Of pleiotropy and trajectories: Does the TGF-β pathway link childhood asthma and chronic obstructive pulmonary disease?
The study of developmental trajectories is where epigenetics truly shines. The "epi" in epigenetics captures the fact that although epigenetic processes also preside over the maintenance and termination of gene expression, the unfolding and remodeling of chromatin architecture are especially critical to prepare genes for regulated transcription. These properties imply being on a path, a trajectory to events that will occur later thanks to epigenetic programming. Thus epigenetics is about timed and timely events. In this article we discuss epigenetic and genetic evidence from several independent studies of asthma, chronic obstructive pulmonary disease, and lung function, which converge to highlight a potential role of the TGF-β gene pathway in these processes. These results raise the possibility that at least in a subset of subjects, these conditions might be functionally connected in ways that need to be further defined but that likely reflect the uniquely pleiotropic nature of TGF-β pathway genes, particularly their ability to control both lung development and immune responses essential for regulation and inflammation. Further characterization of this pathway in longitudinally phenotyped populations might unmask novel trajectories to lung disease that begin in utero and unfold into old age.


[Prospects of material and technical development of the department of anaesthesia and intensive care].
The author of the article came to conclusion that in view of electronics breakthrough, nanotechnology and genetic engineering development it is necessary to reconsider the system of emergency care, anesthesia and intensive care service on the battlefield, reduction of the influence of pathologic factors and secure evacuation to special treatment department. One of the main criteria is constant improvement of material and technical equipment for heavy rescue. Necessity of dislocation, problems with communications infrastructure, poor medical gas supply are the main problems which cause the necessity of development of special equipment which must be equal characteristics and security level of analogues, used in peace time. The last equipment can not be used by troops for various reasons. Probably, due to the absence mass sanitary loss, reduction of medical service in consequence of material and technical equipment must be proven. It is necessary to emphasize, that the department of anaesthesia and intensive care of the Ministry of Defence of the Russian Federation copes with the tasks of war and peacetime throughout the history.


A novel active mouse model for bullous pemphigoid targeting humanized pathogenic antigen.
Bullous pemphigoid (BP), the most common autoimmune blistering disease, is caused by autoantibodies against type XVII collagen (COL17). To establish an active stable BP animal model that demonstrates the persistent inflammatory skin lesions initiated by the anti-human COL17 Abs, we used COL17-humanized (COL17(m-/-,h+)) mice that we recently produced. First, we generated immunodeficient Rag-2(-/-)/COL17-humanized mice by crossing Rag-2(-/-) mice with COL17-humanized mice. Then, splenocytes from wild-type mice that had been immunized by grafting of human COL17-transgenic mouse skin were transferred into Rag-2(-/-)/COL17-humanized mice. The recipient mice continuously produced anti-human COL17 IgG Abs in vivo and developed blisters and erosions corresponding to clinical, histological, and immunopathological features of BP, although eosinophil infiltration, one of the characteristic histological findings observed in BP patients, was not detected in the recipients. Although the depletion of CD8(+) T cells from the immunized splenocytes was found to produce no effects in the recipients, the depletion of CD4(+) T cells as well as CD45R(+) B cells was found to inhibit the production of anti-human COL17 IgG Abs in the recipients, resulting in no apparent clinical phenotype. Furthermore, we demonstrated that cyclosporin A significantly suppressed the production of anti-human COL17 IgG Abs and prevented the development of the BP phenotype in the treated recipients. Although this model in an immunodeficient mouse does not exactly reproduce the induction mechanism of BP in human patients, this unique experimental system targeting humanized pathogenic Ag allows us to investigate ongoing autoimmune responses to human molecules in experimental animal models.


Semiautomated quantification of β-zone parapapillary atrophy using blue light fundus autofluorescence.
To evaluate the reproducibility of measurements of area of β-zone parapapillary atrophy (β-PPA) using blue laser fundus autofluorescence (FAF) and confocal scanning laser ophthalmoscopy reflectance (CSLO) measurements and to assess agreement between the two imaging modalities. Sixty-five eyes of 45 patients (mean age, 68.2 ± 11.3 years) with established or suspected glaucoma from the Diagnostic Innovations in Glaucoma Study (DIGS) were prospectively included. FAF scans were obtained with the Spectralis HRA+OCT and CSLO reflectance images with the HRTII (both from Heidelberg Engineering, Heidelberg, Germany). Two masked graders independently measured β-PPA area on 3 consecutive scans using the semi-automated BluePeak RegionFinder software (BPRF) and on CSLO reflectance images using the optic disc contour line. Reproducibility of β-PPA area measurements was assessed using intraclass correlation coefficients (ICC). Intragrader reproducibility was 0.997 (95% CI, 0.996-0.998) and 0.995 (95% CI, 0.992-0.996) for grader 1 and 2, respectively, using FAF-BPRF, and by CSLO, it was 0.991 (95% CI, 0.986-0.994) and 0.988 (95% CI, 0.982-0.992). Intergrader agreement (ICC) was 0.53 (95% CI, 0.331-0.685) for FAF-BPRF and 0.404 (95% CI, 0.149-0.601) for CSLO (comparison between ICC, p = 0.368). Agreement (ICC) between the two devices was worse for grader 1 (0.356; 95% CI, 0.129-0.549) than grader 2 (0.856; 95% CI, 0.774-0.910) (p < 0.001). Despite excellent intragrader reproducibility for β-PPA measurements with FAF-BPRF and CSLO, intergrader reproducibility is low to moderate. Measurements of β-PPA area obtained with the two instruments are of moderate agreement and, therefore, are not interchangeable.


Kinetic analysis of a mutational hot spot in the EcoRV restriction endonuclease.
The EcoRV endonuclease contacts the minor groove of DNA through a peptide loop encompassing residues 67-72. This loop adapts to distorted DNA in the specific complex and to regular DNA in the nonspecific complex. Random mutagenesis had previously identified glutamine 69 as the key component of the loop and this study reports on mutants with glutamate (Q69E), lysine (Q69K), or leucine (Q69L) at this position. The mutants bound DNA specifically at the EcoRV recognition site in the presence of Ca2+, in the same manner as wild-type EcoRV. In the absence of divalent metals, Q69K and Q69L showed the same nonspecific binding as native EcoRV while Q69E failed to bind DNA. Glutamate at position 69 presumably repels nonspecific DNA whilst allowing the adaptations to specific DNA. Both Q69E and Q69K had severely impaired DNA cleavage activities, while Q69L had a steady-state k(cat) within an order of magnitude of wild-type EcoRV though its primary product was nicked DNA, in contrast to double strand breaks by wild-type EcoRV. The activity of Q69L required higher concentrations of Mg2+ than the wild-type and showed a sigmoidal dependence upon the Mg2+ concentration, indicating two metal ions per strand scission. Transient kinetics on Q69L gave lower rate constants for phosphodiester hydrolysis than wild-type EcoRV and its reaction also involved a slow conformational change preceding DNA cleavage that had no equivalent with the wild-type. Gln69 in EcoRV thus plays key roles in the adjustments of the protein to varied DNA structures and in the alignment of the catalytic functions for DNA cleavage.


Mitral Valve and Subvalvular Repair for Secondary Mitral Regurgitation: Rationale and Clinical Outcomes of the Papillary Muscle Sling.
Secondary mitral regurgitation (MR) is a common finding in patients with dilated cardiomyopathy, and it is associated with poor outcomes. It is the result of incomplete systolic closure of the mitral valve (MV) as a consequence of left ventricular dilatation, papillary muscle displacement with impaired systolic shortening, and mitral leaflet tethering. MV surgery may be performed in cases of significant secondary MR despite guideline-directed medical therapy. However, MV repair, which is most commonly performed with an undersized ring annuloplasty, is associated with a 30-60% recurrence of moderate or greater MR at mid-term follow-up. To improve MV repair durability, several adjunctive subvalvular procedures have been proposed, one of which is the addition of papillary muscle approximation utilizing a papillary muscle sling. Recent studies comparing the outcomes of a conventional undersized ring annuloplasty with a MV repair utilizing a papillary muscle sling have reported a significant reduction in recurrent moderate or severe MR, greater left ventricular reverse remodeling, and improved MV apparatus geometry with the addition of the papillary muscle sling. We present a comprehensive review of the pathophysiology of secondary MR, and the rationale and clinical outcomes of MV repair with papillary muscle sling placement for the treatment of secondary MR.


Mammalian hibernation and regulation of lipid metabolism: a focus on non-coding RNAs.
Numerous species will confront severe environmental conditions by undergoing significant metabolic rate reduction. Mammalian hibernation is one such natural model of hypometabolism. Hibernators experience considerable physiological, metabolic, and molecular changes to survive the harsh challenges associated with winter. Whether as fuel source or as key signaling molecules, lipids are of primary importance for a successful bout of hibernation and their careful regulation throughout this process is essential. In recent years, a plethora of non-coding RNAs has emerged as potential regulators of targets implicated in lipid metabolism in diverse models. In this review, we introduce the general characteristics associated with mammalian hibernation, present the importance of lipid metabolism prior to and during hibernation, as well as discuss the potential relevance of non-coding RNAs such as miRNAs and lncRNAs during this process.


The combined effect of frontal plane tibiofemoral knee angle and meniscectomy on the cartilage contact stresses and strains.
Abnormal tibiofemoral alignment can create loading conditions at the knee that may lead to the initiation and progression of knee osteoarthritis (OA). The degenerative changes of the articular cartilage may occur earlier and with greater severity in individuals with abnormal frontal plane tibiofemoral alignment who undergo a partial or total meniscectomy. In this investigation, subject specific 3D finite element knee models were created from magnetic resonance images of two female subjects to study the combined effect of frontal plane tibiofemoral alignment and total and partial meniscectomy on the stress and strain at the knee cartilage. Different amounts of medial and lateral meniscectomies were modeled and subject specific loading conditions were determined from motion analysis and force platform data during single-leg support. The results showed that the maximum stresses and strains occurred on the medial tibial cartilage after medial meniscectomy but a greater percentage change in the contact stresses and strains occurred in the lateral cartilage after lateral meniscectomy for both subjects due to the resultant greater load bearing role of the lateral meniscus. The results indicate that individual's frontal plane knee alignment and their unique local force distribution between the cartilage and meniscus play an important role in the biomechanical effects of total and partial meniscectomy.


[Effects of cernitin pollen extract (CN-009) on the isolated bladder smooth muscles and the intravesical pressure].
Cernitin pollen extract (CN-009), extract from several pollen species, has been used for urinary dysfunction. As its mode of action has not been clarified, we investigated the action of CN-009 on the isolated bladder smooth muscles of rats, guinea pigs and cats and the intravesical pressure in female rats. CN-009 contracted isolated detrusor muscles of rats, guinea pigs and cats in a concentration-dependent manner. In the guinea pig detrusor muscle, the contractile effect of CN-009 was depressed by atropine, diphenhydramine and increased by cimetidine. In the rat detrusor muscle, the CN-009-induced contraction was depressed by atropine. In adult rats (11-23 weeks old) and aged rats (2 years old), CN-009 showed a dose-dependent increase of intravesical pressure to the same extent in spite of the fact that the aged rats had a lower responsiveness to acetylcholine. In adult rats, the CN-009-induced increase of intravesical pressure was reduced completely by atropine and partly reduced by phentolamine and guanethidine. Three weeks consecutive oral administration of CN-009 tended to increase the basal intravesical pressure and tended to elevate the isoproterenol-induced decrease and serotonin-induced increase in the intravesical pressure. These results suggest that CN-009 contracts the detrusor muscle, a process that is mainly mediated by muscarinic receptor activation. The contraction induced by CN-009 of detrusor muscle causes the increase of intravesical pressure.


Characterization of MHC class I restricted cytotoxic T cell responses to tax in HTLV-1 infected patients with neurologic disease.
To understand the nature of the cytotoxic T cell response generated in human T lymphotropic virus type 1 (HTLV-1)-infected patients with HTLV-1-associated myelopathy/tropical spastic paraparesis, we cloned CTL from the peripheral blood and cerebrospinal fluid from patients with neurologic diseases and demonstrated the presence of HLA-A2, A3, and B14 restricted responses to the HTLV-1 p40x (tax) protein. We identified the minimal amino acid residues within the epitopes required for binding and recognition by HLA-A2- and B14-restricted CTL, identified the critical residues within the peptide sequence defining the HLA-A2-restricted response, and demonstrated that CTL can lyse T cells infected with HTLV-1. This study shows that the CTL response to HTLV-1 tax in patients with neurologic diseases is heterogenous in nature and is not confined to patients of a single HLA haplotype or to a specific region of the tax protein.


Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT.
The Notch signaling pathway acts in both physiological and pathological conditions, including embryonic development and tumorigenesis. In cancer progression, diverse mechanisms are involved in Notch-mediated biological responses, including angiogenesis and epithelial-mesenchymal-transition (EMT). During EMT, the activation of cellular programs facilitated by transcriptional repressors results in epithelial cells losing their differentiated features, like cell–cell adhesion and apical–basal polarity, whereas they gain motility. As it concerns cancer epithelial cells, EMT may be consequent to the evolution of genetic/epigenetic instability, or triggered by factors that can act within the tumor microenvironment. Following a description of the Notch signaling pathway and its major regulatory nodes, we focus on studies that have given insights into the functional interaction between Notch signaling and either hypoxia or estrogen in breast cancer cells, with a particular focus on EMT. Furthermore, we describe the role of hypoxia signaling in breast cancer cells and discuss recent evidence regarding a functional interaction between HIF-1α and GPER in both breast cancer cells and cancer-associated fibroblasts (CAFs). On the basis of these studies, we propose that a functional network between HIF-1α, GPER and Notch may integrate tumor microenvironmental cues to induce robust EMT in cancer cells. Further investigations are required in order to better understand how hypoxia and estrogen signaling may converge on Notch-mediated EMT within the context of the stroma and tumor cells interaction. However, the data discussed here may anticipate the potential benefits of further pharmacological strategies targeting breast cancer progression.


A new taekwondo-specific field test for estimating aerobic power, anaerobic fitness, and agility performance.
The present study aimed to propose a new multidimensional taekwondo-specific test to estimate aerobic power, anaerobic fitness, and agility. Out of sixty-five male volunteers, forty-six, forty-eight, and fifty athletes (18-35 years; black- and red-belt level) were included in the final analysis for aerobic, anaerobic, and agility assessments, respectively. Maximum oxygen uptake (VO2max, using a graded exercise test on a treadmill), anaerobic power (using the 30-s Wingate anaerobic test, WAnT), and agility performance (using the agility T-Test) were measured via non-specific laboratory and field tests across a two-week period. The taekwondo-specific aerobic-anaerobic-agility (TAAA) test comprised six 20-s intervals of shuttle sprints over a 4-m distance, and the execution of roundhouse kicks alternating the legs at the end of each distance, with 10-s rest intervals between the sets. The multiple linear regression revealed that the difference between heart rate (HR) after and 1 minute after the TAAA test (p < 0.001), and body mass index (BMI; p = 0.006) were significant to estimate VO2max. Likewise, there was a very large (R = 0.79) and large (R = 0.55) correlation between the average and maximum number of kicks performed in the TAAA test and the WAnT mean and peak power, respectively (p < 0.001). Moreover, a linear relationship was found between the T-Test and agility performance acquired in the TAAA test (R = 0.74; p < 0.001). The TAAA test can be considered a valid simple tool for monitoring VO2max, anaerobic fitness, and agility in male taekwondo athletes.


Use of stable isotopes and mathematical modelling to investigate human mineral metabolism.
Individuals have varying needs for minerals that are dependent, amongst other things, on their lifestyle, age and genetic makeup. Knowledge of exact individual nutritional requirements should lead to better health, increased quality of life and reduced need for expensive medical care. Bioavailability, nutrient-gene interactions and whole-body metabolism all need to be investigated further if we are to progress towards the goal of defining optimal health and nutritional status. The discussion which follows will critically review the latest developments in the area of metabolism for several of the minerals that are essential for human health: Ca, Zn, Cu and Se. Stable-isotope tracers and mathematical modelling are some of the tools being used to facilitate the greater understanding in uptake, utilisation and excretion of these minerals. Stable isotopes, administered in physiological doses, present little or no risk to volunteers and allow metabolic studies to be carried out in vulnerable population groups such as children and pregnant women. Intrinsic labelling of foodstuffs ensures that the tracer and the native mineral will behave similarly once inside the body. Advances in computing power and software dedicated to solving nutritional problems have made it possible for investigators to use mathematical modelling in their experimental work. Mineral metabolism is ideally suited to a form of modelling known as compartmental analysis, which allows rates of mineral transferand sizes of mineral stores to be calculated accurately without the need for invasive sampling of body tissues.


Stochastic kinetics on networks: when slow is fast.
Most chemical and biological processes can be viewed as reaction networks in which different pathways often compete kinetically for transformation of substrates into products. An enzymatic process is an example of such phenomena when biological catalysts create new routes for chemical reactions to proceed. It is typically assumed that the general process of product formation is governed by the pathway with the fastest kinetics at all time scales. In contrast to the expectation, here we show theoretically that at time scales sufficiently short, reactions are predominantly determined by the shortest pathway (in the number of intermediate states), regardless of the average turnover time associated with each pathway. This universal phenomenon is demonstrated by an explicit calculation for a system with two competing reversible (or irreversible) pathways. The time scales that characterize this regime and its relevance for single-molecule experimental studies are also discussed.


Propulsion of a fin whale (Balaenoptera physalus): why the fin whale is a fast swimmer.
Measurements of an immature fin whale (Balaenoptera physalus), which died as a result of entrapment in fishing gear near Frenchmans Cove, Newfoundland (47 degrees 9' N, 55 degrees 25' W), were made to obtain estimates of volume and surface area of the animal. Detailed measurements of the flukes, both planform and sections, were also obtained. A strip theory was developed to calculate the hydrodynamic performance of the whale's flukes as an oscillating propeller. This method is based on linear, two-dimensional, small-amplitude, unsteady hydrofoil theory with correction factors used to account for the effects of finite span and finite amplitude motion. These correction factors were developed from theoretical results of large-amplitude heaving motion and unsteady lifting-surface theory. A model that makes an estimate of the effects of viscous flow on propeller performance was superimposed on the potential-flow results. This model estimates the drag of the hydrofoil sections by assuming that the drag is similar to that of a hydrofoil section in steady flow. The performance characteristics of the flukes of the fin whale were estimated by using this method. The effects of the different correction factors, and of the frictional drag of the fluke sections, are emphasized. Frictional effects in particular were found to reduce the hydrodynamic efficiency of the flukes significantly. The results are discussed and compared with the known characteristics of fin-whale swimming.


The risk factors of CVA in Jordan.
This study aimed to identify the main risk factors of cerebrovascular accident (CVA) in Jordan. Identification of risk factors may help to reduce the incidence of CVA. A form was prepared for data collection which consisted of two parts to gather biodata and the incidence of risk factors. A sample of 200 patients with CVA (60% men) were randomly selected from various areas of Jordan. An age, region distribution, and gender-matched sample were selected to serve as control. Hypertension in the experimental group (66%) was significantly higher than the control group (32%) p < 0.001. Half of the subjects with stroke had diabetes compared to 22% of the control group (p < 0.001). Cardiovascular diseases were found in 29% of subjects with CVA compared to 14% in the control group (p < 0.001). About 27% of the CVA group had hyperlipidemia in comparison to 13% in the controls (p < 0.002). Smokers represented 54% of the experimental group compared to 30% of the control group (p < 0.05). An important finding in the present study was that about half of the selected subjects with strokes were under the age of 60 years. In conclusion, hypertension, diabetes, cardiovascular diseases, hyperlipidemia, and smoking are risk factors for CVA in Jordan.


Perceived Stress in Adults Aged 65 to 90: Relations to Facets of Time Perspective and COMT Val158Met Polymorphism.
This study examined the relation between perceived stress and time perspective (views of past, present, future) in a population-based sample of older adults (65-90 years, N = 340). The Perceived Questionnaire (PSQ index) was used to measure stress and the Swedish version of the Zimbardo Time Perspective Inventory (S-ZTPI) was used to operationalize time perspective. Unlike the original inventory, S-ZTPI separates positive and negative aspects of a future time perspective and we hypothesized that the Future Negative (FN) scale would be important to account for variations in stress. Additionally, associations with Catechol-O-methyltransferase (COMT) Val158Met polymorphism were examined, motivated by prior associations of this single nucleotide polymorphism (SNP) with stress (or "anxiety") related personality traits. In line with the hypotheses, FN was the strongest predictor of PSQ index scores in multiple regression analyses. In a related vein, the dichotomization of the unitary Future scale increased the association between PSQ scores and a measure of deviations from a balanced time perspective, i.e., the difference between a proposed optimal and observed ZTPI profile. Finally, higher levels of stress as well as higher scores on FN were observed in COMT Val/Val carriers, at least among men. This suggests a shared dopaminergic genetic influence on these variables. Collectively, the results demonstrate that perceived stress is closely linked to time perspective and highlight the need to take negative aspects of a future temporal orientation into account to understand this relation.


Biomechanical analysis of the effectiveness of in-line skating wrist guards for preventing wrist fractures.
The purpose of this investigation was to determine the effectiveness of commercially available wrist guards in preventing wrist fractures. Forty arms were harvested from 20 cadaveric specimens. The forearms from each cadaver, one with a wrist guard and one without a wrist guard, were then fractured using an instron Servohydraulic Material Testing System. The group of forearms tested to failure without wrist guards failed at an average force of 2245 N, while the group tested with wrist guards fractured at an average force of 2285 N, revealing no statistical difference. Similarly, observed fracture patterns were not noted to be different in the two groups. The in-line skating wrist guards tested were not effective in preventing wrist fractures under the experimental conditions of our study.


Anaerobic lignocellulolytic microbial consortium derived from termite gut: enrichment, lignocellulose degradation and community dynamics.
Lignocellulose is the most abundant renewable carbon resource that can be used for biofuels and commodity chemicals production. The ability of complex microbial communities present in natural environments that are specialized in biomass deconstruction can be exploited to develop lignocellulose bioconversion processes. Termites are among the most abundant insects on earth and play an important role in lignocellulose decomposition. Although their digestive microbiome is recognized as a potential reservoir of microorganisms producing lignocellulolytic enzymes, the potential to enrich and maintain the lignocellulolytic activity of microbial consortia derived from termite gut useful for lignocellulose biorefinery has not been assessed. Here, we assessed the possibility of enriching a microbial consortium from termite gut and maintaining its lignocellulose degradation ability in controlled anaerobic bioreactors. We enriched a termite gut-derived consortium able to transform lignocellulose into carboxylates under anaerobic conditions. To assess the impact of substrate natural microbiome on the enrichment and the maintenance of termite gut microbiome, the enrichment process was performed using both sterilized and non-sterilized straw. The enrichment process was carried out in bioreactors operating under industrially relevant aseptic conditions. Two termite gut-derived microbial consortia were obtained from Nasutitermes ephratae by sequential batch culture on raw wheat straw as the sole carbon source. Analysis of substrate loss, carboxylate production and microbial diversity showed that regardless of the substrate sterility, the diversity of communities selected by the enrichment process strongly changed compared to that observed in the termite gut. Nevertheless, the community obtained on sterile straw displayed higher lignocellulose degradation capacity; it showed a high xylanase activity and an initial preference for hemicellulose. This study demonstrates that it is possible to enrich and maintain a microbial consortium derived from termite gut microbiome in controlled anaerobic bioreactors, producing useful carboxylates from raw biomass. Our results suggest that the microbial community is shaped both by the substrate and the conditions that prevail during enrichment. However, when aseptic conditions are applied, it is also affected by the biotic pressure exerted by microorganisms naturally present in the substrate and in the surrounding environment. Besides the efficient lignocellulolytic consortium enriched in this study, our results revealed high levels of xylanase activity that can now be further explored for enzyme identification and overexpression for biorefinery purposes.


Incidence density of hyperuricemia and association between metabolism-related predisposing risk factors and serum urate in Chinese adults: a cohort study.
Evidence regarding the association between metabolism-related indicators and serum urate (SU) is limited. We aimed to obtain the incidence density of hyperuricemia and to explore the association between metabolism-related predisposing risk factors and SU. A total of 48,979 Chinese adults from the Beijing Physical Examination Center were included in the study. The partial least squares path model was used to explore the relationship between SU and metabolism-related risk factors. The generalized additive model was used for smooth curve fitting, showing the sex-specific associations of SU at follow-up with baseline fasting blood glucose (FBG) concentrations and age. The incidence density of hyperuricemia was 78/1000 person-years. Baseline SU, age, sex, obesity, FBG, and lipid metabolism were significantly associated with SU at follow-up (all P values <0.05). Non-linear relationships were found between the baseline FBG concentrations and SU at follow-up, while U-shaped associations were observed between baseline age and SU at follow-up. The SU concentration is associated with several metabolism-related risk factors such as obesity and FBG. Recognition of these associations will aid in a deeper understanding of the multifaceted nature of SU regulation.


Effect of Specific Over Nonspecific VR-Based Rehabilitation on Poststroke Motor Recovery: A Systematic Meta-analysis.
Despite the rise of virtual reality (VR)-based interventions in stroke rehabilitation over the past decade, no consensus has been reached on its efficacy. This ostensibly puzzling outcome might not be that surprising given that VR is intrinsically neutral to its use-that is, an intervention is effective because of its ability to mobilize recovery mechanisms, not its technology. As VR systems specifically built for rehabilitation might capitalize better on the advantages of technology to implement neuroscientifically grounded protocols, they might be more effective than those designed for recreational gaming. We evaluate the efficacy of specific VR (SVR) and nonspecific VR (NSVR) systems for rehabilitating upper-limb function and activity after stroke. We conducted a systematic search for randomized controlled trials with adult stroke patients to analyze the effect of SVR or NSVR systems versus conventional therapy (CT). We identified 30 studies including 1473 patients. SVR showed a significant impact on body function (standardized mean difference [SMD] = 0.23; 95% CI = 0.10 to 0.36; P = .0007) versus CT, whereas NSVR did not (SMD = 0.16; 95% CI = -0.14 to 0.47; P = .30). This result was replicated in activity measures. Our results suggest that SVR systems are more beneficial than CT for upper-limb recovery, whereas NSVR systems are not. Additionally, we identified 6 principles of neurorehabilitation that are shared across SVR systems and are possibly responsible for their positive effect. These findings may disambiguate the contradictory results found in the current literature.


Antimicrobial effect of dried koruk (Vitis vinifera L.) pomace against food-borne pathogens inoculated in kofte.
This study aimed to investigate the antimicrobial effects of various concentrations of dried koruk pomace (1%, 1.5%, and 2%) used in kofte formulations. To detect the inactivation effect of dried koruk pomace on food-borne pathogens, kofte samples were separately inoculated with Escherichia coli O157:H7, Listeria monocytogenes, and Salmonella Typhimurium at high and low levels. During the storage period, E. coli O157:H7, L. monocytogenes, and S. Typhimurium counts of the samples inoculated with high levels were decreased in the range of 1.1-1.3 log CFU/g, 0.1-0.2 log CFU/g and 1.1-1.2 log CFU/g, respectively. When low inoculum levels were used, E. coli O157:H7 and S. Typhimurium counts of the samples were reduced to an undetectable level at the beginning and after 2 months of storage, respectively. Although L. monocytogenes counts of the samples were reduced to an undetectable level immediately, the counts were increased during storage till the end of the fifth month. The results indicated that dried koruk pomace was more effective in eliminating E. coli O157:H7 and S. Typhimurium than L. monocytogenes inoculated in kofte. The results suggest that using dried koruk pomace in kofte formulations is an effective method to improve the safety of the products, especially when low levels of contamination occur.


SCS: cell segmentation for high-resolution spatial transcriptomics.
Spatial transcriptomics promises to greatly improve our understanding of tissue organization and cell-cell interactions. While most current platforms for spatial transcriptomics only offer multi-cellular resolution, with 10-15 cells per spot, recent technologies provide a much denser spot placement leading to subcellular resolution. A key challenge for these newer methods is cell segmentation and the assignment of spots to cells. Traditional image-based segmentation methods are limited and do not make full use of the information profiled by spatial transcriptomics. Here we present subcellular spatial transcriptomics cell segmentation (SCS), which combines imaging data with sequencing data to improve cell segmentation accuracy. SCS assigns spots to cells by adaptively learning the position of each spot relative to the center of its cell using a transformer neural network. SCS was tested on two new subcellular spatial transcriptomics technologies and outperformed traditional image-based segmentation methods. SCS achieved better accuracy, identified more cells and provided more realistic cell size estimation. Subcellular analysis of RNAs using SCS spot assignments provides information on RNA localization and further supports the segmentation results.


Electrical interactions between a rabbit atrial cell and a nodal cell model.
Atrial activation involves interactions between cells with automaticity and slow-response action potentials with cells that are intrinsically quiescent with fast-response action potentials. Understanding normal and abnormal atrial activity requires an understanding of this process. We studied interactions of a cell with spontaneous activity, represented by a "real-time" simulation of a model of the rabbit sinoatrial (SA) node cell, simultaneously being electrically coupled via our "coupling clamp" circuit to a real, isolated atrial myocyte with variations in coupling conductance (Gc) or stimulus frequency. The atrial cells were able to be driven at a regular rate by a single SA node model (SAN model) cell. Critical Gc for entrainment of the SAN model cell to a nonstimulated atrial cell was 0.55 +/- 0.05 nS (n = 7), and the critical Gc that allowed entrainment when the atrial cell was directly paced at a basic cycle length of 300 ms was 0.32 +/- 0.01 nS (n = 7). For each atrial cell we found periodic phenomena of synchronization other than 1:1 entrainment when Gc was between 0.1 and 0.3 nS, below the value required for frequency entrainment, when the atrial cell was directly driven at a basic cycle length of either 300 or 600 ms. In conclusion, the high input resistance of the atrial cells allows successful entrainment of nodal and atrial cells at low values of Gc, but further uncoupling produces arrhythmic interactions.


Molecular evidence for an extinct parent of the tetraploid species Microseris acuminata and M. campestris (Asteraceae, Lactuceae).
To determine the origin of the tetraploid annuals Microseris campestris and M. acuminata, chloroplast RFLP, RAPD and ITS sequence variability among nine populations of the two polyploids and 14 populations of the diploid annuals M. elegans and M. douglasii have been surveyed. Previously described variable chloroplast restriction sites infer M. douglasii as the possible maternal parent of both tetraploid species. However, the chloroplast genome typical for M. douglasii has now also been found in some plants of M. elegans. RAPD analysis revealed 172 polymorphic DNA markers that defined all four species as genetically distinct groups, but demonstrated closer associations between M. douglasii and M. acuminata, and between M. elegans and M. campestris. Sequencing of the ITS-1 and ITS-2 region yielded 73 phylogenetically informative sites. Thirty basepair mutations separated the annual Microseris species from the outgroup, Uropappus lindleyi. The putative interspecific allotetraploid M. campestris contained only one type ITS sequence that, on the basis of eight synapomorphic substitutions was derived from M. elegans. The single ITS of M. acuminata shares six common sites with M. douglasii. Surprisingly, six sites were synapomorphic for the two tetraploids, M. campestris and M. acuminata, suggesting recombination within the ITS of both species with that of a common, now extinct, parental taxon, possibly the donor of the M. douglasii type chloroplasts found in both tetraploids. These results confirm the interpretation of M. campestris as derived from M. douglasii (extinct population) and M. elegans, and resolve the unknown origin of M. acuminata as an intraspecific hybrid between two very distinct populations of M. douglasii, one of them the same extinct M. douglasii form that contributes to M. campestris.


Sambar, an Indian Dish Prevents the Development of Dimethyl Hydrazine-Induced Colon Cancer: A Preclinical Study.
Colon cancer (CC) is the third commonly diagnosed cancer and the second leading cause of mortality in the US when compared to India where prevalence is less. Possible reason could be the vegetarian diet comprising spices used in curry powders. Researchers believe that 70% of the cases are associated with diet. Spices have inherited a rich tradition for their flavor and medicinal properties. Researchers have been oriented towards spices present in food items for their antitumorigenic properties. We investigated the effects of sambar as a preventive measure for 1,2-dimethyl hydrazine (DMH)-induced CC in Wistar albino rats. The animals were divided into three groups (n = 6) namely control, DMH, and sambar. At the end of the experimental period, the animals were killed using anesthesia and the colons and livers were examined. All the treatment groups exhibited a significant change in the number of aberrant crypt foci (ACF). Sambar group showed a significant change in the colonic GSH when compared to both normal and DMH groups. A significant reduction in the liver GSH was noted in the sambar group. Only sambar group showed a significant change in the liver catalase levels when compared to DMH. There was a significant reduction in the colonic nitrite in the sambar-treated group; 2.94 ± 0.29 when compared to DMH control at 8.09 ± 1.32. On the contrary, a significant rise in the liver nitrite levels was observed in the sambar-treated rats. Sambar may prevent the risk of CC when consumed in dietary proportions. Consumption of sambar significantly reduced aberrant crypt foci in DMH-induced colon cancer modelSambar treatment prevented DMH-induced oxidative changes in the colonic tissue, indicating its antioxidant roleSambar comprises a variety of spices that exhibited both pro- and antioxidant properties in different tissues, leading to its overall beneficial effect in this model. Abbreviations used: ACF: aberrant crypt foci, CC: colon cancer, DMH: 1,2-dimethyl hydrazine, GSH: glutathione, IL-6: Interleukin-6, TNF-α: Tumor necrosis factor-alpha.


Association of Poorer Hearing With Longitudinal Change in Cerebral White Matter Microstructure.
There is a dearth of studies that examine the association between poorer hearing and change in cerebral white matter (WM) microstructure. To examine the association of poorer hearing with baseline and change in WM microstructure among older adults. This was a prospective cohort study that evaluated speech-in-noise, pure-tone audiometry, and WM microstructure, as measured by mean diffusivity (MD) and fractional anisotropy (FA), both of which were evaluated by diffusion tensor imaging (DTI) in 17 WM regions. Data were collected between October 2012 and December 2018 and analyzed between March 2019 and August 2019 with a mean follow-up time of 1.7 years. The study evaluated responses to the Baltimore Longitudinal Study of Aging among 356 cognitively normal adults who had at least 1 hearing assessment and DTI session. Excluded were those with baseline cognitive impairment, stroke, head injuries, Parkinson disease, and/or bipolar disorder. Peripheral auditory function was measured by pure-tone average in the better-hearing ear. Central auditory function was measured by signal-to-noise ratio score from a speech-in-noise task and adjusted by pure-tone average. Linear mixed-effects models with random intercepts and slopes were used to examine the association of poorer peripheral and central auditory function with baseline and longitudinal DTI metrics in 17 WM regions, adjusting for baseline characteristics (age, sex, race, hypertension, elevated total cholesterol, and obesity). Of 356 cognitively normal adults included in the study, the mean (SD) age was 73.5 (8.8) years, and 204 (57.3%) were women. There were no baseline associations between hearing and DTI measures. Longitudinally, poorer peripheral hearing was associated with increases in MD in the inferior fronto-occipital fasciculus (β = 0.025; 95% CI, 0.008-0.042) and the body (β = 0.050; 95% CI, 0.015-0.085) of the corpus callosum, but there were no associations of peripheral hearing with FA changes in these tracts. Poorer central auditory function was associated with longitudinal MD increases (β = 0.031; 95% CI, 0.010-0.052) and FA declines (β = -1.624; 95% CI, -2.511 to -0.738) in the uncinate fasciculus. Findings of this cohort study suggest that poorer hearing is related to change in integrity of specific WM regions involved with auditory processing.


Changing renal blood flow following sodium nitroprusside in patients undergoing nephrolithotomy.
During nephrolithotomy in 23 adult patients under sodium thiopental-N2O-O2-fentanyl anesthesia, renal blood flow to one kidney was studied. Muscle relaxation was obtained with pancuronium, and renal blood flow (RBF) was measured with an electromagnetic flow probe. Percutaneous arterial pressures were also recorded. Administration of sodium nitroprusside caused a decrease in RBF in all patients when mean arterial pressure (MAP) was reduced approximately 44 percent below baseline. Patients whose initial RBF was below 300 ml/min showed greater falls in RBF with hypotension. Changes in renal vascular resistance (MAP/RBF) was found to be markedly higher in the "low-flow" group. As expected, the low-flow group started with a higher renal vascular resistance. From these observations, it is felt that more concern should be exercised when planning deliberate hypotension with nitroprusside, especially in patients with decreased renal function.


Editorial Perspective: Medical body modification in youth with gender dysphoria or body dysmorphic disorder - is current practice coherent and evidence-based?
In recent decades, there has been a steady increase in the number of people, including adolescents, undergoing medical body modification (MBM) to alter their physically healthy bodies in invasive and nearly irreversible ways through medical treatment (e.g. surgery). While MBM is often recommended for youth with persisting gender dysphoria (GD), in body dysmorphic disorder (BDD) it has been considered contraindicated. Here, we outline the current controversies surrounding MBM practice and recommendations in adolescents with GD versus those with BDD in order to better understand under what circumstances we may or may not support adolescents who want to change their bodies medically and often irreversibly. We compare the two disorders in terms of the overlap and uniqueness of their behavioural and psychological features. In doing so, we discuss limitations of the existing (often low-quality) evidence for and against MBM in young patients. We conclude that the currently available evidence is too preliminary and far from conclusive to make any robust recommendations in terms of benefits and harms of MBM in youth with persisting GD or BDD. However, we strongly recommend further urgent scientific discussions and systematic research efforts into more robust evaluations and the identification of more precise psychological characteristics that may serve as decision criteria for or against MBM - particularly in those adolescents who did not respond to non-MBM, that is, psychiatric/psychological treatment and psychosocial support, if available at all. This will greatly benefit youth healthcare professionals in their challenging clinical practice of making decisions regarding MBM today and in the future.


[Pancreatic cancer that was diagnosed two years after palliative treatment].
Pancreatic cancer is an aggressive neoplasm, with poor prognosis and survival. As most patients with pancreatic cancer are diagnosed at an advanced stage, the objective of mostly treatment is palliative. Predisposing medical conditions for the development of pancreatic cancer include chronic pancreatitis. The link between the two pathologies is supported in that pancreatic inflammation may play a role in the early development of pancreatic malignancy. The difficulties in discriminating between chronic pancreatitis and adenocarcinoma in the early state, using currently employed diagnosis imaging and tumour marker analysis, result in poor sensitivity and specificity in the diagnosis. We report one case suggestive of pancreatic cancer that was diagnosed two years after palliative treatment.


Metabolite profiling of maize kernels--genetic modification versus environmental influence.
A metabolite profiling approach based on gas chromatography-mass spectrometry (GC-MS) was applied to investigate the metabolite profiles of genetically modified (GM) Bt-maize (DKC78-15B, TXP 138F) and Roundup Ready-maize (DKC78-35R). For the comparative investigation of the impact of genetic modification versus environmental influence on the metabolite profiles, GM maize was grown together with the non-GM near-isogenic comparators under different environmental conditions, including several growing locations and seasons in Germany and South Africa. Analyses of variance (ANOVA) revealed significant differences between GM and non-GM maize grown in Germany and South Africa. For the factor genotype, 4 and 3%, respectively, of the total number of peaks detected by GC-MS showed statistically significant differences (p < 0.01) in peak heights as compared to the respective isogenic lines. However, ANOVA for the factor environment (growing location, season) revealed higher numbers of significant differences (p < 0.01) between the GM and the non-GM maize grown in Germany (42%) and South Africa (10%), respectively. This indicates that the majority of differences observed are related to natural variability rather than to the genetic modifications. In addition, multivariate data assessment by means of principal component analysis revealed that environmental factors, that is, growing locations and seasons, were dominant parameters driving the variability of the maize metabolite profiles.


Evaluating the daily life of child and adolescent psychiatric outpatients during temporary school closure over COVID-19 pandemic: A single-center case-control study in Japan.
This study evaluated the clinical characteristics of mental health of child and adolescent psychiatric patients during temporary school closure throughout the coronavirus 2019 (COVID-19) pandemic in Japan using the Questionnaire - Children with Difficulties (QCD) and other useful psychological rating scales. The participants were those who visited the Department of Child and Adolescent Psychiatry, Kohnodai Hospital. From those 1,463 participants, case and control groups were selected: 92 patients who visited the hospital during the temporary school closure from March 2020 to May 2020 (case group) and randomly sampled sex- and age-matched 92 patients during the pre-COVID period from April 2017 to March 2020 (control group). QCD is a parent-assessed questionnaire designed to evaluate the difficulties of children along the course of a day, right from waking up in the morning to retiring to bed at night. Lower scores indicate stronger difficulties. QCD scores were compared between the two groups in each of the following age groups: elementary school (6-12 years of age) and junior high school (12-15 years of age). In elementary school students, scores "during school" of QCD indicating functioning or disabilities during school hours were 3.31 ± 2.52 and 4.52 ± 2.33 in case group and control group, respectively (p < 0.05). In junior high school students, scores "Attention-Deficit Hyperactivity Disorder Rating Scale (ADHD-RS)" indicating ADHD symptoms were 16.78 ± 12.69 and 11.80 ± 10.40 in case group and control group, respectively (p < 0.05). The findings suggest that the closure of schools due to the pandemic might worsen difficulties among elementary school patients, and hyperactivity and impulsivity might increase among junior high school patients. The long-term impact of stress caused by school closure on child and adolescent psychiatric patients needs to be investigated in the future.


Concentration of transferrin receptor in human placental coated vesicles.
Coated vesicles were purified from human placenta by sedimentation, isopycnic centrifugation, and gel filtration. Quantitative Western blotting of the endogenous transferrin receptor (tfR) demonstrated the presence, on average, of roughly one receptor per vesicle. TfR appeared undersaturated with transferrin. After solubilizing vesicles in nonionic detergent, we looked for evidence of tfR interactions with other proteins. Solubilized tfR had an unexpectedly high mobility by gel filtration, apparently resulting from its self-association. This property was not seen in purified tfR or in tfR from a different cell fraction. The tfR complexes, though noncovalent, were largely resistant to conditions that disassemble coat proteins, and they did not appear to contain any other protein species.


Effects of polycystic ovary syndrome on health-related quality of life.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5-10% of women of reproductive age. The health risks associated with PCOS include infertility, diabetes, metabolic syndrome and endometrial cancer. In this article, we review the tools used to assess health-related quality of life (HRQL) and the current state of knowledge of the effects of PCOS on HRQL in adult women and adolescent girls. A significant body of evidence consistently demonstrates that PCOS has a negative impact on women's HRQL. This impact does not necessarily correlate with clinical measures of disease severity. There is evidence that the effect on HRQL may be mediated by obesity, infertility concerns and menstrual dysfunction. Cross-cultural studies suggest that the effect of PCOS on the HRQL of an individual patient may be specific to the perception, values and culture of that patient.


Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease.
New dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as new potent drugs that may simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting the beta-amyloid (A beta) peptide aggregation through binding to both catalytic and peripheral sites of the enzyme. Particularly, compounds 5 and 6 emerged as the most potent heterodimers reported so far, displaying IC50 values for AChE inhibition of 20 and 60 pM, respectively. More importantly, these dual AChE inhibitors inhibit the AChE-induced A beta peptide aggregation with IC50 values 1 order of magnitude lower than that of propidium, thus being the most potent derivatives with this activity reported up to date. We therefore conclude that these compounds are very promising disease-modifying agents for the treatment of Alzheimer's disease (AD).


Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits.
Subclinical hypothyroidism (SCH) is defined as elevated thyroid stimulating hormone (TSH) with normal levels of free triiodothyronine (FT3) and free thyroxine (FT4). SCH is further classified into a milder condition with TSH levels between 4.0 and 10.0 milli-international units (mIU)/l (mild-SCH) and a severe form with TSH >10.0 mIU/l (severe-SCH). SCH is a common problem (prevalence is greater in women than men), which increases further with increasing age and TSH levels. Even though the risk of progression to overt hypothyroidism is higher in patients with severe-SCH, the risk is also significant in patients having mild-SCH; it has been suggested that every twofold rise in serum TSH would increase the risk from 1 to 4%, which further increases to 38% if thyroid antibodies are positive. Current data have shown increased cardiovascular risk in patients with mild-SCH and have demonstrated some benefits of levothyroxine treatment in reducing these events. However, evidence on the association of mild-SCH and musculoskeletal system, cognitive dysfunction, mood disorders, dyslipidaemia, diabetes and goitre is conflicting. Similarly, the discussion regarding the exact upper limit of normal for serum TSH remains controversial. The data have also shown increased risk of adverse pregnancy outcomes in patient with mild-SCH, with some benefits of thyroxine treatment. The recent available guidelines related to management of patients with serum TSH <10 mIU/l have suggested decisions should be made taking into account the age of the patient, associated risk factors and comorbid conditions. This chronicle review assesses current evidence regarding the risks associated and the recommendations related to benefits of levothyroxine treatment in patients having mild-SCH.


Adult onset distal and proximal myopathy with complete ophthalmoplegia associated with a novel de novo p.(Leu1877Pro) mutation in MYH2.
An MYH2 mutation p.(Glu706Lys) was originally described in a family with autosomal dominant inheritance, where the affected family members presented with multiple congenital contractures and ophthalmoplegia, progressing to a proximal myopathy in adulthood. Another patient with a dominant mutation p.(Leu1870Pro) was described, presenting as a congenital myopathy with ophthalmoplegia. Here, we present a patient with symptoms beginning at age 16 years, of prominent distal but also proximal weakness, bulbar involvement and ophthalmoplegia. Initially, clinically classified as oculopharyngodistal myopathy, the patient was found to carry a novel, de novo MYH2 mutation c.5630T>C p.(Leu1877Pro). This expands the phenotype of dominant MYH2 myopathies with the clinical phenotype overlapping the oculopharyngodistal myopathy spectrum.


Genome sequence of a mesophilic hydrogenotrophic methanogen Methanocella paludicola, the first cultivated representative of the order Methanocellales.
We report complete genome sequence of a mesophilic hydrogenotrophic methanogen Methanocella paludicola, the first cultured representative of the order Methanocellales once recognized as an uncultured key archaeal group for methane emission in rice fields. The genome sequence of M. paludicola consists of a single circular chromosome of 2,957,635 bp containing 3004 protein-coding sequences (CDS). Genes for most of the functions known in the methanogenic archaea were identified, e.g. a full complement of hydrogenases and methanogenesis enzymes. The mixotrophic growth of M. paludicola was clarified by the genomic characterization and re-examined by the subsequent growth experiments. Comparative genome analysis with the previously reported genome sequence of RC-I(MRE50), which was metagenomically reconstructed, demonstrated that about 70% of M. paludicola CDSs were genetically related with RC-I(MRE50) CDSs. These CDSs included the genes involved in hydrogenotrophic methane production, incomplete TCA cycle, assimilatory sulfate reduction and so on. However, the genetic components for the carbon and nitrogen fixation and antioxidant system were different between the two Methanocellales genomes. The difference is likely associated with the physiological variability between M. paludicola and RC-I(MRE50), further suggesting the genomic and physiological diversity of the Methanocellales methanogens. Comparative genome analysis among the previously determined methanogen genomes points to the genome-wide relatedness of the Methanocellales methanogens to the orders Methanosarcinales and Methanomicrobiales methanogens in terms of the genetic repertoire. Meanwhile, the unique evolutionary history of the Methanocellales methanogens is also traced in an aspect by the comparative genome analysis among the methanogens.


BACTERIOLOGY OF SPOILAGE OF FISH MUSCLE. II. INCIDENCE OF SPOILERS DURING SPOILAGE.
A test medium consisting of a sterile raw press juice from fish muscle was used to determine the incidence of spoilage bacteria on stored fillets of English sole (Parophrys vetulus). The initial load of spoilers was shown to be consistently below 10%. This percentage rose but slightly toward the middle of the spoilage runs, and actually declined when spoilage was most apparent both organoleptically and chemically. Further evidence implicating the Pseudomonas and Achromobacter groups in the spoilage of fresh fish is presented.


Biodiversity of the genus Cladophialophora.
Cladophialophora is a genus of black yeast-like fungi comprising a number of clinically highly significant species in addition to environmental taxa. The genus has previously been characterized by branched chains of ellipsoidal to fusiform conidia. However, this character was shown to have evolved several times independently in the order Chaetothyriales. On the basis of a multigene phylogeny (nucLSU, nucSSU, RPB1), most of the species of Cladophialophora (including its generic type C. carrionii) belong to a monophyletic group comprising two main clades (carrionii- and bantiana-clades). The genus includes species causing chromoblastomycosis and other skin infections, as well as disseminated and cerebral infections, often in immunocompetent individuals. In the present study, multilocus phylogenetic analyses were combined to a morphological study to characterize phenetically similar Cladophialophora strains. Sequences of the ITS region, partial Translation Elongation Factor 1-alpha and beta-Tubulin genes were analysed for a set of 48 strains. Four novel species were discovered, originating from soft drinks, alkylbenzene-polluted soil, and infected patients. Membership of the both carrionii and bantiana clades might be indicative of potential virulence to humans.


Common hepatic artery quadrifurcation associated with right hepatic artery from superior mesenteric artery during laparoscopic total splenopancreasectomy.
Hepatobiliopancreatic surgery is challenging becouse of the complexity of resections and reconstructions and variability of vascular anatomy. The arterial vascularization of the liver is susteined by the common hepatic artery (CHA) that originates from the celiac trunk (CT). The CHA bifurcates into the gastroduodenal artery (GDA) and proper hepatic artery (PHA) 0.5-1 cm medial to the common bile duct (CBD), and the PHA bifurcates into a right and a left branch at hepatic hilum. The most frequent variants are the right hepatic artery (RHA) from the superior mesenteric artery (SMA), the left hepatic artery (LHA) from the left gastric artery (LGA) or a combination of these two variants. Herein, we describe the case of a 70 years old woman affected by IPMN of the pancreas with a quadrifurcation of CHA, associated with a RHA off the SMA. Anatomic variant Hepatic artery variant, Hepatic anatomy, Hepatic vascular anatomy.


Diagnostic characteristics of tests: sensitivity, specificity, predictive values and likelihood ratios.
The diagnostic process always involves two sequential steps: the first assesses the patient's clinical situation through data obtained from the history and physical examination, and the second requests tests to confirm the diagnostic hypothesis. The first step belongs to cognitive psychology and has its own biases and learning methods. The second is based on scientific data that defines the discriminatory power of tests from studies comparing a new test (the so-called index test) and the gold standard for diagnosing the disease. In this article we present a classification of the diagnostic characteristics of tests using a 2x2 contingency table. This information can be used to support the rational use of diagnostic tests.


Use of quantitative SPECT/CT reconstruction in 99mTc-sestamibi imaging of patients with renal masses.
Technetium-99m (99mTc)-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) has previously been shown to allow for the accurate differentiation of benign renal oncocytomas and hybrid oncocytic/chromophobe tumors (HOCTs) apart from other malignant renal tumor histologies, with oncocytomas/HOCTs showing high uptake and renal cell carcinoma (RCC) showing low uptake based on uptake ratios from non-quantitative single-photon emission computed tomography (SPECT) reconstructions. However, in this study, several tumors fell close to the uptake ratio cutoff, likely due to limitations in conventional SPECT/CT reconstruction methods. We hypothesized that application of quantitative SPECT/CT (QSPECT) reconstruction methods developed by our group would provide more robust separation of hot and cold lesions, serving as an imaging framework on which quantitative biomarkers can be validated for evaluation of renal masses with 99mTc-sestamibi. Single-photon emission computed tomography data were reconstructed using the clinical Flash 3D reconstruction and QSPECT methods. Two blinded readers then characterized each tumor as hot or cold. Semi-quantitative uptake ratios were calculated by dividing lesion activity by background renal activity for both Flash 3D and QSPECT reconstructions. The difference between median (mean) hot and cold tumor uptake ratios measured 0.655 (0.73) with the QSPECT method and 0.624 (0.67) with the conventional method, resulting in increased separation between hot and cold tumors. Sub-analysis of 7 lesions near the separation point showed a higher absolute difference (0.16) between QPSECT and Flash 3D mean uptake ratios compared to the remaining lesions. Our finding of improved separation between uptake ratios of hot and cold lesions using QSPECT reconstruction lays the foundation for additional quantitative SPECT techniques such as SPECT-UV in the setting of renal 99mTc-sestamibi and other SPECT/CT exams. With robust quantitative image reconstruction and biomarker analysis, there may be an expanded role for SPECT/CT imaging in renal masses and other pathologic conditions.


Specificity of inhibitors of poly(ADP-ribose) synthesis. Effects on nucleotide metabolism in cultured cells.
The effects of inhibitors of poly(ADP-ribose) synthesis on cell growth and several parameters of nucleotide metabolism have been determined. At concentrations which produced similar inhibitions of poly(ADP-ribose) synthesis, 3-acetylaminobenzamide (1 mM) had no effect on L1210 cell growth, 3-aminobenzamide (5mM) was slightly inhibitory and 3-methoxybenzamide (5 mM) was a potent inhibitor of growth. During a 2-h incubation, none of the inhibitors affected ribo- or deoxyribonucleotide concentrations in cells treated with or without N-methyl-N-nitrosourea; however, N-methyl-N-nitrosourea treatment reduced dCTP concentrations by 50%. During a 24-hr incubation, 3-aminobenzamide and 3-acetylaminobenzamide did not lower ribonucleotide concentrations in cells grown with either undialyzed or dialyzed serum. In contrast, 3-methoxybenzamide caused a depletion of UTP in cells grown with undialyzed serum and caused a depletion of all purine and pyrimidine ribonucleotides in cells grown with dialyzed serum. 3-Aminobenzamide and 3-acetylaminobenzamide had no effect on the conversion of hypoxanthine to ATP and GTP but did slightly inhibit incorporation of formate into ATP and GTP. 3-Methoxybenzamide inhibited incorporation of both hypoxanthine and formate into purine ribonucleotides. 3-Aminobenzamide, 3-acetylaminobenzamide, and 3-methoxybenzamide all inhibited glycine incorporation into ATP and GTP and reduced both the incorporation of thymidine into DNA and the apparent specific activity of the dTTP pool. We conclude that inhibition of poly(ADP-ribose) synthesis causes little or no growth inhibition and has no effect on purine or pyrimidine nucleotide synthesis de novo. The effect of all the inhibitors on glycine and formate metabolism may be related to an inhibition of ADP-ribose synthesis or may be a secondary effect of the inhibitors. The growth inhibition and the reduction in nucleotide concentration caused by 3-methoxybenzamide are apparently secondary effects of this drug and may result from an inhibition of phosphoribosyl pyrophosphate synthesis.


Conformational studies of dithymidine boranomonophosphate diastereoisomers.
The boranophosphate ester nucleotides are a new class of nucleic acid analogues that are isoelectronic and isostructural to normal phosphodiester nucleic acids and that maintain the anionic charge of the nucleic acid backbone. The two P-diastereoisomers of dithymidine boranomonophosphates were separated using reverse phase HPLC; the faster and slower eluting isomers are designated as d(TpBT)-1 and d(TpBT)-2, respectively. Conformations of the isomers were studied using-circular dichroism (CD) and NMR, and compared to the analogous phosphate diester, d(TpT). This comparison allowed the effects of the borane group and chirality of the boranophosphate linkage on sugar and base conformations to be assessed. The CD spectra of the diastereoisomers are consistent with both having a B-type conformation. Analysis of the 1H-1H and 1H-31P coupling constants showed that these conformations are similar to those of the unmodified parent dimer; specifically, the 2'-deoxyribose rings prefer the S (C2'-endo) conformation, and the C4'-C5' and C5'-O5' rotamers are primarily in the gamma + and beta + conformations, respectively. Conformational differences between the diastereoisomers and between the modified and unmodified dimers are manifested by differences in the preferences of the 3'-residues to adopt S sugar pucker and beta + conformations. There is reduced preference for the S sugar pucker of the 3'-residue in d(TpBT)-1 relative to d(TpBT)-2, which is similar to d(TpT). There is less preference for the beta + conformation of the 3'-residue in d(TpBT)-2 relative to d(TpBT)-1 and d(TpT). Based on the CD results, the temperature dependences of the thymidine H6 chemical shifts, and the derived sugar ring and backbone conformational parameters, we conclude that the borane group exerts a minimal influence on the sugar conformations and base stacking interactions. Preliminary assignment of the absolute configuration of the pair of SP and RP diastereoisomers to d(TpBT)-1 and d(TpBT)-2, respectively, is made on the basis of enzyme selectivity and NOE difference experiments.


Viologen-Based Covalent Organic Frameworks toward Metal-Free Highly Efficient Photocatalytic Hydrogen Evolution.
Covalent organic frameworks (COFs) have shown promise in the field of photocatalysts for hydrogen evolution. Many studies have been carried out using various electroactive and photoactive moieties such as triazine, imide, and porphyrin to produce COFs with different geometric structures and units. Electron transfer mediators like viologen and their derivatives can accelerate the transfer of electrons from photosensitizers to active sites. Herein, the combination of a biphenyl-bridged dicarbazole electroactive donor skeleton with a viologen acceptor structure is reported for the photocatalytic hydrogen evolution of novel COF structures with various alkyl linkers {TPCBP X-COF [X = ethyl (E), butyl (B), and hexyl (H)]}. The structures became more flexible and exhibited less crystal behavior as the length of the alkyl chain increased according to scanning and transmission electron microscopy images, X-ray diffraction analyses, and theoretical three-dimensional geometric optimization. In comparison, the H2 evolution rate of the TPCBP B-COF (12.276 mmol g-1) is 2.15 and 2.38 times higher than those of the TPCBP H-COF (5.697 mmol h-1) and TPCBP E-COF (5.165 mmol h-1), respectively, under visible light illumination for 8 h. The TPCBP B-COF structure is one of the best-performing catalysts for the corresponding photocatalytic hydrogen evolution in the literature, producing 1.029 mmol g-1 h-1 with a high apparent quantum efficiency of 79.69% at 470 nm. Our strategy provides new aspects for the design of novel COFs with respect to future metal-free hydrogen evolution by using solar energy conversion.


Commentary: Moving towards policy coherence in trade and health.
International trade has brought economic benefits to many countries, but the association of trade and investment liberalisation with poor health outcomes concerns the public health community. The need to secure more 'healthy' trade is a recognised priority, especially as countries move from global to regional/bilateral trade agreements - with greater public health risks. However, a transition towards 'healthier trade' may be hindered by worldview differences between the trade and health communities. There is a tendency for health actors to perceive trade as a threat to population health, and for trade actors to view health as a constraint to trade objectives of reducing barriers to cross-border commercial flows and economic growth. Unless such differing worldviews can be aligned, finding ways forward for addressing public health in trade policy is likely to be difficult. Moving forward will involve understanding the values and drivers of the respective groups, and developing solutions palatable to their various interests. Given the power imbalances between the two areas, it is likely that the health community will have to make the first moves in this respect. This article outlines the key issues involved and suggests areas where such moves have been, and may be made.


XSu(H)2 is an essential factor for gene expression and morphogenesis of the Xenopus gastrula embryo.
The CSL (CBF-1, Suppressor of Hairless, Lag-1) transcriptional factor is an important mediator of Notch signal transduction. It plays a key role in cell fate determination by cell-cell interaction. CSL functions as a transcriptional repressor before the activation of Notch signaling. However, once Notch signaling is activated, CSL is converted into a transcriptional activator. It remains unclear if CSL has any function during early development before neurogenesis, while transcriptional products exist from the maternal stage. Here, we analyzed the function of Xenopus Suppressor of Hairless (XSu(H)) using morpholino antisense oligonucleotides (MO), which interfere with the translation of transcripts. In Xenopus embryos, maternal transcripts of both XSu(H)1 and XSu(H)2 were ubiquitously observed until the blastula stage and thereafter only XSu(H)1 was zygotically transcribed. Knockdown experiments with MO demonstrated that XSu(H)2 depletion caused a decrease in the expression of the Xbrachyury, MyoD and JNK1 genes. Morphological and histological examinations indicated that XSu(H)2 depletion caused abnormal gastrulation, which resulted in severe defects of the notochord and somitic mesoderm. The effect of XSu(H)2-MO was completely rescued by co-injection of XSu(H)2 mRNAs, but not by XSu(H)1 mRNAs. XESR-1, a Notch signaling target gene, inhibited Xbrachyury expression. However, expression of the XESR-1 gene was not induced by depletion of XSu(H)2. Co-injection of the dominant-negative form of XESR-1 could not rescue the suppression of Xbrachyury expression in the XSu(H)2-depleted embryo. These results suggest that XSu(H)2 is involved in mesoderm formation and the cell movement of gastrula embryos in a different manner from the XESR-1-mediated Notch signaling pathway.


Physiographic and entomologic risk factors of malaria in Assam, India.
Fever surveys were conducted in several districts of the Indian state of Assam to ascertain the prevalence of malaria in relation to vector abundance, entomologic inoculation rates (EIRs), and geographic location of human settlements. Anopheles minimus were incriminated, but their relative abundance and biting rates varied among districts, and no significant correlation was observed between these two indicators (r = 0.43, P = 0.34). Plasmodium falciparum was the predominant parasite species except in two districts where P. vivax was the majority parasite. The EIRs per person/night were 0.46-0.71 in P. falciparum-predominant areas and 0.12 in the district where P. vivax predominated. The correlation of percentage of fever cases positive for malaria infection in each district with the corresponding EIR was not significant (r = 0.6, P = 0.21). Malaria cases were detected in all months of the year but peaked during May-June, which corresponded to the months of heavy rainfall. These were also the months with highest incidence of infection with P. falciparum. Malaria cases were observed in all age groups of both sexes, and there was clustering of cases in villages near the vector-breeding habitat (perennial seepage streams), and foothill villages. However, malaria incidences were consistently lower in villages within 5 km of the nearest health care facility, which were in town areas. The data presented are indicative of low-to-moderate levels of malaria transmission by An. minimus, and would be of value for developing future intervention strategies.


Peripheral blood lymphocyte phenotypes in Alzheimer and Parkinson's diseases.
Neuroinflammation is involved in the pathophysiology of various neurological disorders, in particular Alzheimer disease (AD) and Parkinson's disease (PD). Alterations in the blood-brain barrier may allow peripheral blood lymphocytes to enter the central nervous system; these may participate in disease pathogenesis. To evaluate the peripheral blood lymphocyte profiles of patients with AD and PD and their association with the disease and its progression. The study included 20 patients with AD, 20 with PD, and a group of healthy individuals. Ten of the patients with AD and 12 of those with PD were evaluated a second time 17 to 27 months after the start of the study. Lymphocyte subpopulations and their activation status were determined by flow cytometry. All patients underwent neurological examinations using internationally validated scales. Compared to healthy individuals, patients with AD and PD showed significantly higher levels of activated lymphocytes, lymphocytes susceptible to apoptosis, central memory T cells, and regulatory T and B cells. As the diseases progressed, there was a significant decrease in activated cells (CD4+ CD38+ and CD8+ CD38+ in PD and AD, CD4+ CD69+ and CD8+ CD69+ in PD), T cells susceptible to apoptosis, and some regulatory populations (CD19+ CD5+ IL10+ in PD and AD, CD19+ CD5+ IL10+ FoxP3+, CD4+ FoxP3+ CD25+ CD45RO+ in PD). In patients with AD, disease progression was associated with lower percentages of CD4+ CD38+ cells and higher percentages of effector CD4 cells at the beginning of the study. Significant differences were observed between both diseases. This study provides evidence of changes in peripheral blood lymphocyte phenotypes associated with AD and PD and their severity. Considering effective blood-brain communication, our results open new avenues of research into immunomodulation therapies to treat these diseases.


Efficacy of core stability training on upper extremity performance in collegiate athletes.
To determine the efficacy of a five-week core stability training program for collegiate athletes on upper extremity performance measures. Seventy healthy collegiate athletes (age 21.6±1.7years; height 175±4.63 cm; body mass 65.31±5.63 kg) were randomly allocated to experimental (n=35) and control group (n=35). The experimental group has undergone a five-week core stabilisation protocol (three days /week) and regular training, whereas the control group maintained their regular training. The upper quarter Y balance test (UQ-YBT) and Functional throwing performance index (FTPI) were assessed pre and post-training. The results of mixed ANOVA show that there was a significant interaction between time and group variables on YBT (p<0.001, ηp2 =0.759) and FTPI (p<0.001, ηp2 =0.411) after five weeks of core stability training. Statistically, significant improvement was shown in YBT (mean change=15.2, p<0.001) and FTPI (mean change=14.4, p<0.001) in the experimental group; however, there was no significant change observed in both outcomes in the control groups. After five weeks of core stabilisation training program, the measures of UQ-YBT and FTPI were improved, thus advocating the use of a core stabilisation training program among collegiate athletes to enhance their upper extremity performance.


Physical and binding properties of large fragments of human serum albumin.
Three large fragments of human serum albumin were produced by peptic digestion of the native protein [Geisow & Beaven (1977) Biochem. J. 161, 619-625]. Fragment P44 represents residues 1-386 and fragments P29 and P31 represent residues 49-307 and residues 308-584 respectively of the albumin molecule. The large N-terminal fragment P44 has a similar percentage of alpha-helix to stored defatted albumin, although the alpha-helix content of all the fragments is significantly less than that of freshly prepared albumin. The fragment P44 appears to account for all the binding of the hydrophobic probe 8-anilinonaphthalene-1-sulphonate to albumin. N-Acetyl-L-tryptophan binds to this fragment and displaces one of the bound molecules of 8-anilinonaphthalene-1-sulphonate. Bilirubin binds to fragments P44 and P29, and the complexes show similar circular-dichroism spectra to that of the complex between bilirubin and whole albumin. These results are in agreement with affinity-labeling work on albumin with reactive ligands where substitution occurs in the N-terminal region of the molecule. The sharp conformational transitional transition in albumin which is observed between pH4 and 3.5 was absent from the fragments. This isomerization, usually called the N-F transition, probably occurs in intact albumin as a result of the unfolding or separation of the C-terminal third of the protein from the remainder of the molecule.


The Impact of Glyphosate, Its Metabolites and Impurities on Viability, ATP Level and Morphological changes in Human Peripheral Blood Mononuclear Cells.
The toxicity of herbicides to animals and human is an issue of worldwide concern. The present study has been undertaken to assess toxic effect of widely used pesticide-glyphosate, its metabolites: aminomethylphosphonic acid (AMPA) and methylphosphonic acid and its impurities: N-(phosphonomethyl)iminodiacetic acid (PMIDA), N-methylglyphosate, hydroxymethylphosphonic acid and bis-(phosphonomethyl)amine on human peripheral blood mononuclear cells (PBMCs). We have evaluated the effect of those compounds on viability, ATP level, size (FSC-A parameter) and granulation (SSC-A parameter) of the cells studied. Human peripheral blood mononuclear cells were exposed to different concentrations of glyphosate, its metabolites and impurities (0.01-10 mM) for 4 and 24 h. It was found that investigated compounds caused statistically significant decrease in viability and ATP level of PBMCs. The strongest changes in cell viability and ATP level were observed after 24 h incubation of PBMCs with bis-(phosphonomethyl)amine, and particularly PMIDA. Moreover, all studied compounds changed cell granularity, while PMIDA and bis-(phosphonomethyl)amine altered PBMCs size. It may be concluded that bis-(phosphonomethyl)amine, and PMIDA caused a slightly stronger damage to PBMCs than did glyphosate. Changes in the parameters studied in PBMCs were observed only at high concentrations of the compounds examined, which clearly shows that they may occur in this cell type only as a result of acute poisoning of human organism with these substances.


[Computer tomography in malformations, inflammatory and degenerative changes in the spine].
Technical improvements and the use of intrathecal Metrizamide have made computer tomography of the spine a valuable diagnostic method. The value of CT in demonstrating morphological changes in the spine was investigated in 77 examinations of congenital malformation or inflammatory and degenerative disease. Measurements of the spinal canal provide more accurate information than conventional radiology and these are discussed. Intradural injection of contrast medium makes it possible to diagnose abnormalities of the cord by means of CT. Inflammatory changes in the spine and in the paraspinal soft tissues are shown at an early stage. A diagnosis of tumour can be confirmed by CT-controlled needle biopsy. It is usually possible to demonstrate disc prolapse without the use of contrast medium. On the other hand, the investigation of pain following disc operations remains a difficult problem.


Related binding mechanisms for fibrinogen, fibronectin, von Willebrand factor, and thrombospondin on thrombin-stimulated human platelets.
Fibrinogen, fibronectin, von Willebrand factor, and thrombospondin are four large glycoproteins that bind to thrombin-stimulated platelets and influence cellular adhesive functions. The effects of five monoclonal antibodies that react with platelet membrane glycoproteins (GP) IIb and/or IIIa on the binding of these four molecules to stimulated platelets were assessed. Tab and PMI-1, antibodies recognizing GPIIb, had no effect, whereas 10E5 and 2G12, antibodies that immunoprecipitate both GPIIb and IIIa in the presence of calcium, inhibited binding of all four ligands by greater than 85%. T10, an antibody specific for the GPIIb-IIIa complex, produced partial inhibition (60% to 80%) of the binding of each ligand. Inhibitory antibodies were effective in the same dose range for all four proteins and also inhibited binding of fibrinogen, fibronectin, and von Willebrand factor to receptors fixed in an induced state (thrombin-stimulated platelets fixed with paraformaldehyde). Thrombospondin did not bind to these fixed cell preparations. The results suggest that these four adhesive proteins have a related mechanism of binding to thrombin-stimulated platelets. This related mechanism may entail the sharing of some, but not necessarily all, binding sites for the four ligands or a proximal relationship between these binding sites.


Clinical and Epidemiological Patterns of Scrub Typhus, an Emerging Disease in Bhutan.
Scrub typhus (ST) is a vector-borne rickettsial infection causing acute febrile illness. The re-emergence of ST in the Asia-Pacific region represents a serious public health threat. ST was first detected in Bhutan in 2008. However, the disease is likely to be under-diagnosed and under-reported, and the true impact is difficult to estimate. At the end of 2014, the SD Bioline Tsutsugamushi TestTM rapid diagnostic test (RDT) kits became available in all hospitals to assist clinicians in diagnosing ST. We conducted a retrospective descriptive study, reviewing records from all hospitals of Bhutan to identify all RDT-positive clinical cases of ST in Bhutan in 2015. The aim was to evaluate the burden of ST in Bhutan, describe the demographic, spatial and temporal patterns of disease, and identify the typical clinical presentations. The annual incidence of RDT-positive cases of ST reporting to Bhutanese hospitals in 2015 was estimated to be 62 per 100,000 population at risk. The incidence of disease was highest in the southern districts with a subtropical climate and a high level of agricultural production. The highest proportion of cases (87%) was rural residents, with farmers being the main occupational category. The disease was strongly seasonal, with 97% of cases occurring between June and November, coinciding with the monsoon and agricultural production seasons. Common ST symptoms were not specific, and an eschar was noted by clinicians in only 7.4% of cases, which is likely to contribute to an under-diagnosis of ST. ST represents an important and neglected burden, especially in rural communities in Bhutan. The outcomes of this study will inform public health measures such as timely-awareness programmes for clinicians and the public in high-risk areas, to improve the diagnosis, treatment and clinical outcomes of this disease.


Comparison of three different promoter systems for secretory alpha-amylase production in fed-batch cultures of recombinant Saccharomyces cerevisiae.
Cloned gene expression in recombinant Saccharomyces cerevisiae 20B-12 containing three different plasmids was compared in batch and fed-batch cultures. The plasmids pNA3, pNA7, and pNA9 contain the alpha-amylase gene under the control of SUC2, PGK, and GAL7 Promoters, respectively. The synthesis of alpha-amylase was therefore induced by low glucose concentration for the SUC2 and PGK promoters, and by galactose for GAL7 promoter. The specific cell growth rates were similar among cells harboring the three different plasmids; they decreased from 0.35 to 0.38 h(-1) during the cell growth phase to 0.03 to 0.06 h(-1) during the production phase. The secretory alpha-amylase activity of cells harboring plasmid pNA7 was 129 U/mL in fed-batch culture, which was 1.4 and 2 times as high as the activities of cells harboring plasmids pNA3 and pNA9, respectively. The secretion ratios (amount of extracellular alpha-amylase activity/amounts of total alpha-amylase activity) of cells harboring plasmids pNA3, pNA7, and pNA9 were 91.4%, 94.5%, and 95.3%, respectively.


In Silico Drug-Designing Studies on Flavanoids as Anticolon Cancer Agents: Pharmacophore Mapping, Molecular Docking, and Monte Carlo Method-Based QSAR Modeling.
In silico molecular modeling studies were carried out on some newly synthesized flavanoid analogues. Search for potential targets for these compounds was performed using pharmacophore-mapping algorithm employing inverse screening of some representative compounds to a large set of pharmacophore models constructed from human target proteins. Further, molecular docking studies were carried out to assess binding affinity of these compounds to proteins mediating tumor growth. In vitro anticancer studies were carried out on colon cancer cell lines (HCT116) to assess validity of this approach for target identification of the new compounds. Further important structural features of compounds for anticolon cancer activity were assessed using Monte Carlo-based SMILES and hydrogen graph-Based QSAR studies. In conclusion this study have depicted successful and stepwise application of pharmacophore mapping, molecular docking, and QSAR studies in target identification and lead optimization of flavonoids.


[5-Fluorouracil-induced colitis--a review based upon consideration of 6 cases].
At increasing use of high-dose 5-fluorouracil-based chemotherapy for metastatic colorectal and gastric cancer complicated drug-induced colitis is observed more frequently. From May 1998 to November 2000 we observed 6 cases of 5-fluorouracil-induced colitis, in which we looked for involvement of small intestine. We report summing up on the 6 cases including both endoscopic and histological findings in both sites of the gut. In 2 men and 4 women (age 49-78 years) with advanced colon (n = 2), gastric (n = 3 ) and gallbladder (n = 1) cancer a palliative weekly high-dose infusional 5-fluorouracil (2,6 g/m(2)/24 h) and folinic acid (500 mg/m(2)/2 h) chemotherapy was performed. Few days after 1-5 chemotherapy courses the patients were admitted to our hospital with abdominal pain and partly severe watery diarrhea (up to 20 times evacuations/per day). The stool cultures were negative and there were no proof both of clostridium difficile and his toxin A and B. In 4 patients colonoscopy showed different grades of colitis up to diffuse erythema and microlesions, 2 patients had no visible lesions. In 4 patients endoscopy of the upper GI-tract showed a severe inflammation (n = 1) and a fibrinopurulent exsudate, severe edema and isolated ulcerations (n = 3) of jejunum after gastrectomy or duodenum with intact stomach. In the histological assessment different grades of 5-FU-induced colitis without (n = 2) or with (n = 4) involvement of the upper small intestine destruction of the superficial mucosa and crypts (epitheliumapoptosis) were found. 5 patients were treated by antibiotics (vancomycin n = 2, metronidazole n = 3), glucocorticoids (n = 5) and Saccaromyces cerevisiae (n = 3). After 8-10 days the patients were complete free of symptoms. One patient died due to the enterocolitis. The present cases demonstrate that high-dose 5-fluorouracil-based chemotherapy not only induces a colitis but also may involve the upper small intestine tract. Consequently, it represents an increasing and serious adverse event of high-dose chemotherapy. The etiology of the enterocolitis (drug- or bacterial-induced) needs further investigations in order to find a causal therapy and/or prophylaxis.


Diagnostically significant variations in pleural fluid pH in loculated parapneumonic effusions.
Parapneumonic effusions are common, and measurement of pleural pH is one of the most useful measurements in assessing the need for tube drainage. Use of pleural pH assumes that a single measurement conveys a representative picture of pH throughout the effusion. Often effusions are multiloculated, and varying concentrations of nondiffusible acids such as lactic acid, if present in different concentrations, could mean clinically significant variations in pH between locules. If these differences were large, a single pH measurement could misrepresent the "stage" that the parapneumonic effusion had reached. We therefore set out to test the hypothesis that pH varies significantly between locules in complicated parapneumonic effusions. The study was performed in seven consecutive patients presenting to our institution with complicated parapneumonic effusions. In each case, pleural pH was measured in several separate pleural fluid locules, using ultrasound-guided pleural fluid sampling. Significant variations were found in pleural fluid visual appearance, pH, and lactate dehydrogenase between locules in four of seven patients. Three of seven patients had variations, resulting in pH levels both above and below 7.2, which is the threshold used in our institution to indicate the need for tube drainage. This is the first reported series of variation in pleural pH between different locules in complicated parapneumonic effusions. These variations are clinically important and cast light on the mechanisms responsible for the acidosis seen in infected effusions. Physicians should be aware of this when making drainage decisions in these patients using the clinical picture and a single pH result alone.


A chimeric CYP11B1/CYP11B2 gene in glucocorticoid-insuppressible familial hyperaldosteronism.
Although a chimeric gene combining the 11beta-hydroxylase gene (CYP11B1) and the aldosterone synthase gene (CYP11B2) explains the pathophysiology of familial hyperaldosteronism (FH) type I, the contribution of this abnormality to FH type II has not been tested. We screened genomic DNA from a Japanese family with FH type II for the CYP11B1/CYP11B2 gene. The index patient was a 27-year-old woman with hypertension. Hypokalaemia, elevated plasma aldosterone and suppressed plasma renin activity suggested primary aldosteronism. Though computed tomography failed to reveal an adrenal tumour, left adrenalectomy was indicated due to a high aldosterone concentration in left adrenal venous blood. The resected adrenal gland contained an adenoma. As her mother had also been diagnosed with primary aldosteronism due to an adenoma, we administered oral dexamethasone to our patient before the operation and observed the response of the blood pressure and plasma aldosterone concentration for 2 weeks. Both parameters remained elevated during the treatment period, confirming the diagnosis of FH type II. Total DNA was isolated from blood cells of the index patient, her mother, and an unaffected brother. Samples were amplified by polymerase chain reaction using specific primers from CYP11B1 and CYP11B2. Unique DNA fragments of 1.4 kb were obtained from the index patient and her mother, but not from the healthy subject. The CYP11B1/CYP11B2 chimeric gene was found in a Japanese family with FH type II.


Risk factors for urinary tract symptoms in women: beliefs among general practitioners and women and the effect on patient management.
Urinary tract symptoms are common in women. A variety of risk factors have been investigated in the past. One of the more likely risk factors for these symptoms is recent sexual intercourse; another is diaphragm use. Morbidity levels are increasing, although effective antibiotic treatment is available. To study the beliefs of women and their general practitioners (GPs) about urinary tract symptoms and to determine how these may affect management. An interview survey with 113 women consulting with urinary tract symptoms and the 22 GPs they consulted. Doctors and women have similar beliefs about the 'causes' of urinary tract symptoms, but the relative importance differs. Both acknowledge the association with sexual intercourse but fail to communicate about this during the consultation. Patients reported being embarrassed on their own and their GP's behalf if sensitive subjects were raised. Doctors failed to ask women what they thought had caused the symptoms and were also unlikely to suggest to them likely causes. They also reported reticence to do more than prescribe, at least in first consultations, and half of the doctors routinely prescribed antibiotics, regardless of a near patient diagnostic urinary stick test result. The advice given was not necessarily evidence based. GPs need to be more aware of the risk factors associated with urinary tract symptoms in women and should formulate their advice accordingly. The reticence to discuss sensitive subjects by both GPs and patients has implications for the ability to broach sexual matters in any consultation in which they are not the reason or focus for that consultation.


The effect of an SOD derivative (SM-SOD) administration in a burned rat model.
To determine whether superoxide radicals may influence the pathogenesis of burn injury, we investigated the effects of a long-acting, site-directed superoxide dismutase derivative (SM-SOD) on the rats subjected to burn shock. Anesthesized animals were injected intravenously with either 2 ml/kg of saline or SM-SOD (10 mg/kg; dissolved in saline). After 30 min they were subjected to full-thickness burns of about 40% of total body surface area. The 7-day survival rate was significantly higher in the SM-SOD-treated animals than in the untreated controls. Also, administration of SM-SOD markedly inhibited the increase in the levels of thiobarbituric acid reactive metabolites, such as lipid peroxides in the plasma, lung and kidney, and the decrease in plasma protein levels particularly at the early stage of burn injury. These findings suggested that superoxide radicals may play a critical role in the pathogenesis following thermal injury.


Effects of valinomycin on osmotic lysis of zymogen granules and amylase exocytosis from parotid acini.
The role of osmotic swelling of the secretory granules in adenosine 3',5'-cyclic monophosphate (cAMP)-mediated amylase exocytosis was evaluated by use of isolated zymogen granules and saponin-permeabilized acini of the rat parotid gland. The osmotic lysis of the isolated granules was markedly enhanced by the addition of valinomycin (> 10(-9) M) in the presence of isosmotic KSCN or KI medium. However, valinomycin (up to 10(-5) M) did not increase the granule lysis in KCl medium, although the granules were slightly less stable in KCl medium than in K2SO4 or potassium gluconate medium. Guanosine 5'-O-(3-thiotriphosphate) did not affect the granule lysis. Valinomycin alone had no effect on amylase release from saponin-permeabilized parotid acini incubated in KCl medium, but completely abolished cAMP-mediated amylase release in all K+ media used. The inhibition was clearly detected at 0.1 microM valinomycin in KCl medium, not blocked by the addition of 1 mM MgATP to the medium, and was greatly reduced in NaCl medium. cAMP-evoked amylase release was completely inhibited by SCN- and I- (permeant anions), the mean inhibitory dosages of which were approximately 25 and 50 mM, respectively. These results suggest that 1) the membrane of parotid zymogen granules has no detectable Cl- channels responsible for osmotic swelling of the granules, and 2) increase in K+ or anion conductance of the granule does not enhance but inhibits cAMP-mediated amylase exocytosis from parotid acini.