Assessing the effectiveness of speed limit reduction in Edmonton: A case study analysis.
This study evaluates the impact of reducing the default speed limit from 50 km/h to 40 km/h on traffic safety and drivers' behavior in Edmonton, Canada. The research comprehensively examines collision and speed data to assess the outcomes of the new speed limit. Collision data was analyzed across three distinct periods: pre-COVID (2017-2019), the COVID period (2019-2021), and the after-implementation period (August 2021 to July 2022). Speed surveys were conducted on 219 road segments before and after the implementation of the speed limit change. The study utilized a before-and-after with a comparison group approach to evaluate the impact on collisions, using 50 km/h roads that maintained their speed limit throughout as the comparison group. The impact of the reduced speed limit on road safety was assessed by analyzing collision data for two periods, pre-COVID (2017-2019) and COVID (2019-2021), compared to the period after setting the new speed limit (2021-2022). Two-sample t-tests were employed to examine the change in speeds. The analysis revealed statistically significant reductions in the overall number of collisions and injuries and fatalities resulting from collisions, by 25% and 31%, respectively. The study also categorized neighborhoods and roads to demonstrate the areas that experienced the greatest benefits. Speed data showed statistically significant reductions in the average and 85th percentile speeds, with drivers lowering their speeds at 115 locations, accounting for 53% of the surveyed locations. Moreover, higher speed reductions were observed on local roads compared to collector roads, and narrower roads compared to wider roads.. Overall, the study demonstrates that reducing the speed limit can lead to lower speeds and fewer collisions on the roads, creating a safer road environment for drivers, pedestrians, and cyclists. Additionally, it provides a detailed framework for municipalities to evaluate the effectiveness of their speed limit reduction programs.


Influence of hydrodynamics on the growth kinetics of glass-adhering Pseudomonas putida cells through a parallel plate flow chamber.
The objective of this work was to investigate the influence of hydrodynamics on the growth kinetics of surface-adhering Pseudomonas putida cells. The results showed in particular that under non substrate-limiting conditions, the early step of bacterial apparent growth rate is lower than those measured with suspended cells. Contrary to previously cited authors which explain this behavior to the different adhesive properties of the "daughter"-cells (which makes more probable the detachment of these daughter-cells), in our experimental conditions, that explanation does not hold and we show a clear dependence of growth kinetics with flow conditions, due to the formation of boundary layer concentration at low Reynolds number. These results revealed that using Monod law in the modeling of biofilm growth in fixed-biomass processes should be performed with care.


Spinal cord injury without radiographic abnormality in adults.
Spinal cord injury without fractures or bony malalignment on either plain radiographs or computed tomography (SCIWORA) is most commonly found in the paediatric age group. In recent years, magnetic resonance imaging (MRI) has been used to evaluate these patients. The present communication describes SCIWORA in 15 adult patients investigated by MRI. Of the 151 patients with spinal cord injury in 1 year, 15 adult patients had cervical SCIWORA. All patients were evaluated by MRI. The age ranged from 20 - 60 years. Eleven patients had partial cord injury, two had a complete cord syndrome while two had a central cord syndrome. MRI demonstrated an intervertebral disc prolapse in six patients, intramedullary haematoma/contusion in four and cord oedema in four patients. One patient had multiple disc prolapses and associated intramedullary haematoma. Patients with disc prolapse were operated upon and all showed neurological improvement. The rest of the patients were managed conservatively. There was mild improvement in patients with intramedullary haematomas while those with cord oedema alone showed moderate recovery. The pathogenesis of adult SCIWORA is possibly different from that in paediatric age group. Most of the patients with SCIWORA show some abnormality on MR imaging. MRI should therefore be done in all patients with spinal cord injury for diagnostic and prognostic purposes.


Comparative outcomes of younger and older hospitalized patients with inflammatory bowel disease treated with corticosteroids.
Data on the differences in inpatient treatment approaches and outcomes between younger and older patients with inflammatory bowel disease (IBD) are limited. Therefore, we used a parallel cohort study design to compare outcomes between younger and older patients with IBD. All anti-tumor necrosis factor (TNF)-naive patients aged 60 years and older hospitalized at our institution between 2003 and 2011 and treated with corticosteroids for an IBD flare were matched 1:1 to younger patients aged 18 to 50 years. Rates of corticosteroid response, colectomy, and initiation of anti-TNF therapy were compared. Sixty-five patients were identified in each cohort. Median ages were 70 years (range, 60-94) and 30 years (range, 18-50) for the older and younger groups, respectively. Twenty-three percent of older patients were refractory to corticosteroids compared with 38% of the younger cohort (odds ratio, 0.5; 95% confidence intervals, 0.2-1.1). Older corticosteroid-refractory patients had surgery (80% versus 72%) and were started on anti-TNF therapy (20% versus 12%; P = 0.71), at a similar frequency as younger patients. Older steroid-responsive patients were less likely to start an anti-TNF agent during the first year of follow-up than younger patients (7% versus 31%, P = 0.006), but there was no difference in 1-year colectomy rates (27% versus 28%, P = 0.63). Corticosteroid response was similar in older and younger patients hospitalized for IBD. Inpatient treatment for corticosteroid-refractory patients was similar between cohorts. Older corticosteroid-responsive patients were less likely to be treated with an anti-TNF than younger patients.


An empirical study of psychosis in borderline personality disorder.
To assess the nature and prevalence of psychotic symptoms in borderline personality disorder, the authors reviewed the cases of 33 patients meeting DSM-III criteria for borderline personality disorder, using both "narrow" and "broad" definitions of psychosis. Only eight patients displayed psychotic symptoms meeting the "narrow" DSM-III definition; in all of these cases, the symptoms appeared to be attributable to either severe drug abuse or major affective disorder, present simultaneously with borderline personality disorder. The remaining patients displayed only "broadly defined" psychotic symptoms or symptoms that appeared to be under voluntary control. These findings weigh against the assumption that borderline personality disorder lies "on the border" of classical psychotic disorders.


Vulnerability of IDH1-Mutant Cancers to Histone Deacetylase Inhibition via Orthogonal Suppression of DNA Repair.
Exploitation of DNA repair defects has enabled major advances in treating specific cancers. Recent work discovered that the oncometabolite 2-hydroxyglutarate (2-HG), produced by neomorphic isocitrate dehydrogenase 1/2 (IDH1/2) mutations, confers a homology-directed repair (HDR) defect through 2-HG-induced histone hypermethylation masking HDR signaling. Here, we report that IDH1-mutant cancer cells are profoundly sensitive to the histone deacetylase inhibitor (HDACi) vorinostat, by further suppressing the residual HDR in 2-HG-producing cells. Vorinostat downregulates repair factors BRCA1 and RAD51 via disrupted E2F-factor regulation, causing increased DNA double-strand breaks, reduced DNA repair factor foci, and functional HDR deficiency even beyond 2-HG's effects. This results in greater cell death of IDH1-mutant cells and confers synergy with radiation and PARPi, both against cells in culture and patient-derived tumor xenografts. Our work identifies HDACi's utility against IDH1-mutant cancers, and presents IDH1/2 mutations as potential biomarkers to guide trials testing HDACi in gliomas and other malignancies. IMPLICATIONS: IDH1-mutant cells show profound vulnerability to HDACi treatment, alone and with PARPi and radiation, via HDR suppression, presenting IDH1/2 mutations as biomarkers for HDACi use in gliomas and other malignancies.


Acute otitis externa: Consensus definition, diagnostic criteria and core outcome set development.
Evidence for the management of acute otitis externa (AOE) is limited, with unclear diagnostic criteria and variably reported outcome measures that may not reflect key stakeholder priorities. We aimed to develop 1) a definition, 2) diagnostic criteria and 3) a core outcome set (COS) for AOE. COS development according to Core Outcome Measures in Effectiveness Trials (COMET) methodology and parallel consensus selection of diagnostic criteria/definition. Stakeholders from the United Kingdom. Comprehensive literature review identified candidate items for the COS, definition and diagnostic criteria. Nine individuals with past AOE generated further patient-centred candidate items. Candidate items were rated for importance by patient and professional (ENT doctors, general practitioners, microbiologists, nurses, audiologists) stakeholders in a three-round online Delphi exercise. Consensus items were grouped to form the COS, diagnostic criteria, and definition. Candidate COS items from patients (n = 28) and literature (n = 25) were deduplicated and amalgamated to a final candidate list (n = 46). Patients emphasised quality-of-life and the impact on daily activities/work. Via the Delphi process, stakeholders agreed on 31 candidate items. The final COS covered six outcomes: pain; disease severity; impact on quality-of-life and daily activities; patient satisfaction; treatment-related outcome; and microbiology. 14 candidate diagnostic criteria were identified, 8 reaching inclusion consensus. The final definition for AOE was 'diffuse inflammation of the ear canal skin of less than 6 weeks duration'. The development and adoption of a consensus definition, diagnostic criteria and a COS will help to standardise future research in AOE, facilitating meta-analysis. Consulting former patients throughout development highlighted deficiencies in the outcomes adopted previously, in particular concerning the impact of AOE on daily life.


Feasibility and performance of an adaptive contrast-oriented FDG PET/CT quantification technique for global disease assessment of malignant pleural mesothelioma and a brief review of the literature.
Treatment of malignant pleural mesothelioma (MPM) remains very challenging. Assessment of response to treatment is necessary for modifying treatment and using new drugs. Global disease assessment (GDA) by implementing image processing methods to extract more information out of positron emission tomography (PET) images may provide reliable information. In this study we show the feasibility of this method of semi-quantification in patients with mesothelioma, and compare it with the conventional methods. We also present a review of the literature about this topic. Nineteen subjects with histologically proven MPM who had undergone fluoride-18-fluorodeoxyglucose PET/computed tomography ((18)F-FDG PET/CT) before and after treatment were included in this study. An adaptive contrast-oriented thresholding algorithm was used for the image analysis and semi-quantification. Metabolic tumor volume (MTV), maximum and mean standardized uptake volume (SUVmax, SUVmean) and total lesion glycolysis (TLG) were calculated for each region of interest. The global tumor glycolysis (GTG) was obtained by summing up all TLG. Treatment response was assessed by the European Organisation for Research and Treatment of Cancer (EORTC) criteria and the changes of GTG. Agreement between global disease assessment and conventional method was also determined. In patients with progressive disease based on EORTC criteria, GTG showed an increase of 150.7 but in patients with stable or partial response, GTG showed a decrease of 433.1. The SUVmax of patients before treatment was 5.95 (SD: 2.93) and after the treatment it increased to 6.38 (SD: 3.19). Overall concordance of conventional method with GDA method was 57%. Concordance of progression of disease based on conventional method was 44%, stable disease was 85% and partial response was 33%. Discordance was 55%, 14% and 66%. Adaptive contrast-oriented thresholding algorithm is a promising method to quantify the whole tumor glycolysis in patients with mesothelioma. We are able to assess the total metabolic lesion volume, lesion glycolysis, SUVmax, tumor SUVmean and GTG for this particular tumor. Also we were able to demonstrate the potential use of this technique in the monitoring of treatment response. More studies comparing this technique with conventional and other global disease assessment methods are needed in order to clarify its role in the assessment of treatment response and prognosis of these patients.


Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer.
BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.


Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons.
During cellular specification, transcription factors orchestrate cellular decisions through gene regulation. By hijacking these transcriptional networks, human pluripotent stem cells (hPSCs) can be specialized into neurons with different molecular identities for the purposes of regenerative medicine and disease modeling. However, molecular fine tuning cell types to match their in vivo counterparts remains a challenge. Directing cell fates often result in blended or incomplete neuron identities. A better understanding of hPSC to neuron gene regulation is needed. Here, we used single cell RNA sequencing to resolve some of these graded molecular identities during human neurogenesis from hPSCs. Differentiation platforms were established to model neural induction from stem cells, and we characterized these differentiated cell types by 10x single cell RNA sequencing. Using single cell trajectory and co-expression analyses, we identified a co-regulated transcription factor module expressing achaete-scute family basic helix-loop-helix transcription factor 1 (ASCL1) and neuronal differentiation 1 (NEUROD1). We then tested the function of these transcription factors in neuron subtype differentiation by gene knockout in a novel human system that reports the expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis. ASCL1 was identified as a necessary transcription factor for regulating dopaminergic neurotransmitter selection.


In vivo measurement of lower back deformations with Fourier-transform profilometry.
Through the variation of their cross sections, the in vivo response of lower back muscles to low loading in an upright seated posture is explored by the Fourier-transform profilometry technique. The maximization of its sensitivity allows us to reach an adequate resolution for the evaluation of low-back displacements. Refinements of the fringe pattern analysis permit the minimization of errors. The experiments show an asymmetric distribution of the displacement during head rotation movements. Significant contribution of the lower back to grasping exertions is also observed. These results are thought to be useful for early defect detection in the lower back.


[Socio-demographic status of elderly and senile age people died from alcohol-attributable states in Arkhangelsk].
To determine the characteristics of the socio-demographic status of elderly and senile age people died of alcohol-attributable states in Arkhangelsk, data from the medical certificate of death was analyzed. Data of death for persons who died in the city of Arkhangelsk in the period from 1 July 2011 to 30 June 2012 (one year) were copied out. The vast majority of alcohol conditioned deaths among men occurs in middle (working) age, 1/3 of women--over the age of 60 years. The alcohol-attributable mortality revealed the transformation of the structure of women over the age of 60 years compared with the mature age. Gender and age significantly affect the probability of death from alcohol only attribute states after 60 years. The results of the study indicate a different impact on the character of the individual sociodemographic factors on the probability of death from alcohol-attributable states in elderly and senile age.


Enzymatic assembly of overlapping DNA fragments.
Three methods for assembling multiple, overlapping DNA molecules are described. Each method shares the same basic approach: (i) an exonuclease removes nucleotides from the ends of double-stranded (ds) DNA molecules, exposing complementary single-stranded (ss) DNA overhangs that are specifically annealed; (ii) the ssDNA gaps of the joined molecules are filled in by DNA polymerase, and the nicks are covalently sealed by DNA ligase. The first method employs the 3'-exonuclease activity of T4 DNA polymerase (T4 pol), Taq DNA polymerase (Taq pol), and Taq DNA ligase (Taq lig) in a two-step thermocycled reaction. The second method uses 3'-exonuclease III (ExoIII), antibody-bound Taq pol, and Taq lig in a one-step thermocycled reaction. The third method employs 5'-T5 exonuclease, Phusion® DNA polymerase, and Taq lig in a one-step isothermal reaction and can be used to assemble both ssDNA and dsDNA. These assembly methods can be used to seamlessly construct synthetic and natural genes, genetic pathways, and entire genomes and could be very useful for molecular engineering tools.


Multi-functional magnetic nanoparticles for magnetic resonance imaging and cancer therapy.
We have developed a multi-layer approach for the synthesis of water-dispersible superparamagnetic iron oxide nanoparticles for hyperthermia, magnetic resonance imaging (MRI) and drug delivery applications. In this approach, iron oxide core nanoparticles were obtained by precipitation of iron salts in the presence of ammonia and provided β-cyclodextrin and pluronic polymer (F127) coatings. This formulation (F127250) was highly water dispersible which allowed encapsulation of the anti-cancer drug(s) in β-cyclodextrin and pluronic polymer for sustained drug release. The F127250 formulation has exhibited superior hyperthermia effects over time under alternating magnetic field compared to pure magnetic nanoparticles (MNP) and β-cyclodextrin coated nanoparticles (CD200). Additionally, the improved MRI characteristics were also observed for the F127250 formulation in agar gel and in cisplatin resistant ovarian cancer cells (A12780CP) compared to MNP and CD200 formulations. Furthermore, the drug-loaded formulation of F127250 exhibited many folds of imaging contrast properties. Due to the internalization capacity of the F127250 formulation, its curcumin-loaded formulation (F127250-CUR) exhibited almost equivalent inhibition effects on A2780CP (ovarian), MDA-MB-231 (breast), and PC-3 (prostate) cancer cells even though curcumin release was only 40%. The improved therapeutic effects were verified by examining molecular effects using Western blotting and transmission electron microscopic (TEM) studies. F127250-CUR also exhibited haemocompatibility, suggesting a nanochemo-therapeutic agent for cancer therapy.


Rationale and design of the randomized prospective ATLAS study: Avoid Transvenous Leads in Appropriate Subjects.
The defibrillator lead is the weakest part of the transvenous (TV) implantable cardioverter defibrillation (ICD) system and a frequent cause of morbidity. Lead dislodgement, cardiac perforation, insertion-related trauma including pneumothorax and vascular injury, are common early complications of TV-ICD implantation. Venous occlusion, tricuspid valve dysfunction, lead fracture and lead insulation failure are additional, later complications. The introduction of a totally sub-cutaneous ICD (S-ICD) may reduce these lead-related issues, patient morbidity, hospitalizations and costs. However, such benefits compared to the TV-ICD have not been demonstrated in a randomized trial. ATLAS (Avoid Transvenous Leads in Appropriate Subjects) is a multi-centered, randomized, open-label, parallel group trial. Patients younger than 60 years are eligible. If older than 60 years, patients are eligible if they have an inherited heart rhythm disease, or risk factors for ICD-related complication, such as hemodialysis, a history of ICD or pacemaker infection, heart valve replacement, or severe pulmonary disease. This study will determine if using an S-ICD compared to a TV-ICD reduces a primary composite outcome of perioperative complications including pulmonary or pericardial perforation, lead dislodgement or dysfunction, tricuspid regurgitation and ipsilateral venous thrombosis. Five hundred patients will be enrolled from 14 Canadian hospitals, and data collected to both early- (at 6 months) and mid-term complications (at 24 months) as well as mortality and ICD shock efficacy. The ATLAS randomized trial is comparing early- and mid-term vascular and lead-related complications among S-ICD versus TV-ICD recipients who are younger or at higher risk of ICD-related complications.


1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through activation of c-jun N-terminal kinase.
1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) activate the orphan receptors peroxisome proliferator-activated receptor gamma (PPARgamma) and Nur77 and induce receptor-dependent and -independent apoptotic pathways in colon and other cancer cells. Structure-activity studies show that the p-bromo (DIM-C-pPhBr) and p-fluoro (DIM-C-pPhF) analogs, which exhibit minimal activation of Nur77 and PPARgamma, induce expression of CCAAT/enhancer-binding protein homologous protein (CHOP/GADD153) in colon cancer cells. Moreover, among a series of bromo and fluoro C-DIM analogs, their induction of CHOP was dependent on the position of the phenyl substituents (para >/= meta >/= ortho) and required a free indole group. DIM-C-pPhBr and DIM-C-pPhF not only induced CHOP but also activated death receptor 5 (CHOP dependent), cleavage of caspase 8 and poly (ADP ribose) polymerase (PARP) that is consistent with activation of the extrinsic pathway of apoptosis. These responses were associated with the activation of c-jun N-terminal kinase (JNK) pathway since inhibition of JNK inhibited induction of the extrinsic apoptotic pathway by these C-DIMs. However, in contrast to classical inducers of endoplasmic reticulum (ER) stress such as tunicamycin and thapsigargin, the C-DIM compounds did not induce glucose-related protein 78 that is a marker of ER stress. Proapoptotic and anticarcinogenic effects were also observed in athymic nude mice bearing RKO cell xenografts and treated with 30 mg/kg/day DIM-C-pPhBr and this was accompanied by increased JNK phosphorylation in the tumors. Thus, the anticarcinogenic activity of DIM-C-pPhBr in colon cancer cells and tumors is related to a novel ER stress-independent activation of JNK.


Interspecific Variation in Nematode Responses to Metals.
Performing toxicity testing on multiple species with differing degrees of evolutionary relatedness can provide important information on how chemical sensitivity varies among species and can help pinpoint the biological drivers of species sensitivity. Such knowledge could ultimately be used to design better multispecies predictive ecological risk assessment models and identify particularly sensitive species. However, laboratory toxicity tests involving multiple species can also be resource intensive, especially when each species has unique husbandry conditions. We performed lethality tests with 2 metals, copper chloride and zinc chloride, on 5 different nematode species, which are nested in their degree of evolutionary relatedness: Caenorhabditis briggsae, Caenorhabditis elegans, Oscheius myriophila, Oscheius tipulae, and Pristionchus pacificus. All species were successfully cultured and tested concurrently with limited resources, demonstrating that inexpensive, multispecies nematode toxicity testing systems are achievable. The results indicate that P. pacificus is the most sensitive to both metals. Conversely, C. elegans is the least sensitive species to copper, but the second most sensitive to zinc, indicating that species relationships do not necessarily predict species sensitivity. Toxicity testing with additional nematode species and types of chemicals is feasible and will help form more generalizable conclusions about relative species sensitivity. Environ Toxicol Chem 2020;39:1006-1016. © 2020 SETAC.


Reconstitution of oxidative phosphorylation and the adenosine triphosphate-dependent transhydrogenase activity by a combination of membrane fractions from unCA- and uncB- mutant strains of Escherichia coli K12.
1. Membrane preparations from both uncA(-) and uncB(-) mutant strains of Escherichia coli K12, in which electron transport is uncoupled from phosphorylation, were fractionated by washing with a low-ionic-strength buffer. The fractionation gave a ;5mm-Tris wash' and a ;membrane residue' from each strain. This technique, applied to membranes from normal cells, separates the Mg(2+),Ca(2+)-stimulated adenosine triphosphatase activity from the membrane-bound electron-transport chain and the non-energy-linked transhydrogenase activity. 2. Reconstitution of both oxidative phosphorylation and the ATP-dependent transhydrogenase activity was obtained by a combination of the ;membrane residue' from strain AN249 (uncA(-)) with the ;5mm-Tris wash' from strain AN283 (uncB(-)). 3. Valinomycin plus NH(4) (+) inhibited oxidative phosphorylation both in membranes from a normal strain of E. coli and in the reconstituted membrane system derived from the mutant strains. 4. The electron-transport-dependent transhydrogenase activity was located in the membrane residue and was de-repressed in both the mutant strains. 5. The spatial and functional relationships between the proteins specified by the uncA and uncB genes and the transhydrogenase protein are discussed.


Thyroid scanning with 131Cs.
Scanning of the thyroid gland after the administration of radioactive caesium ((131)Cs) was performed in 45 patients; in 38 of these it had been shown that a thyroid nodule failed to accumulate sodium per-technetate ((99m)Tc) or sodum iodide ((131)I). (131)Cs was concentrated in the nodule to a greater degree than in the paranodular thyroid tissue in seven patients, in five of whom thyroid carcinoma was subsequently identified. In five patients (131)Cs accumulated in both the nodule and paranodular tissue, while in the other 26 no (131)Cs uptake occurred in the nodule. In only one of the latter group was the thyroid lesion malignant. Caesium scanning seems to offer a useful supplementary procedure in the investigation of thyroid nodules.


Clinically important drug-drug interactions in primary care.
Drug-drug interactions (DDIs) cause considerable morbidity and mortality worldwide and may lead to hospital admission. Sophisticated computerized drug information and monitoring systems, more recently established in many of the emerging economies, including Malaysia, are capturing useful information on prescribing. Our aim is to report on an investigation of potentially serious DDIs, using a university primary care-based system capturing prescription records from its primary care services. We retrospectively collected data from two academic years over 20 months from computerized databases at the Universiti Sains Malaysia (USM) from users of the USM primary care services. Three hundred and eighty-six DDI events were observed in a cohort of 208 exposed patients from a total of 23,733 patients, representing a 2-year period prevalence of 876·4 per 100,000 patients. Of the 208 exposed patients, 138 (66·3%) were exposed to one DDI event, 29 (13·9%) to two DDI events, 15 (7·2%) to three DDI events, 6 (2·9%) to four DDI events and 20 (9·6%) to more than five DDI events. Overall, an increasing mean number of episodes of DDIs was noted among exposed patients within the age category ≥70 years (P=0·01), an increasing trend in the number of medications prescribed (P<0·001) and an increasing trend in the number of long-term therapeutic groups (P<0·001). We describe the prevalence of clinically important DDIs in an emerging economy setting and identify the more common potentially serious DDIs. In line with the observations in developed economies, a higher number of episodes of DDIs were seen in patients aged ≥70 years and with more medications prescribed. The easiest method to reduce the frequency of DDIs is to reduce the number of medications prescribed. Therapeutic alternatives should be selected cautiously.


Fetal hemoglobin in sickle cell anemia.
Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease, an effect mediated by its exclusion from the sickle hemoglobin polymer. Fetal hemoglobin genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Some patients with sickle cell disease have exceptionally high levels of HbF that are associated with the Senegal and Saudi-Indian haplotype of the HBB-like gene cluster; some patients with different haplotypes can have similarly high HbF. In these patients, high HbF is associated with generally milder but not asymptomatic disease. Studying these persons might provide additional insights into HbF gene regulation. HbF appears to benefit some complications of disease more than others. This might be related to the premature destruction of erythrocytes that do not contain HbF, even though the total HbF concentration is high. Recent insights into HbF regulation have spurred new efforts to induce high HbF levels in sickle cell disease beyond those achievable with the current limited repertory of HbF inducers.


Global transcriptional analysis of Mycoplasma hyopneumoniae following exposure to hydrogen peroxide.
Mycoplasma hyopneumoniae, the causative agent of swine enzootic pneumonia, colonizes the cilia of swine lungs, causing ciliostasis and cell death. M. hyopneumoniae is a component of the porcine respiratory disease complex (PRDC) and is especially problematic for the finishing swine industry, causing the loss of hundreds of millions of dollars in farm revenues worldwide. For successful infection, M. hyopneumoniae must effectively resist oxidative stresses due to the release of oxidative compounds from neutrophils and macrophages during the host's immune response. However, the mechanism that M. hyopneumoniae uses to avert the host response is still unclear. To gain a better understanding of the transcriptional responses of M. hyopneumoniae under oxidative stress, cultures were grown to early exponential phase and exposed to 0.5% hydrogen peroxide for 15 min. RNA samples from these cultures were collected and compared to RNA samples from control cultures using two-colour PCR-based M. hyopneumoniae microarrays. This study revealed significant downregulation of important glycolytic pathway genes and gene transcription proteins, as well as a protein known to activate oxidative stressor cascades in neutrophils. Sixty-nine per cent of the upregulated genes were hypothetical with no known function. This study has also revealed significantly differentially expressed genes common to other environmental stress responses, indicating that further investigation of universal stress response genes of M. hyopneumoniae is merited.


Structure and expression of the maize (Zea mays L.) SUN-domain protein gene family: evidence for the existence of two divergent classes of SUN proteins in plants.
The nuclear envelope that separates the contents of the nucleus from the cytoplasm provides a surface for chromatin attachment and organization of the cortical nucleoplasm. Proteins associated with it have been well characterized in many eukaryotes but not in plants. SUN (Sad1p/Unc-84) domain proteins reside in the inner nuclear membrane and function with other proteins to form a physical link between the nucleoskeleton and the cytoskeleton. These bridges transfer forces across the nuclear envelope and are increasingly recognized to play roles in nuclear positioning, nuclear migration, cell cycle-dependent breakdown and reformation of the nuclear envelope, telomere-led nuclear reorganization during meiosis, and karyogamy. We found and characterized a family of maize SUN-domain proteins, starting with a screen of maize genomic sequence data. We characterized five different maize ZmSUN genes (ZmSUN1-5), which fell into two classes (probably of ancient origin, as they are also found in other monocots, eudicots, and even mosses). The first (ZmSUN1, 2), here designated canonical C-terminal SUN-domain (CCSD), includes structural homologs of the animal and fungal SUN-domain protein genes. The second (ZmSUN3, 4, 5), here designated plant-prevalent mid-SUN 3 transmembrane (PM3), includes a novel but conserved structural variant SUN-domain protein gene class. Mircroarray-based expression analyses revealed an intriguing pollen-preferred expression for ZmSUN5 mRNA but low-level expression (50-200 parts per ten million) in multiple tissues for all the others. Cloning and characterization of a full-length cDNA for a PM3-type maize gene, ZmSUN4, is described. Peptide antibodies to ZmSUN3, 4 were used in western-blot and cell-staining assays to show that they are expressed and show concentrated staining at the nuclear periphery. The maize genome encodes and expresses at least five different SUN-domain proteins, of which the PM3 subfamily may represent a novel class of proteins with possible new and intriguing roles within the plant nuclear envelope. Expression levels for ZmSUN1-4 are consistent with basic cellular functions, whereas ZmSUN5 expression levels indicate a role in pollen. Models for possible topological arrangements of the CCSD-type and PM3-type SUN-domain proteins are presented.


Bibliometrics of Fifty Most-Cited Articles on the Mental Health of Immigrants Living in the United States.
The premise of our study was to identify the 50 most frequently cited articles on the mental and behavioral health of immigrant and refugee populations in the USA using the Thomas Reuters' WOS database. Articles were reviewed for inclusion by a panel comprised of two specialist physicians and a political scientist. Citations ranged from 69 to 520. Almost half of all articles (n = 23) focus on Hispanic populations. 32 articles employed a cross-sectional study design. Sample sizes ranged from 8,000,000 to 20. Over half of all (n = 30) articles were published between 2000 and 2012 in 22 journals, covering 38 research areas. The total number of institutional affiliations was 148, averaging at 3 per article. Our recommendations state: diversify sampling in terms of ethnic and racial backgrounds; develop a uniform instrument for immigrant and refugee mental health; and conduct comparative studies to examine the differences in the mental health among diverse communities.


Isolation of Chlamydia trachomatis by use of 5-iodo-2-deoxyuridine-treated cells.
Irradiated McCoy cells have provided a useful technique for the isolation of Chlamydia trachomatis strains, among which are found the etiological agents of trachoma, inclusion conjunctivitis, and lymphogranuloma venereum. Because irradiation is not always readily available, 5-iodo-2-deoxyuridine (IUDR) treatment of cells was investigated as a substitute procedure. IUDR-treated cells were found to be as sensitive to C. trachomatis infection as were irradiated McCoy cells. Stock chlamydial strains gave similar titers of iodine-stained inclusions in either system. When cells treated with IUDR were compared with irradiated cells for the isolation of C. trachomatis from clinical specimens, 5 of 138 specimens yielded isolates in IUDR-treated cells not found in irradiated ones, and one isolate was obtained from irradiated but not from IUDR-treated cells. In those 56 cases where inclusions were seen in both systems, there were significantly more inclusions in IUDR-treated than in irradiated cells. Although this series of cultures is too small to determine whether IUDR-treated cells are superior to irradiated ones for the isolation of C. trachomatis, the data indicate that IUDR treatment is at least equally effective.


Steroid Modulation of Muscarinic Cholinergic and alpha2-Adrenergic Receptor Density in the Nucleus Intercollicularis of the Japanese Quail.
Androgen modulation of neurotransmitter receptor density was investigated in the nucleus intercollicularis (ICo) of male and female Japanese quail (Coturnix coturnix japonica). ICo appears to play an important role in the neural control of testosterone (T) dependent vocal behaviour. Two receptor types were investigated in this nucleus; muscarinic cholinergic receptors, labelled using [3H]N-methyl scopolamine (NMS) as the ligand, and alpha2-adrenergic receptors, labelled using [3H]p-amino-clonidine (PAC) as the ligand. Changes in receptor density were assessed using in vitro quantitative autoradiography to ensure a high degree of anatomical specificity in the identification of any steroid effects. Gonadectomy was found to reduce the density of both [3H]PAC bindings sites and [3H]NMS in specific subregions of ICo. Gonadectomized animals treated with T had levels of receptor density similar to intact birds. However, the location within ICo of the effects of T was different for each ligand. [3H]NMS binding was modulated only in a rostral subregion of the nucleus while changes in [3H]PAC receptor density were found in the medial and lateral parts of ICo at a more caudal level. These changes in receptor density parallel changes in crowing frequency that are known to occur in males and females following castration and T treatment. The receptor systems may constitute a part of the neurochemical mechanism regulating vocal behaviour.


Molecular synthesis of high-performance near-IR photodetectors with independently tunable structural and optical properties based on Si-Ge-Sn.
This Article describes the development of an optimized chemistry-based synthesis method, supported by a purpose-built reactor technology, to produce the next generation of Ge(1-x-y)Si(x)Sn(y) materials on conventional Si(100) and Ge(100) platforms at gas-source molecular epitaxy conditions. Technologically relevant alloy compositions (1-5% Sn, 4-20% Si) are grown at ultralow temperatures (330-290 °C) using highly reactive tetragermane (Ge(4)H(10)), tetrasilane (Si(4)H(10)), and stannane (SnD(4)) hydride precursors, allowing the simultaneous increase of Si and Sn content (at a fixed Si/Sn ratio near 4) for the purpose of tuning the bandgap while maintaining lattice-matching to Ge. First principles thermochemistry studies were used to explain stability and reactivity differences between the Si/Ge hydride sources in terms of a complex interplay among the isomeric species, and provide guidance for optimizing process conditions. Collectively, this approach leads to unprecedented control over the substitutional incorporation of Sn into Si-Ge and yields materials with superior quality suitable for transitioning to the device arena. We demonstrate that both intrinsic and doped Ge(1-x-y)Si(x)Sn(y) layers can now be routinely produced with defect-free microstructure and viable thickness, allowing the fabrication of high-performance photodetectors on Ge(100). Highlights of these new devices include precisely adjustable absorption edges between 0.87 and 1.03 eV, low ideality factors close to unity, and state-of-the-art dark current densities for Ge-based materials. Our unequivocal realization of the "molecules to device" concept implies that GeSiSn alloys represent technologically viable semiconductors that now merit inclusion in the class of ubiquitous Si, Ge, and SiGe group IV systems.


Evaluation of presynaptic alpha-receptor function in the canine renal vascular bed.
The functional significance of presynaptic alpha-receptor modulation of sympathetic nerves was examined in vivo in the canine renal vascular bed. In pentobarbital-anesthetized dogs, the vasoconstrictor response to renal nerve stimulation and exogenous norepinephrine was compared before and during intra-arterial infusions of epinephrine, oxymetazoline, clonidine, and norepinephrine. Only epinephrine produced a modest decrease in stimulation-induced vasoconstriction at 1 Hz. After pretreatment with desipramine, intra-arterial infusions of epinephrine or norepinephrine did not alter stimulation-induced vasoconstrictor responses relative to exogenous norepinephrine. Further, neither yohimbine nor phentolamine (10(-9) to 10(-3) g, intra-arterial) produced a distinctly increased vasoconstrictor response to nerve stimulation relative to exogenous norepinephrine. Thus, studies using alpha-receptor agonists, antagonists, and inhibition of neuronal uptake failed to reveal a physiologically significant alpha-receptor-mediated negative feedback mechanism for stimulation-induced vasoconstriction in the canine renal vascular bed.


[Interpretation of various ratios of genetic parameters in Hayman's diallelic analysis].
The genetical algebra of diallele analysis was used to interpret some relations of genetic parameters which were not earlier applied in research of genetic control (GC). It was discovered that in the case of gene correlation, the relation H2 greater than H1 is possible, meaning the regression among frequencies of alleles in loci. We demonstrated, in what way to distinguish two reasons for changes in H1, H2 and h2, when an external treatment is applied: Due to frequency changes of dominant and recessive alleles in the majority of loci, in case new loci are involved in GC; Due to changes in dominance contributions. The latter could provide new information about a situation in loci by analysing the changes in h2 and the correlation coefficient of parental trait levels with their dominant properties as well as changes in D. A few experimental examples illustrate the theory implication.


PRO-C3-levels in patients with HIV/HCV-Co-infection reflect fibrosis stage and degree of portal hypertension.
Liver-related deaths represent the leading cause of mortality among patients with HIV/HCV-co-infection, and are mainly related to complications of fibrosis and portal hypertension. In this study, we aimed to evaluate the structural changes by the assessment of extracellular matrix (ECM) derived degradation fragments in peripheral blood as biomarkers for fibrosis and portal hypertension in patients with HIV/HCV co-infection. Fifty-eight patients (67% male, mean age: 36.5 years) with HIV/HCV-co-infection were included in the study. Hepatic venous pressure gradient (HVPG) was measured in forty-three patients. The fibrosis stage was determined using FIB4 -Score. ECM degraded products in peripheral blood were measured using specific ELISAs (C4M, MMP-2/9 degraded type IV collagen; C5M, MMP-2/9 degraded type V collagen; PRO-C3, MMP degraded n-terminal propeptide of type III collagen). As expected, HVPG showed strong and significant correlations with FIB4-index (rs = 0.628; p = 7*10-7). Interestingly, PRO-C3 significantly correlated with HVPG (rs = 0.354; p = 0.02), alanine aminotransferase (rs = 0.30; p = 0.038), as well as with FIB4-index (rs = 0.3230; p = 0.035). C4M and C5M levels were higher in patients with portal hypertension (HVPG>5 mmHg). PRO-C3 levels reflect liver injury, stage of liver fibrosis and degree of portal hypertension in HIV/HCV-co-infected patients. Furthermore, C4M and C5M were associated with increased portal pressure. Circulating markers of hepatic ECM remodeling might be helpful in the diagnosis and management of liver disease and portal hypertension in patients with HIV/HCV coinfection.


Embracing uncertainty: rethinking migration policy through pastoralists' experiences.
Today there is a disjuncture between migration flows that are complex, mixed and constantly evolving and the emerging global migration governance paradigm that seeks to impose clarity, certainty, regularity and order. Addressing the gap between policies and realities, this article explores lessons for migration policy and governance from mobile pastoralists' experience. Using examples from human migration flows within and between Europe and Africa and insights from pastoral systems from India, Italy and Kenya, the article identifies important similarities between international migration and pastoral mobility. We focus on four interconnections: both international migration and pastoral mobility show multi-directional and fragmented patterns; both involve multiple, intersecting socio-economic, political, cultural and environmental drivers; both must respond to non-linear systems, where critical junctures and tipping points undermine clear prediction and forecasts, making social navigation and reliability management more useful concepts than risk-based prediction and control and finally for both uncertainty is not conceived of as a state of crisis but an inherent feature, pregnant with possibility and hope. Building on these four points, and drawing from pastoralists' experiences, we propose some methodological, practical and policy reflections for bridging the disjuncture between migration realities on the ground and global migration governance policies and discourses.


Hand grip strength is associated with fatigue among men with COPD: epidemiological data from northern Sweden.
The aim of this study was to investigate if hand grip strength (HGS) is associated with: 1) fatigue, and specifically clinically relevant fatigue (CRF); 2) low physical activity; and 3) fatigue independent of physical activity level, among individuals with and without COPD. Data were collected from the Obstructive Lung Disease in Northern Sweden (OLIN) COPD-study in 2014. HGS was measured with a hand-grip dynamometer, fatigue and physical activity were assessed by questionnaires; FACIT-Fatigue respectively IPAQ. Among individuals with COPD (n = 389), but not without COPD (n = 442), HGS was lower among those with CRF than those without CRF, significantly so among men (p = 0.001) and close to among women (p = 0.051). HGS was not associated with physical activity levels within any of the groups. HGS was associated with fatigue among men, but not women, with COPD independent of physical activity level, age, height, and smoking habits (Beta = 0.190, 95% CI 0.061-0.319, respectively Beta = 0.048, 95% CI-0.056-0.152), while there were no corresponding significant findings among individuals without COPD. In summary, HGS was associated with CRF among individuals with COPD in this population-based study. Among men with COPD, HGS was associated with fatigue independent of physical activity level and common confounders.


Changes in Prevalence of Health Care-Associated Infections in U.S. Hospitals.
A point-prevalence survey that was conducted in the United States in 2011 showed that 4% of hospitalized patients had a health care-associated infection. We repeated the survey in 2015 to assess changes in the prevalence of health care-associated infections during a period of national attention to the prevention of such infections. At Emerging Infections Program sites in 10 states, we recruited up to 25 hospitals in each site area, prioritizing hospitals that had participated in the 2011 survey. Each hospital selected 1 day on which a random sample of patients was identified for assessment. Trained staff reviewed medical records using the 2011 definitions of health care-associated infections. We compared the percentages of patients with health care-associated infections and performed multivariable log-binomial regression modeling to evaluate the association of survey year with the risk of health care-associated infections. In 2015, a total of 12,299 patients in 199 hospitals were surveyed, as compared with 11,282 patients in 183 hospitals in 2011. Fewer patients had health care-associated infections in 2015 (394 patients [3.2%; 95% confidence interval {CI}, 2.9 to 3.5]) than in 2011 (452 [4.0%; 95% CI, 3.7 to 4.4]) (P<0.001), largely owing to reductions in the prevalence of surgical-site and urinary tract infections. Pneumonia, gastrointestinal infections (most of which were due to Clostridium difficile [now Clostridioides difficile]), and surgical-site infections were the most common health care-associated infections. Patients' risk of having a health care-associated infection was 16% lower in 2015 than in 2011 (risk ratio, 0.84; 95% CI, 0.74 to 0.95; P=0.005), after adjustment for age, presence of devices, days from admission to survey, and status of being in a large hospital. The prevalence of health care-associated infections was lower in 2015 than in 2011. To continue to make progress in the prevention of such infections, prevention strategies against C. difficile infection and pneumonia should be augmented. (Funded by the Centers for Disease Control and Prevention.).


Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice.
Introduction of a high-fat diet to mice results in a period of voracious feeding, known as hyperphagia, before homeostatic mechanisms prevail to restore energy intake to an isocaloric level. Acute high-fat diet hyperphagia induces astrocyte activation in the rodent hypothalamus, suggesting a potential role of these cells in the homeostatic response to the diet. The objective of this study was to determine physiologic role of astrocytes in the acute homeostatic response to high-fat feeding. We bred a transgenic mouse model with doxycycline-inducible inhibition of NFkappaB (NFκB) signaling in astrocytes to determine the effect of loss of NFκB-mediated astrocyte activation on acute high-fat hyperphagia. ELISA was used to measure the levels of markers of astrocyte activation, glial-fibrillary acidic protein (GFAP) and S100B, in the medial basal hypothalamus. Inhibition of NFκB signaling in astrocytes prevented acute high-fat diet-induced astrocyte activation and resulted in a 15% increase in caloric intake (P < 0.01) in the first 24 h after introduction of the diet. These data reveal a novel homeostatic role for astrocytes in the acute physiologic regulation of food intake in response to high-fat feeding.


A food store intervention trial improves caregiver psychosocial factors and children's dietary intake in Hawaii.
Diet-related chronic diseases are at epidemic levels in low-income ethnic minority populations. The purpose of this study is to decrease risk for obesity in children by modifying the food environment and conducting point-of-purchase promotions that will lead to changes in psychosocial factors and behaviors associated with healthier food choices among low-income communities with a preponderance of Native Hawaiians and Pacific Islanders. We implemented an intervention trial over a 9-11-month period in five food stores in two low-income multiethnic communities in Hawaii, targeting both children and their adult caregivers. The Healthy Foods Hawaii (HFH) intervention consisted of an environmental component to increase store stocking of nutritious foods, point-of-purchase promotions, interactive sessions, and involved local producers and distributors. We evaluated the impact of the program on 116 child-caregiver dyads, sampled from two intervention and two comparison areas before and after intervention implementation. Program impacts were evaluated using multivariable linear regression. The HFH program had a significant impact on caregiver knowledge and the perception that healthy foods are convenient. Intervention children significantly increased their Healthy Eating Index (HEI) score for servings of grains, their total consumption of water, and showed an average 8.5 point (out of 90 total, eliminating the 10 points for variety, giving a 9.4% increase) increase in overall HEI score. A food store intervention was effective in improving healthy food knowledge and perception that healthy foods are convenient among caregivers, and increased the consumption of several targeted healthy foods by their children. Greater intensity, sustained food system change, and further targeting for children are needed to show greater and sustained change in food-related behaviors in low-income Native Hawaiian and Pacific Islander communities.


Reproductive isolation and hybridization in sympatric populations of three Dactylorhiza species (Orchidaceae) with different ploidy levels.
The potential for gene exchange between species with different ploidy levels has long been recognized, but only a few studies have tested this hypothesis in situ and most of them focused on not more than two co-occurring species. In this study, we examined hybridization patterns in two sites containing three species of the genus Dactylorhiza (diploid D. incarnata and D. fuchsii and their allotetraploid derivative D. praetermissa). To compare the strength of reproductive barriers between diploid species, and between diploid and tetraploid species, crossing experiments were combined with morphometric and molecular analyses using amplified fragment length polymorphism markers, whereas flow cytometric analyses were used to verify the hybrid origin of putative hybrids. In both sites, extensive hybridization was observed, indicating that gene flow between species is possible within the investigated populations. Bayesian assignment analyses indicated that the majority of hybrids were F(1) hybrids, but in some cases triple hybrids (hybrids with three species as parents) were observed, suggesting secondary gene flow. Crossing experiments showed that only crosses between pure species yielded a high percentage of viable seeds. When hybrids were involved as either pollen-receptor or pollen-donor, almost no viable seeds were formed, indicating strong post-zygotic reproductive isolation and high sterility. Strong post-mating reproductive barriers prevent local breakdown of species boundaries in Dactylorhiza despite frequent hybridization between parental species. However, the presence of triple hybrids indicates that in some cases hybridization may extend the F(1) generation.


[Clinico-anatomic parallels in brain tumors complicated by intracranial hemorrhages].
An analysis of 17 cases of intracranial hemorrhage associated with brain tumours is presented. In two-thirds of observations the tumours were malignant, in one-third they were benign and could be referred to glial ones. Two variants of clinical manifestations of tumour hemorrhages into the brain were identified. The clinical time-course of intracerebral hemorrhages was found to correlate with the characteristics of the pathological structure of tumours. The clinical symptomatology was most pronounced when the hemorrhage was into the healthy brain tissue adjacent to the tumour. Hemorrhages into tumours surrounded with a membrane were less severe.


Intravascular ultrasound classification of atherosclerotic lesions according to American Heart Association recommendation.
Intravascular ultrasound (IVUS) offers a new modality by which to image the vessel wall in high resolution. The aim of the study was to classify atherosclerotic lesions using IVUS according to American Heart Association (AHA) recommendation. IVUS was performed using a 20 or 30 MHz mechanically rotated catheter in 190 patients (aged from 35 to 75 years, mean 59 +/- 9 years) who presented with suspicion of coronary artery disease based on clinical examination. Of the 190 patients, 49 (26%) (group A) were found to have normal or nearly normal coronary arteries, whereas the other 141 (74%) (group B) had significant angiographic stenosis (> 50% luminal narrowing). IVUS image interpretation was based on the recommendation of the Committee on Vascular Lesions of the Council on Atherosclerosis (AHA). In group A, a total of 822 segments were evaluated with IVUS; 444 (54%) were found to have plaque formation. Among these 444 segments, type II lesions were found in 145 (33%), type III lesions in 110 segments (25%), type IV and Va lesions in 169 segments (38%), and type Vb in 18 segments (4%). The severity of plaque area stenosis increased from type II to IV. In group B, only the most stenotic segments (n = 141) on angiography were selected for analysis. No significant differences were found among different lesion types with respect to the severity of plaque area stenosis. Type Vb and Vc lesions presented mainly, but not exclusively, as stable angina, whereas type VI lesions presented mainly as unstable angina. Some patients (12%) with stable angina had complicated lesions (type VIa-VIc). It is now possible to use intravascular ultrasound to classify atherosclerotic lesions according to the AHA recommendations that were based on histological examination. Standardized reports of IVUS can now be based on these recommendations. Even in angiographically normal coronary arteries, advanced atherosclerotic lesions are found, explaining the potential risk of acute coronary syndromes in this group of patients. In patients with angiographically severe coronary disease, clinical symptoms correlate mainly with plaque characteristics, rather than with the severity of stenosis.


Resilience Contributes to Low Emotional Impact of the COVID-19 Outbreak Among the General Population in Italy.
The COVID-19 outbreak is severely affecting the overall mental health with unknown psychological consequences. Although a strong psychological impact is possible, scant evidence is available to date. Past studies have shown that resilience decreases the negative effects of stress. This study aimed to examine depression, anxiety, and stress among the Italian general population during the phase characterized by lockdown, and to investigate the role of resilience as a potential predictor. A total sample of 6,314 Italian people participated in this study. Participants were recruited between March 29 and May 04 2020 through an online survey. The Depression Anxiety Stress Scales-21 (DASS-21) and the Resilience Scale (RS) were administered. Demographic data and lockdown related information were also collected. A correlational analysis was carried out to examine relationships between psychopathological domains and resilience. Three hierarchical regression analyses were conducted using the depression, anxiety, and stress as dependent variables and the resilience as independent variable controlling for age, gender, and education. COVID-19 specific variables were also included in the three regression analyses. A further exploratory analysis was carried out to examine which aspects of resilience predict depression, anxiety, and stress. The prevalence of moderate to extremely severe symptoms among participants was 32% for depression, 24.4% for anxiety, and 31.7% for stress. The sample mean scores on depression, anxiety, and stress were higher than the normal scores reported in the literature. Results of correlational analysis showed that resilience factors, such as meaningfulness, self-reliance, existential aloneness, and equanimity, are inversely associated with depression, anxiety, and stress. Results of regression analyses indicated that resilience was statically significant in predicting depression, anxiety, and stress. Geographic area of residence and infected acquaintances were also significant predictors. Regarding the resilience factors, results revealed that meaningfulness, perseverance, and equanimity were statistically significant in predicting all the DASS-21 scales. About a third of respondents reported moderate to extremely severe depression, anxiety, and stress. The present study suggests that psychological resilience may independently contribute to low emotional distress and psychological ill-being. These findings can help explain the variability of individual responses during the COVID-19 outbreak.


Point of care blood ketone testing of diabetic patients in the emergency department.
The aim of our study was to determine the utility of point-of-care blood ketone testing in diabetic patients presenting to the emergency department. In this prospective, observational clinical study, patients with known or newly diagnosed diabetes mellitus presenting to our tertiary care university emergency department with any nontrauma related medical complaint and a high fingerstick glucose (> or =200 mg/dL) were eligible for inclusion. Capillary blood beta-hydroxybutyrate (beta-HBA), venous blood beta-HBA level, venous blood glucose level, arterial blood gas analysis, and urine ketone dipstickstick were measured in each patient as primary outcome measures. Of the 479 diabetic patients presenting during the study period, a total of 139 diabetic patients with high capillary blood glucose level (> or =200 mg/dL) and a positive capillary blood beta-HBA (> or =0.1 mmol/L) were included in the study. Hyperketonemia (> or =0.42 mmol/L) was found in 48 of these patients by Sigma Diagnostics reference testing (diabetic ketosis in 35%). The calculated blood pH was less than 7.3 in 18 of these 48 patients (ketoacidosis in 31%). Capillary and venous blood beta-hydroxybutyrate levels were not statistically different from each other (P = 0.824). There was a positive correlation between capillary and venous blood beta-HBA levels (r = 0.488, P < 0.001). The sensitivity and specificity of urine ketone dipstick testing and capillary blood ketone testing in determining diabetic ketoacidosis were 66% and 78%, and 72% and 82%; and in determining hyperketonemia (both in diabetic ketosis and diabetic ketoacidosis) were 82% and 54%, and 91% and 56%, respectively. A rapid, bedside capillary blood ketone test for beta-HBA can accurately measure blood concentrations of beta-HBA in diabetic patients in an emergency department setting. This device can be used as a reliable diagnostic test to detect emergency metabolic problems in diabetic patients, such as diabetic ketosis or ketoacidosis.


Social identity bias and communication network clustering interact to shape patterns of opinion dynamics.
Social influence aligns people's opinions, but social identities and related in-group biases interfere with this alignment. For instance, the recent rise of young climate activists (e.g. 'Fridays for Future' or 'Last Generation') has highlighted the importance of generational identities in the climate change debate. It is unclear how social identities affect the emergence of opinion patterns, such as consensus or disagreement, in a society. Here, we present an agent-based model to explore this question. Agents communicate in a network and form opinions through social influence. The agents have fixed social identities which involve homophily in their interaction preferences and in-group bias in their perception of others. We find that the in-group bias has opposing effects depending on the network topology. The bias impedes consensus in highly random networks by promoting the formation of echo chambers within social identity groups. By contrast, the bias facilitates consensus in highly clustered networks by aligning dispersed in-group agents across the network and, thereby, preventing the formation of isolated echo chambers. Our model uncovers the mechanisms underpinning these opposing effects of the in-group bias and highlights the importance of the communication network topology for shaping opinion dynamics.


Handedness, homicide and negative frequency-dependent selection.
Humans exhibit hand preference for most manual activities in which they are specialized. Right- and left-handers have coexisted at least since the Upper Palaeolithic, and left-handers are in the minority in all human populations. The persistence of the polymorphism of handedness is a puzzle because this trait is substantially heritable and several fitness costs are associated with left-handedness. Some countervailing benefit is required to maintain the polymorphism. Left-handers may have a frequency-dependent advantage in fights--the advantage being greater when their frequency is lower. Sports data from Western societies are consistent with this prediction. Here, we show that the frequency of left-handers is strongly and positively correlated with the rate of homicides across traditional societies. It ranges from 3% in the most pacifistic societies, to 27% in the most violent and warlike. This finding is consistent with a frequency-dependent selection mechanism maintaining left-handedness in these societies.


Predicting Pulmonary Complications Following Upper and Lower Abdominal Surgery: ASA vs. ARISCAT Risk Index.
Postoperative pulmonary complications (POPC) account for a substantial proportion of risk related to surgery and anaesthesia. The American Society of Anesthesiologists (ASA) classification and the Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) risk index correlate well with POPC. Here, we compared their accuracy in predicting pulmonary complications following upper and lower abdominal surgery. We retrospectively reviewed the medical records of patients undergoing upper and lower abdominal surgery. We collected patients' demographic data, comorbidities, preoperative pulmonary risk score, laboratory results, surgical data, respiratory tract infection history within one month before surgery, surgical urgency, ASA scores and pulmonary complications within one month after the surgery. We evaluated 241 patients [upper abdominal surgery (UAS) n=121; lower abdominal surgery (LAS) n=120; mean age 55.7±3.1 years]. In the UAS, 55.8% of the patients were male. In LAS, all patients were female. In both groups, the most common POPC was pleural effusion with compressive atelectasis (CA). Regarding risk score, in both groups, patients with high-risk developed a higher rate of pulmonary complications [UAS (50%), LAS (40%)]. In patients with low-risk scores, the rate of pulmonary complications was significantly lower than the intermediate and high-risk groups (p<0.001). A positive correlation was observed between preoperative risk score and complications (UAS r=0.34; LAS r=0.35 p<0.05). No association was observed between the ASA scores and POPC (p=0.8). The ASA classification was found to be a weaker modality than ARİSCAT risk index to predict pulmonary complications after the upper and lower abdominal surgeries.


Epidural cement leakage through pedicle violation after balloon kyphoplasty causing paraparesis in osteoporotic vertebral compression fractures - a report of two cases.
Kyphoplasty is advantageous over vertebroplasty in terms of better kyphosis correction and diminished risk of cement extravasations. Literature described cement leakage causing neurological injury mainly after vertebroplasty procedure; only a few case reports show cement leakage with kyphoplasty without neurological injury or proper cause of leakage. We present a report two cases of osteoporotic vertebral compression fracture treated with kyphoplasty and developed cement leakage causing significant neurological injury. In both cases CT scan was the diagnostic tool to identify cause of cement leakage. CT scan exhibited violation of medial pedicle wall causing cement leakage in the spinal canal. Both patients displayed clinical improvement after decompression surgery with or without instrumentation. Retrospectively looking at stored fluoroscopic images, we found that improper position of trocar in AP and lateral view simultaneously while taking entry caused pedicle wall violation. We suggest not to cross medial pedicle wall in AP image throughout the entire procedure and keeping the trocar in the center of pedicle in lateral image would be the most important precaution to prevent such complication. Our case reports adds the neurological complications with kyphoplasty procedure and suggested that along with other precautions described in the literature, entry with trocar along the entire procedure keeping the oval shape of pedicle in mind (under C-arm) will probably help to prevent such complications.


Estimating marginal and incremental effects in the analysis of medical expenditure panel data using marginalized two-part random-effects generalized Gamma models: Evidence from China healthcare cost data.
Conditional two-part random-effects models have been proposed for the analysis of healthcare cost panel data that contain both zero costs from the non-users of healthcare facilities and positive costs from the users. These models have been extended to accommodate more flexible data structures when using the generalized Gamma distribution to model the positive healthcare expenditures. However, a major drawback with the extended model, which is inherited from the conditional models, is that it is fairly difficult to make direct marginal inference with respect to overall healthcare costs that includes both zeros and non-zeros, or even on positive healthcare costs. In this article, we first propose two types of marginalized two-part random-effects generalized Gamma models (m2RGGMs): Type I m2RGGMs for the inference on positive healthcare costs and Type II m2RGGMs for the inference on overall healthcare costs. Then, the concepts of marginal effect and incremental effect of a covariate on overall and positive healthcare costs are introduced, and estimation of these effects is carefully discussed. Especially, we derive the variance estimates of these effects by following the delta methods and Taylor series approximations for the purpose of making marginal inference. Parameter estimates of Type I and Type II m2RGGMs are obtained through maximum likelihood estimation. An empirical analysis of longitudinal healthcare costs collected in the China Health and Nutrition Survey is conducted using the proposed methodologies.


Cutting edge: transplantation tolerance through enhanced CTLA-4 expression.
Knockout and blocking studies have shown a critical role for CTLA-4 in peripheral tolerance, however, it is unknown whether augmenting CTLA-4 expression actually promotes tolerance. Here we demonstrate a specific and requisite role for CTLA-4 and its up-regulation in tolerance through anti-CD45RB. First, long-term murine islet allograft survival induced by anti-CD45RB is prevented by CTLA4-Ig, which interferes with B7:CTLA-4 interactions. Second, anti-CD45RB is ineffective in recipients lacking CTLA-4, B7-1, and B7-2. In contrast, CTLA4-Ig, which targets B7 on allogeneic cells, promotes long-term engraftment in these mice. Moreover, anti-CD45RB was effective in B7-deficient controls expressing CTLA-4. Finally, in wild-type mice, CTLA-4 expression returned to baseline 17 days after receiving anti-CD45RB, and was refractory to further increase. Transplantation and anti-CD45RB therapy at this time could neither augment CTLA-4 nor prolong engraftment. These data demonstrate a specific role for CTLA-4 in anti-CD45RB-mediated tolerance and indicate that CTLA-4 up-regulation can directly promote allograft survival.


Current status of brachytherapy in Korea: a national survey of radiation oncologists.
The aim of the present study was to acquire information on brachytherapy resources in Korea through a national survey of radiation oncologists. Between October 2014 and January 2015, a questionnaire on the current status of brachytherapy was distributed to all 86 radiation oncology departments in Korea. The questionnaire was divided into sections querying general information on human resources, brachytherapy equipment, and suggestions for future directions of brachytherapy policy in Korea. The response rate of the survey was 88.3%. The average number of radiation oncologists per center was 2.3. At the time of survey, 28 centers (36.8%) provided brachytherapy to patients. Among the 28 brachytherapy centers, 15 (53.5%) were located in in the capital Seoul and its surrounding metropolitan areas. All brachytherapy centers had a high-dose rate system using (192)Ir (26 centers) or (60)Co (two centers). Among the 26 centers using (192)Ir sources, 11 treated fewer than 40 patients per year. In the two centers using (60)Co sources, the number of patients per year was 16 and 120, respectively. The most frequently cited difficulties in performing brachytherapy were cost related. A total of 21 centers had a plan to sustain the current brachytherapy system, and four centers noted plans to upgrade their brachytherapy system. Two centers stated that they were considering discontinuation of brachytherapy due to cost burdens of radioisotope source replacement. The present study illustrated the current status of brachytherapy in Korea. Financial difficulties were the major barriers to the practice of brachytherapy.


DRG Watchdog highlights new financial dimensions of laboratory diagnostics.
As nebulous as the details of the German diagnosis-oriented case reimbursement rate (G-DRGs) might be, one thing is obvious: rapid and accurate diagnostics will be vital in future to the reimbursement of standard cases that reflect the actual outlay. The laboratory that up to now has always been categorized as a potential for savings, now becomes a source of revenue for hospitals. A study initiated by the VDGH provides evidence for this (Clinical Laboratory 2002, 48, 327).


Perinatal risk factors for infantile autism.
Etiologic hypotheses in infantile autism suggest a strong genetic component, as well as possible environmental risks linked to early fetal development. We evaluated the association of maternal, pregnancy, delivery, and infant characteristics and risk of infantile autism. We conducted a case-control study nested within a population-based cohort (all Swedish children born in 1974-1993). We used prospectively recorded data from the Swedish Birth Register, which were individually linked to the Swedish Inpatient Register. Cases were 408 children (321 boys and 87 girls) discharged with a main diagnosis of infantile autism from any hospital in Sweden before 10 years of age in the period 1987-1994, plus 2,040 matched controls. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The risk of autism was associated with daily smoking in early pregnancy (OR = 1.4; CI = 1.1-1.8), maternal birth outside Europe and North America (OR = 3.0; CI = 1.7-5.2), cesarean delivery (OR = 1.6; CI = 1.1-2.3), being small for gestational age (SGA; OR = 2.1; CI = 1.1-3.9), a 5-minute Apgar score below 7 (OR = 3.2, CI = 1.2-8.2), and congenital malformations (OR = 1.8, CI = 1.1-3.1). No association was found between autism and head circumference, maternal diabetes, being a twin, or season of birth. Our findings suggest that intrauterine and neonatal factors related to deviant intrauterine growth or fetal distress are important in the pathogenesis of autism.


Welfare of the minipig with special reference to use in regulatory toxicology studies.
This paper reviews the animal welfare challenges associated with the use of minipigs in toxicology testing, and compares these to published knowledge on the other widely used non-rodent species (dogs and non-human primates). Welfare challenges arise from housing and management of populations under laboratory conditions, and from the procedures carried out for product evaluation. Welfare assessment requires a multidisciplinary approach: cardiovascular parameters, adrenocortical hormones and behaviour are well known parameters. However, reliable non-invasive methods to assess welfare and species-specific benchmarks need further development in minipigs. Husbandry of minipigs (housing, diet, and socialisation needs) to promote good welfare is described in the revised Appendix A of the European Convention (ETS 123). This has been supplemented by knowledge of species biology and expert opinion from experienced minipig users. Challenges when using minipigs in toxicity testing have been reviewed in detail. Although deeper location of the peripheral blood vessels makes blood sampling more challenging, samples can be taken with minimal distress when staff members are well trained. Temporary and chronic vascular catheters can also be used for frequent sampling, and are likely to improve the welfare of the animals. Available training courses with a focus on stress free handling and dosing, as well as surgical placement of temporary and chronic vascular catheters, should be utilised to improve welfare during these procedures. Humane endpoints have been described, mainly based on current industry practices, but further scientific investigations are required. From an animal welfare perspective there are no basic restrictions to using minipigs in toxicity testing that are unique to this species. We conclude that it is easier to keep minipigs to a good standard of welfare under laboratory conditions than it is for dogs or non-human primates, since minipigs are not athletic (like dogs) or arboreal (like non-human primates).


[The clinical laboratory characteristics of 104 cases of cryptococcal meningoencephalitis].
With the purpose of describing the clinical and laboratory characteristics of cryptococcus meningoencephalitis, we reviewed the records of 104 patients admitted with this diagnosis at Couto Maia Hospital, reference for patients with infectious diseases in Salvador-BA Northeastern Brazil, from 1972 to 1996. The patients' age varied from 8 months to 79 years. Sixty-four (61.5%) patients were male. The duration of the disease varied from 2 to 150 days, average 27.7 days. The most common signs and symptoms were headache (92.7%), fever (84.4%) and neck stiffness (83.2%). The cell number in cerebrospinal fluid was greater than 4/mm > or = in 95.8% of the patients with lymphocyte predominance in 86.3% of the cases. The lethality rate was 42.7%.


Genetic control of B cell activation by bacterial lipopolysaccharide is mediated by multiple distinct genes or alleles.
Eleven closely related C3H mouse strains were examined for differences in their DNA synthetic response to a highly discriminatory endotoxin, LPS Escherichia coli K-235. Strains of the C3H line were found to be either high, intermediate, or low responders to endotoxin. Three stains, C3H/St, C3H/Bi, and C3H/CR were high responders. Six strains, C3H/He, C3HfB/He, C3H/Hen, C3Heb/Fej, C3H/DiSn, and C3H/Avy were intermediate responders, suggesting that a mutation producing decreased LPS responsiveness occurred in the C3H/He(C3H/An) strain between 1931 and 1945. Two strains, C3H/HeJ and C3H/Bts were unresponsive due to a mutation that occurred between 1960 and 1968. Breeding experiments among high, intermediate, and low responding strains documented probable codominant genetic control by the genes or alleles in the C3H/HeN and C3H/HeJ strains. In the C3H/HeN x C3H/St cross, dominance of the C3H/St gene over the C3H/He gene was documented, whereas the C3H/HeJ x C3H/St cross indicated codominance of these two genes. These findings may represent either three alleles or three distinct genes in C3H mice. A second X-linked gene locus was documented in the CBA/N strain which also causes impaired B cell responsiveness to LPS E. coli K235 in serum-free conditions. The abnormal gene products in the CBA/N and C3H/HeJ strains exhibit complementarity since F1 female animals from the cross between these two unresponsive strains are responsive to LPS. We conclude that there is at least one distinct X-linked gene locus and either three additional autosomal genes or three possible alleles at one or more autosomal loci which determine the LPS sensitivity of murine B cells.


Activator protein-1 transcription factor mediates bombesin-stimulated cyclooxygenase-2 expression in intestinal epithelial cells.
Colorectal carcinogenesis is a complex, multistep process involving genetic alterations and progressive changes in signaling pathways regulating intestinal epithelial cell proliferation, differentiation, and apoptosis. Although cyclooxygenase-2 (COX-2), gastrin-releasing peptide (GRP), and its receptor, GRP-R, are not normally expressed by the epithelial cells lining the human colon, the levels of all three proteins are aberrantly overexpressed in premalignant adenomatous polyps and colorectal carcinomas of humans. Overexpression of these proteins is associated with altered epithelial cell growth, adhesion, and tumor cell invasiveness, both in vitro and in vivo; however, a mechanistic link between GRP-R-mediated signaling pathways and increased COX-2 overexpression has not been established. We report that bombesin, a homolog of GRP, potently stimulates the expression of COX-2 mRNA and protein as well as the release of prostaglandin E(2) from a rat intestinal epithelial cell line engineered to express GRP-R. Bombesin stimulation of COX-2 expression requires an increase in [Ca(2+)](i), activation of extracellular signal-regulated kinase (ERK)-1 and -2 and p38(MAPK), and increased activation and expression of the transcription factors Elk-1, ATF-2, c-Fos, and c-Jun. These data suggest that the expression of GRP-R in intestinal epithelial cells may play a role in carcinogenesis by stimulating COX-2 overexpression through an activator protein-1-dependent pathway.


[Immunocytochemical identification of the glucagon-secreting cells in gastric mucosa].
Immunocytochemical investigations at the light and electron microscope level, using specific antiglucagon serum, revealed in the gastric oxyntic mucosa of the Dog, the presence of positive cells, undistinguishable ultrastructurally from pancreatic A-cells. No positive reaction was detected in any other gastrointestinal segment. These results suggest that gastric A-cells are responsible for the secretion of gastric glucagon.


Antileishmanial defense in macrophages triggered by tumor necrosis factor expressed on CD4+ T lymphocyte plasma membrane.
In our studies of host defense to the intracellular protozoan Leishmania major, we uncovered a novel mechanism of antileishmanial defense that involves direct cell contact between effector CD4+ lymphocytes and Leishmania-infected macrophages. The mechanism is distinctive because it does not involve lymphokine secretion and induces no cytotoxic effects in the host cells; its expression is antigen-specific and genetically restricted. We now demonstrate that these effector CD4+ cells display tumor necrosis factor (TNF) on their surface and provide evidence that the membrane-associated TNF is involved in the activation of the antileishmanial defense. Using a Leishmania-specific cloned T-T cell hybridoma line (1B6; CD4+, T helper type 1) that activates antileishmanial defense in macrophages through cell contact and does not secrete TNF, we noted that only cells bearing surface TNF (TNF+), but not ones lacking surface TNF (TNF-), exerted these effects. Moreover, the antileishmanial effects excreted by TNF+ 1B6 cells as well as by lymph node CD4+ TNF+ lymphocytes could be blocked with anti-TNF antibody. We propose that membrane-associated TNF on CD4+ T cells may provide a mechanism of targeting activation signals to macrophages in an antigen-specific and genetically restricted manner.


Immature carob pods extract and its fractions prevent lipid metabolism disorders and lipoprotein-rich plasma oxidation in mice: A phytochemical and pharmacological study.
In Morocco carob fruits are used traditionally to treat hypercholesterolemia, diabetes and related diseases. This study was designed to evaluate the hypolipidemic activity of Ceratonia siliqua green pods extract and its fractions in Triton WR-1339 and high fat/cholesterol diet (HFCD) induced hyperlipidemia mice, as well as their ability to prevent lipoproteins oxidation in vitro. High performance liquid chromatography (HPLC) analysis was used to determine the phenolic composition of the immature carob pods extract (HWCE). Antioxidant activities were evaluated using the DPPH radical scavenging test as well as MDA measurement in oxidized lipoprotein rich plasma. Plasma lipids, glucose and biliary total cholesterol, as well as lipids level in liver and feces, were analyzed. The acute oral toxicity was performed in mice single dosed with the HWCE at 2000 and 5000 mg/kg body weight. HPLC analysis shows that gallic acid is the main phenolic compound in the HWCE. The acute oral toxicity assessment revealed that the HWCE is not toxic (LD50 is greater than 5000 mg/kg body weight). In the acute hypolipidemic study, mice treated with the HWCE and its fractions exhibited a significant (P < 0.001) reduction in plasma total cholesterol (TC), triglycerides (TG) and low density lipoprotein-cholesterol (LDL-C) levels. Importantly, immature carob aqueous extract was more effective in lowering mice hypercholesterolemia than its fractions. Indeed, mice fed the HFCD for 12 weeks showed a significant raise in plasma TC, TG and LDL-C, as well as in hepatic and fecal TC and TG levels. The HWCE at 100 and 200 mg/kg body weight significantly (P < 0.001) reversed the plasmatic levels of these lipid parameters, increased plasma HDL-C level, reduced hepatic lipids accumulation, but increased cholesterol level in the bile and fecal lipids excretion. The HWCE decreased also the atherogenic index, the LDL-C/HDL-C ratio and plasma glucose level after 12 weeks' experiment. On the other hand, the HWCE was more effective in preventing mice lipoprotein-rich plasma oxidation than its fractions, with a concentration-dependent manner. C. siliqua green fruits extract could be effective in preventing atherosclerosis and related cardiovascular complications through the inhibition of lipoprotein oxidation and cholesterol clearance.


Using mind-body techniques in dentistry.
Mind-body medicine is a win-win proposition for dentists and their patients. Patients experience less anxiety and less discomfort during procedures. However, it's important to know the advantages and disadvantages if you are considering offering mind-body services in your practice.


Significance of GABA(A) receptor heterogeneity: clues from developing neurons.
Briefly after the landmark discovery by Hanns Möhler that GABA(A) receptors (GABA(A)R) are the site of action of benzodiazepine site ligands, their distribution in the rodent CNS during development was mapped by autoradiography, demonstrating early and widespread expression of GABA(A)R in the brain and spinal cord. Ten years later, the first studies using subunit-specific antibodies revealed unsuspected heterogeneity in the subunit composition of GABA(A)R in developing brain, with striking regional specificity and rapid changes in expression and subcellular localization correlating with the maturation of neuronal circuits. These data contributed to the wealth of evidence that GABAergic neurotransmission, acting both synaptically and extrasynaptically, modulates major steps of neuronal development (proliferation, migration, differentiation, and circuit formation). In immature neurons, GABA(A)R activation leads to neuronal depolarization and activation of Ca(2+) signals, which mediate many of the developmental effects of GABA. Therefore, GABA(A)R heterogeneity might be essential to fine-tune GABA actions in the dynamics of CNS maturation. Furthermore, since a disturbance of GABAergic function during ontogeny can potentially affect many aspects of CNS maturation and contribute to the etiology of major brain disorders, GABA(A)R heterogeneity provides a substrate for the development of a tailored pharmacology targeting specific receptor subtypes. This chapter provides a brief overview of these issues with a special focus on the seminal contributions of Hanns Möhler to the emergence of these concepts of fundamental relevance in today's neuroscience research and pharmacological developments.


Posttraumatic stress disorder, traumatic brain injury, and suicide attempt history among veterans receiving mental health services.
History of posttraumatic stress disorder (PTSD) or traumatic brain injury (TBI) has been found to increase risk of suicidal behavior. The association between suicide attempt history among veterans with PTSD and/or TBI was explored. Cases (N = 81) and 2:1 matched controls (N = 160) were randomly selected from a Veterans Affairs Medical Center clinical database. PTSD history was associated with an increased risk for a suicide attempt (OR = 2.8; 95% CI: 1.5, 5.1). This increased risk was present for those with and without a history of TBI. Results support incorporating PTSD history when assessing suicide risk among veterans with and without TBI.


Loss of Melanopsin Photoreception and Antagonism of the Histamine H3 Receptor by Ciproxifan Inhibit Light-Induced Sleep in Mice.
Light has direct effects on sleep and wakefulness causing arousal in diurnal animals and sleep in nocturnal animals. In the present study, we assessed the modulation of light-induced sleep by melanopsin and the histaminergic system by exposing mice to millisecond light flashes and continuous light respectively. First, we show that the induction of sleep by millisecond light flashes is dose dependent as a function of light flash number. We found that exposure to 60 flashes of light occurring once every 60 seconds for 1-h (120-ms of total light over an hour) induced a similar amount of sleep as a continuous bright light pulse. Secondly, the induction of sleep by millisecond light flashes was attenuated in the absence of melanopsin when animals were presented with flashes occurring every 60 seconds over a 3-h period beginning at ZT13. Lastly, the acute administration of a histamine H3 autoreceptor antagonist, ciproxifan, blocked the induction of sleep by a 1-h continuous light pulse during the dark period. Ciproxifan caused a decrease in NREMS delta power and an increase in theta activity during both sleep and wake periods respectively. The data suggest that some form of temporal integration occurs in response to millisecond light flashes, and that this process requires melanopsin photoreception. Furthermore, the pharmacological data suggest that the increase of histaminergic neurotransmission is sufficient to attenuate the light-induced sleep response during the dark period.


The effects of ouabain on induction of atrioventricular nodal re-entrant paroxysmal supraventricular tachycardia.
Electrophysiological studies utilizing His bundle recordings and atrial extra-stimulus technique were performed in 17 patients (pts) with documented paroxysmal supraventricular tachycardia (PSVT) before and after 0.01 mg/kg, i.v., ouabain. Before ouabaine, echozones(EZ) were demonstrated in 11 patients. After ouabain, EZ were abolished in two, decreased in five, unchanged in three, and increased in one. In one patient, EZ was demonstrated only after ouabain. Eleven patients could sustain PSVT before ouabain; after ouabain, only six patients could sustain PSVT. Analysis of A1-A2, H1-H2 curves revealed 11 patients with discontinous (dual pathway) and six patients with smooth conduction curves. In dual pathway patients, both the fast and slow pathway curves were shifted rightward and upward after ouabain. The changes in EZ were dependent upon the relative rightward shifts of the two pathways. In patients with smooth curves, EZ tended to shift rightward with a critical A-H being achieved at longer A1-A2 intervals after ouabain. In conclusion, the effects of ouabain on PSVT were variable. Beneficial effects included abolition or decrease of EZ and loss of the ability to sustain PSVT. Potentially deleterious effects included widening or new de-elopment of EZ.


Decreased choroidal vascularity index and subfoveal choroidal thickness in vitamin D insufficiency.
To present the effects of vitamin D insufficiency on the choroidal vascularity index, central choroid and central macula. 42 eyes of 42 patients with vitamin D insufficiency and 51 eyes of 51 age- and sex-matched healthy subjects were included in this retrospective, cross-sectional, and comparative study. The macular layer was examined using the retinal mapping mode of the spectral domain Optical coherence tomography (Optovue RTVue XR, Optovue Inc., Fremont, CA). Optical coherence tomography (OCT) images were taken in Enhanced Deep Imaging mode and transferred to Image J program. choroidal vascularity index (CVI) and subfoveal choroidal thickness (SFCT) measurements were evaluated. The mean age of volunteers was 35.4 ± 7.2 years. There was a significant difference in CVI values 67.75±2.4 in the patients with vitamin D insufficiency and 69.22±1.75 in the control group. The SCFT of patients with vitamin D insufficiency and control group were 295.25±42.3 and 335.71±11.6 (p = 0.001, p<0.001 respectively). OCT examination of patients with vitamin D insufficiency showed a decrease in CVI and SCFT values. These results are important in demonstrating the retinochoroidal effects of vitamin D insufficiency.


Occurrence of urease-positive Vibrio parahaemolyticus in Kanagawa, Japan, with specific reference to presence of thermostable direct hemolysin (TDH) and the TDH-related-hemolysin genes.
A total of 132 strains of V. parahaemolyticus isolated from patients and from the suspected causal food items of past food poisoning cases occurring in Kanagawa Prefecture, Japan, were examined for the ability to hydrolyze urea, with specific reference to the presence of the thermostable direct hemolysin gene (tdh) and the gene for thermostable direct hemolysin-related hemolysin (trh). Ten strains belonging to five different O-antigen serotypes were positive for urea hydrolysis (UH+), and four of these strains did not carry tdh. A total of 106 strains carried tdh, but less than 6% of them were UH+, whereas all trh-carrying strains were UH+. The evidence suggests that urea hydrolysis is not a reliable marker for identifying tdh-carrying V. parahaemolyticus strains in Japan (the Pacific Northeast) but may be a marker for trh-carrying strains.


Bilateral renal choriocarcinoma in a postmenopausal woman.
Choriocarcinoma is the most malignant tumor of gestational trophoblastic neoplasia. It grows rapidly and metastasizes to the lung, liver, and less frequently, the brain. Metastases to the kidney are rare in the literature, and bilateral involvement is even more scarce. Renal involvement of choriocarcinoma is highly exceptional and may mimic renal cell carcinoma. Here we report a case of bilateral renal choriocarcinoma presenting 5 years after a history of a total anterior hysterectomy because of a hydatidiform mole.


Effects of combined prenatal stress and toluene exposure on apoptotic neurodegeneration in cerebellum and hippocampus of rats.
Pregnant Wistar rats were exposed to 1500 ppm toluene 6 hr/day from gestational day 7-20 or to chronical mild stress from gestational day 9-20 as single exposure or in combination. Behavioural, immunohistopathological, molecular biological, and neurochemical methods were applied to investigate the offspring for developmental neurotoxicity and level of apoptosis in the brain. The number of apoptotic cells in cerebellum postnatal day 22, 24, and 27 and in hippocampus (postnatal day 22, 24, and 27) were counted after visualization by the TUNEL staining or measured by DNA-laddering technique. Caspase-3 activity was determined in cerebellum (postnatal day 6, 22, 24, and 27) and in hippocampus (postnatal day 6 and 22). TUNEL staining and DNA-laddering technique showed a marked decrease in number of apoptotic cells from postnatal day 22 to 27 in both cerebellum and hippocampus. Apparently, a peak in the number of TUNEL positive cells was identified in cerebellum at postnatal day 22. There was no statistically significant influence of exposure except that DNA-laddering in cerebellum at postnatal day 27 was increased by toluene exposure. Caspase-3 activity decreased in cerebellum and hippocampus with age. At postnatal day 6 stress and toluene, when singly exposed, increased activity in cerebellum whereas co-exposure to stress and toluene did not. Stress increased caspase-3 activity in hippocampus postnatal day 22. There was overall consistency between the results obtained by the three supplementary methods regarding the influence of exposure and age on apoptotic activity in cerebellum and hippocampus. New methods to quantitate the relative level of apoptosis measured as DNA-laddering and the caspase-3 activity in tissue are presented.