Effect of degree of methoxylation and particle size on compression properties and compactibility of pectin powders.
This study examines the effect of the degree of methoxylation (DM) and particle size on compression properties and compactibility of pectin powders. A powder classification system based on sequential handling of compression parameters was applied. A single size fraction (90-125 μm) of pectin powders with DM values ranging from 5-72% was studied. For DM 25%, the effect of different particle size fractions (180-250, 125-180, 90-125, 63-90, 45-63, <45 μm) were investigated. Compression parameters were derived based on time-resolved force-displacement data using Heckel, Kawakita and Shapiro equations. Volume-specific surface area was estimated for powders and tablets. Tablet tensile strength was determined. It was found that all pectin powders displayed low degrees of particle rearrangement and relatively low degrees of fragmentation (class IIA materials). Pectin particles were found to be relatively soft, with a tendency towards softer particles for pectins of higher DM. The overall variation in fragmentation and deformation behavior was limited. Both DM and initial particle size affected the tensile strength of pectin tablets. The difference in surface hydrophobicity caused by the DM was suggested as being responsible for the variation in the mechanical strengths. The study shows that pectin grades with DM ≤ 40% are potential direct compression excipients.


Comparison of the single assessment numeric evaluation method and the Lysholm score.
The purpose of this study was to determine the correlation between the Lysholm knee score and the Single Assessment Numeric Evaluation method. Between March 1995 and December 1996, 201 followup examinations were performed on 130 college age patients who had undergone anterior cruciate ligament reconstructions. These 201 examinations were divided into five routine followup categories: 3 months, 6 months, 1 year, 2 years, and greater than 2 years. The Lysholm score from each patient's followup questionnaire was correlated with his or her Single Assessment Numeric Evaluation rating, as determined by his or her written response to the following question: On a scale from zero to 100, how would you rate your knee today (100 being normal)? All data were gathered prospectively. The mean Lysholm scores and Single Assessment Numeric Evaluation ratings ranged from 84.0 to 93.4 points and 80.0 to 93.3 points, respectively. The correlation coefficients between the Lysholm scores and the Single Assessment Numeric Evaluation ratings ranged from 0.58 to 0.87 points. The results of this study indicate that Single Assessment Numeric Evaluation ratings correlate well with measured Lysholm scores in patients with anterior cruciate ligament reconstruction. The Single Assessment Numeric Evaluation provides clinicians with an alternative mechanism to gather outcomes data with little demand on time and resources.


Retrospective survey on the prevalence and outcome of prior autoimmune diseases in patients with aplastic anemia reported to the registry of the European group for blood and marrow transplantation.
Aplastic anemia (AA) is rarely described after a diagnosis of autoimmune disease (aID). To assess the prevalence of prior aID in patients with AA recorded in the registry of the European Group for Blood and Marrow Transplantation (EBMT) and to evaluate treatment and outcome. 1,251 AA patients from 18 EBMT centers were assessed. Fifty patients (4%) were eligible: 22 males and 28 females with a median age of 46 years at the diagnosis of aID and of 51 years at the diagnosis of AA. Information on the treatment of AA was available in 49 patients: 38 received only immunosuppressive therapy (IST), 8 patients underwent hematopoietic stem cell transplantation (HSCT) - 6 as first-line therapy and 2 after failure of IST - whilst 3 patients had a spontaneous recovery. After a median follow-up of 3.19 years, 32 patients were alive, including 7 of the 8 patients who underwent HSCT. Only 6 of 32 patients who were alive at the last follow-up were receiving IST for AA. Most cases of AA following aID benefitted from IST or HSCT if a matched donor was available. Further prospective investigation is needed to assess the effects of IST on the outcome of underlying aID.


[Role of intermediate products of prothrombin proteolysis by thrombin in the stimulation of the anticoagulation system of blood].
Two components - the intermediate product 1 (P-1) converting under certain conditions into thrombin, and product 2 (P-2) which possesses no such properties were isolated from the products of prothrombin proteolysis by thrombin. The intravenous injection of the P-1 to rats lengthened the blood coagulation time and plasma recalcification. The sum total fibrinolytic activity proved to increase and the fibrinogen concentration - to decrease. A sharp 5-fold rise of the nonfermentative fibrinolysis was observed. It seems that this effect of the anticoagulating and fibrinolytic potential mobilization was stimulated by the response of the second anticoagulating blood system.


Mathematical modeling of toxicity problems in aquaria.
The identification of an actual or potential toxicity problem in an aquatic system immediately poses several questions of practical importance. Is the toxic agent still being added to the system? Where is the toxin coming from? Are the current filtration systems removing it? How soon will it be reduced to an acceptable level? How can it be removed faster? These questions in turn suggest an equally important question. What samples should be examined? Analysis of animal tissues from bioassays is the most common investigative technique in use, but alternatives do exist. Testing of water has not been utilized to its fullest potential. The need for an orderly approach to sampling and interpretation has been a major factor in this under utilization. Mathematical modeling through the use of toxicokinetics can be used to maximize the efficiency of analysis of a toxic accident by water sampling. Strategies of sampling and interpretation of results will be discussed using the tools of toxicokinetic modeling.


Occupational exposures to polycyclic aromatic hydrocarbons and respiratory and urinary tract cancers: an updated systematic review and a meta-analysis to 2014.
Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with an excess risk of respiratory tract and bladder cancers in several industries, but the issue requires further quantification. We updated a previous systematic review by reviewing in details cohort studies on workers employed in selected industries with potential PAH exposure published between 2006 and 2014, and we summarized through a meta-analytic approach the main results of all available cohort studies published between 1958 and 2014 investigating cancers of the respiratory and urinary tracts. Thirteen papers on cohort studies investigating cancer risk in workers exposed to PAHs were retrieved through the literature search. These included workers from aluminum production industries (seven studies), iron and steel foundries (two studies), asphalt workers (two studies), and carbon black production (two studies). In the meta-analysis, an excess risk of respiratory tract cancers (mainly lung cancer) was found in iron and steel foundries [pooled relative risk (RR) 1.31, 95 % confidence interval (CI) 1.08-1.59 from 14 studies], while a weak excess risk (pooled RR 1.08, 95 % CI 0.95-1.23 from 11 studies) emerged for aluminum production. A borderline increase risk was also observed for cancer of the bladder in the aluminum production (pooled RR 1.28, 95 % CI 0.98-1.68 from 10 studies) and in iron and steel foundries (pooled RR 1.38, 95 % CI 1.00-1.91 from 9 studies). This updated review and meta-analysis confirm the increased risk from respiratory tract and bladder cancers in selected PAH-related occupations. It cannot be ruled out whether such excesses are due, at least in part, to possible bias or residual confounding.


The structural origin of the unusual compression behaviors in nanostructured TiO2: insights from first-principles calculations.
First-principles calculations of anatase structured TiO2 and ZrO2 as well as of TiO2-B were carried up to 20 GPa in order to develop an understanding of the unusual compression and pressure-dependent phase transitions reported for nanocrystalline (nc) pure and Zr-doped anatase and nc TiO2-B. The computations, carried out using two global hybrid density functional-Hartree-Fock formulations and all-electron basis sets, reveal sharp lattice hardening along the crystallographic a direction and concurrent lattice softening along c for anatase TiO2 at 10-12 GPa, and smooth anisotropic compression for ZrO2 anatase. Significant structural changes beginning at ∼10 GPa are also predicted for TiO2-B, most dramatically shown by the pressure-dependent change in the monoclinic angle β. These structural changes, resulting from intrinsic crystal structure destabilization under extended pressure metastability, have been suggested as being responsible for the unusual mechanical behaviors reported for pure and Zr-doped nanocrystalline and microcrystalline anatase TiO2 and nc TiO2-B.


Evaluation of different testing tools for the identification of non-gonococcal Neisseria spp. isolated from Lebanese male semen: a strong and significant association with infertility.
The aim was to evaluate several microbiological tools for the identification of non-gonococcal Neisseria spp. isolated from semen samples from Lebanese men and to determine the putative link between the presence of Neisseria commensal species and infertility. Within a cross-sectional retrospective study design, the whole population included in this investigation was divided in 2 categories: 173 patients with symptoms of infertility and 139 patients with normal seminograms. Epidemiological and microbiological investigations were performed for 59 strains of Neisseria through several phenotypic and genotypic tools, including seminograms, an analytical profile index of Neisseria and Haemophilus (API-NH), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), porA PCR, 16S rRNA and rplF gene sequencing, and antimicrobial susceptibility testing. The risk of Neisseria infection was twice as high in infertile patients compared to the control group [odds ratio (OR): 1.95, confidence interval (CI): 1.05-3.65, P =0.03]. Unreliable diagnosis of Neisseria urogenital infection has serious health and social consequences. Our findings showed that API-NH and 16S rRNA sequencing are poor tools to identify Neisseria at the species level. Therefore, reliable diagnosis of cases using MALDI-TOF MS and/or rplF sequencing is needed to provide critical treatment decisions and prevent antimicrobial resistance spreading in the community. This work predicted a strong and significant association between the presence of Neisseria spp. in semen and male infertility among the Lebanese population. For a better understanding of this association, it is recommended that more genomic and large-scale epidemiological investigations are undertaken to reach definitive conclusions.


A Computational Model of the Rainbow Trout Hypothalamus-Pituitary-Ovary-Liver Axis.
Reproduction in fishes and other vertebrates represents the timely coordination of many endocrine factors that culminate in the production of mature, viable gametes. In recent years there has been rapid growth in understanding fish reproductive biology, which has been motivated in part by recognition of the potential effects that climate change, habitat destruction and contaminant exposure can have on natural and cultured fish populations. New approaches to understanding the impacts of these stressors are being developed that require a systems biology approach with more biologically accurate and detailed mathematical models. We have developed a multi-scale mathematical model of the female rainbow trout hypothalamus-pituitary-ovary-liver axis to use as a tool to help understand the functioning of the system and for extrapolation of laboratory findings of stressor impacts on specific components of the axis. The model describes the essential endocrine components of the female rainbow trout reproductive axis. The model also describes the stage specific growth of maturing oocytes within the ovary and permits the presence of sub-populations of oocytes at different stages of development. Model formulation and parametrization was largely based on previously published in vivo and in vitro data in rainbow trout and new data on the synthesis of gonadotropins in the pituitary. Model predictions were validated against several previously published data sets for annual changes in gonadotropins and estradiol in rainbow trout. Estimates of select model parameters can be obtained from in vitro assays using either quantitative (direct estimation of rate constants) or qualitative (relative change from control values) approaches. This is an important aspect of mathematical models as in vitro, cell-based assays are expected to provide the bulk of experimental data for future risk assessments and will require quantitative physiological models to extrapolate across biological scales.


Clinical trial registry use in anaesthesiology systematic reviews: A cross-sectional study of systematic reviews published in anaesthesiology journals and the Cochrane Library.
Publication bias within systematic reviews may result in incorrect conclusions leading to inappropriate clinical decisions and a decreased quality of patient care. Searching clinical trial registries for unpublished studies is one possible solution to minimise publication bias. To examine rates of clinical trial registry searches in systematic reviews published in respected anaesthesiology journals and whether these searches found trials (or data) eligible for inclusion; to compare rates of registry searches between published reviews and similar reviews within the Cochrane Anaesthesia, Critical and Emergency Care Group; to conduct trial registry searches for a subset of reviews, determining whether eligible studies were overlooked; to investigate whether reporting of results in completed anaesthesia trials on ClinicalTrials.gov followed guidelines. A cross-sectional study of systematic reviews published in 10 anaesthesiology journals and the Cochrane Library. PubMed and the Cochrane Library were searched for systematic reviews or meta-analyses. The primary outcome was the number of systematic reviews that searched clinical trial registries for unpublished trials. Secondary outcomes included the number of registered trials in the ClinicalTrial.gov registry and the number of trials reporting trial results which were available on the ClinicalTrials.gov database and which should have been considered in a systematic review. The PubMed search yielded 507 records, and 415 remained after exclusions. Of these, 49 (11.8%) included a search of clinical trial registries. In total, 12 systematic reviews reported finding unpublished data but only five incorporated the data into their analyses. Of the Cochrane reviews, 58.9% (43/73) reported registry searches. Among a sample of 30 systematic reviews that omitted registry searches, we found many studies within the registries that were probably eligible to be included in the systematic reviews. For completed trials within the ClinicalTrials.gov database, only 15.4% reported results. The majority of systematic reviews in anaesthesiology did not include data from clinical trial registries. Exclusion of statistically nonsignificant data may lead to a biased interpretation of the data and hence inappropriate clinical interventions. Registered in University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000021932).


Okadaic acid increases fibronectin synthesis in MC3T3-E1 cells.
Okadaic acid, a potent specific inhibitor of serine/threonine protein phosphatases type 1 and 2A, affects several gene expressions in various cells. To determine whether okadaic acid affects the expression of fibronectin in MC3T3-E1 cells, we measured mRNA level and synthesis of fibronectin by Northern blot hybridization and immunoprecipitation methods, respectively. Okadaic acid (10-50 ng/ml) increased both mRNA level and synthesis of fibronectin in a dose-dependent manner. The increase of fibronectin mRNA by okadaic acid was strongly attenuated by the inhibition of new protein synthesis. The results indicate that okadaic acid, inhibitor of protein phosphatases, increases fibronectin synthesis in MC3T3-E1 cells.


A protocol for a single center, randomized, controlled trial comparing the clinical efficacy of 3% diquafosol and 0.1% hyaluronic acid in diabetic patients with dry eye disease.
The global prevalence of diabetes mellitus (DM) continues to rise and 70% of diabetic individuals have dry eye disease (DED) that leads to subsequent abnormalities of the corneal epithelium, corneal nerves, tear film, or corneal endothelium. In addition, persons with diabetes produce fewer tear secretions than healthy individuals. While several anti-inflammatory drug-based therapies for dry eye in diabetic individuals are currently being administered, their efficacy has not been studied in detail. Therefore, the aim of this study was to compare the effectiveness of 3% diquafosol (DQS) vs 0.1% hyaluronic acid (HA) eye drops in diabetic dry eye patients. This triple-blind randomized, control trial will include 202 diabetic-related DED and will be assigned to DQS (n = 101) and HA (n = 101) one drop, six times per day for 8 weeks. Tear film lipid layer, non-invasive breakup time, conjunctivocorneal staining score, corneal sensitivity, tear MMP-9 levels, meibomian gland expression and quality, tear meniscus height, corneal nerves, immune/inflammatory cell change, conjunctival hyperemia, and ocular surface disease index questionnaire score will be assessed and compared at baseline, week 4, and week 8. This study will be a standardized, scientific, clinical trial designed to evaluate the therapeutic effects and safety of DQS and HA for diabetic dry eye treatment. ClinicalTrials.govNCT05682547. Registered on December 05, 2022.


Multiple sclerosis de novo CNS IgG synthesis. Effect of CNS irradiation.
Megavoltage CNS irradiation was given to 20 patients with clinically definite multiple sclerosis (MS) to determine if de novo CNS IgG synthesis could be eradicated. In all five patients given 1,200 rads, a transient reduction in the de novo CNS IgG synthesis rate was noted. In ten patients given 1,800 rads, the following occurred: a reduction in synthesis rate in three patients, a reduction followed by enhancement in two, only enhancement in four, and no change in one. In all five additional patients, a therapy of adrenocorticotropic hormone (ACTH) followed by prednisone in combination with 1,800 rads produced greater and more persistent decreases in CNS IgG synthesis, but did not block the enhancement effect. Only two of 19 patients who had abnormal CNS IgG synthesis rates had reductions to normal; no patients showed changes in the number or pattern CSF IgG oligoclones. Hence, no treatment eradicated de novo CNS IgG synthesis. A persistent decrease in CSF leukocytes occurred in all 20 patients due to the reduction of small lymphocytes (not dose related). The blood-brain-barrier to albumin concentration was transiently damaged in 11 of 15 patients given irradiation, but when patients were premedicated with ACTH/prednisone therapy, no damage was found. None of the patients demonstrated neurological improvement, change in the activity of their disease, or persistent adverse effects.


[Girls with fragile X syndrome: a model for specific developmental disorders].
The prevalence of specific developmental disorders (SDD) in everyday practice is high, and an interdisciplinary approach is required for their diagnosis and management. The ultimate pathophysiology of these disorders remains a great challenge to researchers and progress is limited by the fact that there are no experimental models that reproduce the cognitive-behavioural complexity of the human being. Girls with fragile X syndrome, which has a wide range of cognitive-behavioural signs and symptoms that allow the clinical features of SDD to coincide in the same person, in whom the intellectual quotient is preserved and for whom our present knowledge of the syndrome does offer pathophysiological structural bases in the central nervous system, may constitute a valuable model to help us understand SDD.


Effects of High-Frequency rTMS on Negative Symptoms and Cognitive Function in Hospitalized Patients With Chronic Schizophrenia: A Double-Blind, Sham-Controlled Pilot Trial.
This study aimed to evaluate the efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral pre-frontal cortex (DLPFC) in ameliorating negative symptoms and cognitive impairments in patients with chronic schizophrenia. Fifty-two patients with chronic schizophrenia were randomly assigned to two groups: active rTMS group and sham rTMS group, with existing antipsychotic drugs combined 20 sessions of 10 Hz active/sham rTMS over DLPFC (20 min/session, 5 times/week). The PANSS, RBANS, and SCWT were used to evaluate the clinical symptoms and cognitive functions of the patients. Our results indicated significant improvements in clinical symptoms (PANSS total and subscale scores) and cognitive functions (RBANS total and subscale scores, card 1 and card 3 of the SCWT test) (All p <0.05) after 4-week intervention both in active and sham rTMS group. Moreover, the active rTMS group showed more effective on ameliorating negative symptoms (p = 0.002), immediate memory (p = 0.016) and delayed memory (p = 0.047) compared to the sham group. Interestingly, PANSS negative symptom scores was negatively correlated with RBANS language scores in the real stimulation group (p = 0.046). The study found that the high frequency rTMS stimulation over left DLPFC as a supplement to antipsychotics may have potential benefits in improving clinical symptoms and cognitive functions in patients with chronic schizophrenia.


Patients' and Clinicians' Perceptions of Antibiotic Prescribing for Upper Respiratory Infections in the Acute Care Setting.
Reducing inappropriate prescribing is key to mitigating antibiotic resistance, particularly in acute care settings. Clinicians' prescribing decisions are influenced by their judgments and actual or perceived patient expectations. Fuzzy trace theory predicts that patients and clinicians base such decisions on categorical gist representations that reflect the bottom-line understanding of information about antibiotics. However, due to clinicians' specialized training, the categorical gists driving clinicians' and patients' decisions might differ, which could result in mismatched expectations and inefficiencies in targeting interventions. We surveyed clinicians and patients from 2 large urban academic hospital emergency departments (EDs) and a sample of nonpatient subjects regarding their gist representations of antibiotic decisions, as well as relevant knowledge and expectations. Results were analyzed using exploratory factor analysis (EFA) and multifactor regression. In total, 149 clinicians (47% female; 74% white), 519 online subjects (45% female; 78% white), and 225 ED patients (61% female; 56% black) completed the survey. While clinicians demonstrated greater knowledge of antibiotics and concern about side effects than patients, the predominant categorical gist for both patients and clinicians was "why not take a risk," which compares the status quo of remaining sick to the possibility of benefit from antibiotics. This gist also predicted expectations and prior prescribing in the nonpatient sample. Other representations reflected the gist that "germs are germs" conflating bacteria and viruses, as well as perceptions of side effects and efficacy. Although individually rational, reliance on the "why not take a risk" representation can lead to socially suboptimal results, including antibiotic resistance and individual patient harm due to adverse events. Changing this representation could alter clinicians' and patients' expectations, suggesting opportunities to reduce overprescribing.


The Association between Vitamin D Insufficiency and Nonalcoholic Fatty Liver Disease: A Population-Based Study.
Previous studies have shown inconsistent results regarding the association between vitamin D insufficiency and nonalcoholic fatty liver disease (NAFLD). We attempted to demonstrate this relationship using population-based data. Vitamin D insufficiency was defined as a 25(OH)D level ≤20 ng/mL. Hepatic steatosis index was calculated to define NAFLD. Significant fibrosis was assessed using Body mass index, AST/ALT Ratio, Diabetes (BARD) score. Logistic regression analyses were performed to determine the relationship between vitamin D insufficiency and NAFLD. Among 1812 participants, 409 (22.6%) had NAFLD. Patients with nonalcoholic fatty liver disease were more likely to be male (56.7%), had higher body mass index (28.1 kg/m²), and had more metabolic syndrome (57.2%). The proportion of vitamin D insufficiency did not differ between NAFLD and non-NAFLD (77.5% vs. 77.4%). Logistic regression analyses showed that BMI, diabetes, and triglyceride level were significantly associated with NAFLD, whereas vitamin D insufficiency was not related. Subgroup analyses involving non-obese participants, male participants, and participants without metabolic syndrome showed similar results. The BARD score and the proportion of significant fibrosis by BARD score did not differ according to vitamin D status. Vitamin D insufficiency was not associated with the presence of NAFLD as assessed by validated noninvasive prediction models.


Insertional mutagenesis and development of malignancies induced by integrating gene delivery systems: implications for the design of safer gene-based interventions in patients.
Effective gene-based interventions for the treatment of genetic disorders, neurodegenerative diseases and cardiovascular maladies require longterm transgene expression in target cells. Integrating viral vector systems based on the genera of the retroviridae and on adeno-associated virus are suitable tools, as the integration of viral vector genomes into the cellular chromosomal DNA allows for a more stable and long-lasting transgene expression than episomal gene-delivery models. Two nonviral gene-delivery systems with integrating properties have also been developed. These are based on the Sleeping Beauty DNA transposon system and on the Streptomyces bacteriophage integrase phiC31. However, the integration of recombinant vector systems may damage the natural genetic arrangement of the target cell. Such genetic alterations are termed insertional mutagenesis, which might result in malignant cell transformation. Insertional mutagenesis caused leukemia in five patients who participated in clinical trials for the treatment of severe combined immunodeficiency (SCID)-X1; sadly, one of the patients died. Gene therapists had to assess the real risk-versus-benefit ratio for the use of retroviral vectors in patients and devise novel strategies to minimize the occurrence of insertional mutagenesis-related malignancies. In this respect, a particular emphasis was placed on the engineering of enhancer-less self-inactivating retroviridae-based systems.


Comparison of radiances observed from satellite and aircraft with calculations by using two atmospheric transmittance models.
An evaluation of two different atmospheric transmittance models is performed by using radiance data from the high-resolution infraRed Sounder (HIRS) instrument onboard the National Oceanic and Atmospheric Administration's NOAA-9 satellite and the airborne high-resolution interferometer sounder (HIS) instrument. Synthetic radiances have been derived from collocated radiosondes by using the television infrared observation satellite (TIROS) operational vertical sounder (TOVS) operational transmittance model and the fast atmospheric signature code (FASCOD2) line-by-line transmittance model for comparison with the two independent instrument observations. Radiance observations in various spectral channels from the HIRS and HIS instruments along with the synthetic radiances derived from the FASCOD2 and operational TOVS transmittance models are used for the performance evaluation. The results of the comparison reveal a significant discrepancy between 707 and 717 cm(-l) in the radiance calculation for both models. Exce llent agreement is observed between observation and calculation for the lower tropospheric long-wave temperature sounding channels. Serious problems are noted with the modeling of water vapor in the operational TOVS transmittance model. In addition, poor performance by FASCOD2 is revealed for the short-wavelength N(2)O-CO(2) HIRS spectral channels. In general the operational TOVS transmittance model is found to be only slightly inferior to the FASCOD2 model. Regarding the performance of the instruments, observations from the NOAA-9 HIRS and the aircraft HIS are comparable in terms of their agreement with theoretical computations.


A Padawan Programmer's Guide to Developing Software Libraries.
With the rapid adoption of computational tools in the life sciences, scientists are taking on the challenge of developing their own software libraries and releasing them for public use. This trend is being accelerated by popular technologies and platforms, such as GitHub, Jupyter, R/Shiny, that make it easier to develop scientific software and by open-source licenses that make it easier to release software. But how do you build a software library that people will use? And what characteristics do the best libraries have that make them enduringly popular? Here, we provide a reference guide, based on our own experiences, for developing software libraries along with real-world examples to help provide context for scientists who are learning about these concepts for the first time. While we can only scratch the surface of these topics, we hope that this article will act as a guide for scientists who want to write great software that is built to last.


2,2',4'-trihydroxychalcone from Glycyrrhiza glabra as a new specific BACE1 inhibitor efficiently ameliorates memory impairment in mice.
Alzheimer's disease (AD) characterizes a progressive neurodegenerative disorder of the brain, while AD patients are afflicted with irreversible loss of neurons and further the intellectual abilities including memory and reasoning. One of the typical hallmarks of AD is the deposition of senile plaque that is contributed mainly by amyloid-beta (Abeta), whose production is initiated by beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1). Inhibition of BACE1 is thereby regarded as an attractive strategy for anti-AD drug discovery. Here, we reported that the natural product 2,2',4'-trihydroxychalcone (TDC) from Glycyrrhiza glabra functioned as a specific non-competitive inhibitor against BACE1 enzyme, and potently repressed beta-cleavage of APP and production of Abeta in human embryo kidney cells-APPswe cells. Moreover, the amelioration ability of this compound against the in vivo memory impairment was further evaluated by APP-PS1 double transgenic mice model. It is discovered that treatment of 9 mg/kg/day of TDC could obviously decrease Abeta production and Abeta plaque formation, while efficiently improve the memory impairment based on Morris water maze test. Our findings thus demonstrated that the natural product TDC as a new BACE1 inhibitor could ameliorate memory impairment in mice, and is expected to be potentially used as a lead compound for further anti-AD reagent development.


Agromyces flavus sp. nov., an actinomycete isolated from soil.
A gram-positive, non-motile strain, designated CPCC 202695(T), was isolated from a soil sample collected from the Qinghai-Tibet plateau, north-west China. Strain CPCC 202695(T) contained rhamnose, glucose and galactose in the cell wall as diagnostic sugars and 2,4-diaminobutyric acid, alanine, glutamic acid and glycine in the peptidoglycan. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol and two unknown glycolipids. MK-12 was the predominant menaquinone and anteiso-C(15 : 0) (34.2 %), iso-C(15 : 0) (19.8 %), iso-C(16 : 0) (12.7 %) and anteiso-C(17 : 0) (11.1 %) were the major fatty acids. 16S rRNA gene sequence similarities (94.2-97.1 %) between the isolate and the type strains of recognized species of the genus Agromyces indicated that strain CPCC 202695(T) was a member of the genus Agromyces. DNA-DNA relatedness clearly separated strain CPCC 202695(T) from its closest relatives. The phenotypic and genotypic data demonstrated that strain CPCC 202695(T) represents a novel species of the genus Agromyces, for which the name Agromyces flavus sp. nov. is proposed. The type strain is CPCC 202695(T) ( = KCTC 19578(T) = CCM 7623(T)).


Low level laser therapy (classes I, II and III) in the treatment of rheumatoid arthritis.
Rheumatoid arthritis (RA) affects a large proportion of the population. Low Level Laser Therapy (LLLT) was introduced as an alternative non-invasive treatment for RA about 10 years ago. LLLT is a light source that generates extremely pure light, of a single wavelength. The effect is not thermal, but rather related to photochemical reactions in the cells. The effectiveness of LLLT for rheumatoid arthritis is still controversial. To assess the effectiveness of LLLT in the treatment of RA. We searched MEDLINE, EMBASE, the registries of the Cochrane Musculoskeletal group and the field of Rehabilitation and Related Therapies as well as the Cochrane Controlled Trials Register up to January 30, 2000. Following an a priori protocol, we selected only randomized controlled trials of LLLT for the treatment of patients with a clinical diagnosis of RA were eligible. Abstracts were excluded unless further data could be obtained from the authors. Two reviewers independently select trials for inclusion, then extracted data and assessed quality using predetermined forms. Heterogeneity was tested with Cochran's Q test. A fixed effects model was used throughout for continuous variables, except where heterogeneity existed, in which case, a random effects model was used. Results were analyzed as weighted mean differences (WMD) with 95% confidence intervals (CI), where the difference between the treated and control groups was weighted by the inverse of the variance. Standardized mean differences (SMD) were calculated by dividing the difference between treated and control by the baseline variance. SMD were used when different scales were used to measure the same concept (e.g. pain). Dichotomous outcomes were analyzed with odds ratios. A total of 204 patients were included in the five placebo-controlled trials, with 112 randomized to laser therapy. Relative to a separate control group, LLLT reduced pain by 70% relative to placebo and reduced morning stiffness duration by 27.5 minutes (95%CI: 2.9 to 52 minutes) and increased tip to palm flexibility by 1.3 cm (95% CI: 0. 8 to 1.7 cm). Other outcomes such as functional assessment, range of motion and local swelling did not differ between groups. There were no significant differences between subgroups based on LLLT dosage, wavelength, site of application or treatment length. For RA, relative to a control group using the opposite hand, there was no difference between the control and treatment hand, but all hands improved in terms of pain relief and disease activity. In summary, LLLT for RA is beneficial as a minimum of a four-week treatment with reductions in pain and morning stiffness. On the one hand, this meta-analysis found that pooled data gave some evidence of a clinical effect, but the outcomes were in conflict, and it must therefore be concluded that firm documentation of the application of LLLT in RA is not possible. Clinicians and researchers should consistently report the characteristics of the LLLT device and the application techniques used. New trials on LLLT should make use of standardized, validated outcomes. Despite some positive findings, this meta-analysis lacked data on how LLLT effectiveness is affected by four important factors: wavelength, treatment duration of LLLT, dosage and site of application over nerves instead of joints.


Figure-ground perception in the awake mouse and neuronal activity elicited by figure-ground stimuli in primary visual cortex.
Figure-ground segregation is the process by which the visual system identifies image elements of figures and segregates them from the background. Previous studies examined figure-ground segregation in the visual cortex of monkeys where figures elicit stronger neuronal responses than backgrounds. It was demonstrated in anesthetized mice that neurons in the primary visual cortex (V1) of mice are sensitive to orientation contrast, but it is unknown whether mice can perceptually segregate figures from a background. Here, we examined figure-ground perception of mice and found that mice can detect figures defined by an orientation that differs from the background while the figure size, position or phase varied. Electrophysiological recordings in V1 of awake mice revealed that the responses elicited by figures were stronger than those elicited by the background and even stronger at the edge between figure and background. A figural response could even be evoked in the absence of a stimulus in the V1 receptive field. Current-source-density analysis suggested that the extra activity was caused by synaptic inputs into layer 2/3. We conclude that the neuronal mechanisms of figure-ground segregation in mice are similar to those in primates, enabling investigation with the powerful techniques for circuit analysis now available in mice.


There is no convincing evidence that working memory training is effective: A reply to Au et al. (2014) and Karbach and Verhaeghen (2014).
The possible cognitive benefits of working memory training programs have been the subject of intense interest and controversy. Recently two meta-analyses have claimed that working memory training can be effective in enhancing cognitive skills in adulthood (Au et al. Behavioural Brain Research 228:(1) 107-115, 2014) and stemming cognitive decline in old age (Karbach & Verhaeghen Psychological Science 25:2027-2037, 2014). The current article critically evaluates these claims. We argue that these meta-analyses produce misleading results because of (1) biases in the studies included, (2) a failure to take account of baseline differences when calculating effect sizes, and (3) a failure to emphasize the difference between studies with treated versus untreated control groups. We present new meta-analyses and conclude that there is no convincing evidence that working memory training produces general cognitive benefits.


Spinal interleukin-24 contributes to neuropathic pain after peripheral nerve injury through interleukin-20 receptor2 in mice.
Neuroinflammation is critically involved in nerve injury-induced neuropathic pain, characterized by local and systemic increased levels of proinflammatory cytokines. Interleukin-24 (IL-24), a key member of the IL-10 family, has been extensively studied for its therapeutic potential in various diseases, including cancer, autoimmune disorders, and bacterial infections, but whether it is involved in the regulation of neuropathic pain caused by peripheral nerve injury (PNI) has not been well established. In this study, we reported that spared nerve injury (SNI) induced a significant upregulation of IL-24 in fibroblasts, neurons, and oligodendrocyte precursor cells (OPCs, also called NG2-glia) in the affected spinal dorsal horns (SDHs), as well as dorsal root ganglions (DRGs). We also found that tumor necrosis factor α (TNF-α) induced the transcriptional expression of IL-24 in cultured fibroblasts, neurons, and NG2-glia; in addition, astrocytes, microglia, and NG2-glia treated with TNF-α exhibited a prominent increase in interleukin-20 receptor 2 (IL-20R2) expression. Furthermore, we evaluated the ability of IL-24 and IL-20R2 to attenuate pain in preclinical models of neuropathic pain. Intrathecal (i.t.) injection of IL-24 neutralizing antibody or IL-20R2 neutralizing antibody could effectively alleviate mechanical allodynia and thermal hyperalgesia after PNI. Similarly, intrathecal injection of IL-24 siRNA or IL-20R2 siRNA also alleviated mechanical allodynia after SNI. The inhibition of IL-24 reduced SNI-induced proinflammatory cytokine (IL-1β and TNF-α) production and increased anti-inflammatory cytokine (IL-10) production. Meanwhile, the inhibition of IL-20R2 also decreased IL-1β mRNA expression after SNI. Collectively, our findings revealed that IL-24/IL-20R might contribute to neuropathic pain through inflammatory response. Therefore, targeting IL-24 could be a promising strategy for treating neuropathic pain induced by PNI.


Health literacy and oral health literacy: are they associated? A cross sectional survey among undergraduate students of tricity (Chandigarh, Mohali, Panchkula), India
Health Literacy is the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate decisions. As with general health; achieving and maintaining oral health requires one to be able to understand, interpret and act on various types of health information. The present study was conducted to determine the association between health literacy and oral health literacy among undergraduate students in tricity (Chandigarh, Mohali, Panchkula), India. A cross-sectional study was conducted among 490 undergraduate students studying in tricity, from randomly selected 10 colleges. The data was collected by a single trained examiner, using a structured proforma. The questionnaire consisted of two parts, REALM-66 and REALD-30. The subject was given a copy of list of words to be pronounced and score one was given for each word pronounced correctly. REALM-66 scores showed that subjects with health literacy level equivalent to fourth- sixth grade is 1%, seventh- eighth grade was 64.4% and 29.6% for ninth grade and above. REALD-30 scores showed that 37.6% subjects had low level of literacy, 33.1% had moderate and 29.3% had high level of literacy. REALM and REALD scores were found to be positively correlated for qualification and genders. To our knowledge, this is the first study reporting association between health and oral health literacy. As the correlations were not strong, thus the results should be regarded as a first step to provide evidence.


[Study of apoptosis manifestations in streptozotocin diabetes mellitus].
The aim of this work was to study manifestations of apoptosis in pancreas, brain and myocardium of rats at the type I diabetes mellitus. To reveal the apoptotic changes in cells, specific damages of DNA were identified by the TUNEL-method. Specific for apoptosis changes in chromatin and cell membranes were found after counterstaining of a specimen by methyl green. In addition, the apoptotic and non-apoptotic cells were differentiated automatically with the help of image analyzing computer system by an index of optical density of cellular nucleus. This method allowed to find out for sure that apoptotic cells were available in all the studied tissues of healthy animals. However the possibility of their revealing by the TUNEL-method depends on the way of tissue fixation. Development of the type I diabetes mellitus was accompanied with an increase in the number of such cells, which gives evidence for an important role of apoptosis in diabetes pathogenesis.


Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells.
PTPN11 encodes the protein tyrosine phosphatase SHP-2, which relays signals from growth factor receptors to Ras and other effectors. Germline PTPN11 mutations underlie about 50% of Noonan syndrome (NS), a developmental disorder that is associated with an elevated risk of juvenile myelomonocytic leukemia (JMML). Somatic PTPN11 mutations were recently identified in about 35% of patients with JMML; these mutations introduce amino acid substitutions that are largely distinct from those found in NS. We assessed the functional consequences of leukemia-associated PTPN11 mutations in murine hematopoietic cells. Expressing an E76K SHP-2 protein induced a hypersensitive pattern of granulocyte-macrophage colony-forming unit (CFU-GM) colony growth in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) that was dependent on SHP-2 catalytic activity. E76K SHP-2 expression also enhanced the growth of immature progenitor cells with high replating potential, perturbed erythroid growth, and impaired normal differentiation in liquid cultures. In addition, leukemia-associated SHP-2 mutations conferred a stronger phenotype than a germline mutation found in patients with NS. Mutant SHP-2 proteins induce aberrant growth in multiple hematopoietic compartments, which supports a primary role of hyperactive Ras in the pathogenesis of JMML.


Monaural vs binaural speech reception threshold and word discrimination scores in the hearing impaired.
Monaural and binaural SRT and speech discrimination scores in a sensorineural hearing-imparied sample (N: 194, aged 3--91 yrs, mn=43 yrs) indicated that while a majority of clients have neither a binaural advantage or disadvantage by these tests, an important minority (5% for SRT, 20% for discrimination) have worse binaural than better-ear scores. Binaural as well as monaural tests of SRT and of speech discrimination should be a standard part of a hearing aid evaluation.


Human differentiation-related gene NDRG1 is a Myc downstream-regulated gene that is repressed by Myc on the core promoter region.
N-Myc downstream-regulated gene 1 (ndrg1) is up-regulated in N-Myc knockout mouse embryos. The human NDRG family consists of 4 highly homologous members and human Ndrg1 exhibits approximately 94% homology with mouse ndrg1. However, the regulatory mechanism of NDRG1 via Myc repression is as yet unknown. We previously identified human NDRG2 and demonstrated that this gene is transcriptionally down-regulated by Myc via Miz-1-dependent interaction with the core promoter region of NDRG2. Here, we provide evidence that human NDRG1 is regulated by Myc in a manner similar to NDRG2. We found that Ndrg1 expression levels were enhanced as Myc expression declined in differentiated cells, but were down-regulated following Myc induction. The data revealed that both N-Myc and c-Myc can repress human NDRG1 at the transcriptional level. We further determined that the core promoter region of human NDRG1 is required for Myc repression, and verified the interaction of Myc with the core promoter region. However, the presence of the protein synthesis inhibitor cycloheximide could reverse the repression of Myc, indicating the indirect repression of human NDRG1 by Myc. Moreover, we found that c-Myc-mediated repression can be inhibited by TSA, an HDACs inhibitor, which suggests the involvement of HDACs in the repression process. Taken together, our results demonstrate that, in common with NDRG2, human NDRG1 can be indirectly transcriptionally down-regulated by Myc via interaction with the NDRG1 core promoter.


[Gene therapy--status and recommendations in Norwegian health care system].
This article presents the main conclusions and the recommendations of a multidisciplinary group of experts appointed by the Norwegian Centre for Health Technology Assessment to assess the potential of gene therapy in clinical medicine. Clinical gene therapy protocols, ongoing or completed with published results, if any, were identified through a systematic survey of descriptive protocols and publications. So far 3,000-4,000 patients have been treated with gene therapy strategies in more than 400 clinical trials. In Norway the six first patients have been treated with gene therapy at The Norwegian Radium Hospital as part of two approved protocols for treatment of cancer. Gene therapy today is dominated by preclinical and clinical research. Most of the gene therapy protocols identified are in early phases (phases I and II) with few patients in each study; only three of the protocols represent phase III studies. Apart from the use of soluble antisense oligonucleotides against cytomegalovirus, gene therapy is not an established treatment modality today. In early clinical studies, however, promising results have been seen in treatment of cancer, in certain forms of cardiovascular diseases and also in a subgroup of inherited severe combined immunodeficiency. The expert group recommends that it is now important to build up national competence in the field in two ways: 1) by building up infrastructure in selected milieus; 2) by starting a national programme for gene therapy research including both preclinical and clinical research. The article also considers ethical and legislative aspects and emphasises that gene therapy should continue to be carefully monitored for side effects.


Robotic pancreaticoduodenectomy in the presence of aberrant or anomalous hepatic arterial anatomy: safety and oncologic outcomes.
Hepatic arterial anomalies (HAAs) are not infrequently encountered during pancreatic resections. In view of the current emergence of the robotic platform as a safe alternative to open surgery in experienced centres, this study sought to determine the implications of HAAs on the safety and oncologic outcomes of robotic pancreaticoduodenectomy (RPD). A prospectively maintained database of patients with HAAs who underwent RPD (RPD + HAA) at a single institution between 2008 and 2013 was retrospectively reviewed. Demographic information and perioperative outcomes of RPD were compared for patients with and without HAAs. A total of 142 patients underwent RPD; 112 (78.9%) did not have and 30 (21.1%) did have HAAs. The majority (90.0%) of RPDs in patients with HAAs were performed for malignant indications and all aberrant vessels were preserved without conversion to laparotomy. There were no statistically significant differences between RPD patients with and without HAAs with respect to preoperative demographics, tumour characteristics, operative metrics (operative time, estimated blood loss, conversion) and postoperative outcomes, including complications, length of stay and readmissions. Negative margin (R0) rates were similar in both groups. Robot-assisted pancreaticoduodenectomy is safe and feasible in patients with HAAs and has outcomes similar to those in patients with normal arterial anatomy.


Molecular and functional evidence for early divergence of an endothelin-like system during metazoan evolution: analysis of the Cnidarian, hydra.
A novel putative endothelin-converting enzyme (ECE) has been cloned from hydra, a freshwater invertebrate that belongs to the second oldest phylum of the animal kingdom. As an integral component of the endothelin system, vertebrate ECE functions in the activation of endothelin (ET) peptides. Vertebrate ETs are (1) the most potent vasoconstrictors known in mammals; and (2) function as essential signaling ligands during development of tissues derived from neural crest cells. To date, only a limited number of immunocytochemical studies have suggested the presence of endothelin-like peptides in invertebrates. Based on structural and functional analyses, we present evidence for a functional endothelin-like system in hydra that is involved in both muscle contraction and developmental processes. These findings indicate the broad use of endothelin systems in metazoans and also indicate that this type of signaling system arose early in evolution even before divergence of protostomes and deuterostomes.


Trajectories of motor function in children with Duchenne muscular dystrophy: A longitudinal study on a Colombian population.
Duchenne Muscular Dystrophy (DMD) is characterized by an initial increase in motor function followed by a plateau phase and then entering a phase of steady decline. However, motor evolution of DMD have not been evaluated in developing countries. Therefore, this study aims to evaluate the trajectory of motor function in a sample of Colombian children with DMD. We included 119 children with DMD aged 4.8-19.3 years (mean follow-up = 1.7 years). A linear mixed model was used with age as the time scale and adjusted for covariates using a stepwise regression. Participants showed a progressive decline in motor skills from the age of 5 years with a decrease in speed around the age of 11 years (p < 0.001). After age 11, the decline in motor function was observed to continue until age 20 but at a slower rate (βAge = -9.64. and βAge2 = 0.18, p < 0.001 for both). Educational inclusion, glucocorticoid treatment and the number of mutated exons were shown to be associated with the motor performance. These findings may indicate that the evolution of DMD maintains similar patterns between high income countries and the Colombian population. They allow us to adapt and develop treatments that impact the population with DMD in Colombia, based in international evidence.


AV nodal reentrant tachycardia with a 2:1 right bundle branch block missed as bidirectional ventricular tachycardia in the first superficial evaluation.
A 95-year old woman was admitted to our emergency unit because of acute abdominal pain. After urgent surgery according to the acute abdomen, she was referred to intensive care unit (ICU) of the emergency unit as she was intubated. It was developed a run of new arrhythmia which was diagnosed by cardiology resident as bidirectional ventricular tachycardia due to beat to beat changing the axis of the QRS. However, a second and more precise evaluation of the abnormal ECG suggested a narrow supraventricular tachycardia, most probably AV nodal reentrant tachycardia with a 2:1 right bundle branch block.


Functional variants in NOS1 and NOS2A are not associated with progressive hearing loss in Ménière's disease in a European Caucasian population.
Hearing loss in Ménière's disease (MD) is associated with loss of spiral ganglion neurons and hair cells. In a guinea pig model of endolymphatic hydrops, nitric oxide synthases (NOS) and oxidative stress mediate loss of spiral ganglion neurons. To test the hypothesis that functional variants of NOS1 and NOS2A are associated with MD, we genotyped three functional variants of NOS1 (rs41279104, rs2682826, and a cytosine-adenosine microsatellite repeat in exon 1f) and the CCTTT repeat in the promoter of NOS2A gene (rs3833912) in two independent MD sets (273 patients in total) and 550 controls. A third cohort of American patients was genotyped as replication cohort for the CCTTT repeat. Neither allele nor genotype frequencies of rs41279104 and rs2682826 were associated with MD, although longer alleles of the cytosine-adenosine microsatellite repeat were marginally significant (corrected p = 0.05) in the Mediterranean cohort but not in a second Galicia cohort. Shorter numbers of the CCTTT repeat in NOS2A were significantly more frequent in Galicia controls (OR = 0.37 [CI, 0.18-0.76], corrected p = 0.04), but this finding could not be replicated in Mediterranean or American case-control populations. Meta-analysis did not support an association between CCTTT repeats and risk for MD. Severe hearing loss (>75 dB) was also not associated with any functional variants studied. Functional variants of NOS1 and NOS2A do not confer susceptibility for MD.


Transgenic Chicks Expressing Interferon-Inducible Transmembrane Protein 1 (IFITM1) Restrict Highly Pathogenic H5N1 Influenza Viruses.
Mammalian cells utilize a wide spectrum of pathways to antagonize the viral replication. These pathways are typically regulated by antiviral proteins and can be constitutively expressed but also exacerbated by interferon induction. A myriad of interferon-stimulated genes (ISGs) have been identified in mounting broad-spectrum antiviral responses. Members of the interferon-induced transmembrane (IFITM) family of proteins are unique among these ISGs due to their ability to prevent virus entry through the lipid bilayer into the cell. In the current study, we generated transgenic chickens that constitutively and stably expressed chicken IFITM1 (chIFITM1) using the avian sarcoma-leukosis virus (RCAS)-based gene transfer system. The challenged transgenic chicks with clinical dose 104 egg infective dose 50 (EID50) of highly pathogenic avian influenza virus (HPAIV) subtype H5N1 (clade 18.104.22.168) showed 100% protection and significant infection tolerance. Although challenged transgenic chicks displayed 60% protection against challenge with the sub-lethal dose (EID50 105), the transgenic chicks showed delayed clinical symptoms, reduced virus shedding, and reduced histopathologic alterations compared to non-transgenic challenged control chickens. These finding indicate that the sterile defense against H5N1 HPAIV offered by the stable expression of chIFITM1 is inadequate; however, the clinical outcome can be substantially ameliorated. In conclusion, chIFITM proteins can inhibit influenza virus replication that can infect various host species and could be a crucial barrier against zoonotic infections.


[The molecular basis of the virulence of Yersinia].
Pathogenic bacteria of the genus Yersinia (Y. enterocolitica, Y. pseudotuberculosis and Y. pestis) are pathogens of the invasive type. Although they provoke diseases as different as plague and enterocolitis, the molecular bases of their virulence appear to be surprisingly similar: a 70 kb plasmid confers a degree of resistance to the primary immune response and the presence or absence of chromosome encoded functions modulates virulence. The knowledge of the virulence functions that now emerges suggests the conversion of Y. enterocolitica as a life carrier.


[Esophageal pH monitoring: factors influencing the definition of normality].
Prolonged esophageal pH-metry has become an irreplaceable investigative tool in diagnosing gastroesophageal reflux. Given the presence of episodes of acid reflux even under physiological circumstances, it is of primary importance to define the range of normal values in order to correctly identify the condition of disease. This task is complicated by the lack of an absolute and objective marker of normality, to be referred to, and by the number of variables that can influence the measurement of the esophageal pH. Among the most important factors that can influence this test there are age, physical exercise, posture and diet. Even voluptuary habits, such as smoking and alcohol intake, could be detrimental in this respect. Then there are many technical factors that can act as sources of relevant errors in measuring and calculating the parameters chosen to discriminate normality from abnormality, the most important ones being as follows: defective electrodes, electrodes that have not been calibrated accurately, electrodes positioned erroneously, interference with the pH readings by mucus, food, aiming at the walls of the esophagus, inconsistent sampling rates among the recording equipment, differences in the software used to automatically analyze the experimental data, failure to recognize and consequently to eliminate the artifacts present in the pH-metry tracings, inadequate "in situ" repeatability of the esophageal pH measurements on the part of paired electrodes that simultaneously record the pH.


Major histocompatibility complex variation in insular populations of the Egyptian vulture: inferences about the roles of genetic drift and selection.
Insular populations have attracted the attention of evolutionary biologists because of their morphological and ecological peculiarities with respect to their mainland counterparts. Founder effects and genetic drift are known to distribute neutral genetic variability in these demes. However, elucidating whether these evolutionary forces have also shaped adaptive variation is crucial to evaluate the real impact of reduced genetic variation in small populations. Genes of the major histocompatibility complex (MHC) are classical examples of evolutionarily relevant loci because of their well-known role in pathogen confrontation and clearance. In this study, we aim to disentangle the partial roles of genetic drift and natural selection in the spatial distribution of MHC variation in insular populations. To this end, we integrate the study of neutral (22 microsatellites and one mtDNA locus) and MHC class II variation in one mainland (Iberia) and two insular populations (Fuerteventura and Menorca) of the endangered Egyptian vulture (Neophron percnopterus). Overall, the distribution of the frequencies of individual MHC alleles (n=17 alleles from two class II B loci) does not significantly depart from neutral expectations, which indicates a prominent role for genetic drift over selection. However, our results point towards an interesting co-evolution of gene duplicates that maintains different pairs of divergent alleles in strong linkage disequilibrium on islands. We hypothesize that the co-evolution of genes may counteract the loss of genetic diversity in insular demes, maximize antigen recognition capabilities when gene diversity is reduced, and promote the co-segregation of the most efficient allele combinations to cope with local pathogen communities.


Identifying infections with respiratory syncytial virus by using specific immunoglobulin G (IgG) and IgA enzyme-linked immunosorbent assays with oral-fluid samples.
Currently, respiratory syncytial virus (RSV) infection is identified in epidemiological studies by virus antigen or nucleic acid detection in combination with serology. Oral-fluid specimens may provide a noninvasive alternative to blood, and oral fluid is more suitable for sampling outside of the clinic setting. We evaluated an indirect enzyme-linked immunosorbent assay for the detection of RSV-specific immunoglobulin G (IgG) and IgA by using oral-fluid samples collected from individuals with RSV infections confirmed by an immunofluorescent antibody test. For five children sampled repeatedly from birth, antibody profiles in oral fluid quite consistently tracked those in paired sera, and RSV infections were detected by rising titers of antibodies of at least one Ig class. Specific IgG responses were generally more reliable than IgA responses, except in early infancy, where the reverse was sometimes true. For a further five young children from whom oral fluid was collected weekly following RSV infection, boosted antibody responses, frequently of a transient nature, lasting a few weeks, were observed; specific IgG responses were of longer duration and more pronounced than specific IgA responses. Our data show significant promise for the use of oral fluid alone in RSV infection surveillance. The observed rapid dynamics of the antibody responses are informative in defining study sampling intervals.


Performance of an Interactive Upper Extremity Peripheral Nerve Training Module Among Medical Students, Radiology Residents, and Fellows: A Multi-institutional Study.
Chronic pain is a common problem and imaging is becoming increasingly utilized in the characterization of peripheral neuropathy, although this topic is not emphasized during medical training. We hypothesized that an electronic module and nerve atlas would be effective in improving comprehension among trainees. In this IRB-approved study, a training module was created that included a side-by-side comparison of normal upper extremity nerves on magnetic resonance imaging and ultrasound (US), with embedded questions and cases, followed by a brief hands-on US scanning session. Thirty volunteers with variable training were enrolled in 1 institution, while 14 volunteers were enrolled in another. Pre- and post-test scores were collected and compared. There was a response rate of 100% at both institutions. At the first institution, subjects were divided into 2 groups: group 1 (16 medical students) and group 2 (14 residents/fellows). There was a baseline deficit of knowledge among both groups, with a mean pretest score of 37.5% and 47.5% for group 1 and group 2, respectively (P = 0.017). After module completion, both groups improved with a mean post-test score of 67.2% for group 1 and 76.1% for group 2. At the second institution, there was similar improvement even if the scanning session was not done. Use of an electronic module helps trainees to become more familiar with peripheral nerve imaging, regardless of level of training. Use of the module, even in the absence of hands-on US scanning, results in an improved understanding of this topic.


Microbial indicators of faecal contamination in waters and sediments of beach bathing zones.
This study presents the results obtained of the microbial characterization of waters and sediments of 18 coastal bathing zones of the south-western coast of the Iberian Peninsula. To make this characterization, two indicators of faecal contamination have been selected: faecal coliforms (FC) and Clostridium perfringens (CP). The results show that low concentrations of FC and CP in water not necessarily implies that their concentration in sediment and elutriates has to be low as well. The highest concentrations were found in locations close to the mouth of rivers, and in beaches of low energy and hence low water renewal, and high accumulation of fine sediments. The concentrations of FC were lower than those obtained for CP in most of the sampling locations. Although quality standards for bathing waters do not take the parameter CP into account, it has been demonstrated that it should be a good indicator of faecal contamination.


Incremental value of live/real time three-dimensional transesophageal echocardiography in the assessment of ventricular septal rupture following acute myocardial infarction.
Ventricular septal rupture is a serious complication following acute myocardial infarctions and is associated with a significant mortality rate. Classically, two-dimensional transthoracic echocardiography has been used to diagnose this complication and visualize its location. Two-dimensional transesophageal echocardiography has supplemented the transthoracic approach by providing more accurate assessment of the defect size and in guiding closure both percutaneously and intraoperatively. This modality, however, is limited to two-dimensional views only, and a greater breadth of information is instead available through the use of three-dimensional transesophageal echocardiography. We present a series of 11 patients in which live/real time three-dimensional transesophageal echocardiography offered incremental benefits over two-dimensional imaging alone.


Connective tissue growth factor promotes chemotaxis of preosteoblasts through integrin α5 and Ras during tensile force-induced intramembranous osteogenesis.
In vertebrates, new bone formation via intramembranous osteogenesis is a critical biological event for development, remodeling, and fracture healing of bones. Chemotaxis of osteoblast lineage cells is an essential cellular process in new bone formation. Connective tissue growth factor (CTGF) is known to exert chemotactic properties on various cells; however, details of CTGF function in the chemotaxis of osteoblast lineage cells and underlying molecular biological mechanisms have not been clarified. The aim of the present study was to evaluate the chemotactic properties of CTGF and its underlying mechanisms during active bone formation through intramembranous osteogenesis. In our mouse tensile force-induced bone formation model, preosteoblasts were aggregated at the osteogenic front of calvarial bones. CTGF was expressed at the osteogenic front, and functional inhibition of CTGF using a neutralizing antibody suppressed the aggregation of preosteoblasts. In vitro experiments using μ-slide chemotaxis chambers showed that a gradient of CTGF induced chemotaxis of preosteoblastic MC3T3-E1 cells, while a neutralizing integrin α5 antibody and a Ras inhibitor inhibited the CTGF-induced chemotaxis of MC3T3-E1 cells. These findings suggest that the CTGF-integrin α5-Ras axis is an essential molecular mechanism to promote chemotaxis of preosteoblasts during new bone formation through intramembranous osteogenesis.


Complications and difficulties in radiolabelling blood cells: a review.
The radiolabelling of blood cells is occasionally problematical. Difficulties occur either with the labelling process itself or after the labelled cells have been reinjected. Failure to label may be due to pharmaceutical factors, such as difficulties with collecting sufficient cells, sedimentation problems or instability of the cell chelator, or problems may arise which are patient-related, such as patient medication or the presence of disease. A number of surveys have been undertaken to assess the possibility of drug interference as a cause of problems with labelling or biodistribution. Leukocyte labelling difficulties occurred in patients who were on multi-drug therapy whose drug regimes included combinations of prednisolone, azathioprine, cyclosporin, ranitidine, nifedipine, cyclophosphamide and naproxen. While a direct causal relationship has not been established, the known adverse effects of the drugs on white cell function and kinetics suggest that patient medication could be an important factor in leukocyte labelling. Red cell labelling difficulties have occurred from time to time and published reports implicate pharmaceutical factors, such as choice of anti-coagulant, level of stannous ion and oxidation of technetium-99m (99Tcm). Patient-related factors such as the presence of disease or drugs have also been implicated. A survey of red cell problems and patient medication showed that difficulties occurred in patients who were treated with combinations of nifedipine, etoposide, idarubicin and cefataxime. In-vitro testing of a number of drugs with 99Tcm-labelled red cells has demonstrated that cyclosporin, nifedipine, verapamil, hydralazine, propranolol, digoxin and Teflon cannulae can affect labelling.


Acute, sublethal cyanide poisoning in mice is ameliorated by nitrite alone: complications arising from concomitant administration of nitrite and thiosulfate as an antidotal combination.
Sodium nitrite alone is shown to ameliorate sublethal cyanide toxicity in mice when given from ∼1 h before until 20 min after the toxic dose as demonstrated by the recovery of righting ability. An optimum dose (12 mg/kg) was determined to significantly relieve cyanide toxicity (5.0 mg/kg) when administered to mice intraperitoneally. Nitrite so administered was shown to rapidly produce NO in the bloodsteam as judged by the dose-dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. It is argued that antagonism of cyanide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity rather than the methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood resulted in the detection of sulfidomethemoblobin by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase, the effects of the two inhibitors being essentially additive under standard assay conditions rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite-thiosulfate combination therapy at sublethal levels of cyanide intoxication.


Low bone mineral density in small for gestational age infants: correlation with cord blood zinc concentrations.
Twenty eight term small for gestational age (SGA) infants and 18 term appropriate for gestational age (AGA) infants were studied prospectively to assess bone mineral density and cord serum zinc concentrations. Growth and nutritional status were evaluated, and bone mineral density was measured by dual energy x ray densitometry of the lumbar spine. Cord serum zinc, parathyroid hormone, osteocalcin, vitamin D metabolite and mineral concentrations were measured. Growth, nutritional status, and bone mineral density (mean (SD) 0.223 (0.032) vs 0.277 (0.032) g hydroxyapatite/cm2) were significantly low in SGA infants. Bone mineral density was linearly related to growth and nutritional measures. Cord serum zinc concentrations were in the normal range and similar in both groups (mean (SD) 13.86 (3.0) vs 13.43 (2.1) mumol/l). It is suggested that SGA infants may not be zinc deficient. Low bone mineral density could be caused by growth and nutritional status deficiencies, the mechanisms for which could be those that reduce nutrient substrate supply to the fetus.


Entomopathogens of Amazonian stick insects and locusts are members of the Beauveria species complex (Cordyceps sensu stricto).
In the Amazon the only described species of Cordyceps sensu stricto (Hypocreales, Cordycipitaceae) that parasitize insects of Orthopterida (orders Orthoptera and Phasmida) are Cordyceps locustiphila and C. uleana. However, the type specimens for both taxa have been lost and the concepts of these species are uncertain. To achieve a more comprehensive understanding of the systematics of these species, collections of Cordyceps from the Amazon regions of Colombia, Ecuador and Guyana were subjected to morphological, ecological and molecular phylogenetic studies. Phylogenetic analyses were conducted on partial sequences of SSU, LSU, TEF, RPB1 and RPB2 nuclear loci. Two new species are proposed including C. diapheromeriphila, a parasite of Phasmida, and C. acridophila, a parasite of the superfamily Acridomorpha (Orthoptera), which is broadly distributed across the Amazon. For C. locustiphila a lectotypification and an epitypification are made. Cordyceps locustiphila is host specific with Colpolopha (Acridomorpha: Romaleidae), and its distribution coincides with that of its host. The phylogenetic placement of these three species was resolved with strong support in the Beauveria clade of Cordyceps s. str. (Cordycipitaceae). This relationship and the morphological similarity of their yellow stromata with known teleomorphs of the clade, suggest that the holomorphs of these species may include Beauveria or Beauveria-like anamorphs. The varying host specificity of the beauverioid Cordyceps species suggest the potential importance of identifying the natural host taxon before future consideration of strains for use in biological control of pest locusts.


Cloning and characterization of XiR1, a locus responsible for dagger nematode resistance in grape.
The dagger nematode, Xiphinema index, feeds aggressively on grape roots and in the process, vectors grapevine fanleaf virus (GFLV) leading to the severe viral disease known as fanleaf degeneration. Resistance to X. index and GFLV has been the key objective of grape rootstock breeding programs. A previous study found that resistance to X. index derived from Vitis arizonica was largely controlled by a major quantitative trait locus, XiR1 (X. index Resistance 1), located on chromosome 19. The study presented here develops high-resolution genetic and physical maps in an effort to identify the XiR1 gene(s). The mapping was carried out with 1,375 genotypes in three populations derived from D8909-15, a resistant selection from a cross of V. rupestris A. de Serres (susceptible) x V. arizonica b42-26 (resistant). Resistance to X. index was evaluated on 99 informative recombinants that were identified by screening the three populations with two markers flanking the XiR1 locus. The high-resolution genetic map of XiR1 was primarily constructed with seven DNA markers developed in this study. Physical mapping of XiR1 was accomplished by screening three bacterial artificial chromosome (BAC) libraries constructed from D8909-15, V. vinifera Cabernet Sauvignon and V. arizonica b42-26. A total of 32 BAC clones were identified and the XiR1 locus was delineated within a 115 kb region. Sequence analysis of three BAC clones identified putative nucleotide binding/leucine-rich repeat (NB-LRR) genes. This is the first report of a closely linked major gene locus responsible for ectoparasitic nematode resistance. The markers developed from this study are being used to expedite the breeding of resistant grape rootstocks.


DNA methylation aging and transcriptomic studies in horses.
Cytosine methylation patterns have not yet been thoroughly studied in horses. Here, we profile n = 333 samples from 42 horse tissue types at loci that are highly conserved between mammalian species using a custom array (HorvathMammalMethylChip40). Using the blood and liver tissues from horses, we develop five epigenetic aging clocks: a multi-tissue clock, a blood clock, a liver clock and two dual-species clocks that apply to both horses and humans. In addition, using blood methylation data from three additional equid species (plains zebra, Grevy's zebras and Somali asses), we develop another clock that applies across all equid species. Castration does not significantly impact the epigenetic aging rate of blood or liver samples from horses. Methylation and RNA data from the same tissues define the relationship between methylation and RNA expression across horse tissues. We expect that the multi-tissue atlas will become a valuable resource.


The Intrinsic Relationship Between Structure and Function of the Sialyltransferase ST8Sia Family Members.
As a subset of glycosyltransferases, the family of sialyltransferases catalyze transfer of sialic acid (Sia) residues to terminal non-reducing positions on oligosaccharide chains of glycoproteins and glycolipids, utilizing CMP-Neu5Ac as the activated sugar nucleotide donor. In the four known sialyltransferase families (ST3Gal, ST6Gal, ST6GalNAc and ST8Sia), the ST8Sia family catalyzes synthesis of α2, 8-linked sialic/polysialic acid (polySia) chains according to their acceptor specificity. We have determined the 3D structural models of the ST8Sia family members, designated ST8Sia I (1), II(2), IV(4), V(5), and VI(6) using the Phyre2 server. Accuracy of these predicted models are based on the ST8Sia III crystal structure as the calculated template. The common structural features of these models are: (1) Their parallel templates and disulfide bonds are buried within the enzymes and are predominately surrounded by helices; (2) The anti-parallel β-sheets are located at the N-terminal region of the enzymes; (3) The mono-sialytransferases (mono-STs), ST8Sia I and ST8Sia VI, contain only a single pair of disulfide bonds, and there are no anti-parallel β-sheets in ST8Sia VI; (4) The Nterminal region of all of the mono-STs are located some distant away from their core structure; (5) These conformational features show that the 3D structures of the mono-STs are less compact than the two polySTs, ST8Sia II and ST8Sia IV, and the oligo-ST, ST8Sia III. These structural features relate to the catalytic specificity of the monoSTs; (6) In contrast, the more compact structural features of ST8Sia II, ST8Sia IV and ST8Sia III relate to their ability to catalyze the processive synthesis of oligo- (ST8Sia III) and polySia chains (ST8Sia II & ST8Sia IV); (7) Although ST8Sia II, III and IV have similar conformations in their corresponding polysialyltransferase domain (PSTD) and polybasic region (PBR) motifs, the structure of ST8Sia III is less compact than ST8Sia II and ST8Sia IV, and the amino acid components of the several three-residue-loops in the two motifs of ST8Sia III are different from that in ST8Sia II and ST8Sia IV. This is likely the structural basis for why ST8Sia III is an oligoST and not able to polysialylate and; (8) In contrast, essentially all amino acids within the threeresidue- loops in the PSTD of ST8Sia II and ST8Sia IV are highly conserved, and many amino acids in the loops and the helices of these two motifs are critical for NCAM polysialylation, as determined by mutational analysis and confirmed by our recent NMR results. In summary, these new findings provide further insights into the molecular mechanisms underlying polyST-NCAM recognition, polySTpolySia/ oligoSia interactions, and polysialylation of NCAM.


[Episiotomy from the perspective of humanized obstetrics: reflections based on social studies of science and technology].
An initial analysis is made of the way obstetricians that defend the humanization of childbirth in Brazil understand and analyze the practice of episiotomy, a conventional technique included in protocols in obstetrics that they had learned in medical training and subsequently abandoned. We present an initial analytical construct through the prism of the social studies of science and technology and raise questions about the neutrality of science and technology and the impartiality of the specialist/scientist. We further point out the relationships that seem to exist between political activity, the production of scientific knowledge, and technical activities in the professional work of the aforementioned obstetricians.


Surface, thermal and hemocompatible properties of novel single stage electrospun nanocomposites comprising polyurethane blended with bio oilTM.
In this work, the physicochemical and blood compatibility properties of prepared PU/Bio oil nanocomposites were investigated. Scanning electron microscope (SEM) studies revealed the reduction of mean fiber diameter (709 ± 211 nm) compared to the pristine PU (969 nm ± 217 nm). Fourier transform infrared spectroscopy (FTIR) analysis exposed the characteristic peaks of pristine PU. Composite peak intensities were decreased insinuating the interaction of the bio oilTM with the PU. Contact angle analysis portrayed the hydrophobic nature of the fabricated patch compared to pristine PU. Thermal gravimetric analysis (TGA) depicted the better thermal stability of the novel nanocomposite patch and its different thermal behavior in contrast with the pristine PU. Atomic force microscopy (AFM) analysis revealed the increase in the surface roughness of the composite patch. Activated partial thromboplastin time (APTT) and prothrombin time (PT) signified the novel nanocomposite patch ability in reducing the thrombogenicity and promoting the anticoagulant nature. Finally the hemolytic percentage of the fabricated composite was in the acceptable range revealing its safety and compatibility with the red blood cells. To reinstate, the fabricated patch renders promising physicochemical and blood compatible nature making it a new putative candidate for wound healing application.


Interlocking intramedullary nailing for ipsilateral fractures of the femoral shaft and distal part of the femur.
A review of the data on 684 fractures of the femur that had been treated with intramedullary nailing led to the identification of twenty-three patients who had had a fracture of the shaft of the femur with an accompanying ipsilateral supracondylar fracture (twelve patients, group I) or a concomitant ipsilateral intercondylar fracture (eleven patients, group II). The group-I fractures had been treated with interlocking nailing without supplemental fixation. In group II, ten fractures were stabilized with interlocking nailing and supplemental screw fixation and one, with interlocking nailing and a supplemental plate and screws. The average time to union for all fractures was nineteen weeks (range, twelve to thirty-six weeks), and the average duration of clinical and radiographic follow-up was thirty months (range, nine to fifty-nine months). In group I, alignment of the femur was within 5 degrees of normal in ten of the twelve fractures. In group II, seven intra-articular fractures healed in anatomical alignment, three had slight articular displacement (1.0 to 3.0 millimeters), and one had displacement of more than 3.0 millimeters. The average range of motion of the knee at the most recent follow-up was 0 to 120 degrees in group I and 0 to 115 degrees in group II. Two patients (both in group II) needed a reoperation for a previously unrecognized fracture of a femoral condyle in the coronal plane; post-traumatic arthritis developed in both. No patient in either group had loss of fixation or failure of the implant. We concluded that ipsilateral diaphyseal, supracondylar, and intercondylar fractures of the femur can be adequately stabilized with interlocking nailing and supplemental intercondylar screw fixation. The presence of a fracture in the coronal plane of a femoral condyle (AO type-B3 and type-C3 injuries) is a relative contraindication to the use of this technique.


Trampoline injuries.
As the popularity of trampolines has increased during the past 10 years, so has the number of injuries sustained using them. Whether there is an actual increase in the risk associated with the use of a trampoline for the same number of exposure hours is not known. The marked increase in emergency room visits related to trampoline injuries might reflect only the increased number of trampolines now available for recreational use or the creative manner in which they are being used. The complex factors related to trampolines, their use, and the possible injuries will be discussed. A liberal use of Internet references will be used because this is where much of the advertising and information available to the public regarding trampolines currently is disseminated.


Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B.
The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of G6b-B results in severe macrothrombocytopenia, myelofibrosis and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans.


Health Care Costs of Alzheimer's and Related Dementias Within a Medicare Managed Care Provider.
Although one third of Medicare beneficiaries are enrolled in Medicare Advantage (MA) plans, there is limited information about the cost of treating Alzheimer disease and related dementias (ADRD) in these settings. The objective of this study was to estimate direct health care costs attributable to ADRD among older adults within a large MA plan. A retrospective cohort design was used to estimate direct total, outpatient, inpatient, ambulatory pharmacy, and nursing home costs for 3 years before and after an incident ADRD diagnosis for 927 individuals diagnosed with ADRD relative to a sex-matched and birth year-matched set of 2945 controls. Adults 65 years of age and older enrolled in the Kaiser Permanente Washington MA plan and the Adult Changes in Thought (ACT) Study, a prospective longitudinal cohort study of ADRD and brain aging. Data on monthly health service use obtained from health system electronic medical records for the period 1992-2012. Total monthly health care costs for individuals with ADRD are statistically greater (P<0.05) than controls beginning in the third month before diagnosis and remain significantly greater through the eighth month following diagnosis. Greater total health costs are driven by significantly (P<0.05) greater nursing home costs among individuals diagnosed with ADRD beginning in the third month prediagnosis. Although total costs were no longer significantly greater at 8 months following diagnosis, nursing home costs remained higher for the people with dementia through the 3 years postdiagnosis we analyzed. Greater total health care costs among individuals with ADRD are primarily driven by nursing home costs.


Dihydrocodeine as an opioid analgesic for the treatment of moderate to severe chronic pain.
Dihydrocodeine (DHC) is a semi-synthetic analogue of codeine which was formed by the hydrogenation of the double tie in the main chain of the codeine molecule. DHC is used as an analgesic, antitussive and antidiarrhoeal agent; it is also used for the treatment of opioid addiction. Limited data is available on the relative potency of DHC to other opioids. The analgesic effect of DHC is probably twice as potent as codeine for the parenteral and slightly stronger for an oral route. DHC possesses approximately 1/6(th) of the morphine analgesic effect when drugs are administered orally. In this article pharmacokinetics, pharmacodynamics, dosing guidelines, adverse effects and clinical studies of DHC in pain management are shown with focus on cancer pain. The impact of CYP2D6 activity on DHC analgesia was discussed and a proposal of calculation equianalgesic doses of DHC to other opioids was put forward.


Chronic air pollution and social deprivation as modifiers of the association between high temperature and daily mortality.
Heat and air pollution are both associated with increases in mortality. However, the interactive effect of temperature and air pollution on mortality remains unsettled. Similarly, the relationship between air pollution, air temperature, and social deprivation has never been explored. We used daily mortality data from 2004 to 2009, daily mean temperature variables and relative humidity, for Paris, France. Estimates of chronic exposure to air pollution and social deprivation at a small spatial scale were calculated and split into three strata. We developed a stratified Poisson regression models to assess daily temperature and mortality associations, and tested the heterogeneity of the regression coefficients of the different strata. Deaths due to ambient temperature were calculated from attributable fractions and mortality rates were estimated. We found that chronic air pollution exposure and social deprivation are effect modifiers of the association between daily temperature and mortality. We found a potential interactive effect between social deprivation and chronic exposure with regards to air pollution in the mortality-temperature relationship. Our results may have implications in considering chronically polluted areas as vulnerable in heat action plans and in the long-term measures to reduce the burden of heat stress especially in the context of climate change.


Maternal prenatal distress exposure negatively associates with the stability of neonatal frontoparietal network.
Maternal prenatal distress (PD), frequently defined as in utero prenatal stress exposure (PSE) to the developing fetus, influences the developing brain and numerous associations between PSE and brain structure have been described both in neonates and in older children. Previous studies addressing PSE-linked alterations in neonates' brain activity have focused on connectivity analyses from predefined seed regions, but the effects of PSE at the level of distributed functional networks remains unclear. In this study, we investigated the impact of prenatal distress on the spatial and temporal properties of functional networks detected in functional MRI data from 20 naturally sleeping, term-born (age 25.85 ± 7.72 days, 11 males), healthy neonates. First, we performed group level independent component analysis (GICA) to evaluate an association between PD and the identified functional networks. Second, we searched for an association with PD at the level of the stability of functional networks over time using leading eigenvector dynamics analysis (LEiDA). No statistically significant associations were detected at the spatial level for the GICA-derived networks. However, at the dynamic level, LEiDA revealed that maternal PD negatively associated with the stability of a frontoparietal network. These results imply that maternal PD may influence the stability of frontoparietal connections in neonatal brain network dynamics and adds to the cumulating evidence that frontal areas are especially sensitive to PSE. We advocate for early preventive intervention strategies regarding pregnant mothers. Nevertheless, future research venues are required to assess optimal intervention timing and methods for maximum benefit.


Selective association of sterol regulatory element-binding protein isoforms with target promoters in vivo.
The mRNAs for all three members of the sterol regulatory element-binding protein (SREBP) family are widely expressed, and the proteins are highly similar. They have potential to both hetero- and homodimerize through their bHLHLZ domains, so it has been difficult to definitively study the role of each one apart from the other two. In the current study, we have utilized cell lines that express only one functional SREBP and the chromatin immunoprecipitation technique to analyze individual SREBP binding to three specific target genes: hydroxymethylglutaryl-CoA reductase (Red), fatty acid synthase (FAS), and squalene synthase (SQS). Our studies show that SREBP-2 binds to promoters for all three genes, and in agreement with the original report using these cells, all three mRNAs are also induced. In the line expressing only SREBP-1a, mRNAs for Red and FAS are induced, but SQS is not. Chromatin immunoprecipitation also shows that SREBP-1a is recruited efficiently to Red and FAS promoters but not to SQS. This observation indicates SREBP-2 selectively binds the SQS promoter and is sufficient to explain the lack of SQS mRNA induction in the SREBP-1a-expressing cells. SREBP-1c protein was not stably recruited to any SREBP target promoter despite being fully active in DNA binding when purified from extracts of the corresponding cells. This is also sufficient to explain the lack of SREBP target gene induction by the singular expression of SREBP-1c. We also show that whereas SREBP-1a and -2 proteins interact efficiently with transcriptional co-activators that modify cellular chromatin, SREBP-1c does not. Taken together, our data support a model suggesting that chromatin modification is required during the initial stage of specific site recognition by SREBPs in native chromatin in vivo.


Ultrafast excited-state dynamics of eosin B: a potential probe of the hydrogen-bonding properties of the environment.
The photophysics of two dyes from the xanthene family, eosin B (EB), and eosin Y (EY) has been investigated in various solvents by femtosecond transient absorption spectroscopy, first, to clarify the huge disparity of the EB fluorescence lifetimes reported in literature, and, second, to understand the mechanism responsible for the ultrafast excited-state deactivation of EB in water. The excited-state lifetime of EB was found to be much shorter in water and in other protic solvents, due to the occurrence of hydrogen-bond assisted nonradiative deactivation. This mechanism is associated with the hydrogen bonds between the solvent molecules and the nitro groups of EB, which become stronger upon optical excitation due to the charge-transfer character of the excited-state. This process is not operative with EY, where the nitro groups are replaced by bromine atoms. Therefore, the excited-state lifetime of EB in solution is directly related to the strength of the solvent as a hydrogen-bond donor, offering the possibility to build a corresponding scale based on the fluorescence quantum yield or lifetime of EB. This scale of hydrogen-bonding strength could be especially useful for studies of liquid interfaces by time-resolved surface second harmonic generation.


Controlled wound repair in guinea pigs, using antimicrobials that alter fibroplasia.
The repair processes of incised wounds depend, in part, on fibroplasia induced by soluble mediators from monocytic macrophages. Two topical antimicrobials were evaluated, each of which effectively controlled wound sepsis and yet each had widely different effects on fibroplasia and wound strength. Paired-incision dermal wounds on the flanks of guinea pigs were treated with a substance containing reactive chlorine (Alcide) or with a compound that is a mixture of two surfactants. One side of each guinea pig was treated with one of the antimicrobials (treated wounds); the opposite side was treated with isotonic saline solution (control wounds). At 7, 10, and 16 days after surgery, tensiometric measurements of C31G (a surfactant)-treated wounds were 99%, 139%, and 195% of control wound values, respectively. Alcide-treated wounds were 76%, 58%, and 88% of control wounds, respectively. Wounds treated with chlorhexidine had reduced strength at 7 days (73%) and at 10 days (78%), but by 14 days, they were similar to control wounds (94%). The main difference between the wounds was the amount of collagen formation. Alcide-treated wounds incorporated less than 50% of the amount of 14C-proline than did the wounds treated with C31G. However, Alcide-treated wounds epithelialized as rapidly as did control wounds, and had minimal scar formation. Microscopic evaluations indicated greatly reduced inflammatory infiltrates in Alcide-treated wounds, indicating that reduced wound strength may be associated with lack of fibroblast-stimulating activity by monocytes.