of the anti-inflammatory and anti-COX-2 trials on AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in AD brain. Understanding the role of COX in AD pathogenesis could contribute to the development of an anti-inflammatory therapy for the treatment or prevention of AD.


Ethanol Extract of Fructus ligustri lucidi Increased Circulating 1,25(OH)2D3 Levels, but Did Not Improve Calcium Balance in Mature Ovariectomized Rats.
Our previous studies found that different extracts or fractions of Fructus ligustri lucidi (FLL) played different roles in altering the regulation of bone and mineral metabolism in different animal models. The present study was designed to compare the actions of FLL ethanol (EE) and water extracts (WE) on bone and mineral metabolism in a 6-month-old mature ovariectomized (OVX) rat model. Our results showed that FLL extracts did not significantly improve systematic Ca balance in mature OVX rats. However, EE, but not WE treatment, significantly increased serum 1,25(OH)2D3 levels in mature OVX rats. An in vitro study using human proximal tubule (HKC-8) cells showed that EE, but not WE, significantly enhanced renal 25-dihydroxyvitamin D3-1[Formula: see text]-hydroxylase (1-OHase) mRNA expressions and simultaneously repressed renal 25-dihydroxyvitamin D3-24-hydroxylase (24-OHase) mRNA expressions. Further investigation indicated that EE could significantly induce the protein expression of 1-OHase, but did not alter 24-OHase expression in HKC-8 cells. Our results demonstrated that EE increased circulating 1,25(OH)2D3 levels in OVX rats, possibly via upregulation of renal 1-OHase expressions in renal proximal tubule cells. Our study indicates that FLL is a natural oral agent that could directly regulate renal vitamin D metabolism in vivo and in vitro.


[Electrophoretic mobility and activity Na,K-ATPase of erytheocytes in rats under stress].
In this paper, we study the relation between the electrophoretic mobility of erythrocytes (EPME) and the activity of Na,K-ATPase of erythrocytes under the action of different types of stress factors (immobilization, hypoxia, radiation exposure), as well as the introduction of stress implementing agents (adrenaline, cortisol, bee and toad venom) rats. Activity of Na,K-ATPase and the change of EPME washed erythrocytes were examined through 15, 120 min and 24 hours after exposure. Found that at the initial stage (15 min after a stress-exposure) decrease of EPME associated with increased enzyme activity and further increase of EPME takes place on the background of the decrease of activity of Na,K-ATPase in all types of alterations, except the actions toad venom and cortisol. Toad venom and cortisol led to reduced activity of Na,K-ATPase and increase of EPME.


A novel method to isolate cells with conditional gene expression using fluorescence activated cell sorting.
An inducible expression system using control elements of the tetracycline resistance operon has recently shown promise for conditional gene expression of any gene of interest. However, intensive screening of multiple independent clones is often required to find cell lines with optimal induction characteristics. By coupling expression of the gene of interest with a fluorescent marker, we have developed a novel fluorescence activated cell sorting (FACS) based strategy to isolate cells with desirable expression characteristics, thus alleviating the laborious isolation and analysis of multiple independent clones.


Molecular modeling and QSAR studies of a set of indole and benzimidazole derivatives as H₄ receptor antagonists.
Histamine is an important biogenic amine, which acts with a group of four G-protein coupled receptors (GPCRs), namely H(1) to H(4) (H(1)R - H(4)R) receptors. The actions of histamine at H(4)R are related to immunological and inflammatory processes, particularly in pathophysiology of asthma, and H(4)R ligands having antagonistic properties could be helpful as antiinflammatory agents. In this work, molecular modeling and QSAR studies of a set of 30 compounds, indole and benzimidazole derivatives, as H(4)R antagonists were performed. The QSAR models were built and optimized using a genetic algorithm function and partial least squares regression (WOLF 5.5 program). The best QSAR model constructed with training set (N = 25) presented the following statistical measures: r (2) = 0.76, q (2) = 0.62, LOF = 0.15, and LSE = 0.07, and was validated using the LNO and y-randomization techniques. Four of five compounds of test set were well predicted by the selected QSAR model, which presented an external prediction power of 80%. These findings can be quite useful to aid the designing of new anti-H(4) compounds with improved biological response.


From the archives of the AFIP. Extraskeletal osseous and cartilaginous tumors of the extremities.
Extraskeletal osseous and cartilaginous tumors and tumorlike conditions of the extremities can often be differentiated radiologically; for those that cannot, knowledge of the spectrum of lesions will allow a suitably ordered differential diagnosis. Of the osseous lesions--myositis ossificans, fibro-osseous pseudotumor, fibrodysplasia ossificans progressiva, soft-tissue osteoma, and extraskeletal osteosarcoma--all but myositis ossificans are relatively rare. Myositis ossificans has a distinct mineralization pattern that can be observed radiologically as a peripheral rim of lamellar bone. Fibro-osseous pseudotumor typically occurs in the digits of the hand and lacks the well-defined zoning pattern of myositis ossificans. The cartilaginous entities include the true tumors, soft-tissue chondroma and extraskeletal chondrosarcoma, and the tumorlike process, synovial osteochondromatosis. The tumors are relatively rare; synovial osteochondromatosis commonly affects middle-aged men, especially in the knee, and is associated with osteoarthritis. The differential diagnosis for these extraskeletal osseous and cartilaginous lesions includes soft-tissue sarcoma, benign mesenchymoma, malignant mesenchymoma (rare), calcified tophi in gout, melorheostosis (rare), pilomatricoma (rare), and tumoral calcinosis (rare).


Molecular evidence for zoonotic transmission of an emergent, highly pathogenic Campylobacter jejuni clone in the United States.
Campylobacter jejuni is a major zoonotic pathogen. A highly virulent, tetracycline-resistant C. jejuni clone (clone SA) has recently emerged in ruminant reservoirs and has become the predominant cause of sheep abortion in the United States. To determine whether clone SA is associated with human disease, we compared the clinical isolates of clone SA from sheep abortions with the human isolates of the PulseNet National Campylobacter databases at the CDC and the FDA using pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and serotyping. The combined SmaI and KpnI PFGE pattern designations of clone SA from sheep were indistinguishable from those of 123 (9.03%) human C. jejuni isolates (total, 1,361) in the CDC database, among which 56 were associated with sporadic infections and 67 were associated with outbreaks that occurred in multiple states from 2003 to 2010. Most of the outbreaks were attributed to raw milk, while the sources for most of the sporadic cases were unknown. All clone SA isolates examined, including PFGE-matched human isolates, belong to sequence type 8 (ST-8) by MLST and serotype HS:1,8, further indicating the clonality of the related isolates from different host species. Additionally, C. jejuni clone SA was identified in raw milk, cattle feces, the feces and bile of healthy sheep, and abortion cases of cattle and goats, indicating the broad distribution of this pathogenic clone in ruminants. These results provide strong molecular and epidemiological evidence for zoonotic transmission of this emergent clone from ruminants to humans and indicate that C. jejuni clone SA is an important threat to public health.


Chemical Treatment of Waste Abaca for Natural Fiber-Reinforced Geopolymer Composite.
The use of natural fibers in reinforced composites to produce eco-friendly materials is gaining more attention due to their attractive features such as low cost, low density and good mechanical properties, among others. This work thus investigates the potential of waste abaca (Manila hemp) fiber as reinforcing agent in an inorganic aluminosilicate material known as geopolymer. In this study, the waste fibers were subjected to different chemical treatments to modify the surface characteristics and to improve the adhesion with the fly ash-based geopolymer matrix. Definitive screening design of experiment was used to investigate the effect of successive chemical treatment of the fiber on its tensile strength considering the following factors: (1) NaOH pretreatment; (2) soaking time in aluminum salt solution; and (3) final pH of the slurry. The results show that the abaca fiber without alkali pretreatment, soaked for 12 h in Al₂(SO₄)₃ solution and adjusted to pH 6 exhibited the highest tensile strength among the treated fibers. Test results confirmed that the chemical treatment removes the lignin, pectin and hemicellulose, as well as makes the surface rougher with the deposition of aluminum compounds. This improves the interfacial bonding between geopolymer matrix and the abaca fiber, while the geopolymer protects the treated fiber from thermal degradation.


Prenatal diagnosis and neonatal monitoring of a fetus with glutaric aciduria type II due to electron transfer flavoprotein (beta-subunit) deficiency.
The prenatal diagnosis of a male fetus with glutaric aciduria type II and the time course of metabolite urinary excretion, starting immediately after birth, are described. Prenatal diagnosis was undertaken at the 17th wk of gestation by immunoblot analysis and pulse labeling experiments of amniocytes and, retrospectively, by stable isotope dilution analysis of six metabolites in amniotic fluid. The results were as follows: 1) The immunochemical analysis on cultured amniocytes showed that the fetus, as the previous index case in this family, was affected with a deficiency of the beta-subunit of electron transfer flavoprotein. 2) Glutarate concentration was significantly increased in the cell-free supernatant of the amniotic fluid. In the postnatal period, most of the organic acids and acylglycines characteristic of the disorder appeared in urine within a week, although an increased excretion of hexanoylglycine was the only biochemical abnormality detectable in the first urine sample collected at 9 h after birth. Growth and development of this infant were normal during the following 6 mo of life, when he was receiving oral supplementation with L-carnitine and riboflavin. It should be underscored that transient abnormalities in routine blood tests (glutamic oxaloacetic transaminase, lactate dehydrogenase, and creatine phosphokinase) were present soon after birth, despite his asymptomatic clinical course. Early detection and aggressive treatment could be effective in such a form of glutaric aciduria type II.


Sympathetic and sensory nerves in control of growth of brown adipose tissue: Effects of denervation and of capsaicin.
The thermogenic function and growth of brown adipose tissue (BAT) are known to be primarily under the control of the sympathetic nervous system. However, BAT also contains nerves containing neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) that are presumed to be sensory nerves. In a previous study we demonstrated an atrophy of BAT in capsaicin-desensitized (CAP-DES) rats. CAP-DES is known to bring about long-lasting impairment of a subpopulation of sensory nerves involved in nociception and characterized by the presence of SP and CGRP. The principal objectives of the present experiments were to find out whether CAP-DES of rats depleted BAT of its sensory neuropeptide, CGRP, whether CAP-DES impaired the sympathetic innervation of BAT and whether the atrophy of BAT induced by CAP-DES resembled that induced by sympathetic denervation. CAP-DES rats had a normal noradrenaline content in BAT (measured by HPLC) but absent CGRP (measured by immunohistochemistry). In CAP-DES rats living at 26 degrees C, BAT had lost 90% of its uncoupling protein (UCP) and 50% of its total protein; its thyroxine 5?-deiodinase (T5?D) concentration was, however, unaltered. Surgical denervation, in contrast, which did not abolish CGRP immunofluorescence in BAT, did not significantly reduce protein or UCP content. Cold-acclimation for 12 days produced large increases in protein and UCP content and T5?D level in intact BAT of control rats. These increases still occurred, although to a lower level, in CAP-DES rats but did not occur surgically denervated BAT. The combination of CAP-DES and surgical denervation resulted in an undetectable level of UCP in BAT of cold-acclimated rats, less than in denervated BAT of control cold-acclimated rats. We conclude that sensory nerves play a role in maintenance of BAT in a warm environment and in cold-induced growth of BAT. This role may be either a trophic effect on mitochondriogenesis or a repressive effect on mitochondrial destruction.


Natural honey and cardiovascular risk factors; effects on blood glucose, cholesterol, triacylglycerole, CRP, and body weight compared with sucrose.
It has been found that honey ameliorates cardiovascular risk factors in healthy individuals and in patients with elevated risk factors. The present study investigated the effect of natural honey on total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triacylglycerole, C-reactive protein (CRP), fasting blood glucose (FBG), and body weight in overweight individuals. There were 55 patients, overweight or obese, who were randomly recruited into the study and assigned into two groups: control group (17 subjects) and experimental group (38 subjects). Patients in the control group received 70 g of sucrose daily for a maximum of 30 days and patients in the experimental group received 70 g of natural honey for the same period. In the control and experimental groups, body weight, body mass index, body fat weight, total cholesterol, LDL-C, HDL-C, triacylglycerole, FBG, and CRP were measured before treatment and at day 31 after the commencement of treatment. Results showed that honey caused a mild reduction in body weight (1.3%) and body fat (1.1%). Honey reduced total cholesterol (3%), LDL-C (5.8), triacylglycerole (11%), FBG (4.2%), and CRP (3.2%), and increased HDL-C (3.3%) in subjects with normal values, while in patients with elevated variables, honey caused reduction in total cholesterol by 3.3%, LDL-C by 4.3%, triacylglycerole by 19%, and CRP by 3.3% (p < 0.05). It is our conclusion that consumption of natural honey reduces cardiovascular risk factors, particularly in subjects with elevated risk factors, and it does not increase body weight in overweight or obese subjects.


Streptococcal R plasmid pIP501: endonuclease site map, resistance determinant location, and construction of novel derivatives.
The streptococcal resistance plasmid pIP501 (30 kilobase pairs [kb]) encodes resistance to chloramphenicol (Cmr) and erythromycin (Emr) and is capable of conjugative transfer among numerous streptococcal species. By using a streptococcal host-vector recombinant DNA system, the Cmr and Emr determinants of pIP501 were localized to 6.3-kb HindIII and 2.1-kb HindIII-AvaI fragments, respectively. pIP501 was lost at a frequency of 22% in Streptococcus sanguis cells grown at 42 degrees C but was stable in cells grown at 37 degrees C (less than 1% frequency of loss). Sequences from a cryptic multicopy plasmid, pVA380-1, were substituted for the pIP501 Emr determinant in vitro, and the resulting recombinant plasmid, designated pVA797, was recovered in transformed S. sanguis cells. The replication of pVA797 was governed by the pVA380-1 sequences based on temperature-stable replication and incompatibility with pVA380-1-derived replicons. The self-ligation of partially cleaved HindIII pIP501 DNA fragments allowed the localization of a pIP501 region involved in autonomous plasmid replication. A small pIP501 derivative (pVA798) obtained from this experiment had a greatly increased copy number but was unstably inherited. Our data indicate that the sequences encoding the resistance determinants and some of the plasmid replication machinery are relatively clustered on the pIP501 molecule. The properties of pVA797 and pVA798 indicate that these molecules will enhance current streptococcal genetic systems from the standpoint of conjugative mobilization (pVA797) and gene amplification (pVA798).


p66Shc--a longevity redox protein in human prostate cancer progression and metastasis : p66Shc in cancer progression and metastasis.
p66Shc, a 66 kDa proto-oncogene Src homologous-collagen homologue (Shc) adaptor protein, is classically known in mediating receptor tyrosine kinase signaling and recently identified as a sensor to oxidative stress-induced apoptosis and as a longevity protein in mammals. The expression of p66Shc is decreased in mice and increased in human fibroblasts upon aging and in aging-related diseases, including prostate cancer. p66Shc protein level correlates with the proliferation of several carcinoma cells and can be regulated by steroid hormones. Recent advances point that p66Shc protein plays a role in mediating cross-talk between steroid hormones and redox signals by serving as a common convergence point in signaling pathways on cell proliferation and apoptosis. This article first reviews the unique function of p66Shc protein in regulating oxidative stress-induced apoptosis. Subsequently, we discuss its novel role in androgen-regulated prostate cancer cell proliferation and metastasis and the mechanism by which it mediates androgen action via the redox signaling pathway. The data together indicate that p66Shc might be a useful biomarker for the prognosis of prostate cancer and serve as an effective target for its cancer treatment.


Dual control of the intracellular pH in aortic smooth muscle cells by a cAMP-sensitive HCO3-/Cl- antiporter and a protein kinase C-sensitive Na+/H+ antiporter.
Two mechanisms are involved in the regulation of the intracellular pH (pHi) of aortic smooth muscle cells: the Na+/H+ antiporter and a Na+-independent HCO3-/Cl- antiporter. The Na+/H+ antiporter acts as a cell alkalinizing mechanism. It is activated by vasopressin and by phorbol esters when cells are incubated in the presence of bicarbonate but is not affected in the absence of bicarbonate. The HCO3-/Cl- antiporter acts as a cell acidifying mechanism. Agents such as forskolin, 8-Br-cAMP, and isoproterenol which raise intracellular cAMP levels inhibit the HCO3-/Cl- antiporter by shifting its pHi dependence in the alkaline direction. Thus, within the same cell type, different hormones control pHi variations by acting on different pHi regulating systems. An increase in pHi can be achieved either by a stimulation of a cell alkalinizing mechanism or by inhibition of a cell acidifying mechanism. A change of the activity of one pHi regulating mechanism modifies the responsiveness of the other to regulatory agents. Bicarbonate turns on the HCO3-/Cl- antiporter, decreases pHi and allows its regulation by protein kinase C through the Na+/H+ antiporter. Inhibition of the HCO3-/Cl- antiporter by cAMP increases the pHi and switches off the protein kinase C-mediated regulation.


Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus.
Staphylococcus aureus is a major cause of skin and soft tissue infection. The bacterium expresses four major proteases that are emerging as virulence factors: aureolysin (Aur), V8 protease (SspA), staphopain A (ScpA), and staphopain B (SspB). We hypothesized that human galectin-3, a β-galactoside-binding lectin involved in immune regulation and antimicrobial defense, is a target for these proteases and that proteolysis of galectin-3 is a novel immune evasion mechanism. Indeed, supernatants from laboratory strains and clinical isolates of S. aureus caused galectin-3 degradation. Similar proteolytic capacities were found in Staphylococcus epidermidis isolates but not in Staphylococcus saprophyticus Galectin-3-induced activation of the neutrophil NADPH oxidase was abrogated by bacterium-derived proteolysis of galectin-3, and SspB was identified as the major protease responsible. The impact of galectin-3 and protease expression on S. aureus virulence was studied in a murine skin infection model. In galectin-3+/+ mice, SspB-expressing S. aureus caused larger lesions and resulted in higher bacterial loads than protease-lacking bacteria. No such difference in bacterial load or lesion size was detected in galectin-3-/- mice, which overall showed smaller lesion sizes than the galectin-3+/+ animals. In conclusion, the staphylococcal protease SspB inactivates galectin-3, abrogating its stimulation of oxygen radical production in human neutrophils and increasing tissue damage during skin infection.


CAAX-box protein, prenylation process and carcinogenesis.
CAAX proteins are widely involved in global cellular functions such as proliferation, differentiation, and carcinogenesis. As an important modulator of biological activity, signal transduction via protein prenylation is a crucial step for most CAAX protein functions, particularly for anchoring these CAAX proteins to cellular membrane system. With a better understanding of the molecular mechanisms of signal transduction and intracellular messaging in this process, CAAX protein prenylation may be of particular importance for elucidating the biologic events in carcinogenesis and provide potential approaches of selectively blocking the downstream signal cascade that allows carcinogenesis. Here, we mainly focus on the prenylation process of the clinically important CAAX box proteins, and their potential as a biomarker or preventive/therapeutic target in carcinogenesis.


High-throughput production and structural characterization of libraries of self-assembly lipidic cubic phase materials.
A protocol is presented for the high-throughput (HT) production of lyotropic liquid crystalline phases from libraries of lipids and lipid mixtures using standard liquid dispensing robotics, implementing methods that circumvent the problems traditionally associated with handling the highly viscous cubic phase. In addition, the ability to structurally characterize lipidic phases and assess functionality for membrane proteins contained within cubic phases, in a HT manner, is demonstrated. The techniques are combined and exemplified using the application of membrane protein crystallization within lipidic cubic phases.


Survival of tooth-implant connections: A systematic review and meta-analysis.
Implant-supported prostheses have considerable biomechanical advantages in partially edentulous patients when compared to other prosthetic options. Given the steady drop in the frequency of patients reporting with complete edentulism, it is not unusual to see situations where teeth and implants can be splinted to provide support for fixed prostheses. A tooth implant prosthesis differs majorly from an implant-supported prosthesis in terms of force dissipation and design. The aim of this systematic review was to compare the survival rates of tooth-implant-supported prostheses with fully implant-supported and fully tooth-supported prostheses. Using the appropriate search terms, PubMed, Google Scholar, and other indexed journals were used to search the English-language literature. According to the review protocols and the PICOS inclusion criteria, the pertinent studies were chosen. The screening of appropriate studies, evaluation of study quality, and data extraction were carried out independently by two reviewers. The pooling of survival data by prostheses failure, implant failure, and marginal bone loss was used in the meta-analysis. The cumulative data of all included studies indicated that tooth-implant-supported prostheses showed a 5-year survival rate of 77%-84% and a 10-year survival rate of 72%. The pooled risk ratio for prostheses failure and implant failure was 0.99 and 1.76, respectively. These results were not statistically significant (P > 0.05). The pooled standard mean difference for marginal bone loss was 0.59, and the results were statistically significant (P < 0.05). A tooth-implant-supported fixed partial denture (FPD) has a similar survival rate when compared to implant-supported FPD or T-FPD.


Qigong improves quality of life in women undergoing radiotherapy for breast cancer: results of a randomized controlled trial.
Radiotherapy may lead to side effects that undermine patients' quality of life (QOL). Although mind-body practices like qigong appear to improve QOL in cancer survivors, little is known about their benefits for patients who are receiving radiotherapy. Thus, in the current randomized controlled trial, the authors examined the efficacy of a qigong intervention on QOL in women with breast cancer during and after treatment. Ninety-six women with breast cancer were recruited from a cancer center in Shanghai, China, and were randomized to a qigong group (N = 49) or a waitlist control group (N = 47). Women in the qigong group attended 5 weekly classes over 5 or 6 weeks of radiotherapy. QOL outcomes (ie, depressive symptoms, fatigue, sleep disturbance, and overall QOL) and cortisol slopes were assessed at baseline, during treatment, at the end of treatment, 1 month later, and 3 months later. The mean age of the women was 46 years (range, 25-64 years). Seven percent of women had stage 0 disease, 25% had stage I disease, 40% had stage II disease, and 28% had stage III disease. Fifty-four percent of women underwent mastectomy. Multilevel analyses revealed that women in the qigong group reported less depressive symptoms over time than women in the control group (P = .05). Women who had elevated depressive symptoms at the start of radiotherapy reported less fatigue (P < .01) and better overall QOL (P < .05) in the qigong group compared with the control group, and these findings were clinically significant. No significant differences were observed for sleep disturbance or cortisol slopes. The current results indicated that qigong may have therapeutic effects in the management of QOL among women who are receiving radiotherapy for breast cancer. Benefits were particularly evident for patients who had preintervention elevated levels of depressive symptoms.


Magnesium-Induced Cell Survival Is Dependent on TRPM7 Expression and Function.
Mg2+ homeostasis is essential for cell survival and the loss of this regulation has been associated with many neurodegenerative diseases, including loss of dopaminergic neurons. Although the neurotoxin-mediated loss of dopaminergic neurons in Parkinson disease models is extensively studied, the ion channel(s) that regulate Mg2+ homeostasis and thus could prevent neuronal cell death is not yet identified. Here, we show that TRPM7 (transient receptor potential melastatin 7) is involved in regulating Mg2+ homeostasis in dopaminergic cells. Importantly, transient loss of TRPM7 decreased intracellular Mg2+ levels and decreased dopaminergic cells/neurons survival. We provide further evidence that both increases in extracellular Mg2+ or transiently increasing TRPM7 levels protected dopaminergic SH-SY5Y cells against neurotoxin-mediated cell death. Neurotoxin treatment significantly decreased TRPM7 levels in both SH-SY5Y cells and the substantia nigra pars compacta region of mice, along with a decrease in Mg2+ influx. Moreover, Mg2+ supplementation showed a concentration-dependent decrease in caspase-3 activity, an increase in cell survival, restored mitochondrial membrane potential, and increase TRPM7 levels in neurotoxin-treated cells. In contrast, transient silencing of TRPM7 inhibited the positive effect of Mg2+ supplementation in protecting against neurotoxins. Whereas, TRPM7 overexpression not only maintained Mg2+ homeostasis but also inhibited caspase 3 activity that induced cell survival. Overall, these results suggest a significant role of TRPM7 channels in Mg2+ homeostasis and the survival of neurotoxin-induced loss of dopaminergic cells.


Correction of the atrophic alveolar ridge by interpositional bone grafting: a progress report.
A retrospective study of postoperative stability and osseous changes was made on nine patients with maxillary or mandibular atrophy who were treated with interpositional bone grafting techniques. There was minimal discernible positional change or resorption of the portion of the maxilla or mandible that was moved by interpositional grafting procedures. Sequential radiographs and cephalometric tracings showed early consolidation of the grafted bone, minimal resorption of the respositioned osseous segments, and a small decrease of alveolar ridge height during an average potsoperative follow-up period of seven months.


Serum inhibin B, FSH, LH and testosterone levels before and after human chorionic gonadotropin stimulation in prepubertal boys with cryptorchidism.
Several studies have indicated that cryptorchidism is associated with degenerative changes in both Sertoli cells and germ cells. The gonadal peptide hormone inhibin B reflects Sertoli cell function. Low inhibin B levels are found in a large portion of formerly cryptorchid men who show compromised seminiferous tubule function. It is not known if inhibin B can be used to demonstrate early damage of seminiferous tubules in prepubertal boys with cryptorchidism. We investigated the relationship between serum levels of inhibin B, testosterone, FSH and LH in 62 prepubertal boys with uni- and bilateral cryptorchidism. Furthermore, we investigated the changes in serum levels of inhibin B and the corresponding changes in serum levels of FSH, LH and testosterone during a short course (3 weeks) of human chorionic gonadotropin (hCG) injections in 18 of these cryptorchid boys. In the 62 prepubertal boys with uni- or bilateral cryptorchidism there were no significant differences in baseline levels (median and range) of inhibin B (88 (20-195) pg/ml vs 78 (35-182) pg/ml; not significant), LH (0.08 (<0.05-0.99) IU/l vs 0.06 (<0.05-1.61) IU/l; not significant) and FSH (0.60 (0.08-3.73) IU/l vs 0.85 (0.25-2.55); not significant) compared with 156 healthy prepubertal boys, and there were no differences in hormonal levels between boys with uni- or bilateral cryptorchidism. There was no correlation between baseline levels of inhibin B and FSH. In boys younger than 9 years, we found no correlation between baseline levels of inhibin B and LH whereas, in boys older than 9 years, baseline levels of inhibin B were positively correlated to baseline LH (Spearman rank correlation coefficient ((R(s))=0.58, P=0.03). Treatment with hCG (1500 IU intramuscularly twice weekly for 3 weeks) resulted in descensus of testes in 9 out of 18 patients. In all boys but one, irrespective of age, hCG induced a marked increase in testosterone into the adult range (from undetectable to 21.8 (7.0-35.4) nmol/l; P<0.001) and completely suppressed FSH and LH levels. Serum levels of inhibin B increased significantly from 116 (50-195) pg/ml to 147 (94-248) pg/ml (P<0.05), but not uniformly. The increase in serum levels of inhibin B was inversely correlated to baseline inhibin B (Rs=-0.52, P=0.03) and baseline FSH (R(s)=-0.59, P<0.01). We therefore suggest that, in the prepubertal testes, inhibin B is secreted from the prepubertal Sertoli cells following hCG, whereas early pubertal testes with more differentiated Sertoli cells are not able to secrete inhibin B in response to hCG stimulation, perhaps due to lack of germ cell-derived betaB-subunits. We found (a) normal inhibin B levels in prepubertal boys with uni- or bilateral cryptorchidism, (b) that hCG stimulated testosterone markedly and suppressed FSH and LH levels and (c) that hCG treatment stimulated inhibin B levels in the youngest cryptorchid boys. In the oldest prepubertal boys no hCG-induced changes in inhibin B were shown.


Parturition date for a given female is highly repeatable within five roe deer populations.
Births are highly synchronized among females in many mammal populations in temperate areas. Although laying date for a given female is also repeatable within populations of birds, limited evidence suggests low repeatability of parturition date for individual females in mammals, and between-population variability in repeatability has never, to our knowledge, been assessed. We quantified the repeatability of parturition date for individual females in five populations of roe deer, which we found to vary between 0.54 and 0.93. Each year, some females gave birth consistently earlier in the year, whereas others gave birth consistently later. In addition, all females followed the same lifetime trajectory for parturition date, giving birth progressively earlier as they aged. Giving birth early should allow mothers to increase offspring survival, although few females managed to do so. The marked repeatability of parturition date in roe deer females is the highest ever reported for a mammal, suggesting low phenotypic plasticity in this trait.


Workplace Violence Prevention: Flagging Practices and Challenges in Hospitals.
Flagging is a standardized way to communicate the risk of patient violence to workers. We add to the limited body of research on flagging by describing hospitals' approaches to and challenges with flagging patients with a history of violent behavior. We used a qualitative case study approach of hospitals in Ontario, Canada and their patient flagging practices. Key informants and our advisory committee identified 11 hospitals to invite to participate. Hospitals assisted in recruiting frontline clinical and allied health workers and managers to an interview or focus group. A document analysis of hospitals' flagging policies and related documents was conducted. Thematic analysis was used to analyze interview and focus group data. Five hospitals participated. Of the five hospitals, four had a flagging policy where frontline clinical workers (n = 58), frontline allied health workers (n = 31), and managers (n = 42) participated in an interview (n = 43) or focus group (n = 15). Participants described three challenges: patient stigmatization, patient privacy, and gaps in policy and procedures. Flagging patients with a history of violent behavior is one intervention that hospitals use to keep workers safe. While violence prevention was important to study participants, a number of factors can affect implementation of a flagging policy. Study findings suggest that hospital leadership should mitigate patient stigmatization (real and perceived) and perception of patient rights infringement by educating all managers and frontline workers on the purpose of flagging and the relationship between occupational health and safety and privacy regulations. Leadership should also actively involve frontline workers who are the most knowledgeable about how policies work in practice.


A catalogue of omics biological ageing clocks reveals substantial commonality and associations with disease risk.
Biological age (BA), a measure of functional capacity and prognostic of health outcomes that discriminates between individuals of the same chronological age (chronAge), has been estimated using a variety of biomarkers. Previous comparative studies have mainly used epigenetic models (clocks), we use ~1000 participants to compare fifteen omics ageing clocks, with correlations of 0.21-0.97 with chronAge, even with substantial sub-setting of biomarkers. These clocks track common aspects of ageing with 95% of the variance in chronAge being shared among clocks. The difference between BA and chronAge - omics clock age acceleration (OCAA) - often associates with health measures. One year's OCAA typically has the same effect on risk factors/10-year disease incidence as 0.09/0.25 years of chronAge. Epigenetic and IgG glycomics clocks appeared to track generalised ageing while others capture specific risks. We conclude BA is measurable and prognostic and that future work should prioritise health outcomes over chronAge.


Next-generation sequencing approach for connecting secondary metabolites to biosynthetic gene clusters in fungi.
Genomics has revolutionized the research on fungal secondary metabolite (SM) biosynthesis. To elucidate the molecular and enzymatic mechanisms underlying the biosynthesis of a specific SM compound, the important first step is often to find the genes that responsible for its synthesis. The accessibility to fungal genome sequences allows the bypass of the cumbersome traditional library construction and screening approach. The advance in next-generation sequencing (NGS) technologies have further improved the speed and reduced the cost of microbial genome sequencing in the past few years, which has accelerated the research in this field. Here, we will present an example work flow for identifying the gene cluster encoding the biosynthesis of SMs of interest using an NGS approach. We will also review the different strategies that can be employed to pinpoint the targeted gene clusters rapidly by giving several examples stemming from our work.


Real-Time Ultrasound Detection of Left Paratracheal Esophagus on Air Entry into the Gastric Antrum in the Induction Period of General Anesthesia: A Prospective, Randomized Study.
Positive-pressure ventilation (PPV) delivered via a facemask during anesthesia induction can result in gastric content being inhaled into the lungs. We hypothesized that the real-time ultrasound left paratracheal esophagus monitoring could more effectively reduce air entry into the stomach than real-time ultrasound monitoring of the gastric antrum (GA). Patients were divided into two groups: study (S; n=30) and control (C; n=30) groups. During the induction of general anesthesia, mask ventilation adopts a pressure control mode. The initial ventilation pressure of both groups was 15 cmH2O. Before anesthesia induction, an ultrasonic probe was used to monitor the cross-sectional area (CSA) of the GA and the presence of gas in the stomach. During and after anesthesia induction, group S used a high-frequency ultrasound probe to observe the entry of air from the left paratracheal esophagus into the GA. The ventilation pressure was gradually reduced over time until no esophageal air was found. In group C, the ventilatory pressure was set maintained at 15 cmH2O and the CSA of the GA and air intake were monitored using an ultrasonic probe. Before and after PPV, the CSA of the GA in group S decreased (P<0.001), whereas the CSA in group C increased (P=0.002). The GA CSA in group C after PPV was larger than in group S after PPV (P=0.002). The proportion of patients who experienced intragastric air intake in group S (23.3%) was significantly lower than that in group C (66.7) (P=0.001). Compared with ultrasound monitoring of the GA, real-time ultrasound detection of LPEOAE into the GA during anesthesia induction was more effective, more sensitive, significantly reduced the prevalence of intragastric air intake, and provided sufficient tidal volume and oxygen for patients.


Differential time course of induction of rat liver microsomal cytochrome P-450 isozymes and epoxide hydrolase by Aroclor 1254.
The time course of induction of rat liver microsomal cytochromes P-450a, P-450b + P-450e, P-450c, and P-450d and epoxide hydrolase has been determined in immature male rats administered a single large dose [1500 mumol (500 mg)/kg body wt] of the polychlorinated biphenyl mixture Aroclor 1254. Differential regulation of these xenobiotic-metabolizing enzymes was indicated by their characteristic patterns of induction. The rate of induction of cytochrome P-450a and epoxide hydrolase was relatively slow, and steady-state levels of these enzymes were maintained from approximately Days 9 to 15 after Aroclor 1254 treatment. In contrast, cytochrome P-450c was maximally induced 2 days after Aroclor 1254 treatment and remained at a constant level through Day 15. Steady-state levels of cytochrome P-450d, beginning 1 week after Aroclor 1254 treatment, were preceded by a fairly rapid rate of induction and possibly by a small decline from maximal levels observed around Days 4 to 5. Like those of the other cytochrome P-450 isozymes and epoxide hydrolase, the levels of cytochromes P-450b + P-450e were constant from Day 9 to 15 after Aroclor 1254 treatment. However, an unexpected but reproducible decline (approximately 25%) in total cytochrome P-450 content observed between Days 4 and 9 after Aroclor 1254 treatment principally reflected a dramatic and totally unanticipated decrease (approximately 45%) in the level of cytochromes P-450b + P-450e. This transient decline in the level of cytochromes P-450b + P-450e was not due to an unusual effect of a mixture of polychlorinated biphenyls, since identical results were obtained with two individual congeners, namely 2,3,4,5,4'-penta- and 2,3,4,5,3',4'-hexachlorobiphenyl, that induced the same isozymes as Aroclor 1254. In contrast, when rats were treated with 2,4,5,2',4',5'-hexachlorobiphenyl, which induces cytochromes P-450a and P-450b + P-450e and epoxide hydrolase but not cytochromes P-450c or P-450d, maximal levels of cytochromes P-450b + P-450e were attained on Day 4 and no decrease was observed over the next 11 days. These results suggest that there may be an interaction in the regulation of induction of certain individual cytochrome P-450 isozymes.


Osteoarthritic knee pain: a behavioral analysis.
This study used behavioral assessment techniques to analyze pain in osteoarthritis (OA) patients. Eighty-seven OA patients having chronic knee pain served as subjects. Pain behavior was evaluated using a standard observation method and functional impairment was assessed using the Arthritis Impact Measurement Scales. Data analysis revealed that pain and limitations in physical activities were the most common functional impairments and that the most frequently observed pain behavior was guarded movement. Predictive analyses indicated that disability support status and scores on a Pain Control and Rational Thinking factor of the Coping Strategies Questionnaire (CSQ) were predictive of functional impairment. Patients receiving disability support payments were much more functionally limited than those not receiving this financial support. Patients scoring high on the Pain Control and Rational Thinking factor of the CSQ were much less functionally impaired, walked a 5 m course more rapidly and moved from a standing to a sitting or reclining position more quickly than patients scoring low on this factor. The implications of these results for behavioral treatment of OA knee pain are discussed.


Comparison of Nidek 3Dx and Donaldson simultaneous stereoscopic disk photography.
We performed a retrospective study on 100 eyes of 55 consecutive patients to compare the stereoscopic quality of simultaneous stereoscopic disk photographs and the reproducibility of optic nerve assessments using the Nidek 3Dx system and the Donaldson fundus camera. Photographs were taken on the same eyes on the same dates and reviewed independently by one clinician three times in a randomized, masked fashion. Mean cup/disk ratios using the Nidek 3Dx system were similar to mean cup/disk ratios using the Donaldson camera. There was significantly less variability of disk analysis using the Nidek 3Dx system than the Donaldson camera (F = 1.6, P = .01, df = 99). Overall mean stereoscopic quality was significantly better with the Nidek system (3.2 +/- 1.15 S.D.) than with the Donaldson camera (2.5 +/- 1.27 S.D., P < .01). Age was the only variable that correlated with stereoscopic quality for both cameras. The new Nidek camera provided significantly better stereoscopic quality images than the Donaldson camera and with significantly more reproducible optic nerve head assessments.


Binding of Herpes Simplex Virus 1 UL20 to GODZ (DHHC3) Affects Its Palmitoylation and Is Essential for Infectivity and Proper Targeting and Localization of UL20 and Glycoprotein K.
Herpes simplex virus 1 (HSV-1) UL20 plays a crucial role in the envelopment of the cytoplasmic virion and its egress. It is a nonglycosylated envelope protein that is regulated as a γ1 gene. Two-hybrid and pulldown assays demonstrated that UL20, but no other HSV-1 gene-encoded proteins, binds specifically to GODZ (also known as DHHC3), a cellular Golgi apparatus-specific Asp-His-His-Cys (DHHC) zinc finger protein. A catalytically inactive dominant-negative GODZ construct significantly reduced HSV-1 replication in vitro and affected the localization of UL20 and glycoprotein K (gK) and their interactions but not glycoprotein C (gC). GODZ is involved in palmitoylation, and we found that UL20 is palmitoylated by GODZ using a GODZ dominant-negative plasmid. Blocking of palmitoylation using 2-bromopalmitate (2-BP) affected the virus titer and the interaction of UL20 and gK but did not affect the levels of these proteins. In conclusion, we have shown that binding of UL20 to GODZ in the Golgi apparatus regulates trafficking of UL20 and its subsequent effects on gK localization and virus replication. We also have demonstrated that GODZ-mediated UL20 palmitoylation is critical for UL20 membrane targeting and thus gK cell surface expression, providing new mechanistic insights into how UL20 palmitoylation regulates HSV-1 infectivity.IMPORTANCE HSV-1 UL20 is a nonglycosylated essential envelope protein that is highly conserved among herpesviruses. In this study, we show that (i) HSV-1 UL20 binds to GODZ (also known as DHHC3), a Golgi apparatus-specific Asp-His-His-Cys (DHHC) zinc finger protein; (ii) a GODZ dominant-negative mutant and an inhibitor of palmitoylation reduced HSV-1 titers and altered the localization of UL20 and glycoprotein K; and (iii) UL20 is palmitoylated by GODZ, and this UL20 palmitoylation is required for HSV-1 infectivity. Thus, blocking of the interaction of UL20 with GODZ, using a GODZ dominant-negative mutant or possibly GODZ shRNA, should be considered a potential alternative therapy in not only HSV-1 but also other conditions in which GODZ processing is an integral component of pathogenesis.


C3G Is Upregulated in Hepatocarcinoma, Contributing to Tumor Growth and Progression and to HGF/MET Pathway Activation.
The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and stage. The potential relevance of C3G upregulation in HCC patients suggested by database analysis remains unknown. We have explored C3G function in HCC and the underlying mechanisms using public patient data and in vitro and in vivo human and mouse HCC models. We found that C3G is highly expressed in progenitor cells and neonatal hepatocytes, whilst being down-regulated in adult hepatocytes and re-expressed in human HCC patients, mouse HCC models and HCC cell lines. Moreover, high C3G mRNA levels correlate with tumor progression and a lower patient survival rate. C3G expression appears to be tightly modulated within the HCC program, influencing distinct cell biological properties. Hence, high C3G expression levels are necessary for cell tumorigenic properties, as illustrated by reduced colony formation in anchorage-dependent and -independent growth assays induced by permanent C3G silencing using shRNAs. Additionally, we demonstrate that C3G down-regulation interferes with primary HCC tumor formation in xenograft assays, increasing apoptosis and decreasing proliferation. In vitro assays also revealed that C3G down-regulation enhances the pro-migratory, invasive and metastatic properties of HCC cells through an epithelial-mesenchymal switch that favors the acquisition of a more mesenchymal phenotype. Consistently, a low C3G expression in HCC cells correlates with lung metastasis formation in mice. However, the subsequent restoration of C3G levels is associated with metastatic growth. Mechanistically, C3G down-regulation severely impairs HGF/MET signaling activation in HCC cells. Collectively, our results indicate that C3G is a key player in HCC. C3G promotes tumor growth and progression, and the modulation of its levels is essential to ensure distinct biological features of HCC cells throughout the oncogenic program. Furthermore, C3G requirement for HGF/MET signaling full activation provides mechanistic data on how it works, pointing out the relevance of assessing whether high C3G levels could identify HCC responders to MET inhibitors.