Are indirect utility measures reliable and responsive in rheumatoid arthritis patients?
Preference-based, generic measures are increasingly being used to measure quality of life and as sources for quality weights in the estimation of Quality Adjusted Life Years (QALYs) in rheumatoid arthritis (RA). However, among the most commonly used instruments (the Health Utilities Index 2 and 3 [HUI2 and HUI3], the EuroQoL-5D [EQ-5D], and the Short Form-6D [SF-6D], there has been little comparative research. Therefore, we examined the reliability and responsiveness of these measures and the Rheumatoid Arthritis Quality of Life (RAQoL) and the Health Assessment Questionnaire (HAQ) in a sample of RA patients. Test-retest reliability was acceptable for all of the instruments with the exception of the EQ-5D. Using two external criteria to define change (a patient transition question and categories of the patient global assessment of disease activity VAS), the RAQoL was the most responsive of the instruments. For the indirect utility instruments, the HUI3 and the SF-6D were the most responsive for measuring positive change. On average, for patients whose RA improved, the absolute change was highest for the HUI3. The HUI3 and the SF-6D appear to be the most responsive of the preference-based instruments in RA. However, differences in the magnitude of the absolute change scores have important implications for cost-effectiveness analyses.


Passive enhancement of the somatosensory P100 and N140 in an active attention task using deviant alone condition.
We investigated the changes in the somatosensory P100 and N140 during passive (reading) versus active tasks (counting, button pressing) and oddball (target=20%, standard=80%) versus deviant alone conditions (standards were omitted). Nine healthy subjects performed the 3 tasks (reading, counting and button pressing) under two conditions. Standard and target electrical stimuli were presented in a random order to the index or middle fingers of the left hand at a constant 800 ms interstimulus interval in the oddball conditions. In the deviant alone conditions, only target stimuli were presented with the same timing as in the oddball conditions. The N140 amplitude increased for the deviant alone stimuli compared with the oddball standard and target stimuli regardless of whether the task was passive or active, indicating passive shifts of attention related to temporal infrequency. The P100 amplitude also increased for the deviant alone stimuli compared with the oddball standard and target stimuli in both passive and active tasks, but the enhancement seemed to be even smaller than that of the N140 amplitude. The somatosensory N140 passively increased even if subjects tried to attend actively to the stimulus source when the deviant alone condition was used. This change in N140 amplitude may be related to a strong orienting effect against a 'silent' background. The present study provided evidence that the N140 is an indicator of passive attention against a silent background when the deviant alone condition or long interstimulus interval was used.


Prameha purvaroopa as diabetes risk predictor - trends from a retrospective cohort study of newly diagnosed type 2 diabetes patients.
Increasing prevalence of type 2 diabetes has shifted the focus of world from its management to prevention. Life style modifications programs related to diabetes prevention are found to delay the progress of prediabetes into diabetes. Reaching out to community with diabetes prevention program however is still a challenge to meet. Of the study: This study proposed to retrospectively screen the presence of prediabetes symptoms depicted in Ayurveda literature in a newly diagnosed diabetic population and to compare this prevalence with non-diabetic and healthy population. The idea is to put weightage upon prediabetes symptoms as a disease predictor if these are available early in the course of the disease. A questionnaire based upon detailed literature survey of three Ayurveda classics from the subject area of prameha (identical to diabetes) identified 22 features under the class of prediabetes. A questionnaire was developed to find the presence of these features in selected diabetic population retrospectively before the onset of diabetes. 141 newly diagnosed diabetics were selected on the basis of a defined inclusion and exclusion criteria and surveyed for chronological presence of prediabetes features as identified through the literature search and validated through a validation process. This feature prevalence was further compared with non-diabetic and healthy population. A significant difference (p < 0.001) was observed in specific symptom occurrence in diabetic population comparing to non-diabetic and healthy control for at least 11 of the selected items. The study observes that few prediabetes features show their clear retrospective presence in diabetic population comparing to non-diabetic and healthy population. This observation can help formulating a risk calculator for future diabetes on the basis of available pre diabetic features in an individual. A prospective cohort study however would be essential to prove any such realistic relation between prediabetes symptoms and future diabetes development among high risk individuals.


Connectivity-behavior analysis reveals that functional connectivity between left BA39 and Broca's area varies with reading ability.
Correlations between temporal fluctuations in MRI signals may reveal functional connectivity between brain regions within individual subjects. Such correlations would be especially useful indices of functional connectivity if they covary with behavioral performance or other subject variables. This study investigated whether such a relationship could be demonstrated in the context of the reading circuit in the brain. The method proved sufficiently powerful to reveal significant correlations between the reading abilities of subjects and the strength of their functional connection between left Brodmann's area 39 and Broca's area during reading. This suggests that the disconnection of the angular gyrus previously reported for dyslexic readers is part of a larger continuum in which poor (but nonimpaired readers) also show reduced connectivity to the region. In addition, it illustrates the potential power of paradigms that examine correlations between behavior and functional brain connections.


A method for the determination of the chemical structure of glycolipids biosynthesized in vitro and the specificity and activity of glycosyltransferases.
A very sensitive method for the qualitative and quantitative investigation of the biosynthesis of the oligosaccharide chains of glycolipids in such tissues as cultured cells, biopsies, or cell organelles, is described. It permits the determination, on an ultramicro-scale, of the specificity of glycosyltransferases in terms of the exact chemical structure of the products that are synthesized from known labeled glycolipid precursors, and defines without ambiguity the precursor-to-product relationship in biosynthetic incubations in vitro.


Fiber from ramie plant (Boehmeria nivea): A novel suture biomaterial.
The quest for developing an ideal suture material prompted our interest to develop a novel suture with advantageous characters to market available ones. From natural origin only silk, cotton and linen fibers are presently available in market as non-absorbable suture biomaterials. In this study, we have developed a novel, cost-effective, and biocompatible suture biomaterial from ramie plant, Boehmeria nivea fiber. Field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDX), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and thermo gravimetric analysis (TGA) results revealed the physicochemical properties of raw and degummed ramie fiber, where the former one showed desirable characteristics for suture preparation. The braided multifilament ramie suture prepared from degummed fiber exhibited excellent tensile strength. The suture found to be biocompatible towards human erythrocytes and nontoxic to mammalian cells. The fabricated ramie suture exhibited significant antibacterial activity against Escherichia coli, Bacillus subtilis and Staphylococcus aureus; which can be attributed to the inherent bacteriostatic ability of ramie plant fiber. In vivo wound closure efficacy was evaluated in adult male wister rats by suturing the superficial wound incisions. Within seven days of surgery the wound got completely healed leaving no rash and scar. The role of the ramie suture in complete wound healing was supported by the reduced levels of serum inflammatory mediators. Histopathology studies confirmed the wound healing ability of ramie suture, as rapid synthesis of collagen, connective tissue and other skin adnexal structures were observed within seven days of surgery. Tensile properties, biocompatibility and wound closure efficacy of the ramie suture were comparable with market available BMSF suture. The outcome of this study can drive tremendous possibility for the utilization of ramie plant fiber for various biomedical applications.


Toll-like receptor 4-related immunostimulatory polysaccharides: Primary structure, activity relationships, and possible interaction models.
Toll-like receptor (TLR) 4 is an important polysaccharide receptor; however, the relationships between the structures and biological activities of TLR4 and polysaccharides remain unknown. Many recent findings have revealed the primary structure of TLR4/MD-2-related polysaccharides, and several three-dimensional structure models of polysaccharide-binding proteins have been reported; and these models provide insights into the mechanisms through which polysaccharides interact with TLR4. In this review, we first discuss the origins of polysaccharides related to TLR4, including polysaccharides from higher plants, fungi, bacteria, algae, and animals. We then briefly describe the glucosidic bond types of TLR4-related heteroglycans and homoglycans and describe the typical molecular weights of TLR4-related polysaccharides. The primary structures and activity relationships of polysaccharides with TLR4/MD-2 are also discussed. Finally, based on the existing interaction models of LPS with TLR4/MD-2 and linear polysaccharides with proteins, we provide insights into the possible interaction models of polysaccharide ligands with TLR4/MD-2. To our knowledge, this review is the first to summarize the primary structures and activity relationships of TLR4-related polysaccharides and the possible mechanisms of interaction for TLR4 and TLR4-related polysaccharides.


Effects of long- and short-term fatiguing stretch-shortening cycle exercises on reflex EMG and force of the tendon-muscle complex.
This study examined the fatigue effects of stretch-shortening cycle exercises of different intensity and duration on stretch reflex EMG and mechanical responses of the triceps surae muscle. Twelve subjects performed either a 10-km run ( n=6) or short but exhaustive rebound exercise on a sledge apparatus ( n=6). Passive reflex tests (mechanically induced ankle dorsiflexions) were examined before, after as well as 2 h, 2 and 7 days after exercise. Mechanical reflex responses were recorded from the ergometer torque signal. An acute contractile failure was observed as large reductions in twitch responses, especially in the sledge subgroup who showed high post-exercise peak blood lactate and an increased EMG/torque ratio. Independently of the exercise, the delayed fatigue analysis revealed strong relationships between the reflex-induced EMG and mechanical changes. In addition to muscle damage, these results may be explained by inhibitory effects via the sensitisation of small muscle afferents particularly during the exercise-induced delayed recovery process.


Clinical results following colonic resection for ulcerative colitis in elderly individuals (elderly-onset vs. nonelderly onset).
The incidence of ulcerative colitis (UC) is increasing, but there are few reports comparing elderly UC patients undergoing colectomy for elderly-onset UC (EO) and nonelderly-onset UC (NEO). The aim of this study was to analyze the differences between EO and NEO patients who underwent UC-related surgery. We identified 1973 patients with UC who underwent colectomy at Hyogo College of Medicine between January 1, 1984, and December 31, 2018. Only patients aged 65 years old and older who underwent colectomy were enrolled in this study (n = 221, 11.2%), and their clinical records were retrospectively reviewed. Patients were divided into two groups according to their age at disease onset: those with onset at younger than 60 years old (NEO) and at 60 years old or older (EO). In the 221 UC patients who underwent colectomy at 65 years old or older, there were 155 cases of EO and 66 cases of NEO. The main surgical indication in NEO patients was colitis-associated cancer/dysplasia (32/66, 47%). In contrast, refractory to medical treatment was the leading cause of surgery in EO patients (80/155, 52%). The distributions of surgical indications were different between the two groups (p < 0.01). The preoperative daily dose of steroids was significantly higher in the EO group than in the NEOgroup (0 mg vs. 10 mg, p < 0.01). The rates of immunosuppressant, infliximab (IFX) and adalimumab use did not differ significantly between the groups. Significantly more patients underwent emergency surgery in the EO group than in the NEO group (14% vs. 35%, p < 0.01). The proportions of patients with postoperative morbidity (Clavien-Dindo grade III or higher) were 17.4% (27/155) in the EO group and 13.6% (9/66) in the NEO group. There was no significant difference between the two groups (p = 0.48). The prognosis of the EO patients who underwent UC-related emergency surgery was worse than that of the NEO patients (p < 0.01). In the EO group, 8 (14.8%) of 54 patients died within 30 postoperative days, while there were no deaths in the NEO group. Among elderly UC patients undergoing UC-related surgery, EO patients undergoing emergency surgery had very poor outcomes, and the mortality rate was 14.8%. In such cases, it is important for physicians and surgeons to begin communication at an early stage so that the optimal surgical timeframe is not missed.


[Stability of pedicle screws in comparison to anterior vertebral body screws after kyphoplasty augmentation].
Aim of the study was to compare stability of pedicle screws and ventral implanted screws after insertion in soft or cured kyphoplasty cement. Pedicle screws were inserted in a total of 40 thoracolumbar vertebrae of 10 different formalin-fixed human specimens: each 10 pedicle screws were implanted in soft (group 1) and cured cement (group 2), each 10 ventral screws were placed in soft (group 3) and cured (group 4) cement. Pedicle screws were then evaluated for biomechanical axial pullout resistance. Mean pull-out force was 452 N (range 60-1 125 N) in group 1, 367 N (range 112-840 N) in group 2, 364 N (range 65-875 N) in group 3 and 271 N (range 35-625 N) in group 4. Implantation of pedicle screws and ventral implanted screws in soft and cured kyphoplasty cement is a sufficient method. We achieved more stability with pedicle screws compared with ventral implanted screws in soft and cured cement. No significant difference was seen.


The process of social participation in primary health care: the case of Palencia, Guatemala.
In 2008, the World Health Organization issued a callback to the principles of primary health care, which renewed interests in social participation in health. In Guatemala, social participation has been the main policy for the decentralization process since the late 1990s and the social development council scheme has been the main means for participation for the country's population since 2002. The aim of this study was to explore the process of social participation at a municipal-level health commission in the municipality of Palencia, Guatemala. Analysis of legal and policy documents and in-depth interviews with institutional and community-level stakeholders of the commission. The lack of clear guidelines and regulations means that the stakeholders own motivations, agendas and power resources play an important part in defining the roles of the participants. Institutional stakeholders have the human and financial power to make policies. The community-level stakeholders are token participants with little power resources. Their main role is to identify the needs of their communities and seek help from the authorities. Satisfaction and the perceived benefits that the stakeholders obtain from the process play an important part in maintaining the commission's dynamic, which is unlikely to change unless the stakeholders perceive that the benefit they obtain does not outweigh the effort their role entails. Without more uniformed mechanisms and incentives for municipalities to work towards the national goal of equitable involvement in the development process, the achievements will be fragmented and will depend on the individual stakeholder's good will.


Postoperative hospital course of patients with history of severe psychiatric illness.
The postoperative hospital course of 54 patients with a past history of psychiatric illness was studied through chart review. Both chronic schizophrenics and chronic depressives tolerated surgical procedures well, without any unusual difficulties or exacerbation of psychiatric illness. They represented no management problems. Patients with acute, severe upset in the preoperative period (regardless of diagnosis) presented most of the management problems postoperatively.


Spontaneous consecutive sensory esotropia: a case series.
We present the first case series of patients with no systemic neurologic disease who experienced a spontaneous conversion from an initial exotropia to a sensory esotropia in the absence of strabismus surgery or chemodenervation. The patients in this series all were exotropic in the first 2 years of life, with the strabismic eye having decreased vision due to unilateral ocular pathology. All patients demonstrated spontaneous conversion to esotropia between 4 and 8 years of age and thereafter clinically demonstrated a high ratio of accommodative convergence to accommodation. There was no discernible relationship between refractive error and the pattern of spontaneous esotropia. The existence of this rare entity may support delayed surgical correction of strabismus in patients with sensory exotropia.


A Review of β-Lactam-Associated Neutropenia and Implications for Cross-reactivity.
To review the incidence, management, and current understanding of the pathophysiology of β-lactam-induced neutropenia and to critically evaluate the practicality and safety of direct substitution to an alternative β-lactam in the setting of this reaction. A literature analysis using the PubMed and Ovid search engines (July 1968 to October 2020) was performed using the search terms neutropenia, leukopenia, β-lactam, nonchemotherapy, agranulocytosis, and G-CSF (granulocyte colony-stimulating factor). The included English-language studies evaluated the incidence, mechanism, and/or management of β-lactam-induced neutropenia in pediatric or adult patients. Drug-induced neutropenia is a well-documented adverse reaction of β-lactam antibiotics, with an incidence of approximately 10% following at least 2 weeks of intravenous therapy. However, multiple gaps in knowledge remain in the mechanism of pathophysiology and optimal management of this reaction. Both direct toxic and immune-mediated mechanisms have been implicated. Although the cornerstone of management includes cessation of the offending agent, controversy exists on the appropriateness of direct substitution or future use of an alternative β-lactam. Given the frequency of use and superiority of β-lactams over alternative therapy for several infectious disease states, practical recommendations are needed on the management and safe use of β-lactams following β-lactam-induced neutropenia. Future use of β-lactams with differing R1 side chains, particularly those from a separate class, should not be deemed contraindicated following β-lactam-induced neutropenia and may be considered when indicated, with close laboratory monitoring.


Zinc-deficiency and the development of malignant lymphoma in rats given a single intragastric dose of N-methyl-N-nitrosourea.
Zinc-deficient rats that had received a single dose of N-methyl-N-nitrosourea (MNU) intragastrically developed malignant lymphomas involving the liver, spleen, lung and kidney, as well as the usual epithelial tumours at the site of administration. Interestingly, the incidence of squamous-cell carcinoma of the pharynx was significantly higher in zinc-deficient rats than in control animals. Since MNU does not require metabolic activation, the development of the malignant lymphomas might be related to the generally depressed immunological state of zinc-deficient rats.


Potato tuber-inducing activities of jasmonic acid and related-compounds (II).
New information is being accumulated for plant-derived oxylipins, such as jasmonic acid (JA) amino acid conjugates. However, these compounds have not being examined for their activity in promoting potato tuber formation. It was found that (-)-JA had the highest activity followed cis-(-)-OPDA, (+)-4, 5-didehydroJA, cis-(+)-OPDA-l-Ile, and (-)-JA-l-Ile, -Leu, -Phe, -Val, although iso-OPDA and 3,7-didehydroJA did not exhibit activity.


Investigation of an Escherichia coli O145 outbreak in a child day-care centre--extensive sampling and characterization of eae- and stx1-positive E. coli yields epidemiological and socioeconomic insight.
On October 29th 2009 the health authorities in the city of Trondheim, Norway were alerted about a case of Shiga toxin-positive E. coli (STEC) O145 in a child with bloody diarrhoea attending a day-care centre. Symptomatic children in this day-care centre were sampled, thereby identifying three more cases. This initiated an outbreak investigation. A case was defined as a child attending the day-care centre, in whom eae- and stx1- but not stx2-positive E. coli O145:H28 was diagnosed from a faecal sample, with multilocus variable number of tandem repeat analysis (MLVA) profile identical to the index isolate. All 61 children, a staff of 14 in the day-care centre, and 74 close contacts submitted faecal samples. Staff and parents were interviewed about cases' exposure to foods and animals. Faecal samples from 31 ewes from a sheep herd to which the children were exposed were analyzed for E. coli O145. Sixteen cases were identified, from which nine presented diarrhoea but not haemolytic uremic syndrome (HUS). The attack rate was 0.26, and varied between age groups (0.13-0.40) and between the three day-care centre departments (0.20-0.50), and was significantly higher amongst the youngest children. Median duration of shedding was 20 days (0-71 days). Children were excluded from the day-care centre during shedding, requiring parents to take compassionate leave, estimated to be a minimum total of 406 days for all cases. Atypical enteropathogenic E. coli (aEPEC) were detected among 14 children other than cases. These isolates were genotypically different from the outbreak strain. Children in the day-care centre were exposed to faecal pollution from a sheep herd, but E. coli O145 was not detected in the sheep. We report an outbreak of stx1- and eae-positive STEC O145:H28 infection with mild symptoms among children in a day-care centre. Extensive sampling showed occurrence of the outbreak strain as well as other STEC and aEPEC strains in the outbreak population. MLVA-typing of the STEC-isolates strongly indicates a common source of infection. The study describes epidemiological aspects and socioeconomic consequences of a non-O157 STEC outbreak, which are less commonly reported than O157 outbreaks.


A predictive model for the diagnosis of non-alcoholic fatty liver disease based on an integrated machine learning method.
Diagnostic markers for non-alcoholic fatty liver disease (NAFLD) are still needed for screening individuals at risk. In recent years, the machine learning method was used to search for the diagnostic markers of multiple diseases. In this study, we developed and validated a machine learning model to diagnose NAFLD using laboratory indicators. NAFLD patients and non-NAFLD controls were recruited in the training and validation cohorts. The laboratory indicators of the participants in the training cohort were collected, and six indicators including alanine aminotransferase/aspartate aminotransferase (ALT/AST), white blood cells (WBC), alpha-L-fucosidase (AFU), hemoglobin (Hb), triglycerides (TG) and gamma-glutamyl transpeptidase (GGT) were screened out with higher weights by an integrate machine learning method. The areas under the receiver operating characteristic curves (AUROCs) for the selected indicators using logistic regression (LR), random forest (RF) and support vector machine (SVM) were 0.814, 0.837 and 0.810, respectively. Then the binary logistic regression was used to construct the predictive model. What's more, the AUROC of the predicted model was 0.732 in the validation cohort of patients with NAFLD. And the combined AUROC of the six parameters was 0.716 in the mouse model fed with high-fat diet (HFD). In summary, we created a predictive model with six laboratory indicators for the diagnosis of NAFLD based on the machine learning method, which has the potential value for the diagnosis of the NAFLD.


The JAK inhibitor ruxolitinib abrogates immune hepatitis instigated by concanavalin A in mice.
Therapeutics that impair the innate immune responses of the liver during the inflammatory cytokine storm like that occurring in COVID-19 are greatly needed. Much interest is currently directed toward Janus kinase (JAK) inhibitors as potential candidates to mitigate this life-threatening complication. Accordingly, this study investigated the influence of the novel JAK inhibitor ruxolitinib (RXB) on concanavalin A (Con A)-induced hepatitis and systemic hyperinflammation in mice to simulate the context occurring in COVID-19 patients. Mice were orally treated with RXB (75 and 150 mg/kg) 2 h prior to the intravenous administration of Con A (20 mg/kg) for a period of 12 h. The results showed that RXB pretreatments were efficient in abrogating Con A-instigated hepatocellular injury (ALT, AST, LDH), necrosis (histopathology), apoptosis (cleaved caspase-3) and nuclear proliferation due to damage (PCNA). The protective mechanism of RXB were attributed to i) prevention of Con A-enhanced hepatic production and systemic release of the proinflammatory cytokines TNF-α, IFN-γ and IL-17A, which coincided with decreasing infiltration of immune cells (monocytes, neutrophils), ii) reducing Con A-induced hepatic overexpression of IL-1β and CD98 alongside NF-κB activation, and iii) lessening Con A-induced consumption of GSH and GSH peroxidase and generation of oxidative stress products (MDA, 4-HNE, NOx) in the liver. In summary, JAK inhibition by RXB led to eminent protection of the liver against Con A-deleterious manifestations primarily via curbing the inflammatory cytokine storm driven by TNF-α, IFN-γ and IL-17A.


TREACT. An expert system consultation program to aid in the diagnosis of transfusion reactions.
We have developed a rule-based, expert system consultation program, TREACT, to aid in the diagnosis of transfusion reactions. Given clinical signs, symptoms, and laboratory results, the program generates diagnoses, alerts the user when a medical director should be called, suggests follow-up actions, and makes recommendations for future transfusion. Diagnoses made by TREACT, including 121 reactions, were compared with those of the medical directors over a 6-month period. The overall diagnostic concordance between the medical directors and the program was 0.777. When this was corrected for chance association (kappa statistic), the concordance was 0.703 (p less than 0.0001), which can be interpreted on a qualitative scale as substantial agreement. The program has also been used successfully as a tool for training new technologists. Other advantages and possibilities that expert systems offer to transfusion medicine are discussed.


WWW-based access to object-oriented clinical databases: the KHOSPAD project.
KHOSPAD is a project aiming at improving the quality of the process of patient care concerning general practitioner-patient-hospital relationships, using current information and networking technologies. The studied application field is a cardiology division, with hemodynamic laboratory and the population of PTCA patients. Data related to PTCA patients are managed by ARCADIA, an object-oriented database management system developed for the considered clinical setting. We defined a remotely accessible view of ARCADIA medical record, suitable for general practitioners (GPs) caring patients after PTCA, during the follow-up period. Using a PC, a modem and Internet, an authorized GP can consult remotely the medical records of his PTCA patients. Main features of the application are related to the management and display of complex data, specifically characterized by multimedia and temporal features, based on an object-oriented temporal data model.


The job analysis of Korean nurses as a strategy to improve the Korean Nursing Licensing Examination.
This study aimed at characterizing Korean nurses' occupational responsibilities to apply the results for improvement of the Korean Nursing Licensing Examination. First, the contents of nursing job were defined based on a focus group interview of 15 nurses. Developing a Curriculum (DACOM) method was used to examine those results and produce the questionnaire by 13 experts. After that, the questionnaire survey to 5,065 hospital nurses was done. The occupational responsibilities of nurses were characterized as involving 8 duties, 49 tasks, and 303 task elements. Those 8 duties are nursing management and professional development, safety and infection control, the management of potential risk factors, basic nursing and caring, the maintenance of physiological integrity, medication and parenteral treatments, socio-psychological integrity, and the maintenance and improvement of health. The content of Korean Nursing Licensing Examination should be improved based on 8 duties and 49 tasks of the occupational responsibilities of Korean nurses.


Aggregation Mode, Host-Guest Chemistry in Water, and Extraction Capability of an Uncharged, Water-Soluble, Liquid Pillar[5]arene Derivative.
An uncharged, water-soluble per-ethylene-glycol pillar[5]arene derivative (1) was synthesized and its aggregation mode, host-guest chemistry in water and extraction ability was explored. Compound 1 is a liquid at room temperature; in water, limited self-aggregation occurred at high concentrations as deduced from diffusion NMR and dynamic light scattering. Compound 1 forms pseudo-rotaxane-like 1 : 1 host-guest complexes with 1,ω-di-substituted alkanes with association constants on the order of 103 -104 m-1 . Interestingly, NMR experiments showed that the guest location relative to the host ring system differs among the different complexes. In proof-of-concept experiments, compound 1 was shown to extract structurally related organic compounds from benzene into water with significant selectivity. Compound 1, which is a liquid at room temperature and has only limited interactions with its side arms, can, in principle, be regarded as a complement to or as a kind of type I porous liquid.


Steroid gradients across the cancerous breast: an index of altered steroid metabolism in breast cancer?
The concentrations of 17 beta-estradiol, estrone, testosterone (T), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate, androstenedione (A), cortisol and prolactin (PRL) were determined in the peripheral venous blood and in the lateral thoracic vein of 14 premenopausal and 34 postmenopausal women who underwent surgery for a breast carcinoma. The difference between the two blood samples, defined as concentration gradient across the cancerous breast, was calculated for all hormones. A significant peripheral-local concentration gradient was found for DHEA and A both in pre- and postmenopausal patients, whereas for T it was observed only in postmenopausal subjects. Furthermore, DHEA and A gradients were correlated to the presence of estrogen receptors as determined by a radioligand binding assay. An inverse relationship between DHEA gradient and the expression of estrogen receptors was observed in premenopausal women, whereas in postmenopausal patients an opposite, although not significant, trend was found. These results suggest that in the cancerous breast: (1) DHEA, A and T (the latter only in postmenopause) could be taken up from plasma, and thus there could be a storage of these steroids inside the breast tissue and/or perhaps some alterations in their local metabolism; (2) androgens could play a different role in breast carcinogenesis in relation to the estrogen circulating levels and to the expression of estrogen receptors.


Tibia valga morphology in osteoarthritic knees: importance of preoperative full limb radiographs in total knee arthroplasty.
Osteoarthritis of the knee is associated with deformities of the lower limb. Tibia valga is a contributing factor to lower limb alignment in valgus knees. We evaluated 97 valgus knees and 100 varus knees. Long-leg films were taken in weight bearing with both knees in full extension. For valgus knees, 52 knees (53%) had a tibia valga deformity. Average tibia valgus deformation was 5.0°. For varus knees, there was only 1 case of tibia valga (1%), with a deformation of 2.5°. The aim of this study was to assess the prevalence of primary tibia valga in valgus and varus knees and understand how it affects our approach to total knee arthroplasty (TKA). We recommend having full-leg length films when planning for TKA in valgus knees.


Batch effects correction for microbiome data with Dirichlet-multinomial regression.
Metagenomic sequencing techniques enable quantitative analyses of the microbiome. However, combining the microbial data from these experiments is challenging due to the variations between experiments. The existing methods for correcting batch effects do not consider the interactions between variables-microbial taxa in microbial studies-and the overdispersion of the microbiome data. Therefore, they are not applicable to microbiome data. We develop a new method, Bayesian Dirichlet-multinomial regression meta-analysis (BDMMA), to simultaneously model the batch effects and detect the microbial taxa associated with phenotypes. BDMMA automatically models the dependence among microbial taxa and is robust to the high dimensionality of the microbiome and their association sparsity. Simulation studies and real data analysis show that BDMMA can successfully adjust batch effects and substantially reduce false discoveries in microbial meta-analyses. An R package" BDMMA" for Windows and Linux is available at https://github.com/DAIZHENWEI/BDMMA/BDMMA, and a version for MacOS is provided at https://github.com/DAIZHENWEI/BDMMA/BDMMA_MacOS. Supplementary data are available at Bioinformatics online.


Treatment patterns of drug-naive patients with type 2 diabetes mellitus: a retrospective cohort study using a Japanese hospital database.
Guidelines for Type 2 diabetes mellitus (T2DM) management in Japan provide physicians the discretion to select treatment options based on patient pathophysiology of the disease. There exists a wide variation of preference for initial antidiabetes drugs (AD). The current database analysis aimed to understand the real world treatment patterns in drug-naive patients with T2DM in Japan. We analyzed data of patients (≥ 18 years) diagnosed with T2DM between October 2012 and September 2016 from the Medical Data Vision, a Diagnosis Procedure Combination database. The primary objective was to determine the proportion of T2DM patients receiving each type of treatment as first-line therapy among the drug-naive cohort. Of the 436,546 drug-naive patients, 224,761 received their first-line T2DM treatment in the outpatient setting. The mean age of the patient population was 65.6 years at index date. Dipeptidyl peptidase-4 (DPP-4) inhibitor was the most prescribed (56.8%) outpatient AD monotherapy, followed by metformin (15.4%). DPP-4 inhibitors were prescribed over metformin in patients with renal disease (odds ratio [OR]: 4.20; p < 0.0001), coronary heart disease and stroke (OR: 2.22; p < 0.0001). Male (OR: 1.03; p = 0.0026), presence of diabetic complications [retinopathy (OR: 1.33; p < 0.0001), neuropathy (OR: 1.05; p = 0.0037), nephropathy (OR: 1.08; p < 0.0001)] and a high baseline HbA1c (OR: 1.45; p < 0.0001) received treatment intensification during 180 days. DPP-4 inhibitors were the most prevalent first-line T2DM treatment followed by metformin in Japan. The findings from this retrospective analysis also support the previously published web survey results and can help understand the real world utilization of T2DM treatment.Trial registration Retrospectively registered.


Development of a quantitative PCR assay for the detection and enumeration of a potentially ciguatoxin-producing dinoflagellate, Gambierdiscus lapillus (Gonyaulacales, Dinophyceae).
Ciguatera fish poisoning (CFP) is an illness contracted through the ingestion of seafood containing ciguatoxins. It is prevalent in tropical regions worldwide, including in Australia. Ciguatoxins are produced by some species of Gambierdiscus. Therefore, screening of Gambierdiscus species identification through quantitative PCR (qPCR), along with the determination of species toxicity, can be useful in monitoring potential ciguatera risk in these regions. In Australia, CFP is prevalent in tropical Queensland and increasingly in sub-tropical regions of Australia, but has a report rate of approximately 10%. Yet the identity, distribution and abundance of ciguatoxin producing Gambierdiscus spp. is largely unknown. In this study, we developed a rapid qPCR assay to quantify the presence and abundance of Gambierdiscus lapillus, a likely ciguatoxic species first described from Australia. We assessed the specificity and efficiency of the qPCR assay. The assay was tested on 25 environmental samples from the Heron Island reef in the southern Great Barrier Reef, a ciguatera endemic region, to determine the presence and patchiness of this species across samples from Chnoospora sp., Padina sp. and Sargassum sp. macroalgal hosts.


Malignant hyperthermia associated with diabetic hyperosmolar hyperglycemic nonketotic state in a young man.
Malignant hyperthermia (MH) is a rare complication that often leads to adverse outcomes, catastrophic events, or death. Although various risk factors and underlying diseases are associated with this condition, unusual presentations may be missed. Malignant hyperthermia is an uncommon complication encountered during the treatment of patients with diabetic ketoacidosis. We present a case of an MH-like syndrome in a young Hispanic man who was diagnosed with new-onset diabetes mellitus and hyperglycemic hyperosmolar nonketotic state. The patient had no obvious risk or precipitating factors for MH.


The Janus-faced nature of prostasomes: their pluripotency favours the normal reproductive process and malignant prostate growth.
Prostasomes are submicron secretory granules synthesized, stored and secreted by the epithelial cells of the human prostate gland. They are membrane-surrounded also in their extracellular appearance and the membrane architecture is composite. They are believed to be life-giving and act as protectors of the spermatozoa in the lower and upper female genital tract on their way to the ovum. Hence, the prostasomes are immunosuppressive and inhibitory of complement activation. Further, they promote sperm's forward motility and have antioxidant and antibacterial capacities. The prostasomes with their many composite abilities seem to turn against the host cell after the age of 50 y being conducive to the transition of the normal prostate epithelial cell into a neoplastic cell and therewith lay the foundations of the very high prevalence of prostate cancer of men of more than 50 y of age.


Proteomic comparison of different synaptosome preparation procedures.
Synaptosomes are frequently used research objects in neurobiology studies focusing on synaptic transmission as they mimic several aspects of the physiological synaptic functions. They contain the whole apparatus for neurotransmission, the presynaptic nerve ending with synaptic vesicles, synaptic mitochondria and often a segment of the postsynaptic membrane along with the postsynaptic density is attached to its outer surface. As being artificial functional organelles, synaptosomes are viable for several hours, retain their activity, membrane potential, and capable to store, release, and reuptake neurotransmitters. Synaptosomes are ideal subjects for proteomic analysis. The recently available separation and protein detection techniques can cope with the reduced complexity of the organelle and enable the simultaneous qualitative and quantitative analysis of thousands of proteins shaping the structural and functional characteristics of the synapse. Synaptosomes are formed during the homogenization of nervous tissue in the isoosmotic milieu and can be isolated from the homogenate by various approaches. Each enrichment method has its own benefits and drawbacks and there is not a single method that is optimal for all research purposes. For a proper proteomic experiment, it is desirable to preserve the native synaptic structure during the isolation procedure and keep the degree of contamination from other organelles or cell types as low as possible. In this article, we examined five synaptosome isolation methods from a proteomic point of view by the means of electron microscopy, Western blot, and liquid chromatography-mass spectrometry to compare their efficiency in the isolation of synaptosomes and depletion of contaminating subcellular structures. In our study, the different isolation procedures led to a largely overlapping pool of proteins with a fairly similar distribution of presynaptic, active zone, synaptic vesicle, and postsynaptic proteins; however, discrete differences were noticeable in individual postsynaptic proteins and in the number of identified transmembrane proteins. Much pronounced variance was observed in the degree of contamination with mitochondrial and glial structures. Therefore, we suggest that in selecting the appropriate isolation method for any neuroproteomics experiment carried out on synaptosomes, the degree and sort/source of contamination should be considered as a primary aspect.


Location of plant species in Norway gathered as a part of a survey vegetation mapping programme.
Georeferenced species data have a wide range of applications and are increasingly used for e.g. distribution modelling and climate change studies. As an integrated part of an on-going survey programme for vegetation mapping, plant species have been recorded. The data described in this paper contains 18.521 registrations of plants from 1190 different circular plots throughout Norway. All species localities are georeferenced, the spatial uncertainty is provided, and additional ecological information is reported. The published data has been gathered from 1991 until 2015. The entries contain all higher vascular plants and pteridophytes, and some cryptogams. Other ecological information is also provided for the species locations, such as the vegetation type, the cover of the species and slope. The entire material is stored and available for download through the GBIF server.


Potentiation of neuronal activity by tonic GluD1 current in brain slices.
Ion channel function of native delta glutamate receptors (GluDR ) is incompletely understood. Previously, we and others have shown that activation of Gαq protein-coupled receptors (GqPCR) produces a slow inward current carried by GluD1R . GluD1R also carries a tonic cation current of unknown cause. Here, using voltage-clamp electrophysiological recordings from adult mouse brain slices containing the dorsal raphe nucleus, we find no role of ongoing G-protein-coupled receptor activity in generating or sustaining tonic GluD1R currents. Neither augmentation nor disruption of G protein activity affects tonic GluD1R currents, suggesting that ongoing G-protein-coupled receptor activity does not give rise to tonic GluD1R currents. Further, the tonic GluD1R current is unaffected by the addition of external glycine or D-serine, which influences GluD2R current at millimolar concentrations. Instead, GqPCR-stimulated and tonic GluD1R currents are regulated by physiological levels of external calcium. In current-clamp recordings, block of GluD1R channels hyperpolarizes the membrane by ~7 mV at subthreshold potentials, reducing excitability. Thus, GluD1R carries a G-protein-independent tonic current that contributes to subthreshold neuronal excitation in the dorsal raphe nucleus.


Pain and quality of life in leprosy patients in an endemic area of Northeast Brazil: a cross-sectional study.
Pain emerges as a challenge in the treatment of leprosy patients. In this study, we describe the prevalence and type of pain in patients with leprosy, and its effect on patients' quality of life in an endemic area of Northeast Brazil. A cross-sectional survey of 260 patients attending leprosy reference centres in Sergipe, Northeast Brazil was conducted. Individuals were assessed for the presence and type of pain, skin sensory loss, peripheral nerve enlargement, touch and pinprick sensations, mechanical allodynia and nerve palpation. Participants completed the Douleur Neuropathique 4 questionnaire, and we also used the Brief Pain Inventory scale and the World Health Organization Quality of Life-BREF instrument to arrive at our results. One hundred and ninety-five (75 %) patients reported pain, mostly of the neuropathic type. Pain was moderate in 84 (43.1 %) and severe in 94 (48.2 %) participants. The presence of pain was associated with disability (p = 0.001), leprosy reactions (p = 0.004) and lower quality of life. Most patients with neuropathic pain were treated with steroids, despite their low efficacy for this type of pain. Pain is highly prevalent among leprosy patients and is associated with low quality of life. Leprosy management should include a systematic assessment of the type of pain a patient experiences in order to provide adequate treatment.


Silver-promoted Friedel-Crafts reaction: concise total synthesis of (-)-ardeemin, (-)-acetylardeemin and (-)-formylardeemin.
Total syntheses of multidrug resistant inhibitors (-)-acetylardeemin 2a, (-)-ardeemin 2b, and (-)-formylardeemin 3 have been achieved within 10 steps starting from bromopyrroloinoline 13. The key step involves direct alkylation of 13 with prenyl tributylstannane 11 to yield 12 via a silver-promoted asymmetric Friedel-Crafts reaction. Highly efficient installation of the isoprenyl group allowed excellent overall yield. Moreover, the substrate scope of the asymmetric Friedel-Crafts reaction of 13 was expanded to include a variety of arenes 14 to afford natural product-like library analogues 15.


Biomechanical optimization of a custom-made positioning and fixing bone plate for Le Fort I osteotomy by finite element analysis.
This study integrates image-processing, finite element (FE) analysis, optimization and CAM techniques to develop a bone plate that can provide precise positioning and fixation for the Le Fort I osteotomy. Two FE 3D models using commercial mini-plate and continuous bone plates were generated by integrating computed tomography images and CAD system for simulations under the worst load condition. The goal driven optimization method was used to examine the system performance using certain minimum output values for relative micro-movement between the two maxillary bone segments and stress for the bone plate to seek maximum reduction volume in a continuous plate. The simulation results indicated that the maximum stress/relative micro-movement was 1269.20MPa/133.66μm and 418.37MPa/92.37μm for the commercial straight mini-plate and continuous fixation types, respectively. The optimal design plate found the volume reduction rate reach 24.3% compared to the continuous bone plate and the decreased variations in stress/relative micro-movement were 65.14% (442.36MPa) and 29.36% (96.53μm) when compared to values obtained from the commercial mini-plate plate. The optimal bone plate can be manufactured using a 5-axes milling machine and fixed onto the freed separate maxillary segments of a rapid prototyping model to provide precise positioning/fixation and present adequate strength/stability in the Le Fort I osteotomy.


Exploiting the use of agro-industrial residues from fruit and vegetables as alternative microalgae culture medium.
There is a need for searching new microalgae species, and the most suitable strategy to increase the cost-effectiveness of a microalgae culture system is to use resources of low costs, such as residues. This study aimed to evaluate the cultivation of microalgae isolated from the Brazilian Northeast region (Lagerheimia longiseta, Monoraphidium contortum, and Scenedesmus quadricauda) in an alternative medium of low cost (biocompost of discarded fruits and vegetables) with a view to possible applications in the food industry. Microalgae cultivated in the conventional synthetic medium was used as control. The cultivation of microalgae in the alternative medium allowed suitable cell growth, and improved the antioxidant activity and the levels of monounsaturated fatty acid and polyunsaturated fatty acid compared to the synthetic medium. The cultivation of S. quadricauda and L. longiseta species in the alternative medium resulted in increased protein content and/or total phenolic content, and improved health indices (lower levels of atherogenic, thrombogenic, and hypercholesterolemic saturated fatty acids indices, and higher levels of desired fatty acids index) compared to cultivation in synthetic medium. The cultivation of M. contortum in the alternative medium contributed to the production of higher lipid content, mainly saturated fatty acid (palmitic acid), which contributed negatively to the health indices. This study proved that S. quadricauda and L. longiseta microalga species from freshwaters have significant potential for distinct applications in functional food industries, and the biocompost of discarded fruits and vegetables is a suitable medium for microalgae cultivation.


Effectiveness of fluoroquinolone antimicrobials in addition to tetracyclines for Japanese spotted fever: A retrospective analysis using a national inpatient database.
This study aim to evaluate the effectiveness of fluoroquinolone (FQ) antimicrobial therapy in combination with tetracyclines (TCs) in patients with Japanese spotted fever (JSF) using a nationwide inpatient database in Japan. We identified hospitalized patients diagnosed with JSF who were enrolled in the Japanese Diagnosis Procedure Combination inpatient database from July 2010 to March 2021. Patients who received FQ plus TC on the day of admission were compared with patients who received TC alone on the day of admission, using inverse probability of treatment weighting. The primary outcome was in-hospital mortality. Secondary outcomes were in-hospital complications, total hospitalization costs, and length of hospital stay. We identified 1060 eligible patients. Of these, 434 (41%) received FQ plus TC on the day of admission and 626 (59%) received TC alone on the day of admission. Inverse probability of treatment weighting showed no statistically significant differences between the groups in in-hospital mortality, in-hospital complications, total hospitalization costs, and length of hospital stay. This study did not show any significantly improved effectiveness using FQ antimicrobials in combination with TCs for treating JSF. Clinicians may need to be cautious in administering FQ and TC antimicrobials concomitantly in routine practice.


Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) serves as an endothelial receptor for advanced glycation end products (AGE).
Advanced glycation end products (AGE) are known to serve as ligands for the scavenger receptors such as SR-A, CD36 and SR-BI. In the current study, we examined whether AGE is recognized by lectin-like oxidized low density lipoprotein receptor-1 (LOX-1). Cellular binding experiments revealed that AGE-bovine serum albumin (AGE-BSA) showed the specific binding to CHO cells overexpressing bovine LOX-1 (BLOX-1), which was effectively suppressed by an anti-BLOX-1 antibody. Cultured bovine aortic endothelial cells also showed the specific binding for AGE-BSA, which was suppressed by 67% by the anti-BLOX-1 antibody. Thus, LOX-1 is identified as a novel endothelial receptor for AGE.


Presence and characteristics of epidermal growth factor receptors in human fetal small intestine and colon.
In the present study, we demonstrate for the first time the presence of important concentrations of EGF binding sites in isolated epithelial cells of both human fetal small intestine and colon as early as 12 weeks gestation. The pattern of EGF binding in the small intestine between 12 and 17 weeks show that binding was significantly higher (2.5-fold) in younger fetuses than in older fetuses. Moreover, the fetal colon exhibited a much higher binding capacity (1.5-2.5 times) than corresponding intestinal cells for all age groups studied. Analysis of Scatchard representations reveal that the concentration of high- and low-affinity binding sites in colonic epithelial cells are twice the values observed in corresponding intestinal cells. The present data raise interesting possibilities as to the role of this growth factor in human fetal gut development.


A case-study approach. Fellows' perceptions of a teaching course.
To determine general and behavioral pediatric fellows' perceptions of a formal teaching course. Qualitative research design using a case-study approach. Children's Hospital in Boston, Mass. All first-year general and behavioral pediatric fellows (n=5) taking the teaching course. A 12-week teaching course given to all participants. Data were collected using questionnaires completed by fellows; focused, open-ended interviews with fellows; and student ratings of fellows' teaching. Analysis revealed that after the course, the fellows perceived "teaching'' as an interactive, student-directed process; attained a greater awareness of the value of feedback; recognized new teaching opportunities; and changed their teaching strategies to reflect student-directed teaching. This formal course influenced fellows' approach to teaching.


Risk of Suicide in Patients With Bipolar Disorder Having Comorbid Chronic Pain Disorders: Insights From the Nationwide Inpatient Sample Data From 2016 to 2018.
Bipolar disorders (BDs) are associated with significant risk of suicide. BD patients (age ≥18 years) admitted to the hospital were identified from the National Inpatient Sample dataset. Based on the secondary diagnosis of chronic pain disorder (CPD), patients were stratified into two groups (1) BD with CPD (BD + CPD) and (2) BD without CPD (BD - CPD). Groups were matched (1:1) for the type of BD and compared for baseline characteristics and suicidal ideation/attempt (SI/SA). Compared with BD - CPD, most patients in the BD + CPD group were older (mean age, 47.6 vs. 40.4 years), female (58.4% vs. 55.2%), and white (77.2% vs. 66.7%). After adjusting for covariates, compared with the BD - CPD group, the BD + CPD group had 21% more risk of SI/SA (odds ratio, 1.21, p < 0.001). CPD is independently associated with the increased risk of suicide among patients with BD. Thus, comorbid CPD among patients admitted for BD can be an essential risk factor for suicide.


Child and adolescent depression intervention overview: what works, for whom and how well?
The authors review the currently available evidence-based treatments of child and adolescent major depressive disorder. Medication monotherapy, namely with selective serotonin reuptake inhibitors, is supported by large clinical trials in adolescents. For mild to moderate depression, cognitive behavior therapy (CBT) and interpersonal therapy are reasonable options as monotherapies. There is also evidence that the combination of medication and CBT is superior to medication alone for accelerating the pace of treatment response and remission, despite some negative studies. Response, remission, and recurrence rates after acute treatment and during long-term follow-ups are also presented and discussed.


Functional organization in the cat's pulvinar complex.
The responses of 192 single units in the cat's pulvinar-complex, comprising the inferior, medial and lateral pulvinar nuclei, were studied in paralysed cats, lightly anaesthetized with N2O/O2 supplemented with pentobarbitone. About 60% of the cells were visually driven and their receptive fields classified as either diffuse, concentric, movement sensitive, direction sensitive or orientation sensitive. The response fields of such cells were commonly large. Response field maps for the movement and direction sensitive cells formed a heterogenous population with uniform on-off fields to more complex arrangements with on- or off-centres, often with only partial surrounds; other cells responded exclusively to moving stimuli. A dual representation of the visual field was found in the pulvinar-complex corresponding to the striate and tectal recipient zones described anatomically by others. The representation in the striate recipient zone comprised an oblique column running medio-laterally and rostro-caudally through the inferior pulvinar and lateral margin of the medial pulvinar. The peripheral visual field was represented laterally and the vertical meridian medially; the upper visual field was represented dorso-laterally in the medial pulvinar and the lower visual field caudo-ventrally within the inferior pulvinar. That this visuotopic organization corresponded to the striate recipient zone was established by tracing the retrograde transport of HRP. Medial to the striate zone evidence for a second visual field representation was found, apparently more randomly organized than the striate zone, corresponding to the presumed tectal recipient zone. These results support the assertion that cytoarchitectural boundaries do not necessarily delineate functional (visuotopically organized) regions. These observations suggest caution when comparing cytoarchitecturally defined regions between species; rather, 'functionally equivalent' regions should be compared.


On the Mathematics of the Fraternal Birth Order Effect and the Genetics of Homosexuality.
Mathematicians have always been attracted to the field of genetics. The mathematical aspects of research on homosexuality are especially interesting. Certain studies show that male homosexuality may have a genetic component that is correlated with female fertility. Other studies show the existence of the fraternal birth order effect, that is, the correlation of homosexuality with the number of older brothers. This article is devoted to the mathematical aspects of how these two phenomena are interconnected. In particular, we show that the fraternal birth order effect implies a correlation between homosexuality and maternal fecundity. Vice versa, we show that the correlation between homosexuality and female fecundity implies the increase in the probability of the younger brothers being homosexual.


Sulfated oligosaccharides block antibodies to many Dictyostelium discoideum acid hydrolases.
The lysosomal hydrolases of the cellular slime mold, Dictyostelium discoideum, possess a common posttranslational modification which is extremely antigenic in rabbits and mice. Rabbit antisera and mouse monoclonal antibodies that recognize this determinant cross-react with a group of at least 40-50 highly negatively charged proteins which include most or all of the lysosomal enzymes. (Knecht, D. A., Dimond, R. L., Wheeler, S., and Loomis, W. F. (1984) J. Biol. Chem. 259, 10633-10640). The present study demonstrates that the determinant is found on certain N-linked oligosaccharides derived from one of these proteins. An esterified sulfate is absolutely required for antigenicity.


Chronic alcohol intake modifies phorbol ester binding in selected rat brain areas.
3H-Phorbol 12,13 dibutyrate binding to rat brain was modified by chronic ethanol treatment. Among the areas examined hippocampus and cortex showed a decrease in Bmax values of 32 and 24% respectively. No significant effect was observed in hypothalamus and cerebellum. In vitro ethanol did not modify the binding in all the areas except at molar concentrations. In hippocampus and cortex the direct measurement of protein kinase C activity indicated that the decrease in phorbol ester binding was accompanied with a concomitant decrease in kinase activity. The results indicate that chronic ethanol treatment leads to an inhibition of brain protein kinase C function.


Polyploidy origin of wheatgrass Douglasdeweya wangii (Triticeae, Poaceae): evidence from nuclear ribosomal DNA internal transcribed spacer and chloroplast trnL-F sequences.
To study hybrid speciation in wheatgrass Douglasdeweya wangii and to investigate the evolutionary pattern of nuclear ribosomal DNA (nrDNA) internal transcribed spacer sequences (ITSs) in allotetraploids, DNA sequence variation of ITSs and chloroplast trnL-F sequences from D. wangii and its putative donors were analyzed. The ITSs revealed that D. wangii had an StP genome composition. Most accessions of D. wangii had one parental ITS copy in their genome, one accession had two parental ITSs. The trnL-F sequences revealed an especially close relationship of Pseudoroegneria to all D. wangii individuals included, and the two accessions of Pseudoroegneria tauri (PI401324 and PI401331) were maternal candidates of the studied D. wangii individuals. Both of ITS and trnL-F trees suggested multiple origins and recurrent hybridization of D. wangii. Thus, the results suggested that: (1) the St and P genome in allotetraploid D. wangii were donated by Pseudoroegneria and Agropyron, respectively;(2) Pseudoroegneria was the maternal donor of D. wangii, and P. tauri 26 (accession PI401324) and P. tauri 27 (accession PI401331) were most likely the potential candidates of maternal donors; (3) D. wangii individuals studied here showed multiple origins and experienced recurrent hybridization; and (4) bidirectional interlocus concerted evolution of ITSs had occurred in most D. wangii accessions, while in one accession concerted evolution among homeologous loci did not occur.


Imaging and minimally invasive endovascular therapy in the management of portal vein thrombosis.
Thrombosis of the portal venous system, although rare in the general population, is commonly diagnosed in patients with specific underlying conditions including prothrombotic diseases, cirrhosis, hepatobiliary malignancy, and intraabdominal inflammation. Recent improvements in imaging have played a fundamental role in increased detection of portal vein thrombosis (PVT), frequently reported in asymptomatic patients as an incidental finding. Minimally invasive, endovascular therapy is a medically rational option to achieve recanalization of the portal vein as an adjunct to conservative medical management. This review focuses on the advances in imaging modalities to diagnose, stage and follow-up PVT, and gives a short overview of the available endovascular techniques in this field.


Mental illness and criminal violence.
This article examines the relationship between criminal violence and mental illness. Our data suggest that mentally ill persons tend to have an increased risk for committing violent offenses, and that the violent offending by these individuals tends to be recidivistic. Our findings suggest that parents who have both committed violent offenses and experienced a psychiatric hospitalization increase the risk of violent offending among their offspring. We propose the hypothesis that mentally ill parents transmit a biological characteristic which may genetically predispose their child towards criminal violence. Prenatal disturbances during critical periods of fetal development may provide clues regarding the etiology of criminal violence.


Direct comparison between two quantitative assays in the measurement of maternal anti-HPA-1a antibody in neonatal alloimmune thrombocytopenia (NAIT).
Around 80% of severe neonatal alloimmune thrombocytopenia (NAIT) cases in the Caucasian population are due to anti-HPA-1a antibodies. However, the relationship between anti-HPA-1a antibody quantity and severity of NAIT has been subject to debate, possibly due to discrepant results between studies incorporating different assays (such as ELISA and MAIPA) and the number of samples. The aim of this study was to compare the level of maternal anti-HPA-1a antibodies in the same samples, using two different methods; quantitative ELISA and quantitative MAIPA. At the same time, the relationship between the maternal anti-HPA-1a antibody quantity and the newborn platelet count was examined. Plasma samples were obtained from HPA-1a negative mothers giving birth to children with different platelet counts (i.e. NAIT vs normal platelet count). The antibody levels were quantified blindly in the respective assays using standards calibrated against the international standard NIBSC 03/152. A linear correlation was observed between quantitative MAIPA and quantitative ELISA results. However, there were many individual variations giving a mean ratio of disagreement between the quantitative ELISA and quantitative MAIPA of 2.84. Furthermore, regression analysis revealed a significant relation between anti-HPA-1a antibody quantity measured by MAIPA, but not ELISA, and the newborn platelet count. The results indicate that differences observed between various studies with regard to NAIT severity and anti-HPA-1a quantity could partly be due to different assays used.


Serial chest CT in cryptogenic organizing pneumonia: Evolutional changes and prognostic determinants.
Cryptogenic organizing pneumonia (COP) is corticosteroid responsive but residual computed tomography (CT) chest changes are often noted. The present study examined clinical and HRCT features of COP in which there was incomplete resolution. We studied 93 patients with histopathologically confirmed COP and serial HRCT imaging. Clinical features were assessed, and serial CT images were analysed. Uni- and multivariate analyses were performed to determine clinical or imaging factors related to incomplete resolution on CT. Complete resolution on CT imaging was seen in 21/93 patients (23%) and residual abnormalities were seen in 72/93 patients (77%). In univariate analysis, total lesion (P = 0.036), degree of consolidation (P = 0.011), treatment duration (P < 0.001) and single-breath carbon monoxide diffusing capacity of lung (P = 0.021) were significantly associated with residual imaging abnormalities. In multivariate analysis, extent of consolidation (P = 0.018; odds ratio (OR) = 14.92) and treatment duration (P = 0.011; OR = 1.32) remained as significant factors linked to residual abnormalities. CT images in unresolved COP were akin to fibrotic non-specific interstitial pneumonia (fNSIP) in 53/72 (74%) patients. Clinical, radiological and lung diffusion measurements were related to incomplete resolution on CT after COP. Imaging abnormalities on CT chest generally resembled fNSIP.


High intensity light emitting diode array as an alternative exposure source for the fabrication of electrophoretic microfluidic devices.
A commercially available array of light emitting diodes (LEDs), namely a UV Shark series LED high flux array, was evaluated as a light source for photolithographic patterning of SU-8 photoresist for the fabrication of templates suitable to make poly(dimethylsiloxane) (PDMS) microchips for electrophoresis. At a distance of 15 cm from the substrate, a relatively even intensity of 0.76+/-0.05 mW/cm(2) was obtained over an area sufficient for patterning a 10 cm (4 in.) silicon wafer. The exposure source was evaluated using a spiral mask design covering a 10 cm wafer. PDMS replicates of this template made in a 25 microm thick layer of SU-8 3025 showed little variation in width over the surface of the substrate, with a variation of 3.2% RSD (n=36) and a maximum range in widths of 7.8% of the mean channel width. The use of the optional metal reflector available with the LED array provided partial collimation of the light allowing near vertical structures to be produced across the entire wafer, something which was not possible without the reflector. SU-8 masters prepared using the LED array were compared to masters made using an alternative cheap lithographic source, namely a gel crosslinker. The SU-8 features were much narrower with the LED array than the crosslinker due to the multiple light sources in the crosslinker. A PDMS microchip made using a SU-8 template created using the Shark UV LED array was used for the electrophoretic separation of three anionic fluorescent dyes, with efficiencies up to 32,000 plates. Given that the LED array can be purchased and assembled for less than US$ 500, the Shark UV LED array is a promising alternative to more expensive lithographic light sources and will have significant appeal to many researchers wishing to undertake research in microfluidics around the world.


Plasma hormones, metabolites, milk production, and cholesterol levels in Murrah buffaloes fed with Asparagus racemosus in transition and postpartum period.
Ten dry and pregnant Murrah buffaloes were selected to investigate the effect of Asparagus racemosus feeding on hormones, metabolites, milk yield, and plasma cholesterol levels. The treatment groups of buffaloes were fed with A. racemosus (shatavari) @ 150 g/day/animal during prepartum and @ 300 g/day/animal during the postpartum period. Blood samples collected on -6, -4, -2-week, day of parturition (0), and +2, +4, and +6-week postpartum were analyzed for plasma total cholesterol, triglycerides, HDL, low-density lipoproteins (LDL), prolactin, cortisol, and blood metabolites. Milk samples collected at weekly intervals (+1, +3, +5, and 7 weeks) were analyzed for total milk fat cholesterol. Prepartum plasma cholesterol concentrations were significantly higher in treatment group over the control (P < 0.05). Mean plasma triglycerides, LDL cholesterol, HDL cholesterol, glucose, and nonesterified fatty acid (NEFA) levels varied nonsignificantly between groups. Plasma prolactin and cortisol concentrations were significantly (P < 0.01) more in treatment group than in control group. On day of parturition, plasma prolactin, cortisol, LDL, and plasma total cholesterol were higher (P < 0.01) in treatment group buffaloes in comparison to control group. A. racemosus feeding significantly (P < 0.01) increased plasma prolactin, cortisol (P < 0.01), and milk fat cholesterol (P < 0.05) without affecting total cholesterol, HDL, LDL, glucose, and NEFA concentrations. The buffaloes of treatment group produced more milk (@ 0.526 kg/animal/day) suggesting thereby that A. racemosus is galactopoietic. It was concluded that feeding of A. racemosus increases plasma prolactin and cortisol and decreased plasma total cholesterol and LDL concentration.


Plasma lipids, lipoproteins and apoproteins in a case of apo C-II deficiency.
A new case of apo C-II deficiency is described. The patient had plasma triglyceride levels ranging from 10.2-30.5 mmol/l. Apo C-II deficiency was confirmed by gel electrophoresis, isoelectric focusing and immunochemistry. In this patient plasma lipoproteins were mainly chylomicrons and very low density lipoproteins, LDL and HDL levels being very low. Infusion of normal plasma effectively reduced plasma triglycerides and enhanced low density and high density lipoproteins cholesterol levels. These data suggest that in vivo a precursor-product relationship exists between triglyceride rich lipoproteins and LDL and HDL, and further stress the role of the lipoprotein lipase-apo C-II system in modulating these metabolic interconversions.


Association of Parkinson disease age of onset with DRD2, DRD3 and GRIN2B polymorphisms.
Dopamine and glutamate are crucial neurotransmitters in Parkinson disease (PD). While recent large meta-analyses reported that genetic variation of dopamine (DRD2, DRD3) and glutamine (NMDA, GRIN2B) neurotransmitter receptors was not associated with PD risk, they could conceivably influence PD phenotype. We studied the association of these receptor polymorphisms relating to PD age of onset. There were 664 PD patients and 718 controls, all Caucasian, with stored DNA at Mayo Clinic, Jacksonville, Florida. Genotyping was performed for DRD2 (Taq 1A, rs1800497), DRD3 (rs6280), and NMDA (GRIN2B, rs7301328) polymorphisms with ABI Taqman assays. Single nucleotide polymorphism associations with age of onset were evaluated using dominant, recessive, and additive genotypic models. DRD3 variant carriers had an approximate 4.4-year decrease in mean age of onset when both copies of the minor allele were present (P = 0.0034) and an approximate 1.5-year decrease in mean age at onset for every additional minor allele (P = 0.023) (recessive and additive models, respectively). There was no association with age of onset for DRD2 or GRIN2B under any statistical model (all P ≥ 0.22). The DRD3 (rs6280) polymorphism, but not DRD2 (Taq1A) or GRIN2B, influences younger PD age of onset in the US Caucasian population. Validation of these findings in larger studies with other ethnic groups is indicated.


Compartment syndrome of the forearm following an electromyographic assessment.
We present a case of compartment syndrome after electromyographic study of the upper limbs. The cause was the unintentional punction and laceration of the ulnar artery while the electromyography was being performed.


Interactions between bladder tumor cells as tumor spheroids from the cell line J82 and human endothelial cells in vitro.
Multicellular tumor spheroids (MCTS) are a reliable model of nonvascularized tumor cell aggregates showing a well defined three-dimensional growth pattern and are comparable with small metastatic cancer cell complexes in blood circulation. In the present study we have established a co-culture system of multicellular bladder tumor spheroids with human endothelial cells on extracellular matrix (ECM) in order to investigate morphological and proliferative changes of endothelial and tumor cells within a defined time of cell-cell interaction. The MCTS--endothelial cell--extracellular matrix complex was observed within coculture periods from 1/2 to seven days. Morphological changes (light microscopy, scanning and electron microscopy) indicated that MCTS are not influenced by cocultured endothelial cells. The tumor cells invaded into the ECM after degradation of endothelial cells in the center of the contact zone. Endothelial cells, however, showed degenerative changes as well as a complex reaction in their proliferation activities. We could recognize an initial increase of proliferation of endothelial cells next to the MCTS. Later on, endothelial cells next to invading tumor cells showed changes in morphological polarity. The model system used has the advantage of using human tumor tissue. It distinguishes between basic cellular mechanisms like adherence, migration, DNA synthesis and proliferation in the study of the contact of tumor cells and vascular endothelial cells as an important event in hematogenous tumor spread.


Intermittent GnRH antagonist plus progestin contraception conserving tonic ovarian estrogen secretion and reducing progestin exposure.
The present study was designed to evaluate the effectiveness of a once-weekly regimen of GnRH antagonist followed by a progestin as a potential new contraceptive method. On menstrual cycle days 2, 9, 16, and 23 (onset of menses = Day 1) monkeys were divided into two groups: 1) those injected sc with 0.1 mg/kg Nal-Glu GnRH antagonist in saline and those given only vehicle (control). On cycle days 15 to 26, each treated female was administered 25 micrograms norgestimate/day orally. This was continued for three treatment cycles (84 days). Weekly injections of Nal-Glu GnRH antagonist effectively blocked completion of folliculogenesis, ovulation, and corpus luteum function as judged by serum LH, E2, and P levels. Serum progesterone was undetectable (less than 0.1 ng/ml) during the treatment cycles. Importantly, serum estradiol levels during GnRH antagonist plus norgestimate treatments were maintained at 35 +/- 7 pg/ml. Upon the cessation of norgestimate treatment on day 26 in each cycle, menses uniformly began within 2 or 3 days. Regarding recovery, apparently normal and presumably ovulatory menstrual cycles, as judged by timely estradiol elevations, midcycle LH surges, and luteal phase progesterone patterns, were manifest immediately following termination of the final GnRH antagonist plus norgestimate treatment cycle. Endometrial biopsies removed on day 26 of control cycles, and on day 26 of the third treatment cycle revealed appropriate late secretory phase endometrium having tortuous endometrial glands and superficial stromal edema. Histological sections of ovaries removed at the end of the GnRH antagonist plus norgestimate treatment revealed multiple small and medium-sized developing and atretic follicles, having maintained serial ablation of the potentially maturing follicles.(ABSTRACT TRUNCATED AT 250 WORDS)


Rapid estimation of the biochemical methane potential of plant biomasses using Fourier transform mid-infrared photoacoustic spectroscopy.
Biochemical methane potential (BMP) is a very important characteristic of a given feedstock for optimisation of its use in biogas production. However, the long digestion time needed to determine BMP is the main limitation for the use of this assay during the operation of anaerobic digesters to produce biogas. Fourier transform mid-infrared photoacoustic spectroscopy (FTIR-PAS) was used to predict the BMP of 87 plant biomasses. The developed calibration model was able to explain 81% of the variance in the measured BMP of a selected test set with a root mean square error (RMSE) of 40NLCH4kg(-1) of volatile solids (VS) and a ratio of performance to deviation (RPD) of 2.38. The interpretation of the regression coefficients used in the calibration revealed a positive correlation of BMP with easily degradable compounds (amorphous cellulose, hemicellulose and aliphatic compounds) and a negative correlation with inhibitors of cellulose hydrolysis (lignin, hemicellulose).


Critical role of glutamine metabolism in cardiomyocytes under oxidative stress.
Metabolic remodeling in cardiomyocytes is deeply associated with the pathogenesis of heart failure (HF). Glutaminolysis is an anaplerotic pathway that incorporates α-ketoglutarate (αKG) derived from glutamine into the tricarboxylic acid (TCA) cycle. It is well known that cancer cells depend on glutamine for their increased energy demand and proliferation; however, the physiological roles of glutamine metabolism in failing hearts remain unclear. To investigate the regulatory mechanisms and biological effects of glutamine metabolism in oxidative stress-induced failing myocardium. The intracellular levels of glutamine, glutamate, and αKG were significantly decreased by H2O2 stimulation in rat neonatal cardiomyocytes (RNCMs). To better understand the metabolic flux in failing myocardium, we performed a stable isotope tracing study and found that glutaminolysis was upregulated in RNCMs under oxidative stress. Consistent with this, the enzymatic activity of glutaminase (Gls), which converts glutamine to glutamate, was augmented in RNCMs treated with H2O2. These findings suggest that glutamine anaplerosis is enhanced in cardiomyocytes under oxidative stress to compensate for the reduction of αKG. Furthermore, the inhibition of Gls reduced cardiac cell viability, ATP production, and glutathione (GSH) synthesis in RNCMs with H2O2 stimulation. Finally, we evaluated the effects of αKG on failing myocardium and observed that dimethyl α-ketoglutarate (DMKG) suppressed oxidative stress-induced cell death likely due to the enhancement of intracellular ATP and GSH levels. Our study demonstrates that under oxidative stress, glutaminolysis is upregulated to compensate for the loss of αKG and its replenishment into the TCA cycle, thereby exerting cardioprotective effects by maintaining ATP and GSH levels. Modulation of glutamine metabolism in failing hearts might provide a new therapeutic strategy for HF.


The use of a chimaeric sero-muscular flap to prevent anastomotic leakage in head and neck reconstruction with free ileocolon flap.
In simultaneous reconstructions of cervical oesophagus and voice mechanism with free ileocolon flap, one of the most cumbersome complications is the anastomotic leakage at the junction between the colon and thoracic oesophagus. Since 2007, a chimaeric sero-muscular flap has been islanded from the distal end of the voice tube to cover the anterior aspect of the colo-oesophageal junction. Fourteen patients undergoing reconstruction of the hypopharyngo-laryngectomy defects were consecutively treated with the sero-muscular flap. The leakage rate was compared with a group of 15 patients who were reconstructed with a free ileocolon flap prior to the adoption of the new procedure. All flaps survived completely. Swallowing function (scores 5-7), was restored in 69% of the patients. Speech function was restored (scores 4-5) in 59% of the patients. In the treatment group, only one patient suffered from anastomotic leakage compared to four patients in the control group. The chimaeric sero-muscular flap can secure the colo-oesophageal junction, improving the healing process and preventing delays in the administration of adjuvant therapy.


Pleasure and preference in a two-dimensional sensory space.
A matrix of 25 gustatory stimuli combined five sucrose concentrations (0.15 to 2.35 mole/l) with five temperatures (10 to 50 degrees C) or sournesses (pH 1.8 to 5.7). On four different days at the same time of day ten healthy young men served as subjects. Sweet pleasure/displeasure vs. temperature pleasure/displeasure was studied in four subjects and sweet pleasure/displeasure vs. sourness pleasure/displeasure in six subjects. Throughout the first session the 25 stimuli were presented for 5 s each and the subject gave a magnitude estimate of his pleasure or displeasure in response to one dimension of the matrix (e.g. sweetness) regardless of the other. Similarly, throughout the second session, the same stimuli were presented and the subject rated his pleasure or displeasure in response to the second dimension of the matrix (e.g. sourness or temperature) regardless of the first. For the third session however, the subject himself was invited to mix samples, this to allow a behavioural choice in one dimension of the matrix the other being imposed (e.g. he could mix sucrose and water ad libitum for five imposed temperatures). For the last session the subject could adjust the previously imposed dimension, the other previously adjustable dimension being now imposed (e.g. he could modify temperature for five imposed sucrose concentrations). The results of the first two sessions showed that pleasure/displeasure resulted from a two-dimensional combination of the taste modalities offered. The results of the last two sessions showed that the subjects tended to maximize their sensory pleasure. The operant choices coincided with the ratings obtained in the first two sessions. Whether a dimension of the matrix was imposed or operantly adjustable made no difference on the results; the subjects tended to maximize sensory pleasure in the imposed dimension as well as in the adjustable dimension. The subjects therefore maximized their pleasure in the two-dimensional space offered.


Endosonographic monitoring of Sphinkeeper® prostheses movements: does physical activity have an impact?
The Sphinkeeper® procedure for treating faecal incontinence (FI) may be associated with potential implant migration (IM) and dislocation (ID), with considerable variations regarding their occurrence and effects on consecutive functional outcome. This study assessed IM and ID following the Sphinkeeper® procedure and its correlation with physical activity. This was a prospective observational clinical study of ten patients undergoing Sphinkeeper® operation due to FI between August 2020 and November 2020 at the Medical University of Vienna. Patients were followed-up after 1, 2, 3 and 6 months and 1 year postoperatively. Each follow-up visit included endosonographic monitoring of protheses location and manometric examinations. Additionally, functional outcome and physical activity were assessed using validated standardized questionnaires. The median number of prostheses implanted was 10 (IQR 9-10). The St. Mark's incontinence (SMS) score improved significantly until the last follow-up (p = 0.049), without observing a significant effect on the physical SF-12 score. The median rate of implants leading to IM and ID was 3 (range 1-4) and 2 (range 1-2) after 3 months of follow-up. A strong association of deltaSMS with number of dislocated prostheses at one month after Sphinkeeper® implantation was observed (r = 0.654, p = 0.078). Physical activity, assessed by the international physical activity questionnaire, did not have an impact on the correct prosthesis placement (1 month: p = 0.527; 2 months: p = 0.886; 3 months: p = 0.180; 6 months: p = 0.111). IM and ID of Sphinkeeper® prostheses occurred frequently early after surgery and affected functional outcome negatively. Physical activity did not have an influence on the implants displacement.


Psychological characteristics of individuals high and low in their ability to cope with tinnitus.
Seventy-seven individuals with tinnitus were assessed with a variety of standardized psychological tests and scales assessing subjective loudness, annoyance, and ability to cope with the tinnitus. Significant correlations were found between coping ability and psychological test scores. Based on their responses on the coping scale, subjects were classified as "high copers" (N = 45) or "low copers" (N = 32). For comparison purposes, the two tinnitus groups were also compared to a group of chronic pain (headache) patients (N = 34) and to a group of nonheadache/non-tinnitus controls (N = 65). Results revealed the low coping tinnitus subjects to be significantly more psychologically distressed than the high copers. Of interest, the low copers were very similar in their psychological profiles to the chronic pain patients, while the high copers were similar to the non-patient control subjects. Implications of these results are discussed.


Utilization of mental health services over a given period.
The utilization of the mental health services was studied over a 2-year period for a cohort of 211 consecutively admitted patients from a catchment area in Oslo. A cumulative index for service consumption showed that 10% of the patients used 75% of the service resources. A bi-variate and a multi-variate analysis showed how psychopathology and sociodemographic factors contributed to the degree of service consumption.


Occult gastrointestinal carcinoma causing metastatic clostridial soft-tissue infection. Report of two cases.
The association between nontraumatic, metastatic, clostridial soft-tissue infection and malignancy is well recognized, particularly when Clostridium septicum is involved. This report presents two patients with nontraumatic, metastatic, soft-tissue infection due to C. septicum and reviews the English medical literature. Eighty-four percent of the reported patients were found to have colon carcinoma, which was postulated to be the portal of entry. Prognosis is poor, but early recognition and antimicrobial therapy with prompt and aggressive surgical intervention, both for the soft-tissue infection and the abdominal process, may lower the high mortality.


Light-potentiation of acoustic startle response (ASR) and monoamine efflux related to fearfulness in Fyn-deficient mice.
Fyn tyrosine kinase deficient mice are known to show increased fearfulness. We investigated the fear response of these mice using the light-potentiation of the acoustic startle response (ASR) and examined its neurochemical correlates using in vivo microdialysis. Female homozygous Fyn-deficient mice showed an enhancement of the startle amplitude under a bright light while heterozygotes and wild-types did not show such a change. Along with these behavioral findings, the homozygous Fyn-deficient mice showed an increase in extracellular serotonin (5-HT) and dopamine (DA) in the prefrontal cortex and 5-HT in the hippocampus when they were exposed to bright light, while heterozygous and wild-type mice did not show such changes. These results suggest that the increased fearfulness of Fyn-deficient mice is related to enhanced serotonergic and dopaminergic activity in the prefrontal cortex and limbic system.


Different types of glomerulopathic light chains interact with mesangial cells using a common receptor but exhibit different intracellular trafficking patterns.
Patients with plasma cell dyscrasias may have circulating light chains (LCs), some of which are nephrotoxic. Nephrotoxic LCs can affect the various renal compartments. Some of these LCs may produce predominantly proximal tubular damage, while others are associated with distal nephron obstruction (the so-called "myeloma kidney"). Both these are considered tubulopathic (T) LCs. A receptor has been found in proximal tubular cells (cubilin/megalin complex), which mediates the absorption of LCs and is involved in the pathogenesis of tubulopathies that occurs in these patients. Another group of nephrotoxic LCs is associated with glomerular damage and these are considered as glomerulopathic (G). These patients with G-LCs may develop AL-amyloidosis (AL-Am) or LC deposition disease (LCDD). Recent evidence indicates that the physicochemical characteristics (amino-acid composition and conformation of the variable region) of a given nephrotoxic LC may be the most significant factor in determining the type and location of renal damage within the nephron. Other factors may also be involved, including yet uncharacterized host factors that may include genetic polymorphism, among others. Interestingly, the amount of LC production by the clone of plasma cells does not correlate directly with the severity of the renal alterations. Understanding the nature of the interactions between G-LCs and mesangial cells (MCs) is crucial to define key steps that may be targeted for therapeutic purposes. Experimental studies have delineated important aspects pertaining to interactions between G-LCs and MCs, indicating that these interactions are receptor mediated. The data presented in the current study support a single receptor present on MCs for both LCDD and AL-LCs, as clearly demonstrated with competition and colocalization immunofluorescence (IF) studies. This receptor resides in caveolae present on the plasma membrane of HMCs and is overexpressed when HMCs are incubated with G-LCs but not TLCs. Caveolae play a fundamental role in receptor-mediated endocytosis, a crucial process in the internalization of AL-LCs and amyloidogenesis. LC internalization is clathrin mediated. The data also indicate that intracellular trafficking in MCs is different for AL-LCs and LCDD-LCs. AL-LCs are delivered to the mature lysosomal compartment where amyloid formation occurs. LCDD-LCs alter mesangial function and phenotype by interacting with the MC surface membranes through similar receptors as the AL-LCs. The data also demonstrated that cubilin and megalin were absent on MCs, so the receptor involved is different from the one already characterized in the proximal tubules.


Interleukin-15 suppresses hepatitis B virus replication via IFN-β production in a C57BL/6 mouse model.
Interleukin-15 (IL-15) is a pleiotropic cytokine known to modulate both innate and adaptive immunity. It is suggested that IL-15 may play an important role in the regulation of immune response to hepatitis B virus (HBV). We investigated whether IL-15 could modulate the immune response to HBV. A mouse model for HBV tolerance was established by hydrodynamical injection of pAAV/HBV1.2 plasmid into C57BL/6 mice. This HBV-carrier mouse was simultaneously hydrodynamically injected with either an IL-15-expression plasmid pLIVE-IL-15 or a mock control vector pLIVE-EGFP. The serum levels of HBsAg and HBeAg were measured by radioimmunoassay. Hydrodynamic injection of the plasmid pLIVE-IL-15 resulted in sustained high level of IL-15 in mouse serum, along with the markedly decreased serum HBsAg and HBeAg titres and liver HBV DNA levels. IL-15 also induced anti-HBV activity in T cell- and B cell-deficient Rag1(-/-) mice. Interestingly, despite an increase in NK cell numbers in both spleen and liver of IL-15 treated mice, the anti-HBV effect of IL-15 was neither dependent on presence of NK cells nor on production of IFN-γ. Furthermore, IL-15 could exert anti-HBV function independent of the common IL-2γ(c) R. Lastly, we found that IFN-β expression in the liver and serum was significantly up-regulated by liver expression of IL-15, and blockade of IFN-β function abrogated the anti-HBV activity of IL-15. Liver over-expression of IL-15 may suppress HBV replication in an IFN-β-dependent manner.


Wide QRS tachycardia: multiple mechanisms in a patient after myocardial infarction.
A 34-year-old man was hospitalized for extensive antero-apical myocardial infarction. Eight weeks after discharge from the hospital, he had intermittent rapid palpitations. During several episodes, a rapid, regular, wide-QRS-complex tachycardia with left bundle branch (LBB) morphology was recorded. All antiarrhythmic agents administered to the patient were unsuccessful in alleviating his symptoms, which were thought to be due to supraventricular tachycardia (SVT) with aberration. An electrophysiologic study was performed and revealed three morphologically distinct types of wide complex tachyarrhythmias: 1) Tachycardia 1 was determined to be A-V re-entry with antegrade conduction utilizing the normal A-V conducting system and retrograde conduction over a concealed accessory pathway located in the left A-V groove; 2) tachycardia 2 was identified as ventricular tachycardia (VT); and 3) tachycardia 3 was considered to be a second morphologic type of ventricular tachycardia as the morphology was identical to some of the episodes documented clinically. The patient was treated with oral amiodarone which was unsuccessful until combined with quinidine; this regimen has suppressed recurrence of VT during a four-month period of follow-up. The occurrence of wide-QRS-complex tachycardia in this patient immediately suggested the diagnosis of VT, but our other findings were unexpected. This case illustrates the need for considering all possible mechanisms when seeking to manage tachyarrhythmias, even if the diagnosis appears obvious.


Endothelium-dependent relaxation to hydrogen peroxide in canine basilar artery: a potential new cerebral dilator mechanism.
In prostglandin F2alpha(PGF2alpha)-precontracted isolated canine basilar arterial rings, hydrogen peroxide (H2O2) produced endothelium-dependent relaxations at concentrations of from 4.4 x 10(-7) - approximately 4.4 x 10(-5) M. Removal of extracellular Ca2+ ([Ca2+]0) attenuated the relaxant effects of H2O2. Complete inhibition of H2O2 relaxant action was obtained after buffering intracellular Ca2+ ([Ca2+]i), in the endothelial cells, with 10 microM 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). The H2O2-induced relaxations could be abolished completely by 1200 u/ml catalase and was suppressed significantly by 0.5 microM atropine, 150 microM NG-monomethyl-arginine (L-NMMA), 50 microM NG-nitro-L-arginine methyl ester (L-NAME), 1 microM Fe2+, or 5 microM methylene blue. These inhibitory effects of L-NMMA, L-NAME, or atropine could be reversed partly by 50 microM L-arginine. The Fe2+ inhibition of H2O2-stimulated relaxation was reduced significantly by either 1 mM deferoxamine (a Fe2+ chelator) or 100 microM dimethyl sulfoxide (DMSO, a *OH scavenger). Such relaxant effects of H2O2 were enhanced, significantly, by an acetylcholinesterase antagonist, neostigmine. A variety of pharmacological antagonists (of diverse vasodilator agents) could not inhibit the relaxant action of H2O2. Our observations suggest that at suitable pathophysiological concentrations, H2O2 could induce release of an endothelium-derived relaxing factor (EDRF), probably nitric oxide (NO), from endothelial cells of the canine cerebral artery. The H2O2 relaxant effects are clearly Ca2+-dependent, require formation of cyclic guanosine monophosphate (cGMP), and may be associated with release of endogenous acetylcholine (ACh).


Phylogenomics shows that novel tapeworm-like traits of haplozoan parasites evolved from within the Peridiniales (Dinoflagellata).
Haplozoans are intestinal parasites of marine annelids with bizarre traits, including a differentiated and dynamic trophozoite stage that resembles the scolex and strobila of tapeworms. Described originally as "Mesozoa", comparative ultrastructural data and molecular phylogenetic analyses have shown that haplozoans are aberrant dinoflagellates; however, these data failed to resolve the phylogenetic position of haplozoans within this diverse group of protists. Several hypotheses for the phylogenetic position of haplozoans have been proposed: (1) within the Gymnodiniales based on tabulation patterns on the trophozoites, (2) within the Blastodiniales based on the parasitic life cycle, and (3) part of a new lineage of dinoflagellates that reflects the highly modified morphology. Here, we demonstrate the phylogenetic position of haplozoans by using three single-trophozoite transcriptomes representing two species: Haplozoon axiothellae and two isolates of H. pugnus collected from the Northwestern and Northeastern Pacific Ocean. Unexpectedly, our phylogenomic analysis of 241 genes showed that these parasites are unambiguously nested within the Peridiniales, a clade of single-celled flagellates that is well represented in marine phytoplankton communities around the world. Although the intestinal trophozoites of Haplozoon species do not show any peridinioid characteristics, we suspect that uncharacterized life cycle stages may reflect their evolutionary history within the Peridiniales.