Clinical Effect of Sex-Specific Cutoff Values of High-Sensitivity Cardiac Troponin T in Suspected Myocardial Infarction.
It is currently unknown whether the uniform (universal clinical practice for more than 2 decades) or 2 sex-specific cutoff levels are preferable when using high-sensitivity cardiac troponin T (hs-cTnT) levels in the diagnosis of acute myocardial infarction (AMI). To improve the management of suspected AMI in women by exploring sex-specific vs uniform cutoff levels for hs-cTnT. In an ongoing prospective, diagnostic, multicenter study conducted at 9 emergency departments, the present study evaluated patients enrolled from April 21, 2006, through June 5, 2013. The participants included 2734 adults presenting with suspected AMI. Duration of follow-up was 2 years, and data analysis occurred from June 5 to December 21, 2015. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including measurements of serial hs-cTnT blood concentrations twice: once using the uniform 99th percentile cutoff value level of 14 ng/L and once using sex-specific 99th percentile levels of hs-cTnT (women, 9 ng/L; men, 15.5 ng/L). Diagnostic reclassification in women and men using sex-specific vs the uniform cutoff level in the diagnosis of AMI. Of the 2734 participants, 876 women (32%) and 1858 men (68%) were included. Median (interquartile range) age was 68 (55-77) and 59 (48-71) years, respectively. With the use of the uniform cutoff value, 127 women (14.5%) and 345 men (18.6%) received a final diagnosis of AMI. Among these, at emergency department presentation, levels of hs-cTnT were already above the uniform cutoff value in 427 patients (sensitivity, 91.3% [95% CI, 85%-95.6%] in women vs 90.7% [95% CI, 87.1%-93.5% in men]; specificity, 79.2% [95% CI, 76.1%-82.1%] in women vs 78.5% [95% CI, 76.4%-80.6%] in men). After readjudication using sex-specific 99th percentile levels, diagnostic reclassification regarding AMI occurred in only 3 patients: 0.11% (95% CI, 0.02-0.32) of all patients and 0.6% (95% CI, 0.13-1.85) of patients with AMI. The diagnosis in 2 women was upgraded from unstable angina to AMI, and the diagnosis in 1 man was downgraded from AMI to unstable angina. These diagnostic results were confirmed when using 2 alternative pairs of uniform and sex-specific cutoff values. The uniform 99th percentile should remain the standard of care when using hs-cTnT levels for the diagnosis of AMI.


[Poor quality of sleep associated with low adherence to highly active antiretroviral therapy in Peruvian patients with HIV/AIDS].
This cross-sectional study analyzed the association between poor quality of sleep and adherence to highly active antiretroviral therapy (HAART) in 389 Peruvian patients with HIV/AIDS. Poor quality of sleep was measured with the Pittsburgh Sleep Quality Index (PSQI) and adherence with the CEAT-VIH (Peruvian adaptation). A Poisson generalized linear model with robust standard errors was used to estimate prevalence ratios and 95%CI. A crude model showed that mild, moderate, and severe poor quality of sleep were associated with inadequate treatment adherence. In the adjusted model for variables associated in the bivariate analysis or variables theoretically associated with adherence, only moderate/severe poor quality of sleep remained associated (PR = 1.34, 95%CI: 1.17-1.54; and PR = 1.34, 95%CI: 1.16-1.57, respectively). The study concluded that moderate/severe poor quality of sleep was independently associated with adherence to HAART. Assessing quality of sleep may be helpful in the comprehensive evaluation of HIV patients.


Sexual antagonism in haplodiploids.
Females and males may face different selection pressures, such that alleles conferring a benefit in one sex may be deleterious in the other. Such sexual antagonism has received a great deal of theoretical and empirical attention, almost all of which has focused on diploids. However, a sizeable minority of animals display an alternative haplodiploid mode of inheritance, encompassing both arrhenotoky, whereby males develop from unfertilized eggs, and paternal genome elimination (PGE), whereby males receive but do not transmit a paternal genome. Alongside unusual genetics, haplodiploids often exhibit social ecologies that modulate the relative value of females and males. Here, we develop a series of evolutionary-genetic models of sexual antagonism for haplodiploids, incorporating details of their molecular biology and social ecology. We find that: (1) PGE promotes female-beneficial alleles more than arrhenotoky, and to an extent determined by the timing of elimination-and degree of silencing of-the paternal genome; (2) sib-mating relatively promotes female-beneficial alleles, as do other forms of inbreeding including limited male-dispersal, oedipal-mating, and the pseudo-hermaphroditism of Icerya purchasi; (3) resource competition between related females inhibits the invasion of female-beneficial alleles; and (4) sexual antagonism foments conflicts between parents and offspring, endosymbionts and hosts, and maternal- and paternal-origin genes.


A multilocular radiolucency of mandible as the first evidence of multiple myeloma: A clinico-radiographic case report.
The incidence of multiple myeloma (MM) affecting the jaws is 30% and on rare occasions the oral involvement can be the first indication of the disease. Authors report a case of MM in a 40-year-old woman who presented with a multilocular radiolucent lesion in the left mandible initially mistaken as an ameloblastoma. Conventional radiographs revealed a multilocular lesion on the molar region. Computed tomography (CT) and 3 dimensional CT revealed lytic, space occupying lesion perforating the inferior cortex. Magnetic resonance imaging (MRI) revealed a hypointense lesion on T1 weighted image and hyperintense lesion on T2 weighted image. Histopathological and lab investigations lead to the diagnosis of MM. MRI is superior in depicting the size of the lesion as compared to CT and conventional radiographs.


Clinical Assessment of Fluid Balance is Incomplete for Colorectal Surgical Patients.
Fluid balance for the surgical patient has been proven very important for the postoperative outcome and development of complications. The aim of this study was to evaluate, for the first time in modern times, the accordance between nurse-based fluid charting (cumulated fluid balance) and body weight change for general surgical patients. This was a descriptive study with prospectively collected data from two clinical randomized multicenter trials. A total of 113 patients from American Society of Anesthesiology group I-III undergoing elective colorectal surgery were included. Cumulated fluid balance and body weight change were charted preoperatively and daily at the same time during a postoperative period of 6 days. Differences were calculated by subtracting cumulated fluid balance from body weight change (1 g = 1 mL), and agreement was assessed by making Bland-Altman plots as well as Pearson correlations. From day 1 to 4, the mean difference between cumulated fluid balance and body weight change was below 0.4 kg/L. On day 5 and 6, the discrepancies increased with mean differences of, respectively, 1.2 kg/L (p < 0.002*) and 2 kg/L (p < 0.0001*). Bland-Altman plots showed increasingly poor agreement for all postoperative days with wide limits of agreement, ranging from more than 6 kg/L to almost 10 kg/L. Pearson correlations were moderate to strong at all times ranging from 0.437 (day 1) to 0.758 (day 4). The accordance between cumulated fluid balance and body weight change for colorectal surgical patients is relatively good for the first four postoperative days, however, with large uncertainty, whereas on the fifth and sixth postoperative day, the discrepancy is statistically and clinically significant. The fluid chart cannot stand alone in interpretation of the patient's fluid balance; body weight and clinical judgment is indispensable.


Molecular determinants of cardiac K(ATP) channel activation by epoxyeicosatrienoic acids.
We have previously reported that epoxyeicosatrienoic acids (EETs), the cytochrome P450 epoxygenase metabolites of arachidonic acid, are potent stereospecific activators of the cardiac K(ATP) channel. The epoxide group in EET is critical for reducing channel sensitivity to ATP, thereby activating the channel. This study is to identify the molecular sites on the K(ATP) channels for EET-mediated activation. We investigated the effects of EETs on Kir6.2delta C26 with or without the coexpression of SUR2A and on Kir6.2 mutants of positively charged residues known to affect channel activity coexpressed with SUR2A in HEK293 cells. The ATP IC50 values were significantly increased in Kir6.2 R27A, R50A, K185A, and R201A but not in R16A, K47A, R54A, K67A, R192A, R195A, K207A, K222A, and R314A mutants. Similar to native cardiac K(ATP) channel, 5 microM 11,12-EET increased the ATP IC50 by 9.6-fold in Kir6.2/SUR2A wild type and 8.4-fold in Kir6.2delta C26. 8,9- and 14,15-EET regioisomers activated the Kir6.2 channel as potently as 11,12-EET. 8,9- and 11,12-EET failed to change the ATP sensitivity of Kir6.2 K185A, R195A, and R201A, whereas their effects were intact in the other mutants. 14,15-EET had a similar effect with K185A and R201A mutants, but instead of R195A, it failed to activate Kir6.2R192A. These results indicate that activation of Kir6.2 by EETs does not require the SUR2A subunit, and the region in the Kir6.2 C terminus from Lys-185 to Arg-201 plays a critical role in EET-mediated Kir6.2 channel activation. Based on computer modeling of the Kir6.2 structure, we infer that the EET-Kir6.2 interaction may allosterically change the ATP binding site on Kir6.2, reducing the channel sensitivity to ATP.


Type 1 diabetes mellitus caused by treatment with low-dose interferon-α in a melanoma patient.
Interferon-α (INF-α) is used as an adjuvant treatment for high-risk cutaneous melanoma. It has a large variety of potentially severe and irreversible side effects and can contribute toward the development of autoimmune disease. We report a case of a 59-year-old woman who developed type 1 diabetes following the use of low-dose IFN-α for the adjuvant treatment of stage IIB melanoma. Fifteen months after initiating IFN-α, she presented with blood glucose of 1126 mg/dl, hyponatremia, and microalbuminuria. Antibodies to glutamic acid decarboxylase and islet antigen-2 were negative and C-peptide was markedly reduced. There was no personal or family history of any autoimmune conditions. Reinforced insulin treatment and volume substitution with saline and glucose as a counter-regulation was started. To the best of our knowledge, this is the first reported case of low-dose IFN-α-induced type 1 diabetes. Clinicians should closely evaluate the pros and cons of IFN-α treatment in an adjuvant setting and remain mindful of the possibility of drug-induced autoimmune disease.


Oxidative rearrangements during fungal biosynthesis.
Oxidative rearrangements are key reactions during the biosyntheses of many secondary metabolites in fungi. This review highlights the most important examples of these reactions and aims to draw together key mechanistic themes to allow a better understanding and future exploitation of this key class of fungal catalysts.


Dermal matrices and bioengineered skin substitutes: a critical review of current options.
Over recent decades, scientists and surgeons have collaborated to develop various bioengineered and synthetic products as an alternative to skin grafts. Despite the numerous articles and reviews written about dermal skin substitutes, there is no general consensus. This article reviews dermal skin scaffolds used in clinical applications and experimental settings. For scaffold evaluation, we focused on clinical and/or histological results, and conclusions are listed. Explanations for general trends were sought based on existing knowledge about tissue engineering principles and wound healing mechanisms. Decellularized dermis seems to remain the best option with no other acellular scaffold being clinically proven to gain better results yet. In general, chemically cross-linked products were seen to be less effective in skin tissue engineering. Biocompatibility could be enhanced by preseeding substitutes with fibroblasts to allow some natural scaffold remodeling before product application. Skin substitutes are a useful tool in plastic and reconstructive surgery practices as an alternative to skin grafts. In the choice of substitute, the general plastic surgery principle of replacing like tissue with like tissue seems to be still standing, and products most resembling the natural dermal extracellular matrix should be preferred.


Acupuncture for smoking cessation.
Acupuncture and related techniques are promoted as a treatment for smoking cessation in the belief that they may reduce nicotine withdrawal symptoms. The objective of this review is to determine the effectiveness of acupuncture and the allied therapies of acupressure, laser therapy and electrostimulation, in smoking cessation in comparison with: a) sham treatment, b) other interventions, or c) no intervention. We searched the Cochrane Tobacco Addiction Group trials register, Cochrane Controlled Trials Register, Medline, Embase, BIOSIS Previews, PsycINFO, Science and Social Sciences Citation Index, AMED and CISCOM. Date of last search January 2002. Randomised trials comparing a form of acupuncture, acupressure, laser therapy or electrostimulation with either sham treatment, another intervention or no intervention for smoking cessation. We extracted data in duplicate on the type of smokers recruited, the nature of the acupuncture and control procedures, the outcome measures, method of randomisation, and completeness of follow-up. We assessed abstinence from smoking at the earliest time-point (before 6 weeks), at six months and at one year or more follow-up in patients smoking at baseline. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Those lost to follow-up were counted as continuing to smoke. Where appropriate, we performed meta-analysis using a fixed effects model. We identified 22 studies. Acupuncture was not superior to sham acupuncture in smoking cessation at any time point. The odds ratio (OR) for early outcomes was 1.22 (95% confidence interval 0.99 to 1.49); the OR after 6 months was 1.50 (95% confidence interval 0.99 to 2.27) and after 12 months 1.08 (95% confidence interval 0.77 to 1.52). Similarly, when acupuncture was compared with other anti-smoking interventions, there were no differences in outcome at any time point. Acupuncture appeared to be superior to no intervention in the early results, but this difference was not sustained. The results with different acupuncture techniques do not show any one particular method (i.e. auricular acupuncture or non-auricular acupuncture) to be superior to control intervention. Based on the results of single studies, acupressure was found to be superior to advice; laser therapy and electrostimulation were not superior to sham forms of these therapies. There is no clear evidence that acupuncture, acupressure, laser therapy or electrostimulation are effective for smoking cessation.


Histone folds mediate selective heterodimerization of yeast TAF(II)25 with TFIID components yTAF(II)47 and yTAF(II)65 and with SAGA component ySPT7.
We show that the yeast TFIID (yTFIID) component yTAF(II)47 contains a histone fold domain (HFD) with homology to that previously described for hTAF(II)135. Complementation in vivo indicates that the yTAF(II)47 HFD is necessary and sufficient for vegetative growth. Mutation of highly conserved residues in the alpha1 helix of the yTAF(II)47 HFD results in a temperature-sensitive phenotype which can be suppressed by overexpression of yTAF(II)25, as well as by yTAF(II)40, yTAF(II)19, and yTAF(II)60. In yeast two-hybrid and bacterial coexpression assays, the yTAF(II)47 HFD selectively heterodimerizes with yTAF(II)25, which we show contains an HFD with homology to the hTAF(II)28 family We additionally demonstrate that yTAF(II)65 contains a functional HFD which also selectively heterodimerizes with yTAF(II)25. These results reveal the existence of two novel histone-like pairs in yTFIID. The physical and genetic interactions described here show that the histone-like yTAF(II)s are organized in at least two substructures within TFIID rather than in a single octamer-like structure as previously suggested. Furthermore, our results indicate that ySPT7 has an HFD homologous to that of yTAF(II)47 which selectively heterodimerizes with yTAF(II)25, defining a novel histone-like pair in the SAGA complex.


Selective kinase inhibitors as tools for neuroscience research.
Signal transduction cascades, including the MAPK, PI3 kinase, Ca(2+) and PKC pathways, play important roles in neurons downstream of multiple signals including neurotrophins and neurotransmitters. Small molecule kinase inhibitors that block these pathways provide a powerful way of studying the in vivo or cellular roles of these signaling systems. Over the last 15 years there has been a major effort by the pharmaceutical industry to develop kinase inhibitors as potential drugs for a variety of diseases including cancer and auto-immunity. As a result of this there are now many compounds available that can be used as research tools. One major drawback is however that many of these compounds are not truly selective for a single kinase, and therefore the possibility that their cellular effects may be due to an off target activity must be considered. This problem has been brought into sharp relief by modern in vitro screening methods that allow an inhibitor to be screened against a significant proportion of the kinome. In this review we discuss the advantages and problems with the use of kinase inhibitors as research tools and describe some of the available compounds that target pathways important to neurons.


Diminished Sphenous Compartment Connective Tissue Elasticity has Little Impact on Low Grade Venous Insufficiency: An Ultrasound Shearwave Elastography Study.
Greater Saphenous Vein (GSV) courses within saphenous compartment, an adipose-filled space bound by fasciae provides structural support. Ultrasound Shear-Wave Elastography (SWE) provides objective and quantitative data on tissue shear elasticity modulus. This study aims to analyze possible associations between early stage GSV insufficiency and saphenous intracompartmental SWE measurements. Two-hundred consecutive patients, ages 22 to 81 (mean=44.3) years, with venous insufficiency symptoms underwent Doppler and SWE examinations. Patients had no visible or palpable sign of venous disease or had telangiectasia and reticular veins only. Analyses regarding patient age, gender, presence of venous insufficiency of GSV proper and intracompartmental connective tissue elasticity were performed. Ninety-six patients had Doppler evidence for either bilateral or unilateral insufficiency of GSV proper at mid-thigh level. Intracompartmental elasticity of patients with venous insufficiency (mean=4.36±2.24 kilopascals; range 1.55 to 10.44 kPa) did not differ significantly from those with normal veins (mean=4.82±2.61 kPa; range 2.20 to 12.65 kPa) (p=0.231). No threshold for predicting the presence of venous insufficiency could be determined. Neither were there any correlations between age, gender and intracompartmental elasticity. In patients with unilateral insufficiency, however, elastography values around insufficient veins were significantly lower compared to contralateral normal GSV (p<0.001). Many intrinsic and patient factors affect intracompartmental connective tissue elastography measurements; thus, cut-off values obtained from specific populations have limited generalizability. Nevertheless, statistically significant intrapatient differences of intracompartmental elasticity among diseased and normal saphenous veins indicate that lack of elastic support from surrounding connective tissues contributes to venous insufficiency in early stages.


The effect of diet in infancy on asthma in young adults: the Merthyr Allergy Prevention Study.
Early infant diet might influence the risk of subsequent allergic disease. The Merthyr Allergy Prevention Study (MAPS) was a randomised controlled trial in infants at high risk of allergic disease. The trial determined whether a cow's milk exclusion diet for the first 4 months of life decreased the risk of allergic disease including asthma compared with a normal diet. A soya milk preparation was offered to those in the intervention group. A standardised questionnaire for allergic disease was completed at ages 1, 7, 15 and 23 years, with clinical assessment at 1, 7 and 23 years. The effect of the intervention on the risk of atopy, asthma and wheeze at age 23 years was determined. 487 subjects entered the study; at age 23 years 299 completed the questionnaire, of which 119 attended clinical assessment. Subjects randomised to the intervention group had a significantly increased risk of atopy (adjusted OR 2.97, 95% CI 1.30 to 6.80; p=0.01) and asthma (OR 2.07, 95%CI 1.09 to 3.91; p=0.03) at age 23 years, but not wheeze (OR 1.43, 95%CI 0.87 to 2.37; p=0.16). Earlier exposure to cow's milk was associated with a decreased risk of wheeze and asthma at age 23 years, while earlier exposure to soya milk was associated with an increased risk of atopy and asthma. In infants at high risk of allergic disease, either cow's milk exclusion or early soya milk introduction for the first 4 months of life increases the risk of atopy, wheeze and asthma in adulthood.


Multilayer films composed of phenylboronic acid-modified dendrimers sensitive to glucose under physiological conditions.
Layer-by-layer (LbL) multilayer films were prepared using phenylboronic acid-modified poly(amidoamine) dendrimers and poly(vinyl alcohol) (PVA) in order to investigate the glucose sensitivity of the films. We used dendrimer derivatives modified with 3-carboxyphenylboronic acid (3CPBA-D) and 3-carboxy-5-nitrophenylboronic acid (3C5NPBA-D) to evaluate the effect of electron-withdrawing nitro groups on glucose sensitivity. PVA/3CPBA-D and PVA/3C5NPBA-D films were prepared on the surface of a quartz slide from PVA and 3CPBA-D or 3C5NPBA-D solutions at pH 7.0, 8.0, and 9.0 through boronate ester bonds. The dendrimer-based LbL films were stable at pH 7.0-9.0, whereas they decomposed in acidic media because of the instability of the boronate ester linkages. The pH threshold of decomposition was at pH 6.0-7.0 for both films. The PVA/3C5NPBA-D film was more stable than the PVA/3CPBA-D film in this range. Both films decomposed in response to glucose under physiological conditions (pH 7.4 buffer solution containing 150 mM NaCl at 37 °C), and the decomposition depended on the glucose concentration. The PVA/3C5NPBA-D film was more sensitive to glucose than the PVA/3CPBA-D film, probably due to the higher binding affinity of 3C5NPBA-D to glucose under physiological conditions. The higher response of the PVA/3C5NPBA-D film was explained by the electron-withdrawing effect of the nitro substituent on the phenylboronic acid ring. The results suggest that dendrimer-based LbL films could be used for glucose-triggered release systems.


The polyamine oxidase inhibitor MDL-72,527 selectively induces apoptosis of transformed hematopoietic cells through lysosomotropic effects.
Polyamine oxidase functions in the polyamine catabolic pathway, converting N1-acetyl-spermidine and -spermine into putrescine (Put) and spermidine (Spd), respectively, thereby facilitating homeostasis of intracellular polyamine pools. Inhibition of polyamine oxidase in hematopoietic cells by a specific inhibitor, N,N'-bis(2,3-butadienyl)-1,4-butanediamine (MDL-72,527), reduces the levels of Put and Spd and induces the accumulation of N1-acetylated Spd. Although previously thought to be relatively nontoxic, we now report that this inhibitor overrides survival factors to induce cell death of several immortal and malignant murine and human hematopoietic cells, but not of primary myeloid progenitors. Cells treated with MDL-72,527 displayed biochemical changes typical of apoptosis, and cell death was associated with the down-regulation of the antiapoptotic protein Bcl-X(L). However, enforced overexpression of Bcl-X(L), or treatment with the universal caspase inhibitor zVAD-fmk, failed to block MDL-72,527-induced apoptosis in these hematopoietic cells. Despite decreases in Put and Spd pools, MDL-72,527-induced apoptosis was not blocked by cotreatment with exogenous Put or Spd, nor was it influenced by overexpression or inhibition of the polyamine biosynthetic enzyme ornithine decarboxylase. Significantly, MDL-72,527-induced apoptosis was associated with the rapid formation of numerous lysosomally derived vacuoles. Malignant leukemia cells were variably sensitive to the lysosomotropic effects of MDL-72,527, yet pretreatment with the ornithine decarboxylase inhibitor L-alpha-difluoromethylornithine sensitized all of these leukemia cells to the deleterious effects of the inhibitor by stimulating its intracellular accumulation. The lysosomotropic nature of select polyamine analogues may, thus, provide a novel chemotherapeutic strategy to selectively induce apoptosis of malignant hematopoietic cells.


Associations between community income and cancer survival in Ontario, Canada, and the United States.
The objectives of this study were as follows: (1) to compare the magnitude of the association between socioeconomic status (SES) and cancer survival in the Canadian province of Ontario with that in the United States (U.S.), and (2) to compare cancer survival in communities with similar SES in Ontario and in the U.S. The Ontario Cancer Registry provided information about all cases of invasive cancer diagnosed in Ontario from 1987 to 1992, and the Surveillance, Epidemiology and End Results Registry (SEER) provided information about all cases diagnosed in the SEER regions of the U.S. during the same time period. Census data provided information about SES at the community level. The product-limit method was used to describe cause-specific survival. Cox proportional hazards models were used to describe the association between SES and the risk of death from cancer. There were significant associations between SES and survival for most cancer sites in both the U.S. and Ontario, but the magnitude of the association was usually larger in the U.S. In the poorest communities, there were significant survival advantages in favor of cancer patients in Ontario for many disease groups, including cancers of the lung, head and neck region, cervix, and uterus. However, in upper- and middle-income communities, there were significant survival advantages in favor of the U.S. for all cases combined and for several individual diseases, including cancers of the breast, colon and rectum, prostate, and bladder. The association between SES and cancer survival is weaker in Ontario than it is in the U.S. This is due to a combination of better survival among patients in the poorest communities and worse survival among patients in the wealthier communities of Ontario relative to those in the U.S.


Crystal structure of the complex between Pseudomonas effector AvrPtoB and the tomato Pto kinase reveals both a shared and a unique interface compared with AvrPto-Pto.
Resistance to bacterial speck disease in tomato (Solanum lycopersicum) is activated upon recognition by the host Pto kinase of either one of two sequence-unrelated effector proteins, AvrPto or AvrPtoB, from Pseudomonas syringae pv tomato (Pst). Pto induces Pst immunity by acting in concert with the Prf protein. The recently reported structure of the AvrPto-Pto complex revealed that interaction of AvrPto with Pto appears to relieve an inhibitory effect of Pto, allowing Pto to activate Prf. Here, we present the crystal structure of the Pto binding domain of AvrPtoB (residues 121 to 205) at a resolution of 1.9A and of the AvrPtoB(121-205)-Pto complex at a resolution of 3.3 A. AvrPtoB(121-205) exhibits a tertiary fold that is completely different from that of AvrPto, and its conformation remains largely unchanged upon binding to Pto. In common with AvrPto-Pto, the AvrPtoB-Pto complex relies on two interfaces. One of these interfaces is similar in both complexes, although the primary amino acid sequences from the two effector proteins are very different. Amino acid substitutions in Pto at the other interface disrupt the interaction of AvrPtoB-Pto but not that of AvrPto-Pto. Interestingly, substitutions in Pto affecting this unique interface also cause Pto to induce Prf-dependent host cell death independently of either effector protein.


Conformational dynamics of bacterial and human cytoplasmic models of the ribosomal A-site.
The aminoacyl-tRNA binding site (A-site) is located in helix 44 of small ribosomal subunit. The mobile adenines 1492 and 1493 (Escherichia coli numbering), forming the A-site bulge, act as a functional switch that ensures mRNA decoding accuracy. Structural data on the oligonucleotide models mimicking the ribosomal A-site with sequences corresponding to bacterial and human cytoplasmic sites confirm that this RNA motif forms also without the ribosome context. We performed all-atom molecular dynamics simulations of these crystallographic A-site models to compare their conformational properties. We found that the human A-site bulge is more internally flexible than the bacterial one and has different base pairing preferences, which result in the overall different shapes of these bulges and cation density distributions. Also, in the human A-site model we observed repetitive destacking of A1492, while A1493 was more stably paired than in the bacterial variant. Based on the dynamics of the A-sites we suggest why aminoglycoside antibiotics, which target the bacterial A-site, have lower binding affinities and anti-translational activities toward the human variant.


Regarding "Stress management and In Vitro Fertilization (IVF): A pilot randomized controlled trial".
Koumparou et al.1 recently published a randomized controlled trial (RCT) on the effectiveness of psychological interventions (stress management training, SMT) for women planning in vitro fertilization (IVF). They concluded that while the effect of SMT was limited in terms of IVF outcome, it resulted in a significant reduction of stress levels in infertile patients. Since most women undergoing infertility treatment are exposed to high psychological stress,2 this study may be of great value in demonstrating the need for proactive SMT to maintain infertile women's mental health and motivation to continue treatment. However, we are concerned that the reliability of this RCT has been compromised in several ways. First, the registration of the RCT was not clearly stated. According to The CONsolidated Standards of Reporting Trials (CONSORT) 2010 guidelines, a prospective registration of the RCT is required, which prevents unnecessary concerns about the bias of results selection.3,4 Second, the lack of specific figures on the background of the participants in the case and control groups risks distorting the RCT results. The article states that there was no significant difference between the two groups. However, since aging and prolonged infertility treatment increase the psychological burden on infertile patients,5 detailed background information is necessary to interpret the results of an RCT accurately. Selection bias could not be determined, which weakened the validity of this RCT. Furthermore, the absence of any mention of case dropout makes the conclusions of this RCT uncertain; a discussion of cases demonstrating difficulty in completing an 8-week psychological program would clarify whether temporary SMT would show efficacy for patients. Finally, it is essential to note that the details of IVF have not been clarified. Since the timing of the SMT and IVF-ET cycles or details of the IVF-ET protocol were not shown, this RCT could not be used as a reference for IVF facilities to actually operate SMT. There is no doubt that psychological interventions are necessary for infertile patients exposed to high psychological stress, but this RCT has many details that have not been clarified, and the conclusions are attenuated. As details become clearer, this RCT will provide a foundation for the active use of SMT in infertility treatment settings.


Discontinuation of maintenance treatment in bipolar disorder: risks and implications.
There is abundant evidence for substantial long-term prophylactic efficacy of lithium in bipolar manic-depressive disorders. Interruption of such treatment carries an extraordinarily high risk of recurrence within several months, even after several years of stability. Even a sharp reduction in dose may carry some risk. Gradual discontinuation of lithium was accompanied by markedly reduced risk of early recurrence. There is suggestive evidence that the phenomenon of high risk of recurrence after abrupt interruption of maintenance treatment may occur with other disorders and treatments, including neuroleptics in schizophrenia and possibly antidepressants in recurrent depression. The phenomenon of discontinuation-associated iatrogenic risk of early recurrence of major psychiatric illness has clear clinical implications. These include the need to evaluate safer methods of interrupting long-term maintenance treatment, particularly when clinical indications for rapid cessation are compelling and gradual discontinuation is not feasible. Questions also arise concerning interpretation of existing experimental studies of maintenance treatments that require interruption of treatment, reduction of dose, or crossover to a placebo, as well as the ethical and scientifically unambiguous design of future studies of this kind.


Type B-2 coxsackievirus meningitis in pregnancy. A case report.
Although enteroviral meningitis complicating pregnancy is a rare occurrence, it can lead to serious antenatal and neonatal complications. The majority of neonatal enteroviral infections are transmitted from a perinatally infected mother. We treated a woman for type B-2 coxsackievirus meningitis diagnosed in pregnancy. Three weeks after the acute maternal infection was diagnosed, a preterm neonate with no evidence of enteroviral infection was delivered. The neonate had no detectable IgM or virus-specific IgG at birth and later demonstrated IgG seroconversion to the coxsackievirus isolated from the mother. Intrapartum or postpartum exposure to the coxsackievirus is the suspected mode of transmission. Other factors in addition to passively acquired virus-specific IgG may offer neonatal protection to fetuses exposed to perinatal enteroviral infections.


Rapid activation of Stat3 and ERK1/2 by nicotine modulates cell proliferation in human bladder cancer cells.
Cigarette smoke is a major risk factor for bladder cancer. The main component in cigarette smoke, nicotine, can be detected in the urine of smokers. Nicotine has been implicated as a cocarcinogen that promotes lung cancer development through prosurvival pathways. Although the mechanisms of nicotine-induced cell proliferation have been well studied in lung epithelial cells, the molecular mechanism of its action in bladder epithelial cells is still unclear. The aims of this study were to investigate whether there is nicotine-induced bladder epithelial cell proliferation and to identify the signaling transduction pathway regulated by nicotine. We found that nicotine simultaneously activates Stat3 and extracellular signal regulated kinase 1/2 (ERK1/2) in T24 cells. Stat3 activation via nicotinic acetylcholine receptor (nAChR)/protein kinase C signaling pathway was closely linked to Stat3 induction and nuclear factor-kappaB DNA binding activity, which is associated with Cyclin D1 expression and cell proliferation. ERK1/2 activation through nAChR and beta-adrenoceptors plays a dual role in cell proliferation; it phosphorylates Stat3 at Ser727 and regulates cell proliferation. We conclude that through nAChR and beta-adrenoceptors, nicotine activates ERK1/2 and Stat3 signaling pathways, leading to Cyclin D1 expression and cell proliferation. This is the first study to investigate signaling effects of nicotine in bladder cells. The current findings suggest that people exposed to nicotine could be at risk for potential deleterious effects, including bladder cancer development.


Oncological role of HMGA2 (Review).
The high mobility group A2 (HMGA2) protein is a non‑histone architectural transcription factor that modulates the transcription of several genes by binding to AT‑rich sequences in the minor groove of B‑form DNA and alters the chromatin structure. As a result, HMGA2 influences a variety of biological processes, including the cell cycle process, DNA damage repair process, apoptosis, senescence, epithelial‑mesenchymal transition and telomere restoration. In addition, the overexpression of HMGA2 is a feature of malignancy, and its elevated expression in human cancer predicts the efficacy of certain chemotherapeutic agents. Accumulating evidence has suggested that the detection of HMGA2 can be used as a routine procedure in clinical tumour analysis.


Kidney transplantation outcomes in patients with IgA nephropathy and other glomerular and non-glomerular primary diseases in the new era of immunosuppression.
Kidney transplant (KTx) recipients with IgAN as primary disease, were compared with recipients with other causes of renal failure, in terms of long-term outcomes. Ninety-nine KTx recipients with end-stage kidney disease (ESKD) due to IgAN, were retrospectively compared to; i/ a matched case-control group of patients with non-glomerular causes of ESKD, and ii/ four control groups with ESKD due to glomerular diseases; 44 patients with primary focal segmental glomerulosclerosis (FSGS), 19 with idiopathic membranous nephropathy (IMN), 22 with lupus nephritis (LN) and 21 with pauci-immune glomerulonephritis (PIGN). At end of the observation period, graft function and survival, were similar between KTx recipients with IgAN and all other groups, but the rate of disease recurrence in the graft differed significantly across groups. The rate of IgAN recurrence in the graft was 23.2%, compared to 59.1% (p<0.0001) in the FSGS group, 42.1% (p = 0.17) in the IMN group, and 0% in the LN and PIGN groups (p = 0.01). IgAN recipients, who were maintained with a regimen containing tacrolimus, experienced recurrence less frequently, compared to those maintained with cyclosporine (p = 0.01). Graft loss attributed to recurrence was significantly higher in patients with FSGS versus all others. Recipients with IgAN as primary disease, experienced outcomes comparable to those of recipients with other causes of ESKD. The rate of IgAN recurrence in the graft was significantly lower than the rate of FSGS recurrence, but higher than the one recorded in recipients with LN or PIGN. Tacrolimus, as part of the KTx maintenance therapy, was associated with lower rates of IgAN recurrence in the graft, compared to the rate cyclosporine.


Accelerated heavy particles and the lens II. Cytopathological changes.
To assess more fully the risk to normal tissue exposed to accelerated heavy particles in the space program and during radiotherapy on earth, the cytopathological effects of a variety of doses of accelerated (570 MeV/amu) Argon (40Ar) ions on the rat lens were investigated. Time-course analyses of lenses exposed to a 1 Gy (100 rad)-dose revealed that the effects of the particles on mitotic index, nuclear fragmentation, and meridional row (MR) cytoarchitecture were qualitatively similar to those caused by 185 kVp x-rays. The effects of dose on the lens epithelium was also examined at 67 wk post-irradiation. The mitotic index returned to normal levels by that time; however, the biological effectiveness (RBE) of 40Ar relative to x-rays, in causing MR disorganization, increased with decreasing dose and closely resembled the RBE for cataractogenesis. The RBE data are consonant with the view that radiation cataracts are the result of damage to the lens epithelial population, which is later expressed as aberrant differentiation during fibergenesis.


Empowerment in farmers' occupational health services.
This study attempted to develop farmers' health and farmers occupational health services (FOHS) by examining the effects and feasibility of empowered farmers' teams on walk-through surveys of Finnish dairy farms. FOHS personnel of the health centre in three municipalities selected three farmer teams for the intervention group. Each team consisted of three or four couples. The selected comparison group resembled the intervention group. The number of the farms was 31 in the intervention group and 33 in the comparison group. Before and after the intervention each subject responded to questionnaires. The initial walk-through survey was carried out in 1998-1999, and the follow-up took place in 2000-2001. During the follow-up the FOHS personnel identified the changes made after the initial surveys on the farms. The farmers and FOHS personnel also underwent a thematic interview. Altogether 217 changes were made, half of them to improve ergonomics, and 87 of the 217 were extensive. The empowered farmer groups produced more changes in the work environment. The use of empowered farmer groups is feasible in walk-through surveys, and the approach can be easily learned. Empowered groups are also a challenge for FOHS personnel, and they enrich the work of these workers. The farmers want more varied measures for work-site health promotion, and, particularly, they feel that an occupational health physician should be present on walk-through surveys.


Sulfate adsorption properties of acid-sensitive soils in the Athabasca oil sands region in Alberta, Canada.
The risk of soil acidification is high in the Athabasca oil sands region (AOSR) in Alberta, Canada, due to elevated SO(2) emission and the resultant acid deposition to sensitive, coarse-textured soils. Understanding the sulfate adsorption characteristics of soils sensitive to acidification will help establish critical loads of acid deposition in AOSR. Sulfate adsorption properties were evaluated and relationships between sulfate adsorption and soil properties were examined for soils in two contrasting watersheds (NE7 and SM8) in AOSR. The experimental data fitted well to both the Langmuir and the Freundlich models. The sulfate adsorption capacity was greater for soils in SM8 than in NE7 (p<0.01), even though it was relatively low in both watersheds as compared to other acid-sensitive soils in eastern North America. Based on the additional sulfate adsorbed when a soil was treated with 40mL of 200mg SO(4)(2-) L(-1) solution, the weakly developed Podzolic B horizon (Bfj)in NE7 could adsorb more sulfate than the Ae horizon while no difference was found among other horizons. In SM8, the Bfj and illuviated B (Bt) horizons had greater ability to adsorb sulfate than the other horizons, likely caused by the presence of muscovite in the Bfj and Bt horizons. The additional sulfate adsorbed accounted for about 80% of the total sulfate adsorption capacity and was correlated with pH(NaF) (soil pH extracted with 1 MNaF) and ΔpH(NaF)(the difference between pH(NaF) and pH measured with deionized water), with the following relationships: sulfate adsorption (mg SO(4)(2-) kg(-1))=exp(2.03 pH(NaF) - 18.0)+50.2 (R(2)=0.63, p<0.001) and sulfate adsorption (mg SO(4)(2-) kg(-1))=exp(1.83 ΔpH(NaF) - 6.57) + 48.9 (R(2)=0.70, p<0.001). The ΔpH(NaF) was likely a better indicator of the soil's sulfate adsorption capacity than pH(NaF) as the former excludes the effect of soil acidity. Our study indicates that the soil's capacity to adsorb sulfate should be considered in determining the critical load for acid deposition in AOSR in Alberta.


Metabolic Parameters in Patients with Prader-Willi Syndrome and DiGeorge Syndrome with Respect to Psychopathological Manifestation.
The purpose of our study was to compare the metabolic parameters in two genetic syndromes with a proven high risk of developing psychiatric comorbidities. These comorbidities, especially mood and psychotic disorders, may be associated with a risk of obesity, type 2 diabetes and other components of metabolic syndrome regardless of antipsychotic treatment. Two groups of children diagnosed with Prader - Willi syndrome (PWS) (n = 20) and DiGeorge syndrome (DGS) (n = 18), aged 7-18 years, were enrolled. Behavioral symptoms and co-occurring psychopathological symptoms were assessed using the Child Behavior Checklist (CBCL). The levels of following biochemical parameters were measured: glucose, insulin, high-sensitivity C-reactive protein, total cholesterol, low- and high-density lipoproteins (LDL and HDL), triglycerides and non-HDL cholesterol. Additionally, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated. There were significantly higher levels of insulin and non-HDL in patients with PWS compared to those with DGS. The scores of four CBCL subscales (social problems, thought problems, delinquent behavior and aggressive behavior) were significantly higher in PWS patients. Higher scores of the CBCL-thought problems were associated with significantly higher levels of insulin as well as HOMA-IR. Patients with PWS seem to be more prone to develop subclinical metabolic dysregulation, in terms of elevated non-HDL levels and insulin levels, compared to DGS patients. Altered insulin sensitivity, present in both groups, even though it is not a specific risk factor, might be related to thought problems associated with psychosis.


Infratemporal Fossa Abscesses: A Systematic Review of Cases.
We have attempted to characterize the clinical presentations and management of infratemporal fossa abscesses with the goal of improving awareness and promoting earlier diagnosis and treatment for this rare condition. an extensive systematic search was performed through Pubmed/Medline, CINAHL (EBSCOhost), and Web of Science. Two authors screened out studies by abstracts, and a third resolved any conflicts. The remaining studies were assessed by full-text assessment, leaving 43 studies for data extraction. sixty-seven patients were included from the final 43 studies. The patients were predominantly male (56.7%), and the average age of patients was 44.3 years (standard deviation (SD) 19.8 years). Risk factors most commonly odontogenic, whether the etiology was through tooth extraction (n = 30, 44.8%) or infection (n = 17, 25.4%). Symptoms on presentation included pain (n = 40, 83.3%), swelling (n = 39, 81.3%), and trismus (n = 36, 75.0%). Twenty-two (32.8%) patients were managed with intraoral incision and drainage (I&D), 18 (26.9%) with extraoral I&D. After treatment, 45 of the 48 (93.8%) patients from the case reports and series were deemed to have achieved complete resolution. Infratemporal fossa abscesses are rare, but they may be associated with serious neurologic and systemic complications. Although prompt diagnosis paramount in avoiding these sequelae, patients often experienced delays in diagnosis. Surgical drainage and extended antibiotic therapy is recommended.


Physical dependence produced by long duration, low dose chronic barbital treatment.
Barbiturate physical dependence was produced by twice-daily administration of Na barbital to cats according to the "low" dose barbiturate protocol (Okamoto et al., J. Pharmacol. Exp. Ther. 207: 906, 1978). The duration of treatment was 1, 2, 3, 5, 9 or 14 weeks. Pharmacodynamic tolerance was assessed by relating the degree of neurofunctional impairment to the blood barbital concentration at the time when the functional test was performed. Evaluation of withdrawal was based on whole-animal observation and subjective assessment of overt withdrawal signs. Motor activity and withdrawal convulsions were monitored continuously by an activity recording device. It was found that the pharmacodynamic tolerance and physical dependence continued to develop throughout the treatment period and no apparent ceiling on these phenomena was observed. The "low" level chronic dosing merely prolonged the time required to develop physical dependence of severity comparable to that produced by shorter durations of "high" level chronic dosing.


A modular multi-branched system for endovascular repair of bilateral common iliac artery aneurysms.
To describe a modular stent-graft for cases of bilateral common iliac aneurysm. The aortic aneurysm is repaired using a standard bifurcated modular system (Zenith). A modified bifurcated component is deployed with its trunk in one limb of the original aortic stent-graft, its long limb in the external iliac artery, and its short limb in the iliac aneurysm just above the internal iliac orifice. A flexible extension is introduced from the right brachial artery and used to bridge the gap between the short limb of the modified bifurcated component and the left internal iliac artery. Endovascular repair of bilateral iliac aneurysm is feasible using a modular stent-graft with separate branches to the internal and external iliac arteries.


Nonpharmacological interventions for 'no-option' refractory angina patients.
Refractory angina pectoris (RAP) defined as chronic anginal chest pain because of coronary artery disease (CAD) is a major problem. The increase in the number of patients with RAP in recent years is because of the increasing aging population and improved survival rates among patients with CAD. Management of patients with RAP is often extremely challenging. In this review, we present several interventional approaches for RAP, including device therapies, lifestyle intervention, and cell therapies. Some of these treatments are currently used in the management of RAP, whereas other treatments are under investigation.


[Gastrointestinal disorders in Guatemala and their relation with parasitic infections].
To determine the frequency of symptoms sugestive of functional gastrointestinal disorders and their relation to parasite infections in a developing nation. 174 consecutive patients was seen in a gastroenterology clinic in Solola (Guatemala). Symptoms suggestive of irritable bowel syndrome was diagnosed in 37 patients (21%), irritable bowel syndrome with dyspeptic syndrome in 26 (15%) and dyspeptic syndrome in 24 (14%). Forty-two patients (24%) had been diagnosed of parasitation in the past. Such patients had a higher risk of suffering symptoms suggestives with functional gastrointestinal disorder (OR 6,335 CI 95% 2.72-14-75). Fifty-nine patients (34%) were subjected to parasite examination in stools; of these, 13 proved positive. In this same group of patients the risk of functional gastrointestinal problems was likewise higher among the subjects with parasite infection (p < 0.05). In turn, 41 patients (49%) with symptoms suggestives of gastrointestinal functional disorders were or had previously been diagnosed of parasite infection. Symptoms suggestives of functional gastrointestinal disorders are frequent in developing regions and its was in relation to intestinal parasites.


Can cyclin-dependent kinase 4/6 inhibitors convert inoperable breast cancer relapse to operability? A case report.
Pathological complete response (pCR) is rare in hormone receptor-positive (HR+) HER2-negative breast cancer (BC) treated with either endocrine therapy (ET) or chemotherapy. Radical resection of locoregional relapse, although potentially curative in some cases, is challenging when the tumor invades critical structures. The oral cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with ET has obtained a significant increase in objective response rates and progression-free survival in patients with advanced BC and is now being evaluated in the neoadjuvant setting. We present a clinical case of a patient with an inoperable locoregional relapse of HR+ HER2-negative BC who experienced pCR after treatment with palbociclib. We report the clinical case of a 60-year-old patient who presented with an inoperable locoregional relapse of HR+, HER2-negative BC 10 years after the diagnosis of the primary tumor. During a routine follow-up visit, breast magnetic resonance imaging and positron emission tomography/computed tomography revealed a 4-cm lesion in the right subclavicular region, infiltrating the chest wall and extending to the subclavian vessels, but without bone or visceral involvement. Treatment was begun with palbociclib plus letrozole, converting the disease to operability over a period of 6 mo. Surgery was performed and a pCR achieved. Of note, during treatment the patient experienced a very uncommon toxicity characterized by burning tongue and glossodynia associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. A reduction in the dose of palbociclib did not provide relief and treatment with the inhibitor was thus discontinued, resolving the tongue symptoms. Laboratory exams were unremarkable. Given that this was a late relapse, the tumor was classified as endocrine-sensitive, a condition associated with high sensitivity to palbociclib. This case highlights the potential of the cyclin-dependent kinase 4/6 inhibitor plus ET combination to achieve pCR in locoregional relapse of BC, enabling surgical resection of a lesion initially considered inoperable.


Nosocomial infections in surgical patients: developing valid measures of intrinsic patient risk.
For surgeons or hospitals to compare their rates of wound infection meaningfully, the analysis must first control for the mix of intrinsic infection risk of their patients. Research over the past century has led to the development of several intrinsic risk indexes that can be used to stratify the wound infection rates so that valid comparisons can be made within risk strata. For an intrinsic risk index to be useful for comparing rates, it must control for all of the important intrinsic risk constructs; merely being statistically associated with infection rates does not ensure that a risk index will be useful. Understanding how a risk index can be both parsimonious and comprehensive requires consideration of the competing principles of multicollinearity and orthogonality. Various techniques of multivariate analysis are used to develop multivariate risk indexes, but the success of the process depends on having all of the important orthogonal risk constructs represented in the pool of predictor variables available for the analysis, either directly by variables in the pool or by demonstrated multicollinearity. Despite recent advances in risk measurement, many important questions remain.


Electrospun organic-inorganic nanohybrids as sustained release drug delivery systems.
In this work, the non-steroidal anti-inflammatory drugs ibuprofen (ibu) and ketoprofen (ket), both poorly soluble in water, were first intercalated into layered double hydroxide (LDH) nanoparticles. The drug-LDH composites were then mixed with poly(ε-caprolactone) (PCL) at 5% and 10% w/w ratios and processed into fibers via electrospinning, yielding organic-inorganic nanohybrids. PCL/drug fibers were additionally prepared as controls. The average diameter of the fibers ranged from 400 to 1000 nm. The fibers are found to be smooth and cylindrical, with the LDH-containing systems having more homogenous fibers than those without the inorganic filler. From in vitro drug release tests, it was determined that more than 90% of the intercalated ibu and ket were released from the drug-LDH nanohybrids within the first 4 hours. Similarly, more than 60% of the incorporated drug was freed from the PCL/drug fibers in this time period. However, the release rates of both ibu and ket from the drug-LDH loaded PCL fibers were significantly slower. Only 44-48% of ibu was released from the PCL/ibu-LDH system after 5 days, while the amount released in the case of ket was 20-25%. In addition, drug release was still ongoing after 5 days for all the PCL/drug-LDH samples. These systems are thus proposed to have potential as implantable drug delivery systems.


Disrupted oogenesis in the frog Xenopus tropicalis after exposure to environmental progestin concentrations.
Levonorgestrel is a synthetic progesterone commonly used in pharmaceuticals (e.g., in contraceptives). It is found in sewage treatment plant effluents at concentrations up to 30 ng/L and was recently shown to pose a threat to egg laying in fish. Information on the susceptibility of adult amphibians to progestin toxicity is lacking. The present study aimed to 1) characterize progestogenic effects on the full cycle of oogenesis (egg development) in frogs and 2) determine female amphibians' susceptibility to reproductive impacts from progestogenic compounds in the environment. Sexually mature female Xenopus tropicalis were exposed to levonorgestrel via the surrounding water for 7 days (0, 51, or 307 ng/L) or 28 days (0, 1.3, 18, 160, or 1240 ng/L). Their ovaries were analyzed histologically with respect to frequencies of immature (in early meiotic prophase I), previtellogenic, vitellogenic, mature, and atretic oocytes. The 28-day exposure caused reduced proportions of oocytes at immature, vitellogenic, and mature stages, and increased proportions of previtellogenic oocytes compared with the control. The lowest tested concentration, 1.3 ng/L, increased the proportions of previtellogenic oocytes and reduced the proportions of vitellogenic oocytes, indicating inhibited vitellogenesis. The present study shows that progestin concentrations found in the aquatic environment impaired oogenesis in adult frogs. Our results indicate that progestogenic effects on oocyte development include interrupted germ cell progression into meiosis and inhibited vitellogenesis. Considering the crucial role of oogenesis in female fertility, our results indicate that progestogenic pollutants may pose a threat to reproduction in wild amphibian populations.


Assessment of Korea's Orthopedic Research Activities in the Top 15 Orthopedic Journals, 2008-2017.
Bibliometrics is increasingly used to assess the quantity and quality of scientific research output in many research fields worldwide. This study aims to update Korea's worldwide research productivity in the field of orthopedics using bibliometric methods and to provide Korean surgeons and researchers with insights into such research. Articles published in the top 15 orthopedic journals between 2008 and 2017 were retrieved using the Web of Science. The number of articles, citations and h-index (Hirsch index), funding sources, institutions, and journal patterns were analyzed. Of the total 39,494 articles, Korea's contribution accounted for 5.6% (2,161 articles), ranking fifth in the world in the number of publications. Korea ranked sixth (with 29,456) for total citations worldwide but ranked 17th (13.64) in terms of average citation per item and 14th (55) in terms of h-index. Korea showed the most prolific productivity in the field of sports medicine and arthroscopy. The institution that produced the highest number of publications was Seoul National University (n = 386, 17.9%). Orthopedic research in South Korea demonstrated high productivity in terms of the number of publications in high-quality journals between 2008 and 2017. However, total citations and average citations per article were still relatively low. Efforts should be made to increase citation rates for further improvement in research productivity in the field of orthopedics.


Poly n-butylcyanoacrylate (PNBCA) nanocapsules as a carrier for NSAIDs: in vitro release and in vivo skin penetration.
The aim of this work was to prepare poly n-butylcyanoacrylate (PNBCA) nanocapsules loaded with indomethacin and to evaluate the ability of this carrier system to deliver the drug systemically after its topical application. Poly n-butylcyanoacrylate (PNBCA) nanocapsules of indomethacin were prepared by interfacial polymerization. The physicochemical characterization of the PNBCA nanocapsules was performed by measuring the drug content by HPLC and analyzing the particle size using scanning electron microscopy. The in vitro permeation of indomethacin through excised rat skin and an artificial membrane was determined for PNBCA nanocapsules in pH 7.4 phosphate buffer (I), and in PLF-127 gel (II) and were compared against indomethacin incorporated into 25%w/w PLF-127 gel alone (III). The in vivo percutaneous absorption of indomethacin following the application of the PNBCA nanocapsules and a 25%w/w Pluronic F-127 (PLF-127) gel (III) was monitored by the determination of drug plasma levels in rats. The drug loading results indicated that approximately 76.6% of indomethacin was loaded onto the PNBCA nanocapsules; the average particle size was 188 nm. The in vitro results indicated a rank order for the three formulations (I, II and III) in both the flux at steady state and the cumulative amounts permeated at 8 hrs. The higher drug plasma levels over 6 hrs of indomethacin PNBCA nanocapsules are in agreement with the determined in vitro permeation results. The presented data show that indomethacin loaded PNBCA nanocapsules can improve the transdermal delivery of indomethacin compared to a conventional gel formulation using Pluronic F-127. This might be due to their ultra fine particle size and their hydrophilic and hydrophobic surface characteristics.


Betulinic acid inhibits the migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis.
The aggressive phenotype displayed by fibroblast-like synoviocytes (FLSs) contributes to cartilage and bone destruction in rheumatoid arthritis (RA). Betulinic acid has been demonstrated to have a positive therapeutic effect on tumor, inflammation and immune disorder, however, the effects of betulinic acid on RA FLSs have not been verified. Therefore, in the present study, we observed the effect of betulinic acid on the migration and invasion of RA FLSs and explored its underlying signal mechanisms. Our results showed that betulinic acid treatment suppressed the migration, invasion and reorganization of the actin cytoskeleton of RA FLSs. In addition, we found that the mRNA expression of IL-1β, IL-6, IL-8 and IL-17A were markedly down-regulated by treatment with betulinic acid in TNF-α-induced RA FLSs. To gain insight into the molecular mechanisms, we evaluated the effect of betulinic acid on NF-κB activation in RA FLSs. The results indicated that betulinic acid treatment reduced the TNF-α-induced activation of NF-κB signal pathway and the NF-κB nuclear accumulation. We also observed that treatment with betulinic acid attenuated synovial inflammation and joint destruction in mice with CIA. Taken together, these results suggest that betulinic acid inhibits the migration and invasion of RA FLSs by blocking NF-κB signal pathway activation.


Nanodiamonds with silicon vacancy defects for nontoxic photostable fluorescent labeling of neural precursor cells.
Nanodiamonds (NDs) containing silicon vacancy (SiV) defects were evaluated as a potential biomarker for the labeling and fluorescent imaging of neural precursor cells (NPCs). SiV-containing NDs were synthesized using chemical vapor deposition and silicon ion implantation. Spectrally, SiV-containing NDs exhibited extremely stable fluorescence and narrow bandwidth emission with an excellent signal to noise ratio exceeding that of NDs containing nitrogen-vacancy centers. NPCs labeled with NDs exhibited normal cell viability and proliferative properties consistent with biocompatibility. We conclude that SiV-containing NDs are a promising biomedical research tool for cellular labeling and optical imaging in stem cell research.


Genomic responses to selection for tame/aggressive behaviors in the silver fox (Vulpes vulpes).
Animal domestication efforts have led to a shared spectrum of striking behavioral and morphological changes. To recapitulate this process, silver foxes have been selectively bred for tame and aggressive behaviors for more than 50 generations at the Institute for Cytology and Genetics in Novosibirsk, Russia. To understand the genetic basis and molecular mechanisms underlying the phenotypic changes, we profiled gene expression levels and coding SNP allele frequencies in two brain tissue specimens from 12 aggressive foxes and 12 tame foxes. Expression analysis revealed 146 genes in the prefrontal cortex and 33 genes in the basal forebrain that were differentially expressed, with a 5% false discovery rate (FDR). These candidates include genes in key pathways known to be critical to neurologic processing, including the serotonin and glutamate receptor pathways. In addition, 295 of the 31,000 exonic SNPs show significant allele frequency differences between the tame and aggressive populations (1% FDR), including genes with a role in neural crest cell fate determination.


[Bcl-2 as a prognostic factor in different molecular genetic subtypes of breast cancer].
It is well known that breast cancers (BC) are divided into 4 molecular genetic subgroups (luminal A, luminal B, HER2/neu-positive, and triple-negative (TNBC). The purpose of the investigation was to comparatively estimate the pattern of expression of Bcl-2, known as a good prognostic marker of BC, in different molecular genetic subgroups and to study the correlation of this protein with proliferative activity index and genetic aberrations on chromosome 17. The investigation covered 290 samples of invasive ductal BC. Bcl-2 expression was identified in 14% of HER2/neu-positive and TNBC cases while 77% of luminal B tumors and 100% of luminal A ones expressed Bcl-2. Loss of Bcl-2 expression correlated with clinically more aggressive BCs having a high proliferative activity and amplification of HER2/neu and chromosome 17 centromere. This may suggest the poor prognosis of luminal B, HER2/neu-positive and TNBC with no Bcl-2 expression and calls for further investigations on larger samples.


Identification and characterization of PshBII, a second FA/FB-containing polypeptide in the photosynthetic reaction center of Heliobacterium modesticaldum.
All known Type I photosynthetic reaction centers harbor three [4Fe-4S] clusters named F(X), F(A) and F(B) that function as terminal electron acceptors. We reported earlier that F(A) and F(B) in the homodimeric Type I reaction center from Heliobacterium modesticaldum reside on a loosely bound 54 amino acid protein named PshB. Time-resolved optical spectroscopy and low temperature EPR spectroscopy showed that on illumination, electrons were transferred from F(X) (-) to F(A) and F(B) at both cryogenic and room temperatures. Interestingly, the gene that codes for PshB, HM1_1462, is part of a predicted dicistronic operon that contains a second gene, named HM1_1461, which codes for a second ferredoxin-like protein with high sequence homology to PshB, including the two traditional [4Fe-4S] cluster binding motifs. RT-PCR results confirm that both genes are transcribed as a single transcript. We have cloned the HM1_1461 gene through PCR amplification of the H. modesticaldum chromosomal DNA and overexpressed the apoprotein in Escherichia coli. Reconstitution studies with inorganic reagents have shown that the holoprotein harbors ~8 iron and ~8 sulfide atoms in the form of two [4Fe-4S] clusters. Incubation of the reconstituted holoprotein with heliobacterial reaction center cores results in a charge-separated state characteristic of electron transfer past the F(X) cluster to the terminal [4Fe-4S] clusters F(A) and F(B). These results suggest that the HM1_1461 product, which we have named PshBII, is capable of functioning in lieu of PshB (renamed PshBI) as an alternative terminal electron transfer protein. Thus, unlike PS I, to which PsaC is tightly bound, two loosely bound ferredoxins, PshBI and PshBII, are capable of interacting with the heliobacterial reaction center. The presence of two, loosely bound F(A)/F(B) proteins represents a significant shift in our understanding of structure-function relationships in Type I reaction centers.


Early readmissions to the department of medicine as a screening tool for monitoring quality of care problems.
With growing awareness of medical fallibility, researchers need to develop tools to identify and study medical mistakes. We examined the utility of hospital readmissions for this purpose in a prospective case-control study in a large academic medical center in Israel. All patients with nonelective readmissions to 2 departments of medicine within 30 days of discharge were interviewed, and their medical records were carefully examined with emphasis on the index admission. Patient data were compared to data for age- and sex-matched controls (n = 140) who were not readmitted. Medical records of readmitted and control patients were blindly evaluated by 2 senior clinicians who independently identified potential quality of care (QOC) problems during the index admission. Inhospital and late mortality was determined 6 months after discharge.Over a period of 3 months there were 1988 urgent admissions; 1913 discharges and subsequently 271 unplanned readmissions occurred (14.1% of discharges). Readmissions occurred an average of 10 days after discharge, and readmitted patients were sicker than controls (mean, 4.3 vs. 3.3 diagnoses per patient), although their length of stay was similarly short (3.4 +/- 2.8 d). Analysis of all readmissions revealed QOC problems in 90/271 (33%) of readmissions, 4.5% of hospitalizations. All were deemed preventable. Interobserver agreement was good (83%, kappa = 0.67). Among matched controls, only 8/140 admissions revealed QOC problems (6%, p < 0.001) (k = 0.77). The preventable readmissions mostly involved a vascular event or congestive heart failure; they occurred within a mean of 10 +/- 8 days of the index admission, and their inpatient mortality was 6.7% vs. 1.7% among readmissions that had no QOC problems (odds ratio, 4.1; 95% confidence interval, 1.0-16.7). The main pitfalls identified during the index admission included incomplete workup (33%), too short hospital stay (31%), inappropriate medication (44%), diagnostic error (16%), and disregarding a significant laboratory result (12%). In many patients more than 1 pitfall was identified (mean, 1.5 per patient). Risk factors for preventable readmission include older age and living in an institution (p < 0.05). Almost two-thirds of the readmitted patients with QOC problems were discharged after spending 2 days or fewer at the hospital. In conclusion, unplanned readmissions within 30 days of discharge are frequent, more prevalent in sicker patients, and possibly associated with increased mortality. In a third of readmitted patients a QOC problem can be identified, and these problems are preventable. Thus, readmission may be used as a screening tool for potential QOC problems in the department of medicine. Routine monitoring of all readmissions may provide a simple cost-effective means of identifying and addressing medical mistakes.


Regulation and function of arginine vasopressin in pregnant sheep.
The aim of this study was to investigate the regulation and function of arginine vasopressin (AVP) in pregnant sheep. The mean plasma osmolality of nonpregnant ewes (298 +/- 1.0 mosmol/kg, n = 8) was not significantly different from that of late pregnant ewes (295 +/- 1.1 mosmol/kg, n = 21). The mean resting plasma [AVP] of nonpregnant ewes (4.1 +/- 0.6 pg/ml,n = 8) was not significantly different from that of pregnant ewes (3.3 +/- 0.3 pg/ml,n = 21). In a series of dehydration experiments it was established that the slope of the function relating log [AVP] to plasma osmolality for pregnant ewes (n = 13) was not significantly different from the slope of the function relating log [AVP] to plasma osmolality for nonpregnant ewes (n = 4). When AVP was infused into water-loaded ewes, a significant decrease in urinary flow rate and free water clearance occurred at an infusion rate of 0.003 microgram/h in both the pregnant (n = 4) and nonpregnant (n = 4) animals. Both groups achieved negative free water clearance at an infusion rate of 0.01 microgram/h. These findings suggest that pregnancy does not alter the relationship between plasma osmolality and plasma [AVP] or the renal responsiveness to AVP in sheep.


Large-scale brain systems in ADHD: beyond the prefrontal-striatal model.
Attention-deficit/hyperactivity disorder (ADHD) has long been thought to reflect dysfunction of prefrontal-striatal circuitry, with involvement of other circuits largely ignored. Recent advances in systems neuroscience-based approaches to brain dysfunction have facilitated the development of models of ADHD pathophysiology that encompass a number of different large-scale resting-state networks. Here we review progress in delineating large-scale neural systems and illustrate their relevance to ADHD. We relate frontoparietal, dorsal attentional, motor, visual and default networks to the ADHD functional and structural literature. Insights emerging from mapping intrinsic brain connectivity networks provide a potentially mechanistic framework for an understanding of aspects of ADHD such as neuropsychological and behavioral inconsistency, and the possible role of primary visual cortex in attentional dysfunction in the disorder.


Enzymology of one-carbon metabolism in methanogenic pathways.
Methanoarchaea, the largest and most phylogenetically diverse group in the Archaea domain, have evolved energy-yielding pathways marked by one-carbon biochemistry featuring novel cofactors and enzymes. All of the pathways have in common the two-electron reduction of methyl-coenzyme M to methane catalyzed by methyl-coenzyme M reductase but deviate in the source of the methyl group transferred to coenzyme M. Most of the methane produced in nature derives from acetate in a pathway where the activated substrate is cleaved by CO dehydrogenase/acetyl-CoA synthase and the methyl group is transferred to coenzyme M via methyltetrahydromethanopterin or methyltetrahydrosarcinapterin. Electrons for reductive demethylation of the methyl-coenzyme M originate from oxidation of the carbonyl group of acetate to carbon dioxide by the synthase. In the other major pathway, formate or H2 is oxidized to provide electrons for reduction of carbon dioxide to the methyl level and reduction of methyl-coenzyme to methane. Methane is also produced from the methyl groups of methanol and methylamines. In these pathways specialized methyltransferases transfer the methyl groups to coenzyme M. Electrons for reduction of the methyl-coenzyme M are supplied by oxidation of the methyl groups to carbon dioxide by a reversal of the carbon dioxide reduction pathway. Recent progress on the enzymology of one-carbon reactions in these pathways has raised the level of understanding with regard to the physiology and molecular biology of methanogenesis. These advances have also provided a foundation for future studies on the structure/function of these novel enzymes and exploitation of the recently completed sequences for the genomes from the methanoarchaea Methanobacterium thermoautotrophicum and Methanococcus jannaschii.


Peptidergic regulation of stress-induced eating.
By use of the model of stress-induced (mild tail pinch) eating we have examined the interrelationships of peptides and monoamines responsible for regulating this behavior. We have shown that the synthetic opiate analog, D-Ala2-Met-enkephalinamide (1 microgram), when administered intracerebroventricularly (icv) reverses the suppressive effects of the serotonin agonist, quipazine (40 micrograms icv), the beta-agonist, isoproterenol (40 micrograms icv), and the alpha-antagonist, phentolamine (150 micrograms icv), and partially reversed the effects of atropine (2.5 mg/kg sc) and the dopamine antagonist haloperidol (0.5 mg/kg sc). The opiate antagonist naloxone (10 mg/kg sc) suppressed tail-pinch-induced eating, and this effect could not be reversed by the GABA-agonist muscimol (500 ng icv) nor norepinephrine (20 micrograms icv). The putative satiety hormones cholecystokinin-octapeptide (5 micrograms/kg sc) and bombesin (5 micrograms/kg sc) suppressed stress-induced eating. The suppressive effect of these substances was reversed by a number of known appetite stimulants viz., D-Ala2-Met-enkephalinamide, diazepam, muscimol, and propanolol. Norepinephrine reversed the suppressive effect of bombesin but not that of cholecystokinin. Based on these results we present a hypothetical model to partially explain the peptidergic-monoamine regulation of stress-induced eating.


Severe hypernatremic dehydration in a newborn infant.
A female infant presented with severe hypernatremic dehydration and failure to thrive two weeks after birth. The diagnosis and management of the infant are described, highlighting the need for follow-up and support after early discharge of newborns.


[Systemic control in rural perinatal health care ("Triple Ten Management")].
Using "Triple Ten Management" as the basic method, we conducted research on a standard model of rural perinatal health care in our province. The "Triple Ten Management" includes: (1) controlling ten commonest high risk pregnancies; (2) application of ten perinatal monitoring techniques; (3) ten concerted managing regimes of rural perinatal care. Being verified in test points of 38 townships in 13 counties for one year, the model has been proved to be suitable for rural status and effective. The maternal mortality of the test points was reduced from 6.11/10,000 to 3.58/10,000; the perinatal mortality from 22.18% to 18.44% and the incidences of eclampsia and neonatal tetanus were also significantly reduced.


Treatments for Trauma-Induced Coagulopathy: Protocol for a Systematic Review and Meta-Analysis.
Trauma-induced coagulopathy (TIC) is a common and potentially life-threatening coagulopathy as a result of traumatic injury, characterized by abnormal blood clotting and bleeding. Although several treatments have been proposed for TIC, their effectiveness and safety remain unclear. Further, numerous systematic reviews and meta-analyses on trauma have been conducted; however, to our knowledge, there is no systematic review and meta-analysis that specifically focuses on TIC management. Therefore, a comprehensive synthesis of the available evidence on interventions for TIC is needed. This systematic review and meta-analysis aim to evaluate the effectiveness and safety of interventions for the management of TIC. We will conduct a systematic review and meta-analysis of randomized and nonrandomized controlled trials as well as observational studies regarding severe trauma in patients with TIC. The interventions will include administration of coagulation factor concentrates, tranexamic acid, and blood component products. The control group will be managed with an ordinal transfusion or administered placebo. The primary outcome will be in-hospital mortality. We will search the electronic databases of MEDLINE (PubMed), Web of Science, and the Cochrane Central Register of Controlled Trials. Two reviewers will independently screen the titles and abstracts, retrieve the full text of the selected articles, and extract essential data. We will apply uniform criteria for evaluating the risk of bias associated with individual randomized controlled trials and nonrandomized trials based on the Cochrane risk-of-bias tool. Risk ratio values will be expressed as point estimates with 95% CIs. Continuous variables will be expressed as the mean difference along with their 95% CIs and P values. We will assess the strength of evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. This review will be the first systematic review and meta-analysis providing information on the effectiveness and safety of interventions for the management of TIC, including the administration of coagulation factor concentrates, tranexamic acid, and blood component products. Ethics approval and patient consent were not required for this study protocol, as we conducted a systematic review and meta-analysis of publicly available data, without any direct involvement of human participants. We will summarize the selection of the eligible studies using a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart. The results will be presented in a table summarizing the evidence. The results of the meta-analysis will be depicted using figures and forest plots. This systematic review will provide updated information on the efficacy and safety of using coagulation factor concentrates, tranexamic acid, and blood component products for patients with TIC. To our knowledge, there is no systematic review and meta-analysis that specifically focuses on treatments for TIC. UMIN registry UMIN000050170; https://tinyurl.com/yr8pcrj6. DERR1-10.2196/49582.


Rapid in situ RNA imaging based on Cas12a thrusting strand displacement reaction.
RNA In situ imaging through DNA self-assembly is advantaged in illustrating its structures and functions with high-resolution, while the limited reaction efficiency and time-consuming operation hinder its clinical application. Here, we first proposed a new strand displacement reaction (SDR) model (Cas12a thrusting SDR, CtSDR), in which Cas12a could overcome the inherent reaction limitation and dramatically enhance efficiency through energy replenishment and by-product consumption. The target-initiated CtSDR amplification was established for RNA analysis, with order of magnitude lower limit of detection (LOD) than the Cas13a system. The CtSDR-based RNA in situ imaging strategy was developed to monitor intra-cellular microRNA expression change and delineate the landscape of oncogenic RNA in 66 clinic tissue samples, possessing a clear advantage over classic in situ hybridization (ISH) in terms of operation time (1 h versus 14 h) while showing comparable sensitivity and specificity. This work presents a promising approach to developing advanced molecular diagnostic tools.


T lymphocytes in implant-associated posttraumatic osteomyelitis: Identification of cytotoxic T effector cells at the site of infection.
In implant-associated posttraumatic osteomyelitis, a massive infiltration of leukocytes into the infected site is seen. As described previously, the most infiltrated cells were highly activated polymorphonuclear neutrophils. In addition, a considerable T-cell infiltrate was noted. Whereas our previous work was mainly concerned with the phenotypical and functional characterization of the polymorphonuclear neutrophils, we now analyzed T lymphocytes of 32 patients with implant-associated posttraumatic osteomyelitis. We found evidence for an expansion of CD8 T cells in the peripheral blood of the patients and for an infiltration of these cells into the infected site. Further analysis of the surface-receptor pattern by three-color cytofluorometry revealed that the majority of these cells belonged to the cytotoxic-effector phenotype. Of note is that cytotoxic T cells are generally associated with virus infection. Thus, the detection of those cells in patients with bacterial infection was rather unexpected and points to a novel, not yet appreciated, role of CD8 T cells also in the defense of bacterial infections.


Use of Erythropoietin-Stimulating Agents (ESA) in Patients With End-Stage Renal Failure Decided to Forego Dialysis: Palliative Perspective.
Normochromic normocytic anemia is a common complication in chronic kidney disease (CKD) and is associated with many adverse clinical consequences. Erythropoiesis-stimulating agents (ESAs) act to replace endogenous erythropoietin for patients with end-stage renal disease having anemia. Today, ESAs remain the main tool for treating anemia associated with CKD. In current practice, the use of ESA is not limited to the patients on renal replacement therapy but has extended to nondialysis patients under palliative care (PC). Current evidence on ESA usage in patients with CKD decided to forego dialysis often have to take reference from studies conducted in other groups of patients with CKD, including pre-dialysis patients and those on renal replacement therapy. There is paucity of studies targeting use of ESAs in renal PC patients. Small-scale retrospective study in renal PC patients had suggested clinical advantage of ESAs in terms of hemoglobin improvement, reduction in fatigue, and hospitalization rate. With the expected growth in elderly patients with CKD decided to forego dialysis and manage conservatively, there remains an urgent need to call for large-scale prospective trial in exploring efficacy of ESAs in this population, targeting on quality of life and symptoms improvement outcome. This article also reviews the mechanism of action, pharmacology, adverse effects, and clinical trial evidence for ESA in patients with CKD under renal PC.


Quantitative prediction of the effect of genetic variation using hidden Markov models.
With the development of sequencing technologies, more and more sequence variants are available for investigation. Different classes of variants in the human genome have been identified, including single nucleotide substitutions, insertion and deletion, and large structural variations such as duplications and deletions. Insertion and deletion (indel) variants comprise a major proportion of human genetic variation. However, little is known about their effects on humans. The absence of understanding is largely due to the lack of both biological data and computational resources. This paper presents a new indel functional prediction method HMMvar based on HMM profiles, which capture the conservation information in sequences. The results demonstrate that a scoring strategy based on HMM profiles can achieve good performance in identifying deleterious or neutral variants for different data sets, and can predict the protein functional effects of both single and multiple mutations. This paper proposed a quantitative prediction method, HMMvar, to predict the effect of genetic variation using hidden Markov models. The HMM based pipeline program implementing the method HMMvar is freely available at https://bioinformatics.cs.vt.edu/zhanglab/hmm.


Stim and Orai mediate constitutive Ca2+ entry and control endoplasmic reticulum Ca2+ refilling in primary cultures of colorectal carcinoma cells.
Store-operated Ca2+ entry (SOCE) provides a major Ca2+ entry route in cancer cells. SOCE is mediated by the assembly of Stim and Orai proteins at endoplasmic reticulum (ER)-plasma membrane junctions upon depletion of the ER Ca2+ store. Additionally, Stim and Orai proteins underpin constitutive Ca2+ entry in a growing number of cancer cell types due to the partial depletion of their ER Ca2+ reservoir. Herein, we investigated for the first time the structure and function of SOCE in primary cultures of colorectal carcinoma (CRC) established from primary tumor (pCRC) and metastatic lesions (mCRC) of human subjects. Stim1-2 and Orai1-3 transcripts were equally expressed in pCRC and mCRC cells, although Stim1 and Orai3 proteins were up-regulated in mCRC cells. The Mn2+-quenching technique revealed that constitutive Ca2+ entry was significantly enhanced in pCRC cells and was inhibited by the pharmacological and genetic blockade of Stim1, Stim2, Orai1 and Orai3. The larger resting Ca2+ influx in pCRC was associated to their lower ER Ca2+ content as compared to mCRC cells. Pharmacological and genetic blockade of Stim1, Stim2, Orai1 and Orai3 prevented ER-dependent Ca2+ release, thereby suggesting that constitutive SOCE maintains ER Ca2+ levels. Nevertheless, pharmacological and genetic blockade of Stim1, Stim2, Orai1 and Orai3 did not affect CRC cell proliferation and migration. These data provide the first evidence that Stim and Orai proteins mediate constitutive Ca2+ entry and replenish ER with Ca2+ in primary cultures of CRC cells. However, SOCE is not a promising target to design alternative therapies for CRC.


Peripheral vascular resistance and regional blood flows in hypertensive Dahl rats.
The aim of this study was to determine whether different organs undergo similar increases in vascular resistance with hypertension in the Dahl salt-sensitive rat. Cardiac output and organ blood flows were measured with microspheres in anesthetized salt-sensitive and salt-resistant rats fed a high- (7%) or normal- (0.45%) salt diet for 4 wk. High salt intake produced hypertension only in salt-sensitive rats. Cardiac index for the hypertensive group was not different from that for any other group, whereas peripheral resistance index was elevated in proportion to arterial pressure. There were no differences among groups in the fraction of cardiac output supplying the myocardium, intestine, diaphragm, spinotrapezius muscle, or gracilis muscle. The fraction of cardiac output supplying the kidneys was lower in salt-sensitive rats (13%) than in salt-resistant rats (17%) and, among salt-sensitive rats, lowest in the high-salt group. Therefore all the organs studied contribute to increased total peripheral resistance in the hypertensive Dahl rat, with the renal vasculature undergoing the largest resistance increase. Different muscles undergo similar increases in vascular resistance, despite differences in the microvascular abnormalities accompanying salt-induced hypertension.


The Effect of Single Accreditation on Medical Student Match Rates in Surgical Specialties.
Introduction The year 2020 marked the first year in which a match under single accreditation took place. Both osteopathic (DO) and allopathic (MD) students would participate in the first match cycle without a dedicated DO match system. Our primary objective was to investigate how single accreditation has impacted the DO applicants attempting to match into surgical specialties. Our secondary objective was to investigate the impact of single accreditation at the program director (PD) level and whether or not this process would see a change in DO PD distribution in previously American Osteopathic Association (AOA)-approved programs. Method Information on number of applicants and post-match positions was gathered from AOA and National Residency Match Program (NRMP) websites. Credentials of PDs were obtained from the Accreditation Council on Graduate Medical Education website. Based on the available data, the following surgical specialties were compared for the years 2020, 2018, and 2016: General Surgery, Neurological Surgery (NSGY), Orthopedic Surgery, Otolaryngology/ENT (ENT), Plastic Surgery, and Thoracic Surgery. Data from 2016 were not included in the results as the AOA match results analysis was insufficient and unable to be directly compared to the NRMP data. Results of matched DO and MD applicants were compared using bivariate analysis. A p-value of <0.05 was considered significant. Results From the year 2018 to 2020, the DO applicants saw a decrease of 3% in the total number of matched postgraduate year 1 spots in surgical specialties. NRMP results from 2020 saw that 51.7% of DO applicants matched and 67.7% (p < 0.001) of MD applicants matched for the specialties examined. Percent of matched:applied for DO applicants was lower than MD applicants in the fields of NSGY (p < 0.001), ENT (p < 0.001), Plastic Surgery (p < 0.001), General Surgery (p < 0.001), and Thoracic Surgery (p = 0.011). After evaluating 60 former AOA General Surgery programs, 56% were found to have MD as PD. Another 26 former AOA surgical programs were investigated, and 58% were found to have MD PD. Conclusion Single accreditation has impacted the match process now that a large number of both MD and DO applicants are using the NRMP match system for postgraduate placement. Based on the available data, our results indicate that in the examined surgical specialties, there is a statistically significant difference in the number of MD and DO residents.


A practical toolbox for the effective transition of adolescents and young adults with asthma and allergies: An EAACI position paper.
Adolescence is a critical stage of rapid biological, emotional and social change and development. Adolescents and young adults (AYA) with asthma and allergies need to develop the knowledge and skills to self-manage their health independently. Healthcare professionals (HCP), parents and their wider network play an essential role in supporting AYA in this process. Previous work showed significant limitations in transition care across Europe. In 2020, the first evidence-based guideline on effective transition for AYA with asthma and allergies was published by EAACI. We herein summarize practical resources to support this guideline's implementation in clinical practice. For this purpose, multi-stakeholder Task Force members searched for resources in peer review journals and grey literature. These resources were included if relevant and of good quality and were pragmatically rated for their evidence-basis and user friendliness. Resources identified covered a range of topics and targeted healthcare professionals, AYA, parents/carers, schools, workplace and wider community. Most resources were in English, web-based and had limited evidence-basis. This position paper provides a valuable selection of practical resources for all stakeholders to support effective transitional care for AYA with asthma and allergies. Future research should focus on developing validated, patient-centred tools to further assist evidence-based transition care.


Host MicroRNA hsa-miR-494-3p Promotes EV71 Replication by Directly Targeting PTEN.
Many cellular processes are driven by spatially and temporally regulated microRNAs (miRNAs)-dependent signaling events. Substantial evidence collected over the years indicates that miRNAs are pivotal regulators that contribute to the initiation and development of EV71-related disorders. Importantly, so far, no clinical trial has been undertaken to address the effect of miRNAs on EV71-related diseases. In this study, we show that EV71 infection results in up-regulation of hsa-miR-494-3p levels, and that EV71-induced hsa-miR-494-3p impacts PI3K/Akt signaling pathway by targeting PTEN. However, very little is known about the relationship between hsa-miR-494-3p and EV71 infection. The overall goal of the study is to get a better insight into whether or not hsa-miR-494-3p is involved in the EV71 infection. We found that the EV71 infection induces cellular apoptosis, and that this process can be counteracted by the over-expression of hsa-miR-494-3p mimics. We also present evidence that cell lines deficient in hsa-miR-494-3p are more sensitive to EV71-induced cell death than the corresponding control cells. Collectively, these findings confirm and extend the pervious observation suggesting that disturbances in miRNAs expression can influence EV71 propagation. In addition, they lend strong support to the ideas that hsa-miR-494-3p-mediated signaling pathway plays an important role in the EV71 replication, and that this may have profound implications on our views on EV71-related diseases.


Anxiety and depression in patients with alpha-1 antitrypsin deficiency: current insights and impact on quality of life.
Chronic physical illness is associated with significant vulnerability for emotional disorders. Some studies suggest anxiety and depression are common comorbidities in individuals with alpha-1 antitrypsin deficiency (AATD). Many aspects of AATD contribute to quality of life impairment. Delays in diagnosis, high costs of disease treatment, and inherited genetic risk add to the symptom burden of lung or liver disease to alter quality of life. Whether anxiety and depression independently contribute to quality of life impairment remains unproven. In this article, we aim to review current literature examining the impact of anxiety and depression on the quality of life of AATD-affected individuals. Multifaceted approaches may best meet the needs of a heterogeneous population and are the best future strategies to minimize these emotional impacts and assure highest quality of life possible. More research studies are needed to achieve this ambitious goal and make life of AATD-affected individuals better by minimizing the effects of anxiety and depression.


Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study.
Although hemostatic factors contribute to acute coronary syndromes and atherogenesis, few studies have prospectively evaluated the association between multiple hemostatic factors and coronary heart disease incidence. The Atherosclerosis Risk in Communities Study recruited 14,477 adults from 45 to 64 years of age who were initially free of coronary heart disease. Coronary disease risk factors and several plasma hemostatic factors were measured, and incidence of coronary heart disease was ascertained during an average follow-up of 5.2 years. Age-, race-, and field center-adjusted relative risks of coronary heart disease were significantly elevated (P < or = .05) per higher value of fibrinogen (relative risk: men, 1.76; women, 1.54), white blood cell count (men, 1.68; women, 2.23), factor VIII coagulant activity (women, 1.25), and von Willebrand factor antigen (men, 1.20; women, 1.18). Adjustment for other risk factors attenuated these associations for fibrinogen (adjusted relative risk: men, 1.48; women, 1.21), and it eliminated the white blood cell count, factor VIII, and von Willebrand factor associations, consistent with the other risk factors either confounding or partly operating through their effects on the hemostatic variables. Adjusted standardized relative risks of total mortality, ranging from 1.13 to 1.37, were also elevated (P < .05) in relation to these four factors. There was no association of coronary disease incidence with factor VII, protein C, antithrombin III, or platelet count. Elevated levels of fibrinogen, white blood cell count, factor VIII, and von Willebrand factor are risk factors and may play causative roles in coronary heart disease. However, their measurement in healthy adults appears to add little to prediction of coronary events beyond that of more established risk factors.