[Neural tube dysraphia at the level of the midbrain in alcoholic embryopathy].
Forty-four 5-12-week embryos obtained from mothers who abused alcohol during pregnancy were examined for brain development. Six cases of dysraphia of the neural tube at the midbrain level were revealed. In two cases, it was defined as primary. This was confirmed by the impairment of neurulation in the neural tube, by the growth of the ends of the neural plate, not yet grown together (hyperplasia), and derangement of the mesoderm (partial cranioschisis). The use of alcohol might be the most probable cause that gave rise to dysraphia. In these cases, the teratogenic termination period was referred to the first 4 weeks of pregnancy. In 4 cases, the secondary rupture of the walls of the midbrain, i.e. secondary dysraphia of the traumatic genesis was established.


The influence of influenza virus infections on the development of tuberculosis.
Recently, it was shown that interferon-γ mediated immune responses, which play a major role in the control of infection with Mycobacterium tuberculosis (Mtb), can be inhibited by type I interferons. Since type I interferons are abundantly induced during viral infections, we hypothesized that infections with influenza viruses might play a role in the development of active TB disease either directly after exposure to Mtb or through reactivation of latent Mtb infection. To explore this hypothesis we investigated in a retrospective study whether newly diagnosed adult tuberculosis patients from Indonesia had had recent influenza infection. Plasma samples from TB patients and controls were assayed for antibodies against two subtypes of at that time relevant, seasonal influenza A viruses. Overall, no correlation was observed with the presence of antibodies and manifest tuberculosis. Still, antibody titers against circulating A/H3N2 influenza virus were slightly enhanced in tuberculosis patients as compared to controls, and highest in cases of advanced tuberculosis. This suggests that tuberculosis patients were recently infected with influenza, before clinical manifestation of the disease. Alternatively, the production of antibodies and susceptibility to tuberculosis may be influenced by a common confounding factor, for example the ability of patients to induce interferon-α. We conclude that in an endemic country like Indonesia, an influenza virus infection is not a major determinant for developing clinically manifest tuberculosis.


[Effect of electroacupuncture on morphological changes and apoptosis of substantia nigra cells in Parkinson's disease rats].
To observe the influence of electroacupuncture (EA) of "Fengfu" (GV16) and "Taichong" (LR3) on morphological changes and apoptotic percentage of substantia nigra cells so as to explore its underlying mechanism in relieving Parkinson's disease. Forty Wistar rats were randomly divided into normal control, sham-operation (sham), model and EA groups, with 10 rats in each. The Parkinson's disease model was established by micro-injection of 6-hydroxyl-dopamine (6-OHDA) into the right striatum. EA (2 Hz, 1 mA) was applied to "Fengfu"(GV16) and "Taichong" (LR3) for 30 min, once daily for 2 weeks. HE staining, Nissl staining and immunohistochemical staining were conducted for observing the morphological changes of substantia nigra pars compacta (SNc) and striatum, and the tyrosine hydroxylase(TH) immuno-reaction (IR) positive neurons and nerve fibers. The apoptosis was detected by flow cytometry. Compared to the normal control and sham groups, the total number of TH-IR positive neurons and Nissl-stained cells, and OD value of TH-IR positive nerve fibers in the SNc on the 6-OHDA-lesioned side were significantly lower in the model group (P < 0.01). Compared with the model group, the aforementioned 3 indexes of the EA group were increased obviously (P < 0.01). The percentage of apoptosis of SNc on the 6-OHDA-lesioned side was obviously lower in the EA group than in the model group (P < 0.01), but still obviously higher than in the normal group and sham group (P < 0.01). Electroacupuncture therapy can significantly increase the number of neurons of substantia nigra and the density of striatum nerve fibers,and reduce the apoptotic percentage of substantia nigra cells in the Parkinsonian rats, which may contribute to its effect in relieving Parkinson's disease.


[Alcohol congeners and their implications for medicolegal assessment of drunkeness].
Ethanol is the main psychoactive ingredient of alcoholic beverages. Together with water it makes their major part. The other substances contained in alcoholic beverages are called congeners. Some of them come from the original substance of the beverage, some come from the fermentation or mellowing process. Except giving the drink its specific taste, scent and colour, congeners also have a non-negligible direct influence on the alcohol consumer. Nowadays, methods of identification thousands of alcohol congeners are available. Analyzing chemical compounds of alcoholic beverages have only recently gained its importance, when it helped to estimate the basic chemical composition of the particular alcoholic beverages. Mentioned method is able to identify an exact type of alcoholic beverage which a man consumed before the blood sample necessary for the detection had been taken from him. It becomes irreplaceable especially in forensic assessment of the drunkenness in case an alcoholised person, responsible for any crime, excuses himself that he was drinking only after the act/crime (e.g. traffic accident) had happened. It can also help to aprove/disprove a testimony of an accused person that he/she was unaware of being given alcohol into his/her non-alcoholic beverage. Development of the new chemical methods analyzing alcohol congeners are of a great benefit for any forensic expert-medical doctor dealing with the field of forensic alcohology. However, he/she must be aware that interaction of alcohol congeners with the human organism follows different laws in comparison to alcohol/ethanol itself. alcohol - congener - alcohol congener analysis - forensic alcohology.


A new clustering method identifies multiple sclerosis-specific T-cell receptors.
To characterize T-cell receptors (TCRs) and identify target epitopes in multiple sclerosis (MS). Peripheral blood mononuclear cells were obtained from 39 MS patients and 19 healthy controls (HCs). TCR repertoires for α/β/δ/γ chains, TCR diversity, and V/J usage were determined by next-generation sequencing. TCR β chain repertoires were compared with affectation status using a novel clustering method, Grouping of Lymphocyte Interactions by Paratope Hotspots (GLIPH). Cytomegalovirus (CMV)-IgG was measured in an additional 113 MS patients and 93 HCs. Regulatory T cells (Tregs) were measured by flow cytometry. TCR diversity for all four chains decreased with age. TCRα and TCRβ diversity was higher in MS patients (P = 0.0015 and 0.024, respectively), even after age correction. TRAJ56 and TRBV4-3 were more prevalent in MS patients than in HCs (pcorr = 0.027 and 0.040, respectively). GLIPH consolidated 208,674 TCR clones from MS patients into 1,294 clusters, among which two candidate clusters were identified. The TRBV4-3 cluster was shared by HLA-DRB1*04:05-positive patients (87.5%) and predicted to recognize CMV peptides (CMV-TCR). MS Severity Score (MSSS) was lower in patients with CMV-TCR than in those without (P = 0.037). CMV-IgG-positivity was associated with lower MSSS in HLA-DRB1*04:05 carriers (P = 0.0053). HLA-DRB1*04:05-positive individuals demonstrated higher CMV-IgG titers than HLA-DRB1*04:05-negative individuals (P = 0.017). CMV-IgG-positive patients had more Tregs than CMV-IgG-negative patients (P = 0.054). High TCRα/TCRβ diversity, regardless of age, is characteristic of MS. Association of a CMV-recognizing TCR with mild disability indicates CMV's protective role in HLA-DRB1*04:05-positive MS.


Calcium-induced human keratinocyte differentiation requires src- and fyn-mediated phosphatidylinositol 3-kinase-dependent activation of phospholipase C-gamma1.
We have previously demonstrated that phospholipase C (PLC)-gamma1 is required for calcium-induced human keratinocyte differentiation. In the present study, we investigated whether the activation of PLC-gamma1 by nonreceptor kinases such as src and fyn plays a role in mediating this process. Our results showed that the combination of dominant negative src and fyn blocked calcium-stimulated PLC-gamma1 activity and human keratinocyte differentiation, whereas each separately has little effect. However, unlike the activation of PLC-gamma1 by epidermal growth factor, calcium-induced activation of PLC-gamma1 was not a result of direct tyrosine phosphorylation. Therefore, we examined an alternative mechanism, in particular phosphatidylinositol 3,4,5-triphosphate (PIP3) formed as a product of phosphatidylinositol 3-kinase (PI3K) activity. PIP3 binds to and activates PLC-gamma1. The combination of dominant negative src and fyn blocked calcium-induced tyrosine phosphorylation of the regulatory subunit of PI3K, p85alpha, and the activity of the catalytic subunit of PI3K. PI3K inhibitors blocked calcium activation of PLC-gamma1 as well as the induction of keratinocyte differentiation markers involucrin and transglutaminase. These data indicate that calcium activates PLC-gamma1 via increased PIP3 formation mediated by c-src- and fyn-activated PI3K. This activation is required for calcium-induced human keratinocyte differentiation.


Bioeconomic factors of beef heifer maturity to consider when establishing criteria to optimally select and/or retain herd replacements.
Understanding the biology of heifer maturity and its relationship to calving difficulty and subsequent breeding success is a vital step in building a bioeconomic model to identify optimal production and profitability. A limited dependent variable probit model is used to quantify the responses among heifer maturities, measured by a maturity index (MI), on dystocia and second pregnancy. The MI account for heifer age, birth BW, prebreeding BW, nutrition level, and dam size and age and is found to be inversely related to dystocia occurrence. On average there is a 2.2% increase in the probability of dystocia with every 1 point drop in the MI between the MI scores of 50 and 70. Statistically, MI does not directly alter second pregnancy rate; however, dystocia does. The presence of dystocia reduced second pregnancy rates by 10.67%. Using the probability of dystocia predicted from the MI in the sample, it is found that on average, every 1 point increase in MI added 0.62% to the probability of the occurrence of second pregnancy over the range represented by the data. Relationships among MI, dystocia, and second pregnancy are nonlinear and exhibit diminishing marginal effects. These relationships indicate optimal production and profitability occur at varying maturities, which are altered by animal type, economic environment, production system, and management regime. With these captured relationships, any single group of heifers may be ranked by profitability given their physical characteristics and the applicable production, management, and economic conditions.


Targeting IRAK1 in T-cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) represents expansion of cells arrested at specific stages of thymic development with the underlying genetic abnormality often determining the stage of maturation arrest. Although their outcome has been improved with current therapy, survival rates remain only around 50% at 5 years and patients may therefore benefit from specific targeted therapy. Interleukin receptor associated kinase 1 (IRAK1) is a ubiquitously expressed serine/threonine kinase that mediates signaling downstream to Toll-like (TLR) and Interleukin-1 Receptors (IL1R). Our data demonstrated that IRAK1 is overexpressed in all subtypes of T-ALL, compared to normal human thymic subpopulations, and is functional in T-ALL cell lines. Genetic knock-down of IRAK1 led to apoptosis, cell cycle disruption, diminished proliferation and reversal of corticosteroid resistance in T-ALL cell lines. However, pharmacological inhibition of IRAK1 using a small molecule inhibitor (IRAK1/4-Inh) only partially reproduced the results of the genetic knock-down. Altogether, our data suggest that IRAK1 is a candidate therapeutic target in T-ALL and highlight the requirement of next generation IRAK1 inhibitors.


Body Temperature Regulation in Hot Environments.
Organisms in hot environments will not be able to passively dissipate metabolically generated heat. Instead, they have to revert to evaporative cooling, a process that is energetically expensive and promotes excessive water loss. To alleviate these costs, birds in captivity let their body temperature increase, thereby entering a state of hyperthermia. Here we explore the use of hyperthermia in wild birds captured during the hot and dry season in central Nigeria. We found pronounced hyperthermia in several species with the highest body temperatures close to predicted lethal levels. Furthermore, birds let their body temperature increase in direct relation to ambient temperatures, increasing body temperature by 0.22°C for each degree of increased ambient temperature. Thus to offset the costs of thermoregulation in ambient temperatures above the upper critical temperature, birds are willing to let their body temperatures increase by up to 5°C above normal temperatures. This flexibility in body temperature may be an important mechanism for birds to adjust to predicted increasing ambient temperatures in the future.


Oculomotor, Vestibular, and Reaction Time Tests in Mild Traumatic Brain Injury.
Mild traumatic brain injury is a major public health issue and is a particular concern in sports. One of the most difficult issues with respect to mild traumatic brain injury involves the diagnosis of the disorder. Typically, diagnosis is made by a constellation of physical exam findings. However, in order to best manage mild traumatic brain injury, it is critically important to develop objective tests that substantiate the diagnosis. With objective tests the disorder can be better characterized, more accurately diagnosed, and studied more effectively. In addition, prevention and treatments can be applied where necessary. Two cohorts each of fifty subjects with mild traumatic brain injury and one hundred controls were evaluated with a battery of oculomotor, vestibular and reaction time related tests applied to a population of individuals with mild traumatic brain injury as compared to controls. We demonstrated pattern differences between the two groups and showed how three of these tests yield an 89% sensitivity and 95% specificity for confirming a current diagnosis of mild traumatic brain injury. These results help better characterize the oculomotor, vestibular, and reaction time differences between those the mild traumatic brain injury and non-affected individuals. This characterization will allow for the development of more effective point of care neurologic diagnostic techniques and allow for more targeted treatment which may allow for quicker return to normal activity.


Bibliometric analysis of studies about acute myeloid leukemia conducted globally from 1999 to 2018.
A bibliometric study is performed to analyze publication patterns in a specific research area and to establish a landscape model that can be used to quantitatively weigh publications. This study aimed to investigate AML research networks and to conduct a trend-related keyword analysis. We analyzed 48,202 studies about AML published from 1999 to 2019 in the Web of Science Core Collection. The network analysis was conducted using the R&R studio software. The journal Blood had the highest number of published articles with an h-index of 410. The USA had the highest number of total publications (18,719, 38.3%) and research funded by the government, institutions, and pharmaceutical companies (5,436, 10.8%). The institute with the largest number of publications was the MD Anderson Cancer Center. Kantarjian H, Garcia-Manero G, and Ravandi F were the leading authors of publications about AML. Keyword analysis revealed that FLT 3, micro-RNA, and NK cell topics were the hotspots in the cell and gene area in all publications. The overall AML research landscape is popular in the field of translational research as it can identify molecular, cell, and gene studies conducted by different funding agencies, countries, institutions, and author networks. With active funding and support from the Chinese government, the productivity of scientific research is increasing not only in the AML field but also in the medical/health-related science field.


Influence of total intravenous anesthesia, entropy and laparoscopy on oxidative stress.
Recent studies have correlated postoperative mortality with anesthetic mortality, especially with the depth of anesthesia and systolic blood pressure (SBP). The aim of this study is to evaluate the effects of the depth of total intravenous anesthesia (TIVA) using remifentanil and propofol, performed with monitoring of response entropy (RE) on blood concentrations of oxidative stress markers (TBARS and glutathione) during laparoscopic operations. Twenty adult patients, ASA I, BMI 20-26 kg.m(-2), aged 20 to 40 years, were randomly distributed into two groups: Group I underwent anesthetic-surgical procedure with RE maintained between 45 and 59, and Group II underwent anesthetic-surgical procedure with RE between 30 and 44. In both groups, the remifentanil and propofol infusion was controlled by the effector site (Es), adjusted to maintain RE desired values (Groups I and II) and always assessing the suppression rate (SR). Patients were evaluated in six periods: M1 (immediately before anesthesia), M2 (before tracheal intubation [TI]), M3 (5-minutes after TI), M4 (immediately before pneumoperitoneum [PPT]), M5 (1-minute after PPT), and M6 (1-hour after the operation). The following parameters were assessed at all times: SBP, DBP, HR, RE, SR, TBARS, and glutathione. We found increases in TBARS and glutathione in M5, both in Group I and Group II (p<0.05), with higher values in Group II, and SR in three patients in Group II, immediately after PPT. Increased markers in Group I (M5) suggests an increase in anaerobic metabolism (AM) in the splanchnic circulation while the highest values seen in Group II (GII > GI in M5, p<0.05%) suggest interference of another factor (deep anesthesia) responsible for the increase in AM, probably as a result of increased autonomic nervous system depression and minor splanchnic self-regulation.


Potential migration of buoyant LNAPL from intermediate level waste (ILW) emplaced in a geological disposal facility (GDF) for U.K. radioactive waste.
A safety case for the disposal of Intermediate Level (radioactive) Waste (ILW) in a deep geological disposal facility (GDF) requires consideration of the potential for waste-derived light non-aqueous phase liquid (LNAPL) to migrate under positive buoyancy from disposed waste packages. Were entrainment of waste-derived radionuclides in LNAPL to occur, such migration could result in a shorter overall travel time to environmental or human receptors than radionuclide migration solely associated with the movement of groundwater. This paper provides a contribution to the assessment of this issue through multiphase-flow numerical modelling underpinned by a review of the UK's ILW inventory and literature to define the nature of the associated ILW LNAPL source term. Examination has been at the waste package-local GDF environment scale to determine whether proposed disposal of ILW would lead to significant likelihood of LNAPL migration, both from waste packages and from a GDF vault into the local host rock. Our review and numerical modelling support the proposition that the release of a discrete free phase LNAPL from ILW would not present a significant challenge to the safety case even with conservative approximations. 'As-disposed' LNAPL emplaced with the waste is not expected to pose a significant issue. 'Secondary LNAPL' generated in situ within the disposed ILW, arising from the decomposition of plastics, in particular PVC (polyvinyl chloride), could form the predominant LNAPL source term. Released high molecular weight phthalate plasticizers are judged to be the primary LNAPL potentially generated. These are expected to have low buoyancy-based mobility due to their very low density contrast with water and high viscosity. Due to the inherent uncertainties, significant conservatisms were adopted within the numerical modelling approach, including: the simulation of a deliberately high organic material--PVC content wastestream (2D03) within an annular grouted waste package vulnerable to LNAPL release; upper bound inventory estimates of LNAPLs; incorporating the lack of any hydraulic resistance of the package vent; the lack of any degradation of dissolved LNAPL; and, significantly, the small threshold displacement pressure assumed at which LNAPL is able to enter initially water-saturated pores. Initial scoping calculations on the latter suggested that the rate at which LNAPL is able to migrate from a waste package is likely to be very small and insignificant for likely representative displacement pressure data: this represents a key result. Adopting a conservative displacement pressure, however, allowed the effect of other features and processes in the system to be assessed. High LNAPL viscosity together with low density contrast with water reduces LNAPL migration potential. Migration to the host rock is less likely if waste package vent fluxes are small, solubility limits are high and path lengths through the backfill are short. The capacity of the system to dissolve all of the free LNAPL will, however, depend on groundwater availability. Even with the conservatisms invoked, the overall conclusion of model simulations of intact and compromised (cracked or corroded) waste packages, for a range of realistic ILW LNAPL scenarios, is that it is unlikely that significant LNAPL would be able to migrate from the waste packages and even more unlikely it would be sufficiently persistent to reach the host rock immediately beyond the GDF.


Dual targeting of mTOR and aurora-A kinase for the treatment of uterine Leiomyosarcoma.
The significance of mTOR activation in uterine leiomyosarcoma (ULMS) and its potential as a therapeutic target were investigated. Furthermore, given that effective therapies likely require combination mTOR blockade with inhibition of other targets, coupled with recent observations suggesting that Aurora-A kinase (Aurk-A) deregulations commonly occur in ULMS, the preclinical impact of dually targeting both pathways was evaluated. Immunohistochemical staining was used to evaluate expression of activated mTOR components in a large (>200 samples) ULMS tissue microarray. Effects of mTOR blockade (using rapamycin) and Aurk-A inhibition (using MLN8237) alone and in combination on human ULMS cell growth, cell-cycle progression, and apoptosis were assessed in cellular assays. Drug interactions were determined via combination index analyses. The antitumor effects of inhibitors alone or in combination were evaluated in vivo. Enhanced mTOR activation was seen in human ULMS samples. Increased pS6RP and p4EBP1 expression correlated with disease progression; p4EBP1 was found to be an independent prognosticator of patient outcome. Rapamycin inhibited growth and cell-cycle progression of ULMS cell strains/lines in culture. However, only a cytostatic effect on tumor growth was found in vivo. Combining rapamycin with MLN8237 profoundly (and synergistically) abrogated ULMS cells' growth in culture; interestingly, these effects were seen only when MLN8237 was preadministered. This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo. mTOR and Aurk-A pathways are commonly deregulated in ULMS. Preclinical data support further exploration of dual mTOR and Aurk-A therapeutic blockade for human ULMS.


Mortality of New York children with sickle cell disease identified through newborn screening.
Long-term follow-up of newborn screening for conditions such as sickle cell disease can be conducted using linkages to population-based data. We sought to estimate childhood sickle cell disease mortality and risk factors among a statewide birth cohort with sickle cell disease identified through newborn screening. Children with sickle cell disease identified by newborn screening and born to New York residents in 2000-2008 were matched to birth and death certificates. Mortality rates were calculated (using numbers of deaths and observed person-years at risk) and compared with mortality rates for all New York children by maternal race/ethnicity. Stratified analyses were conducted to examine associations between selected factors and mortality. Among 1,911 infants with sickle cell disease matched to birth certificates, 21 deaths were identified. All-cause mortality following diagnosis was 3.8 per 1,000 person-years in the first 2 years of life and 1.0 per 1,000 person-years at ages 2-9 years. The mortality rate was significantly lower among children of foreign-born mothers and was significantly higher among preterm infants with low birth weight. The mortality rates were not significantly higher for infants after 28 days with sickle cell disease than for all New York births, but they were 2.7-8.4 times higher for children 1 through 9 years old with homozygous sickle cell disease than for those of all non-Hispanic black or Hispanic children born to New York residents. Estimated mortality risk in children with homozygous sickle cell disease remains elevated even after adjustment for maternal race/ethnicity. These results provide evidence regarding the current burden of child mortality among children with sickle cell disease despite newborn screening.Genet Med 17 6, 452-459.


Identification by Comprehensive Bioinformatics Analysis of KIF15 as a Candidate Risk Gene for Triple-Negative Breast Cancer.
Previous studies have shown that kinesin family proteins (KIFs) play an indispensable roles in several types of cancer. However, the expression and clinical significance of KIFs in triple-negative breast cancer remain unclear. In this study, the role of KIF15, including gene expression analysis, methylation characteristic, CNV characteristic, and miRNA target regulation, was evaluated using multiple bioinformatic tools based on TCGA database. Quantitative real-time PCR and Western blot were used to determine the expression level of KIF15 in triple-negative breast cancer cell lines. Then, functional experiments were employed to explore the effects of KIF15 on tumor growth and metastasis in triple-negative breast cancer. Our data showed that KIF15 was significantly upregulated in triple-negative breast cancer (TNBC). Functionally, downregulation of KIF15 significantly facilitated apoptosis and G2/M phase arrest, and inhibited the migration and invasion of TNBC cells. The mechanism of action of KIF15 was closely related to DNA replication checkpoint and cell cycle regulation in TNBC based on GSEA. In addition, bioinformatics analysis demonstrated that high expression of KIF15 in TNBC was correlated with copy number aberration and DNA methylation levels. Our findings suggest that KIF15 is a novel oncogene in TNBC and provide us a strong evidence that it might be served as a potential clinical target and biomarker in triple-negative breast cancer.


What does evidence tell us about the use of gait robotic devices in patients with multiple sclerosis? A comprehensive systematic review on functional outcomes and clinical recommendations.
There is growing evidence on the efficacy of gait robotic rehabilitation in patients with multiple sclerosis (MS), but most of the studies have focused on gait parameters. Moreover, clear indications on the clinical use of robotics still lack. As part of the CICERONE Italian Consensus on Robotic Rehabilitation, the aim of this systematic review was to investigate the existing evidence concerning the role of lower limb robotic rehabilitation in improving functional recovery in patients with MS. We searched for and systematically reviewed evidence-based studies on gait robotic rehabilitation in MS, between January 1st, 2010 and December 31st, 2020, in the following databases: Cochrane Library, PEDro, PubMed and Google Scholar. The study quality was assessed by the 16-item assessment of multiple systematic reviews 2 (AMSTAR 2) and the 10-item PEDro scale for the other research studies. After an accurate screening, only 17 papers were included in the review, and most of them (13 RCT) had a level II evidence. Most of the studies used the Lokomat as a grounded robotic device, two investigated the efficacy of end-effectors and two powered exoskeletons. Generally speaking, robotic treatment has beneficial effects on gait speed, endurance and balance with comparable outcomes to those of conventional treatments. However, in more severe patients (EDSS >6), robotics leads to better functional outcomes. Notably, after gait training with robotics (especially when coupled to virtual reality) MS patients also reach better non-motor outcomes, including spasticity, fatigue, pain, psychological well-being and quality of life. Unfortunately, no clinical indications emerge on the treatment protocols. The present comprehensive systematic review highlights the potential beneficial role on functional outcomes of the lower limb robotic devices in people with MS. Future studies are warranted to evaluate the role of robotics not only for walking and balance outcomes, but also for other gait-training-related benefits, to identify appropriate outcome measures related to a specific subgroup of MS subjects' disease severity.


Experimental models of human cortical malformations: from mammals to 'acortical' zebrafish.
Human neocortex controls and integrates cognition, emotions, perception and complex behaviors. Aberrant cortical development can be triggered by multiple genetic and environmental factors, causing cortical malformations. Animal models, especially rodents, are a valuable tool to probe molecular and physiological mechanisms of cortical malformations. Complementing rodent studies, the zebrafish (Danio rerio) is an important model organism in biomedicine. Although the zebrafish (like other fishes) lacks neocortex, here we argue that this species can still be used to model various aspects and brain phenomena related to human cortical malformations. We also discuss novel perspectives in this field, covering both advantages and limitations of using mammalian and zebrafish models in cortical malformation research. Summarizing mounting evidence, we also highlight the importance of translationally-relevant insights into the pathogenesis of cortical malformations from animal models, and discuss future strategies of research in the field.


Post-grafting of silica surfaces with pre-functionalized organosilanes: new synthetic equivalents of conventional trialkoxysilanes.
This article describes recent advances that have been made in the development of methods for post-grafting of silica surfaces using functionalized organosilanes. While procedures employing conventional trialkoxysilane precursors have been utilized to immobilize organic and biological molecules onto inorganic supports, such as silica and glass, they have intrinsic limitations including sensitivity to hydrolysis and slow reaction rates. In this context, new synthetic equivalents to conventional trialkoxysilanes and new grafting methods have been devised to overcome these drawbacks and improve post-grafting processes. A key feature of the new strategies is the stability of the immobilizing groups that enables the silane precursors to be functionalized and purified without decomposition before immobilization. Recent developments made in the design of immobilization methods, which employ non-catalytic and catalytic approaches, are described.


Clinical and molecular genetic findings in autosomal dominant OPA3-related optic neuropathy.
Leber hereditary optic neuropathy and autosomal dominant optic atrophy are the two most common inherited optic neuropathies. The latter has been associated with mutations in the OPA1 and OPA3 genes. To date, only six families with OPA3-associated dominant optic atrophy have been reported. In order to identify additional families, we performed Sanger sequencing of the OPA3 gene in 75 unrelated optic neuropathy patients. Affected individuals from two families were found to harbour the c.313C > G, p.(Gln105Glu) change in heterozygous state; this genetic defect has been previously reported in four dominant optic atrophy families. Intra- and interfamilial variability in age of onset and presenting symptoms was observed. Although dominant OPA3 mutations are typically associated with optic atrophy and cataracts, the former can be observed in isolation; we report a case with no lens opacities at age 38. Conversely, it is important to consider OPA3-related disease in individuals with bilateral infantile-onset cataracts and to assess optic nerve health in those whose vision fail to improve following lens surgery. The papillomacular bundle is primarily affected and vision is typically worse than 20/40. Notably, we describe one subject who retained normal acuities into the fifth decade of life. The condition can be associated with extraocular clinical features: two affected individuals in the present study had sensorineural hearing loss. The clinical heterogeneity observed in the individuals reported here (all having the same genetic defect in OPA3) suggests that the molecular pathology of the disorder is likely to be complex.


Report on an outbreak of postinjection abscesses due to Mycobacterium abscessus, including management with surgery and clarithromycin therapy and comparison of strains by random amplified polymorphic DNA polymerase chain reaction.
An outbreak of postinjection abscesses occurred in Barranquilla, Colombia, and was associated with local injections of lidocaine given in a single physician's office. Over a 5-month period, 350 (18%) of approximately 2,000 injected patients developed localized cutaneous abscesses or cellulitis; of 210 abscess specimens that were cultured, 205 were positive for rapidly growing mycobacteria, subsequently identified as Mycobacterium abscessus. The source of the outbreak was not identified. M. abscessus could not be characterized by pulsed-field gel electrophoresis, but all isolates were identical in terms of drug and heavy metal resistance patterns and random amplified polymorphic DNA PCR profiles. We believe this is the first report of the use of this latter technique for investigation of an outbreak due to M. abscessus. Therapy with a combination of surgical excision and 3-6 months' administration of clarithromycin was successful for 95% of 148 patients treated in this manner; in contrast, therapy was successful for less than one-third of patients treated with surgery alone or clarithromycin alone. This is the largest of the nine known outbreaks of postinjection abscesses that have occurred due to rapidly growing mycobacteria and is the first in which an effective method of therapy was demonstrated.


Accidental ingestion of a cholecalciferol-containing rodent bait in a dog.
A diagnosis of cholecalciferol toxicity in a young dog was made on the basis of adequate history and the finding of extremely elevated serum calcium levels. The traditional treatment of fluid therapy, diuresis and corticosteroids resulted in lowering the serum calcium levels over a 5-d period. The dog displayed clinical signs of severe depression, anorexia and intermittent vomiting during this time interval. Serum calcium levels rose on day 6 and remained elevated up until the dog was euthanized on day 9. Gross and histopathological examinations revealed diffuse metastatic mineralization throughout the body, particularly involving the lung, kidney, atria and stomach. The amount of cholecalciferol ingested was determined well below the lethal dose reported in dogs. This report indicates that young dogs may be much more susceptible to the lethal effects of this compound than initially believed.


Consensus dietary guidelines for healthy living and prevention of obesity, the metabolic syndrome, diabetes, and related disorders in Asian Indians.
India is undergoing rapid nutritional transition, resulting in excess consumption of calories, saturated fats, trans fatty acids, simple sugars, salt and low intake of fiber. Such dietary transition and a sedentary lifestyle have led to an increase in obesity and diet-related non-communicable diseases (type 2 diabetes mellitus [T2DM], cardiovascular disease [CVD], etc.) predominantly in urban, but also in rural areas. In comparison with the previous guidelines, these consensus dietary guidelines include reduction in the intake of carbohydrates, preferential intake of complex carbohydrates and low glycemic index foods, higher intake of fiber, lower intake of saturated fats, optimal ratio of essential fatty acids, reduction in trans fatty acids, slightly higher protein intake, lower intake of salt, and restricted intake of sugar. While these guidelines are applicable to Asian Indians in any geographical setting, they are particularly applicable to those residing in urban and in semi-urban areas. Proper application of these guidelines will help curb the rising "epidemics" of obesity, the metabolic syndrome, hypertension, T2DM, and CVD in Asian Indians.


An Edge-Fog Secure Self-Authenticable Data Transfer Protocol.
Development of the Internet of Things (IoT) opens many new challenges. As IoT devices are getting smaller and smaller, the problems of so-called "constrained devices" arise. The traditional Internet protocols are not very well suited for constrained devices comprising localized network nodes with tens of devices primarily communicating with each other (e.g., various sensors in Body Area Network communicating with each other). These devices have very limited memory, processing, and power resources, so traditional security protocols and architectures also do not fit well. To address these challenges the Fog computing paradigm is used in which all constrained devices, or Edge nodes, primarily communicate only with less-constrained Fog node device, which collects all data, processes it and communicates with the outside world. We present a new lightweight secure self-authenticable transfer protocol (SSATP) for communications between Edge nodes and Fog nodes. The primary target of the proposed protocol is to use it as a secure transport for CoAP (Constrained Application Protocol) in place of UDP (User Datagram Protocol) and DTLS (Datagram Transport Layer Security), which are traditional choices in this scenario. SSATP uses modified header fields of standard UDP packets to transfer additional protocol handling and data flow management information as well as user data authentication information. The optional redundant data may be used to provide increased resistance to data losses when protocol is used in unreliable networks. The results of experiments presented in this paper show that SSATP is a better choice than UDP with DTLS in the cases, where the CoAP block transfer mode is used and/or in lossy networks.


Osteogenic potential of BMP-2-releasing self-assembled membranes.
We report here the use of novel self-assembling collagen-hyaluronic acid (HyA) membranes to deliver bone morphogenetic protein-2 (BMP-2) for orthopedic applications. Prior work has demonstrated that collagen-HyA membranes are formed initially through electrostatic interactions between the oppositely charged collagen and HyA molecules, and that membrane growth is driven by osmotic pressure imbalances between the collagen and HyA solutions. The purpose of this study was to investigate the potential of incorporating charged growth factors such as BMP-2 within the membrane for regenerative medicine applications. Membrane material properties, protein mass loss, and release kinetics of BMP-2, as well as biocompatibility and osteogenic potential in vitro and in vivo using a subcutaneous mouse model were assessed. Scanning electron microscopy and mechanical testing confirmed no loss of structural or mechanical integrity upon BMP-2 incorporation into the membranes. Slow and steady release of the growth factor was demonstrated with 17% of total loaded BMP-2 released over the course of 49 days. To test biocompatibility and osteogenic potential in vitro, human mesenchymal stem cells were cultured on collagen-HyA membranes and showed greater proliferation rates (for up to 28 days) on membranes without BMP-2, but a greater alkaline phosphatase activity and osteocalcin production on membranes releasing BMP-2. In vivo subcutaneous implantation of the membranes showed a minimal immune response with osteoblasts and mineral deposits present in the ectopic site for BMP-2-releasing membranes, further demonstrating the potential of the BMP-2-releasing membranes to induce osteogenic differentiation. This study presents a novel strategy to create self-assembled membranes using two biocompatible molecules that can deliver bioactive agents in a sustained manner to induce a local regenerative response.


Oil-in-water microemulsions stabilized by 3-(N,N- dimethylalkylammonio)propanesulfonate surfactants of varying alkyl chain length: Solubilisation of testos-terone propionate.
Solubilisation of the poorly-water soluble drug, testosterone propionate, in co-surfactant-free, dilutable, oil-in-water microemulsions stabilized by zwitterionic surfactants of varying alkyl chain length, namely 3-(N,N-dimethyloctylammonio)propanesulfonate and 3-(N,N-dimethyldodecylammonio)propanesulfonate and containing one of four ethyl ester oils, has been investigated. Both 3-(N,N-dimethyloctylammonio)propanesulfonate and 3-(N,N-dimethyldodecylammonio)propanesulfonate-stabilized microemulsions containing two short chain length oils, ethyl butyrate and ethyl caprylate, while only 3-(N,N-dimethyldodecylammonio)propanesulfonate formed microemulsions incorporating the longer chain length oils, ethyl palmitate and ethyl oleate, albeit to a very much reduced extent. Significantly the microemulsions containing the short chain length oils, ethyl butyrate and ethyl caprylate solubilised more testosterone propionate than the corresponding micelles. However, an inverse correlation existed between testosterone propionate solubility in the bulk oil and solubilisation in the microemulsions, in that ethyl caprylate containing microemulsions solubilised more testosterone propionate than those containing an equivalent amount of ethyl butyrate, despite the drug being more soluble in ethyl butyrate. These results suggest that drug solubility in bulk oil is a poor indicator of drug solubility in microemulsions containing that oil, and whether or not the addition of oil improves drug solubility is dependent upon on how it is incorporated within the microemulsion. The longer the chain length of the oil, the more likely the oil is to form a core in the microemulsion droplet, resulting in an additional locus of drug solubilisation and the possibility of an enhanced solubilisation capacity.


Comparative pathogenesis of piscirickettsiosis in Atlantic salmon (Salmo salar L.) post-smolt experimentally challenged with LF-89-like and EM-90-like Piscirickettsia salmonis isolates.
Piscirickettsiosis (SRS) is the most prevalent bacterial disease in Chilean salmon aquaculture and is responsible for high economic losses. The aim of this study was to comparatively characterize the pathogenesis of SRS in post-smolt Atlantic salmon during the early and late stages of infection with Piscirickettsia salmonis LF-89-like (PS-LF-89) and EM-90-like (PS-EM-90) using a cohabitation challenge. The pathogenesis of cohabitant fish infected with the two isolates was relatively different due to cohabitant fish infected with PS-EM-90 showing higher cumulative mortality and shorter time until death compared with PS-LF-89 fish. PS-LF-89 caused an SRS infection characterized by kidney and liver lesions, whereas PS-EM-90 caused systemic and haemorrhagic disease characterized by kidney, liver, heart, brain, skeletal muscle and intestine lesions. Decreased serum concentration of total proteins and albumin as well as increased serum ALT, AST and creatinine levels in fish infected with both isolates confirmed that changes in liver and kidney function occurred during infection. Tissue damage, expressed as an SRS histoscore, showed a strong positive correlation with the bacterial load expressed as abundance of P. salmonis 16S rRNA transcripts in the livers and kidneys of fish affected with either isolate, but the correlation was significantly higher in fish infected with PS-EM-90. The results contribute to improving the understanding of the bacteria-host interaction.


Impact of temperature and time storage on the microbial detection of oral samples by Checkerboard DNA-DNA hybridization method.
Molecular diagnosis methods have been largely used in epidemiological or clinical studies to detect and quantify microbial species that may colonize the oral cavity in healthy or disease. The preservation of genetic material from samples remains the major challenge to ensure the feasibility of these methodologies. Long-term storage may compromise the final result. The aim of this study was to evaluate the effect of temperature and time storage on the microbial detection of oral samples by Checkerboard DNA-DNA hybridization. Saliva and supragingival biofilm were taken from 10 healthy subjects, aliquoted (n=364) and processed according to proposed protocols: immediate processing and processed after 2 or 4 weeks, and 6 or 12 months of storage at 4°C, -20°C and -80°C. Either total or individual microbial counts were recorded in lower values for samples processed after 12 months of storage, irrespective of temperatures tested. Samples stored up to 6 months at cold temperatures showed similar counts to those immediately processed. The microbial incidence was also significantly reduced in samples stored during 12 months in all temperatures. Temperature and time of oral samples storage have relevant impact in the detection and quantification of bacterial and fungal species by Checkerboard DNA-DNA hybridization method. Samples should be processed immediately after collection or up to 6 months if conserved at cold temperatures to avoid false-negative results.


Synthesis of α-glucan in mycobacteria involves a hetero-octameric complex of trehalose synthase TreS and Maltokinase Pep2.
Recent evidence established that the cell envelope of Mycobacterium tuberculosis, the bacillus causing tuberculosis (TB), is coated by an α-glucan-containing capsule that has been implicated in persistence in a mouse infection model. As one of three known metabolic routes to α-glucan in mycobacteria, the cytoplasmic GlgE-pathway converts trehalose to α(1 → 4),α(1 → 6)-linked glucan in 4 steps. Whether individual reaction steps, catalyzed by trehalose synthase TreS, maltokinase Pep2, and glycosyltransferases GlgE and GlgB, occur independently or in a coordinated fashion is not known. Here, we report the crystal structure of M. tuberculosis TreS, and show by small-angle X-ray scattering and analytical ultracentrifugation that TreS forms tetramers in solution. Together with Pep2, TreS forms a hetero-octameric complex, and we demonstrate that complex formation markedly accelerates maltokinase activity of Pep2. Thus, complex formation may act as part of a regulatory mechanism of the GlgE pathway, which overall must avoid accumulation of toxic pathway intermediates, such as maltose-1-phosphate, and optimize the use of scarce nutrients.


Structural and biochemical insights to the role of the CCR4-NOT complex and DDX6 ATPase in microRNA repression.
MicroRNAs (miRNAs) control gene expression by regulating mRNA translation and stability. The CCR4-NOT complex is a key effector of miRNA function acting downstream of GW182/TNRC6 proteins. We show that miRNA-mediated repression requires the central region of CNOT1, the scaffold protein of CCR4-NOT. A CNOT1 domain interacts with CNOT9, which in turn interacts with the silencing domain of TNRC6 in a tryptophan motif-dependent manner. These interactions are direct, as shown by the structure of a CNOT9-CNOT1 complex with bound tryptophan. Another domain of CNOT1 with an MIF4G fold recruits the DEAD-box ATPase DDX6, a known translational inhibitor. Structural and biochemical approaches revealed that CNOT1 modulates the conformation of DDX6 and stimulates ATPase activity. Structure-based mutations showed that the CNOT1 MIF4G-DDX6 interaction is important for miRNA-mediated repression. These findings provide insights into the repressive steps downstream of the GW182/TNRC6 proteins and the role of the CCR4-NOT complex in posttranscriptional regulation in general.


The effects of stress-induced cortisol responses on approach-avoidance behavior.
High glucocorticoid stress-responses are associated with prolonged freezing reactions and decreased active approach and avoidance behavior in animals. The present study was designed to investigate the effects of cortisol responses and trait avoidance on approach-avoidance behavior in humans. Twenty individuals were administered a computerized approach-avoidance (AA)-task before and after stress-induction (Trier Social Stress Test). The AA-task involved a reaction time (RT) task, in which participants made affect congruent and affect incongruent arm movements towards positive and threatening social stimuli. Affect congruent responses involved arm extension (avoidance) in response to angry faces and arm flexion (approach) in response to happy faces. Reversed responses were made in affect incongruent instruction conditions. As expected, participants with high cortisol responses showed significantly decreased RT congruency-effects in a context of social stress. Low trait avoidance was also associated with diminished congruency-effects during stress. However, the latter effect disappeared after controlling for the effects of cortisol. In sum, in agreement with animal research, these data suggest that high cortisol responses are associated with a decrease in active approach-avoidance behavior during stress. These findings may have important implications for the study of freezing and avoidance reactions in patients with anxiety disorders, such as social phobia and post-traumatic stress disorder.


Osteopenia and osteoporosis in patients with end-stage liver disease caused by hepatitis C and alcoholic liver disease: not just a cholestatic problem.
Although best characterized in chronic cholestatic liver disease, osteopenic bone disease and fracturing are well-recognized complications of cirrhosis, particularly after liver transplantation. We sought to compare the prevalence of osteopenia and osteoporosis, to assess the effect of orthotopic liver transplantation (OLT) on bone density, and to determine fracture rates before and after OLT in three groups of patients with advanced cirrhosis: patients with cirrhosis from hepatitis C virus (HCV) alone, from alcohol abuse (ALD), and from HCV in conjunction with alcohol abuse (HCV+ALD). Between 1991 and 2001, 207 consecutive patients who underwent OLT for HCV (68 patients), ALD (66), and HCV+ALD (73) were assessed clinically, biochemically, radiologically, and by bone densitometry. The baseline mean T score was lower in the HCV group than in the ALD group (-1.43 versus -0.87, P =.048) despite ALD patients having more advanced liver disease; patients with HCV+ALD had intermediate T scores. The pattern of significant bone loss at 4 months and 12 months was similar for all three groups. The baseline fracture rate was lowest in the HCV group and highest in the ALD group, despite the latter having the highest bone density. Fractures occurred in 17% of patients in the first year after transplantation, the majority being vertebral compression fractures. Patients with cirrhosis caused by HCV, ALD, or a combination of both should be screened for osteopenia, especially before OLT.


Student learning about UK health services in a cross-border curriculum partnership; the London-Cyprus experience.
This article was migrated. The article was marked as recommended. Purpose of the article Cross border partnerships require curricula, faculty and students to negotiate challenges associated with national regulatory frameworks, contexts and cultures. This study investigated student attitude and behaviours when encountering learning about health services in host and home students in the context of problem based learning. Materials and Methods First year graduate entry students' health systems interest and exposure and their perceptions of the dynamics of learning in PBL were investigated via a questionnaire comprising open and closed questions. Results and Conclusions Results showed a difference between home and host students in the ways they learned about home health systems and their attitudes to the value of learning about home and international health systems. There was no difference in the quantity of health service related learning objectives generated. Both groups reported noticing differences between the PBL cases and clinical practice, however, perceptions of the reasons for the differences varied between home and host students. We are interested in the way in which this perception of difference was reported as either a stimulus or a barrier to learning.


Nitric oxide acutely inhibits neuronal energy production. The Committees on Neurobiology and Cell Physiology.
Disruption of mitochondrial respiration has been proposed as an action of nitric oxide (NO) responsible for its toxicity, but the effects of NO on the energetics of intact central neurons have not been reported. We examined the effects of NO on mitochondrial function and energy metabolism in cultured hippocampal neurons. The application of NO from NO donors or from dissolved gas produced a rapid, reversible depolarization of mitochondrial membrane potential, as detected by rhodamine-123 fluorescence. NO also produced a progressive concentration-dependent depletion of cellular ATP over 20 min exposures. The energy depletion produced by higher levels of NO (2 microM or more) was profound and irreversible and proceeded to subsequent neuronal death. In contrast to the effects of NO, mitochondrial protonophores produced complete depolarizations of mitochondrial membrane potential but depleted the neuronal ATP stores only partially. Inhibitors of mitochondrial oxidative phosphorylation (rotenone or 3-nitropropionic acid) or of glycolysis (iodoacetate plus pyruvate) also produced only partial ATP depletion, suggesting that either process alone could partially maintain ATP stores. Only by combining the inhibition of glycolytic energy production with the inhibition of mitochondria could the effects of NO in depleting energy and inducing delayed toxicity be duplicated. These results show that NO has rapid inhibitory actions on mitochondrial metabolism in living neurons. However, the severe ATP-depleting effects of high concentrations of NO are not fully explained by the direct effects on mitochondrial activity alone but must involve the inhibition of glycolysis as well. These inhibitory effects on energy production may contribute to the delayed toxicity of NO in vitro and in ischemic stroke.


Pharmacokinetic Evaluation of a Cannabidiol Supplement in Horses.
Cannabidiol (CBD) products have gained popularity among horse owners despite limited evidence regarding pharmacokinetics. The purpose of this study was to describe the pharmacokinetic profile of multiple doses of an orally administered cannabidiol product formulated specifically for horses. A randomized 2-way crossover design was used. Seven horses received 0.35 or 2.0 mg/kg CBD per os every 24 hours for 7 total doses, separated by a 2-week washout. Plasma CBD and delta-9-tetrahydrocannabinol (THC) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) daily through day 10, then on day 14 after beginning CBD administration. On the final day of CBD administration, plasma CBD and THC were quantified at multiple times. After administration of 0.35 mg/kg of CBD, the Cmax of CBD was 6.6 ± 2.1 ng/mL while Tmax was 1.8 ± 1.2 hour, whereas the Cmax for THC was 0.7 ± 0.6 ng/mL with a Tmax of 2.5 ± 1 hour. After administration of 2.0 mg/kg of CBD, the Cmax of CBD was 51 ± 14 ng/mL with a mean Tmax of 2.4 ± 1.1 hour and terminal phase half-life of 10.4 ± 6 hour, whereas the Cmax of THC was 7.5 ± 2.2 ng/mL with a Tmax of 2.9 ± 1.1 hour. Oral administration of a cannabidiol product at 0.35 mg/kg or 2.0 mg/kg once daily for 7 days was well-tolerated. Based on plasma CBD levels obtained, dose escalation trials in the horse evaluating clinical efficacy at higher mg/kg dose rates are indicated.


Anti cariogenic effect of terminalia chebula.
Terminalia chebula is one of the traditional medicines used in the treatment of many diseases and possesses a wide variety of therapeutic activities. The aim of this study was to determine the antimicrobial properties of Terminalia chebula against oral pathogens related to caries. In this study, Antimicrobial activity was tested using Kirby bouer method by streaking. Total phenol and total flavonoid content were analysed. Twenty high caries risk patients were subjected to rinse aqueous extract of Terminalia chebula. Salivary samples were collected for pH and microbial screening. Oral pathogens were identified by qualitative biochemical analysis. The total phenol content of extract was found to be 21.33 ±1.633 (mean ± SD) and total flavonoids was found to be 23.17 ± 2.317 (mean ± SD). There was a gradual increase in pH till 45mts post-rinse when compared to pre-rinse was observed. Antimicrobial effect of Terminalia Chebula aganist microbes showed that there was a significant reduction between the pre-rinse and post-rinse samples. These promising findings suggested the presence of antimicrobial activity of Terminalia Chebula against oral pathogens and proven to be an effective alternate antimicrobial agent.


Risk factors for primary Helicobacter pylori resistance in Bulgarian children.
Risk factors for primary Helicobacter pylori resistance in 186 children with gastroduodenal diseases (44 from villages/small towns and 130 from large towns/cities) in 2000-2003 were tested. Susceptibility was tested by a limited agar dilution method. Overall resistance rates to metronidazole, clarithromycin, tetracycline and both metronidazole and clarithromycin were 14.5, 11.9, 3.3 and 4.3 %, respectively. No amoxycillin resistance was observed. Tetracycline resistance was found in six children aged 7-18 years. Clarithromycin resistance was more common in children from small towns/villages (22.7 %) than in those from large towns/cities (8.5 %, P < 0.05). There were no significant differences (P > 0.05) in resistance rates between children from northern Bulgaria and those from southern regions. Resistance rates in duodenal ulcer patients and other children were, respectively, 10.5 and 15 % (P > 0.20) for metronidazole and 10.5 and 12 % (P > 0.20) for clarithromycin. No combined resistance to metronidazole and clarithromycin was found in 22 children aged 1-7 years and in 34 children living in northern Bulgaria. There were no significant associations of resistance with sex and age group (1-7- versus 8-18-year-old children) for all antibacterial agents tested. In conclusion, primary H. pylori resistance was absent (for metronidazole + clarithromycin) or low (4.5 % for clarithromycin) in children aged 1-7 years. Place of residence was associated with clarithromycin resistance rates.


Endometrial cancer in the family-cancer database.
Endometrial cancer was studied in the Swedish Family-Cancer Database, updated in 1999 to cover individuals born after 1934 with their biological parents, totaling 9.6 million persons. Cancer data were obtained from the Swedish Cancer Registry from 1958 to 1996 and included over 20,000 cases of endometrial cancer. Seventy-six families were identified in which both the mother and the daughter had endometrial cancer, giving a familial standardized incidence ratio (SIR) of 3.19 for daughters and 2.78 for mothers. The risk depended inversely on the age at diagnosis, and the risk was almost 10 in daughters who were diagnosed before age 50 when their mothers were also diagnosed before that age. The discordant cancer site that associated with endometrial cancer between the two generations was colon, with a SIR of 1.44-1.68. However, when the maternal endometrial cancer was diagnosed before age 50, increased SIRs were observed in daughters or sons for rectal, pancreatic, nervous system, breast, and ovarian cancers. Second cancers were followed in females diagnosed with endometrial cancer, and the highest overall risks were observed for ovarian and connective tissue cancers; colorectal cancers were also clearly in excess. Among the other family members of the 76 families in which both mother and daughter were affected with endometrial cancer, there were 11 cases of colorectal cancer. When a sister was affected in such families, the SIR of endometrial cancer was 31.40, and the median diagnostic age was several years lower than in endometrial cancer families in which no colorectal cancers were found. Many of these families may have hereditary nonpolyposis colorectal carcinoma syndrome. However, the risk of endometrial cancer was increased even in families presenting no colorectal cancers.


Prevalence of common disease-associated variants in Asian Indians.
Asian Indians display a high prevalence of diseases linked to changes in diet and environment that have arisen as their lifestyle has become more westernized. Using 1200 genome-wide polymorphisms in 432 individuals from 15 Indian language groups, we have recently shown that: (i) Indians constitute a distinct population-genetic cluster, and (ii) despite the geographic and linguistic diversity of the groups they exhibit a relatively low level of genetic heterogeneity. We investigated the prevalence of common polymorphisms that have been associated with diseases, such as atherosclerosis (ALOX5), hypertension (CYP3A5, AGT, GNB3), diabetes (CAPN10, TCF7L2, PTPN22), prostate cancer (DG8S737, rs1447295), Hirschsprung disease (RET), and age-related macular degeneration (CFH, LOC387715). In addition, we examined polymorphisms associated with skin pigmentation (SLC24A5) and with the ability to taste phenylthiocarbamide (TAS2R38). All polymorphisms were studied in a cohort of 576 India-born Asian Indians sampled in the United States. This sample consisted of individuals whose mother tongue is one of 14 of the 22 "official" languages recognized in India as well as individuals whose mother tongue is Parsi, a cultural group that has resided in India for over 1000 years. Analysis of the data revealed that allele frequency differences between the different Indian language groups were small, and interestingly the variant alleles of ALOX5 g.8322G>A and g.50778G>A, and PTPN22 g.36677C>T were present only in a subset of the Indian language groups. Furthermore, a latitudinal cline was identified both for the allele frequencies of the SNPs associated with hypertension (CYP3A5, AGT, GNB3), as well as for those associated with the ability to taste phenylthiocarbamide (TAS2R38). Although caution is warranted due to the fact that this US-sampled Indian cohort may not represent a random sample from India, our results will hopefully assist in the design of future studies that investigate the genetic causes of these diseases in India. Our results also support the inclusion of the Indian population in disease-related genetic studies, as it exhibits unique genotype as well as phenotype characteristics that may yield new insights into the underlying causes of common diseases that are not available in other populations.


How physician/administrator teams work in small groups. Six steps to make it happen.
The physician/administrator team is frequently supported as the preferred model for physician group governance. Perhaps an obvious model for large groups, it remains true that the largest percentage of physicians are practicing in groups of 10 or fewer. This article explores the applicability of the physician/administrator team concept for small group practices. The article covers the significance of the physician/administrator team in managed care settings, difference in governance structures between large and small groups, the need for physicians to be willing to share leadership in organizations they own, understanding empowerment in small groups, the manager's need to assume more responsibility and how to form the team.


Pinning of fermionic occupation numbers.
The Pauli exclusion principle is a constraint on the natural occupation numbers of fermionic states. It has been suspected since at least the 1970s, and only proved very recently, that there is a multitude of further constraints on these numbers, generalizing the Pauli principle. Here, we provide the first analytic analysis of the physical relevance of these constraints. We compute the natural occupation numbers for the ground states of a family of interacting fermions in a harmonic potential. Intriguingly, we find that the occupation numbers are almost, but not exactly, pinned to the boundary of the allowed region (quasipinned). The result suggests that the physics behind the phenomenon is richer than previously appreciated. In particular, it shows that for some models, the generalized Pauli constraints play a role for the ground state, even though they do not limit the ground-state energy. Our findings suggest a generalization of the Hartree-Fock approximation.


Practice guidelines for management of cervical cancer in Korea: a Korean Society of Gynecologic Oncology Consensus Statement.
Clinical practice guidelines for gynecologic cancers have been developed by academic society from several countries. Each guideline reflected their own insurance system and unique medical environment, based on the published evidence. The Korean Society of Gynecologic Oncology (KSGO) published the first edition of practice guidelines for gynecologic cancer treatment in late 2006; the second edition was released in July 2010 as an evidence-based recommendation. The Guidelines Revision Committee was established in 2015 and decided to develop the third edition of the guidelines in an advanced format based on evidence-based medicine, embracing up-to-date clinical trials and qualified Korean data. These guidelines cover strategies for diagnosis and treatment of primary and recurrent cervical cancer. The committee members and many gynecologic oncologists derived key questions through discussions, and a number of relevant scientific literature were reviewed in advance. Recommendations for each specific question were developed by the consensus conference, and they are summarized here, along with the details. The objective of these practice guidelines is to establish standard policies on issues in clinical practice related to the management in cervical cancer based on the results in published papers to date and the consensus of experts as a KSGO Consensus Statement.


A combination of astragaloside I, levistilide A and calycosin exerts anti-liver fibrosis effects in vitro and in vivo.
Liver fibrosis is excessive accumulation of extracellular matrix proteins that results from various chronic liver diseases. Hepatic stellate cells (HSCs) play an essential role in the pathogenesis of liver fibrosis. Danggui Buxue Tang (DBT) is a classic formula of Chinese traditional medicine. We previously showed that DBT could ameliorate liver fibrosis in rats. However, the bioactive components of DBT in the treatment of liver fibrosis remain unknown. In this study we evaluated 14 ingredients from DBT in human hepatic stellate cell line LX-2, and found that astragaloside I (A), levistilide A (L) and calycosin (C) produced synergistic proliferation inhibition on LX-2 cells and TGF-β1-activated LX-2 cells. Thus, we prepared a mixture of them, and named this combination as ALC formula. Using high-content screening and Western blot assay we revealed that the ALC formula significantly reduced the expression of α-SMA and collagen I in LX-2 cells. The in vivo anti-fibrosis effects of ALC formula were evaluated in a liver fibrosis model in C57BL/6 mice established through injection of dimethylnitrosamine (DMN 2 mg/kg, ip) for 4 weeks. In the third week, the nice were injected with ALC formula (astragaloside I 44.21 mg/kg per day, levistilide A 6 mg/kg per day and calycosin 3.45 mg/kg per day; ip) or sorafenib, a positive control drug (6 mg/kg per day, ip) for 2 weeks. We found that administration of the ALC formula markedly decreased collagen deposition, hydroxyproline (Hyp) content and α-SMA expression levels in the liver tissues compared to the model mice. In conclusion, the present study demonstrates for the first time that astragaloside I, levistilide A and calycosin may be the 3 main bioactive components in DBT; their combination exerts anti-liver fibrosis effects in vitro and in vivo.


Behavior-dependent directional tuning in the human visual-navigation network.
The brain derives cognitive maps from sensory experience that guide memory formation and behavior. Despite extensive efforts, it still remains unclear how the underlying population activity unfolds during spatial navigation and how it relates to memory performance. To examine these processes, we combined 7T-fMRI with a kernel-based encoding model of virtual navigation to map world-centered directional tuning across the human cortex. First, we present an in-depth analysis of directional tuning in visual, retrosplenial, parahippocampal and medial temporal cortices. Second, we show that tuning strength, width and topology of this directional code during memory-guided navigation depend on successful encoding of the environment. Finally, we show that participants' locomotory state influences this tuning in sensory and mnemonic regions such as the hippocampus. We demonstrate a direct link between neural population tuning and human cognition, where high-level memory processing interacts with network-wide visuospatial coding in the service of behavior.


Second cancer following cancers of the buccal cavity and pharynx in Connecticut, 1935-1982.
Patients diagnosed in Connecticut from 1935 to 1982 with cancers of the tongue, gum, floor, and other parts of the mouth, or pharynx experienced twofold to threefold increased risks of developing a second primary cancer. The excesses were most prominent [relative risk (RR) greater than or equal to 10] for subsequent oral and esophageal cancers but also were observed for cancers at other sites in the digestive and respiratory tracts. The increased risks, which affected both men and women and persisted over time, are most likely related to increased alcohol and tobacco consumption in the patients developing second primaries. The proportion of persons developing a new primary was 9% among the 2,120 patients with cancer of the tongue, 14% for the 3,063 patients with cancer in the gum, floor, or other parts of the mouth, and 8% among the 2,637 persons with pharynx cancer. If one considers that the average length of follow-up was only 3.4 years, these percentages are high and indicate the need for continued surveillance of patients with oral and pharyngeal cancers. Small overall excesses of subsequent cancer occurred among patients with initial lip (RR = 1.3) or salivary gland cancers (RR = 1.2), with twofold risks of oral and respiratory cancers evident for both tumors.


Implant design and intraosseous stability of immediately placed implants: a human cadaver study.
The objective of this study was to explore effects of implant macrodesign and diameter on initial intraosseous stability and interface mechanical properties of immediately placed implants. Mandibular premolars of four fresh-frozen human cadavers were extracted. Ø 4.1/4.8 mm ITI TE, Ø 4.1 and 4.8 mm solid screw synOcta ITI implants were placed into freshly prepared extraction sockets. Resonance frequency analysis was conducted to quantify primary implant stability quotient (ISQ). Installation torque value (ITV) and removal torque value (RTV) of the implants were measured using a custom-made strain-gauged torque wrench connected to a data acquisition system at a sample rate of 10,000 Hz. The vertical defect depth around the collar of each implant was measured directly by an endodontic spreader. The bone-implant contact was determined in digitalized images of periapical radiographs and expressed as percentage bone contact. The ISQ values of the TE implant was higher than the Ø 4.1 mm implant (P<0.01), and comparable with the Ø 4.8 mm implants (P>0.05). ITVs and RTVs of TE and Ø 4.8 mm implants were higher than the Ø 4.1 mm implant, although the differences between groups were statistically insignificant (P>0.05). The vertical defect depths around all types of implants were similar. In the radiographic analyses, percentage bone-implant contact of the TE and Ø 4.8 mm implants were comparable at the marginal bone region and both were higher than that of the Ø 4.1 mm ITI implant. Nonparametric correlations between groups revealed a significant correlation between ITV and RTV (r=0.838; P<0.001), but not between ISQ values and ITVs and RTVs (P>0.05). Immediately placed ITI TE implant leads to initial intraosseous stability and interface mechanical properties comparable with a wide diameter implant.


Comparative primate reproductive endocrinology: advancements important in domestic breeding programs.
Recent advancements in primate reproductive endocrinology were reviewed with special emphasis given to hormonal patterns indicative of ovulation, technics for early pregnancy diagnosis, comparison of steroidal and gonadotropic hormonal patterns among various primates during advanced gestation, and identification of the individual contributions of the maternal, fetal, and placental compartments to the hormonal milieu of pregnancy. Each of these topics was examined according to its application to the management aspects of primate breeding.


Nesting behavior of Centris (Hemisiella) vittata Lepeletier (Hymenoptera: Apidae) in an area of the Cerrado in the northeast of the State of Maranhão, Brazil.
The nesting behavior of Centris (Hemisiella) vittata Lepeletier was studied in the Urbano Santos Cerrado in the northeast of Maranhão State, Brazil. To date, this species has only been studied in trap-nests. The nesting behavior of this species in a natural condition is recorded for the first time. Nesting occurred in preexisting holes in dead trunks of aroeira, Astronium myracrodruon (Anacardiaceae), at the end of the rainy season. The cells were constructed with a mixture of sand and oil. After finishing the nests, females used only oil to line the entrance wall. Two females collected sand at the same time to build their nests, and another one was seen collecting resources at Byrsonima sp. (Malpighiaceae). The pollen load of one bee was analyzed and was found to contain mainly Hymenaea courbaril (Leg-Caesalpiniaceae). Development from egg to adult took about 60 days. Protandry was observed, being males smaller than females. The nests were parasitized by Coleoptera and Diptera. However, the females only showed aggressive behavior against females of the same species or genus.


Urokinase-type plasminogen activator contributes to amiloride-sensitive sodium retention in nephrotic range glomerular proteinuria in mice.
Activation of sodium reabsorption by urinary proteases has been implicated in sodium retention associated with nephrotic syndrome. The study was designed to test the hypothesis that nephrotic proteinuria in mice after conditional deletion of podocin leads to urokinase-dependent, amiloride-sensitive plasmin-mediated sodium and water retention. Ten days after podocin knockout, urine and faeces were collected for 10 days in metabolic cages and analysed for electrolytes, plasminogen, protease activity and ability to activate γENaC by patch clamp and western blot. Mice were treated with amiloride (2.5 mg kg-1 for 2 days and 10 mg kg-1 for 2 days) or an anti-urokinase-type plasminogen activator (uPA) targeting antibody (120 mg kg-1 /24 h) and compared to controls. Twelve days after deletion, podocin-deficient mice developed significant protein and albuminuria associated with increased body wt, ascites, sodium accumulation and suppressed plasma renin. This was associated with increased urinary excretion of plasmin and plasminogen that correlated with albumin excretion, urine protease activity co-migrating with active plasmin, and the ability of urine to induce an amiloride-sensitive inward current in M1 cells in vitro. Amiloride treatment in podocin-deficient mice resulted in weight loss, increased sodium excretion, normalization of sodium balance and prevention of the activation of plasminogen to plasmin in urine in a reversible way. Administration of uPA targeting antibody abolished urine activation of plasminogen, attenuated sodium accumulation and prevented cleavage of γENaC. Nephrotic range glomerular proteinuria leads to urokinase-dependent intratubular plasminogen activation and γENaC cleavage which contribute to sodium accumulation.


Prosthetic rehabilitation of extensive facial defects.
Patients with extensive surgical defects of the palate, orbit, or nose are difficult to rehabilitate. Prosthetic rehabilitation in these areas often shortens hospitalization, speeds recovery, and reduces medical expenses. Specific factors in planning treatment are directed toward successful prosthetic rehabilitation, using a team approach, careful patient selection, and specific surgical principles keyed to each facial region.


Responses of neurons in VPL and VPL-VL region of the cat to algesic stimulation of muscle and tendon.
1. The responses evoked by electrical stimulation of cutaneous and muscle nerves, by noxious and innocuous mechanical stimulation of muscle, tendon, and cutaneous tissues, and by intra-arterial (ia) injection of algesic substances (potassium, bradykinin) into arteries supplying the gastrocnemius-soleus muscle (GS) were studied in single neurons located in the ventroposterolateral nucleus (VPL) and in the transitional zone between VPL and the ventrolateral nucleus (VL) of cats lightly anesthetized with thiopenthal. Such chemical stimulation of the muscles has been shown to activate muscular groups III and IV axons specifically (43, 44) and presumably is nociceptive in character (14, 17, 31). 2. One hundred eight neurons were tested. Eighty-three of the units responded only to various types of cutaneous stimulation of the hindlimb. The other 25 responded to algesic stimulation of muscle and/or tendon. Of these latter 25, 7 had no apparent cutaneous receptive field although 4 of them responded to electrical stimulation of the common peroneal and/or sural nerve. Thus, only three neurons responded exclusively to algesic chemical and noxious mechanical stimulation of the muscle. Of the other 18 neurons, 14 had cutaneous receptive fields restricted to the hindlimb and often responded to non-noxious repetitive light stroking and to noxious pinching with a high-frequency discharge. Four cells (two of which had cutaneous input only from low-threshold mechanoreceptors) had complex and large receptive fields extending to more than one limb. 3. Potassium was a more potent muscle receptor stimulant than bradykinin, the latter only weakly exciting 3 neurons of 24 tested with both substances. The responses to potassium were rapid (approximately 4.0 s in latency) and tended to be greater (have higher response rates) for the units that responded to cutaneous as well as muscle/tendon stimulation. 4. Most neurons that responded to noxious deep stimulation had a threshold for the GS nerve volley in the group III fiber range. The few neurons with thresholds slightly below the group III range did not respond to activation of group I or II muscle spindle afferents by intra-arterial application of succinylcholine or by stretching the muscle. 5. Neurons with responses to any of the muscle, tendon, or cutaneous nociceptive stimuli were located at the ventral and dorsal periphery of VPL and in the VPL-VL transitional zone. 6. These results strongly suggest that there exist regions within the lateral diencephalon of cats that are capable of processing nociceptive information and that these regions are located at the periphery of VPL.


Formononetin ameliorates muscle atrophy by regulating myostatin-mediated PI3K/Akt/FoxO3a pathway and satellite cell function in chronic kidney disease.
Muscle atrophy is a common complication in chronic kidney disease (CKD). Inflammation and myostatin play important roles in CKD muscle atrophy. Formononetin (FMN), which is a major bioactive isoflavone compound in Astragalus membranaceus, exerts anti-inflammatory effects and the promotion of myogenic differentiation. Our study is based on myostatin to explore the effects and mechanisms of FMN in relation to CKD muscle atrophy. In this study, CKD rats and tumour necrosis factor α (TNF-α)-induced C2C12 myotubes were used for in vivo and in vitro models of muscle atrophy. The results showed that FMN significantly improved the renal function, nutritional status and inflammatory markers in CKD rats. Values for bodyweight, weight of tibialis anterior and gastrocnemius muscles, and cross-sectional area (CSA) of skeletal muscles were significantly larger in the FMN treatment rats. Furthermore, FMN significantly suppressed the expressions of MuRF-1, MAFbx and myostatin in the muscles of CKD rats and the TNF-α-induced C2C12 myotubes. Importantly, FMN significantly increased the phosphorylation of PI3K, Akt, and FoxO3a and the expressions of the myogenic proliferation and differentiation markers, myogenic differentiation factor D (MyoD) and myogenin in muscles of CKD rats and the C2C12 myotubes. Similar results were observed in TNF-α-induced C2C12 myotubes transfected with myostatin-small interfering RNA (si-myostatin). Notably, myostatin overexpression plasmid (myostatin OE) abolished the effect of FMN on the phosphorylation of the PI3K/Akt/FoxO3a pathway and the expressions of MyoD and myogenin. Our findings suggest that FMN ameliorates muscle atrophy related to myostatin-mediated PI3K/Akt/FoxO3a pathway and satellite cell function.


Congenital arhinia.
Congenital absence of the nose or arhinia is a rare defect of embryogenesis, often associated with other anomalies. It is potentially a life-threatening condition and requires the presence of a highly skilled neonatal resuscitation team at the time of delivery. The associated anomalies often have a significant impact on the immediate as well as long-term outcome of the neonate. Parental counselling is thus vital and a multidisciplinary team approach is required to optimise the neonatal outcome. A neonate with congenital arhinia is reported and the literature reviewed to suggest guidelines for the management of such cases.


Perspectives of Pediatric Providers Regarding Clinical Use of Pharmacogenetics.
A major goal of the current personalized medicine era is to utilize pharmacogenetics (PGx) in order to influence how medications and therapies are prescribed by providers. However, disparities for prescribing medications between adults and children exist. Research has shown that children are not just small adults and there are different challenges for pediatric providers in regards to ordering and interpreting PGx tests. The goal of this study was to obtain an initial understanding of current pharmacogenetic testing by pediatric providers, as well as determine perceived barriers. We distributed an online survey to pediatric providers at six different institutions across the U.S. Of the 252 respondents who completed the survey, 24 percent reported previously ordering PGx tests, however, over 90 percent of respondents reported they would feel more comfortable ordering and interpreting results with the assistance of a pharmacist, geneticist, genetic counselor or PGx expert. Additionally, participants identified specific barriers towards the utilization of PGx testing, as well as suggested solutions to overcome these barriers, including increasing provider education regarding testing, collaboration through a multidisciplinary team approach and established PGx programs. As the pharmacogenetic field continues to demonstrate clinical utility in the pediatric population, it will be important to continuously identify and address barriers that exist for providers to allow for more successful implementation of PGx in the pediatric setting, as well as enhance patient care.


Bessel annular apodizers: imaging characteristics.
Apodizers with relatively high transmittance over an annular region of the exit pupil can reduce the sensitivity to defocusing and to spherical aberration [Opt. Lett. 11, 487 (1986)]. Here, we analyze the imaging properties (pupil functions, point spread functions, optical transfer functions, and Strehl ratios) of the Bessel type of annular apodizers. We also show some computer-simulated images, obtained with and without this kind of annular apodizer.


Tumor targeting with a (99m)Tc-labeled AS1411 aptamer in prostate tumor cells.
AS1411, a 26-base guanine-rich oligonucleotide aptamer, has high affinity to nucleolin, mainly on tumor cell surfaces. In this study, a modified AS1411 was labeled with (99m)Tc and evaluated as a potential tumor-targeting agent for imaging. The AS1411 aptamer was conjugated with HYNIC and labeled with (99m)Tc in the presence a co-ligand. Radiochemical purity and stability testing of the (99m)Tc-HYNIC-AS1411 aptamer were carried out with thin layer chromatography and a size-exclusion column in normal saline and human serum. Cellular nucleolin-specific binding, cellular internalization in DU-145 cells, as high levels of nucleolin expression, were performed. Additionally, biodistribution in normal mice and DU-145 tumour-bearing mice was assessed. Radiolabeling of the aptamer resulted in a reasonable yield and radiochemical purity after purification. The aptamer was stable in normal saline and human serum, and cellular experiments demonstrated specific binding of the AS1411 aptamer to the nucleolin protein. Based on biodistribution assessment of (99m)Tc-HYNIC-AS1411, rapid blood clearance was seen after injection and it appears that the excretion route was via the urinary system at 1 h post-injection. Tumours also showed a higher accumulation of radioactivity with this labeled aptamer. (99m)Tc-AS1411 can be a potential tool for the molecular imaging of nucleolin-overexpressing cancers.


A high-throughput effector screen identifies a novel small molecule scaffold for inhibition of ten-eleven translocation dioxygenase 2.
Ten-eleven translocation dioxygenases (TETs) are the erasers of 5-methylcytosine (mC), the central epigenetic regulator of mammalian DNA. TETs convert mC to three oxidized derivatives with unique physicochemical properties and inherent regulatory potential, and it initializes active demethylation by the base excision repair pathway. Potent small molecule inhibitors would be useful tools to study TET functions by conditional control. To facilitate the discovery of such tools, we here report a high-throughput screening pipeline and its application to screen and validate 31.5k compounds for inhibition of TET2. Using a homogenous fluorescence assay, we discover a novel quinoline-based scaffold that we further validate with an orthogonal semi-high throughput MALDI-MS assay for direct monitoring of substrate turnover. Structure-activity relationship (SAR) studies involving >20 derivatives of this scaffold led to the identification of optimized inhibitors, and together with computational studies suggested a plausible model for its mode of action.


Erythrocyte microtubule assembly in vitro. Determination of the effects of erythrocyte tau, tubulin isoforms, and tubulin oligomers on erythrocyte tubulin assembly, and comparison with brain microtubule assembly.
Two tubulin variants, isolated from chicken brain and erythrocytes and known to have different peptide maps and electrophoretic properties, are demonstrated to exhibit different assembly properties in vitro: 1) erythrocyte tubulin assembles with greater efficiency (lower critical concentration, greater elongation rate) but exhibits a lower nucleation rate than brain tubulin, and 2) erythrocyte tubulin readily forms oligomers whose presence significantly retards the rate of elongation, suggesting that tubulin oligomers may also be important for determining the rate of assembly and the length of microtubules in erythrocytes. Erythrocyte tubulin isolated by cycles of in vitro assembly-disassembly is also demonstrated to contain a 67-kDa tau factor that greatly enhances microtubule nucleation but has little effect on elongation rates or critical concentration. Immunofluorescence microscopy with tau antibody indicates that tau is specifically associated with marginal band microtubules, suggesting that it may be important for determining microtubule function in vivo.


Phase synchronization in a sparse network of randomly connected neurons under the effect of Poissonian spike inputs.
This article investigates the emergence of phase synchronization in a network of randomly connected neurons by chemical synapses. The study uses the classic Hodgkin-Huxley model to simulate the neuronal dynamics under the action of a train of Poissonian spikes. In such a scenario, we observed the emergence of irregular spikes for a specific range of conductances and also that the phase synchronization of the neurons is reached when the external current is strong enough to induce spiking activity but without overcoming the coupling current. Conversely, if the external current assumes very high values, then an opposite effect is observed, i.e., the prevention of the network synchronization. We explain such behaviors considering different mechanisms involved in the system, such as incoherence, minimization of currents, and stochastic effects from the Poissonian spikes. Furthermore, we present some numerical simulations where the stimulation of only a fraction of neurons, for instance, can induce phase synchronization in the non-stimulated fraction of the network, besides cases in which for larger coupling values, it is possible to propagate the spiking activity in the network when considering stimulation over only one neuron.


Trends in postacute care and staffing in US nursing homes, 2001-2010.
The objective of this study was to document the growth of postacute care and contemporaneous staffing trends in US nursing homes over the decade 2001 to 2010. We integrated data from all US nursing homes longitudinally to track annual changes in the levels of postacute care intensity, therapy staffing and direct-care staffing separately for freestanding and hospital-based facilities. All Medicare/Medicaid-certified nursing homes from 2001 to 2010 based on the Online Survey Certification and Reporting System database merged with facility-level case mix measures aggregated from resident-level information from the Minimum Data Set and Medicare Part A claims. We created a number of aggregate case mix measures to approximate the intensity of postacute care per facility per year, including the proportion of SNF-covered person days, number of admissions per bed, and average RUG-based case mix index. We also created measures of average hours per resident day for physical and occupational therapists, PT/OT assistants, PT/OT aides, and direct-care nursing staff. In freestanding nursing homes, all postacute care intensity measures increased considerably each year throughout the study period. In contrast, in hospital-based facilities, all but one of these measures decreased. Similarly, therapy staffing has risen substantially in freestanding homes but declined in hospital-based facilities. Postacute care case mix acuity appeared to correlate reasonably well with therapy staffing levels in both types of facilities. There has been a marked and steady shift toward postacute care in the nursing home industry in the past decade, primarily in freestanding facilities, accompanied by increased therapy staffing.


Attitudes toward help-seeking and duration of untreated mental disorders in a sectorized Athens area of Greece.
The purpose of the present study was to investigate the association of opinions towards seeking psychiatric help with the duration of untreated mental disorders in a sectorized Athens area, served by a Community Mental Health Centre. The sample consisted of 134 individuals who had sought help from health or mental health non sectorized services prior to their visit to the Centre (group A) and 156 individuals whose visit to the Center was their first ever contact with a mental health service (group B). Opinions were assessed by the "Attitudes Toward Seeking Professional Psychological Help scale. Both groups were selected from a total of 1,008 individuals who had visited the Centre in four consecutive years. The duration of untreated mental disorders was found to be shorter in group A compared to group B. Males and females of both groups, who had visited the Centre in a time period shorter than 12 months since the onset of their psychopathology, expressed more positive views towards help-seeking, compared to their counterparts with longer duration of untreated mental disorder. The variables of gender (females), age at symptom onset (younger) and education (higher) predicted a shorter duration without psychiatric treatment and more positive views about the necessity of help-seeking. More severe type of diagnoses was associated with shorter durations before accessing care. Our findings underline that mental health awareness programs are clearly required in order to strengthen the early recognition of the need for help- seeking. The development of liaison and outreach activities could also prevent prolonged delays in psychiatric treatment.


Rapid Bacterial Detection during Endodontic Treatment.
Bacteria present in the root canal (RC) space following an RC treatment (RCT) can lead to persistent infections, resulting in treatment failure and the need for reintervention or extraction. Currently, there are no standardized methods in use to clinically detect bacterial presence within RC spaces. The use of paper point sampling and fluorescence staining was shown to be a rapid method, able to detect residual bacteria following treatment. The study demonstrated that Calcein acetoxymethyl (AM) proved to be a suitable dye for detecting vital bacteria within mature endodontic biofilms, with an improved sensitivity over colony-forming unit counting in a stressed biofilm model. Furthermore, in a clinical trial with primary RCTs, 53 infected teeth were sampled in vivo, and increased detection of vital cells was found when compared with colony-forming unit counting, highlighting the sensitivity of the technique in detecting low cell numbers. By combining fluorescent staining and microspectroscopy with software-based spectral analysis, successful detection of vital cells from RCs was possible after 5 min of Calcein AM incubation. Application of this technology during RCT has the potential to reduce persistent infections through vital cell detection and additional treatment. Furthermore, this technique could be applied to antimicrobial research and disinfection control in clinical settings ( ClinicalTrials.gov NCT03055975).


[FRancilian Oncogeriatric Group (FROG)'s focus on management of elderly patients with bladder cancer].
Bladder cancer is diagnosed more often in the elderly. The most effective treatment strategies are mostly very aggressive and are not applicable to all patients in a very heterogeneous population. However, effective options exist to treat the most vulnerable subjects. A multidisciplinary approach including a geriatric assessment is essential for optimal adaptation of treatment. The FRancilian Oncogeriatric Group (FROG) conducted a comprehensive literature search in order to review the applicable therapeutic options according to oncological and geriatric settings. International recommendations are essential to harmonize the management of elderly patients with bladder cancer.


Clocking the Lyme spirochete.
In order to clear the body of infecting spirochetes, phagocytic cells must be able to get hold of them. In real-time phase-contrast videomicroscopy we were able to measure the speed of Borrelia burgdorferi (Bb), the Lyme spirochete, moving back and forth across a platelet to which it was tethered. Its mean crossing speed was 1,636 microm/min (N = 28), maximum, 2800 microm/min (N = 3). This is the fastest speed recorded for a spirochete, and upward of two orders of magnitude above the speed of a human neutrophil, the fastest cell in the body. This alacrity and its interpretation, in an organism with bidirectional motor capacity, may well contribute to difficulties in spirochete clearance by the host.


The mechanism of altered neural function in a rat model of acute colitis.
Distal colitis induced in rats by trinitrobenzene sulfonic acid (TNBS) causes a suppression of [3H]noradrenaline release from the myenteric plexus, of inflamed distal colon, as well as in noninflamed regions of colon and ileum. The aim of this study was to explore the mechanisms underlying these neural changes in TNBS colitis. Colitis was induced by intrarectal administration of TNBS, and the animals were killed on day 5. Inflammation was assessed by measuring myeloperoxidase (MPO) activity, and noradrenaline release was measured as 3H release from rats myenteric plexus preparations preloaded with [3H]noradrenaline. These end points were examined: (1) after administration of the locally active steroid budesonide; (2) in congenitally athymic rats; and (3) in rats treated with the interleukin 1 receptor antagonist (IL-1ra) to interleukin 1 beta. In colitis, both topical budesonide and systemic IL-1ra treatments attenuated the suppression of KCl-evoked 3H release from longitudinal muscle myenteric plexus in both inflamed and noninflamed segments. However, neither of these treatments altered MPO activity. A similar suppression of [3H]noradrenaline release was observed in athymic rats after TNBS, although there was a substantially greater increase in MPO activity compared with euthymic rats with colitis. TNBS-induced colitis alters myenteric nerve function at inflamed and noninflamed sites via a steroid-sensitive and interleukin 1-mediated process that does not require T lymphocytes.