Investigation of the Properties and Effects of Salvia Officinalis L. on the Viability, Steroidogenesis and Reactive Oxygen Species (ROS) Production in TM3 Leydig Cells in Vitro.
The aim of our study was to reveal the in vitro effects of Salvia officinalis L. (37.5, 75, 150, 200, 250, 300 and 600 µg/ml) extract on the TM3 Leydig cell viability, membrane integrity, steroidogenesis and reactive oxygen species production after 24 h and 48 h cultivation. For the present study, the extract prepared from Salvia officinalis L. leaves was analysed by high performance liquid chromatography (HPLC) for selected flavonoids and phenolic acids followed by a determination of its free radicals scavenging activity (DPPH). Furthermore, Leydig cell viability was assessed by the mitochondrial toxicity assay (MTT), while the membrane integrity was evaluated by 5- carboxyfluorescein diacetate-acetoxymethyl ester (5-CFDA-AM). The level of steroid hormones was performed by enzyme-linked immunosorbent assay (ELISA) from the culture media, while the superoxide radical generation was measured by the nitroblue tetrazolium chloride (NBT) assay. The results show that experimental concentrations did not damage the cell membrane integrity and viability when present at below 300 µg/ml, it was only at 600 µg/ml that a significant (P<0.05) cell viability decline was observed after a 48 h cultivation. A significant (P<0.05) stimulation of testosterone secretion was recorded at 250 µg/ml for 24 h, while the prolonged cultivation time significantly (P<0.05) increased the testosterone and progesterone production at 150, 200, 250 and 300 µg/ml. Furthermore, none of the selected doses exhibited significant ROS-promoting effects however, the highest dose of Salvia initiated the free radical scavenging activity in cultured mice Leydig cells.


Cyclical thrombocytosis, acquired von Willebrand syndrome and aggressive non-melanoma skin cancers are common in patients with Philadelphia-negative myeloproliferative neoplasms treated with hydroxyurea.
Abstract Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea complications have been reported in Philadelphia-negative myeloproliferative neoplasms (MPNs), but their incidence and clinical consequences have not been defined in a large cohort of patients. We conducted a retrospective analysis of 188 consecutive patients with MPNs specifically addressing the incidence of these complications. Cyclical thrombocytosis was documented in 29 patients (15%), the majority of whom were receiving hydroxyurea. Acquired von Willebrand syndrome was identified in 17 of the 84 screened patients (20%), but was not associated with any major bleeding complications. Non-melanoma skin cancers were reported in 51 patients (27%). Hydroxyurea-related fever occurred in nine of 149 patients (6%) who received hydroxyurea. Seventy-three patients (39%) experienced a total of 98 major thrombotic events, with the majority of these occurring prior to or within 3 months of the diagnosis. Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea-related complications are not infrequent in MPNs and have important clinical consequences for management.


Comparative personality judgments: replication and extension of robust findings in personality perception using an alternative method.
The scientific study of accuracy in personality judgment typically involves the utilization of rating scales to make absolute decisions about a target individual. Although this method has many merits, it restricts some experimental options and is further removed from ecological validity than one would desire. These studies represent an attempt to develop an alternative methodology for the study of personality judgment--specifically for use in explorations of judgment process. A series of photo sets containing pictures of 3 individuals, each representing a different level of a specific personality trait, was created. The participant's task was to select high and low scorers on a dimension from the photos. Study 1 demonstrates that people can select targets with extreme scores from a photo lineup at a rate better than chance across several personality dimensions. Study 2 shows that this ability has some degree of temporal consistency. Study 3 represents an improvement on the general method via enhanced criteria for stimulus selection, incorporating both self and peer reports.


Tracing the phylogeography of human populations in Britain based on 4th-11th century mtDNA genotypes.
Some of the transitional periods of Britain during the first millennium A.D. are traditionally associated with the movement of people from continental Europe, composed largely of invading armies (e.g., the Roman, Saxon, and Viking invasions). However, the extent to which these were migrations (as opposed to cultural exchange) remains controversial. We investigated the history of migration by women by amplifying mitochondrial DNA (mtDNA) from ancient Britons who lived between approximately A.D. 300-1,000 and compared these with 3,549 modern mtDNA database genotypes from England, Europe, and the Middle East. The objective was to assess the dynamics of the historical population composition by comparing genotypes in a temporal context. Towards this objective we test and calibrate the use of rho statistics to identify relationships between founder and source populations. We find evidence for shared ancestry between the earliest sites (predating Viking invasions) with modern populations across the north of Europe from Norway to Estonia, possibly reflecting common ancestors dating back to the last glacial epoch. This is in contrast with a late Saxon site in Norwich, where the genetic signature is consistent with more recent immigrations from the south, possibly as part of the Saxon invasions.


Imipenem Resistance in Clostridium difficile Ribotype 017, Portugal.
We describe imipenem-resistant and imipenem-susceptible clinical isolates of Clostridium difficile ribotype 017 in Portugal. All ribotype 017 isolates carried an extra penicillin-binding protein gene, pbp5, and the imipenem-resistant isolates had additional substitutions near the transpeptidase active sites of pbp1 and pbp3. These clones could disseminate and contribute to imipenem resistance.


Genetic control of serum antibody responses of inbred mice to type 1 and type 2 fimbriae from Actinomyces viscosus T14V.
Antibodies reactive with type 1 and type 2 fimbriae from Actinomyces viscosus T14V specifically inhibit the adherence of A. viscosus T14V to salivary pellicle-coated tooth surfaces and other bacteria, and these antibodies are thought to modulate colonization by this microorganism. These studies were done to determine whether previously noted differences in the antibody responses of inbred mice to type 1 and type 2 fimbriae might be under genetic control. The serum immunoglobulin G (IgG) and IgM antibody responses of inbred, F1 hybrid, and H-2 congenic mice, immunized with A. viscosus T14V cells, were analyzed by enzyme-linked immunosorbent assays for antibodies reactive with A. viscosus T14V whole-cell type 1 and type 2 fimbriae. The results confirmed earlier findings and indicated striking variations in the amounts of IgG anti-type 1 (23-fold) and anti-type 2 (48-fold) fimbria antibodies elicited. The responses of the 17 inbred strains tested showed a relatively continuous distribution from high to low, as well as marked differences in the responses of H-2 and Igh-C identical strain pairs. An analysis of the responses of F1 hybrid and H-2 congenic mice indicated dominance of the low-responder gene(s) and control by H-2-linked genes. Antisera from two high-responder strains inhibited in vitro bacterial adherence to a much greater degree than antisera from a low-responding strain. These data suggest polygenic control of the magnitude of the IgG anti-type 1 and anti-type 2 fimbria antibody responses by H-2-linked genes as well as background genes not associated with H-2 or Igh-C loci.


Immunostaining of Lgr5, an intestinal stem cell marker, in normal and premalignant human gastrointestinal tissue.
Lgr5 has recently been identified as a murine marker of intestinal stem cells. Its expression has not been well characterized in human gastrointestinal tissues, but has been reported in certain cancers. With the increasing appreciation for the role of cancer stem cells or tumor-initiating cells in certain tumors, we sought to explore the expression of Lgr5 in normal and premalignant human gastrointestinal tissues. Using standard immunostaining, we compared expression of Lgr5 in normal colon and small intestine vs. small intestinal and colonic adenomas and Barrett's esophagus. In the normal tissue, Lgr5 was expressed in the expected stem cell niche, at the base of crypts, as seen in mice. However, in premalignant lesions, Lgr5+ cells were not restricted to the crypt base. Additionally, their overall numbers were increased. In colonic adenomas, Lgr5+ cells were commonly found clustered at the luminal surface and rarely at the crypt base. Finally, we compared immunostaining of Lgr5 with that of CD133, a previously characterized marker for tumor-initiating cells in colon cancer, and found that they identified distinct subpopulations of cells that were in close proximity, but did not costain. Our findings suggest that (1) Lgr5 is a potential marker of intestinal stem cells in humans and (2) loss of restriction to the stem cell niche is an early event in the premalignant transformation of stem cells and may play a role in carcinogenesis.


Prevalence and severity of malocclusion in adolescent Kuwaitis.
Our aim was to evaluate prevalence and severity of malocclusion in an adolescent Kuwaiti population. Using a stratified cluster sampling method and excluding non-Kuwaitis, subjects with mesial migration and/or loss of first molars, and subjects with orthodontic treatment experience without availability of initial study models, we examined 1,299 Kuwaitis (674 boys and 625 girls) of mean age 13.2 +/- 0.4 years in a regular well lit classroom. We scored molar and canine relationship, overjet, overbite, anterior and posterior cross bite as well as spacing and irregularity of the incisors using gloves, mirrors, rulers, and spatulas. Fourteen, 15, and 71% met the criteria for almost ideal, mild, and moderate to severe malocclusion, respectively. Of the 86% with malocclusion, occurrence of class 1, half step class 2, full step class 2, half step class 3, and full step class 3 was 57.8, 24.9, 6.3, 8.8, and 2.2% for the first molars, and 36.1, 50.0, 6.2, 5.4, and 2.3% for the canines, respectively. Incisor malalignment was the most prevalent malocclusion trait (73.2%). Overjet > or = 9.5 mm occurred in less than 1.5%, open bite in less than 3.5%, deep bite with gingival contact in less than 2.0%, complete posterior cross bite in less than 1.5%, and complete anterior crossbite in less than 2.0%. Median diastema was present in about 2/3 of the cases with maxillary anterior spacing as opposed to only about 1/3 of those with mandibular spacing. Our findings suggest that more than 70% of young adolescent Kuwaitis have moderate to severe malocclusion, with incisor malalignment as the most prevalent malocclusion trait.


Quantifying the impact of physical distance measures on the transmission of COVID-19 in the UK.
To mitigate and slow the spread of COVID-19, many countries have adopted unprecedented physical distancing policies, including the UK. We evaluate whether these measures might be sufficient to control the epidemic by estimating their impact on the reproduction number (R0, the average number of secondary cases generated per case). We asked a representative sample of UK adults about their contact patterns on the previous day. The questionnaire was conducted online via email recruitment and documents the age and location of contacts and a measure of their intimacy (whether physical contact was made or not). In addition, we asked about adherence to different physical distancing measures. The first surveys were sent on Tuesday, 24 March, 1 day after a "lockdown" was implemented across the UK. We compared measured contact patterns during the "lockdown" to patterns of social contact made during a non-epidemic period. By comparing these, we estimated the change in reproduction number as a consequence of the physical distancing measures imposed. We used a meta-analysis of published estimates to inform our estimates of the reproduction number before interventions were put in place. We found a 74% reduction in the average daily number of contacts observed per participant (from 10.8 to 2.8). This would be sufficient to reduce R0 from 2.6 prior to lockdown to 0.62 (95% confidence interval [CI] 0.37-0.89) after the lockdown, based on all types of contact and 0.37 (95% CI = 0.22-0.53) for physical (skin to skin) contacts only. The physical distancing measures adopted by the UK public have substantially reduced contact levels and will likely lead to a substantial impact and a decline in cases in the coming weeks. However, this projected decline in incidence will not occur immediately as there are significant delays between infection, the onset of symptomatic disease, and hospitalisation, as well as further delays to these events being reported. Tracking behavioural change can give a more rapid assessment of the impact of physical distancing measures than routine epidemiological surveillance.


Lactobacillus plantarum TW1-1 Alleviates Diethylhexylphthalate-Induced Testicular Damage in Mice by Modulating Gut Microbiota and Decreasing Inflammation.
Diethylhexylphthalate (DEHP), acting as an endocrine disruptor, disturbed reproductive health. Here, we evaluated the effects of Lactobacillus plantarum TW1-1 (L. plantarum TW1-1) on DEHP-induced testicular damage in adult male mice. Results showed that oral supplementation of L. plantarum TW1-1 significantly increased the serum testosterone concentration, enhanced the semen quality, and attenuated gonad development defects in DEHP-exposed mice. L. plantarum TW1-1 also alleviated DEHP-induced oxidative stress and inflammatory responses by decreasing the mRNA expression and serum protein concentration of different inflammatory factors [tumor necrosis factor-α, interleukin (IL)-1β and IL-6]. Furthermore, L. plantarum TW1-1 significantly reduced DEHP-induced intestinal hyper-permeability and the increase in the serum lipopolysaccharide level. Gut microbiota diversity analysis revealed that L. plantarum TW1-1 shifted the DEHP-disrupted gut microbiota to that of the control mice. At phylum level, L. plantarum TW1-1 reversed DEHP-induced Bacteroidetes increase and Firmicutes decrease, and restored Deferribacteres in DEHP-exposed mice. Spearman's correlation analysis showed that Bacteroidetes, Deferribacteres, and Firmicutes were associated with DEHP-induced testicular damage. In addition, the ratio of Firmicutes to Bacteroidetes (Firm/Bac ratio) significantly decreased from 0.28 (control group) to 0.13 (DEHP-exposed group), which was restored by L. plantarum TW1-1 treatment. Correlation analysis showed that the Firm/Bac ratio was negatively correlated with testicular damage and inflammation. These findings suggest that L. plantarum TW1-1 prevents DEHP-induced testicular damage via modulating gut microbiota and decreasing inflammation.


[Personified monitoring of acute coronary syndrome and its outcomes in elderly patients. Angina. Heart failure (overview).]
Review is about current information on the features of heart failure and angina diagnosis and monitoring in elderly and senile patients. One of the main problem in patients over 65 years is comorbidity, which requires corrective action in the risk stratification and prediction of clinical outcomes. The priority of non-invasive diagnostic tests is noted. Authors of the article recommend frailty as an obligatory part of diagnostic process in patients with heart failure and angina due to a clear connection with the worst prognosis in terms of quality of life, hospitalization and mortality.


Urinary excretion of 2,5-hexanedione and peripheral polyneuropathies workers exposed to hexane.
Forty shoe factory workers who were exposed to hexane were investigated to see if there was a correlation between electroneuromyographic changes indicative of neuropathy and urinary excretion of 2,5-hexanedione. Urinary samples were analyzed for the presence of the metabolic products of n-hexane and its isomers. Electrodiagnostic examination was carried out following the urinary sampling. A rating scale was used to obtain a cumulative numeric index of electrodiagnostic findings. 2,5-Hexanedione and gamma-valerolactone were discovered in all cases, while 2-hexanol was found in 11 cases. 2,5-Hexanedione was the main metabolite in most cases (39 of 40). Only in 1 case was a low level of 2-methyl-2-pentanol detected; 3-methyl-2-pentanol was never detected. Metabolic products of cyclohexane were present in about one-fifth of the cases, while trichloroethanol, a metabolic product of trichoroethylene, was nearly always present, all at very low concentrations. Electromyographic abnormalities significant for early detection of toxic polyneuropathy were found in 14 cases. A statistically significant correlation of the electroneuromyographic scoring on the urinary concentrations of measured metabolites was observed only with 2,5-hexanedione and gamma-valerolactone, both derived from n-hexane. Since gamma-valerolactone is probably not a true metabolite of n-hexane, our results support the hypothesis that polyneuropathies in shoemakers are due to 2,5-hexanedione. For practical purposes the urinary concentration of 2,5-hexanedione can serve as a predictive measurement for early detection of neurotoxic lesions at preclinical states.


A review on patient-specific facial and cranial implant design using Artificial Intelligence (AI) techniques.
Researchers and engineers have found their importance in healthcare industry including recent updates in patient-specific implant (PSI) design. CAD/CAM technology plays an important role in the design and development of Artificial Intelligence (AI) based implants.The across the globe have their interest focused on the design and manufacturing of AI-based implants in everyday professional use can decrease the cost, improve patient's health and increase efficiency, and thus many implant designers and manufacturers practice. The focus of this study has been to manufacture smart devices that can make contact with the world as normal people do, understand their language, and learn to improve from real-life examples. Machine learning can be guided using a heavy amount of data sets and algorithms that can improve its ability to learn to perform the task. In this review, artificial intelligence (AI), deep learning, and machine-learning techniques are studied in the design of biomedical implants. The main purpose of this article was to highlight important AI techniques to design PSIs. These are the automatic techniques to help designers to design patient-specific implants using AI algorithms such as deep learning, machine learning, and some other automatic methods.


Retinal Nerve Fiber Layer Thickness Measurement by Spectral-Domain Optical Coherence Tomography in Patients with Major Depressive Disorder.
In recent years, an increasing number of studies have researched retinal nerve fiber layer (RNFL) changes in neurodegenerative disorders. In this study, our aim was to determine structural RNFL changes in patients with major depressive disorder. A total of 30 patients with major depressive disorder and 30 age- and sex-matched controls were recruited. Using optical coherence tomography (OCT), the peripapillary RNFL thickness in major depressive disorder patients and control subjects was measured and compared at each location. Patients with major depressive disorder did not show a statistically significant reduction in overall peripapillary RNFL thickness. Our study showed that RNFL thickness is not reduced in major depressive disorder patients and that OCT is not a useful tool for diagnosing and monitoring the progression of major depressive disorder. This study suggests that the pathophysiology of unipolar depression is different than in neurodegenerative disorders, pervasive developmental disorders, schizophrenia, and bipolar disorder.


Has dialysis payment reform led to initial racial disparities in anemia and mineral metabolism management?
Implementation of the Medicare ESRD prospective payment system (PPS) and changes to dosing guidelines for erythropoiesis-stimulating agents (ESAs) in 2011 appear to have influenced use of injectable medications among dialysis patients. Given historically higher ESA and vitamin D use among black patients, we assessed the effect of these policy changes on racial disparities in the management of anemia and mineral metabolism. Analyses used cross-sectional monthly cohorts for a period-prevalent sample of 7384 maintenance hemodialysis patients at 132 facilities from the Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor. Linear splines with knots at each policy change were used in survey-weighted regressions to estimate time trends in hemoglobin (Hgb), erythropoietin (EPO) dose, intravenous (IV) iron dose, ferritin, transferrin saturation (TSAT) concentration, parathyroid hormone (PTH), IV vitamin D dose, cinacalcet use, and phosphate binder use. From August 2010 to December 2011, mean Hgb declined from 11.5 to 11.0 g/dl (P<0.001), mean EPO dose declined from 20,506 to 14,777 U/wk (P<0.001), and mean serum PTH increased from 340 to 435 pg/ml (P<0.001). No meaningful differences by race were observed regarding the rates of change of management practices or laboratory measures (all P>0.21). Mean EPO and vitamin D dose and serum PTH levels remained higher in blacks. Despite evidence that anemia and mineral metabolism management practices have changed significantly over time, there was no immediate indication of racial disparities resulting from implementation of the PPS or ESA label change. Further studies are needed to examine effects among patient and facility subgroups.


A Bayesian phase I-II clinical trial design to find the biological optimal dose on drug combination.
In recent years, combined therapy shows expected treatment effect as they increase dose intensity, work on multiple targets and benefit more patients for antitumor treatment. However, dose -finding designs for combined therapy face a number of challenges. Therefore, under the framework of phase I-II, we propose a two-stage dose -finding design to identify the biologically optimal dose combination (BODC), defined as the one with the maximum posterior mean utility under acceptable safety. We model the probabilities of toxicity and efficacy by using linear logistic regression models and conduct Bayesian model selection (BMS) procedure to define the most likely pattern of dose-response surface. The BMS can adaptively select the most suitable model during the trial, making the results robust. We investigated the operating characteristics of the proposed design through simulation studies under various practical scenarios and showed that the proposed design is robust and performed well.


Understanding the placebo effect. Part 2: underlying psychological & neurobiological processes.
Placebo and nocebo effects are interesting and complex phenomena. In this article, I discuss some findings about the psychological and neurobiological processes that may underlie these effects on the basis of studies of pain, Parkinson's disease, and depression. From a psychological perspective, expectancy and conditioning theories have been used to explain placebo and nocebo effects. These psychological processes may be translated into physiological effects through overlapping brain circuits that are important for cognitive information processing, analgesia, and reward expectations. These brain circuits may represent a fundamentally important common underlying pathway that mediates placebo and nocebo effects in many conditions. Understanding these effects is important for designing clinical treatment studies and interpreting their results and is highly relevant for clinical practices.


GsLRPK, a novel cold-activated leucine-rich repeat receptor-like protein kinase from Glycine soja, is a positive regulator to cold stress tolerance.
Plant LRR-RLKs serve as protein interaction platforms, and as regulatory modules of protein activation. Here, we report the isolation of a novel plant-specific LRR-RLK from Glycine soja (termed GsLRPK) by differential screening. GsLRPK expression was cold-inducible and shows Ser/Thr protein kinase activity. Subcellular localization studies using GFP fusion protein indicated that GsLRPK is localized in the plasma membrane. Real-time PCR analysis indicated that temperature, salt, drought, and ABA treatment can alter GsLRPK gene transcription in G. soja. However, just protein induced by cold stress not by salinity and ABA treatment in tobacco was found to possess kinase activity. Furthermore, we found that overexpression of GsLRPK in yeast and Arabidopsis can enhance resistance to cold stress and increase the expression of a number of cold responsive gene markers.


Biological effects of canatoxin in different insect models: evidence for a proteolytic activation of the toxin by insect cathepsinlike enzymes.
Canatoxin is a toxic protein isolated from the jackbean, Canavalia ensiformis. The toxin injected intraperitoneally is lethal for mice and rats; however, it is inactive if given orally. In this study, Manduca sexta (L.) (Lepidoptera), Schistocerca americana (Drury) (Orthoptera), Drosophila melanogaster (L.) (Diptera), Aedes aegypti (L.) (Diptera), Rhodnius prolixus (Stål) (Hemiptera), and Callosobruchus maculatus (F.) (Coleoptera) were fed on canatoxin-containing diets. No effects were seen in M. sexta, S. americana, D. melanogaster, or A. aegypti. No traces of canatoxin were found in their feces, suggesting that the protein was digested completely by these insects, which characteristically have a trypsin-based digestion. In contrast, canatoxin was lethal for insects displaying cathepsin-based digestion. Thus, for C. maculatus, a diet containing 0.25% wt:wt canatoxin caused complete inhibition of larval growth. When R. prolixus were fed on canatoxin, 2 effects were seen: impairment of water excretion and increased lethality 48-96 h after feeding. The lethal effect of canatoxin in R. prolixus was blocked partially or completely when the digestion of the toxin by R. prolixus midgut enzymes was impaired. The data showed that canatoxin is highly toxic when ingested by some species of insects but not affecting others, probably in correlation with the characteristics of the digestive process of the insect.


Constant vs auto-continuous positive airway pressure in patients with sleep apnea hypopnea syndrome and a high variability in pressure requirement.
Auto-continuous positive airway pressure (CPAP) has been reported to have no more efficacy than constant CPAP in unselected patients with sleep apnea hypopnea syndrome (SAHS). The aim of this study was to evaluate patients judged to be good candidates for auto-CPAP because of a high within-night variability in pressure requirement. Single-blind, randomized, cross-over study (2 x 8 weeks) to compare auto-CPAP with constant CPAP. Outpatients with moderate-to-severe SAHS attending the chest clinic. Patients were equipped at home in the auto-CPAP mode (model GK418A; Malinckrodt; Nancy, France), using a 4- to 14-cm H(2)O pressure range. Those individuals having a high within-night variability in pressure requirement, assessed at the end of a 14-day run-in period, were included in the cross-over study. Auto-CPAP was compared with constant CPAP (according to a titration night in the sleep laboratory) in terms of compliance, efficacy on apneas (assessed from the pressure monitor), and sleepiness (assessed on the Epworth sleepiness scale). Of 90 consecutive patients with SAHS, 27 patients were selected for a within-night variability in pressure requirement exceeding a given threshold. After completion of the cross-over, 24 patients were evaluable. The median percentage of nights the machine was used was 95.5% (range, 45 to 100%) on constant CPAP, and 96.5% (range, 40 to 100%) on auto-CPAP; the median apnea index recorded by the device was 0.40/h (range, 0 to 2.40/h) on constant CPAP, and 0.45/h (range, 0 to 5.80/h) on auto-CPAP (differences not significant). The mean Epworth sleepiness score was significantly (p < 0.01) lower on auto-CPAP (5.1; SD, 2.8) than on constant CPAP (6.1; SD, 2.8). In patients selected for a high within-night variability in pressure requirement, auto-CPAP administered via a GK418A device was equivalent to constant CPAP based on a titration night in the sleep laboratory. Subjective ratings for sleepiness were slightly lower on auto-CPAP.


Application of semi-continuous culture on membrane filters for the study of activated sludge bacteria.
Bacterial population of activated sludge flocs from the petrochemical wastewater purification plant was studied by semi-continuous culture on membrane filters. Almost all (90%) of bacterial cells in the flocs were metabolically active. Only a small fraction of bacteria in the flocs was able to use phenol or ethylene glycol as the sole source of carbon. At higher concentrations of these compounds growth of the bacteria was strongly retarded.


Diversity in healthcare: time to get REAL!
Cross-cultural healthcare involves three key issues: racial and ethnic disparities in the quality of healthcare provided to minority patients; cross-cultural value differences between immigrant patients and Western medical providers; and providing language access and assistance to limited English proficient (LEP) and disabled persons. Addressing these key issues represents a compelling diversity agenda for a new generation of healthcare executives. This article describes each of these challenges and the cutting-edge strategies that leading healthcare organizations are using to address them.


Preauricular infratemporal fossa surgical approach: modifications of the technique and surgical indications.
A retrospective clinical analysis was performed to evaluate the effectiveness of the preauricular infratemporal fossa (ITF) surgical approach using modifications based on tumor pathology and extension, without compromising outcomes. Patients were surgically treated for tumors involving the ITF via a preauricular surgical approach during 1990 to 2000. Their clinical charts were reviewed to determine the association among pathological variables, details of the surgical procedure, and outcomes. Tumors in 65 patients were categorized as "malignant" and "benign." The malignant group included 44 patients (mean age, 49.5 years). Squamous cell carcinoma was the most common pathology followed by sarcomas. To achieve complete tumor resection, the ITF approach and dissection were combined with other procedures in 74% of these patients. No surgical complications were encountered in 74.4%, and a clinical cure was obtained in 55% of patients (follow-up, 2 years). The benign group included 21 patients (mean age, 36.7 years). Juvenile angiofibromas and meningiomas constituted most of the tumors in this group. An ITF approach alone was sufficient to achieve complete tumor excision in 66.7% of these patients. A clinical cure was achieved in 85% of patients (follow-up, 2 years), and 76.2% had no surgical complications. Chi-square tests revealed significant correlations between tumor extensions and surgical treatment variables. These were more evident in the malignant group, indicating the use of wider surgical exposures and more aggressive, extirpative surgery. The preauricular surgical approach to the ITF can be used to achieve a complete resection of a variety of tumors arising from or extending into the ITF. This approach can be tailored to the nature of the tumor and its extensions.


The use and safety of medications known to affect driving in Jordan: A cross-sectional study.
The aim of this study was to estimate the main driving-impairing medications used by drivers in Jordan, the reported frequency of medication side effects, the frequency of motor vehicle crashes (MVCs) while using driving-impairing medicines, as well as factors associated with MVCs. A cross-sectional study involving 1,049 individuals (age 18-75 years) who are actively driving vehicles and taking at least one medication known to affect driving (anxiolytics, antidepressants, hypnotics, antiepileptics, opioids, sedating antihistamines, hypoglycemic agents, antihypertensives, central nervous system [CNS] stimulants, and herbals with CNS-related effects) was conducted in Amman, Jordan, over a period of 8 months (September 2013-May 2014) using a structured validated questionnaire. Sixty-three percent of participants noticed a link between a medicine taken and feeling sleepy and 57% stated that they experience at least one adverse effect other than sleepiness from their medication. About 22% of the participants reported having a MVC while on medication. Multiple logistic regression analysis showed that among the participants who reported having a crash while taking a driving-impairing medication, the odds ratios were significantly higher for the use of inhalant substance (odds ratio [OR] = 2.787, P = .014), having chronic conditions (OR = 1.869, P = .001), and use of antiepileptic medications (OR = 2.348, P = .008) and significantly lower for the use of antihypertensives (OR = 0.533, P = .008). The study results show high prevalence of adverse effects of medications with potential for driving impairment, including involvement in MVCs. Our findings highlight the types of patient-related and medication-related factors associated with MVCs in Jordan, such as inhalant use, presence of chronic conditions, and use of antiepileptics.


Numerical method for high accuracy index of refraction estimation for spectro-angular surface plasmon resonance systems.
An eigenvector analysis based algorithm is presented for estimating refractive index changes from 2-D reflectance/dispersion images obtained with spectro-angular surface plasmon resonance systems. High resolution over a large dynamic range can be achieved simultaneously. The method performs well in simulations with noisy data maintaining an error of less than 10(-8) refractive index units with up to six bits of noise on 16 bit quantized image data. Experimental measurements show that the method results in a much higher signal to noise ratio than the standard 1-D weighted centroid dip finding algorithm.


GABA Application Enhances Drought Stress Tolerance in Wheat Seedlings (Triticum aestivum L.).
In this study, the effects of γ-aminobutyric acid (GABA) on physio-biochemical metabolism, phenolic acid accumulation, and antioxidant system enhancement in germinated wheat under drought stress was investigated. The results showed that exogenous GABA reduced the oxidative damage in wheat seedlings caused by drought stress and enhanced the content of phenolics, with 1.0 mM being the most effective concentration. Six phenolic acids were detected in bound form, including p-hydroxybenzoic acid, vanillic acid, syringic acid, p-coumaric acid, ferulic acid, and sinapic acid. However, only syringic acid and p-coumaric acid were found in free form. A total of 1.0 mM of GABA enhanced the content of total phenolic acids by 28% and 22%, respectively, compared with that of drought stress, on day four and day six of germination. The activities of phenylalanine ammonia lyase (PAL), cinnamic acid 4-hydroxylase (C4H) and 4-coumarate coenzyme A ligase (4CL) were activated by drought stress plus GABA treatment. Antioxidant enzyme activities were also induced. These results indicate that GABA treatment may be an effective way to relieve drought stress as it activates the antioxidant system of plants by inducing the accumulation of phenolics and the increase in antioxidant enzyme activity.


Impact of ceftibuten on intestinal microflora: in vitro and in vivo studies.
The present study examines the possible interference of ceftibuten on intestinal microflora. In 60 germ-free mice, an intestinal microflora similar to the human one was implanted. The mice were then treated with a single dose and twice the therapeutic dose of ceftibuten. In another experiment, ten human volunteers were given ceftibuten in doses equivalent to 400 mg/day for 7 days in order to evaluate the ceftibuten faecal concentration, the possible interference on microflora and the quantity of indacan (as a measure of the bacterial metabolism in the gut) excreted in one day. The results obtained in vivo and in vitro have shown that ceftibuten in therapeutic doses does not alter the equilibrium of normal intestinal microflora.


Exploring Context with Deep Structured Models for Semantic Segmentation.
We propose an approach for exploiting contextual information in semantic image segmentation, and particularly investigate the use of patch-patch context and patch-background context in deep CNNs. We formulate deep structured models by combining CNNs and Conditional Random Fields (CRFs) for learning the patch-patch context between image regions. Specifically, we formulate CNN-based pairwise potential functions to capture semantic correlations between neighboring patches. Efficient piecewise training of the proposed deep structured model is then applied in order to avoid repeated expensive CRF inference during the course of back propagation. For capturing the patch-background context, we show that a network design with traditional multi-scale image inputs and sliding pyramid pooling is very effective for improving performance. We perform comprehensive evaluation of the proposed method. We achieve new state-of-the-art performance on a number of challenging semantic segmentation datasets.


Should topiramate be initial therapy in the management of idiopathic intracranial hypertension?: A literature review.
Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology that primarily affects obese women of childbearing age. Symptoms include disabling headaches, visual disturbances, and intracranial noises (pulsatile tinnitus). Currently, no standardized treatment guidelines are available and the current management focuses on weight loss and acetazolamide use. There is an increasing body of evidence suggesting that the initial use of topiramate may be considered in IIH treatment. Acetazolamide is the recommended initial treatment for IIH, with topiramate often used as a second-line agent. Topiramate has multiple benefits to indicate it would pose effective in IIH management. Through varying mechanisms, it leads to weight loss and improves migraine headache control, the most common headache phenotype in IIH. Topiramate also inhibits the carbonic anhydrase enzyme like acetazolamide to reduce intracranial pressure and treat papilledema. The safety profile of topiramate is comparable or superior to acetazolamide. To date, there are limited studies comparing topiramate to acetazolamide or other treatment modalities in IIH. Based on its varying mechanisms of action, topiramate is a strong potential treatment agent for IIH, yet acetazolamide is often chosen first-line. However, the data supporting use of acetazolamide or topiramate is inefficient to designate one agent preferred over the other. There is a need for further studies assessing topiramate use in the treatment of IIH, and comparing topiramate use to other treatment modalities.


A Dhdds K42E knock-in RP59 mouse model shows inner retina pathology and defective synaptic transmission.
Retinitis pigmentosa (RP) defines a group of hereditary progressive rod-cone degenerations that exhibit a common phenotype caused by variants in over 70 genes. While most variants in the dehydrodolichyl diphosphate synthase (DHDDS) gene result in syndromic abnormalities, some variants cause non-syndromic RP (RP59). DHDDS encodes one subunit of the enzyme cis-prenyltransferase (CPT), which is required for the synthesis of dolichol (Dol), that is a necessary protein glycosylation cofactor. We previously reported the creation and initial characterization of a knock-in (KI) mouse model harboring the most prevalent RP59-associated DHDDS variant (K42E) to understand how defects in DHDDS lead to retina-specific pathology. This model exhibited no profound retinal degeneration, nor protein N-glycosylation defects. Here, we report that the Dol isoprenylogue species in retina, liver, and brain of the K42E mouse model are statistically shorter than in the corresponding tissues of age-matched controls, as reported in blood and urine of RP59 patients. Retinal transcriptome analysis demonstrated elevation of many genes encoding proteins involved in synaptogenesis and synaptic function. Quantitative retinal cell layer thickness measurements demonstrated a significant reduction in the inner nuclear layer (INL) and total retinal thickness (TRT) beginning at postnatal (PN) ∼2 months, progressively increasing to PN 18-mo. Histological analysis revealed cell loss in the INL, outer plexiform layer (OPL) disruption, and ectopic localization of outer nuclear layer (ONL) nuclei into the OPL of K42E mutant retinas, relative to controls. Electroretinograms (ERGs) of mutant mice exhibited reduced b-wave amplitudes beginning at PN 1-mo, progressively declining through PN 18-mo, without appreciable a-wave attenuation, relative to controls. Our results suggest that the underlying cause of DHDDS K42E variant driven RP59 retinal pathology is defective synaptic transmission from outer to inner retina.


Four main therapeutic keys for Parkinson's disease: A mini review.
Parkinson's disease (PD) is characterized by motor and cognitive dysfunctions. The progressive degeneration of dopamine-producing neurons that are present in the substantia nigra pars compacta (SNpc) has been the main focus of study and PD therapies since ages. In this manuscript, a systematic revision of experimental and clinical evidence of PD-associated cell process was conducted. Classically, the damage in the dopaminergic neuronal circuits of SNpc is favored by reactive oxidative/nitrosative stress, leading to cell death. Interestingly, the therapy for PD has only focused on avoiding the symptom progression but not in finding a complete reversion of the disease. Recent evidence suggests that the renin-angiotensin system imbalance and neuroinflammation are the main keys in the progression of experimental PD. The progression of neurodegeneration in SNpc is due to the complex interaction of multiple processes. In this review, we analyzed the main contribution of four cellular processes and discussed in the perspective of novel experimental approaches.


Polycyclic Aromatic Hydrocarbons in Ologe Lagoon and Effects of Benzo[b]fluoranthene in African Catfish.
Ologe Lagoon is an important water body that receives effluents from neighboring industries. These effluents may increase the levels of anthropogenic contaminants in the lagoon, thereby creating stressors for aquatic organisms. To assess the occurrence of polycyclic aromatic hydrocarbons (PAHs) in Ologe Lagoon, along with the histopathological, biochemical and genotoxic effects of the most prevalent PAH compound. An initial field study was performed to determine the concentrations of PAHs in Ologe Lagoon, followed by a chronic toxicity test to assess the effects of the most prevalent PAH compound in a fish model (Clarias gariepinus). High molecular weight PAHs were more predominant than low molecular weight PAHs in the lagoon, with B[b]F being the most predominant. The formation of micronuclei and binuclei was induced by a 10-fold increase over the present environmental concentration of B[b]F in Ologe Lagoon. Histopathological studies showed that epithelial necrosis, fused lamellae, shortened lamellae, and desquamation were the major histological anomalies induced by ERCs of B[b]F. Results from the biochemical assay indicated that ERCs of B[b] F increased aspartate aminotransferase and alanine transaminase levels in fish. Glutathione-S-transferase, superoxide dismutase and catalase were inhibited in the exposed fish, whereas malondialdehyde was significantly increased. Concentrations of fluoranthene, pyrene, benzo[a]anthracene, and benzo[a] pyrene in the surface water of Ologe Lagoon were above the Canadian Council of Ministers of the Environment's (CCME) safe limits, suggesting that the water may not be safe for domestic uses, and the present concentration of B[b]F in Ologe Lagoon may be chronically toxic to aquatic organisms, in terms of oxidative stress and hepatotoxicity. The authors declare no competing financial interests.


[Cholesterol crystal embolisms due to systemic thrombolysis of an acute myocardial infarct].
A 63-year-old male patient admitted with acute inferior myocardial infarction was treated with tissue plasminogen activator (rt-PA) and heparin. 4 hours after the initiation of the rt-PA infusion he showed painful cutaneous alterations on the lower trunk, mistaken as drug-induced rash and later correctly identified as livedo reticularis. Simultaneously, renal function deteriorated. Assuming hypersensitivity vasculitis, we instituted immunosuppressive treatment which proved to be ineffective. Skin biopsy including the deeper layers showed multiple cholesterol emboli. Anticoagulants were stopped and we noticed no further cholesterol embolism or further decline of renal function. 10 previous publications have mentioned a causal relationship between systemic fibrinolytic treatment and the cholesterol crystal embolism syndrome. In 7 cases, however, angiographic procedures were used or the interval between fibrinolysis and the occurrence of cholesterol crystal embolism was too long to exclude spontaneous or heparin-induced cholesterol crystal embolism. The short interval in our own case points clearly to the systemic fibrinolytic therapy as the culprit. We would like to draw attention to the possibility that in individuals with advanced atherosclerotic lesions of the aorta or major arteries, systemic fibrinolytic treatment of myocardial infarction may give rise to the cholesterol crystal embolism syndrome.


Development and validation of a resistance and virulence gene microarray targeting Escherichia coli and Salmonella enterica.
A microarray was developed to simultaneously screen Escherichia coli and Salmonella enterica for multiple genetic traits. The final array included 203 60-mer oligonucleotide probes, including 117 for resistance genes, 16 for virulence genes, 25 for replicon markers, and 45 other markers. Validity of the array was tested by assessing inter-laboratory agreement among four collaborating groups using a blinded study design. Internal validation indicated that the assay was reliable (area under the receiver-operator characteristic curve=0.97). Inter-laboratory agreement, however, was poor when estimated using the intraclass correlation coefficient, which ranged from 0.27 (95% confidence interval 0.24, 0.29) to 0.29 (0.23, 0.34). These findings suggest that extensive testing and procedure standardization will be needed before bacterial genotyping arrays can be readily shared between laboratories.


Diffusion tensor MR imaging tractography of the pyramidal tracts correlates with clinical motor function in children with congenital hemiparesis.
Children with congenital hemiparesis have greater asymmetry in diffusion parameters of the pyramidal tracts compared with control subjects. We hypothesized that the asymmetry correlates with the severity of hemiparesis and that diffusion metrics would be abnormal in the affected tracts and normal in the unaffected tracts. Fifteen patients with congenital hemiparesis and 17 age-matched control subjects were studied with diffusion tensor MR imaging tractography. Hemipareses were scored as mild, moderate, or severe. We measured tract-specific diffusion parameters (fractional anisotropy, mean, and directional diffusion coefficients) of the pyramidal tracts. We compared tract-specific parameters and asymmetry between the right and left tracts of the differing severity groups and control subjects. We observed many different causes of congenital hemiparesis including venous infarction, arterial infarction, and polymicrogyria. Clinical severity of hemiparesis correlated with asymmetry in fractional anisotropy (P < .0001), transverse diffusivity (P < .0001), and mean diffusivity (P < .03). With increasing severity of hemiparesis, fractional anisotropy decreased (P < .0001) and transverse diffusivity (P < .0001) and mean diffusivity (P < .02) increased in the affected pyramidal tract compared with controls. Diffusion metrics in the unaffected tract were similar to those in the control subjects. Asymmetry in fractional anisotropy, transverse diffusivity, and mean diffusivity, as well as the degree of abnormality in the actual values of the affected pyramidal tracts themselves, correlates with the severity of motor dysfunction in infants and children with congenital hemiparesis from different causes. This suggests that abnormalities detected by diffusion tensor MR imaging tractography in the affected pyramidal tract are related to the functional ability of the affected pyramidal tract, regardless of the etiology of motor dysfunction.


Discovery of a GPR40 Superagonist: The Impact of Aryl Propionic Acid α-Fluorination.
GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated insulin secretion from pancreatic beta cells and incretion release from enteroendocrine cells of the small intestine. GPR40 full agonists exhibit superior glucose lowering compared to partial agonists in preclinical species due to increased insulin and GLP-1 secretion, with the added benefit of promoting weight loss. In our search for potent GPR40 full agonists, we discovered a superagonist which displayed excellent in vitro potency and superior efficacy in the Gαs-mediated signaling pathway. Most synthetic GPR40 agonists have a carboxylic acid headgroup, which may cause idiosyncratic toxicities, including drug-induced-liver-injury (DILI). With a methyl group and a fluorine atom substituted at the α-C of the carboxylic acid group, 19 is not only highly efficacious in lowering glucose and body weight in rodent models but also has a low DILI risk due to its stable acylglucuronide metabolite.


Improving disulfide connectivity prediction with sequential distance between oxidized cysteines.
Predicting disulfide connectivity precisely helps towards the solution of protein structure prediction. In this study, a descriptor derived from the sequential distance between oxidized cysteines (denoted as DOC) is proposed. An approach using support vector machine (SVM) method based on weighted graph matching was further developed to predict the disulfide connectivity pattern in proteins. When DOC was applied, prediction accuracy of 63% for our SVM models could be achieved, which is significantly higher than those obtained from previous approaches. The results show that using the non-local descriptor DOC coupled with local sequence profiles significantly improves the prediction accuracy. These improvements demonstrate that DOC, with a proper scaling scheme, is an effective feature for the prediction of disulfide connectivity. The method developed in this work is available at the web server PreCys (prediction of cys-cys linkages of proteins).


[Endoscopic findings in the upper digestive tract in patients with terminal chronic kidney failure].
We studied patients undergoing hemodialysis awaiting renal transplantation who had routine endoscopy as preoperative evaluation. Medical histories of 71 patients transplanted between 1982-1989 were reviewed retrospectively in order to determine the results of the upper gastrointestinal lesions. At the time of the endoscopy the predictive variables studied were: age, sex, BUN, creatinine, hemoglobin, hematocrit, calcium and time on hemodialysis. The patients were divided in two groups: those with lesions and a control group without lesions. The comparison between the two groups was done using unpaired t-test for continual variables, X2 for dichotomous variables and p < 0.05 was considered as statistically significant. Thirty two patients (45%) had lesions in the upper gastrointestinal tract, in the esophagus: 17%, stomach 30% and duodenum: 23%. Age was the only predictive variables statistically significant for gastric lesions. We conclude that gastrointestinal lesions are frequent in patients with end stage renal failure. The gastric lesions were the most frequent and appeared in older patients. We recommend endoscopic studies in all end stage renal failure patients as part of the pre transplant evaluation. We also suggest endoscopy as follow up after transplantation.


Effect of Resistance Exercise on Arterial Stiffness during the Follicular and Luteal Phases of the Menstrual Cycle.
Acute high-intensity resistance exercise increases arterial stiffness. Changes in blood concentrations of estrogen and progesterone associated with the menstrual cycle affect the degree of arterial stiffness. Therefore, high-intensity resistance exercise may affect arterial stiffness differently depending on the phase of the menstrual cycle. The purpose of this study was to investigate the effects of different phases of the menstrual cycle on arterial stiffness after one session of resistance exercise. The participants were 9 eumenorrheic females (21.3±0.8 years). All participants performed 5 sets of 5 repetitions using 80% of the one repetition maximum (1RM) bench press and 5 sets of 10 repetitions using 70% of the 1RM biceps curl during both the follicular and luteal phases. Brachial-ankle pulse wave velocity (baPWV), blood pressure, and heart rate were measured before (baseline) and at 30 and 60 min after completing the resistance exercises. During the follicular phase, baPWV was significantly increased at 30 and 60 min after the resistance exercise compared with baseline (P<0.05), whereas during the luteal phase, no significant differences were observed after the resistance exercise. These results suggest that high-intensity resistance exercise affects arterial stiffness differently depending on the phase of the menstrual cycle.


Acid-base chemical mechanism of homocitrate synthase from Saccharomyces cerevisiae.
Homocitrate synthase (acetyl-coenzyme A:2-ketoglutarate C-transferase; E.C. 22.214.171.124) catalyzes the condensation of AcCoA and alpha-ketoglutarate to give homocitrate and CoA. The enzyme was found to be a Zn-containing metalloenzyme using inductively coupled plasma mass spectrometry. Dead-end analogues of alpha-ketoglutarate were used to obtain information on the topography of the alpha-ketoglutarate binding site. The alpha-carboxylate and alpha-oxo groups of alpha-ketoglutarate are required for optimum binding to coordinate to the active site Zn. Optimum positioning of the alpha-carboxylate, alpha-oxo, and gamma-carboxylate of alpha-ketoglutarate is likely mimicked by the location in space of the 2-carboxylate, pyridine nitrogen, and 4 carboxylate of pyridine 2,4-dicarboxylate. The pH dependence of the kinetic parameters was determined to obtain information on the chemical mechanism of homocitrate synthase. The V profile is bell shaped with slopes of 1 and -1, giving pKa values of 6.7 and 8.0, while V/K(AcCoA) exhibits a slope of 2 on the acidic side with an average pKa value of 6.6 and a slope of -2 on basic side of the profile with an average pKa value of 8.2. The V/K(alpha-Kg) pH-rate profile exhibits a single pKa of 6.9 on the acidic side and two on the basic side with an average value of 7.8. The pH dependence of the Ki for glyoxylate, a competitive inhibitor vs alpha-ketoglutarate, gives a pKa of 7.1 for a group, required to be protonated for optimum binding. Data suggest a chemical mechanism for the enzyme in which alpha-ketoglutarate first binds to the active site Zn via its alpha-carboxylate and alpha-oxo groups, followed by acetyl-CoA. A general base then accepts a proton from the methyl of acetyl-CoA, and a general acid protonates the carbonyl of alpha-ketoglutarate in the formation of homocitryl-CoA. The general acid then acts as a base in deprotonating Zn-OH2 in the hydrolysis of homocitryl-CoA to give homocitrate and CoA. A solvent deuterium kinetic isotope effect of 1 is measured for homocitrate synthase, while a small pH-independent primary kinetic deuterium isotope effect (approximately 1.3) is observed using deuterioacetyl-CoA. Data suggest rate-limiting condensation to form the alkoxide of homocitryl-CoA, followed by hydrolysis to give products.


Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease.
Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ∼20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.


Acrodysostosis: report of a 13-year-old boy with review of literature and metacarpophalangeal pattern profile analysis.
We report on a 13-yr-old boy with acrodysostosis, a review of 30 cases in the literature, and metacarpophalangeal pattern profile (MCPP) analysis. The prominent manifestations (present in greater than 75% of cases) of this condition include nasal and maxillary hypoplasia, peripheral dysostosis, first ray hyperplasia of the foot, acromesomelic brachymelia, decreased interpedicular distance, advanced skeletal maturation and mental retardation. Results of chromosome studies have been normal. An autosomal dominant inheritance pattern was reported in two families. Maternal and paternal ages were 2 and 3 yr, respectively, above the average age of the general parent population, which suggests that advanced parental age may be a factor in the cause of this condition. A characteristically abnormal MCPP was found in our patient and in 16 additional cases studied from the literature. A mean MCPP was developed for the syndrome. MCPP analysis may be useful as a diagnostic tool in patients suspected to have acrodysostosis.


Transcranial direct current stimulation produces long-lasting attenuation of cocaine-induced behavioral responses and gene regulation in corticostriatal circuits.
Transcranial direct current stimulation (tDCS) is a non-invasive method to modulate cortical excitability. This technique is a promising emerging tool to treat several neuropathologies, including addiction. We have previously shown in mice that repeated tDCS normalizes pathological behaviors associated with chronic nicotine exposure. Here, we evaluated, in adult female mice, the impact of tDCS on cocaine-induced behavior and gene regulation in corticostriatal circuits implicated in psychostimulant addiction. Anodal tDCS was applied transcranially over the frontal cortex. Three weeks after repeated tDCS, we investigated the induction of a gene expression marker (Zif268) by cocaine (25 mg/kg) in 26 cortical and 23 striatal regions using in situ hybridization histochemistry. We also assessed place preference conditioning by cocaine (5, 10 and 25 mg/kg). tDCS pretreatment increased basal expression and attenuated cocaine (25 mg/kg)-induced expression of Zif268 in specific corticostriatal circuits. Cocaine-induced locomotor activation (25 mg/kg) and place preference conditioning (5 and 25 mg/kg) were also reduced. These results demonstrate that tDCS can attenuate molecular and behavioral responses to cocaine for several weeks. Together, our findings provide pre-clinical evidence that such electrical brain stimulation may be useful to modify the psychostimulant addiction risk.


Cultural Adaptations in Clinical InteractiONs (CoACtION): a multi-site comparative study to assess what cultural adaptations are made by clinicians in different settings.
Culture influences models of mental illness, help-seeking behaviours and outcomes of interventions. Cultural competency training has been developed to improve clinician practice in addressing these issues. The study aims to identify to what extent culturally competent and informed interactions are used by clinicians in England and how patients experience these interaction. Clinicians and non-white western patients were recruited to complete a questionnaire on culturally adapted practice in 25 areas of England. Clinicians are much more likely to rate their practice as clinically competent whereas patients were more likely to disagree that services were completely culturally competent. Length of time working as clinicians, receipt of specific cultural competence training and a higher percentage of caseload from non-white western backgrounds all increased clinician's perception that their practice was culturally competent. Clinicians recognised the importance of cultural competency but the disparity between their assessment of whether they achieved this and that of patients must be addressed. Ethics approval was obtained via proportionate review from the London - Central Research Ethics Committee (REC Ref no: 17/LO/1962). Study registration: UK Clinical Research Network Portfolio: 36744.


[Proatherogenic lipid metabolism disturbances in impaired glucose tolerance].
The role of Impaired Glucose Tolerance (IGT) in the pathogenesis of cardiovascular complications is still underestimated. Besides proven doubled risk of diabetes mellitus, IGT patients present wide range of atherogenic disturbances such as insulin resistance, proinflammatory and procoagulant state and proatherogenic lipid changes. This paper reviews lipid metabolism disorders, such as elevation of free fatty acids and triglycerides level, structural changes of LDL (high level of "small dense" and modified LDL), HDL particles and more, as well as visceral obesity often observed in patients with IGT. Untreated IGT leads to diabetes mellitus and cardiovascular complications, consequently increasing risk of myocardial infarction and stroke. This supports the need for treatment at the stadium of IGT The therapy of Impaired Glucose Tolerance should be focused on body mass reduction, improvement of insulin sensitivity and lipid disturbances correction. The most common approach for overweight persons is a balanced-calorie diet and lifestyle change. According to several surveys the drugs reducing insulin resistance, such as biguanides or thiazolidinediones, as well as those improving lipid disorders (fibrates) seem to be efficient, but it needs to be confirmed in randomized clinical trials.


A technique for verifying the input response function of neutron time-of-flight scintillation detectors using cosmic rays.
An accurate interpretation of DD or DT fusion neutron time-of-flight (nTOF) signals from current mode detectors employed at the Z-facility at Sandia National Laboratories requires that the instrument response functions (IRF's) be deconvolved from the measured nTOF signals. A calibration facility that produces detectable sub-ns radiation pulses is typically used to measure the IRF of such detectors. This work, however, reports on a simple method that utilizes cosmic radiation to measure the IRF of nTOF detectors, operated in pulse-counting mode. The characterizing metrics reported here are the throughput delay and full-width-at-half-maximum. This simple approach yields consistent IRF results with the same detectors calibrated in 2007 at a LINAC bremsstrahlung accelerator (Idaho State University). In particular, the IRF metrics from these two approaches and their dependence on the photomultipliers bias agree to within a few per cent. This information may thus be used to verify if the IRF for a given nTOF detector employed at Z has changed since its original current-mode calibration and warrants re-measurement.


Perception of risk of developing diabetes in offspring of type 2 diabetic patients.
The risk of developing diabetes is high in the offspring of patients with type 2 diabetes. There have been no studies to assess the offspring's awareness of the risk of developing diabetes. The aim of this study was to investigate how the male offspring of type 2 diabetic patients assess their likelihood of developing diabetes. One hundred and one non-diabetic men with one or both parents having type 2 diabetes, aged 19-28 years, were recruited. Thirty-nine subjects (38.6%) were concerned about diabetes and 85 (84.2%) considered diabetes a serious problem. However, only 10 (9.9%) thought they might develop diabetes and 9 (8.9%) had previously attended diabetes education programs with their parents. The educational level amongst the diabetic parents was the only independent predictor of perception of the increased risk. Age, body mass index, waist-to-hip ratio, educational level and the perception of diabetes as a serious problem were not associated with perception of the increased risk. Most offspring of diabetic parents lacked knowledge about the increased risk amongst family members. We suggest that physicians and diabetic educators should provide knowledge about the increased risk of developing diabetes in offspring and the benefit of lifestyle modification to delay or prevent the development of the disease.


Synthesis of aromatic compounds containing a 1,1-dialkyl-2-trifluoromethyl group, a bioisostere of the tert-alkyl moiety.
1,1-Dialkyl-2-perfluoroalkyl compounds, which are potential metabolically stable bioisosteres of the tert-alkyl moiety, have been synthesized from the corresponding tertiary alcohols using titanium (IV) chloride-dimethylzinc or trimethylaluminium as the source of the methyl group. The synthetic methods proved to be versatile for synthesizing 1,1-dimethyl-2,2,2-trifluoroethyl compounds and analogs, including compounds containing aromatic and heterocyclic rings.


Oyster Shell Protein and Atomic Force Microscopy of Oyster Shell Folia.
The organic layers within biominerals often are viewed as sheets that may function in part to limit and define the underlying crystal structure, as well as to promote formation of the next mineral layer. Some insights into the nature of the sheets were revealed by atomic force microscopy (AFM) of surfaces of freshly cleaved fragments of oyster shell folia. Visible in the micrographs were arrays of globular structures that resembled the globules seen in isolated oyster shell protein bound to calcite, mica, and glass. The results of chemical treatment showed that the foliar globules slowly dissolved in 5.25% NaOCl or 1 N NaOH, reacted with an antibody prepared against an isolated oyster shell protein, and were hydrolyzed by several proteolytic enzymes. These morphological and chemical observations suggested that protein was a significant component of the foliar globules. Although they might also have a significant mineral content, the foliar globules were not effective as nucleators of CaCO3 crystal formation at low levels of supersaturation in artificial seawater. Overall, the results suggested that molecules of oyster shell protein may agglomerate and combine with mineral to form a surface of complex topography that coats the calcite laths but exhibits no obvious correspondence to any specific crystallographic plane.


Rationally Designed α-Conotoxin Analogues Maintained Analgesia Activity and Weakened Side Effects.
A lack of specificity is restricting the further application of conotoxin from Conus bullatus (BuIA). In this study, an analogue library of BuIA was established and virtual screening was used, which identified high α7 nicotinic acetylcholine receptor (nAChR)-selectivity analogues. The analogues were synthesized and tested for their affinity to functional human α7 nAChR and for the regulation of intracellular calcium ion capacity in neurons. Immunofluorescence, flow cytometry, and patch clamp results showed that the analogues maintained their capacity for calcium regulation. The results of the hot-plate model and paclitaxel-induced peripheral neuropathy model indicated that, when compared with natural BuIA, the analgesia activities of the analogues in different models were maintained. To analyze the adverse effects and toxicity of BuIA and its analogues, the tail suspension test, forced swimming test, and open field test were used. The results showed that the safety and toxicity of the analogues were significantly better than BuIA. The analogues of BuIA with an appropriate and rational mutation showed high selectivity and maintained the regulation of Ca2+ capacity in neurons and activities of analgesia, whereas the analogues demonstrated that the adverse effects of natural α-conotoxins could be reduced.


Expanded indications for transconjunctival trabeculectomy flap suturing: postoperative choroidal effusion and dysesthesia.
To assess the efficacy of transconjunctival trabeculectomy flap suturing (TTFS) in improving choroidal effusions and bleb dysesthesia resulting from overfiltration after trabeculectomy. Retrospective review. The study involved 15 eyes of 15 patients. Patients underwent TTFS for choroidal effusions and bleb dysesthesia following trabeculectomy using mitomycin C. The scleral flap was sutured through the conjunctiva as an outpatient clinic procedure. There were 11 patients who had choroidal effusions and 4 patients were identified with dysesthesia. The average duration of choroidal effusion prior to TTFS was 2.1 ± 2.3 months and 3 ± 2 months in the dysesthesia group. At the final follow-up (25 ± 17 months) the mean intraocular pressure improved from 4.1 ± 2.1 mm Hg before suturing to 8.1 ± 3.6 mm Hg (p < 0.007) for the patients with choroidal effusion and from 4.2 ± 0.6 mm Hg to 8. 7 ± 3.5 mm Hg (p = 0.05) for the patients with dysesthesia. In both groups, resolution of the signs and symptoms was achieved in all cases. The mean time to resolution of choroidal effusions was 5.5 ± 8.6 weeks and the mean time to resolution of dysesthesia was 2 ± 0.8 weeks. None of the patients had serious complications such as failure of the trabeculectomy or visual loss. Transconjunctival suturing of the trabeculectomy scleral flap is a simple and effective surgical method for the treatment of cases of choroidal effusions or dysesthesia resulting from trabeculectomy.


Increased health services use by severely obese patients undergoing emergency surgery: a retrospective cohort study.
The aim of this study was to assess perioperative outcomes in obese patients undergoing emergency surgery. We retrospectively reviewed the charts of all adult (> 17 yr) patients admitted to the acute care emergency surgery service at the University of Alberta Hospital between January 2009 and December 2011 who had a body mass index (BMI) of 35 or higher. Patients were divided into subgroups for analysis based on "severe" (BMI 35-39.9) and "morbid" obesity (BMI ≥ 40). Multivariate logistic regression was performed to identify predictors of in-hospital mortality after controlling for confounding factors. Data on 111 patients (55% women, median BMI 39) were included in the final analysis. Intensive care unit (ICU) support was required for 40% of patients. Postoperative complications occurred in 42% of patients, and 31% required reoperation. Overall in-hospital mortality was 17%. Morbidly obese patients had increased rates of reoperation (40% v. 23%, p = 0.05) and increased lengths of stay compared with severely obese patients (14.5 v. 6.0 d, p = 0.09). Age (odds ratio [OR] 1.08 per increment) and preoperative ICU stay (OR 12) were significantly associated with in-hospital mortality after controlling for confounding, but BMI was not. Obese patients requiring emergency surgery represent a complex patient population at high risk for perioperative morbidity and mortality. Greater resources are required for their care, including ICU support, repeat surgery and prolonged ICU stay. Future studies could help identify predictors of reoperation and strategies to optimize nutrition, rehabilitation and resource allocation.


Suprafamilial relationships among Rodentia and the phylogenetic effect of removing fast-evolving nucleotides in mitochondrial, exon and intron fragments.
The number of rodent clades identified above the family level is contentious, and to date, no consensus has been reached on the basal evolutionary relationships among all rodent families. Rodent suprafamilial phylogenetic relationships are investigated in the present study using approximately 7600 nucleotide characters derived from two mitochondrial genes (Cytochrome b and 12S rRNA), two nuclear exons (IRBP and vWF) and four nuclear introns (MGF, PRKC, SPTBN, THY). Because increasing the number of nucleotides does not necessarily increase phylogenetic signal (especially if the data is saturated), we assess the potential impact of saturation for each dataset by removing the fastest-evolving positions that have been recognized as sources of inconsistencies in phylogenetics. Taxonomic sampling included multiple representatives of all five rodent suborders described. Fast-evolving positions for each dataset were identified individually using a discrete gamma rate category and sites belonging to the most rapidly evolving eighth gamma category were removed. Phylogenetic tree reconstructions were performed on individual and combined datasets using Parsimony, Bayesian, and partitioned Maximum Likelihood criteria. Removal of fast-evolving positions enhanced the phylogenetic signal to noise ratio but the improvement in resolution was not consistent across different data types. The results suggested that elimination of fastest sites only improved the support for nodes moderately affected by homoplasy (the deepest nodes for introns and more recent nodes for exons and mitochondrial genes). The present study based on eight DNA fragments supports a fully resolved higher level rodent phylogeny with moderate to significant nodal support. Two inter-suprafamilial associations emerged. The first comprised a monophyletic assemblage containing the Anomaluromorpha (Anomaluridae + Pedetidae) + Myomorpha (Muridae + Dipodidae) as sister clade to the Castorimorpha (Castoridae + Geomyoidea). The second suprafamilial clustering identified a novel association between the Sciuromorpha (Gliridae + (Sciuridae + Aplodontidae)) and the Hystricomorpha (Ctenodactylidae + Hystricognathi) which together represents the earliest dichotomy among Rodentia. Molecular time estimates using a relaxed Bayesian molecular clock dates the appearance of the five suborders nearly contemporaniously at the KT boundary and this is congruent with suggestions of an early explosion of rodent diversity. Based on these newly proposed phylogenetic relationships, the evolution of the zygomasseteric pattern that has been used for a long time in rodent systematics is evaluated.


Theoretical study of the structures and electronic properties of all-surface KI and CsI nanocrystals encapsulated in single walled carbon nanotubes.
The structural and electronic properties of all-surface KI and CsI crystals encapsulated in single-walled carbon nanotubes are investigated theoretically with an ionic and atomistic approach using the GULP program. The short-range interactions, derived from Dirac-Fock wavefunctions, were augmented with damped dipole-dipole and dipole-quadrupole dispersive attractions. The uncorrelated interionic interactions computed using the relativistic crystal ion and relativistic integral programs accounted for anion in-crystal modifications while being exact given the ion wavefunctions. All the short-range correlation energies and the uncorrelated interactions between the ions and carbon atoms were computed using the density functional theory of a uniform electron gas of infinite extent. Unphysical self-interactions were removed by scaling the exchange interaction with a Rae factor derived from a study of the adsorption of noble gases on graphite. The predictions for the nonencapsulated crystals agreed well with those previously derived from a global analytic theory based on the Born model. This provided a good description of the contraction of the interplane distance (b) relative to the separation (R(e)) in the rocksalt structured bulk material although failing to account for the observed dilation of the intraplane ionic separations (a). Introduction of the interactions with the nanotube wall, including the ion-nanotube dispersive attractions, increased the predicted a values although these were still significantly smaller than experiment. The predicted b separations were reduced compared with those for the nonencapsulated crystals to values significantly less than observed. It is explained why introducing any ion-nanotube interactions that are sufficiently attractive as to reproduce the experimental a values must significantly underestimate the b separations. The partial transfer of anion electrons to the nanotube carbon atoms, not considered hitherto, was described by decomposing the intra-atomic interactions of both the nanotube pi- and the iodide 5p-electrons into an effective one-electron term plus the repulsion between electrons in the same orbital. These energies were derived from electronic structure computations with the additional interspecies electrostatic repulsions derived from the GULP program. Structural predictions are presented as a function of the number (n) of electrons transferred from each anion. For both KI and CsI, the structure predicted by that computation, which minimized the total energy, in contrast to the other calculations, agreed well with experiment reproducing both the significant dilation of a and the smaller contraction of b. The respective n values (n(t)) predicting the lowest energies are 0.278 and 0.285. These results are supported by comparing the experimental frequencies of Raman modes attributable to vibrations of nanotubes encapsulating KI with the corresponding frequencies for systems where independently known numbers of electrons were transferred to the nanotubes. In both the encapsulated KI and CsI systems, the charge transfer is driven by the reduction of the electron repulsion on delocalizing some anion charge over the significantly greater number of nanotube carbon atoms. A simplified analytic model, which reproduces the charge transfers, explains why n(t) is slighter larger for CsI and also predicts that n(t) will be insensitive to the structure of the nanotube.


Inhibition of the Inflammasome Activity of NLRP3 Attenuates HDM-Induced Allergic Asthma.
Inhaled allergens promote inflammatory response, tissue damage, and airway hyperresponsiveness in the lungs, leading to allergic asthma. NLRP3, as an immune sensor of infections and cellular stress, is associated with the development and exacerbation of asthma. However, the mechanism by which NLRP3 affects asthma requires further investigation. Here, we showed that inhaled house dust mite (HDM) promotes NLRP3 inflammasome activation in the lungs and specifically induces the maturation of caspase-1 and IL-1β in alveolar macrophages (AMs). Using Nlrp3-mutant mice, we found that NLRP3 promotes the inflammatory response and pathogenesis in HDM-induced allergic asthma in an inflammasome-dependent manner. Treatment with RRx-001, an NLRP3 inhibitor, significantly reduced inflammatory cell infiltration and mucus secretion in the airway. Our results showed that NLRP3 in myeloid cells promoted the development and progression of allergic asthma in an inflammasome-dependent manner. Small molecules targeting the NLRP3 inflammasome may provide new treatment options for this disease.


Association of Khat Use Disorder and Antisocial Personality Disorder Among Inmates in Ethiopia: A Cross-Sectional Study.
Objective: To examine the relationship between khat use disorder and antisocial personality disorder in newly admitted inmates in a correctional facility in Ethiopia. Methods: A cross-sectional study using successive sampling was conducted among 411 new inmates from April 20 to July 19, 2019. The Alcohol, Smoking, and Substance Involvement Screening Test was utilized to measure khat use. DSM-5 diagnostic criteria were used to identify antisocial personality disorder. Environmental, criminal, and clinical backgrounds of the inmates were also evaluated. Results: The prevalence of current khat use and khat use disorder was 49.4% and 37%, respectively. The prevalence of khat use disorder among inmates with antisocial personality disorder was 76%. Inmates with antisocial personality disorder were twice as likely as those without antisocial personality disorder to have khat use disorder (adjusted odds ratio [AOR] = 2; 95% CI, 1.2-3.4). Punishment for misconduct in prior imprisonment (AOR = 3; 95% CI, 1.6-5.3), family history of alcohol use (AOR = 2; 95% CI, 1.3-3.5), and chronic physical illness (AOR = 5.3; 95% CI, 2.4-11.8) were significantly associated with khat use disorder. Conclusions: The prevalence of khat use disorder was higher among inmates with antisocial personality disorder, and antisocial personality disorder is linked to khat use disorder. The findings of this study suggest the need for the establishment of a mental health system in all prison institutions in Ethiopia to enhance early screening for underlying medical conditions, history of substance use, and antisocial personality disorder. Those inmates with identified substance use need detoxification therapy and motivational interviews after prison admission. Prim Care Companion CNS Disord 2023;25(5):22m03470. Author affiliations are listed at the end of this article.


Second-harmonic diffraction from holographic volume grating.
The full polarization property of holographic volume-grating enhanced second-harmonic diffraction (SHD) is investigated theoretically. The nonlinear coefficient is derived from a simple atomic model of the material. By using a simple volume-grating model, the SHD fields and Mueller matrices are first derived. The SHD phase-mismatching effect for a thick sample is analytically investigated. This theory is justified by fitting with published experimental SHD data of thin-film samples. The SHD of an existing polymethyl methacrylate (PMMA) holographic 2-mm-thick volume-grating sample is investigated. This sample has two strong coupling linear diffraction peaks and five SHD peaks. The splitting of SHD peaks is due to the phase-mismatching effect. The detector sensitivity and laser power needed to measure these peak signals are quantitatively estimated.


Voltage regulation of connexin channel conductance.
Voltage is an important parameter that regulates the conductance of both intercellular and plasma membrane channels (undocked hemichannels) formed by the 21 members of the mammalian connexin gene family. Connexin channels display two forms of voltage-dependence, rectification of ionic currents and voltage-dependent gating. Ionic rectification results either from asymmetries in the distribution of fixed charges due to heterotypic pairing of different hemichannels, or by channel block, arising from differences in the concentrations of divalent cations on opposite sides of the junctional plaque. This rectification likely underpins the electrical rectification observed in some electrical synapses. Both intercellular and undocked hemichannels also display two distinct forms of voltage-dependent gating, termed Vj (fast)-gating and loop (slow)-gating. This review summarizes our current understanding of the molecular determinants and mechanisms underlying these conformational changes derived from experimental, molecular-genetic, structural, and computational approaches.


Effects of sprint interval exercise dose and sex on circulating irisin and redox status markers in adolescent swimmers.
Irisin and redox status markers seem to share common pathways of exercise-induced upregulation. The aim of the present study was to assess the effects of sprint interval swimming exercise dose and sex on the circulating levels of irisin and redox status markers in adolescent swimmers. Sixteen male and 16 female adolescent swimmers completed two sets of 4 × 50 m maximal freestyle swimming with a send-off time of 90 s, separated by 10 min of passive recovery. Venous blood samples were obtained pre-exercise (Pre), after the first set (Post1) and after the second set (Post2). Males had higher irisin levels than females. Reduced glutathione (GSH, μmol g Hb-1) increased from 8.6 (2.2) [pooled males and females, mean (SD) throughout] at Pre to 9.4 (2.1) at Post1 and Post2. Total antioxidant capacity (μmol DPPH mL-1) increased from 0.89 (0.17) at Post1 to 0.94 (0.16) at Post2. 8-hydroxy-2´-deoxyguanosine (ng mL-1) increased from 20.9 (6.9) at Pre and 21.5 (7.1) at Post1 to 25.0 (10.9) at Post2. Overall, sprint interval swimming exercise induced small but potentially effective changes in the studied parameters. Exercise dose influenced the GSH and 8-OHdG responses, and sex affected irisin levels.


Enhanced antimicrobial de-escalation for pneumonia in mechanically ventilated patients: a cross-over study.
Antibiotics are commonly administered to hospitalized patients with infiltrates for possible bacterial pneumonia, often leading to unnecessary treatment and increasing the risk for resistance emergence. Therefore, we performed a study to determine if an enhanced antibiotic de-escalation practice could improve antibiotic utilization in mechanically ventilated patients with suspected pneumonia cared for in an academic closed intensive care unit (ICU). This was a prospective cross-over trial comparing routine antibiotic management (RAM) and enhanced antimicrobial de-escalation (EAD) performed within two medical ICUs (total 34 beds) at Barnes-Jewish Hospital, an academic referral center. Patients in the EAD group had their antibiotic orders and microbiology results reviewed daily by a dedicated team comprised of a second-year critical care fellow, an ICU attending physician and an ICU pharmacist. Antibiotic de-escalation recommendations were made when appropriate based on microbiologic test results and clinical response to therapy. There were 283 patients evaluable, with suspected pneumonia requiring mechanical ventilation: 139 (49.1%) patients in the RAM group and 144 (50.9%) in the EAD group. Early treatment failure based on clinical deterioration occurred in 33 (23.7%) and 40 (27.8%) patients, respectively (P = 0.438). In the remaining patients, antimicrobial de-escalation occurred in 70 (66.0%) and 70 (67.3%), respectively (P = 0.845). There was no difference between groups in total antibiotic days ((median (interquartile range)) 7.0 days (4.0, 9.0) versus 7.0 days (4.0, 8.8) (P = 0.616)); hospital mortality (25.2% versus 35.4% (P = 0.061)); or hospital duration (12.0 days (6.0, 20.0) versus 11.0 days (6.0, 22.0) (P = 0.918). The addition of an EAD program to a high-intensity daytime staffing model already practicing a high-level of antibiotic stewardship in an academic ICU was not associated with greater antibiotic de-escalation or a reduction in the overall duration of antibiotic therapy. ClinicalTrials.gov, NCT02685930 . Registered on 26 January 2016.


Profiling Long Non-coding RNA expression Using Custom-Designed Microarray.
Long non-coding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. The abnormal expression of lncRNAs has been implicated in a range of many human diseases, including cancer. To date, a small number of functional lncRNAs have been well characterized. lncRNA expression profiling may help to identify useful molecular biomarkers and targets for novel therapeutic approaches. In this chapter, we describe a highly efficient lncRNA expression profiling method using a custom-designed microarray.


Shell Growth and Structure of Planktonic Foraminifera.
Planktonic foraminiferal tests show bilamellar additions to each chamber and develop a "secondary thickening" in the form of a calcite crust in late ontogeny. The evidence presented indicates that additional calcium carbonate is deposited upon the original bilamellar test and that maximum calcite crust thickness is attained at depths greater than 500 meters.


Ondansetron induced blindness: a pharmacovigilance database study.
Ondansetron is an antiemetic drug (AED) used to prevent and treat nausea and vomiting. The summary of product characteristics reports a rare risk of transient blindness primarily during IV injections, notably with the concomitant use of chemotherapeutic agents. We aimed to refine the characterization of ondansetron-induced blindness. We performed a descriptive and a case/non-case analysis using VigiBase®. Cases were defined as reports of adverse drug reactions (ADRs) related to blindness: amaurosis, amaurosis fugax, blindness. Non-cases were all other recorded reactions. Reporting risk of blindness-related ADRs was assessed using a disproportionality analysis and expressed as Reporting Odds Ratios (ROR). 138,315 ADRs were reported with AEDs, including 136 blindness-related ADRs, among them 44 (32.4%) with ondansetron. For ondansetron users, blindness-related ADRs occurred mainly on the first day. Out of the 25 patients with known outcomes, 18 (72.0%) were recovering or had recovered, 7 (28.0%) patients had not recovered There were no statistical differences in the number of cases for IV or oral users and for users or not of chemotherapeutic agents. Compared with other AEDs, ondansetron was associated with an increase in the reporting risk of blindness-related ADRs (ROR = 4.00 [2.79-5.72], p < 0.001). Rarely blindness can occur following intravenous or oral administration of ondansetron.


Collaborative Deprescribing in Borderline Personality Disorder: A Narrative Review.
After participating in this activity, learners should be better able to:• Assess medication management in patients with borderline personality disorder (BPD)• Evaluate the role of deprescribing as an active intervention in patients with BPD treated with polypharmacy ABSTRACT: Psychopharmacology in borderline personality disorder (BPD) is complicated by comorbid disorders, substance use, sensitivity to side effects, risk of self-harm through medication misuse, and intense but transient symptoms. Patients' relationships with medications may range from tenuous to highly enmeshed, and may profoundly influence the response to treatment. For these reasons, awareness of current evidence and flexible approaches are particularly relevant to prescribing in BPD. In this narrative review, we illustrate the current status of medication management in BPD by focusing on polypharmacy. We use a single vignette to explore the limitations of prescribing multiple medications and the factors contributing to polypharmacy. With the same vignette, and using the framework of deprescribing, we describe how medication regimens can be reduced to a necessary minimum. Deprescribing, originally developed in geriatric medicine, is an active intervention that involves a risk-benefit analysis for each medication, keeping in mind the patient's medical and psychiatric status and his or her preferences and values. Deprescribing lends itself well to use in psychiatry and especially in BPD because of its emphasis on the patient's preferences and on repeated conversations to revisit and update decisions. In addition to elaborating on the deprescribing framework, we provide recommendations for conducting these critical discussions about medications in BPD, with particular attention to the patient's relationship to the medication. Finally, we summarize our recommendations and strategies for implementing flexible and responsive medication management for patients with BPD. We suggest areas of future research, including testing the efficacy of targeted intermittent medication treatments.


Assessment of the antioxidant activity of an olive oil total polyphenolic fraction and hydroxytyrosol from a Greek Olea europea variety in endothelial cells and myoblasts.
Olive oil (OO) constitutes the basis of the Mediterranean diet, and it seems that its biophenols, such as hydroxytyrosol (HT) may scavenge free radicals, attracting distinct attention due to their beneficial effects in many pathological conditions, such as cancer. To the best of our knowedge, this is the first study in which the functional properties of an OO total polyphenolic fraction (TPF) and pure HT were examined in order to determine their antioxidant effects at a cellular level in endothelial cells and myoblasts. The test compounds were isolated using a green gradient‑elution centrifugal partition chromatography‑based method that allows the isolation of large volumes of OO in a continuous extraction procedure and with extremely low solvent consumption. For the isolation of HT, a combination of two chromatographic techniques was used, which is effective for the recovery of pure compounds from complex natural extracts. Moreover, TPF and HT exhibited potent free radical scavenging activity in vitro. The cells were treated with non‑cytotoxic concentrations and their redox status [in terms of glutathione (GSH) and reactive oxygen species (ROS) levels] was assessed. TPF extract was less cytotoxic than HT, and the observed differences between the two cell lines used suggest a tissue‑specific activity. Finally, flow cytometric analysis revealed that both TPF and HT improved the redox status by increasing the levels of GSH, one of the most important antioxidant molecules, in both endothelial cells and myoblasts, while the ROS levels were not significantly affected.


[For a history of medical teaching in the 'Marche". Libraries and universities: Lancisi and the University Library of Urbino].
During the Modern Age, in the Marche, in the Pontifical State, it was possible to study medicine and to obtain a degree in medicine in Macerata, Fermo, Urbino, Camerino and Fano. In these cities, from the end of the XVII century to the beginning of the XIX century, public libraries were founded also to support academic teaching. Private collections of medical books, generally formed in Rome, arrived in the Marche to increase the newborn public libraries. In 1720 Pope Clemens XI founded a public library in the monastery of Saint Francis in Urbino. In this library the medical books were bequeathed by the famous Roman physician Giovanni Maria Lancisi. The present article provides the first results of a research, which aims at identifying Lancisi's medical books.


Circulating galanin and IL-6 concentrations in gestational diabetes mellitus.
The aim of this study is to compare galanin and IL-6 levels in pregnant women with gestational diabetes mellitus (GDM) and normal glucose tolerance (NGT). Also association of insulin resistance markers, galanin and IL-6 was investigated. The study registered 30 pregnant women with GDM and 30 pregnant women with NGT. Fasting venous blood samples were collected from all patients. Galanin and IL-6 levels were measured by an enzyme-linked immunosorbent assay. Galanin and IL-6 levels were found higher in pregnant women with GDM (p < 0.001). A significant positive correlation was determined between galanin concentrations and glucose (r = 0.240, p = 0.065), insulin (r = 0.681, p < 0.001), HbA1c (r = -0.644, p < 0.001), IL-6 (r = 0.783, p < 0.05) and oral glucose challenge test results (r = 0.745, p < 0.001) in pregnant women included in study, whereas no significant association was determined between galanin and gestational age (r = 0.058, p = 0.662), body mass index (r = -0.019, p = 0.886). Galanin and IL-6 were found to be significantly associated with insulin resistance markers in GDM, thus may play important roles in regulation of glucose hemostasis.


In vitro reconstituted skin as a tool for biology, pharmacology and therapy: a review.
Various culture procedures, suitable to maintain the differentiated phenotype of various types of cells in vitro, have been devised during the past decade. These culture systems use macromolecular components extracted from extracellular matrixes or synthetic polymers which provide cells with a three-dimensional, spatially structured support. Substantial information has come from the use of collagen lattices. Many types of cells, of mesenchymal or other origin, are able to organize collagen fibrils in these models and to form a connective tissue-like structure. Prerequisites for this process are active function of the cytoskeleton and the expression of alpha(2)beta(1) integrin collagen receptors. Interaction of cells with such a matrix has profound effects on morphologic status, proliferation, cellular metabolism, and state of differentiation. The in vitro procedures reviewed and described in this article offer the possibility to combine different types of cells to approximate the in vivo environment and to investigate such physiologic processes as cell-cell and cell-matrix interactions which are otherwise not easily accessible. In pathologic conditions of the skin, these models have proven to be useful tools in investigating diseases relating to impaired recognition of extracellular matrix structures or alterations of cytoskeletal assembly. In pharmacologic and toxicologic studies, activity of drugs and potentially useful therapeutic substances has been evaluated. The use of cells and matrix components derived from skin has lead to refined systems which could be adapted and extended to other organs in an attempt to better understand pathophysiologic mechanisms.