Morphological and behavioral impact of AAV2/5-mediated overexpression of human wildtype alpha-synuclein in the rat nigrostriatal system.
The discovery of the involvement of alpha-synuclein (α-syn) in Parkinson's disease (PD) pathogenesis has resulted in the development and use of viral vector-mediated α-syn overexpression rodent models. The goal of these series of experiments was to characterize the neurodegeneration and functional deficits resulting from injection of recombinant adeno-associated virus (rAAV) serotype 2/5-expressing human wildtype α-syn in the rat substantia nigra (SN). Rats were unilaterally injected into two sites in the SN with either rAAV2/5-expressing green fluorescent protein (GFP, 1.2 x 10(13)) or varying titers (2.2 x 10(12), 1.0 x 10(13), 5.9 x 10(13), or 1.0 x 10(14)) of rAAV2/5-α-syn. Cohorts of rats were euthanized 4, 8, or 12 weeks following vector injection. The severity of tyrosine hydroxylase immunoreactive (THir) neuron death in the SN pars compacta (SNpc) was dependent on vector titer. An identical magnitude of nigrostriatal degeneration (60-70% SNpc THir neuron degeneration and 40-50% loss of striatal TH expression) was observed four weeks following 1.0 x 10(14) titer rAAV2/5-α-syn injection and 8 weeks following 1.0 x 10(13) titer rAAV2/5-α-syn injection. THir neuron degeneration was relatively uniform throughout the rostral-caudal axis of the SNpc. Despite equivalent nigrostriatal degeneration between the 1.0 x 10(13) and 1.0 x 10(14) rAAV2/5-α-syn groups, functional impairment in the cylinder test and the adjusting steps task was only observed in rats with the longer 8 week duration of α-syn expression. Motor impairment in the cylinder task was highly correlated to striatal TH loss. Further, 8 weeks following 5.9 x 10(13) rAAV2/5-α-syn injection deficits in ultrasonic vocalizations were observed. In conclusion, our rAAV2/5-α-syn overexpression model demonstrates robust nigrostriatal α-syn overexpression, induces significant nigrostriatal degeneration that is both vector and duration dependent and under specific parameters can result in motor impairment that directly relates to the level of striatal TH denervation.


Diagnosis of external root resorption in teeth close and distant to zirconium implants: influence of acquisition parameters and artefacts produced during cone beam computed tomography.
To assess the influence of artefacts, the metal artefact reduction (MAR) tool and kilovoltage (kVp) on the diagnosis of simulated external root resorption (ERR) in teeth close and distant to zirconium implants in cone beam computed tomography (CBCT) images. Cavities (0.62 mm in diameter and 0.19 mm deep) were created in the apical thirds of 12 roots on the buccal, lingual, distal or mesial surface; ten roots served as controls. The roots were randomly positioned in the first and second right and left premolar sockets of a dry human mandible, and a zirconium implant was placed in the socket of the first right molar. A ProMax 3D unit varying kVp (70, 80, or 90 kVp) and with the MAR tool activated or not was used to obtain CBCT scans. Five examiners evaluated all images to determine the area under the receiver operating characteristic (ROC) curve, sensitivity and specificity. The ROC values and sensitivity were not affected by MAR or artefacts regardless of the distance to the implant (P > 0.05), whilst increasing kVp from 70 to 90 led to a significant increase in these values (P = 0.0202 and 0.0199, respectively). Specificity was not affected by the factors studied (P > 0.05). Amongst the factors studied, only kVp influenced the diagnosis of simulated external root resorption in CBCT images. Increasing kVp from 70 to 90 improved the accuracy in diagnosing the simulated lesions.


Advancing Rights-Based Family Planning from 2020 to 2030.
An assessment in 2019 by Family Planning 2020 of progress on rights-based family planning since 2012 highlighted the development of tools and guidelines that identify and explain rights in relation to family planning, promotion of rights-based approaches to programing, strengthened accountability, and measurement of rights-focused outcomes. The assessment was also forward-looking, asking what aspects of rights-based family planning still need attention moving from 2020 to 2030. This paper draws on interviews with 23 key informants from governments, civil society, and youth focused organizations, implementing partners, and bi-lateral and multilateral organizations from Africa, Asia and the Pacific, Europe and North America, all working on family planning and engaged in various roles with the FP2020 partnership at global and national levels, along with documentation of FP2030 partnership plans. The interviews were conducted as part of the assessment and included questions to respondents for their recommendations on rights-based family planning moving towards 2030. Respondents agreed that rights should be at the center of the vision for family planning, with attention to rights literacy, accountability and equity, including adolescent and youth leadership. They noted the need for consistent political and financial support, and incorporating rights into result-based financing programming. While respondents noted the need for development and dissemination of practical tools and training materials, along with rights metrics and implementation research, they stressed the importance of focusing work on rights at the country level. Respondents also acknowledged that institutionalizing rights-based family planning will require enhanced commitment and funding from both donors and countries to ensure programming - and success - over the long term. Amplifying civil society and particularly adolescent and youth voices will be key to engaging governments to support both rights-based programming and provide funding. Review of initial planning under FP2030 related to each of the recommendations suggests that the new partnership is seeking to addressing each of them. As the family planning field looks beyond 2020 to 2030, this paper provides a roadmap for building on the gains made over the past decade to effectively tackle the challenges remaining to ensure that programming to achieve the vision of the FP2030 Partnership is rights-based.


Caregiving actions: Outgrowths of the family caregiver's conceptions of care.
Caregiving actions emanate from the family caregiver's care meanings. Therefore, this article presents caregiving actions as outgrowths of the family caregiver's cultural conceptions of care and as situated within constraining sociocultural factors. Qualitative data were collected through interviews and participant observations from 18 purposively selected family caregivers of people living with HIV/AIDS (PLWAs) in Addis Ababa, Ethiopia. Three lines of caregiving actions performed by the participating family caregivers are presented: nutritional and medication care actions, physical care actions, and psychological and spiritual care actions. We have also explicated the problematic situations and sociocultural factors constraining the family caregivers in performing the caregiving actions. This study underlines the significance of addressing such problematic situations as are raised, as well as the sociocultural issues that constrain the family caregivers' agentic scope for planning and executing caregiving actions.


The effects of alkylated xanthines on cyclic AMP accumulation in dog thyroid slices exposed to carbamylcholine.
In dog thyroid slices stimulated by thyrotropin (TSH), activation of muscarinic cholinergic receptors leads to a decrease in cyclic AMP levels. Previous studies have established that carbamylcholine enhances cyclic GMP levels and inhibits cyclic AMP accumulation. Several experimental data have suggested that these effects are mediated by an increase in intracellular Ca2+ levels. The inhibition of cyclic AMP accumulation results in accelerated catabolism. Dog thyroid phosphodiesterase activity is due to a mixture of three enzyme forms: a calmodulin-sensitive form, a cyclic GMP-stimulated form and a cyclic AMP-specific form. This report is concerned with the comparison of the effects of several phosphodiesterase inhibitors on cell-free phosphodiestease activity and on cyclic nucleotide accumulation in intact cells. Alkylated xanthines, 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724), and 2-O-propoxyphenyl-8-azapurin-6-one (M & B 22948) were studied as inhibitors of partially purified dog thyroid phosphodieterases and for their ability to alter cyclic AMP and cyclic GMP accumulation in dog thyroid slices that had been stimulated with TSH and/or carbamylcholine. 1-Methyl-3-isobutylxanthine (MIX) and 7-benzyl MIX were the most potent inhibitors of phosphodiesterase activities in the crude soluble and particulate fractions but exhibited no selectivity for inhibiting cyclic AMP or cyclic GMP hydrolysis. In dog thyroid slices stimulated by TSH and in the absence of carbamylcholine, Ro 20-1724 and 1-isoamyl-3-isobutylxanthine (IIX) were the most effective compounds to potentiate the accumulation of cyclic AMP. The rank order of abilities to potentiate cyclic AMP accumulation in dog thyroid slices stimulated by TSH paralleled the rank order of potencies to inhibit the cyclic AMP-specific phosphodiesterase. In the presence of carbamylcholine, the observed decrease in cyclic AMP levels was attenuated by MIX, 8-methoxymethyl MIX (8-MeOMe MIX), 7-benzyl MIX, and M & B 22948, the most potent inhibitors of the calmodulin-sensitive phosphodiesterase. MIX, 8-MeOMe MIX, and 7-benzyl MIX inhibited the cyclic GMP-stimulated phosphodiesterase in the same rank order of potencies as the calmodulin-sensitive enzyme, but M & B 22948 did not significantly inhibit the cyclic GMP-stimulated enzyme activity. IIX and Ro 20-1724 did not alter the carbamylcholine-induced inhibition of cyclic AMP accumulation.(ABSTRACT TRUNCATED AT 400 WORDS)


The subcellular localization of di- and tri-peptide hydrolase activity in guinea-pig small intestine.
1. Two different subcellular fractionation techniques were applied to guinea-pig intestinal mucosa and the composition of the brush borders prepared by the two methods were compared. 2. By using a kinetic assay system the subcellular distribution of activity against ten dipeptides and five tripeptides was studied. 3. Only small amounts (5-10%) of activity against dipeptides were found in the brush-border region, the enzymes being concentrated in the cytosol. 4. Significant amounts (10-60%) of activity against tripeptides were found in the brush border with the remainder largely present in the soluble fraction. 5. The relevance of these studies to the localization in vivo and the possible role of peptidases in protein digestion is discussed.


Virtual reality neurosurgery: a simulator blueprint.
This article details preliminary studies undertaken to integrate the most relevant advancements across multiple disciplines in an effort to construct a highly realistic neurosurgical simulator based on a distributed computer architecture. Techniques based on modified computational modeling paradigms incorporating finite element analysis are presented, as are current and projected efforts directed toward the implementation of a novel bidirectional haptic device. Patient-specific data derived from noninvasive magnetic resonance imaging sequences are used to construct a computational model of the surgical region of interest. Magnetic resonance images of the brain may be coregistered with those obtained from magnetic resonance angiography, magnetic resonance venography, and diffusion tensor imaging to formulate models of varying anatomic complexity. The majority of the computational burden is encountered in the presimulation reduction of the computational model and allows realization of the required threshold rates for the accurate and realistic representation of real-time visual animations. Intracranial neurosurgical procedures offer an ideal testing site for the development of a totally immersive virtual reality surgical simulator when compared with the simulations required in other surgical subspecialties. The material properties of the brain as well as the typically small volumes of tissue exposed in the surgical field, coupled with techniques and strategies to minimize computational demands, provide unique opportunities for the development of such a simulator. Incorporation of real-time haptic and visual feedback is approached here and likely will be accomplished soon.


Structural domains involved in the regulation of transmitter release by synapsins.
Synapsins are a family of neuron-specific phosphoproteins that regulate neurotransmitter release by associating with synaptic vesicles. Synapsins consist of a series of conserved and variable structural domains of unknown function. We performed a systematic structure-function analysis of the various domains of synapsin by assessing the actions of synapsin fragments on neurotransmitter release, presynaptic ultrastructure, and the biochemical interactions of synapsin. Injecting a peptide derived from domain A into the squid giant presynaptic terminal inhibited neurotransmitter release in a phosphorylation-dependent manner. This peptide had no effect on vesicle pool size, synaptic depression, or transmitter release kinetics. In contrast, a peptide fragment from domain C reduced the number of synaptic vesicles in the periphery of the active zone and increased the rate and extent of synaptic depression. This peptide also slowed the kinetics of neurotransmitter release without affecting the number of docked vesicles. The domain C peptide, as well as another peptide from domain E that is known to have identical effects on vesicle pool size and release kinetics, both specifically interfered with the binding of synapsins to actin but not with the binding of synapsins to synaptic vesicles. This suggests that both peptides interfere with release by preventing interactions of synapsins with actin. Thus, interactions of domains C and E with the actin cytoskeleton may allow synapsins to perform two roles in regulating release, whereas domain A has an actin-independent function that regulates transmitter release in a phosphorylation-sensitive manner.


Differences in midterm outcomes in infants with hypoplastic left heart syndrome diagnosed with necrotizing enterocolitis: NPCQIC database analysis.
Neonates with hypoplastic left heart syndrome (HLHS) are at increased risk for necrotizing enterocolitis (NEC). Initial hospital outcomes are well described, but minimal midterm data exist. Goal of this study was to compare outcomes of HLHS infants with NEC (HLHS-NEC) to HLHS without NEC (HLHS-nNEC) during the interstage period. Data were reviewed from 55 centers using the NPC-QIC database. Case-control study with one HLHS-NEC matched to HLHS-nNEC neonates in a 1:3 ratio based on institutional site, type of surgical repair, and gestational age ±1 week was performed. Baseline demographics as well as outcome data were recorded. The t tests or chi-square tests were performed as appropriate. There were 57 neonates in the HLHS-NEC (14 Norwood-BT, 37 Norwood-RVPA, and 6 hybrid) and 171 neonates in the HLHS-nNEC group. There were significant differences between the HLHS-NEC versus HLHS-nNEC for presence of atrioventricular valve regurgitation (7% vs 2%), use of extracorporeal membrane oxygenation (11% vs 2%), hospital stay (60.4 ± 30.0 vs 36.3 ± 33.6 days), Z-score weight at discharge (-2.1 vs -1.6), incidence of no oral intake (33% vs 14%), and use of formula only nutrition at discharge (61% vs 29%), respectively. There were no significant differences between groups in readmission rates due to adverse gastrointestinal events, use of gastrointestinal medications, interstage deaths, or Z-score weight at time of second surgery. HLHS-NEC continued to be more likely to be entirely tube dependent for enteral intake at time prior to the second procedure (39% vs 15%). Despite similar baseline characteristics, HLHS-NEC infants had significant differences in hospital course compared with HLHS-nNEC neonates. In addition, HLHS-NEC infants were less likely to be fed orally during the entire interstage period. Future studies are needed minimize NEC in this high risk population to possibly improve oral feeds.


Measurement scales on the continuum.
In a seminal article in 1946, S. S. Stevens noted that the numerical measures then in common use exhibited three admissible groups of transformations: similarity, affine, and monotonic. Until recently, it was unclear what other scale types are possible. For situations on the continuum that are homogeneous (that is, objects are not distinguishable by their properties), the possibilities are essentially these three plus another type lying between the first two. These types lead to clearly described classes of structures that can, in principle, be incorporated into the classical structure of physical units. Such results, along with characterizations of important special cases, are potentially useful in the behavioral and social sciences.


Current standards in abdominal cavity ultrasound examination in children.
Technological progress forces us to present after several years the updated standards in ultrasound examination of newborns, infants and older children. It should be emphasized that the examination of the youngest patients requires one to use high-class equipment. Lack of cooperation on the part of the child and imaging small structures constitute a huge challenge for the examiner. The work presents equipment requirements, the technology of examining the abdominal cavity in children and the manner of preparing the examination result. Moreover, modern expectations as regards ultrasound surgery equipment, where children are subject to examination have been presented. The minimum set of transducers the ultrasound apparatus should be equipped with has also been pointed out as well as the minimum requirements concerning image recording. Extending the scope of transducers over "minimum" significantly raises the imaging possibilities in pediatrics. Standard preparation of children for ultrasound has been discussed, taking into consideration the age of the patient and indications. It is essential to understand that it differs from standard preparation for examination in the case of adults. The technique of examining the abdominal cavity has been described, which enables the repeatability of examinations and ensuring making all the available structures visible. It proves imperative especially in the case of a large number of examinations. Attention should be paid particularly to the urinary system imaging - owing to the greatest incidence of congenital diseases in that system.


Hereditary hemolytic disorders among the Ashram school children in Mayurbhanj district of Orissa.
Hemoglobinopathy and allied hemolytic disorders are important genetic and public health problems in Orissa. These cause high degree of hemolytic anemia, morbidity and mortality in the vulnerable populations. A total of 465 Ashram School children aged 6-15 years belonging to Bathudi, Bhumiz, Kolha and Santal tribes in six localities of Mayurbhanj district of Orissa were screened for hemoglobinopathy, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, ABO and Rhesus blood groups serology and any other hereditary condition. The sickle cell trait (Hb AS) was detected in Santal (1.0%), Bathudi (1.0%) and Bhumiz (0.9%) tribals. No case of homozygous sickle cell disease was detected among the tribes of Mayurbhanj district. The beta-thalassemia trait was detected in Santal (8.0%), Kolha (2.0%), Bhumiz (1.7%) and other tribal (3.8%) students. Sickle cell hemoglobinopathy and beta-thalassemia are prevalent in this district among the tribes, but the frequency is very low. The prevalence of G-6-PD deficiency is considerably high (7.7-9.8%) among the tribes of Mayurbhanj district in Orissa. Out of total 43 G-6-PD deficient subjects, there were 32 males, 9 heterozygote females and 2 homozygous females. This shows that the antimalarial drugs should be administered with caution as these cause hemolytic anemia, sometimes fatal also. The distribution of ABO and Rhesus blood groups shows the preponderance of B blood group (33.8%) over O (29.6%) and 2.1% cases of Rhesus negativity were detected among the Bathudi tribe. This pattern is consistent with the characteristic features of tribal populations in India.


Survival rate of gastric cancer in Iran; a systematic review and meta-analysis.
In this study, we aimed to estimate one- to five-year survival rates in Iranian patients with gastric cancer (GC). In addition, we preformed subgroup analyses and meta-regression to explore possible sources of heterogeneity between studies. According to literatures, there has been increasing attention to the long-term survival rate in patients with GC in Iran. However, results have been inconsistent and remain controversial in overall survival rates. Literature searches were conducted using PubMed, Scopus, and ISI, as well as Magiran, Medlib, SID, and Iran Medex databases. Studies were pooled and summary one to five survival rates were calculated. Univariate and multivariate regression analyses were used to explore possible sources of heterogeneity among studies. Subgroup analyses were also conducted. Analyses were conducted using the STATA statistical software package. Final analysis of 29361 patients from 26 eligible studies was performed. The overall survival rate (one to five years) in all studies, by meta-analysis of 24, 14, 23, 12 and 22 studies were 52%, 31%, 24%, 22%, and 15%, respectively. Meta-regression analysis showed an increase in one- and five-year survival rate over the time (Reg Coef = 0.016, p= 0.04) and (Reg Coef= 0.021, p= 0.049), respectively. Positive heterogeneity was observed between quality of papers and data sources (P<0.001). More than half of GC deaths happened in the first year at diagnosis, and another 30% plus they occurred during the second year after confirmed diagnosis. Our results admit lower survival rates in Iran, similar to other developing countries.


The totally extraperitoneal method versus Lichtenstein's technique for inguinal hernia repair: a systematic review with meta-analyses and trial sequential analyses of randomized clinical trials.
Lichtenstein's technique is considered the reference technique for inguinal hernia repair. Recent trials suggest that the totally extraperitoneal (TEP) technique may lead to reduced proportions of chronic pain. A systematic review evaluating the benefits and harms of the TEP compared with Lichtenstein's technique is needed. The review was performed according to the 'Cochrane Handbook for Systematic Reviews'. Searches were conducted until January 2012. Patients with primary uni- or bilateral inguinal hernias were included. Only trials randomising patients to TEP and Lichtenstein were included. Bias evaluation and trial sequential analysis (TSA) were performed. The error matrix was constructed to minimise the risk of systematic and random errors. Thirteen trials randomized 5404 patients. There was no significant effect of the TEP compared with the Lichtenstein on the number of patients with chronic pain in a random-effects model risk ratio (RR 0.80; 95% confidence interval (CI) 0.61 to 1.04; p = 0.09). There was also no significant effect on number of patients with recurrences in a random-effects model (RR 1.41; 95% CI 0.72 to 2.78; p = 0.32) and the TEP technique may or may not be associated with less severe adverse events (random-effects model RR 0.91; 95% CI 0.73 to 1.12; p = 0.37). TSA showed that the required information size was far from being reached for patient important outcomes. TEP versus Lichtenstein for inguinal hernia repair has been evaluated by 13 trials with high risk of bias. The review with meta-analyses, TSA and error matrix approach shows no conclusive evidence of a difference between TEP and Lichtenstein on the primary outcomes chronic pain, recurrences, and severe adverse events.


Online monitoring of cell metabolism for studying pharmacodynamic effects.
To characterize modes of action of substances and their cytotoxic effects Bionas GmbH has developed a new screening system to allow the continuous recording of how an active substance can act (Bionas 2500 analyzing system). In the pharmaceutical industry it is important to acquire as much information as possible about the metabolic effects of an active substance. Most classical pre-clinical studies are very expensive and time-consuming. Often they are so-called end-point tests which require many individual tests before approximate statements can be made about how an effect takes its course. With the Bionas 2500 analyzing system metabolically relevant data including oxygen consumption, acidification rate and the adhesion (cell impedance) of cells can be measured in parallel, online and label-free. Using e.g. ion-sensitive field effect-transistors (ISFET) and electrode structures it is possible to observe metabolic parameters non-invasively and continuously over longer periods of time. The system has already been established for several cell models, cell lines as well as primary cells. It also offers the advantage that regenerative effects can be observed during the same test run.


Identification of the naturally occurring flavin of nitroalkane oxidase from fusarium oxysporum as a 5-nitrobutyl-FAD and conversion of the enzyme to the active FAD-containing form.
Nitroalkane oxidase from Fusarium oxysporum catalyzes the oxidation of nitroalkanes to aldehydes with production of nitrite and hydrogen peroxide. The UV-visible absorbance spectrum of the purified enzyme shows a single absorption peak at 336 nm with an extinction coefficient of 7.4 mM-1 cm-1. Upon denaturation of the enzyme at pH 7.0, a stoichiometric amount of FAD is released. The spectral properties of the enzyme as isolated are consistent with an N(5) adduct of the flavin. This is not due to a covalent linkage with the protein, since the free flavin adduct can be isolated from the enzyme at pH 2.1. The free flavin adduct shows an absorbance spectrum with a lambdamax at 346 nm (10.7 mM-1 cm-1) and is not fluorescent. Under alkaline conditions the free adduct decays, yielding FAD; the rate of this process is pH-dependent with a pKa of 7.4. Adduct decay is also observed with the native enzyme; in this case, however, the rate of decay is 160-fold slower (at pH 8.0) and not dependent on pH. During this process a large increase in enzymatic activity ( approximately 26-fold at pH 7.0) is observed, the rate of which is equal to the rate of flavin adduct conversion to FAD. Thus, the native flavin adduct is not active but can be converted to FAD, the active form of the flavin. Maximal activation is pH- and FAD-dependent; two groups with pKa values of 5.65 +/- 0. 25 and 8.75 +/- 0.05 must be unprotonated and protonated, respectively. The m/z- of the free flavin adduct is 103.0645 higher than that of FAD, as determined by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. This corresponds to a molecule of nitrobutane linked to FAD. A mechanism is proposed for the formation in vivo of the nitrobutyl-FAD of nitroalkane oxidase.


Causal Responsibility Division of Chronological Continuous Treatment Based on Change-Point Detection.
This paper introduces a novel approach, called causal relation quantification, based on change-point detection to address the issue of harmonic responsibility division in power systems. The proposed method focuses on determining the causal effect of chronological continuous treatment, enabling the identification of crucial treatment intervals. Within each interval, three propensity-score-based algorithms are executed to assess their respective causal effects. By integrating the results from each interval, the overall causal effect of a chronological continuous treatment variable can be calculated. This calculated overall causal effect represents the causal responsibility of each harmonic customer. The effectiveness of the proposed method is evaluated through a simulation study and demonstrated in an empirical harmonic application. The results of the simulation study indicate that our method provides accurate and robust estimates, while the calculated results in the harmonic application align closely with the real-world scenario as verified by on-site investigations.


The role of transcription factors in atrial fibrillation.
Atrial fibrillation (AF) is a complex disease that results from genetic and environmental factors and their interactions. In recent years, genome-wide association studies (GWAS) and family-based linkage analysis have found amounts of genetic variants associated with AF. Some of them lie in coding sequences and thus mediate the encoded proteins, some in non-coding regions and influence the expression of adjacent genes. These variants exert influence on the development of cardiovascular system and normal cardiac electrical activity in different levels, and eventually contribute to the occurrence of AF. Among these affected genes, as a crucial means of transcriptional regulation, several transcription factors play important roles in the pathogenesis of AF. In this review, we will focus on the potential role of PITX2, PRRX1, ZHFX3, TBX5, and NKX2.5 in AF.


MELD score can predict early mortality in patients with rebleeding after band ligation for variceal bleeding.
To investigate the outcomes, as well as risk factors for 6-wk mortality, in patients with early rebleeding after endoscopic variceal band ligation (EVL) for esophageal variceal hemorrhage (EVH). Among 817 EVL procedures performed for EVH between January 2007 and December 2008, 128 patients with early rebleeding, defined as rebleeding within 6 wk after EVL, were enrolled for analysis. The rate of early rebleeding after EVL for acute EVH was 15.6% (128/817). The 5-d, 6-wk, 3-mo, and 6-mo mortality rates were 7.8%, 38.3%, 55.5%, and 58.6%, respectively, in these early rebleeding patients. The use of beta-blockers, occurrence of hypovolemic shock, and higher model for end-stage liver disease (MELD) score at the time of rebleeding were independent predictors for 6-wk mortality. A cut-off value of 21.5 for the MELD score was found with an area under ROC curve of 0.862 (P < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value were 77.6%, 81%, 71.7%, and 85.3%, respectively. As for the 6-mo survival rate, patients with a MELD score ≥ 21.5 had a significantly lower survival rate than patients with a MELD score < 21.5 (P < 0.001). This study demonstrated that the MELD score is an easy and powerful predictor for 6-wk mortality and outcomes of patients with early rebleeding after EVL for EVH.


Risk factors for cranial cruciate ligament rupture in dogs participating in canine agility.
Cranial cruciate ligament rupture (CCLR) is one of the most common causes of pelvic limb lameness in dogs. Risk factors for CCLR include breed (especially large and giant breeds), body weight, gender and spay/neuter status, and age. Few studies have evaluated physical activity and fitness indicators, however, as risk factors for disease. This study used an online questionnaire distributed primarily via social media to assess risk factors for CCLR in dogs actively engaged in agility training or competition to determine demographic and physical activity factors associated with rupture. Data from 260 dogs with CCLR were compared to similar data from 1006 dogs without CCLR. All dogs were actively training or competing in agility at the time of CCLR or the time of data submission, respectively. Physical characteristics associated with increased risk of CCLR included younger age, spayed female sex, greater body weight, and greater weight to height ratio. Agility activities associated with increased odds ratios included competition in events sponsored by the North American Dog Agility Council (NADAC), competing at novice and intermediate levels, and competing in fewer than 10 events/year. Odds ratios were lower in dogs that competed in events sponsored by United Kingdom Agility International (UKI). Other activities associated with increased odds ratio for CCLR included involvement in flyball activities and short walks or runs over hilly or flat terrain on a weekly basis. Activities associated with decreased odds ratio included involvement in dock diving, barn hunt, nosework, or lure coursing/racing activities and participation in core balance and strength exercises at least weekly. These results are consistent with previous studies demonstrating that body weight and spay/neuter status are risk factors for CCLR in dogs. This is the first report to demonstrate that risk of CCLR in agility dogs is decreased in dogs that engage in regular core strengthening exercises, compete more frequently, compete at higher levels, and compete in more athletically challenging venues.


Visual strategies underpinning the development of visual-motor expertise when hitting a ball.
It is well known that skilled batters in fast-ball sports do not align their gaze with the ball throughout ball-flight, but instead adopt a unique sequence of eye and head movements that contribute toward their skill. However, much of what we know about visual-motor behavior in hitting is based on studies that have employed case study designs, and/or used simplified tasks that fall short of replicating the spatiotemporal demands experienced in the natural environment. The aim of this study was to provide a comprehensive examination of the eye and head movement strategies that underpin the development of visual-motor expertise when intercepting a fast-moving target. Eye and head movements were examined in situ for 4 groups of cricket batters, who were crossed for playing level (elite or club) and age (U19 or adult), when hitting balls that followed either straight or curving ('swinging') trajectories. The results provide support for some widely cited markers of expertise in batting, while questioning the legitimacy of others. Swinging trajectories alter the visual-motor behavior of all batters, though in large part because of the uncertainty generated by the possibility of a variation in trajectory rather than any actual change in trajectory per se. Moreover, curving trajectories influence visual-motor behavior in a nonlinear fashion, with targets that curve away from the observer influencing behavior more than those that curve inward. The findings provide a more comprehensive understanding of the development of visual-motor expertise in interception. (PsycINFO Database Record


Low-level pilin expression allows for substantial DNA transformation competence in Neisseria gonorrhoeae.
The gonococcal pilus is a major virulence factor that has well-established roles in mediating epithelial cell adherence and DNA transformation. Gonococci expressing four gonococcal pilin variants with distinct piliation properties under control of the lac regulatory system were grown in different levels of the inducer isopropyl-beta-D-thiogalactopyranoside (IPTG). These pilin variants expressed various levels of pilin message and pilin protein in response to the level of IPTG in the growth medium. Moreover, posttranslational modifications of the variant pilin proteins were detected, including S-pilin production and glycosylation. The ratio of the modified and unmodified pilin forms did not substantially change with different levels of pilin expression, showing that these modifications are not linked to pilin expression levels. DNA transformation competence was also influenced by IPTG levels in the growth medium. Substantial increases in transformation competence over an isogenic, nonpiliated mutant were observed when limited amounts of three of the pilin variants were expressed. Immunoelectron microscopy showed that when limited amounts of pilin are expressed, pili are rare and do not explain the pilin-dependent transformation competence. This pilin-dependent transformation competence required prepilin processing, the outer membrane secretin PilQ, and the twitching-motility-regulating protein PilT. These requirements show that a fully functional pilus assembly apparatus is required for DNA uptake when limited pilin is produced. We conclude that the pilus assembly apparatus functions to import DNA into the bacterial cell in a pilin-dependent manner but that extended pili are not required for transformation competence.


Cell wall extensins in root-microbe interactions and root secretions.
Extensins are cell wall glycoproteins, belonging to the hydroxyproline-rich glycoprotein (HRGP) family, which are involved in many biological functions, including plant growth and defence. Several reviews have described the involvement of HRGPs in plant immunity but little focus has been given specifically to cell wall extensins. Yet, a large set of recently published data indicates that extensins play an important role in plant protection, especially in root-microbe interactions. Here, we summarise the current knowledge on this topic and discuss the importance of extensins in root defence. We first provide an overview of the distribution of extensin epitopes recognised by different monoclonal antibodies among plants and discuss the relevance of some of these epitopes as markers of the root defence response. We also highlight the implication of extensins in different types of plant interactions elicited by either pathogenic or beneficial micro-organisms. We then present and discuss the specific importance of extensins in root secretions, as these glycoproteins are not only found in the cell walls but are also released into the root mucilage. Finally, we propose a model to illustrate the impact of cell wall extensin on root secretions.


DNA mismatch repair deficiency and outcomes of patients with locally advanced gastric cancer treated with preoperative docetaxel, oxaliplatin, and S-1 plus surgery and postoperative S-1 or surgery plus postoperative S-1: a sub-analysis of the phase 3 PRODIGY trial.
The benefit of adjuvant chemotherapy for locally advanced gastric cancer (LAGC) patients with DNA mismatch repair (MMR) deficiency (D-MMR) is controversial due to concerns about its potential detrimental effect. The PRODIGY trial showed the survival benefit of adding preoperative docetaxel, oxaliplatin, and S-1 (DOS) to surgery plus postoperative S-1 for LAGC patients. In this sub-analysis, we evaluated the benefit of preoperative DOS according to MMR status. Among patients enrolled in the PRODIGY trial treated with either preoperative DOS followed by surgery and postoperative S-1 (CSC arm), or surgery and postoperative S-1 (SC arm) at Asan Medical Center (n = 249), those in the full analysis set with available tissue to assess MMR status were included in the present analysis. A total of 231 patients (CSC arm, n = 108; SC arm, n = 123) were included (median age, 58 years [range, 27-75]), and 21 patients (CSC arm, n = 8 [7.4%]; SC arm, n = 13 [10.6%]) had D-MMR tumors. Progression-free survival and overall survival tended to be superior in the CSC arm than in the SC arm among D-MMR patients (HR 0.48 [95% CI 0.09-2.50]; log-rank P = 0.37 and HR 0.55 [95% CI 0.11-2.86]; log-rank P = 0.46, respectively), as well as among proficient MMR (P-MMR) patients (HR 0.68 [95% CI 0.46-1.03]; log-rank P = 0.07 and HR 0.75 [95% CI 0.49-1.14]; log-rank P = 0.17, respectively). Preoperative DOS followed by surgery and postoperative S-1 may be considered a treatment option for LAGC patients regardless of MMR status.


Potential mineralization of four herbicides in a ground water--fed wetland area.
Herbicides may leach from agricultural fields into ground water feeding adjacent wetlands. However, only little is known of the fate of herbicides in wetland areas. The purpose of the study was to examine the potential of a riparian fen to mineralize herbides that could leach from an adjacent catchment area. Slurries were prepared from sediment and ground water collected from different parts of a wetland representing different redox conditions. The slurries were amended with O2, NO3-, SO4(2-), and CO2, or CO2 alone as electron acceptors to simulate the in situ conditions and their ability to mineralize the herbides mecoprop, metsulfuron-methyl, isoproturon and atrazine. In addition, the abundance of bacteria able to utilize O2, NO3-, SO4(2-) + CO2, and CO2 as electron acceptors was investigated along with the O2-reducing and methanogenic potential of the sediment. The recalcitrance to bacterial degradation depended on both the type of herbicide and the redox conditions pertaining. Mecoprop was the most readily degraded herbicide, with 36% of [ring-U-14C]mecoprop being mineralized to 14CO2 under aerobic conditions after 473 d. In comparison, approximately 29% of [phenyl-U-14C]metsulfuron-methyl and 16% of [ring-U-14C]isoproturon mineralized in aerobic slurries during the same period. Surprisingly, 8 to 13% of mecoprop also mineralized under anaerobic conditions. Neither metsulfuron-methyl nor isoproturon were mineralized under anaerobic conditions and atrazine was not mineralized under any of the redox conditions examined. The present study is the first to report mineralization of meco-prop in ground water in a wetland area, and the first to report mineralization of a phenoxyalcanoic acid herbicide under both aerobic and anaerobic conditions.


Heterodyne schlieren system.
A new heterodyne technique for the quantitative analysis of schlieren images is described. The technique is based on phase measurements of signals generated by a photodetector observing the variations in light intensity caused by a traveling grating of slits located at the knife-edge plane of a conventional schlieren system. The phase of the signal is proportional to the displacement of the slit image on the knife-edge plane as a result of the light deflection passing through a phase object. The displacement is proportional to the ray deflection angle and hence to the local gradient of the index of refraction. The technique, which is quantitatively precise and sensitive, is demonstrated by measurement of deflections caused by a lens with a focal length of f = 20 m. A displacement of 0.22 mm and a deflection of an angle of 5.2 x 10(-4) rad were detected.


The efficacy of reservoirs in bleaching trays.
Thirty patients were selected to bleach their maxillary teeth. Vacuum-formed trays were fabricated for the maxillary arch so that only one quadrant of bleaching tray had reservoirs. Nupro Gold 10% carbamide peroxide gel was given to patients. They were instructed to place a drop of gel in each tooth area and wear the trays twice a day for two-hour periods. After 10 days the patients were evaluated for shade changes in each quadrant. No clinical difference was observed in the after-shade match of the two quadrants. It appears that the addition of blockout spacers to create reservoirs does not increase the success of home bleaching.


Arg72Pro polymorphism of TP53 gene and the risk of skin cancer: a meta-analysis.
TP53 gene is one of the most important tumor suppressor genes. We undertook this meta-analysis to explore the association between TP53 Arg72Pro polymorphism and the risk of skin cancer mainly in Caucasians. We searched PubMed for case-control studies published up to March 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. A total of 5276 skin cancer cases and 5315 controls from 20 studies were included. Overall, no significant association between TP53 Arg72Pro polymorphism and skin cancer was observed in all genetic contrast models (Pro/Pro versus Arg/Arg, Pro/Arg versus Arg/Arg, Pro/Pro + Pro/Arg versus Arg/Arg, Pro/Pro versus Arg/Arg + Pro/Arg, Pro allele versus Arg allele). Similar results were obtained in the stratified analysis by ethnicity and histological types of skin cancer, such as melanoma, squamous cell carcinoma and basal cell carcinoma. Power calculations indicated that some studies were underpowered. No publication bias was found by using the funnel plot and Egger's test. This meta-analysis indicated that TP53 Arg72Pro polymorphism probably had little association with skin cancer susceptibility mainly in Caucasians. However, larger sample-size studies are required to verify the conclusion as low statistical powers.


The changing demographic pattern in asthma related to sex and age. A study of 13,651 patients on sodium cromoglycate (Intal).
A total of 13,651 patients diagnosed as suffering from asthma and who were prescribed Intal are reviewed with regard to age and sex. It is found that in infancy and the prepubertal ages, males far outnumber females. There is a changeover during the ages 14 to 20 years to female predominance. At 60 years of age and above there is an equality in proportions by sex. Observations are made on age limitations for Intal therapy. That a hormonal factor or imbalance of hormonal factors is present in asthma is suggested.


Shelter availability and human attitudes as drivers of rock hyrax (Procavia capensis) expansion along a rural-urban gradient.
While anthropogenic land-use changes threaten wildlife globally, some species take advantage of such changes and disperse into urban areas. The wildlife in urban areas often promotes conflicts with humans, notably when the animals are associated with the spread of zoonotic diseases. In Israel, current urban invasion of rock hyraxes (Procavia capensis) draws public attention, since the species is a reservoir host of cutaneous leishmaniasis, a serious skin disease. The rock hyrax, however, has seldom been studied in densely populated areas, and the drivers for its urban expansion, as well as its abilities to live and spread in core urban areas, are relatively unknown. Here, we explore the rock hyrax expansion to urban areas process by examining the availability, characteristics and use of shelter along an urban gradient. Our findings suggest that a series of factors determines shelter availability and quality for the rock hyrax, which facilitates its dispersion across the urban gradient. We found that rock hyraxes from the Judean Desert expand to the peri-urban region of Jerusalem by colonizing new rocky shelters formed as by-products of urban development. With their populations reaching extreme densities in this area and saturating the available shelters, there is some spill over to the adjacent core urban areas where they colonize littered sites, which are made available due to the local socio-economic conditions and cultural norms of waste disposal and illegal placement of temporary structures. Our work emphasizes the significance of the urban gradient approach for studying the mechanisms promoting wildlife expansion to cities. Our findings suggest that changes in shelter availability and quality due to urban development, and cultural norms promote shifts of the hyrax population by pushing from the already established areas and pulling into new environment across the urban gradient.


Proton pump inhibitors and hospitalization with hypomagnesemia: a population-based case-control study.
Some evidence suggests that proton pump inhibitors (PPIs) are an under-appreciated risk factor for hypomagnesemia. Whether hospitalization with hypomagnesemia is associated with use of PPIs is unknown. We conducted a population-based case-control study of multiple health care databases in Ontario, Canada, from April 2002 to March 2012. Patients who were enrolled as cases were Ontarians aged 66 years or older hospitalized with hypomagnesemia. For each individual enrolled as a case, we identified up to four individuals as controls matched on age, sex, kidney disease, and use of various diuretic classes. Exposure to PPIs was categorized according to the most proximate prescription prior to the index date as current (within 90 days), recent (within 91 to 180 days), or remote (within 181 to 365 days). We used conditional logistic regression to estimate the odds ratio for the association of outpatient PPI use and hospitalization with hypomagnesemia. To test the specificity of our findings we examined use of histamine H2 receptor antagonists, drugs with no causal link to hypomagnesemia. We studied 366 patients hospitalized with hypomagnesemia and 1,464 matched controls. Current PPI use was associated with a 43% increased risk of hypomagnesemia (adjusted odds ratio, 1.43; 95% CI 1.06-1.93). In a stratified analysis, the risk was particularly increased among patients receiving diuretics, (adjusted odds ratio, 1.73; 95% CI 1.11-2.70) and not significant among patients not receiving diuretics (adjusted odds ratio, 1.25; 95% CI 0.81-1.91). We estimate that one excess hospitalization with hypomagnesemia will occur among 76,591 outpatients treated with a PPI for 90 days. Hospitalization with hypomagnesemia was not associated with the use of histamine H2 receptor antagonists (adjusted odds ratio 1.06; 95% CI 0.54-2.06). Limitations of this study include a lack of access to serum magnesium levels, uncertainty regarding diagnostic coding of hypomagnesemia, and generalizability of our findings to younger patients. PPIs are associated with a small increased risk of hospitalization with hypomagnesemia among patients also receiving diuretics. Physicians should be aware of this association, particularly for patients with hypomagnesemia. Please see later in the article for the Editors' Summary.


Emergency surgical treatment for patients with acute leukemia.
A series of 21 emergency operations performed upon 19 patients with acute leukemia was reviewed. The most common procedure performed was laparotomy for intra-abdominal emergency complications which was associated with a high mortality (58 per cent), especially in those patients with leukemia not in remission (78 per cent). Patients who underwent extra-abdominal procedures, even with leukemia not in remission, had a low mortality (14 per cent). All five patients who were operated upon while in remission survived. The most accurate prognostic signs associated with postoperative mortality were abnormal white blood cell counts and development of leukemia not in remission. Early surgical intervention is advised combined with intensive supportive care to improve survival rates of patients with acute leukemia who undergo emergency surgical procedures.


Comprehensive characterization of adipogenesis-related genes in colorectal cancer for clinical significance and immunogenomic landscape analyses.
Colorectal cancer (CRC) is a major global health concern, necessitating the identification of biomarkers and molecular subtypes for improved clinical management. This study aims to evaluate the clinical value of adipogenesis-related genes and molecular subtypes in CRC. A comprehensive analysis of adipogenesis-related genes in CRC was performed using publicly available datasets (TCGA and GEO database) and bioinformatics tools. Unsupervised cluster analysis was employed to identify the molecular subtypes of CRC, while LASSO regression analysis was utilized to develop a risk prognostic model. The immunogenomic patterns and immunotherapy analysis were used to predict patient response to immunotherapy. Furthermore, qPCR analysis was conducted to confirm the expression of the identified key genes in vitro. Through the analysis of RNAseq data from normal and tumor tissues, we identified 50 differentially expressed genes. Unsupervised cluster analysis identified two subtypes (Cluster A and Cluster B) with significantly different survival outcomes. Cluster A and B displayed differential immune cell compositions and enrichment in specific biological pathways, providing insights into potential therapeutic targets. A risk-scoring model was developed using five ARGs, which successfully classified patients into high and low-risk groups, showing distinct survival outcomes. The model was validated and showed robust predictive performance. High-risk patients exhibited altered immune cell proportions and gene expression patterns compared to low-risk patients. In qPCR validation, four out of the five key genes were consistent with the results of bioinformatics analysis. Overall, the findings of our investigation offer valuable understanding regarding the clinical relevance of ARGs and molecular subtypes in CRC, laying the groundwork for improved precision medicine applications and personalized treatment modalities.


BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population.
The tumor necrosis factor (TNF) family member B cell activating factor (BAFF) binds B cells and enhances B cell receptor-triggered proliferation. We find that B cell maturation antigen (BCMA), a predicted member of the TNF receptor family expressed primarily in mature B cells, is a receptor for BAFF. Although BCMA was previously localized to the Golgi apparatus, BCMA was found to be expressed on the surface of transfected cells and tonsillar B cells. A soluble form of BCMA, which inhibited the binding of BAFF to a B cell line, induced a dramatic decrease in the number of peripheral B cells when administered in vivo. Moreover, culturing splenic cells in the presence of BAFF increased survival of a percentage of the B cells. These results are consistent with a role for BAFF in maintaining homeostasis of the B cell population.


Vision-Related Quality of Life After Vitrectomy: Cross-Sectional Study from Jordan.
In the era of patient-centered medical care, using objective clinical measures to assess patient-centered outcomes in all aspects became a necessity, and pars plana vitrectomy (PPV) is a major ophthalmic surgical procedure used for the treatment of vitreoretinal disorders aiming to improve their vision-related quality of life. To study the impact of PPV on visual quality of life by assessing its effect on common daily activities, to assess its association with various factors, and to explore the relations between these factors and postoperative visual function. Vision-related quality of life for 87 patients who underwent PPV was assessed using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) by phone call interviews. Variables assessed include age, gender, indication of surgery, duration since surgery, preoperative best-corrected visual acuity (BCVA), postoperative BCVA, fellow eye BCVA, medical history and lens status. The factors significantly affecting the total score were postoperative visual acuity and fellow eye VA. Upon analyzing the effect of the indication on total score, a significant difference was found with the highest being for those who had dropped lens as the indication for surgery and the lowest was for those with tractional retinal detachment (TRDs) and inflammatory indications. Subscale analysis and visual acuity improvement were also varying between indications. VRQOL significantly improves after PPV, the improvement is variable with different indications, being the greatest for those with dropped lens and the least for TRDs and endophthalmitis, with postoperative VA being the most important factor affecting the VRQOL score.


[Primary adrenal insufficiency in children].
Primary adrenal insufficiency is a rare pediatric condition, which can be presented as chronic or acute forms, especially during stress. The clinical features are unspecific and include weakness, nausea and vomiting, abdominal pain and diarrhea, arterial hypotension, hypoglycemia and dehydration. The etiology can be acquired such as infectious, hemorrhagic and drug-induced disorders, or be dependent on a genetic origin, such as congenital adrenal hyperplasia, Addisons disease, congenital adrenal hypoplasia, adrenoleucodystrophy, or deposit disorders of the adrenal gland. The familial history, presence of consanguinity, adjacent diseases and associate factors, should be considered to confirm the diagnosis. Laboratory investigation includes cortisol, ACTH and the determination of the steroidogenic precursors. The ACTH stimulation test is performed in intermediate conditions. Adrenal auto-antibodies quantitation and molecular studies can be helpful to confirm specific diseases. A substitutive glucocorticoid and mineralocorticoid therapy should be started as soon as the diagnosis is confirmed. The treatment aimed to control the symptoms with the smaller dose that can allow an adequate growth and pubertal development.


C-reactive protein and electrocardiographic ST-segment depression additively predict mortality: the Strong Heart Study.
This study was designed to examine whether high-sensitivity C-reactive protein (CRP) and electrocardiographic (ECG) ST-segment depression (STD) have additive utility for predicting cardiovascular disease (CVD) death and all-cause death (ACD). C-reactive protein, a marker of systemic inflammation, and ECG STD, an index of myocardial ischemia and hypertrophy, independently predict mortality. Electrocardiograms and CRP levels were examined in 2,155 American Indian participants in the second Strong Heart Study examination. ST-segment depression >/=50 microV (n = 127) and CRP >7.0 mg/l (defining the upper quartile of CRP levels, n = 540) were considered abnormal. After 5.2 +/- 1.2 years follow-up there were 95 CVD deaths and 310 ACD. In univariate Cox analyses, the combination of CRP and ECG STD improved risk stratification compared to either alone, with the presence of both CRP >7.0 and ECG STD associated with a 7.7-fold increased risk of CVD death (95% confidence interval [CI] 3.3 to 18.2) and a 6.5-fold increased risk of ACD (95% CI 4.1 to 10.3). After adjustment for age, gender, and relevant risk factors, the combination of high CRP and STD remained predictive of CVD death and ACD, with the presence of both abnormal CRP and STD associated with the highest risks of CVD death (hazard ratio [HR] 3.2, 95% CI 1.1 to 10.5) and ACD (HR 3.9, 95% CI 2.1 to 7.2) and the presence of either high CRP or abnormal STD associated with intermediate risks of CVD death (HR 2.2, 95% CI 1.4 to 3.4) and ACD (HR 1.5, 95% CI 1.2 to 2.0). The combination of ECG STD and CRP increases the risk of mortality, demonstrating the additive impacts of active inflammation and preclinical CVD on prognosis.


Pinworm in pregnancy.
A case of enterobiasis in pregnancy that presented as copious nocturnal vaginal discharge is reported. Enterobius vermicularis is the most common parasite infecting humans. Transmission can be fecal-oral or via fomites, and recently arrived immigrants from developing countries and individuals who live in households with young children are particularly at risk. Pinworms are most frequently found in the gastrointestinal tract but can also enter the vagina and bladder. Patients typically present with nocturnal anal itching, and diagnosis can be made by clinical history. Treatment includes an antihelminthic agent for the patient and members of the household as well as home hygiene measures to prevent transmission.


A robust split-luciferase-based cell fusion screening for discovering myogenesis-promoting molecules.
Myogenesis-promoting chemicals are an important source of new pharmaceuticals for the treatment of skeletal muscle atrophy that impairs quality of life. This report presents a robust and quantitative bioluminescence-based assay for screening myogenesis-promoting compounds in chemical libraries. The assay system consists of two stable C2C12 myoblast cell lines, each of which expresses either an N-terminal or a C-terminal split luciferase fragment fused to a naturally split DnaE intein as an indicator for cell fusion. Cell fusion during myogenesis induces bioluminescence in the cytosol because of the reconstitution of luciferases. The luminescence intensity quantitatively represents the progress in the cell fusion and therefore indicates the extent of myogenesis. We applied this assay system to a high-throughput screening of myogenesis-promoting compouns in 1191 pharmacologically proven bioactive small molecules, which revealed two chemical compounds as myogenesis-promoting compounds: Imatinib and Doxazosin mesylate. The assay system enabled a robust and quantitative evaluation of the extent of myogenesis through simple luminescence measurements, and is expected to be widely applicable for high-throughput screening of cell fusion-promoting and inhibiting molecules.


Treatment of Enterocutaneous Fistulas, Then and Now.
An enterocutaneous fistula (ECF) is an aberrant connection between the gastrointestinal tract and the skin or atmosphere (enteroatmospheric fistula [EAF]). Multimodal treatment includes surgical procedures, nutrition support, and wound care. We evaluated our practice and compared our outcomes with previous results published from our institution. We performed a retrospective analysis of hospitalized ECF/EAF patients admitted between January 2011 and November 2015. Patients with internal fistulas; active inflammatory bowel disease; malignancy; radiation treatment; end-stage renal, hepatic, or cardiac disease; and active alcoholism were excluded. Data collected included demographics, fistula characteristics, nutrition therapy, treatment, operative success, and hospital mortality. Parametric and nonparametric tests for independent and paired groups were performed. Thirty-one patients were included in the analysis. The median (interquartile range) age was 60 (53-76) years, and 81% were female. Parenteral nutrition was initially prescribed in 80% of patients, but 61% received enteral nutrition (EN) at some point during their hospitalization. Two patients were fed by fistuloclysis. Eighty percent of the patients underwent surgical repair a median of 12 months after diagnosis with 92% operative success. Surgical repair had a modest correlation with home discharge (ρ = 0.517, P = .003). A large proportion of patients (77%) were discharged home. The in-hospital mortality at our institution decreased from 44% in 1960 to 21% in 1970 to 3% in the current study. Modern treatment of ECF/EAF, including EN and advanced local wound care, is associated with improvements in clinical outcomes such as hospital mortality.


Analog Coupled Oscillator Based Weighted Ising Machine.
We report on an analog computing system with coupled non-linear oscillators which is capable of solving complex combinatorial optimization problems using the weighted Ising model. The circuit is composed of a fully-connected 4-node LC oscillator network with low-cost electronic components and compatible with traditional integrated circuit technologies. We present the theoretical modeling, experimental characterization, and statistical analysis our system, demonstrating single-run ground state accuracies of 98% on randomized MAX-CUT problem sets with binary weights and 84% with 5-bit weight resolutions. Solutions are obtained within 5 oscillator cycles, and the time-to-solution has been demonstrated to scale directly with oscillator frequency. We present scaling analysis which suggests that large coupled oscillator networks may be used to solve computationally intensive problems faster and more efficiently than conventional algorithms. The proof-of-concept system presented here provides the foundation for realizing such larger scale systems using existing hardware technologies and could pave the way towards an entirely novel computing paradigm.


Synthesis and biological evaluation of 14-alkoxymorphinans. 18. N-substituted 14-phenylpropyloxymorphinan-6-ones with unanticipated agonist properties: extending the scope of common structure-activity relationships.
The synthesis, biological, and pharmacological evaluations of 14beta-O-phenylpropyl-substituted morphinan-6-ones are described. The most striking finding of this study was that all of the compounds from the novel series of differently N-substituted 14beta-O-phenylpropylmorphinans acted as powerful opioid agonists. Even with N-substituents such as cyclopropylmethyl and allyl, which are usually associated with distinct antagonist properties, only agonists were obtained. Compared to morphine, the N-cyclopropylmethyl derivative 15 showed considerably increased potency in the in vivo assays in mice (600-fold in the tail-flick assay, 60-fold in the paraphenylquinone writhing test, and 400-fold in the hot-plate assay). Remarkably, most of the new ligands were nonselective and exhibited binding affinities in the subnanomolar range at opioid receptors (mu, kappa, delta), with the N-propyl derivative 19 displaying the highest affinity for the mu-receptor (K(i) = 0.09 nM).


New molecular forms of human liver alcohol dehydrogenase: isolation and characterization of ADHIndianapolis.
The biochemical determinants of alcoholism and genetic correlates for the variability in man's response to alcohol have remained obscure until recently. The identification of genetically determined isoenzymes of alcohol dehydrogenase with different catalytic properties may bear importantly upon this problem. New molecular forms of human liver alcohol dehydrogenase (ADH; alcohol:NAD+ oxidoreductase, EC 188.8.131.52) have recently been identified in 16% of the liver specimens from an urban population from Indianapolis, Indiana [Bosron, W. F., Li, T.-K. & Vallee, B. L. (1979) Biochem. Biophys. Res. Commun. 91, 1549-1555]. The distinguishing features of these specimens were (i) they showed activity optima for ethanol oxidation at both pH 7.0 and 10.0 and (ii) they formed electrophoretic bands cathodic to the beta beta isoenzyme. From such livers, three new ADH forms have now been isolated, one of which has a single pH optimum at 7.0 and two of which have dual optima at pH 7.0 and 10.0. These new forms were designated ADHIndianapolis forms 1,2, and 3, respectively. They can be differentiated from previously described ADH isoenzymes, including the so-called "atypical" isoenzyme, by their electrophoretic mobility, pH optima, and Km for ethanol (approximately 60 mM at pH 7.5). Based upon the electrophoretic pattern of livers containing ADHIndianapolis and the mobility of the three isolated molecular forms, ADHIndianapolis may be the result of polymorphism at the ADH2 gene locus, which codes for the beta subunit.


Antibody-independent targeted quantification of TMPRSS2-ERG fusion protein products in prostate cancer.
Fusions between the transmembrane protease serine 2 (TMPRSS2) and ETS related gene (ERG) represent one of the most specific biomarkers that define a distinct molecular subtype of prostate cancer. Studies of TMPRSS2-ERG gene fusions have seldom been performed at the protein level, primarily due to the lack of high-quality antibodies suitable for quantitative studies. Herein, we applied a recently developed PRISM (high-pressure high-resolution separations with intelligent selection and multiplexing)-SRM (selected reaction monitoring) strategy for quantifying ERG protein in prostate cancer cell lines and tumors. The highly sensitive PRISM-SRM assays provided confident detection of 6 unique ERG peptides in both TMPRSS2-ERG positive cell lines and tissues, but not in cell lines or tissues lacking the TMPRSS2-ERG rearrangement, clearly indicating that ERG protein expression is significantly increased in the presence of the TMPRSS2-ERG gene fusion. Significantly, our results provide evidence that two distinct ERG protein isoforms are simultaneously expressed in TMPRSS2-ERG positive samples as evidenced by the concomitant detection of two mutually exclusive peptides in two patient tumors and in the VCaP prostate cancer cell line. Three peptides, shared across almost all fusion protein products, were determined to be the most abundant peptides, providing "signature" peptides for detection of ERG over-expression resulting from TMPRSS2-ERG gene fusion. The PRISM-SRM assays provide valuable tools for studying TMPRSS2-ERG gene fusion protein products in prostate cancer.


NHERF1 regulates parathyroid hormone receptor desensitization: interference with beta-arrestin binding.
Type 1 parathyroid hormone receptor (PTH1R) activation, desensitization, internalization, and recycling proceed in a cyclical manner. The Na(+)/H(+) exchange regulatory factor 1 (NHERF1) is a cytoplasmic adapter protein that regulates trafficking and signaling of several G protein-coupled receptors (GPCRs) including the PTH1R. The mineral ion wasting and bone phenotype of NHERF1-null mice suggests that PTH1R may interact with NHERF1. The objective of this study was to examine the effect of NHERF1 on PTH1R desensitization. Using rat osteosarcoma T6-N4 cells expressing the endogenous PTH1R, in which NHERF1 expression could be induced by tetracycline, PTH1R desensitization was assessed by measuring adenylyl cyclase activity after successive PTH challenges. PTH1R-mediated adenylyl cyclase responses were desensitized by repetitive PTH challenges in a concentration-dependent manner, and desensitization was inhibited by NHERF1. NHERF1 blocked PTH-induced dissociation of the PTH1R from Galpha(s). Blocking PTH1R endocytosis did not mitigate PTH1R desensitization. Reducing constitutive NHERF1 levels in human osteosarcoma SAOS2 cells, which express both endogenous PTH1R and NHERF1, with short hairpin RNA directed against NHERF1 restored PTH1R desensitization. Mutagenesis of the PDZ-binding domains or deletion of the NHERF1 MERM domain demonstrated that both are required for inhibition of receptor desensitization. A phosphorylation-deficient PTH1R exhibited reduced desensitization and interaction with beta-arrestin2 compared with wild-type PTH1R. NHERF1 inhibited beta-arrestin2 binding to wtPTH1R but had no effect on beta-arrestin2 association with pdPTH1R. Such an effect may protect against PTH resistance or PTH1R down-regulation in cells harboring NHERF1.


Accurate charge densities from powder X-ray diffraction - a new version of the Aarhus vacuum imaging-plate diffractometer.
In recent years powder X-ray diffraction has proven to be a valuable alternative to single-crystal X-ray diffraction for determining electron-density distributions in high-symmetry inorganic materials, including subtle deformation in the core electron density. This was made possible by performing diffraction measurements in vacuum using high-energy X-rays at a synchrotron-radiation facility. Here we present a new version of our custom-built in-vacuum powder diffractometer with the sample-to-detector distance increased by a factor of four. In practice this is found to give a reduction in instrumental peak broadening by approximately a factor of three and a large improvement in signal-to-background ratio compared to the previous instrument. Structure factors of silicon at room temperature are extracted using a combined multipole-Rietveld procedure and compared with ab initio calculations and the results from the previous diffractometer. Despite some remaining issues regarding peak asymmetry, the new diffractometer yields structure factors of comparable accuracy to the previous diffractometer at low angles and improved accuracy at high angles. The high quality of the structure factors is further assessed by modelling of core electron deformation with results in good agreement with previous investigations.


ω-3 polyunsaturated fatty acid supplementation does not influence body composition, insulin resistance, and lipemia in women with type 2 diabetes and obesity.
To evaluate the influence of ω-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation on body composition, insulin resistance, and lipemia of women with type 2 diabetes, the authors evaluated 41 women (60.64 ± 7.82 years) with high blood pressure and diabetes mellitus in a randomized and single-blind longitudinal intervention study. The women were divided into 3 groups: GA (2.5 g/d fish oil), GB (1.5 g/d fish oil), and GC (control). The capsules with the supplement contained 21.9% of eicosapentaenoic acid and 14.1% of docosapentaenoic acid. Biochemical (glucose, glycated hemoglobin, total and fractional cholesterol, triglycerides, and insulin) and anthropometric (body mass, stature, waist circumference [WC], and body composition) evaluations were performed before and after the 30 days of intervention. Homeostasis model assessment-insulin resistance and the Quantitative Insulin Sensitivity Check Index were used to evaluate the insulin resistance and insulin sensitivity (IS), respectively. GB presented a greater loss of body mass and WC (P < .05), greater frequency of glycemic and total cholesterol reduction, and an increase of high-density lipoprotein cholesterol compared with GA. Thus, a high dose of ω-3 PUFA can reduce IS. A lower dose of ω-3 PUFA positively influenced body composition and lipid metabolism.


Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial.
Healthy lifestyle factors are associated with maintenance of erectile function in men. To determine the effect of weight loss and increased physical activity on erectile and endothelial functions in obese men. Randomized, single-blind trial of 110 obese men (body mass index > or =30) aged 35 to 55 years, without diabetes, hypertension, or hyperlipidemia, who had erectile dysfunction that was determined by having a score of 21 or less on the International Index of Erectile Function (IIEF). The study was conducted from October 2000 to October 2003 at a university hospital in Italy. The 55 men randomly assigned to the intervention group received detailed advice about how to achieve a loss of 10% or more in their total body weight by reducing caloric intake and increasing their level of physical activity. Men in the control group (n = 55) were given general information about healthy food choices and exercise. Erectile function score, levels of cholesterol and triglycerides, circulating levels of interleukin 6, interleukin 8, and C-reactive protein, and endothelial function as assessed by vascular responses to l-arginine. After 2 years, body mass index decreased more in the intervention group (from a mean [SD] of 36.9 [2.5] to 31.2 [2.1]) than in the control group (from 36.4 [2.3] to 35.7 [2.5]) (P<.001), as did serum concentrations of interleukin 6 (P =.03), and C-reactive protein (P =.02). The mean (SD) level of physical activity increased more in the intervention group (from 48 [10] to 195 [36] min/wk; P<.001) than in the control group (from 51 [9] to 84 [28] min/wk; P<.001). The mean (SD) IIEF score improved in the intervention group (from 13.9 [4.0] to 17 [5]; P<.001), but remained stable in the control group (from 13.5 [4.0] to 13.6 [4.1]; P =.89). Seventeen men in the intervention group and 3 in the control group (P =.001) reported an IIEF score of 22 or higher. In multivariate analyses, changes in body mass index (P =.02), physical activity (P =.02), and C-reactive protein (P =.03) were independently associated with changes in IIEF score. Lifestyle changes are associated with improvement in sexual function in about one third of obese men with erectile dysfunction at baseline.


The importance of connections between the cell wall integrity pathway and the unfolded protein response in filamentous fungi.
In the external environment, or within a host organism, filamentous fungi experience sudden changes in nutrient availability, osmolality, pH, temperature and the exposure to toxic compounds. The fungal cell wall represents the first line of defense, while also performing essential roles in morphology, development and virulence. A polarized secretion system is paramount for cell wall biosynthesis, filamentous growth, nutrient acquisition and interactions with the environment. The unique ability of filamentous fungi to secrete has resulted in their industrial adoption as fungal cell factories. Protein maturation and secretion commences in the endoplasmic reticulum (ER). The unfolded protein response (UPR) maintains ER functionality during exposure to secretion and cell wall stress. UPR, therefore, influences secretion and cell wall homeostasis, which in turn impacts upon numerous fungal traits important to pathogenesis and biotechnology. Subsequently, this review describes the relevance of the cell wall and UPR systems to filamentous fungal pathogens or industrial microbes and then highlights interconnections between the two systems. Ultimately, the possible biotechnological applications of an enhanced understanding of such regulatory systems in combating fungal disease, or the removal of natural bottlenecks in protein secretion in an industrial setting, are discussed.


Elbow Ulnar Collateral Ligament Tears in 2023: Evaluation and Management.
The ulnar collateral ligament, also called the medial collateral ligament of the elbow, is the primary stabilizer against valgus loads. This ligament can be traumatically torn, such as in an elbow dislocation, or can tear through attritional damage with overhead sports. Although baseball pitching is the most common contributor, these injuries also occur with volleyball, gymnastics, and javelin throwing. Patients most commonly report a history of medial elbow pain with associated loss of command, control, and throw velocity. The ulnar nerve lies directly superficial to the posterior band of the ulnar collateral ligament and ulnar neuritis is commonly associated with ulnar collateral ligament pathology. Nonsurgical treatment, including rest from activity, flexor-pronator strengthening, and possible platelet-rich plasma injections, can be considered for partial-thickness tears. Surgical treatment can be considered for patients in whom nonsurgical treatment fails and full-thickness tears. Historically, surgical treatment involved reconstruction of the ligament with a tendon graft. Ipsilateral palmaris longus autograft has been the most commonly used graft, but contralateral palmaris, autograft hamstring tendons, and allograft tendon have also been used. This procedure has a high rate of return to play and a low complication rate, but most athletes require 12 to 18 months to fully return. More recently, repair of the ligament, with the addition of a biologic ingrowth ligament augmentation suture, has demonstrated similarly high rates of return to play and low complication rates, with a full return to play in 6 months.


Usability of the Ranibizumab 0.5 mg Prefilled Syringe: Human Factors Studies to Evaluate Critical Task Completion by Healthcare Professionals.
A ranibizumab prefilled syringe (PFS) has been approved by the U.S. Food and Drug Administration. Here we evaluate the use of the ranibizumab PFS for intravitreal injection by assessing whether the PFS enables healthcare providers to successfully prepare and administer an injection without prior training. Simulated-use and actual-use human factors usability studies. Retina specialists and ophthalmic medical personnel. In a simulated-use summative usability study, retina specialists (n = 15) and ophthalmic medical personnel (n = 15) prepared the ranibizumab PFS and performed injections into a model eye. In an actual-use formative usability study (ClinicalTrials.gov identifier: NCT02698566), three assistants and three retina specialists prepared the PFS and performed intravitreal injections, respectively, in study eyes of patients with retinal diseases (n = 35). Twelve tasks specific to the unpacking, preparing, and properly administering the PFS for intravitreal injection were evaluated by a study assessor. Task performances were evaluated for use errors, close calls, and operational difficulties. Post-injection subjective user evaluations were performed to assess ease of use. All participants successfully performed all essential and safety-critical tasks without use error in both the simulated-use and actual-use human factors usability studies. The majority of participants rated the tasks required to use the ranibizumab PFS as "Easy" or "Very Easy." Both the simulated-use and actual-use usability studies yielded consistent data, showing that healthcare professionals are able to use the ranibizumab PFS by successfully performing all critical tasks involved in preparing and delivering an intravitreal injection. The simulated-use usability testing was sufficiently realistic and representative of real-world use, and was appropriate and preferred over actual-use usability testing for proper evaluation of the product user interface.LAY ABSTRACT: Ranibizumab is approved in the United States to treat various eye conditions, including neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization. It is administered as an injection into the eye once a month, and is available in a vial from which medication needs to be withdrawn using a standard syringe with a 19-gauge filter needle. The filter needle is then replaced by a smaller gauge needle for the intravitreal injection. The recent U.S. Food and Drug Administration approval of a 0.5 mg ranibizumab prefilled syringe eliminates the need for withdrawing medication from a vial and changing needles prior to use. The studies described in this report assessed the usability of the ranibizumab prefilled syringe by retina specialists and ophthalmic medical personnel in simulated- and actual-use settings. Twelve tasks that included unpacking, preparing, and properly administering the prefilled syringe for intravitreal injection were evaluated by a study assessor. Task performances were evaluated for use errors, close calls, and operational difficulties. Participants successfully performed all the tasks without any critical errors in both simulated-use and actual-use human factors usability studies, and most participants found the syringe to be "Easy" or "Very Easy" to use.


Evaluation of Anatomically Designed Flocked Rectal Swabs for Use with the BioFire FilmArray Gastrointestinal Panel for Detection of Enteric Pathogens in Children Admitted to Hospital with Severe Gastroenteritis.
Diagnosing diarrheal disease is difficult in part due to challenges in obtaining and transporting a bulk stool specimen, particularly in resource-limited settings. We compared the performance of flocked rectal swabs to that of traditional bulk stool samples for enteric pathogen detection using the BioFire FilmArray gastrointestinal panel in children admitted to four hospitals in Botswana with community onset severe gastroenteritis. Of the 117-matched flocked rectal swab/stool pairs, we found no significant difference in pathogen detection rates between the flocked rectal swab samples and traditional bulk stool sampling methods for any bacterial (168 versus 167, respectively), viral (94 versus 92, respectively), or protozoan (18 versus 18, respectively) targets. The combination of flocked rectal swab samples with FilmArray testing allows for the rapid diagnosis of infectious gastroenteritis, facilitating a test-and-treat approach for infections that are life-threatening in many resource-limited settings. The culture recovery rates for bacterial pathogens utilizing this approach need to be assessed.


Correlation of exhaled nitric oxide levels and airway inflammation markers in stable asthmatic patients.
Monitoring of inflammation is an important factor in asthma management. The gold standard for measuring direct airway inflammation is bronchial biopsy specimens taken from proximal airways through a fiberoptic bronchoscope. As a noninvasive procedure, the use of exhaled nitric oxide (FENO) for monitoring airway inflammation has been reported in many studies. The aim of this study was to evaluate the correlation of FENO with direct measurements of airway inflammation in biopsy specimens and pulmonary function tests (PFT). Histopathologic features were observed on bronchial biopsy specimens obtained from nine stable mild-moderate asthmatics. Each subject had measurements of PFT, FENO levels, blood eosinophil count, and bronchoscopy with bronchial biopsies and bronchoalveolar lavage. Five subjects with forced expiratory volume in 1 second >80% had methacholine challenge test. None of the subjects had prior anti-inflammatory therapy for asthma. No correlation was found between PFT, blood eosinophil count, and FENO levels. There was a negative correlation between PC20 and FENO. Though there was no correlation between bronchial biopsy eosinophil, monocyte and lymphocyte counts, and FENO, we found a weak positive correlation between total inflammatory cell count in bronchial biopsies and FENO levels. A negative significant correlation was found between FENO levels and epithelial desquamation (p<0.05, r=-0.7). These results suggest that, FENO levels reflect the increased number of activated inflammatory cells in airways and the negative correlation with epithelial desquamation reflects the role of epithelium in NO syntheses. FENO should not be interpreted as a specific inflammation marker for asthma.


Position paper on mesotherapy.
Mesotherapy is a controversial cosmetic procedure which has received publicity among the lay people, in the internet and in the media. It refers to minimally invasive techniques which consist of the use of intra- or subcutaneous injections containing liquid mixture of compounds (pharmaceutical and homeopathic medications, plant extracts, vitamins and other ingredients) to treat local medical and cosmetic conditions. This position paper has examined the available evidence and finds that acceptable scientific evidence for its effectiveness and safety is lacking. IADVL taskforce, therefore would like to state that the use of this technique remains controversial at present. Further research and well-designed controlled scientific studies are required to substantiate the claims of benefit of this mode of therapy.


From private practice to public policy.
A dentist describes her journey from private practice to legislative assistant. Beginning with work in the ADA's Government Relations Office and then through the American Dental Association's Congressional Fellowship, Dr. Skoulas has now taken a full-time position monitoring and developing legislation for Congressman Edward J. Markey.


HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988-2007).
In the literature, there exists a wide range of human papillomavirus (HPV) DNA prevalence for head and neck squamous cell carcinoma (HNSCC), especially in relation to methods of viral detection and the lesion site. We estimated the pooled prevalence of HPV DNA in biopsies of HNSCC generically grouped versus oral squamous cell carcinoma (OSCC) in relation to the method of viral DNA detection, with the primary end point of verifying if these two variables (specification of tumour site and method of HPV DNA identification) influence the datum on HPV assay. By means of MEDLINE/PubMED/Ovid databases, we selected studies examining paraffin-embedded (PE) biopsies of HNSCC and OSCC. According to the inclusion criteria, 62 studies were analyzed. The following data were abstracted: sample size, HPV DNA prevalence, methods of detection [PCR and in situ hybridization (ISH)] and HPV genotypes. After testing the heterogeneity of the studies by the Cochran Q test, metanalysis was performed using the random effects model. The pooled prevalence of HPV DNA in the overall samples (Sigma: 4852) was 34.5%, in OSCC it was 38.1% and in the not site-specific HNSCC was 24.1%. With regard to the detection method, PCR-based studies reported a higher prevalence rate than ISH-based rates (34.8, versus 32.9%) especially in the OSCC subgroup (OSCC PCR based: 39.9%). These findings support the assumption that a correct distinction of HNSCC by site, together with the use of more sensitive HPV DNA detection methods, should be considered as essential prerogatives in designing future investigations into viral prevalence in head and neck tumors.


Molecular signaling in bioengineered tissue microenvironments.
Biological tissues and organs consist of specialized living cells arrayed within a complex structural and functional framework known generally as the extracellular matrix (ECM). The great diversity observed in the morphology and composition of the ECM contributes enormously to the properties and function of each organ and tissue. For example, the ECM contributes to the rigidity and tensile strength of bone, the resilience of cartilage, the flexibility and hydrostatic strength of blood vessels, and the elasticity of skin. The ECM is also important during growth, development, and wound repair: its own dynamic composition acts as a reservoir for soluble signaling molecules and mediates signals from other sources to migrating, proliferating, and differentiating cells. Artificial three-dimensional substitutes for ECM, called tissue scaffolds, may consist of natural or synthetic polymers or a combination of both. Scaffolds have been used successfully alone and in combination with cells and soluble factors to induce tissue formation or promote tissue repair. Appropriate numbers of properly functioning living cells are central to many tissue-engineering strategies, and significant efforts have been made to identify and propagate pluripotent stem cells and lineage-restricted progenitor cells. The study of these and other living cells in artificial microenvironments, in turn, has led to the identification of signaling events important for their controlled proliferation, proper differentiation, and optimal function.


Opioid mu, delta, and kappa receptor-induced activation of phospholipase C-beta 3 and inhibition of adenylyl cyclase is mediated by Gi2 and G(o) in smooth muscle.
In neurons and transformed cell lines, opioid receptors are coupled to various signaling mechanisms involved in Ca2+ mobilization, including inhibition or activation of Ca2+ channels and phospholipase C-beta (PLC-beta), the enzyme responsible for generation of the Ca2+ mobilizing messenger inositol-1,4,5-trisphosphate [Ins(1,4,5)P3]. In the current study, we used selective PLC-beta and G protein antibodies to identify the PLC-beta isozyme activated by opioid receptors in intestinal smooth muscle and the G proteins to which the PLC-beta isozyme and adenylyl cyclase are coupled. [D-Pen2,D-Pen5]Enkephalin, a delta receptor agonist, stimulated Ins(1,4,5)P3 formation, Ca2+ release, and contraction; inhibited forskolin-stimulated cAMP formation in dispersed muscle cells; and stimulated phosphoinositide hydrolysis in plasma membranes; all of the effects were blocked by pertussis toxin. [D-Pen2,D-Pen5]Enkephalin-stimulated Ins(1,4,5)P3 formation, Ca2+ release, and contraction in permeabilized muscle cells and phosphoinositide hydrolysis in plasma membranes were selectively blocked by G beta antibody and PLC-beta 3 antibody; contractions stimulated by [D-Ala2,N-MePhe4,Gly-ol5]enkephalin, a mu receptor agonist, and U-69,593, a kappa receptor agonist, were also blocked by G beta and PLC-beta 3 antibodies. Inhibition of forskolin-stimulated cAMP formation by delta, mu, and kappa receptor agonists was partially blocked by G alpha i2 and G alpha o antibodies and additively blocked by a combination of the antibodies. The delta, mu, and kappa receptor agonists stimulated the binding of guanosine-5'-O-(3-thio)triphosphate to the alpha subunits of Gi2 and G(o) but not to the alpha subunits of other G proteins. We conclude that opioid mu, delta, and kappa receptors are selectively coupled to Gi2 and G(o) in intestinal smooth muscle. The beta gamma subunits of both G proteins activate PLC-beta 3, thereby stimulating Ins(1,4,5)P3-dependent Ca2+ release and smooth muscle contraction, whereas the alpha subunits inhibit adenylyl cyclase activity.


Triage and management of pericardial effusion.
Pericardial effusion may be detected as an incidental finding during echocardiography or following a diagnostic imaging study for a symptomatic patient. When a pericardial effusion is detected the first step is to assess its size, hemodynamic importance, and possible associated diseases. The more common causes of pericardial effusions include infections (viral, bacterial, especially tuberculosis), cancer, connective tissue diseases, pericardial injury syndromes, metabolic causes (i.e. hypothyroidism), myopericardial and aortic diseases. The relative frequency of different causes depends on the local epidemiology, the hospital setting and the diagnostic protocol that has been adopted. Many cases still remain idiopathic in developed countries, whereas tuberculosis is the dominant cause in developing countries. Specific testing should be performed according to clinical suspicion. The presence of elevated inflammatory markers and other criteria (chest pain, pericardial rubs, ECG changes) suggest pericarditis and management should be directed accordingly. Treatment should be targeted at the etiology as much as possible. Nevertheless, when diagnosis is still unclear, or idiopathic and inflammatory markers are elevated, empiric anti-inflammatory therapy may be worthwhile. A true isolated effusion may not require a specific treatment if the patient is asymptomatic, but large ones have a theoretical risk of progression to cardiac tamponade (up to one-third) if subacute with signs of right-sided collapse, and especially chronic (>3 months). Pericardiocentesis alone may be curative for large effusions but recurrences are also common and pericardiectomy or less invasive options (i.e. pericardial window) should be considered whenever fluid re-accumulates (especially with tamponade), becomes loculated, or biopsy material is required.


Data on the demographics, education, health and infrastructure: Wolaita Zone, Ethiopia.
This data article presents a comprehensive data set about Wolaita Zone (Ethiopia), and the Woredas / Districts within it. The tables cover administrative, demographic, educational, agricultural, transport, and water aspects of the zone. The majority of the data is from 2013/2014, however, a few tables provide trend data over recent years. The evidence shows rapid population growth, significant educational challenges, limitations of health coverage, disparities of agricultural extension service provision and potable water. The data are otherwise not available to researchers and these data sets enable greater contextualization for any on-going or future research within the zone. The data were provided by the Zonal Administration in 2015, and were part of a research project that was approved by the Ethiopian Public Health Institute and supported by the Regional Health Bureau.


Genetic variation associated with cardiovascular risk in autoimmune diseases.
Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD) risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA) on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNFα and IFNγ cytokine pathways). The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity.


Total Parenteral Nutrition Standardization and Electronic Ordering to Reduce Errors: a Quality Improvement Initiative.
Total parenteral nutrition (TPN) provides vital intravenous nutrition for patients who cannot tolerate enteral nutrition but is susceptible to medical errors due to its formulation, ordering, and administrative complexities. At Johns Hopkins All Children's Hospital, 22% of TPN orders required clarification of errors and averaged 10 minutes per order for error correction by pharmacists. Quality improvement methodology improved patient safety by standardizing TPN formulations and incorporating TPN ordering processes into the electronic medical record. A multidisciplinary group of providers developed standardized TPN solutions for neonatal and pediatric patients. Inclusion, exclusion, and discontinuation criteria were defined. The primary outcome measure was reducing TPN ordering error rate, and secondary outcomes were improving TPN ordering and processing time along with reducing blood draws. Through multiple plan-do-study-act cycles, we standardized TPN solutions, incorporated them in the electronic medical record, monitored blood draws, and evaluated resource efficiency. Data were analyzed using chi-square tests of independence and t tests for 2 independent samples. The TPN ordering error rate significantly decreased from baseline of 22% to 3.2% over the final quarter of the study period, χ2 (1, N = 2,467) = 89.13, P < 0.001. Order processing time fell from 10 to 5 minutes by project end. The average number of blood draws decreased significantly from 6.2 (SD = 3.12) blood draws to 4.3 (SD = 2.13) in the last quarter of the study, t (506) = 5.97, P < 0.001. Standardizing TPN and transitioning to electronic ordering effectively and significantly reduced ordering errors and processing time. It also substantially improved resource efficiency by reducing the number of blood draws.