Influence of preprocedural glycemic control on clinical outcomes of endovascular therapy in diabetic patients with lower extremity artery disease: an analysis from a Korean multicenter retrospective registry cohort.
The influence of intensive glucose control in diabetic patients on the macrovascular outcomes is controversial. Thus, this study aimed to elucidate the effect of preprocedural hemoglobin A1c (HbA1c) on clinical outcomes after endovascular therapy for lower extremity artery disease (LEAD) in diabetic patients. Diabetic patients were enrolled from the retrospective cohorts of a Korean multicenter endovascular therapy registry and were divided according to the HbA1c level during index admission into the optimal (< 7.0%) or suboptimal (≥ 7.0%) glycemic control groups. The primary endpoints were major adverse limb events (MALE, a composite of major amputation, minor amputation, and reintervention). Of the 1103 patients enrolled (897 men, mean age 68.2 ± 8.9 years), 432 (39.2%) were classified into the optimal glycemic control group and 671 (60.8%) into the suboptimal glycemic control group. In-hospital events and immediate procedural complications were not different between the two groups. The suboptimal group showed a trend towards a higher incidence of MALE than the optimal group (log-rank p = 0.072). Although no significant differences were found between the two groups in terms of overall survival or amputation, the risk of reintervention was significantly higher in the suboptimal group (log-rank p = 0.048). In the multivariate Cox regression model, suboptimal glycemic control was one of the independent predictors for reintervention. When our data were analyzed according to the initial presentation, suboptimal preprocedural HbA1c significantly increased the incidence of MALE compared with optimal preprocedural HbA1c only in patients with intermittent claudication. In diabetic patients undergoing endovascular therapy for LEAD, suboptimal preprocedural HbA1c is associated with an increased risk of adverse limb events, especially in patients with intermittent claudication. Further prospective research will be required to validate the role of more intensive glycemic control on the reduction of adverse limb events in diabetic patients undergoing endovascular therapy for LEAD.


Factors influencing the scientific performance of Momentum grant holders: an evaluation of the first 117 research groups.
The Momentum program launched in 2009 provides funding of up to 1 million Euro to establish new, independent research groups at Hungarian academic institutions. Here, our aim was to determine factors associated with the scientific output of these research groups. Publication data were downloaded from the Hungarian Scientific Work Archive (www.mtmt.hu), impact factor data were obtained from Thomson Reuters (jcr.incites.thomsonreuters.com), and journal ranks were extracted from the Scimago Journal Rank database (www.scimagojr.com). Investigated input features for each grant holder include gender, degree, targeted category, international mobility, international grants, number of publications, total number of citations, H-index, best publications, impact factors in the last 2 years, and assessment scores provided by the experts. Evaluated performance indicators include cumulative impact factor, number of D1 publications, and number of first/last author D1 publications during the grant running time. Grant holders' publication output increased by 23 and 52% for life sciences and material sciences researchers. Scientific performance was independent from gender, degree, international grants, category applied for, and citations received for the best pre-grant publication. Those with international mobility had significantly lower scientific output (yearly impact factor, number of D1 publications, number of first/last author publications). Scores received from grant review experts were independent from later publication activity. The strongest correlations were observed between scientific output and total number of citations, H-index, and impact factor in the last 2 years pre-grant. In summary, group leaders with a dynamic publication track record were able to attain the most additional momentum. Our results can help accelerate and improve future grant review processes.


Adhesion and activation molecules expressed by human natural killer cells.
Our study concerns the expression and the regulation of adhesion and activation receptors on human NK cells. In particular we provide evidence on: a) the expression on fresh human NK cells of VLA-4, VLA-5 and VLA-6, extracellular matrix (ECM) receptors of integrin family capable of mediating their adhesion to FN and LM; b) the role of PKC on the regulation of CD16, a differentiation antigen associated with FcγR type III expressed by all NK cells, which mediate ADCC activity and trigger lymphokine production.


Comparison of two contraceptive pills containing drospirenone and 20 μg or 30 μg ethinyl estradiol for polycystic ovary syndrome.
To compare the effects of 30 μg and 20 μg ethinyl estradiol (EE) among women with polycystic ovary syndrome (PCOS). In a randomized study, patients with PCOS, a history of six or fewer menstrual cycles in the previous 12 months, and abnormal body hair growth were enrolled at a center in Kolkata, India, between May 1, 2012, and January 31, 2014. Participants were randomly assigned (1:1) using a computer-generated randomization table to receive an oral contraceptive pill containing 3mg drospirenone and either 30 μg EE or 20 μg EE. Patients were followed up after 6 and 12 months. The primary outcome was the absolute change in the free androgen index. Participants were masked to group assignment but investigators were not. Analyses were by intention to treat. Overall, 112 patients were enrolled. At 6 months, the free androgen index had decreased by 4.96±6.01 among patients receiving 30 μg (n=55) and by 4.81±6.03 among those receiving 20 μg (n=57; P=0.89). At 12 months, the decrease from baseline was 5.23±5.79 with 30 μg and 4.99±5.86 with 20 μg (P=0.82). Among patients with PCOS, an oral contraceptive pill containing 20 μg EE has similar effects on androgen levels to those of a pill containing 30 μg. CTRI/2012/04/002571.


Susceptibility to oxidative stress of mussels (Mytilus galloprovincialis) in the Venice Lagoon (Italy).
The aim of this study was to evaluate the susceptibility to pollutant mediated oxidative stress of the Mediterranean mussel Mytilus galloprovincialis in the Venice lagoon (Italy). In June 2003, mussels from a farm were transplanted to eight sites in the lagoon for five weeks. Oxidative stress responses were measured by: (i) total oxyradical scavenging capacity (TOSC) assay, for an overall evaluation of the oxidative stress response capability; (ii) catalase (CAT), as a key enzyme involved in the antioxidant defence system; (iii) malondialdehyde (MDA), as an indicator of lipid peroxidation, to evaluate an oxidative damage; (iv) metallothioneins (MTs), as they play a role in the antioxidant defence. The TOSC analysis revealed a reduced capability to eliminate: (i) peroxyl radical in mussels transplanted at Palude della Rosa, Valle Millecampi and Chioggia; (ii) hydroxyl radical at Campalto and Valle Millecampi; (iii) peroxynitrite at Valle Millecampi. Inhibition in CAT activity, observed in all the monitored sites, confirms the presence of an oxidative pressure in transplanted mussels. In addition, Pearson correlation analysis was performed in order to observe possible links between the various parameters. The PCA was a powerful tool to discriminate impacted sites, suggesting that the mussels transplanted throughout the Venice lagoon were subjected to different levels of oxidative pressure. Furthermore, it provided an easy and useful tool to summarize the obtained results.


The postmitotic midbody: Regulating polarity, stemness, and proliferation.
Abscission, the final stage of cell division, requires well-orchestrated changes in endocytic trafficking, microtubule severing, actin clearance, and the physical sealing of the daughter cell membranes. These processes are highly regulated, and any missteps in localized membrane and cytoskeleton dynamics often lead to a delay or a failure in cell division. The midbody, a microtubule-rich structure that forms during cytokinesis, is a key regulator of abscission and appears to function as a signaling platform coordinating cytoskeleton and endosomal dynamics during the terminal stages of cell division. It was long thought that immediately following abscission and the conclusion of cell division, the midbody is either released or rapidly degraded by one of the daughter cells. Recently, the midbody has gained prominence for exerting postmitotic functions. In this review, we detail the role of the midbody in orchestrating abscission, as well as discuss the relatively new field of postabscission midbody biology, particularly focusing on how it may act to regulate cell polarity and its potential to regulate cell tumorigenicity or stemness.


The effect of light-emitting diode (590/830 nm)-based low-level laser therapy on posttraumatic edema of facial bone fracture patients.
Posttraumatic edema in facial bone fracture patients may interfere with the operation field and delay the schedule. Thus, swiftly reducing the edema alleviates patient discomfort and advances the operation date. Ice packing and compression bandages are often used for such a purpose, but such methods are often inconvenient for the face. In this study, we aim to analyze the effect of light-emitting diode (LED) (590/830 nm)-based low-level laser therapy (LLLT) in posttraumatic edema in facial bone fracture patients. We conducted a prospective cohort study of 40 patients who were admitted to a single institution for facial bone fracture. The patients were divided into two groups of 20 each, treated either with LLLT or with sham treatment light. We used an LLLT device that consists of planar LED-based arrays with double wavelengths 590 nm and 830 nm. The patients were treated with either true or sham light from posttraumatic day 1-5, twice a day. After each treatment, the volume of a patient's face was measured with a 3-dimensional camera. We analyzed and compared the changes in facial edema. The Wilcoxon rank sum test was conducted for statistical comparison of the two groups, and significance was set to the level of p < 0.05. The sex ratio and mean age of the two groups were of little difference. The fracture sites included the nasal bone, orbital wall, zygomaticomaxillary bone, mandible, and frontal sinus. Mechanisms of injury included fall, assault, traffic accident, sports, and gunshot. The total operation rate of both groups was equal to 85%. Our analysis showed a 16.5% reduction of edema in the LLLT group and 7.3% in the sham light group. The edema reduction was statistically significantly greater in the LLLT group than in the sham light group (p < 0.047). LED-based LLLT is recently receiving attention worldwide for its cost-effectiveness and large coverage area compared to traditional laser therapy. Recent studies support its effectiveness in various areas such as wound healing, skin rejuvenation, and pain alleviation. In this study, we treated facial bone fracture patients with LED-based LLLT, and showed its effectiveness in reducing posttraumatic edema.


The effects of photoperiod on the switching of myometrial contractility patterns of pregnant baboons: relationship to surgery and parturition.
Pregnant baboons were studied to determine the precise time of the switch from myometrial contractures to contractions in relation to photoperiod after laparotomy and at parturition. We compared the patterns recorded in baboons to those we have previously reported in pregnant rhesus monkeys to determine fundamental primate characteristics. Seven pregnant baboons (126-160 days' gestation) were instrumented with femoral arterial and venous catheters and electrodes for myometrial electromyogram. All animals were subjected to a 14-hour light:10-hour dark photoperiod. Myometrial activity was monitored using a computer-based data acquisition system. Onset time for all switches was noted and standardized against time of lights off. Animals were studied at three stages of pregnancy (stage 1, first 10 days after laparotomy; stage 2, more than 10 days after laparotomy and more than 10 days before cesarean; and stage 3, 10 days before cesarean section or vaginal delivery). All baboons demonstrated myometrial switches for a variable number of days preceding parturition. Onset of darkness was 0 hours. Average time of stage 1 switch onset was 2.17 +/- 0.60 hours and was not different from stage 3 switch onset, which was -1.00 +/- 0.27 hours. Myometrial contractile patterns showed clear photoperiodicity in the switch from contractures to contractions in late pregnancy in the baboon. The relationship of the switch from contractures to contractions was not altered by surgical laparotomy. There was a significant difference in the time of switch in relation to photoperiod between pregnant rhesus monkeys and baboons. However, the fact that a significant photoperiod exists in both species indicates a fundamental similarity in the switch from contractures to contractions in primate pregnancy.


Comparison of two enzyme immunometric assays to measure tumor necrosis factor-alpha in human serum.
Tumor necrosis factor-alpha is a 17.5 kDa, 157 amino acid protein that is a potent lymphoid factor, which exerts cytotoxic effects on a wide range of tumor cells and other target cells. TNF-alpha has been suggested to play a pro-inflammatory role by influencing transendothelial migration of monocytes and elicits the expression of proteolytic enzymes by macrophages and smooth muscle cells within the atherosclerotic plaque. We compared two methods for the quantitative determination of human tumor necrosis factor-alpha in serum samples. Either kit follows the same assay procedure. Serum samples do not need to be diluted before sampling. Standard is provided lyophilized and serial dilutions after reconstitution generate the standard point curves. The tests are enzyme immunometric assays based on a standard 96-well microtiter plate. The wells are coated with anti-human TNF-alpha antibody. The range of the standard curve is similar in both kits. It spans from 1000 through 15.6 pg/mL. The median TNF-alpha concentration in samples measured by Pierce assay (n=368) was 4.23 pg/mL, (range, 1.34-77.2 pg/mL). A very different median was obtained for the same specimen measured with the Titerzyme EIA (median, 176.96 pg/mL; range, 54.7-283.9 pg/mL; n=364). Substantial significant differences were observed between the two methods. Our results show that the two kits are unmatchable for results they can give when TNF-alpha concentrations are measured in serum samples. One reason of this disagreement could be the matrix effect or a cross-reactivity of one of the two methods. This study shows that the determination of human serum TNF-alpha needs to be standardized, especially when a comparison of results is required.


Characterization of a new TEM-type beta-lactamase resistant to clavulanate, sulbactam, and tazobactam in a clinical isolate of Escherichia coli.
A clinical Escherichia coli strain highly resistant to the combinations of amoxicillin-clavulanate, ampicillin-sulbactam, and piperacillin-tazobactam was isolated from a patient with a community-acquired urinary tract infection who was previously treated with amoxicillin-clavulanate. These resistances were carried by a 45-kb conjugative plasmid encoding for a single beta-lactamase with a pI of 5.4. Cloning and sequencing of the new beta-lactamase, IRT-3, revealed identity with the blaT1 gene encoding the TEM-1 beta-lactamase except for a replacement of the methionine residue at position 67 by isoleucine and of the methionine residue at position 180 by threonine. Both mutations were segregated by the construction of hybrid genes, and only the mutation at methionine at position 67 was related to resistance to the suicide inhibitors. The inhibitory effects of clavulanate, sulbactam, and tazobactam on the TEM-1 enzyme were substantially decreased in comparison with those on IRT-3, as indicated by the 50% inhibitory concentrations.


Alarming incidence of genital mycoplasmas among HIV-1-infected MSM in Jiangsu, China.
Males who have sex with men (MSM) are considered at high risk of blood-borne and sexually transmitted infections (STIs), mainly due to the practice of unsafe sex, often combined with drug use and needle-sharing. A cross-sectional study was designed for the detection of genital mycoplasmas during the period from March 2009 to May 2010 in Jiangsu province. This work was approved by the Research ethics Committee of Jiangsu Centers for Diseases Prevention and Control (CDC), and written consent was obtained from all participants. In total, 243 human immunodeficiency virus-1 (HIV-1)-infected MSM were screened in this study. Over half of them reported a history of sexual activity with females (65.0 %), and 26.3 % reported a history of sexually transmitted diseases (STDs) other than HIV. 44.0 % of patients were in the first 2 years of their HIV infection, and 72.4 % were still in HIV progression. Of the 243 analyzed samples, all were positive for at least one kind of mycoplasma. The infection rates of Mycoplasma genitalium, M. fermentans, M. penetrans, and M. pirum were 25.5, 9.9, 2.5, and 18.5 %, respectively. The M. genitalium infection was associated with a history of sexual activity with females, and those who had sex with females showed higher infection rates. Six M. penetrans-positive patients were still in HIV infection progression and did not receive highly active antiretroviral therapy (HAART). Men who perform this particular behavior are at higher risk of Mycoplasma infections. Further molecular and epidemiological cohort studies with larger populations are needed in order to identify the role of Mycoplasma infections in HIV-1-infected MSM.


Primary enforcement seat belt laws are effective even in the face of rising belt use rates.
A recent systematic literature review found that primary enforcement laws are more effective at increasing seat belt use than secondary laws in the United States. This report re-examines the studies included in the systematic review to explore whether the benefits of a primary law differ based on: (1) the baseline seat belt use rate; or (2) whether or not the primary law replaces a secondary law. States that directly enacted primary laws showed larger increases in observed seat belt use (median increase of 33 percentage points). These laws were enacted in the mid-1980s, when baseline belt use rates were below 35%. Smaller, but substantial increases in belt use were observed in states that replaced secondary with primary laws (median increase of 14 percentage points). Baseline belt use rates in these states ranged from 47 to 73%. Primary safety belt laws can further increase seat belt use even in states with relatively high baseline levels of belt use.


[First outcomes, since being full member of Eurotransplant. A single center experience of cadaveric kidney transplantation].
The first renal transplantation was completed in 1991 at the University of Debrecen. In 2013 Hungary joined Eurotransplant. The authors retrospectively compared the trends. Comparison between Period A (from January 1, 2008 to August 31, 2013) and Period B (from September 1, 2013 to October 22, 2015). The proportion of living transplants rose from 3.5% to 9.1 %. During period B over 25% of utilized donors were over 60 years of age. Recipients with body mass index above 30 kg/m(2) increased from 12% to 31%. Prevalence of diabetes among recipients rose twofold. Uretero-neocystostomy was used during period A (99%) while in period B end to side uretero-ureteral anastomosis has also gained popularity (68%). In 2013 the authors introduced routine use of induction treatment. Acute rejection rate decreased from 34% to 8%. The rate of surgical complications did not change. Acute bacterial infections decreased from 41% to 33%. Cumulative renal allograft 1, 3 and 5 year survival rates were 86.6%, 85% and 82.7% in group A vs. projected rates 88%, 84% and 84% in group B, respectively. Despite the growing proportion of expanded criteria donors, the authors were able to maintain a low incidence of delayed graft function and a favorable graft survival. Since 2013 the authors introduced treatments for acute humoral rejection according to international standards.


A comparison of four stimulation patterns in axillary block.
Insufficient spread of the local anesthetic toward the retroarterial region of the neurovascular space may be responsible for inconsistent anesthesia of the upper limb after single-injection axillary block. We hypothesized that injection of the local anesthetic on a single radial-nerve stimulation would produce the same extent of anesthesia as either a single median-nerve stimulation, a double-stimulation technique (radial and musculocutaneous nerves), or a triple-stimulation technique (radial, musculocutaneous, and median nerves). One hundred twenty patients were randomly assigned to receive an axillary block by either median-nerve, radial-nerve, radial-nerve plus musculocutaneous-nerve, or triple-nerve stimulation with 40 mL of plain 1.5% mepivacaine. Patients were assessed for sensory block by the pinprick method at 5 and 20 minutes. Radial-nerve stimulation produced more extensive anesthesia than did median-nerve stimulation. The rate of anesthesia at 20 minutes in the median-nerve cutaneous distribution was similar after median-nerve stimulation or radial-nerve stimulation. The ulnar nerve was more frequently blocked at 20 minutes after radial-nerve stimulation than after median-nerve stimulation. Extent of anesthesia at 20 minutes after radial-nerve plus musculocutaneous-nerve stimulation was similar to that produced by triple-nerve stimulation, except for lower rates of anesthesia that corresponded to the median nerve. All of the differences were statistically significant. Musculocutaneous-nerve stimulation and radial-nerve stimulation play predominant roles in the success of axillary brachial plexus block, although a triple-nerve stimulation technique is still required to produce complete anesthesia of the upper limb.


A new deep learning-based method for the detection of gait events in children with gait disorders: Proof-of-concept and concurrent validity.
The stance and swing phases of the gait cycle are defined by foot strike (FS) and foot off (FO). Accurate determination of these events is thus an essential component of 3D motion recordings processing. Several methods have been developed for the automatic detection of these events (based on the heuristics of 3D marker position, velocity and acceleration), however the results may be inaccurate due to the high variability that is intrinsic to pathological gait. For this reason, gait events are still commonly determined manually, which is a tedious process. Here we propose a new application (DeepEvent) of a long short term memory recurrent neural network for the automatic detection of gait events. The 3D position and velocity of the markers on the heel, toe and lateral malleolus were used by the network to determine FS and FO. The method was developed from 10526 FS and 9375 FO from 226 children. DeepEvent predicted FS within 5.5 ms and FO within 10.7 ms of the gold standard (automatic determination using force platform data) and was more accurate than common heuristic marker trajectory-based methods proposed in the literature and another deep learning method. A sensitivity analysis showed that DeepEvent mainly used the toe and heel markers (z-axis (longitudinal) position and velocity) at the beginning and end of gait cycle to predict FS, and the toe marker (x-axis (anterior/posterior) velocity and z-axis position and velocity) at around 60% of the gait cycle to predict FO.


The first case of Protothecosis zopfii in China.
Report of first case of Protothecosis zopfii in China and causes the skin infection in the world. By clinical and laboratory examinations to confirm the diagnosis and the response to treatment. By the review of literatures to confirm the first case of human skin infection in the world. From the literatures and the clinical picture, it is confirmed that this is the first case report of Protothecosis zopfii of skin in the world. The first case of Protothecosis zopfii in human being was reported and successfully treated with local infiltration of Diflucan (fluconazole) 3 ml (2 mg/ml)/week x 4.


Influence of maternal and paternal IQ on offspring health and health behaviours: evidence for some trans-generational associations using the 1958 British birth cohort study.
Individuals scoring poorly on tests of intelligence (IQ) have been reported as having increased risk of morbidity, premature mortality, and risk factors such as obesity, high blood pressure, poor diet, alcohol and cigarette consumption. Very little is known about the impact of parental IQ on the health and health behaviours of their offspring. We explored associations of maternal and paternal IQ scores with offspring television viewing, injuries, hospitalisations, long standing illness, height and BMI at ages 4 to 18 using data from the National Child Development Study (1958 birth cohort). Data were available for 1446 mother-offspring and 822 father-offspring pairs. After adjusting for potential confounding/mediating factors, the children of higher IQ parents were less likely to watch TV (odds ratio (95% confidence interval) for watching 3+ vs. less than 3hours per week associated with a standard deviation increase in maternal or paternal IQ: 0.75 (0.64, 0.88) or 0.78 (0.64, 0.95) respectively) and less likely to have one or more injuries requiring hospitalisation (0.77 (0.66, 0.90) or 0.72 (0.56, 0.91) respectively for maternal or paternal IQ). Children whose parents have low IQ scores may have poorer selected health and health behaviours. Health education might usefully be targeted at these families.


Adolescent exposure to food and beverage marketing on social media by gender: a pilot study.
The objective of this research was to determine if, based on gender, adolescents were exposed to different marketing techniques that promoted food and beverages over social media. A secondary analysis of adolescent boy (n 26) and girl (n 36) exposures (n 139) to food and beverage marketing was conducted. Mann-Whitney U and Fisher's exact tests were conducted to compare the number, healthfulness and the marketing techniques of exposures viewed by boys and girls. Ottawa, Ontario, Canada. Sixty-two adolescents aged 12-16 years. Boys and girls were exposed to similar volumes of food marketing instances (median = 2 for both boys and girls, Mann-Whitney U = 237, P = 0·51) per 10-min period of social media use. More girls viewed products that were excessive in total fat compared to boys (67 % v. 35 %, P = 0·02). Boys were more likely to view instances of food marketing featuring a male as the dominant user (50 % v. 22 %, P = 0·03), appeals to achievement (42 % v. 17 %, P = 0·04), an influencer (42 % v. 14 %, P = 0·02) and appeals to athleticism (35 % v. 11 %, P = 0·03), whereas girls were more likely to view instances of food marketing featuring quizzes, surveys or polls (25 % v. 0 %, P = 0·01). Food and beverage companies utilise marketing techniques that differ based on gender. More research examining the relationship between digital food and beverage marketing and gender is required to inform the development of gender-sensitive policies aimed at protecting adolescents from unhealthy food marketing.


Associations between specific serum IgE response and 6 variants within the genes IL4, IL13, and IL4RA in German children: the German Multicenter Atopy Study.
Among many published studies of specific IgE response or atopy, only a few showed positive marginal effects for 6 potentially functional single nucleotide polymorphisms (SNPs; C-590T in the IL4 gene, C-1055T and Arg130Gln in the IL13 gene, and Ile50Val, Ser478Pro, and Gln551Arg in the IL4RA gene). SNPs were commonly considered individually, and therefore the true effect could be masked by other genes or environmental factors. We tested the relationship between these 6 SNPs and sensitization to food, mite, cat, and outdoor allergens in unrelated German children drawn from the Multicenter Atopy Study. Gene-gene and gene-environment interactions were also evaluated. Multiple logistic regression models were used for the analyses of 4 sensitization outcomes. The variant C-1055T was significantly associated with increased risk of sensitization to food and outdoor allergens, with odds ratios of 3.49 (95% CI, 1.52-8.02) and 2.27 (95% CI, 1.04-4.94), respectively. The effects of the TT genotype on food sensitization appear to depend on variants in the IL4RA gene, in which marginally significant interaction terms were observed. Significant evidence supported an interaction between exposure to maternal smoking and variant Gln551Arg on risk of cat sensitization. In addition, we found that the effect of variant C-590T on sensitization to mite depended on Der p 1 allergen levels in carpet dust samples. These findings not only suggested that variants in the IL4, IL13, and IL4RA genes play an important role in controlling specific IgE response but also strengthened our understanding of gene-gene and gene-environment interaction on the development of specific sensitization in this study population.


Chromatin accessibility analysis identifies the transcription factor ETV5 as a suppressor of adipose tissue macrophage activation in obesity.
Activation of adipose tissue macrophages (ATMs) contributes to chronic inflammation and insulin resistance in obesity. However, the transcriptional regulatory machinery involved in ATM activation during the development of obesity is not fully understood. Here, we profiled the chromatin accessibility of blood monocytes and ATMs from obese and lean mice using assay for transposase-accessible chromatin sequencing (ATAC-seq). We found that monocytes and ATMs from obese and lean mice exhibited distinct chromatin accessibility status. There are distinct regulatory elements that are specifically associated with monocyte or ATM activation in obesity. We also discovered several transcription factors that may regulate monocyte and ATM activation in obese mice, specifically a predicted transcription factor named ETS translocation variant 5 (ETV5). The expression of ETV5 was significantly decreased in ATMs from obese mice and its downregulation was mediated by palmitate stimulation. The decrease in ETV5 expression resulted in macrophage activation. Our results also indicate that ETV5 suppresses endoplasmic reticulum (ER) stress and Il6 expression in macrophages. Our work delineates the changes in chromatin accessibility in monocytes and ATMs during obesity, and identifies ETV5 as a critical transcription factor suppressing ATM activation, suggesting its potential use as a therapeutic target in obesity-related chronic inflammation.


Obinutuzumab: A Review in Rituximab-Refractory or -Relapsed Follicular Lymphoma.
Obinutuzumab (Gazyva®, Gazyvaro®) is a recombinant, monoclonal, humanized and glycoengineered, type II, anti-CD20, IgG1 antibody. It has recently been granted an additional indication for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen. In the primary analysis of the large, phase III GADOLIN study, induction therapy with obinutuzumab plus bendamustine followed by obinutuzumab maintenance prolonged progression-free survival (PFS) to a statistically significant extent relative to induction with bendamustine monotherapy in patients with indolent non-Hodgkin's lymphoma (iNHL). The improvement in PFS was largely driven by the subgroup of patients with follicular lymphoma, who also had prolonged overall survival (OS) in a planned updated analysis. Obinutuzumab had a generally manageable tolerability profile in these patients; mild to moderate infusion-related reactions (IRRs) were the most common treatment-emergent adverse events (AEs) and neutropenia the most common grade 3 or 4 treatment-related AEs. Although additional studies and longer-term data are needed to further assess treatment benefits with obinutuzumab, current evidence indicates that obinutuzumab is a useful treatment option for patients with rituximab-refractory or -relapsed follicular lymphoma.


Comprehensive proteomic analysis of sea cucumbers (Stichopus japonicus) in thermal processing by HPLC-MS/MS.
Thermal processing is the most frequently adopted processing technology for sea cucumbers, which can significantly affect their protein composition. In this paper, three thermal processing methods high pressure steaming (HPS), atmospheric pressure boiling (APB), and atmospheric pressure steaming (APS) were adopted and protein compositions of both body walls and cooking liquors by thermal processing stichopus japonicus were systematically analysis by proteomic strategy. The total proteins loss rates of body walls were 11.6%, 13.0%, and 14.8% for HPS, APS, and APB methods, respectively. However, the main types of protein composition were retained. Similar mechanisms of protein loss may exist even if different thermal processing were applied. The most frequent hydrolysis sites in thermal processing were phenylalanine, leucine, asparagine, and tyrosine at both C and N terminals. This study provides theoretical guidance for optimizing the industry thermal processing of sea cucumbers.


Burden of dry eye disease in Germany: a retrospective observational study using German claims data.
To evaluate the clinical and economic burden of dry eye disease (DED) among affected patients in Germany. Adult patients (≥18 years) with ≥1 confirmed diagnosis of DED during the study period (2008-2015) were identified from the medical claims of ~3.6 million insured patients from Betriebskrankenkassen, a German statutory health insurance database. Prevalence (per 1000 patients) and incidence (per 1000 person-years at risk) were estimated, and demographic and clinical characteristics, treatment history (excluding over-the-counter tear supplements), healthcare resource use (HCRU) and costs were assessed. In this population, the prevalence of DED increased from 20.24 in 2008 to 23.13 per 1000 patients in 2014. Overall incidence was 6.24 per 1000 person-years at risk (2008-2015). Prevalence and incidence increased with age and were higher in women. Mean age at index was 63.4 years (incident cohort, n = 35 026). The most common ocular comorbidity was cataract (48.5%), and ~36% of patients were dispensed a reimbursed DED-specific medication during the postindex period - most commonly, corticosteroids alone (13.2%) or in combination with anti-infectives (21.8%). HCRU was high in patients with DED, mostly due to comorbidities. HCRU and associated costs were highest in patients ≥60 years. Total costs during the postindex period were higher in the DED cohort than among matched controls (€117 million versus €107 million; p < 0.001). This retrospective database analysis provides a better understanding of the epidemiology, clinical characteristics, real-world treatment patterns, HCRU and costs associated with DED in patients living in Germany.


The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Recommendations for intracranial pressure monitoring technology.
In patients who require ICP monitoring, a ventricular catheter connected to an external strain gauge transducer or catheter tip pressure transducer device is the most accurate reliable method of monitoring ICP and enables therapeutic CSF drainage. Clinically significant infections or hemorrhage associated with ICP devices causing patient morbidity are rare and should not deter the decision to monitor ICP. Parenchymal catheter tip pressure transducer devices measure ICP similar to ventricular ICP pressure but have the potential for significant measurement differences and drift due to the inability to recalibrate. These devices are advantageous when ventricular ICP is not obtained or if there is obstruction in the fluid couple. Subarachnoid or subdural fluid coupled devices and epidural ICP devices are currently less accurate.


Screen for New Antimicrobial Natural Products from the NCI Program for Natural Product Discovery Prefractionated Extract Library.
The continuing emergence of antibiotic-resistant microbes highlights the need for the identification of new chemotypes with antimicrobial activity. One of the most prolific sources of antimicrobial molecules has been the systematic screening of natural product samples. The National Institute of Allergy and Infectious Diseases and the National Cancer Institute here report a large screen of 326,656 partially purified natural product fractions against a panel of four microbial pathogens, resulting in the identification of >3000 fractions with antifungal and/or antibacterial activity. A small sample of these active fractions was further purified and the chemical structures responsible for the antimicrobial activity were elucidated. The proof-of-concept study identified many different chemotypes, several of which have not previously been reported to have antimicrobial activity. The results show that there remain many unidentified antibiotic compounds from nature.


Development of intervention-related quality indicators for renal clinical pharmacists using a modified Delphi approach.
To develop a list of renal Quality Indicator Drug therapy problems (QI-DTPs) that serve to advance renal pharmacy practice to improve patient care. Eighteen (18) renal, clinical pharmacists participated in an internet-based three-round modified Delphi survey. Each of the three rounds took approximately 2 weeks to complete. Panellists rated 30-candidate renal QI-DTPs using seven selection criteria and one overall consensus criterion on a nine-point Likert scale. Consensus was reached if 75% or more of panellists assigned a score of 7-9 on the consensus criterion during the third Delphi round. All panellists completed three rounds of Delphi survey. Seventeen-candidate renal QI-DTPs met the consensus definition. A Delphi panel of renal clinical pharmacists successfully identified 17 consensus renal QI-DTPs. Assessment and implementation of these QI-DTPs will serve to advance renal pharmacy practice and improve patient care.


Diabetes update: Your guide to the latest ADA standards.
The authors highlight the latest changes in the ADA standards and review recommendations of particular relevance for family physicians.


[The Multiple Sclerosis Documentation System MSDS. Discussion of a documentation standard for multiple sclerosis].
The MSDS (multiple sclerosis documentation system) has been developed at the Department of Neurology, Technical University of Dresden, Germany, during the last 4 years. The first version of this database application has been in use since October 2000. The MSDS manages information on MS patients, their treating physicians, patient history (symptoms, other diseases, biographical history, family history, habits, medication), clinical signs, results of laboratory examinations (blood chemistry, autoantibodies, borrelia serology, evoked potentials, cranial and spinal cord magnetic resonance imaging), clinical scores relevant for MS, and biosamples. In principle, MSDS allows online data input and semiautomatically generates reports to all general practitioners and neurologists treating the respective patient. Patient information sheets and internal treatment guidelines are part of the system. During a 3-month evaluation, the first version of MSDS was tested at eight university multiple sclerosis ambulatory care units and one general neurology hospital. The overall judgement was favorable. Suggestions for changes and improvements, as well as practical experiences, were considered when developing MSDS 2.0, which will be available by the end of 2001.


Battling Alarm Fatigue in the Pediatric Intensive Care Unit.
Pediatric intensive care unit nurses can be exposed to hundreds of alarms per patient they care for each shift. The exposure to so many alarms can cause nurses to be desensitized to future alarms and thus increase the time to respond to alarms. This is one of the largest patient safety concerns within health care today. Steps should be taken to mitigate the number of alarms nurses experience so that they can properly respond to actionable alarms.


Distal hypospadias repair using the needle point bipolar cutting-coagulation forceps.
To determine the outcome of distal hypospadias repairs performed using bipolar diathermy (BD) for all the dissection. Retrospective review of 310 patients undergoing distal hypospadias (264 subcoronal/distal penile and 46 coronal/glanular) over a 11-year period. Median age at surgery was 2.0 years (range 9 months-15 years). Caudal anesthesia was performed in all patients. All children underwent an in situ tubularization of the urethral plate, which was combined with midline incision of the plate in 30 (10%). Preputial reconstruction was performed in 303 (98%) patients. BD forceps was used for coagulation and for all the dissection including skin incision, elevation of glans wings, separation of the corpus spongiosum from the corpora cavernosa, and urethral plate incision, when deemed appropriate. The authors assessed surgical complications and cosmetic results. The latter using the hypospadias objective score (HOSE), with a score ≥ 14 considered as acceptable. The average operative time was 70 min. There was no postoperative bleeding or hematomas that required surgical intervention. There were no wound infections or necrosis. Complications occurred in 37 patients (11.9%). Urethral fistula formation was the commonest (n = 18). Postoperative persistent preputial swelling occurred in 3.5% of cases. Two hundred twelve patients (90.6%) had a HOSE score ≥ 14, and no patient required revision surgery for skin problems after a median follow-up of 8.1 (range 1.2-13.1) years. The study is limited by its retrospective nature and by the fact that a number of other pre-operative, intra-operative, and postoperative variables can affect outcome. Bipolar diathermy can be safely used for distal hypospadias repairs. It allowed careful control of intra-operative bleeding and also clear visualization of tissue planes. Complication rate overall compares favorably with the literature, and cosmetic results were satisfactory.


Peripheral intravenous catheter insertion and therapy administration: simulator learning.
Obtaining, positioning and managing intravenous access is complex but common procedure in nursing care practice. Learning the right knowledge and skills during basic nurse education is an essential goal. The use of simulators allows for a better acquisition of skills, guaranteeing safety for patients and nursing students. However, the literature is still lacking on the use of simulation for intravenous cannulation procedures and device management, presenting few conflicting results. The aim of this study was to examine the effect of simulator-based learning on vascular access management in a population of nursing students. Using comparative observational study design we evaluated the effect of simulator learning on vascular access management in a nursing student population. The differences between the scores at t1 between the groups of students are significant for obtaining vascular access with relative management of the device and intravenous therapy (t = 3.062, p = 0.001), while at t0, albeit with strong differences in scores means (t = 0.061, p = 0.871) are not statistically significant. Early use of the simulator is also fundamental over time (t = 5.362, p = 0.001). Furthermore, the satisfaction noted by the students during the clinical simulations improves with the increase in the number of the same, as it can influence the single performance. Nursing training based on the use of simulators favors a better acquisition of skills compared to traditional didactic.


Emulsification liquid-liquid microextraction based on deep eutectic solvent: An extraction method for the determination of benzene, toluene, ethylbenzene and seven polycyclic aromatic hydrocarbons from water samples.
In this study, for the first time, a simple, inexpensive and sensitive method named emulsification liquid-liquid microextraction based on deep eutectic solvent (ELLME-DES) was used for the extraction of benzene, toluene, ethylbenzene (BTE) and seven polycyclic aromatic hydrocarbons (PAHs) from water samples. In a typical experiment, 100μL of DES (as water-miscible extraction solvent) was added to 1.5mL of sample solution containing target analytes. A homogeneous solution was formed immediately. Injection of 100μL of THF (as emulsifier agent) into homogeneous solution provided a turbid state. After extraction, phase separation (aqueous phase/DES rich phase) was performed by centrifugation. DES rich phase was withdrawn by a micro-syringe and submitted to isocratic reverse-phase HPLC with UV detection. Under optimum conditions obtained by response surface methodology (RSM) and desirability function (DF), the calibration graphs were linear in the concentration range from 10 to 200μg/L for benzene, 10-400μg/L for toluene, 1-400μg/L for ethylbenzene, biphenyl, chrysene and fluorene, and 0.1-400μg/L for anthracene, benzo[a]pyrene, phenanthrene and pyrene. The coefficients of determination (r(2)) and limits of detection were 0.9924-0.9997 and 0.02-6.8μg/L, respectively. This procedure was successfully applied to the determination of target analytes in spiked water samples. The relative mean recoveries ranged from 93.1 to 103.3%.


Carbonic anhydrase inhibitors: design of membrane-impermeant copper(II) complexes of DTPA-, DOTA-, and TETA-tailed sulfonamides targeting the tumor-associated transmembrane isoform IX.
The synthesis and carbonic anhydrase (CA, EC 220.127.116.11) inhibitory activity of two series of aromatic sulfonamides and their Cu(II) derivatives, incorporating metal-complexing moieties of the DTPA, DOTA, and TETA type are reported. The new compounds were designed in such a way as to possess high affinity for Cu(II) ions, exploiting four pendant carboxylate moieties in the DTPA derivatives, as well as the cyclen/cyclam macrocyles, and three pendant acetate moieties in the DOTA and TETA derivatives. The new derivatives showed modest inhibition of the cytosolic isoform CA I (K(I) values in the range of 66-2130 nM), were better CA II inhibitors (K(I) values in the range of 21-360 nM), and excellent inhibitors of the tumor-associated isoform CA IX (K(I) values in the range of 4.1-110 nM), with selectivity ratios for the inhibition of the tumor (CA IX) over the cytosolic (CA II) isozyme in the range of 10.74-20.88 for the best derivatives. Copper complexes were more inhibitory than the corresponding ligand sulfonamides, and showed membrane impermeability, thus, having the possibility to specifically target the transmembrane CA IX that has an extracellular active site. Incorporation of radioactive copper isotopes in this type of CA inhibitor may lead to interesting diagnostic/therapeutic applications for such compounds.


Gene transfer preferentially selects MHC class I positive tumour cells and enhances tumour immunogenicity.
The modulated expression of MHC class I on tumour tissue is well documented. Although the effect of MHC class I expression on the tumorigenicity and immunogenicity of MHC class I negative tumour cell lines has been rigorously studied, less is known about the validity of gene transfer and selection in cell lines with a mixed MHC class I phenotype. To address this issue we identified a C26 cell subline that consists of distinct populations of MHC class I (H-2D/K) positive and negative cells. Transient transfection experiments using liposome-based transfer showed a lower transgene expression in MHC class I negative cells. In addition, MHC class I negative cells were more sensitive to antibiotic selection. This led to the generation of fully MHC class I positive cell lines. In contrast to C26 cells, all transfectants were rejected in vivo and induced protection against the parental tumour cells in rechallenge experiments. Tumour cell specificity of the immune response was demonstrated in in vitro cytokine secretion and cytotoxicity assays. Transfectants expressing CD40 ligand and hygromycin phosphotransferase were not more immunogenic than cells expressing hygromycin resistance alone. We suggest that the MHC class I positive phenotype of the C26 transfectants had a bearing on their immunogenicity, because selected MHC class I positive cells were more immunogenic than parental C26 cells and could induce specific anti-tumour immune responses. These data demonstrate that the generation of tumour cell transfectants can lead to the selection of subpopulations that show an altered phenotype compared to the parental cell line and display altered immunogenicity independent of selection marker genes or other immune modulatory genes. Our results show the importance of monitoring gene transfer in the whole tumour cell population, especially for the evaluation of in vivo therapies targeted to heterogeneous tumour cell populations.


A historical to present-day account of efforts to answer the question: "what puts the brakes on mammalian hair cell regeneration?".
Hearing and balance deficits often affect humans and other mammals permanently, because their ears stop producing hair cells within a few days after birth. But production occurs throughout life in the ears of sharks, bony fish, amphibians, reptiles, and birds allowing them to replace lost hair cells and quickly recover after temporarily experiencing the kinds of sensory deficits that are irreversible for mammals. Since the mid 1970s, researchers have been asking what puts the brakes on hair cell regeneration in mammals. Here we evaluate the headway that has been made and assess current evidence for alternative mechanistic hypotheses that have been proposed to account for the limits to hair cell regeneration in mammals.


Effect of ionic strength on the organization and dynamics of membrane-bound melittin.
Melittin, a cationic hemolytic peptide, is intrinsically fluorescent due to the presence of a single functionally important tryptophan residue. We have previously shown that the sole tryptophan of melittin is localized in a motionally restricted environment in the membrane interface. We have monitored the effect of ionic strength on the organization and dynamics of membrane-bound melittin utilizing fluorescence and circular dichroism (CD) spectroscopic approaches. Our results show that red edge excitation shift (REES) of melittin bound to membranes is sensitive to the change in ionic strength of the medium. This could be attributed to a change in the immediate environment around melittin tryptophan with increasing ionic strength due to differential solvation of ions. Interestingly, the rotational mobility of melittin does not appear to be affected with change in ionic strength. In addition, fluorescence parameters such as lifetime and acrylamide quenching of melittin indicate an increase in water penetration in the membrane interface upon increasing ionic strength. Our results suggest that the solvent dynamics and water penetration in the interfacial region of the membranes are significantly affected at physiologically relevant ionic strength. These results assume significance in the overall context of the influence of ionic strength in the organization and dynamics of membrane proteins and membrane-active peptides.


Opposite effects of low versus high dose haloperidol treatments on spontaneous and apomorphine induced motor behavior: evidence that at a very low dose haloperidol acts as an indirect dopamine agonist.
Anti-psychotic drugs are antagonists at the dopamine D2 receptors and repeated administration can lead to the development of dopamine receptor supersensitivity. In two experiments, separate groups of rats were administered 10 daily low or high doses of the typical anti-psychotic drug haloperidol (0.03 or 1.0 mg/kg). The high dose decreased locomotion whereas, the low dose increased locomotion. After 5 days of withdrawal, all groups received 2.0 mg/kg apomorphine on 5 successive days. The apomorphine treatments given to the vehicle group generated a progressive locomotion sensitization effect and this effect was potentiated by pre-exposure to 0.03 mg/kg haloperidol. Initially, the prior high dose of haloperidol exaggerated the apomorphine locomotor stimulant effect but with repeated apomorphine treatments desensitization developed. Following a 5-day withdrawal period an apomorphine challenge test was conducted and apomorphine sensitization was absent in the haloperidol high dose pre-exposure group but potentiated in the low dose pre-exposure group. In the second replication experiment a conditioning test instead of a sensitization challenge test was conducted 5 days after completion of the 5-day apomorphine treatment protocol. The repeated apomorphine treatments induced conditioned hyper- locomotion and this conditioned effect was prevented by the prior high dose haloperidol pre-exposure but enhanced by the prior low dose haloperidol pre-exposure. Two new key findings are (a) that a low dose haloperidol regimen can function as a dopamine agonist and these effects persist after withdrawal and (b) that repeated apomorphine treatments can desensitize D2 receptors previously sensitized by a high dose haloperidol treatment regimen.


[Foot and ankle ability measure: Validation of a Spanish version with 29 items in rehabilitation setting].
The Foot and Ankle Ability Measure (FAAM) is an internationally widely used outcome measure of foot and ankle disorders available in several languages. The purpose of this study was to develop and validate a FAAM Spanish-version with 29 items of Activities of Daily Living (ADL) and SPORT subscales in rehabilitation setting. A two-stage observational study was conducted. The FAAM was cross-culturally adapted to Spanish through a double-forward translation and a double-backward translation; the psychometric properties were then validated. The participants (n = 147), with various chronic foot and ankle disorders, completed the Spanish version of the Foot and Ankle Ability Measure ADL and SPORT, SF-36, and a pain intensity visual analogue scale (Pain VAS). The full sample was used to determine the factor structure, the internal consistency, and the convergent criterion validity, and a subgroup (n = 46) was used to determine the reliability at 48-72 h. The factor structure of Spanish version of FAAM ADL and SPORT subscales were both one-dimensional, demonstrating high internal consistency (α = 0.97 and α = 0.93, respectively). The reliability values were ICC = 0.90 and ICC = 0.76, respectively. The convergent validity criterion of Spanish version of FAAM with the Pain VAS (r = 0.50) and Physical Function of SF-36 (r = 0.64) were moderately correlated. The Spanish version of FAAM with 29 items are a valid foot and ankle disorder outcome measure with similar psychometric properties to the original version and versions in other languages.


Nadir CA-125 level as prognosis indicator of high-grade serous ovarian cancer.
The capacity of nadir CA-125 levels to predict the prognosis of epithelial ovarian cancer remains controversial. This study aimed to explore whether the nadir CA-125 serum levels could predict the durations of overall survival (OS) and progression free survival (PFS) in patients with high-grade serous ovarian cancer (HG-SOC) from the USA and PRC. A total of 616 HG-SOC patients from the MD Anderson Cancer Center (MDACC, USA) between 1990 and 2011 were retrospectively analyzed. The results of 262 cases from the Jiangsu Institute of Cancer Research (JICR, PRC) between 1992 and 2011 were used to validate the MDACC data. The CA-125 immunohistochemistry assay was performed on 280 tissue specimens. The Cox proportional hazards model and the log-rank test were used to assess the associations between the clinicopathological characteristics and duration of survival. The nadir CA-125 level was an independent predictor of OS and PFS (p < 0.01 for both) in the MDACC patients. Lower nadir CA-125 levels (≤10 U/mL) were associated with longer OS and PFS (median: 61.2 and 16.8 months with 95% CI: 52.0-72.4 and 14.0-19.6 months, respectively) than their counterparts with shorter OS and PFS (median: 49.2 and 10.5 months with 95% CI: 41.7-56.7 and 6.9-14.1 months, respectively). The nadir CA-125 levels in JICR patients were similarly independent when predicting the OS and PFS (p < 0.01 for both). Nadir CA-125 levels less than or equal to 10 U/mL were associated with longer OS and PFS (median: 59.9 and 15.5 months with 95% CI: 49.7-70.1 and 10.6-20.4 months, respectively), as compared with those more than 10 U/mL (median: 42.0 and 9.0 months with 95% CI: 34.4-49.7 and 6.6-11.2 months, respectively). Baseline serum CA-125 levels, but not the CA-125 expression in tissues, were associated with the OS and PFS of HG-SOC patients in the MDACC and JICR groups. However, these values were not independent. Nadir CA-125 levels were not associated with the tumor burden based on second-look surgery (p = 0.09). Patients who achieved a pathologic complete response had longer OS and PFS (median: 73.7 and 20.7 months with 95% CI: 63.7-83.7 and 9.5-31.9 months, respectively) than those with residual tumors (median: 34.6 and 10.6 months with 95% CI: 6.9-62.3 and 4.9-16.3 months, respectively). The nadir CA-125 level was an independent predictor of OS and PFS in HG-SOC patients. Further prospective studies are required to clinically optimize the chances for a complete clinical response of HG-SOC cases with higher CA-125 levels (>10 U/mL) at the end of primary treatment.


Expression of bystin in reactive astrocytes induced by ischemia/reperfusion and chemical hypoxia in vitro.
In this study, we investigated the effects of ischemia/reperfusion and chemical hypoxia on the morphology, cell viability and expression of bystin and glial fibrillary acidic protein (GFAP) in primary cultured astrocytes which were prepared by the subculture method. The astrocytes in Hank's medium without glucose and serum (oxygen-glucose deprivation, ischemic cells) were first exposed to 1% O2 and then to 21% O2 (normoxia), or treated with different concentrations of CoCl2 or NaN3 for different periods. Relevant observations and measurements were then conducted. The findings showed that treatment with 1% O2 for 0.5 or 3 h could induce a characteristic 'reactive' morphology and a significant increase in cell viability and total protein amount. The western blot analysis showed that treatment with 1% O2 for 0.5 or 3 h also induced a significant increase in the expression of bystin and that the response of bystin to mild ischemia was much more sensitive than that of GFAP. Similar results were also found in the cells treated with mild chemical hypoxia. The data demonstrated for the first time that mild ischemia and hypoxia could activate astrocytes and that bystin is a much more sensitive marker in activated astrocytes induced by ischemia and hypoxia as compared to GFAP. The significant up-regulation of bystin suggests that bystin may play an important role in the activation of astrocytes as well as in the neuroprotective role of hypoxic and ischemic preconditioning.


Conformation-activity relationships of cyclo-constrained micro/delta opioid agonists derived from the N-terminal tetrapeptide segment of dermorphin/deltorphin.
The N-terminal tetrapeptide segments of dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) and deltorphin (Tyr-D-Ala-Phe-Asp/Glu-Val-Val-Gly-NH(2)) are agonists at the opioid receptors micro and delta, respectively. [D-Arg(2), Lys(4)]-dermorphin-(1-4) amide (Tyr-D-Arg-Phe-Lys-NH(2), DALDA) and [Dmt(1)]DALDA (where Dmt is 2',6'-dimethyltyrosine) are among the most potent and selective micro-agonists reported to date, both in vitro (having picomolar micro receptor affinity) and in vivo. In this communication, conformation-activity studies of the following four cyclic analogs of DALDA are presented and discussed: the lead peptide S(2),S(4)-cyclo (Tyr-D-Cys-Phe-Cys-NH(2)), constrained by means of an S(4.2)--S(4.4) disulfide between Cys(2) and Cys(4); its two cis and trans C(4.2)--C(4.4)-olefinic dicarba analogs, and the product of saturation of them both. They are potent nonselective or moderately micro-selective opioid agonists in vitro.They have been synthesized and tested earlier [Berezowska I, Chung NN, Lemieux C, Wilkes BC, and Schiller PW, Acta Biochim Polon 53, 2006, 73-76]. We have studied their conformations using NMR and molecular dynamics. With major conformational constraints imposed by the 11-membered ring spanning residues 2-4, they show well defined conformations of this ring, while the exocylic Tyr(1) and Phe(3) side chains still have significant conformational freedom. The more active and selective micro versus delta disulfide and saturated dicarba agonists seem to have in common: (i) their ring structures more flexible than those of the other two and (ii) their ring structures similar to each other and more diverse than those in the other two. Given this and the small size of the peptides having confirmed bioactivity profiles, there is a chance that their conformations determined in solution approach receptor-bound conformations.


Chemiluminescent carbon nanodots for dynamic and guided antibacteria.
Advanced antibacterial technologies are needed to counter the rapid emergence of drug-resistant bacteria. Image-guided therapy is one of the most promising strategies for efficiently and accurately curing bacterial infections. Herein, a chemiluminescence (CL)-dynamic/guided antibacteria (CDGA) with multiple reactive oxygen species (ROS) generation capacity and chemiexcited near-infrared emission has been designed for the precise theranostics of bacterial infection by employing near-infrared emissive carbon nanodots (CDs) and peroxalate as CL fuels. Mechanistically, hydrogen peroxide generated in the bacterial microenvironment can trigger the chemically initiated electron exchange between CDs and energy-riched intermediate originated from the oxidized peroxalate, enabling bacterial induced inflammation imaging. Meanwhile, type I/II photochemical ROS production and type III ultrafast charge transfer from CDs under the self-illumination can inhibit the bacteria proliferation efficiently. The potential clinical utility of CDGA is further demonstrated in bacteria infected mice trauma model. The self-illuminating CDGA exhibits an excellent in vivo imaging quality in early detecting wound infections and internal inflammation caused by bacteria, and further are proven as efficient broad-spectrum antibacterial nanomedicines without drug-resistance, whose sterilizing rate is up to 99.99%.


Single step synthesis, characterization and applications of curcumin functionalized iron oxide magnetic nanoparticles.
Magnetic iron oxide nanoparticles have been well known for their applications in magnetic resonance imaging (MRI), hyperthermia, targeted drug delivery, etc. The surface modification of these magnetic nanoparticles has been explored extensively to achieve functionalized materials with potential application in biomedical, environmental and catalysis field. Herein, we report a novel and versatile single step methodology for developing curcumin functionalized magnetic Fe3O4 nanoparticles without any additional linkers, using a simple coprecipitation technique. The magnetic nanoparticles (MNPs) were characterized using transmission electron microscopy, X-ray diffraction, fourier transform infrared spectroscopy and thermogravimetric analysis. The developed MNPs were employed in a cellular application for protection against an inflammatory agent, a polychlorinated biphenyl (PCB) molecule.


One-click investigation of shape influence of silver nanostructures on SERS performance for sensitive detection of COVID-19.
Sensitive and accurate detection of SARS-CoV-2 methods is meaningful for preventing and controlling the novel coronavirus. The detection techniques supporting portable, onsite, in-time, and online data transfer are urgently needed. Here, we one-click investigated the shape influence of silver nanostructures on SERS performance and their applications in the sensitive detection of SARS-CoV-2. Such investigation is achieved by adjusting multiple parameters (concentration, potential, and time) on the integrated electrochemical array, thus various morphologies (e.g., bulk, dendritic, globular, and spiky) can be one-click synthesized. The SERS performance results indicated that dendritic nanostructures are superior to the other three with an order of magnitude signal enhancement. Such on-electrode dendritic silver substrate also represents high sensitivity (LOD = 7.42 × 10-14 M) and high reproducibility (RSD = 3.67%) toward the SARS-CoV-2 RNA sequence detection. Such approach provides great potentials for rapid diagnosis and prevention of diverse infectious diseases.


Failure of centrosome migration causes a loss of motile cilia in talpid(3) mutants.
Loss of function mutations in the centrosomal protein TALPID3 (KIAA0586) cause a failure of primary cilia formation in animal models and are associated with defective Hedgehog signalling. It is unclear, however, if TALPID3 is required only for primary cilia formation or if it is essential for all ciliogenesis, including that of motile cilia in multiciliate cells. FOXJ1, a key regulator of multiciliate cell fate, is expressed in the dorsal neuroectoderm of the chicken forebrain and hindbrain at stage 20HH, in areas that will give rise to choroid plexuses in both wt and talpid(3) embryos. Wt ependymal cells of the prosencephalic choroid plexuses subsequently transition from exhibiting single short cilia to multiple long motile cilia at 29HH (E8). Primary cilia and long motile cilia were only rarely observed on talpid(3) ependymal cells. Electron microscopy determined that talpid(3) ependymal cells do develop multiple centrosomes in accordance with FOXJ1 expression, but these fail to migrate to the apical surface of ependymal cells although axoneme formation was sometimes observed. TALPID3, which normally localises to the proximal centrosome, is essential for centrosomal migration prior to ciliogenesis but is not directly required for de novo centriologenesis, multiciliated fate, or axoneme formation.


Protein kinase C activity and isoform expression during early postnatal development of rat myocardium.
Total protein kinase C (PKC) activity, its isoform expression, and concentration and fatty acid (FA) composition of diacylglycerol (DAG) were determined in the left ventricular myocardium of the rat during early postnatal development (d 2, 3, 5, 7, and 10). PKC activity measured by the incorporation of 32P into histone IIIS decreased between d 2 and 10 in the homogenate as well as in cytosolic, membrane (100,000 g), and nuclear-cytoskeletal-myofilament fractions (1000 g). Likewise, the expression of PKC isoforms (alpha, delta, and epsilon) determined by immunoblotting generally declined during the period analyzed, although with a variable pattern. In the membrane and nuclear cytoskeletal myofilament fractions, PKCdelta and PKCepsilon expression decreased markedly by d 3, returning to or close to the d 2 level immediately on d 5. PKCalpha expression in the membrane fraction remained almost unchanged by d 7, declining thereafter. PKCdelta and PKCepsilon were associated predominantly with particulate fractions, whereas PKCalpha was more abundant in the cytosolic fraction. DAG concentration exhibited a significant decline by d 5, consistent with the decrease in maximal PKC activity. The unsaturation index of FA in DAG tended to decrease on d 3 owing to the lowered proportion of all polyunsaturated FA of n-6 and n-3 series. These results demonstrate that the developmental decrease in PKC activity and expression in the rat myocardium is not linear and that subcellular localization of the enzyme exhibits isoform-specific day-by-day changes during the early postnatal period. These changes are compatible with the view that PKC signaling may be involved in the control of a rapid switch of myocardial growth pattern during the first week of life.


Ways to harness the built environment of ambulatory cancer facilities for comprehensive patient support: A review of the literature.
To review patient experiences of the architectural elements conducive to a supportive or healing-promoting environment in the context of ambulatory oncology care. A comprehensive review of original peer-reviewed qualitative studies conducted to reveal the meaning and significance of patient experience in this context was undertaken. Studies were identified through electronic databases including Ovid MEDLINE, CINAHL, PubMed and Embase. No time limit was applied and language was restricted to English. The generated records were screened at the titles and abstracts level by the first reviewer, with full text assessment conducted by both authors. Main themes were extracted in an excel file and a narrative synthesis strategy was used to systematically gather evidence and explain the findings. The guidelines of the Centre for Reviews and Dissemination have been followed in the searching and reporting of the essential matters relevant to this review. Eleven original studies were selected; in addition to these, fourteen other studies that did not fully meet the selection criteria, however held important information relevant to the scope of the review, were considered to expand the discussion with relevant information to ambulatory cancer facilities. The findings of these studies were synthesized into five major themes: stimulating and homely environments; flexibility and environmental enrichment; social support; complementary support and engagement; and physical and sensory support. The paper identified key architectural design qualities that have the potential to support treatment and empower patients, with particular reflection on patients undergoing intravenous anti-cancer treatment within ambulatory settings. It provides examples in which designing the built environment with people in mind and providing tailored solutions to meet their actual needs and preferences may help cancer patients cope with the emotional and physical challenges of the disease and its treatment and support a general experience of patient-centred care. A conceptual framework that articulates the principal constituents of a supportive environment is tentatively proposed, extending existing theoretical propositions to facilitate further investigation of this context.


Development of a fungal spore aerosol generator: test with Cladosporium cladosporioides and Penicillium citrinum.
As the first step to develop efficient means to control fungal spore bioaerosols, we designed, manufactured, and evaluated a fungal spore aerosol generator. We studied the physical and biological properties of the fungal spore bioaerosols on two common fungal species. The results demonstrated that the fungal spore bioaerosol generator effectively produces fungal spore bioaerosols.


Feasibility of bisegmentectomy 7-8 is independent of the presence of a large inferior right hepatic vein.
Right superior liver resection or bisegmentectomy 7-8 is defined as the anatomical removal of segments 7 and 8 of the liver. According to recent reports, this type of resection requires the presence of a large accessory right inferior hepatic vein to drain the remaining segment 6. However, anatomic studies have shown that segment 6 has multiple veins presenting several anastomosis with the surrounding hepatic veins. Therefore, the maintenance of the veins from segment 5 that ultimately drain into the middle hepatic vein can be enough to assure venous drainage of both segments. Describe an alternative technique for bisegmentectomy 7-8 using intrahepatic glissonian access in patients with absence of a large inferior right hepatic vein. The technique was successfully performed in four consecutive patients without immediate or long-term venous or venous related complications. Bisegmentectomy 7-8 may increase resectability rate in patients with bilateral lesions and may also enhance the opportunity to perform repeated resections in cases of tumor recurrence. Our study confirms the anatomical assumption that bisegmentectomy 7-8 did not result in segmental outflow block even in the absence of a thick inferior right hepatic vein and therefore should be performed more often than reported so far. The absence of this vein should not be a straightforward indication for right hepatectomy in cases where a liver-sparing procedure such as bisegmentectomy 7-8 can be safely employed.


Risk factors for disease progression in COVID-19 patients.
Coronavirus disease (COVID-19) is rapidly spreading worldwide. Although 10-20% of patients with COVID-19 have severe symptoms, little is known about the risk factors related to the aggravation of COVID-19 symptoms from asymptomatic or mild to severe disease states. This retrospective study included 211 patients who were asymptomatic or with mild presentations of COVID-19. We evaluated the differences in demographic and clinical data between the cured (discharged to home) and transferred (aggravated to severe-stage COVID-19) groups. A multivariate logistic analysis showed that body temperature, chills, initial chest X-ray findings, and the presence of diabetes were significantly associated with predicting the progression to severe stage of COVID-19 (p < 0.05). The odds ratio of transfer in patients with COVID-19 increased by 12.7-fold for abnormal findings such as haziness or consolidation in initial chest X-ray, 6.32-fold for initial symptom of chills, and 64.1-fold for diabetes. Even if patients are asymptomatic or have mild symptoms, clinicians should closely observe patients with COVID-19 presenting with chills, body temperature > 37.5 °C, findings of pneumonia in chest X-ray, or diabetes.


Variation in the virulence of strains of Mycoplasma pulmonis related to susceptibility to killing by macrophages in vivo.
The virulence of five strains of Mycoplasma pulmonis, as judged by their ability to survive in the respiratory tract and induce pneumonia in CBA mice, was related to the ability of viable organisms to persist in the peritoneal cavity. This appeared to be the result of differences in the ability of the strains to resist killing by peritoneal macrophages in vivo. It is suggested that resistance to phagocytosis by macrophages is an important determinant of virulence for M. pulmonis.


Ethyl 2-[(E)-({2,4-dimeth-oxy-6-[2-(4-meth-oxy-phen-yl)ethen-yl]benzyl-idene}amino)-oxy]acetate.
In the title compound, C22H25NO6, the C=C double bond linking the benzene rings adopts an E configuration and the dihedral angle between the rings is 47.1 (2)°. The oxime unit contains a C=N double bond, which also has an E configuration. In the crystal, pairs of C-H⋯N hydrogen bonds generate inversion dimers and weak C-H⋯O inter-actions link the dimers into chains propagating along the b-axis direction.


Prevalence of undiagnosed diabetes mellitus and associated factors among adult residents of Bahir Dar city, northwest Ethiopia: a community-based cross-sectional study.
To assess the prevalence of undiagnosed diabetes mellitus (DM) and associated factors among adult inhabitants of Bahir Dar city, northwest Ethiopia. A community-based cross-sectional study was conducted on adults (n=607) of Bahir Dar city from 10 March to 20 May 2018. Data were collected using structured interviewer-administered questionnaire, and anthropometric measurements were taken from each participant. Fasting blood sugar (FBS) level was determined by samples taken early in the morning and readings of FBS≥126 mg/dL were classified as diabetes. The multivariate logistic regression model was fitted to identify the predictors of undiagnosed DM; adjusted OR (AOR) with a 95% CI was computed to assess the strength of associations. The study revealed that the prevalence of undiagnosed DM was 10.2% with 95% CI 7.9 to 12.9. Ever checked blood glucose level (AOR=1.91, 95% CI 1.03 to 3.51), don't know the symptoms of diabetes (AOR=2.06, 95% CI 1.08 to 3.89), family history of DM (AOR=2.5, 95% CI 1.21 to 5.18) and body mass index (BMI) ≥25 kg/m2 (AOR=1.98, 95% CI 1.09 to 3.60) were factors associated with undiagnosed DM. The magnitude of undiagnosed diabetes was high. Family history of DM, ever checked blood glucose level, don't know about the symptoms of diabetes and overweight BMI were predictors of undiagnosed DM. Hence, screening and treatment are mandatory for high-risk groups. In addition, this study suggests frequent screening for those with family history and awareness creating about the disease for early detection and treatment.


Fatty acid and phospholipase A2 plasma levels in children with autism.
To evaluate fatty acid plasma levels, phospholipase A2 activity, and the developmental profiles of children with autism vs. control subjects. Twenty four children with autism underwent laboratory analysis for fatty acid quantification using gas chromatography and PLA2 activity determination by fluorometric assay. No correlation was observed between the developmental quotient and fatty acid plasma levels. Phospholipase A2 activity was significantly higher among autistic children compared with controls. The study did not show a correlation between fatty acid and phospholipase A2 plasma levels and the developmental profile of children with autism.


Analysis of the conserved acidic residues in the regulatory domain of PhoB.
The PhoB protein from Escherichia coli is a member of the two-component signal transduction pathway that controls an adaptive response to limiting phosphate. Activation involves its phosphorylation on a conserved aspartate. Site-directed mutations were introduced at conserved acidic residues. The E9D, D10E, D10N, E11A, E11D and E11Q mutants were each able to induce alkaline phosphatase under low phosphate growth conditions whereas the E9A, D10A, D53A, D53E and D53N could not. The E9Q mutant was constitutively active. Phosphorylation assays showed that only the E9D, E11A, E11Q and E11D mutants were phosphorylated by acetyl phosphate. Most mutants also displayed defects in magnesium binding.


Design and evaluation of oral formulation for apixaban.
Non-valvular atrial fibrillation (NVAF) is a common form of cardiac arrhythmia that affects 1-1.5% of adults and roughly 10% of elderly adults with dysphagia. Apixaban is an anticoagulant referred to as a factor Xa inhibitor, which has been shown to reduce the risk of stroke and systemic embolism in cases of NVAF. Our objective in the current study was to formulate an orally disintegrating film to facilitate the administration of apixaban to elderly patients who have difficulty swallowing. Researchers have used a wide variety of cellulose-based or non-cellulose-based polymers in a variety of combinations to achieve specific characteristics related to film formation, disintegration performance, drug content, in vitro drug release, and stability. One of the two formulations in this study was specify that bioequivalence criteria met with respect to Cmax of the reference drug (ELIQUIS®) in terms of pharmacokinetic profile. Further research will be required to assess the applicability of orodispersible films created using colloidal polymers of high and low molecular weights to other drugs with poor solubility in water.


The evolution of multiple sclerosis in Spain over the last decade from the patient's perspective.
Updated information about self-reported experience and satisfaction with care of MS patients (PwMS) in Spain is scarce. We aim to describe, from PwMS' perspective, the disease impact, the quality of life and the satisfaction level with the social and healthcare support in Spain, and its evolution over the last decade. Multicentre observational study, based on a cross-sectional nationwide survey, completed by 432 PwMS in Spain throughout 2018. The results were compared with those of a similar study carried out in 2007 (370 patients), whose database was retrieved as baseline information. 432 patients recruited from 61 neurology units fully completed the study e-survey (mean age: 43.7 years; 71.4% women). The personal profile of patients was largely similar between the 2007 and 2018 samples. The proportion of patients who identified themselves as having relapsing-remitting MS was higher in 2018 (77.1% vs. 56.7 in 2007; p = 0.0001). Overall, 2018 patients considered themselves more labour-active, less disabled, more independent in movement, and as higher family income earners. The proportion of patients satisfied or very satisfied with healthcare services accessibility increased over time (54.9% in 2007 vs. 66.2 in 2018; p = 0.0009). Similarly, more patients considered their health condition to be good or very good in 2018 (55.8% vs. 33.7% in 2007; p = 0.0001). In contrast, there seems to be little progress in social support terms and opportunities equality. Health condition of PwMS seems to have improved over the last decade, which could be the result of an increasingly effective health care. However, more social protection measures are needed.


Effect of live yeast supplementation and feeding frequency in male finishing pigs subjected to heat stress.
In growing pigs, reduced growth during heat stress (HS) is mainly related to decreased feed intake. The study aimed to determine whether the reported positive effects of live yeast (LY) supplementation in HS pigs were due to a modified feeding behaviour or energy metabolism, and if these can be replicated by imposing an increased meal frequency. The effect of LY supplementation (0 (NS) v. 100 (LY) g/ton of feed), and of feeding window (FW) (unlimited or Unli, 2FW of 1 h each and 8FW of 15 min each) were measured in entire male finishing pigs (n 36). Ambient temperature was at 22°C during the thermoneutral (TN) period (5 d) and at 28°C during the HS period (5 d). Heat exposure decreased DM intake (DMI) and retained energy (RE) (-627 and -460 kJ·kg BW-0·60 · d-1, respectively; P < 0·01). During HS, LY supplementation in Unli pigs decreased inter-meal intervals (P = 0·02) attenuating HS effect on DMI which tended to improve RE (P = 0·09). NS - 8FW had higher DMI and RE than NS - 2FW (P < 0·05) but protein deposition (PD) were similar. Supplemented pigs had higher PD during HS regardless of FW (+18 g · d-1; P = 0·03). Comparing the 2FW groups, improved heat tolerance of LY-supplemented pigs were due to improved insulin sensitivity (P < 0·05) and latent heat loss capacity after a meal (P < 0·05) allowing them to increase their DMI (via an increased number of meals) and thus their energy efficiency. Imposing an increased meal frequency improved DMI in HS pigs but did not replicate positive effects of LY on PD.


Clinical, histopathological, and immunohistochemical spectrum of hepatolithiasis: a tertiary care center-based study from north India.
Hepatolithiasis (HL), an uncommon disease among Indians, occurs due to a complex interplay of various structural and functional factors. We retrospectively evaluated the clinical and histopathological spectrum of HL (N = 19) with immunohistochemical evaluation for biliary apomucins and canalicular transporter proteins, both crucial for lithogenesis. Nineteen surgically resected cases were included. Histopathology was systematically evaluated. Immunohistochemistry for apomucins (MUC1, MUC2, MUC4, MUC5AC, and MUC6) and canalicular transporter proteins (BSEP and MDR3) was applied to all cases. The median age was 51 years with female preponderance (F:M = 1.4:1). The stone was cholesterol-rich in 71.4% and pigmented in 28.6% (n = 14). Histopathology showed variable large bile-duct thickening due to fibrosis and inflammation with peribiliary gland hyperplasia. Structural causes (Caroli disease, choledochal cyst, and post-surgical complication) were noted in 15.8% of cases (secondary HL). Expression of gel-forming apomucin MUC1, MUC2, and MUC5AC was seen in either bile duct epithelia or peribiliary glands in 84.2%, 10.5%, and 84.2% cases respectively. Loss of canalicular expression of MDR3 was noted in 42.1% of cases while BSEP was retained in all. Primary HL in the north Indian population can be associated with the loss of MDR3 expression (with retained BSEP) and/ or a shift in the phenotype of biliary apomucins to gel-forming apomucins. The former factor alters the bile acid/ phospholipid ratio while the latter parameter promulgates crystallization. In conjunction, these factors are responsible for the dominantly cholesterol-rich stones in the index population.


Thermal proteome profiling for unbiased identification of direct and indirect drug targets using multiplexed quantitative mass spectrometry.
The direct detection of drug-protein interactions in living cells is a major challenge in drug discovery research. Recently, we introduced an approach termed thermal proteome profiling (TPP), which enables the monitoring of changes in protein thermal stability across the proteome using quantitative mass spectrometry. We determined the intracellular thermal profiles for up to 7,000 proteins, and by comparing profiles derived from cultured mammalian cells in the presence or absence of a drug we showed that it was possible to identify direct and indirect targets of drugs in living cells in an unbiased manner. Here we demonstrate the complete workflow using the histone deacetylase inhibitor panobinostat. The key to this approach is the use of isobaric tandem mass tag 10-plex (TMT10) reagents to label digested protein samples corresponding to each temperature point in the melting curve so that the samples can be analyzed by multiplexed quantitative mass spectrometry. Important steps in the bioinformatic analysis include data normalization, melting curve fitting and statistical significance determination of compound concentration-dependent changes in protein stability. All analysis tools are made freely available as R and Python packages. The workflow can be completed in 2 weeks.


Consequences of suboptimal communication for patients with limited English proficiency in the intensive care unit and suggestions for a way forward: A qualitative study of healthcare team perceptions.
To understand the healthcare team's perceptions of the negative consequences of suboptimal communication and their recommendations to improve communication with patients and families who have Limited English Proficiency (LEP) in the Intensive Care Unit (ICU). We performed a qualitative study using semi-structured interviews of physicians, nurses, and interpreters from 3 ICUs at Mayo Clinic Rochester, between November 2017 and April 2018. We identified 5 consequences of suboptimal communication: 1) Suboptimal assessment and treatment of patient symptoms, 2) Unmet patient and family expectations, 3) Decreased patient autonomy, 4) Unmet end of life wishes and 5) Clinician Distress. Recommendations to improve communication include: 1) Education and training for patients,families, clinicians and interpreters, 4) Greater integration of interpreters into the ICU team 5) Standardized timeline for goals of care conversations with patients and families with LEP. Patients with LEP are at risk of experiencing suboptimal communication with the healthcare team in the ICU. There are several educational and quality improvement strategies that ICUs and institutions can take to mitigate these issues.


Cardiometabolic Risk and Dietary Behaviors in Middle-School Children Consuming School-Sourced Lunch.
Childhood obesity remains a major public health issue. This study assessed the association between school-sourced lunches and cardiometabolic risk factors in middle-school students. Data from health behavior surveys and physiologic screenings in a Michigan middle-school wellness program between 2005 and 2019 were used to analyze the association of school lunch consumption with cardiometabolic risk factors (overweight/obesity, non-fasting lipids/glucose, blood pressure) and dietary behaviors (fruit/vegetable consumption, intake of sugar-sweetened beverages/foods). Students were divided into three groups based on their responses to the survey item if they 1) always, 2) sometimes, or 3) never consumed school-sourced lunches. Groups were compared using descriptive statistics and chi-squared tests. Students consuming school-sourced lunches were more likely to have overweight or obesity, without significant differences in total, HDL, or LDL cholesterol. There was no difference in non-fasting glucose levels, blood pressure, or resting heart rate. Students consuming school sourced lunch were more likely to have increased sugary and fatty food or beverage consumption. Students consuming school sourced lunch were more likely to attend school in a low or middle socioeconomic status region. In this large cohort of middle-school children, consuming school-sourced lunches was associated with a greater prevalence of overweight and obesity and consumption of fatty foods and sugary beverages. School-based interventions should target methods to reduce consumption of sugary beverages and unhealthy snacks and promote consumption of fruits and vegetables, particularly among high-risk individuals.


NGF and NT-3 exert differential effects on the expression of neuropeptides in the suprachiasmatic nucleus of rats withdrawn from ethanol treatment.
Some neurotrophins have the capability of enhancing neuropeptide expression in several regions of the brain. It was also recently shown that NGF, infused over 1 month, offsets the decreased synthesis and expression of vasopressin (VP) and vasoactive intestinal polypeptide (VIP) in the suprachiasmatic nucleus (SCN) of rats submitted to chronic ethanol treatment and withdrawal. In the present study we examined the effectiveness of neutrotrophin-3 (NT-3) in promoting such effects, given that SCN neurons express both the high and the low affinity receptors for this neurotrophin. NT-3 was intraventricularly infused during 10 days to rats withdrawn from prolonged ethanol treatment. The total number, and the mean somatic volume, of VP- and VIP-immunoreactive neurons was compared with the estimates obtained from control rats and withdrawn rats treated with either NGF or cerebrospinal fluid during the same period. The infusion of cerebrospinal fluid and of NT-3 did not prevent the reduction in the number of peptide-producing neurons induced by withdrawal from ethanol treatment. Conversely, NGF infusion increased their number to control levels and led to neuronal hypertrophy. Our results show that, unlike NGF, NT-3 does not display the capacity of enhancing neuropeptide expression in the SCN. Because SCN neurons express the low affinity p75(NTR), which is equally activated by both neurotrophins, our results additionally indicate that the effects of NGF upon SCN neurons are not receptor-mediated. Taken together, our data suggest that indirect mechanisms, rather than direct neutrophin signaling, are likely to mediate the trophic effects exerted by NGF upon SCN neurons.


Prostacyclin-induced rundown of N-methyl-D-aspartate receptor currents in HEK293 cells is protein kinase A-dependent and NR2 subunit-selective.
Previous studies in neurons have demonstrated a rapid decrease in NMDA receptor currents following tyrosine kinase inhibition or exposure to platelet-derived growth factor (PDGF). Inhibitors of protein kinase A (PKA) block the PDGF-induced rundown suggesting a multistep pathway that leads to decreased amplitudes of NMDA-activated currents. In this study, HEK293 cells expressing different NMDA receptor subunits were used to study the effects of prostacyclin receptor-mediated PKA activation on the magnitude of glutamate-activated currents. The prostacyclin agonist iloprost induced a rapid and time-dependent depression of otherwise stable glutamate-activated currents in cells expressing NR1-2a/2A or NR1-2a/2D receptors but not NR1-2a/2B or NR1-2a/2C receptors. This rundown was prevented by treatment of cells with the PKA inhibitor H89. The iloprost effect persisted in cells coexpressing NR1-2a/2A receptors and either wild-type or mutant Src kinase (SrcS17A). Co-expression of PSD-95 with NR1-2a/2A receptors reduced but did not eliminate the extent of rundown. Iloprost also produced current rundown in cells expressing NR1-2a and a C-terminal truncated NR2A subunit (NR2A1050stop) but not in those transfected with an NR2A tyrosine mutant (Y842F). The iloprost-induced rundown of wild-type NR1-2a/2A receptors was prevented by prior exposure of cells to hypertonic sucrose. These results suggest that PKA influences the functional activity of NMDA receptors in an NR2 subunit-selective fashion.


Mitral valve reconstruction in the elderly population.
The technique, efficacy, and long-term results of mitral valve reconstruction have been well demonstrated and reported by Carpentier and other investigators. However, most of the results reported have been in patients aged less than 65 years. Between April 1985 and September 1988, we performed mitral valve reconstruction in 176 patients using Carpentier's classification and technique for repair. Ages ranged from 15 to 86 years (mean age, 63 years). Of the repairs, 96/176 (55%) had concomitant cardiac procedures. Patients aged 65 years or more accounted for 52% (92/176) of the population and 35% (65/176) were more than 70 years old. Hospital mortality (30 day) was 4% (4/84) in the group aged less than 65 years. Hospital mortality for the group aged more than 65 years was 12% (11/92), compared with an overall 8.5% mortality. These results suggest an increased morbidity with mitral valve repair in the patients aged more than 65 years, but this group represents an even higher risk group with mitral valve replacement.


Aluminum exposure induces central nervous system impairment via activating NLRP3-medicated pyroptosis pathway.
Aluminum is an environmental toxicant whose long-term exposure is closely associated with nervous system impairment. This study mainly investigated neurological impairment induced by subchronic aluminum exposure via activating NLRP3-medicated pyroptosis pathway. In vivo, Kunming mice were exposed to AlCl3 (30.3 mg/kg, 101 mg/kg and 303 mg/kg) via drinking water for 3 months, and administered with Rsv (100 mg/kg) by gavage for 1 month. Cognitive impairment was assessed by Morris water maze test, and pathological injury was detected via H&E staining. BBB integrity, pyroptosis and neuroinflammation were evaluated through western blotting and immunofluorescence methods. In vitro, BV2 microglia was treated with AlCl3 (0.5 mM, 1 mM and 2 mM) to sensitize pyroptosis pathway. The protein interaction was verified by co-immunoprecipitation, and neuronal damage was estimated via a conditioned medium co-culture system with BV2 and TH22 cells. Our results showed that AlCl3 induced mice memory disorder, BBB destruction, and pathological injury. Besides, aluminum caused glial activation, sensitized DDX3X-NLRP3 pyroptosis pathway, released cytokines IL-1β and IL-18, initiating neuroinflammation. BV2 microglia treated with AlCl3 emerged hyperactivation and pyroptotic death, and Ddx3x knockdown inhibited pyroptosis signaling pathway. DDX3X acted as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome and G3BP1 stress granules. Furthermore, aluminum-activated microglia had an adverse effect on co-cultured neurons and destroyed nervous system homeostasis. Aluminum exposure could induce pyroptosis and neurotoxicity. DDX3X determined live or die via selectively regulating pro-survival stress granules or pro-death NLRP3 inflammasome. Excessive activation of microglia might damage neurons and aggravate nerve injury.


Diagnosis and Management of Alopecia Areata: A Saudi Expert Consensus Statement (2023).
Alopecia areata (AA) is a complex autoimmune disease manifesting as a chronic inflammatory disease characterized by non-scarring patches of hair loss over the face, scalp, and body. Several treatments have been proposed for AA, but none are curative nor achieve a state of remission. The present consensus statement aims to present the evidence- and experience-based recommendations on the diagnosis and management of AA in Saudi Arabia. The Ministry of Health in Saudi Arabia has opted to initiate a meeting of a multidisciplinary group to discuss and concede on this topic. Eight dermatology experts and clinical pharmacists convened in eight consensus meetings. All content presented in this document was agreed upon by this working group, including diagnosis and severity assessment, prognostic indicators, and therapeutic options for AA. Special consideration was given to special patient populations including pediatric patients and patients with less frequent presentations of AA. Updates of the current recommendations will take place as new evidence evolves in the treatment of AA.


Mortality at 120 days after prostatic biopsy: a population-based study of 22,175 men.
Trans-rectal ultrasound guided biopsy of the prostate represents the diagnostic standard for prostate cancer, but its mortality rate has never been examined. We performed a population-based study of 120-day mortality after prostate biopsy in 22,175 patients, who underwent prostate biopsy between 1989 and 2000. The control group consisted of 1,778 men aged 65-85 years (median 69.5), who did not undergo a biopsy. Univariable and multivariable logistic regression analyses were performed in 11,087 of 22,175 (50%) men subjected to prostate biopsy, to identify predictors of 120-day mortality. Variables were age at biopsy, baseline Charlson comorbidity index and cumulative number of biopsy procedures. We externally validated the model's predictors in the remaining 50% of men. Overall 120-day mortality after biopsy was 1.3% versus 0.3% (p < 0.001) in the control group. Of men aged < or = 60 years, 0.2% died within 120 days versus 2.5% aged 76-80. Zero Charlson comorbidity score yielded 0.7% mortality versus 2.2%, if 3-4. First ever biopsy procedures carried a higher mortality risk than subsequent procedures (1.4 vs. 0.8 vs. 0.6%). In the multivariable model, first ever biopsy, increasing age and comorbidity predicted higher mortality. Overall, the model's variables were 79% accurate in predicting the probability of 120-day mortality after biopsy. In conclusion, our data suggest that prostate biopsy might predispose to higher mortality rate. The certainty of this association remains to be proven.