Surgical management of closed, isolated proximal phalanx fractures in the long fingers: Functional outcomes and complications of 87 fractures.
Finger fractures are the most common skeletal injuries of the upper limbs. The purpose of this study was to evaluate the functional outcomes and complications after surgical management of isolated, closed fractures of the proximal phalanx (PP) of the hand (thumb excluded). Surgical management was indicated in 87 PP fractures. Fractures were reduced and fixed with pins, screws or a plate. Functional outcomes were assessed through the range of motion (ROM) in flexion-extension, hand and finger strength, and the QuickDASH and PRWHE scores. Fixation was done with pins in 32 cases, screws in 41 cases, and a plate in 14 cases. Rehabilitation was started an average of 1.7 weeks after surgery. There was no significant difference in the functional outcomes based on either fracture type or surgical approach. Nevertheless, the following significant differences were observed: PRWHE score (P=0.017) by injured finger; proximal interphalangeal (PIP) ROM (P=0.037) by fixation type; and grip strength (P=0.019), Quick DASH (P=0.017), and PRWHE (P=0.045) by rehabilitation delay. The most common clinical complications were minor malrotation and cold intolerance. Radiological assessment showed complete union in all cases. Surgical management of PP fractures leads to good functional outcomes, including a satisfactory recovery of finger ROM. The functional recovery of a fractured digit is dependent on the right fixation choice, complete bone union, and early rehabilitation. We suggest using screw fixation to achieve patient satisfaction and optimal functional recovery of closed, isolated PP fractures of the long fingers.


How are observed actions mapped to the observer's motor system? Influence of posture and perspective.
Previous studies using transcranial magnetic stimulation (TMS) have shown that during the observation of actions performed by others, the observer's primary motor cortex (M1) becomes facilitated in a highly muscle specific fashion. Here, we used TMS to explore the effect of posture, perspective and body side on muscle specific facilitation of left M1. Subjects viewed video's showing left and right hand extension (palm-down) movements from a first person or third person perspective with their hand posture either congruent (palm-down) or incongruent (palm-up) to the posture of the observed model. Data indicated that facilitation of left M1 was substantially different for observing actions executed with the right (contralateral) or left (ipsilateral) hand. For right hand actions, facilitation of left M1 was shown to be highly specific to the muscle used in the observed action ('intrinsic mapping'). During the observation of left hand stimuli, only half of the subjects displayed this muscle specific facilitation, whereas in the other half, M1 was facilitated according to the observed movement direction ('extrinsic mapping'). Absolute effect magnitude was particularly high when right hand actions were observed from a first person perspective, whereas, for left hand actions, the third person perspective was more efficient. The degree of postural congruency between body parts of the observer and observed model only mildly influenced M1 facilitation. Since action observation is increasingly considered in rehabilitation therapies, the present findings may help identifying the most effective conditions for stimulating the motor system during action observation.


Cellular sources and immune functions of interleukin-9.
Interleukin-9 (IL-9) has attracted renewed interest owing to the identification of its expression by multiple T helper (T(H)) cell subsets, including T(H)2 cells, T(H)9 cells, T(H)17 cells and regulatory T (T(Reg)) cells. Here, we provide a broad overview of the conditions that are required for cells to produce IL-9 and describe the cellular targets and nature of the immune responses that are induced by IL-9.


Chemotherapy for gestational trophoblastic tumours hastens menopause by 3 years.
Chemotherapy may induce acute ovarian failure, but in women who retain gonadal function throughout chemotherapy, the late effects upon ovarian function are unknown. A retrospective controlled survey was performed to ascertain whether chemotherapy for gestational trophoblastic tumours (GTT) results in premature menopause. Questionnaires were sent to 1,489 women diagnosed between 1971 and 1990 with GTT, including 1089 who had received chemotherapy and 400 who had not received chemotherapy (controls). Responses were obtained from 972 chemotherapy-treated patients and 327 controls. 124 women were not evaluable for menopause date as they had undergone hysterectomy as part of the treatment for GTT or had developed permanent amenorrhoea during chemotherapy. Overall, 172 women reported that they were postmenopausal, including 157 women who had received chemotherapy. The median age at menopause for the evaluable population was 50 years (range 25-56 years). The age at menopause was significantly earlier in the treated arm (median 50, range 25-56 years) than in the controls (median 53, range 40-57 years) (logrank test chi 2 = 12.6, P = 0.0004). Menopause occurred significantly earlier in women treated with combination chemotherapy (median 49, range 25-56 years) compared with single agent methotrexate (median 51, range 25-56 years) (logrank test chi 2 = 8.3, P = 0.004). However, the age at completion of chemotherapy in the treated arm did not influence the age of menopause (proportional Hazards chi 2 = 1.99, P = 0.16). Chemotherapy for GTT induces menopause 3 years earlier than it occurs in women with GTT who do not receive chemotherapy. Although the difference is statistically significant, the magnitude is modest and most women can be reassured that neither fertility nor postmenopausal osteoporosis will be greatly affected.


Synthesis and Structural Characterization of Bioactive PHA and γ-PGA Oligomers for Potential Applications as a Delivery System.
The (trans)esterification reaction of bacterial biopolymers with a selected bioactive compound with a hydroxyl group was applied as a convenient method for obtaining conjugates of such compound. Tyrosol, a naturally occurring phenolic compound, was selected as a model of a bioactive compound with a hydroxyl group. Selected biodegradable polyester and polyamide, poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P(3HB-co-4HB)) and poly-γ-glutamic acid (γ-PGA), respectively, were used. The (trans)esterification reactions were carried out in melt mediated by 4-toluenesulfonic acid monohydrate. The structures of (trans)esterification products were established at the molecular level with the aid of ESI-MS² (electrospray ionization tandem mass spectrometry) and/or ¹H NMR (nuclear magnetic resonance) techniques. Performed analyses confirmed that the developed method leads to the formation of conjugates in which bioactive compounds are covalently bonded to biopolymer chains. The amount of covalently bonded bioactive compounds in the resulting conjugates depends on the type of biopolymers applied in synthesis.


[A description of children and adolescents with somatic unexplained physical symptoms in a Dutch mental health care institution].
Medically unexplained symptoms (MUS) occur frequently in children and adolescents. Treatment of MUS in children and adolescents takes place mainly in mental health care (MHC) institutions, as does the treatment of adults with MUS. However, there is hardly any literature about the prevalence of MUS in children and adolescents in MHC. To study the prevalence of MUS in children and adolescents in Dutch MHC. Comparisons were drawn between children and adolescents with MUS and those without MUS who had been referred to a Dutch MHC institution. Children and adolescents with MUS had more anxiety and depression and more introvert personality characteristics than children and adolescents without MUS. However, the quality of life of children and adolescents with MUS was similar to that of children and adolescents without MUS. One in five children and adolescents in Dutch MHC had MUS. These children and adolescents had introverted personality characteristics and showed anxious and depressed behavior, withdrawn-depressed behavior, and thought problems. The quality of life of children and adolescents with MUS and those without MUS was below average.


Characteristics of directly observed treatment short-course workers in Taiwan.
Little is known about the characteristics of health workers. The objective of this study was to figure out the characteristics of different types of health workers involved in Directly Observed Treatment Short-course (DOTS) work. The study comprised of 444 community health workers and 822 potential DOTS workers; the participants attended the training course and completed structured questionnaires. The questionnaires were then analyzed to investigate the knowledge, stigmatization, and accountability of community health partnerships (ACHPs) in tuberculosis (TB) control. Our study results found statistically significant differences in TB knowledge scores (p < 0.001) and ACHPs scores (p < 0.001), but not in stigmatization scores (p = 0.541) among the participants. Analysis of variance of stigmatization factors 2 and 3 differed significantly among participants (p < 0.001 for both factors). Level of education (Odds ratio, OR = 1.69) and stigmatization factor 3 [avoidance (OR = 1.25)] were found to be negative factors, whereas knowing a patient with TB (OR = 0.75), having TB knowledge (OR = 0.78), and high scores in stigmatization factor 1 [attribution (OR = 0.87)] were found to be positive factors. The main factor explaining why DOTS workers did not enter into a contract was avoidance, and that main reason why they chose to become employed was sympathy. Potential DOTS workers who know a patient with TB, have high TB knowledge, and have high attribution concerns are more likely to remain under contract.


Effects of exercises performed in the work environment on occupational stress: A systematic review.
Technological advances stimulate labor transformations in such a way that the search for productivity, goals and market competitiveness leads industries and companies to neglect the health and safety of their workers. There is a gap in the literature regarding means of intervention using physical exercises (PE), with details remaining unknown in terms of appropriate exercise prescriptions or types that minimize the effects of occupational stress. to verify the effects on workers' stress of PE performed in the work environment. this systematic review searched for randomized controlled trials (RCTs) in 08 databases (MEDLINE, Cochrane, BIREME, LILACS, EBSCOhost, SCOPUS, Web of Science and Embase), in English and Portuguese, published between 2017 and 2021. The PICOS strategy was used to determine inclusion, being P: male and female workers; I: exercises performed in the work environment; C: control group without intervention; O: occupational stress; and S: controlled experiments. Methodological quality, risk of bias and reliability of assessments were analyzed using the TESTEX, Risk of Bias 2, and Kappa scales. A total of 07 articles were included, of which, most had good methodological quality and unclear risk of bias. The intra- and inter-rater reliability test of methodological quality showed excellent agreement. As a limitation, the fragility in allocation concealment, blinding and absence of treatment analysis was noted in the studies evaluated. PE in the workplace might have positive effects on reducing occupational stress, but further studies must be conducted to better clarify this. This review was registered with PROSPERO (CRD42022304106).


Antimicrobial usage on 72 farrow-to-finish pig farms in Japan from 2015 to 2017.
In Japan veterinary antimicrobials are used most in the pig production sector. However, there is a paucity of data on the quantity of antimicrobials used on pig farms in Japan. This study describes antimicrobial use on Japanese pig farms in 2015, 2016 and 2017 in terms of mg of active ingredient per kg of PCU (population correction unit). Data on antimicrobial use from a total of 72 farrow-to finish farms over these three years were used in the study. The results revealed that the average use of antimicrobials in 2015, 2016 and 2017 was 304.8 (SD = 226.3), 311.2 (SD = 241.0) and 342.9 (SD = 291.3) mg/kg PCU, respectively. Most (97%) of the antimicrobials were administered orally. The most commonly used antimicrobials were tetracyclines, followed by macrolides, penicillins and sulfonamides. Tohoku was the region in which the lowest quantities of antimicrobial were used whilst South Kanto was the region in which the largest amount was used. The use of antimicrobials was on the increase in the North Kanto, South Kanto and Kyushu regions.


Real-life experience with Dulaglutide: Analysis of clinical effectiveness to 24 months.
Dulaglutide is an agonist of "glucagon-like peptide type 1″ receptors (arGLP1). The clinical efficacy of this molecule is based on reductions in glycosylated hemoglobin (HbA1c) and weight, data shown in the pivotal AWARD studies. We propose a retrospective and multicenter study that allows evaluating the effectiveness of dulaglutide at 24 months after treatment began, under conditions of usual clinical practice, and comparing the results obtained with those that are reflected in the controlled trials. The results show a reduction in the HbA1c levels -1.4% at 6 M and this reduction were maintained throughout 12 M and 24 M (p < 0.001). Plasma glucose showed significant reductions around -30 mg / dL at 6 months (p < 0.001) that remained until the end of the follow-up at 12 and 24 M, respectively. The weight decreased significantly at 6 M (p < 0.001) but continued decreasing at 12 and 24 M, showing statistically significant differences (p: 0.001). Our results are similar to those obtained in pivotal clinical trials and confirm these benefits in real life.


Blockade of different subtypes of α(1)-adrenoceptors produces opposite effect on heart chronotropy in newborn rats.
We compared the effects of blockade of α(1A)-, α(1B)-, and α(1D)-subtypes of α(1)-adrenoceptors on the cardiac rhythm in newborn rats. Different responses of the heart were observed after blockade of several subtypes of α(1)-adrenoceptors. Administration of WB 4101, a selective blocker of α(1A)-adrenoceptors, increased heart rate, while blockade of α(1AD)-adrenoceptors with BMY 7378 decelerated of heart rhythm. Blockade of α(1B)-adrenoceptors with chloroethylclonidine produced no significant effects on heart chronotropy.


Mesoscopic simulation studies on micellar phases of Pluronic P103 solution.
The microphase separation dynamics of the triblock copolymer surfactant P103 [(ethylene oxide)17(propylene oxide)60(ethylene oxide)17] was investigated by a dynamic variant of mean-field density functional theory. Different self-assembled aggregates, spherical micelles, micellar clusters and disk-like micelles, are explored in the solution. The spherical micelle above critical micelle concentration (CMC) is a dense core consisting mainly of PPO and a hydrated PEO swollen corona, and is in good agreement with the experimental results concerning their structures. At a concentration of 10-15%, micellar clusters with a larger PPO core form as a result of coalescence among spherical micelles. At concentrations above 16% by volume, a series of disk-like micelles come into being. The order parameters show that spherical micelles are easily formed, while the micellar clusters or disk-like micelles need a longer time to reach steady equilibrium. The results show that mesoscopic simulation can augment experimental results on amphiphilic polymers, and provide some mesoscopic information at the mesoscale level.


Hemodialysis for infants, children, and adolescents.
Children with chronic kidney disease stage 5 requiring dialysis can be treated by peritoneal or hemodialysis. In the United Kingdom nearly twice as many children receive peritoneal dialysis compared with hemodialysis. Technical aspects of pediatric hemodialysis are challenging and include the relative size of extracorporeal circuit and child's blood volume, assessment of adequacy,technical and complications of vascular access. Alternatives to standard hospital-based hemodialysis are also increasingly available. Optimizing nutritional status with the support of specialist pediatric dietitians is key to the management of children receiving hemodialysis. The effects of chronic illness on growth and school achievement, as well as the psychological, emotional, and social development of the child should not be underestimated. This review focuses on the above elements and highlights common pediatric practice in the United Kingdom.


Obstacles and opportunities for targeting the effector T cell response in type 1 diabetes.
Autoreactive lymphocytes display a programmed set of characteristic effector functions and phenotypic markers that, in combination with antigen-specific profiling, provide a detailed picture of the adaptive immune response in Type 1 diabetes (T1D). The CD4+ T cell effector compartment (referred to as "Teff" in this article) has been extensively analyzed, particularly because the HLA genes most strongly associated with T1D are MHC class II alleles that form restriction elements for CD4+ T cell recognition. This "guilt by association" can now be revisited in terms of specific immune mechanisms and specific forms of T cell recognition that are displayed by Teff found in subjects with T1D. In this review, we describe properties of Teff that correlate with T1D, and discuss several characteristics that advance our understanding of disease persistence and progression. Focusing on functional disease-associated immunological pathways within these Teff suggests a rationale for next-generation clinical trials with targeted interventions. Indeed, immune modulation therapies in T1D that do not address these properties of Teff are unlikely to achieve durable clinical response.


Application of machine learning (individual vs stacking) models on MERRA-2 data to predict surface PM2.5 concentrations over India.
The spatial coverage of PM2.5 monitoring is non-uniform across India due to the limited number of ground monitoring stations. Alternatively, Modern-Era Retrospective Analysis for Research and Applications, Version 2 (MERRA-2), is an atmospheric reanalysis data used for estimating PM2.5. MERRA-2 does not explicitly measure PM2.5 but rather follows an empirical model. MERRA-2 data were spatiotemporally collocated with ground observation for validation across India. Significant underestimation in MERRA-2 prediction of PM2.5 was observed over many monitoring stations ranging from -20 to 60 μg m-3. The utility of Machine Learning (ML) models to overcome this challenge was assessed. MERRA-2 aerosol and meteorological parameters were the input features used to train and test the individual ML models and compare them with the stacking technique. Initially, with 10% of randomly selected data, individual model performance was assessed to identify the best model. XGBoost (XGB) was the best model (r2 = 0.73) compared to Random Forest (RF) and LightGBM (LGBM). Stacking was then applied by keeping XGB as a meta-regressor. Stacked model results (r2 = 0.77) outperformed the best standalone estimate of XGB. Stacking technique was used to predict hourly and daily PM2.5 in different regions across India and each monitoring station. The eastern region exhibited the best hourly prediction (r2 = 0.80) and substantial reduction in Mean Bias (MB = -0.03 μg m-3), followed by the northern region (r2 = 0.63 and MB = -0.10 μg m-3), which showed better output due to the frequent observation of PM2.5 >100 μg m-3. Due to sparse data availability to train the ML models, the lowest performance was for the central region (r2 = 0.46 and MB = -0.60 μg m-3). Overall, India's PM2.5 prediction was good on an hourly basis compared to a daily basis using the ML stacking technique.


A simple and fast LC-MS/MS method for the simultaneous determination of tenofovir alafenamide and tenofovir in human plasma.
A simple and fast liquid chromatography-tandem mass spectrometry method was established and validated for the simultaneous determination of tenofovir alafenamide (TAF) and tenofovir (TNF) in human plasma. A simple protein precipitation procedure was employed to extract analytes from plasma. Chromatographic separation was performed on an Eclipse Plus C18 column utilizing a fast gradient elution starting with 2% of 2 mM ammonium acetate-formic acid (100/0.1, v/v) followed by increasing the percentage of acetonitrile. Detection was performed on a tandem mass spectrometer equipped with an electrospray ionization source operated in the positive ionization mode, using the transitions m/z 477.2 → m/z 346.1 for TAF and m/z 288.1 → m/z 176.1 for TNF. TAF-d5 and TNF-d7 were used as the internal standard of TAF and TNF, respectively. The method was validated in the concentration ranges 1.25-500 ng/mlfor TAF and 0.300-15.0 ng/ml for TNF with acceptable accuracy and precision.


The Metabolome of Carbapenem-Resistant Klebsiella pneumoniae Infection in Plasma.
Carbapenem-resistant Klebsiella pneumoniae- (CR-Kp-) mediated infections represent a challenge for clinical practitioners due to their expanding prevalence in hospital environments and antibiotic resistance. However, few studies have shown metabolic changes of carbapenem-resistant Klebsiella pneumoniae and CR-Kp-negative patients, and relevant studies are urgently needed. In this study, we comprehensively profile the metabolites of 20 CR-Kp-positive and 18 CR-Kp-negative patients in plasma by using 2D gas chromatography-time-of-flight mass spectrometry (GC×GC-TOFMS). We identified 58 metabolites that were carbapenem-resistant Klebsiella pneumoniae-associated. N-Acetyl glucosamine, butanedioic acid, and myoinositol play a significant character in CR-Kp infection. Our study provides valuable data to serve as potential targets for developing therapies against CR-Kp infection.


A continuous fluorescent enzyme assay for early steps of lipid A biosynthesis.
UDP-N-acetylglucosamine acyltransferase (LpxA) and UDP-3-O-(R-3-hydroxyacyl)-glucosamine acyltransferase (LpxD) catalyze the first and third steps of lipid A biosynthesis, respectively. Both enzymes have been found to be essential for survival among gram-negative bacteria that synthesize lipopolysaccharide and are viable targets for antimicrobial development. Catalytically, both acyltransferases catalyze an acyl-acyl carrier protein (ACP)-dependent transfer of a fatty acyl moiety to a UDP-glucosamine core ring. Here, we exploited the single free thiol unveiled on holo-ACP after transfer of the fatty acyl group to the glucosamine ring using the thiol-specific labeling reagent, ThioGlo. The assay was continuously monitored as a change in fluorescence at λ(ex)=379 nm and λ(em)=513 nm using a microtiter plate reader. This assay marks the first continuous and nonradioactive assay for either acyltransferase.


Surface-attached and suspended bacterial community structure as affected by C/N ratios: relationship between bacteria and fish production.
Bacteria play crucial roles in the combined system of substrate addition and C/N control, which has been demonstrated to improve aquaculture production. However, the complexity of surface-attached bacteria on substrates and suspended bacteria in the water column hamper further application of this system. This study firstly applied this combined system into the culture of grass carp, and then explored the relationship between microbial complexes from surface-attached and suspended bacteria in this system and the production of grass carp. In addition, this study investigated bacterial community structures as affected by four C/N ratios using Illumina sequencing technology. The results demonstrated that the weight gain rate and specific growth rate of grass carp in the CN20 group (C/N ratio 20:1) were the highest (P < 0.05), and dietary supplementation of the microbial complex had positive effects on the growth of grass carp (P < 0.05). Sequencing data revealed that, (1) the proportions of Verrucomicrobiae and Rhodobacter (surface-attached), sediminibacterium (suspended), and emticicia (surface-attached and suspended) were much higher in the CN20 group compared with those in the other groups (P < 0.05); (2) Rhodobacter, Flavobacterium, Acinetobacter, Pseudomonas, Planctomyces, and Cloacibacterium might be important for the microbial colonization on substrates; (3) as the C/N ratio increased, proportions of Hydrogenophaga (surface-attached and suspended), Zoogloea, and Flectobacillus (suspended) increased, but proportions of Bacillus, Clavibacter, and Cellvibro (surface-attached and suspended) decreased. In summary, a combined system of substrate addition and C/N control increased the production of grass carp, and Verrucomicrobiae and Rhodobacter in the surface-attached bacterial community were potential probiotic bacteria that contributed to the enhanced growth of grass carp.


Biological reflect of Adiponectin hormone in postpartum marital satisfaction and depression scores.
There is a growing body of evidence regarding the association between Adiponectin and mental disorders. We aim to evaluate the association between serum level of Adiponectin hormone and postpartum depression and marital satisfaction scores. A prospective cohort study of 90 pregnant women was conducted in Mahdieh Hospital, Tehran, Iran. Blood samples were collected during the first 24 h after delivery. The serum Adiponectin concentration was measured with an Enzyme-Linked Immunosorbent Assay (ELISA) kit. The depression score was measured using a validated Iranian version of the Edinburgh Postnatal Depression Scale (EPDS) questionnaire at six weeks (6-weeks) and twelve weeks (12-weeks) after delivery. Using the Kansas questionnaire at twelve weeks (12-weeks) after delivery, the marital satisfaction score was measured. The measurements were compared between two groups, satisfied and dissatisfied mothers. P-values lower than 0.05 were considered significant. The mean serum level of Adiponectin was significantly higher in the dissatisfied group. It was 10.9 ± 13.4 μg/ml and 15.2 ± 17.7 μg /ml in the satisfied and dissatisfied groups, respectively (P = 0.04). The postpartum depression scores of 6- and 12-weeks after delivery were significantly higher in the dissatisfied group. At 6-weeks after delivery, the postpartum depression scores were 3.6 ± 3 and 8.7 ± 5.6 in satisfied and dissatisfied groups, respectively. Those were 2.7 ± 2.7 and 7.6 ± 5 at 12-weeks after delivery, respectively. There was a significant difference statistically (P < 0.001). Mothers in the dissatisfied group, experienced higher depression scores at 12-weeks postpartum while they had shown higher serum Adiponectin levels at the first 24 h after delivery.


Effect of estrus synchronization protocols on plasma progesterone profile and fertility in postpartum anestrous Kankrej cows.
The study was aimed at induction/synchronization of estrus in postpartum anestrous Kankrej cows of zebu cattle maintained at an organized farm. The study included use of different hormone protocols, viz., Ovsynch, CIDR (controlled internal drug release), Ovsynch plus CIDR, and Heatsynch with estimation of plasma progesterone on days 0, 7, 9/11 (artificial insemination--AI) and on day 20 post-AI following fixed time insemination. Thirty selected anestrous animals were divided into five equal groups (four treatment and one control), and the findings were compared with the normal cyclic control group of six cows. All the protocols were initiated in cows with postpartum anestrous period of more than 4 months, considering the day of first GnRH injection or CIDR insertion as day 0. The animals were bred by fixed time artificial insemination. Pregnancy was confirmed per rectum on day 60 post-AI in non-return cases. The conception rates at induced/first heat in Ovsynch, CIDR, Ovsynch + CIDR, and Heatsynch protocols were 33.33, 66.66, 50.00 and 16.67%, respectively. The corresponding overall conception rates of three cycles post-treatment were 50.00% (3/6), 100.00% (6/6), 66.66% (4/6), and 50.00% (3/6). In normal cyclic and anestrous control groups, the pooled pregnancy rates were 83.33% (5/6) and 16.67% (1/6), respectively. The pooled mean plasma progesterone (nanograms per milliliter) concentrations were significantly (P < 0.05) higher on day 7 in Ovsynch (5.727 ± 1.26), CIDR (4.37 ± 0.66), Ovsynch plus CIDR (3.55 ± 0.34), and Heatsynch (5.92 ± 1.11) protocols as compared with their corresponding values obtained on days 0, 9/11 (AI), and on day 20 post-AI. In anestrous control group, the mean progesterone concentration at the beginning of experiment was 0.67 ± 0.33 ng/ml, which was at par with values of all other groups. The overall plasma progesterone levels on the day of initiating treatment were low in all groups, with smooth small inactive ovaries palpated per rectum twice at 10 days interval, suggesting that most of the animals used in the study were in anestrous phase. Mean (± SE) values of plasma progesterone (nanograms per milliliter) on day 20 post-AI were higher in conceived cows than the non-conceived cows of all the groups, but differed significantly (P < 0.05) only in normal cyclic group. These results suggest that use of different hormone protocols particularly Ovsynch, CIDR, and Ovsynch + CIDR may serve as an excellent tool for induction and synchronization of estrus and improvement of conception rate in postpartum anestrous Kankrej cows.


Phase II study of gemcitabine, cisplatin, and infusional fluorouracil in advanced pancreatic cancer.
This phase II study was undertaken to determine the efficacy of adding infusional fluorouracil (FU) to the chemotherapy doublet of gemcitabine and cisplatin in patients with advanced pancreatic cancer. The eligibility criteria included histologically or cytologically confirmed adenocarcinoma of the pancreas that was either unresectable or metastatic. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m2 intravenously (IV) on days 1, 8, and 15; cisplatin 50 mg/m2 IV on days 1 and 15; and FU 175 mg/m2/d from days 1 to 15 by continuous IV infusion. Cycles were repeated every 28 days. Objective tumor response and toxicity were evaluated according to the World Health Organization criteria. A total of 47 patients (median age, 57 years; males, 59%) were enrolled. Sixteen patients had locally advanced (LA) disease, and 31 patients had metastatic disease. A total of 183 cycles of chemotherapy were administered. In patients with metastatic disease (n = 31), the probability of survival at 6 and 12 months was 66% and 34%, respectively. Objective partial response or stable disease was observed in 26% (90% confidence interval [CI], 0.14 to 0.41) and 61% (90% CI, 0.45 to 0.74) of patients, respectively. In patients with LA disease (n = 16), there were three partial responses (19%; 90 CI, 0.07 to 0.39). One patient in this group was successfully resected after FU-based radiotherapy. The most common grade 3 to 4 toxicities were neutropenia (60%), thrombocytopenia (42%), and anemia (26%). Thirteen patients were hospitalized for treatment-related complications. The combination of gemcitabine, cisplatin, and infusional FU has significant activity in patients with advanced pancreatic cancer.


Antileishmanial activity of 2-amino-thiophene derivative SB-200.
Leishmaniasis, presenting the highest number of cases worldwide is one of the most serious Neglected Tropical Diseases (NTDs). Clinical manifestations are intrinsically related to the host's immune response making immunomodulatory substances the target of numerous studies on antileishmanial activity. The currently available drugs used for treatment present various problems including high toxicity, low efficacy, and associated drug resistance. The search for therapeutic alternatives is urgent, and in this context, thiophene derivatives appear to be a promising therapeutic alternative (many have shown promising anti-leishmanial activity). The objective of this study was to investigate the antileishmanial activity of the 2-amino-thiophenic derivative SB-200. The thiophenic derivative was effective in inhibiting the growth of Leishmania braziliensis, Leishmania major, and Leishmania infantum promastigotes, obtaining respective IC50 values of 4.25 μM, 4.65 μM, and 3.96 μM. For L. infantum, it was demonstrated that the antipromastigote effect of SB-200 is associated with cell membrane integrity losses, and with morphological changes observed during scanning and transmission electron microscopy. Cytotoxicity was performed for J774.A1 macrophages and VERO cells, to obtain a CC50 of 42.52 μM and a SI of 10.74 for macrophages and a CC50 of 39.2 μM and an SI of 9.89 for VERO cells. The anti-amastigote activity of SB-200 revealed an IC50 of 2.85 μM and an SI of 14.97 against macrophages and SI of 13.8 for VERO cells. The anti-amastigote activity of SB-200 is associated with in vitro immunomodulation. For acute toxicity, SB-200 against Zophobas morio larvae permitted 100% survival. We conclude that the 2-amino-thiophenic derivative SB-200 is a promising candidate for in vivo anti-leishmania drug tests to evaluate its activity, efficacy, and safety.


Multi-layered polydopamine coatings for the immobilization of growth factors onto highly-interconnected and bimodal PCL/HA-based scaffolds.
For bone tissue engineering applications, scaffolds that mimic the porous structure of the extracellular matrix are highly desirable. Herein, we employ a PCL/HA-based scaffold with a double-scaled architecture of small pores coupled to larger ones. To improve the osteoinductivity of the scaffold, we incorporate two different growth factors via polydopamine (PDA) coating. As a first step, we identify the maximum amount of PDA that can be deposited onto the scaffold. Next, to allow for the deposition of a second PDA layer which, in turn, will allow to increase the loading of growth factors, we incorporate a dithiol connecting layer. The thiol groups covalently react with the first PDA coating through Michael addition while also allowing for the incorporation of a second PDA layer. We load the first and second PDA layers with bone morphogenic protein-2 (BMP2) and vascular endothelial growth factor (VEGF), respectively, and evaluate the osteogenic potential of the functionalised scaffold by cell viability, alkaline phosphatase activity and the expression of three different osteogenesis-related genes of pre-seeded human mesenchymal stem cells. Through these studies, we demonstrate that the osteogenic activity of the scaffolds loaded with both BMP2 and VEGF is greater than scaffolds loaded only with BMP2. Importantly, the osteoinductivity is higher when the scaffolds are loaded with BMP2 and VEGF in two different PDA layers. Taken together, these results indicate that the as-prepared scaffolds could be a useful construct for bone-tissue applications.


Reassessment of sphenoid dysplasia associated with neurofibromatosis type 1.
Sphenoid dysplasia associated with neurofibromatosis type 1 is classically thought to be primarily related to abnormal development of the sphenoid bone. We investigated the possibility that these changes may be progressive. We conducted a retrospective review of sphenoid bone changes in all patients with craniofacial neurofibromatosis type 1 who had undergone CT (31 patients) and MR imaging (seven patients) at our facility. A review of repeat images of 20 patients permitted analysis of progressive sphenoid bone changes. Eighteen patients had abnormalities of the sphenoid wings, 13 of whom also had enlargement of the middle cranial fossa compatible with descriptions of classic sphenoid dysplasia. All the patients with sphenoid dysplasia had neurofibromas in the ipsilateral superficial temporal fossa that were often contiguous with a radiologically abnormal temporo-squamosal suture. All except one had tumor infiltration in the deep orbit, contiguous with the sphenoid wings. Four patients had radiologic evidence of progressive sphenoid bone changes over time. The origin of sphenoid bone changes may be multifactorial. A modified concept of sphenoid dysplasia is proposed that emphasizes interaction between neurofibromas and sphenoid bone during skull development.


Prospective analysis of nutritional status normalization after spinal reconstructive surgery.
A prospective analysis of nutritional status after surgery in 57 spinal reconstructive surgery patients. To determine the length of time required for patients to return to their preoperative nutritional baseline and to investigate risk factors for patients with prolonged normalization. The preoperative nutritional status of spinal reconstructive surgery patients appears to be an important parameter of surgical morbidity, complication rates (especially wound healing), patient acceptance, and overall surgical success. The nutritional parameters of albumin, pre-albumin, total protein, transferrin, and the absolute lymphocyte count were investigated before surgery and at various time points after surgery. Forty-four patients (Group A) with an average 6.4 fusion levels returned to their preoperative baseline nutritional values by 6 weeks after surgery, whereas 13 patients (Group B) with a statistically increased number of fusion levels of 13.8 (P = 0.0009) took 12 weeks or longer to return to their preoperative baseline. Risk factors for prolonged normalization (Group B) included increased total number of fusion levels, especially 10 or more (P < 0.05); patients undergoing circumferential fusions (P < 0.05); and, to a lesser extent, older patients undergoing multiple fusion levels (P = 0.055). These data are important when counseling spinal reconstructive surgery patients before surgery and provides information to those patients who may benefit from perioperative nutritional supplementation.


Induction of lupus autoantibodies by adjuvants.
Exposure to the hydrocarbon oil pristane induces lupus specific autoantibodies in non-autoimmune mice. We investigated whether the capacity to induce lupus-like autoimmunity is a unique property of pristane or is shared by other adjuvant oils. Seven groups of 3-month-old female BALB/cJ mice received a single intraperitoneal injection of pristane, squalene (used in the adjuvant MF59), incomplete Freund's adjuvant (IFA), three different medicinal mineral oils, or saline, respectively. Serum autoantibodies and peritoneal cytokine production were measured. In addition to pristane, the mineral oil Bayol F (IFA) and the endogenous hydrocarbon squalene both induced anti-nRNP/Sm and -Su autoantibodies (20% and 25% of mice, respectively). All of these hydrocarbons had prolonged effects on cytokine production by peritoneal APCs. However, high levels of IL-6, IL-12, and TNFalpha production 2-3 months after intraperitoneal injection appeared to be associated with the ability to induce lupus autoantibodies. The ability to induce lupus autoantibodies is shared by several hydrocarbons and is not unique to pristane. It correlates with stimulation of the production of IL-12 and other cytokines, suggesting a relationship with a hydrocarbon's adjuvanticity. The potential to induce autoimmunity may complicate the use of oil adjuvants in human and veterinary vaccines.


Circadian Rhythm Sleep-Wake Disorders in Older Adults.
The timing, duration, and consolidation of sleep result from the interaction of the circadian timing system with a sleep-wake homeostatic process. When aligned and functioning optimally, this allows for wakefulness throughout the day and a long consolidated sleep episode at night. Changes to either the sleep regulatory process or how they interact can result in an inability to fall asleep at the desired time, difficulty remaining asleep, waking too early, and/or difficulty remaining awake throughout the day. This mismatch between the desired timing of sleep and the ability to fall asleep and remain asleep is a hallmark of a class of sleep disorders called the circadian rhythm sleep-wake disorders. In this updated article, we discuss typical changes in the circadian regulation of sleep with aging; how age influences the prevalence, diagnosis, and treatment of circadian rhythm sleep disorders; and how neurologic diseases in older patient impact circadian rhythms and sleep.


Quantitative determination of G6Pase activity in histochemically defined zones of the liver acinus.
Qualitative histochemical G6Pase distribution patterns obtained with an improved method (Teutsch, 1978) served as the basis for a zonal microdissection of the liver acinus. G6Pase activity was determined quantitatively in tissue samples of zones 1 and 3 by a microfluorometric method (Burch et al., 1978). Using a correlation system it could be demonstrated that the histochemical distribution pattern obtained with the improved method was in better agreement with quantitatively estimated zonal differences of G6Pase activity, both in fed and starved female rats, than with the Wachstein and Meisel medium (1956). From a total of 50 tissue samples analyzed the following average G6Pase activities were calculated: in fed animals 15.36 +/- 3.48 U/g dry weight in zone 1, and 9.28 +/- 2.15 U/g dry weight in zone 3; in starved female rats 42.50 +/- 8.20 U/g dry weight in zone 1, and 29.25 +/- 5.68 U/g dry weight in zone 3. The qualitative histochemical as well as quantitative zonal differences of G6Pase activities are taken as further support for the hypothesis of metabolic zonation of liver parenchyma.


Effects of angiotensin I-converting enzyme inhibitor and angiotensin II type 1 receptor blocker on the right ventricular sarcoglycans and dystrophin after left coronary artery ligation.
We examined the effects of trandolapril and candesartan on changes in the levels of sarcoglycans and dystrophin in the right ventricle of rats with the left coronary artery ligation. Hemodynamic and morphological alterations suggested the development of hypertrophy of the right ventricle and chronic heart failure by the 8th week. By the end of the 8th week, alpha- and beta-sarcoglycans and dystrophin were decreased. Increases in mu- and m-calpains in the hypertrophied right ventricle were associated with an elevation of casein-proteolytic activity in the cytosolic fraction. Oral administration of 3 mg/kg/day trandolapril or 1 mg/kg/day candesartan from the 2nd to 8th week after the left coronary artery ligation attenuated decreases in alpha-sarcoglycan and dystrophin and reduced the increased proteolytic activity. The results suggest that attenuation of decreases in sarcoglycans and dystrophin is a possible mechanism underlying trandolapril- and candesartan-mediated improvement of structural and functional alterations of the right ventricle in the coronary artery-ligated rat.


Increase in hypothalamic pro-opiomelanocortin gene expression in response to prolonged low level lead exposure.
Lead, an environmental pollutant, has been long recognized as a neurotoxic agent. Several reports have recently described behavioral disturbances caused by low level lead exposure. Lead-induced changes in neurotransmitter metabolism in the brain may help to elucidate the molecular basis for the observed behavioral alterations. In this study, the influence of low level lead exposure on the hypothalamic expression of rat opioid genes was examined. Determination of relative opioid mRNA levels revealed a dramatic increase of pro-opiomelanocortin (POMC) mRNA concentrations in response to lead. This increase was found to be specific, developmentally regulated, reversible and dependent on prolonged lead exposure. These findings may provide substantial evidence for the possible connections between early environmental inputs and the expression of neuropeptide genes in the brain.


Demonstration of functional acetylcholinesterase on the soma of individual neurones of Aplysia by in vivo microspectrophotometry.
The presence of functional acetylcholinesterase is demonstrated in vivo on somatic membranes of single ganglionic neurones of Aplysia using concurrently microspectrophotometry and electrophysiology. The similarity of the effects of an irreversible blocker of acetylcholinesterase and of phospholipase C from Bacillus cereus suggests that acetylcholinesterase is anchored in the membrane via phosphatidylinositol.


Concentric and eccentric strength of trunk muscles in osteitis pubis soccer players.
Osteitis pubis refers to a painful, inflammatory condition involving the pubic bones, pubic symphysis, and adjacent structures. So, the aims of the study were to evaluate the strength of trunk muscles of soccer players suffering from osteitis pubis, and to compare the agonist/antagonist ratio of trunk muscles in osteitis pubis athletes with that of healthy athletes. Twenty-five soccer male athletes with osteitis pubis, and 25 healthy soccer athletes. Peak torque/body weight (PT/BW) was recorded from trunk muscles during isokinetic concentric and eccentric contraction modes at a speed of 120°/s for healthy and osteitis pubis soccer players. There was a significant decrease in concentric contraction of back muscles in osteitis pubis group (p=0.01). A significant decrease in eccentric contraction of abdominal muscles was also recorded in osteitis pubis group (p=0.008). Concentric abdominal/back muscles ratio was significantly higher in osteitis pubis group (p=0.016), with no significant difference in eccentric abdominal/back muscles ratio between both groups (p>0.05). Osteitis pubis group displayed concentric weakness of back muscle and eccentric weakness of abdominal muscles that lead to disturbance of the normal concentric abdominal/back ratio.


Estimation of kinetics of mercury detoxification from low-inoculum batch cultures of Pseudomonas aeruginosa PU21 (Rip64).
The growth rate of Pseudomonas aeruginosa PU21 (Rip64) and the mercury detoxification rate were determined by using low-inoculum batch cultures. In order to attain invariant culture conditions for the determination of growth kinetics in mercury-containing Pseudomonas minimal media (PMM), the initial cell concentrations were adjusted to approx. 100 cells per ml, and the initial mercury concentrations used were less than 2 micrograms Hg2+ per ml. It was found that the specific growth rate decreased as mercury concentration increased. The relationship between specific growth rate and glucose concentration was found to follow Monod kinetics. The mercury detoxification rate was determined for the viable cells and the dying (non-growing) cells.


Rabbit Soft Tissue Surgery.
This article summarizes the available information on different soft tissue surgical procedures in rabbits, based on the literature and the authors' experiences, emphasizing the differences between rabbits and the more familiar dogs and cats. The major surgical principles in rabbits are discussed, and common surgical procedures, such as abdominal exploration, gastrotomy, enterotomy, liver lobectomy, nephrectomy, cystotomy, cystectomy, ovariohysterectomy, ovariectomy, orchidectomy, are described.


AGONOTES: A Robot Annotator for Argonaute Proteins.
The argonaute protein (Ago) exists in almost all organisms. In eukaryotes, it functions as a regulatory system for gene expression. In prokaryotes, it is a type of defense system against foreign invasive genomes. The Ago system has been engineered for gene silencing and genome editing and plays an important role in biological studies. With an increasing number of genomes and proteomes of various microbes becoming available, computational tools for identifying and annotating argonaute proteins are urgently needed. We introduce AGONOTES (Argonaute Notes). It is a web service especially designed for identifying and annotating Ago. AGONOTES uses the BLASTP similarity search algorithm to categorize all submitted proteins into three groups: prokaryotic argonaute protein (pAgo), eukaryotic argonaute protein (eAgo), and non-argonaute protein (non-Ago). Argonaute proteins can then be aligned to the corresponding standard set of Ago sequences using the multiple sequence alignment program MUSCLE. All functional domains of Ago can further be curated from the alignment results and visualized easily through Bio::Graphic modules in the BioPerl bundle. Compared with existing tools such as CD-Search and available databases such as UniProt and AGONOTES showed a much better performance on domain annotations, which is fundamental in studying the new Ago. AGONOTES can be freely accessed at http://i.uestc.edu.cn/agonotes/. AGONOTES is a friendly tool for annotating Ago domains from a proteome or a series of protein sequences.


Absolute bioavailability and noncompartmental analysis of intravenous and intramuscular Cefotan (cefotetan) in normal volunteers.
Cefotetan (1 g) was administered to 12 normal volunteers as a 30 minute intravenous infusion and as an intramuscular injection. The pharmacokinetic parameters were estimated using noncompartmental analysis. The mean +/- SD maximum plasma concentration, terminal half-life, and systemic clearance after intravenous infusion were 158 +/- 21 micrograms/mL, 4.54 +/- 1.05 hours, and 29.1 +/- 3.8 mL/min/1.73 m2, respectively. Renal clearance and nonrenal clearance accounted for 63.1% and 36.9% of the systemic clearance, respectively. The mean +/- SD maximum plasma concentration, time to maximum concentration, terminal half-life, and absolute bioavailability after intramuscular injection were 75.5 +/- 8.7 micrograms/mL, 1.33 +/- 0.48 hours, 4.32 +/- 0.77 hours, and 0.931 +/- 0.193, respectively. Moment analysis gave average +/- SD mean residence times (MRT) of 4.98 +/- 0.75 and 5.86 +/- 0.77 hours after intravenous and intramuscular administration, respectively. The average +/- SD mean absorption time (MAT) after intramuscular injection was 1.11 +/- 0.57 hours. The mean +/- SD steady-state volume of distribution after intravenous infusion was 0.129 +/- 0.024 L/kg. The mean +/- SD cumulative percentage of the dose excreted in the urine in 24 hours were 61.1 +/- 11.4% and 50.4 +/- 13.5% after intravenous and intramuscular dosing, respectively. The maximum urinary cefotetan concentrations occurred during the first 2 hours after dosing by both routes of administration. Cefotetan tautomer was detected in the plasma and urine of all subjects after both routes of administration, but the mean concentrations were only minimal compared to those for cefotetan. In conclusion, intramuscular cefotetan (1 g) is rapidly and almost completely absorbed.(ABSTRACT TRUNCATED AT 250 WORDS)


Do you know your students' basic clinical skills exposure?
Undergraduate medical education in the United States is changing. Many medical schools have developed a set of basic clinical skills (BCS) that all students are required to have mastered; however, very few have acquired objective information regarding specific student experiences. The purpose of this study was to determine the BCS encounters for junior medical students at a large midwestern university utilizing a handheld personal digital assistant (PDA). A core curriculum of BCS was proposed and involved 52 procedures/skills. An electronic BCS database was developed utilizing HanDBase software and then placed on a PDA (Palm) and distributed to 25 third-year medical students randomly as they entered their clinical year. Students logged their skill encounters for 9 months and then electronically transferred the database by e-mail. Students participated in 1,115 procedural/skill encounters (range 17 to 90; median 41; average 44.6). Of the 52 core BCS, all students performed 10. Fewer than 50% of students had any exposure to very common skills. Thirty-four percent of skill encounters occurred at a county hospital, 19% at a clinic, 10% at a university hospital, 10% at a private hospital, 7% at a VA hospital, 4% at a children's hospital, and 16% at miscellaneous locations. The PDA devices were simple and convenient to use, while allowing for easy transfer and tabulation of database information by electronic mail. Significant gaps in BCS exposure were noted across the curriculum. Mentor sign-off on the PDA permitted early feedback opportunities. We can now begin to reward educators for skills mentoring and perform formal assessment of BCS within specific clerkships to enhance future educational objectives.


Improvement of alkali solubility of cellulose with enzymatic treatment.
Cellulose was treated with different extracellular microbial enzymes. The treatment of cellulose with the enzymes can improve alkaline solubility. Both endoglucanase and crude cellulase decreased the average degrees of polymerization ([see text]) and improved the alkaline solubility of cellulose most efficiently. The composition of the enzyme, the type of cellulosic materials, pretreatment, and the treatment conditions are the key factors for its effective processing, using the enzymes to improve on alkaline solubility of cellulose. The improvement in the alkaline solubility is caused by the decrease in [see text] and hydrogen bond because of enzymatic hydrolysis.


Evidence of endocrine alteration in the red mullet, Mullus barbatus from the NW Mediterranean.
Red mullet (Mullus barbatus) were collected from different sampling sites (NW Mediterranean) in spring and autumn, with the aim of assessing potential alterations of the endocrine system. Alkylphenols were measured in fish bile as an indicator of estrogenic exposure. Key enzymatic activities involved in both synthesis (ovarian 17beta-hydroxysteroid dehydrogenases and P450 aromatase) and metabolism of steroids were assessed together with histological alterations of the gonads. During the spring sampling, delayed gamete maturation, intersexuality, fibrosis, and depressed ovarian P450 aromatase activity were observed in organisms from the most polluted sites. During the autumn sampling, those effects were less evident, indicating that fish might be more susceptible to endocrine disrupting chemicals during the reproductive period. Nonetheless, enhanced glucuronidation of testosterone and estradiol was observed. Overall, this work provides first evidences of significant alterations in the endocrine system of red mullet from highly impacted areas in the NW Mediterranean.


Involvement of human interleukin 6 in experimental cachexia induced by a human uterine cervical carcinoma xenograft.
In this experimental study, the authors examined the role of various cytokines in the development of cancer cachexia. After in vitro culture and selection of a single clone of tumor cells, a growing uterine cervical carcinoma from human origin was implanted subcutaneously in nude mice. Body weight and tumor volume were measured throughout the study period; tissue wasting was assessed by weighing the gastrocnemius muscle and the peri-ovarian white adipose tissue. Serum and tumor cytokine concentrations, including human G-CSF, murine and human tumor necrosis factor (TNF)- proportional, variant, IFN-gamma, interleukin (IL)-1 proportional, variant and IL-6, were determined by ELISA at the end of the study. Two months after implantation, the tumor (4% of carcass weight) induced severe loss of adipose tissue (-95%) and muscle mass (-49%). Human IL-6 (0.38 +/- 0.19 ng/ml) and human G-CSF were detected in the serum and the tumor tissue of these animals; none of the cytokines of murine origin was detected in the serum, except IL-6 (0.14 +/- 0.05 ng/ml). Treatment with neutralizing anti-human IL-6 antibodies reduced plasma IL-6 and G-CSF levels and significantly increased host carcass weight (16%) and fat mass (353%). The authors conclude that human IL-6 produced by tumor cells is an essential mediator of cachexia in this model.


Melatonin suppresses chronic restraint stress-mediated metastasis of epithelial ovarian cancer via NE/AKT/β-catenin/SLUG axis.
Chronic stress has been shown to facilitate progression of epithelial ovarian cancer (EOC), however, the neuro-endocranial mechanism participating in this process still remains unclear. Here, we reported that chronic restraint stress (CRS) promoted the abdominal implantation metastasis of EOC cells and the expression of epithelial-mesenchymal transition-related markers in tumor-bearing mouse model, including TWIST, SLUG, SNAIL, and β-catenin. We observed that β-catenin co-expressed with SLUG and norepinephrine (NE) in tumor tissues obtained from nude mice. Further ex vivo experiments revealed that NE promoted migration and invasion of ovarian cancer cells and SLUG expression through upregulating expression and improving transcriptional function of β-catenin in vitro. A human phosphor-kinase array suggested that NE activated various kinases in ovarian cancer cells, and we further confirmed that AKT inhibitor reduced NE-mediated pro-metastatic impacts and activation of the β-catenin/SLUG axis. Furthermore, the expression levels of NE and β-catenin were examined in ovarian tumor tissues by using tumor tissue arrays. Results showed that the expression levels of both NE and β-catenin were associated with poor clinical stage of serous EOC. Moreover, we found that melatonin (MLT) effectively reduced the abdominal tumor burden of ovarian cancer induced by CRS, which was partially related to the inhibition of the NE/AKT/β-catenin/SLUG axis. Collectively, these findings suggest a novel mechanism for CRS-mediated ovarian cancer metastasis and MLT has a potential therapeutic efficacy against ovarian cancer.


Natural Products Originated from the Oxidative Coupling of Tyrosine and Tryptophan: Biosynthesis and Bioinspired Synthesis.
The oxidative coupling of tyrosine and tryptophan units is a pivotal step in the total synthesis of some peptide-derived marine and terrestrial natural products, such as the diazonamides, azonazine and tryptorubin A. This Minireview details the biosynthesis and bioinspired synthesis of natural products with such structures. A special focus is put on the challenges of the synthesis of these natural products and the innovative solutions adopted by synthetic chemists.


Author Correction: Area-based conservation in the twenty-first century.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Since decades antibodies are used for diagnosis e. g. by detecting patient antibodies that specifically bind to Influenza virus proteins. We predict these diagnostic questions will be parallelized to diagnose all known disease specific antibodies at once. These tests will ask in addition, which unknown antibodies patrol in a patient's blood, and what exactly they bind to. Thereby, we expect to find antibody species that correlate to hitherto enigmatic diseases or have specialized functions.


Septin 2 interacts with dengue virus replication complex proteins and participates in virus replication in mosquito cells.
Septins are a family of GTP-binding proteins identified in insects and mammals. Septins are components of the cytoskeleton and participate in cytokinesis, chromosomal segregation, intracellular vesicular traffic, and response to pathogens. Human septin 6 was identified as necessary for hepatitis C virus replication. Information about host factors necessary for flavivirus replication in mosquitoes is scarce. Thus, the role of septins in the replicative cycle of dengue virus in Aedes spp. derived cells was investigated. Through bioinformatic analysis, sequences of septin-like proteins were identified. Infected mosquito cells showed increased expression of Sep2. Colocalization analysis, proximity ligation and immunoprecipitation assays indicated that Sep2 interacts with proteins E, NS3 and NS5, but not NS1. Immunoelectron microscopy evidenced the presence of AalSep2 in replicative complexes. Finally, silencing of Sep2 expression resulted in a significant decrease in virus progeny, indicating that Sep2 is a host factor participating in dengue virus replication in mosquito cells.


Therapeutic effects of metformin for noise induced hearing loss.
This study aimed to investigate the healing effect of metformin on noise induced hearing loss (NIHL) by measuring audiological, biochemical and histological parameters. 32 rats were divided into four groups (Group 1: Noise, Group 2: Noise + Metformin, Grup 3: Metformin, Grup 4: Control). Broadband noise was applied to Group 1 and Group 2 after basal measurements. Measuring audiological (distortion product otoacoustic emission (DPOAE) and Auditory Brainstem Response (ABR)), biochemical (total antioxidant status (TAS), total oxidant status (TOS), oxidative status index (OSI), DNA damage, IL-1 beta, IL-6, TNF alfa, HSF-1 and COX-2) and histological parameters. Group 2 had significant decreases in ABR thresholds on day 7 and day 14 compared to day 1. DPOAE values of Group 2 on the 7th and 14th days were significantly higher than the post-noise levels. DNA damage, TOS and OSI values of Group 1 were significantly higher than the other groups. The Cox-2 value of Group 1 was higher than all other groups. The HSF-1 value of Group 2 was significantly higher than that of Group 1. In terms of IL-1 Beta, IL-6 and TNF-alpha values, there was no significant difference between groups 2, 3 and 4 and these values were significantly lower than group 1. In histopathological results of our study, no significant difference was found between the groups being exposed to noise and the control group. This study showed that early period of Metformin treatment has therapeutic effect on NIHL.


Uptake of COVID-19 vaccines among healthcare workers and the effect of nudging interventions: A mixed methods study.
During the coronavirus disease (COVID-19) pandemic, vaccination of healthcare workers (HCWs) has a critical role because of their high-risk exposure and being a role model. Therefore, we aimed to investigate vaccine hesitancy and the role of mandatory polymerase chain reaction (PCR) testing and education for vaccine uptake. We conducted an explanatory sequential designed observational mixed-methods study, including quantitative and qualitative sections consecutively in two different pandemic hospitals between 15 September 2021 and 1 April 2022. The characteristics of vaccinated and unvaccinated HCWs were compared. The vaccine hesitancy scales were applied, and the effect of nudging, such as mandatory PCR and education, were evaluated. In-depth interviews were performed to investigate the COVID-19 vaccine hesitancy among HCWs according to Health Belief Model. In total, 3940 HCWs were included. Vaccine hesitancy was more common among males than females, the ancillary workers than other health professions, and nonmedical departments than other departments. After the mandatory weekly PCR request nudge, 83.33 % (130/156) vaccine-hesitant HCWs were vaccinated, and 8.3 % (13/156) after the small group seminars and mandatory PCR every two days. The rate of COVID-19 vaccination was raised from 95.5 % to 99.67 % (3927/3940). At the end of in-depth interviews (n = 13), the vaccine hesitancy determinants were distrust, fear of uncertainty, immune confidence and spirituality, the media effect, social pressure, and obstinacy. The nudging interventions such as mandatory PCR testing and small group seminars helped raise the rate of COVID-19 vaccination; the most effective one is mandatory PCR.


Alendronate enhances osseointegration in a murine implant model.
Administration of bisphosphonates following total joint arthroplasty might be beneficial to reduce aseptic loosening. However, their effects on peri-implant bone formation and bone-implant interface strength have not been investigated yet. We used a physiologically loaded mouse implant model to investigate the short-term effects of postoperative systemic alendronate on osseointegration. A titanium implant with a rough surface was inserted in the proximal tibiae of 17-week-old female C57BL/6 mice (n = 44). Postimplantation mice were given alendronate (73 μg/kg/days, n = 22) or vehicle (n = 22) 5 days/week. At 7- and 14-day postimplantation, histology and histomorphometry were conducted. At 28 days, microcomputed tomography and biomechanical testing were performed (n = 10/group). Postoperative alendronate treatment enhanced osseointegration, increasing maximum pullout load by 45% (p < .001) from 19.1 ± 4.5 N in the control mice to 27.6 ± 4.9 N in the treated mice, at day 28 postimplantation. Alendronate treatment increased the bone volume fraction by 139% (p < .001) in the region distal to the implant and 60% (p < .05) in the peri-implant region. At 14-day postimplantation, alendronate treatment decreased the number of osteoclasts per bone perimeter (p < .05) and increased bone volume fraction (p < .01) when compared with the control group. Postimplantation, short-term alendronate treatment enhanced osseointegration as demonstrated by increased bone mass, trabecular bone thickness, and maximum pullout load. Alendronate decreased peri-implant osteoclasts while preserving peri-implant osteoblasts and endothelial cells, in turn, increasing bone volume fraction. This data supports the postoperative clinical use of bisphosphonates, especially in patients with high risks of aseptic loosening.


Detection of specific UL49 sequences of Marek's disease virus CVI988/Rispens strain using loop-mediated isothermal amplification.
Marek's disease (MD) is a tumoral disease of chickens that can be controlled by vaccines based on non-pathogenic strains of turkey herpesvirus (HVT), SB-1 strain belonging to serotype 2, or the attenuated CVI988/Rispens strain belonging to serotype 1 of Marek's disease virus (MDV). Currently, the 'gold standard' in MD prophylaxis is the Rispens strain-based vaccine which protects against very virulent MDV and disease onset. Previous studies have shown that loop-mediated isothermal amplification (LAMP) is a rapid alternative to polymerase chain reaction (PCR) for detection and differentiation of HVT, SB-1 and virulent MDV strains. The aim of this study was to develop and evaluate a novel LAMP assay for the detection of the UL49 Rispens-specific region. This assay was validated using material from infected chicken embryo fibroblasts (CEFs) and tissue samples from vaccinated chickens. The analytical sensitivity of the assay was 10-times higher than PCR and reliably amplified 0.1 log10 TCID50/ml. The MDV Rispens was also detected at 18h after infection of CEFs. The results showed LAMP to be selective and a sensitive method to detect Rispens as early as 3 d.p.v. in all internal organs of chickens. Furthermore, the method was also capable to detect Rispens in 5 out of 26 chickens originating from different flocks. A mismatch amplification mutation assay (MAMA-PCR) confirmed the presence of Rispens strain in all LAMP-positive chickens. This is the first report of the specific visual detection of Rispens in vitro and in vivo using LAMP. The method may be useful for monitoring of successful chicken vaccination as well as in vitro studies in infected cell cultures.


Determination of mental competency, a neurological perspective.
This article discusses the evaluation of the capacity of a person to make informed decisions about financial matters, independent living, and informed consent for medical treatment and research. Determination of capacity is a function for which most physicians have little training. The determination of competency for a general medical patient may be assessed by a combination of a bedside mental status examination such as the MMSE and a questionnaire such as the Aid To Capacity Evaluation (ACE 1999). For patients with focal neurological deficits such as aphasia, further evaluation of specific cognitive and language functions is needed; Alexander (Arch Neurol 45:23-6, 1988) suggested 7 specific functions to be assessed. Finally, in dementing illnesses, evaluation by the MMSE and a questionnaire such as the CCTI, or Capacity to Consent to Treatment Instrument (Marson et al. Arch Neurol 52:949-54, 1995) is needed. Dementia includes several separate syndromes of neurodegenerative disease, and in many of these conditions, focal deficits such as aphasia may necessitate a more thorough neuropsychological evaluation.


Epicanthal fold correction: our experience and comparison among three kinds of epicanthoplasties.
Epicanthal fold, which is unique to Asian population, forms a web across and covering the medial canthus. It often impairs the beauty of the eyelids and the outcome of double-eyelid blepharoplasty that is popular in Asians. Although many surgical procedures have been reported, most of them were only description of a single technique. Comparison among techniques will help form universally accepted algorithm or consensus in epicanthus treatment. We want to present our experience of three kinds of epicanthoplasties: horizontal incision method, Z-plasty and V-W plasty and a detailed comparison among these surgical techniques. From 2005 to 2011, the authors had performed epicanthoplasties in 252 cases, in which 220 cases simultaneously underwent a double-eyelid surgery. The choice of technique was based on presurgical evaluation of severity of epicanthal fold. Horizontal incision method was used for majority of mild epicanthal fold. Z-plasty mainly applied to moderate cases and V-W plasty was chosen for severe ones. In addition to skin rearrangement in medial canthic region, underlying orbicularis oculi muscle and thick subcutaneous tissue also needed treatment for effective release. The degree of postoperative scarring and epicanthal fold correction were reviewed. All these three methods produced satisfactory long-term results with alleviation of the skinfold and formation of vivid upper eyelid crease. No complete recurrence was observed. Horizontal incision method left an inconspicuous scar and V-W plasty might cause a relatively obvious scar. Persistent hypertrophic scars were observed in 12 patients and gradually faded after injection of diprospan. In conclusion, preoperative evaluation of skinfold severity, making a rational choice and careful implementation of surgical technique available are important in effective correction of epicanthal fold.


Development of a markerless genetic exchange method for Methanosarcina acetivorans C2A and its use in construction of new genetic tools for methanogenic archaea.
A new genetic technique for constructing mutants of Methanosarcina acetivorans C2A by using hpt as a counterselectable marker was developed. Mutants with lesions in the hpt gene, encoding hypoxanthine phosphoribosyltransferase, were shown to be >35-fold more resistant to the toxic base analog 8-aza-2,6-diaminopurine (8ADP) than was the wild type. Reintroduction of the hpt gene into a Delta hpt host restored 8ADP sensitivity and provided the basis for a two-step strategy involving plasmid integration and excision for recombination of mutant alleles onto the M. acetivorans chromosome. We have designated this method markerless exchange because, although selectable markers are used during the process, they are removed in the final mutants. Thus, the method can be repeated many times in the same cell line. The method was validated by construction of Delta proC Delta hpt mutants, which were recovered at a frequency of 22%. Additionally, a Methanosarcina-Escherichia shuttle vector, encoding the Escherichia coli proC gene as a new selectable marker, was constructed for use in proC hosts. Finally, the markerless exchange method was used to recombine a series of uidA reporter gene fusions into the M. acetivorans proC locus. In vitro assay of beta-glucuronidase activity in extracts of these recombinants demonstrated, for the first time, the utility of uidA as a reporter gene in Methanosarcina: A >5,000-fold range of promoter activities could be measured by using uidA: the methyl-coenzyme M reductase operon fusion displayed approximately 300-fold-higher activity than did the serC gene fusion, which in turn had 16-fold-higher activity than did a fusion to the unknown orf2 gene.


Bilateral testicular biopsy in men with varicocele.
Fifty-two infertile men with varicoceles were subjected to bilateral testicular biopsy to detect the effect of the varicocele on each testis. The results indicate that varicocele can result in infertility primarily through sloughing of immature cells or through arrest of spermatogenesis at the spermatid or primary spermatocyte stage. The effect is bilateral but is more marked on the varicocele side. However, the presence of a varicocele could not explain the infertility of seven men with normal biopsies and of four men with a normal biopsy on the varicocele side and arrest on the other side.


Non-Invasive radial pressure wave analysis may digitally predict women's risks of type 2 diabetes (T2DM): A case and control group study.
Women not only have worse diabetes complications, but also have menstrual cycle, pregnancy, and menopause which can make managing diabetes more difficult. The aim of this study was to investigate if radial pressure wave analysis may non-invasively screen for women's risk of type 2 diabetes. Spectrum analysis of the radial pressure wave was performed to evaluate the first five harmonic components, C1 to C5. The study consisted of a total of 808 non-pregnant female subjects aged 20-95 over the period of 4 years, and 404 of them were diagnosed with Type 2 diabetes as the case group. The first five harmonic components are significantly different in a comparison of the case group and the control group. In the logistic regression analysis, T2DM was found to be associated with C1 (OR = 1.055, CI = 1.037-1.074, p < 0.001), C2 (OR = 1.051, CI = 1.019-1.085, p = 0.002), and C3 (OR = 0.972, CI = 0.950-0.994, p = 0.013). In the Receiver Operating Characteristic curve analysis, the Area Under Curve of using C3 only (70%, p <0.05), weighted C1, C2 and C3, (75%, p < 0.05), and weighted C1, C2 and C3 and Body mass Index (84%, p <0.05) were tested for the accuracy on how well these tests separate the women into the groups with and without the T2DM. We thus concluded that pulse spectrum was a non-invasive predictor for women's risk of T2DM.


Inequality in Care and Differences in Outcome Following Stroke in People With ESRD.
Stroke rate and mortality are greater in individuals with end-stage renal disease (ESRD) than in those without ESRD. We examined discrepancies in stroke care in ESRD patients and their influence on mortality. This is a national record linkage cohort study of hospitalized stroke individuals from 2005 to 2013. Presentation, measures of care quality (admission to stroke unit, swallow assessment, antithrombotics, or thrombolysis use), and outcomes were compared in those with and without ESRD after propensity score matching (PSM). We examined the effect of being admitted to a stroke unit on survival using Kaplan-Meier and Cox survival analyses. A total of 8757 individuals with ESRD and 61,367 individuals with stroke were identified. ESRD patients (n =486) experienced stroke over 34,551.9 patient-years of follow-up; incidence rates were 25.3 (dialysis) and 4.5 (kidney transplant)/1000 patient-years. After PSM, dialysis patients were less likely to be functionally independent (61.4% vs. 77.7%; P < 0.0001) before stroke, less frequently admitted to stroke units (64.6% vs. 79.6%; P < 0.001), or to receive aspirin (75.3% vs. 83.2%; P = 0.01) than non-ESRD stroke patients. There were no significant differences in management of kidney transplantation patients. Stroke with ESRD was associated with a higher death rate during admission (dialysis 22.9% vs.14.4%, P = 0.002; transplantation: 19.6% vs. 9.3%; P = 0.034). Managing ESRD patients in a stroke unit was associated with a lower risk of death at follow-up (hazard ratio: 0.68; 95% confidence interval: 0.55-0.84). Stroke incidence is high in ESRD. Individuals on dialysis are functionally more dependent before stroke and less frequently receive optimal stroke care. After a stroke, death is more likely in ESRD patients. Acute stroke unit care may be associated with lower mortality.


Uncovering diversity in the development of central noradrenergic neurons and their efferents.
Uncovering the mechanisms that underlie central noradrenergic neuron heterogeneity is essential to understanding selective subtype vulnerability to disease and environmental insult. Using recombinase-based intersectional genetic fate mapping we have previously demonstrated that molecularly distinct progenitor populations give rise to mature noradrenergic neurons differing in their anatomical location, axon morphology and efferent projection pattern. Here we review the findings from our previous study and extend our analysis of the noradrenergic subpopulation defined by transient developmental expression of Hoxb1. Using a combination of intersectional genetic fate mapping and analysis of a targeted loss of function mutation in Hoxb1, we have now uncovered additional heterogeneity based on the requirement of some noradrenergic neurons for Hoxb1 expression. By comparing the distribution of noradrenergic neurons derived from the Hoxb1 expression domain in wild-type and mutant mice, we demonstrate that Hoxb1 expression is required by a subset of neurons in the pons. Additional fate mapping, using a Hoxb1 enhancer element that drives Cre recombinase expression exclusively in rhombomere 4 of the hindbrain, reveals the existence of a subpopulation of noradrenergic neurons in the pons with more restricted axonal targets than the full Hoxb1-derived subpopulation. The unique projection profile of this newly defined subpopulation suggests that it may be functionally distinct. These analyses shed new light on the molecular determinants of noradrenergic identity in the pons and the overall complexity of the central noradrenergic system. This article is part of a Special Issue entitled SI: Noradrenergic System.


Do radiomics or diffusion-tensor images provide additional information to predict brain amyloid-beta positivity?
The aim of the present study was to predict amyloid-beta positivity using a conventional T1-weighted image, radiomics, and a diffusion-tensor image obtained by magnetic resonance imaging (MRI). We included 186 patients with mild cognitive impairment (MCI) who underwent Florbetaben positron emission tomography (PET), MRI (three-dimensional T1-weighted and diffusion-tensor images), and neuropsychological tests at the Asan Medical Center. We developed a stepwise machine learning algorithm using demographics, T1 MRI features (volume, cortical thickness and radiomics), and diffusion-tensor image to distinguish amyloid-beta positivity on Florbetaben PET. We compared the performance of each algorithm based on the MRI features used. The study population included 72 patients with MCI in the amyloid-beta-negative group and 114 patients with MCI in the amyloid-beta-positive group. The machine learning algorithm using T1 volume performed better than that using only clinical information (mean area under the curve [AUC]: 0.73 vs. 0.69, p < 0.001). The machine learning algorithm using T1 volume showed better performance than that using cortical thickness (mean AUC: 0.73 vs. 0.68, p < 0.001) or texture (mean AUC: 0.73 vs. 0.71, p = 0.002). The performance of the machine learning algorithm using fractional anisotropy in addition to T1 volume was not better than that using T1 volume alone (mean AUC: 0.73 vs. 0.73, p = 0.60). Among MRI features, T1 volume was the best predictor of amyloid PET positivity. Radiomics or diffusion-tensor images did not provide additional benefits.


alpha-Synuclein expression in the brain and blood during abstinence from chronic alcohol drinking in mice.
alpha-Synuclein is a presynaptic protein proposed to serve as a negative regulator of dopaminergic neurotransmission. Recent research has implicated alpha-synuclein in chronic neuroadaptations produced by psychostimulant and opiate use, as well as in genetically determined susceptibility to alcoholism in humans. The aim of our study was to characterize the changes in alpha-synuclein expression after short-term abstinence from chronic alcohol drinking in mice. Male C57BL/6J mice were allowed to drink increasing concentrations of alcohol in the two-bottle choice procedure. Then the mice were given constant access to an 8% alcohol solution and water for 32 days, and were sacrificed 2 h, 24 h or 48 h after alcohol withdrawal. RT-PCR, in situ hybridization and Western blotting techniques were used to measure alpha-synuclein mRNA and protein levels in the brain and blood. alpha-Synuclein protein levels were elevated by up to 80% in the amygdala of mice withdrawn from alcohol for 24 h or 48 h. No changes in alpha-synuclein levels were found in the mesencephalon or striatum/accumbens. The levels of alpha-synuclein mRNA remained unchanged in all brain regions examined (the striatum, nucleus accumbens, amygdala, substantia nigra, ventral tegmental area). alpha-Synuclein mRNA was up-regulated in the whole blood 48 h after alcohol withdrawal. The accumulation of alpha-synuclein in the amygdala, observed in this study, seems to be a common feature of alcohol and opiate abstinence. This finding suggests a role of alpha-synuclein in common neuroadaptations produced by long-term alcohol and drug use. Although alpha-synuclein expression in the blood seems unrelated to that in the brain, it may serve as a peripheral biomarker of chronic alcohol consumption.


Clinical Presentation and Diagnosis of Neuroendocrine Tumors.
Neuroendocrine tumors (NETs) are slow-growing neoplasms capable of storing and secreting different peptides and neuroamines. Some of these substances cause specific symptom complexes, whereas others are silent. They usually have episodic expression, and the diagnosis is often made at a late stage. Although considered rare, the incidence of NETs is increasing. For these reasons, a high index of suspicion is needed. In this article, the different clinical syndromes and the pathophysiology of each tumor as well as the new and emerging biochemical markers and imaging techniques that should be used to facilitate an early diagnosis, follow-up, and prognosis are reviewed.


Long and short sleep duration and psychotic symptoms in adolescents: Findings from a cross-sectional survey of 15 786 Japanese students.
Sleep problems during adolescence affect current and subsequent mental health and are associated with experiences of psychotic symptoms. Recent studies have suggested that short sleep duration increases the risk of experiencing psychotic symptoms in the general adolescent population; however, whether long sleep duration is associated with an increased risk of psychotic symptoms in adolescence remains unclear. The present study aimed to examine the relationships between long sleep duration, short sleep duration, and the risk of experiencing psychotic symptoms in adolescence. Cross-sectional survey data from 15,786 junior and senior high school students (12- to 15-year-olds and 15- to 18-year-olds, respectively) in Japan were collected and analyzed using logistic regression analysis after controlling for covariates, including depressive symptoms. Long sleep duration was associated with a 1.6- to 2.8-fold increased risk of psychotic symptoms in male but not in female adolescents. Short sleep duration was also related with a 1.6- to 2.9-fold increased risk of experiencing psychotic symptoms, except for 15- to 18-year-old female adolescents. The present study suggested that adolescents with long and short sleep duration should be assessed for their risk of experiencing psychotic symptoms regardless of concurrent depressive symptoms.


Actinic reticuloid. A clinical photobiologic, histopathologic, and follow-u study of 16 patients.
We report a detailed clinical, histopathologic, and photobiologic study of 16 Dutch patients with actinic reticuloid. All were middle-aged or elderly men who had persistent plaques on light-exposed skin only (two patients), extension of lesions to nonexposed areas (four patients), or prolonged or persistent episodes of erythroderma (10 patients). They were sensitive to UVB, UVA, and visible light. In 10 of 13 patients tested, the dermal infiltrate contained predominantly suppressor T cells. Many also had a reversed helper-suppressor T cell ratio. Circulating lymphocytes with deeply indented nuclei were present in all but were most pronounced in the most photosensitive erythrodermic patients. Tolerance induction therapy with UVB irradiation produced an excellent or good response in 13 of 15 patients. One patient responded to cyclosporine therapy.


Serpiginous choroiditis in a referral clinic in India: visual field changes and clinical correlates.
To report the visual field changes in patients with serpiginous choroiditis as seen in a referral clinic in India. A retrospective noncomparative case series was conducted. Twenty-nine eyes of 17 patients who were diagnosed with serpiginous choroiditis were included in the study. Clinical findings were recorded. Visual field was measured with a Humphrey visual field analyzer. Information obtained was entered into SPSS 17.0 and analyzed. There was a male preponderance (8:2). Age at presentation ranged from 14 to 53 years. Eleven subjects (64.7%) had bilateral involvement at presentation. Mean visual acuity improved to 0.35 after treatment. Visual field changes were seen in 28 eyes and the mean deviation value was maintained after treatment (-8.5, 7.19 SD). Multiple foci of defects (usually central or paracentral scotoma co-existing with isolated field defects in the nasal or temporal field) were the commonest form of visual field defect detected. Patients with serpiginous choroiditis had a stable visual field defects after 6 months of treatment. The need for visual field monitoring in these patients is underscored.


Bile acid analysis in human disorders of bile acid biosynthesis.
Bile acids facilitate the absorption of lipids in the gut, but are also needed to maintain cholesterol homeostasis, induce bile flow, excrete toxic substances and regulate energy metabolism by acting as signaling molecules. Bile acid biosynthesis is a complex process distributed across many cellular organelles and requires at least 17 enzymes in addition to different metabolite transport proteins to synthesize the two primary bile acids, cholic acid and chenodeoxycholic acid. Disorders of bile acid synthesis can present from the neonatal period to adulthood and have very diverse clinical symptoms ranging from cholestatic liver disease to neuropsychiatric symptoms and spastic paraplegias. This review describes the different bile acid synthesis pathways followed by a summary of the current knowledge on hereditary disorders of human bile acid biosynthesis with a special focus on diagnostic bile acid profiling using mass spectrometry.


Phase I study of intracarotid PCNU.
A phase I study of the intracarotid administration of PCNU was conducted in patients with intracerebral tumors recurring after cranial radiation. Seventeen patients were treated including 16 with recurrent gliomas or glioblastomas and 1 with recurrent brain metastases from adenocarcinoma of the lung. An additional patient received a vertebral artery infusion of PCNU for a recurrent glioblastoma. Seven of 17 patients receiving intracarotid PCNU responded for a response rate of 41%. If only evaluable patients with gliomas are considered, the response rate was 44%. Tumor grade at time of initial diagnosis, exposure to prior chemotherapy, and dose of PCNU did not appear to have a major impact on response rate. Zubrod performance status 3 patients had a lower response rate (25%) than did patients with performance status 1 or 2 (response rate 63%). Thrombocytopenia and reversible central nervous system toxicity were dose limiting at a PCNU dose of 110 mg/m2. Two patients had possible permanent central nervous system toxicity. Three patients had permanent ipsilateral visual impairment, including one at the lowest dose used into the carotid artery (60 mg/m2). Orbital pain appeared to be substantially less than that seen with intracarotid BCNU but headaches may have been somewhat more common. The single patient receiving a vertebral artery infusion developed marked headaches and restlessness after receiving 25 mg/m2 of a planned 75 mg/m2 treatment into the vertebral artery and the treatment had to be discontinued. Symptoms were rapidly reversible upon stopping the medication. Our overall impression is that intracarotid PCNU causes less ocular pain but more transient central nervous system toxicity than does intracarotid BCNU.(ABSTRACT TRUNCATED AT 250 WORDS)


Evidence that leukocyte function-associated antigen-1 is involved in recirculation and homing of human lymphocytes via high endothelial venules.
We report the results of mAb inhibition studies of human lymphocyte-high endothelial venule interaction in vitro. These studies in which T cells from both normal donors and from a LFA-1-deficient patient were used indicate that in addition to a system of organ-specific 90-kDa "homing" receptors on lymphocytes, LFA-1 is also involved in lymphocyte recirculation and homing.


Knock-in mice bearing constitutively active αIIb(R990W) mutation develop macrothrombocytopenia with severe platelet dysfunction.
To date, several mutations that induce constitutive activation of integrin αIIbβ3 have been identified in congenital macrothrombocytopenia. Of these, αIIb(R995W) is the most prevalent mutation observed in Japanese patients with αIIbβ3-related congenital macrothrombocytopenia. The present study aimed to explore the effects of constitutive activation of the αIIb(R995W) mutation on platelet production, morphology, and function. We generated αIIb(R990W) knock-in (KI) mice corresponding to human αIIb(R995W). Platelet counts of heterozygous (hetero) and homozygous (homo) KI mice were decreased by ~10% and ~25% relative to those of wild-type (WT) mice, respectively, with increase in platelet size. Decrease in absolute reticulated platelet numbers in steady state, delayed recovery from thrombocytopenia induced by anti-platelet antibody and impaired response to exogenous thrombopoietin administration suggested impaired platelet production in KI mice. WT and KI mice showed no significant differences in the number of megakaryocytes and ploidy of megakaryocytes, whereas proplatelet formation was significantly impaired in homo mice. We observed a slight but significant reduction in platelet lifespan in homo mice. The homo mice showed dramatic reduction in αIIbβ3 expression in platelets, which was accompanied by severe in vivo and in vitro platelet dysfunction. The αIIb(R990W) KI mice developed macrothrombocytopenia, which was primarily attributed to impaired proplatelet formation. In addition, homo KI mice showed marked downregulation in αIIbβ3 expression in platelets with severe impaired platelet function, similar to Glanzmann thrombasthenia.


Levels of arsenic in alcohol-related liver disease.
Increased levels of arsenic were found in serum and urine and in hair and nails of patients suffering from alcohol-related liver disease (ALD). Various surveys were conducted in different places to find the cause for high arsenic in ALD. It was found that patients were consuming 'home made brew' which was contaminated with arsenic.


Simple adaptive sparse representation based classification schemes for EEG based brain-computer interface applications.
One of the main problems related to electroencephalogram (EEG) based brain-computer interface (BCI) systems is the non-stationarity of the underlying EEG signals. This results in the deterioration of the classification performance during experimental sessions. Therefore, adaptive classification techniques are required for EEG based BCI applications. In this paper, we propose simple adaptive sparse representation based classification (SRC) schemes. Supervised and unsupervised dictionary update techniques for new test data and a dictionary modification method by using the incoherence measure of the training data are investigated. The proposed methods are very simple and additional computation for the re-training of the classifier is not needed. The proposed adaptive SRC schemes are evaluated using two BCI experimental datasets. The proposed methods are assessed by comparing classification results with the conventional SRC and other adaptive classification methods. On the basis of the results, we find that the proposed adaptive schemes show relatively improved classification accuracy as compared to conventional methods without requiring additional computation.


Optic nerve fibre lesions in adult cats: pattern of recovery of spatial vision.
Partial deafferentation in the pre-geniculate optic pathways of the adult cat was produced by micro-injection of diphtheria toxin. In this lesion a certain proportion of fibres was damaged while neighbouring fibres remained unaffected. Behavioural methods were used to study the time course, pattern, and extent of recovery of spatial vision after such lesions. Cats were trained to discriminate square-wave gratings from blank fields. A range of grating sizes (0.13--2.61 cycles/degree) at high contrast were presented each day and when performance was consistently 100%, the lesion was placed. At 24 h post-lesion and serially thereafter grating discrimination was tested. Contrast sensitivity was also measured before and after the lesion. All cats recovered to pre-lesion performance levels. The time course of recovery was characterized by an early rapid phase followed by a longer slower phase. The early recovery was temporally coincident with dispersal of oedema at the site of the lesion, while the later slower recovery probably represented a functional reorganization at the synapse. Optic nerve fibre analyses at one year post-lesion showed reduction in fibre content ranging from 33 to 77% in different cats without shift in the fibre size histograms. The length of recovery time was directly related to the magnitude of fibre loss. The return of spatial frequency perception was hierarchical - first medium (1--4 days), then low (1--2 months) and finally high spatial frequencies (5--8 months). Possible mechanisms are discussed and it is suggested that such a pattern of psychophysical results could be accounted for by date than the X-type.


Anaesthesia techniques for midazolam and flumazenil--an overview.
Midazolam, the latest benzodiazepine agonist, may be used in doses of 0.15 to 0.2 mg.kg-1 for induction of anaesthesia. It provides good correlation between plasma concentration and anaesthetic effect with an interindividual variability of only 20-25%. On this basis, dosage recommendations for midazolam in total intravenous anaesthesia techniques are possible, aiming at hypnotic plasma concentrations of at least 250 ng.ml-1. Due to its biological half-life of 150-180 min and interindividual differences in drug susceptibility, prolonged recovery periods have been observed that can safely and reliably be antagonised by flumazenil, if necessary. It is recommended that flumazenil be administered carefully by titration in increments of 0.1 mg.min-1 to avoid emergence reactions by awakening too fast (tachycardia, hypertension). Usually a mean total dose of 0.4-0.5 mg will lead to prompt awakening.


Structural and functional evolution of the basal ganglia in vertebrates.
While a basal ganglia with striatal and pallidal subdivisions is 1 clearly present in many extant anamniote species, this basal ganglia is cell sparse and receives only a relatively modest tegmental dopaminergic input and little if any cortical input. The major basal ganglia influence on motor functions in anamniotes appears to be exerted via output circuits to the tectum. In contrast, in modern mammals, birds, and reptiles (i.e., modern amniotes), the striatal and pallidal parts of the basal ganglia are very neuron-rich, both consist of the same basic populations of neurons in all amniotes, and the striatum receives abundant tegmental dopaminergic and cortical input. The functional circuitry of the basal ganglia also seems very similar in all amniotes, since the major basal ganglia influences on motor functions appear to be exerted via output circuits to both cerebral cortex and tectum in sauropsids (i.e., birds and reptiles) and mammals. The basal ganglia, output circuits to the cortex, however, appear to be considerably more developed in mammals than in birds and reptiles. The basal ganglia, thus, appears to have undergone a major elaboration during the evolutionary transition from amphibians to reptiles. This elaboration may have enabled amniotes to learn and/or execute a more sophisticated repertoire of behaviors and movements, and this ability may have been an important element of the successful adaptation of amniotes to a fully terrestrial habitat. The mammalian lineage appears, however, to have diverged somewhat from the sauropsid lineage with respect to the emergence of the cerebral cortex as the major target of the basal ganglia circuitry devoted to executing the basal ganglia-mediated control of movement.


Dopaminergic innervation of interneurons in the rat basolateral amygdala.
The basolateral nuclear complex of the amygdala (BLC) receives a dense dopaminergic innervation that plays a critical role in the formation of emotional memory. Dopamine has been shown to influence the activity of BLC GABAergic interneurons, which differentially control the activity of pyramidal cells. However, little is known about how dopaminergic inputs interface with different interneuronal subpopulations in this region. To address this question, dual-labeling immunohistochemical techniques were used at the light and electron microscopic levels to examine inputs from tyrosine hydroxylase-immunoreactive (TH+) dopaminergic terminals to two different interneuronal populations in the rat basolateral nucleus labeled using antibodies to parvalbumin (PV) or calretinin (CR). The basolateral nucleus exhibited a dense innervation by TH+ axons. Partial serial section reconstruction of TH+ terminals found that at least 43-50% of these terminals formed synaptic junctions in the basolateral nucleus. All of the synapses examined were symmetrical. In both TH/PV and TH/CR preparations the main targets of TH+ terminals were spines and distal dendrites of unlabeled cells. In sections dual-labeled for TH/PV 59% of the contacts of TH+ terminals with PV+ neurons were synapses, whereas in sections dual-labeled for TH/CR only 13% of the contacts of TH+ terminals with CR+ cells were synapses. In separate preparations examined in complete serial sections for TH+ basket-like innervation of PV+ perikarya, most (76.2%) of TH+ terminal contacts with PV+ perikarya were synapses. These findings suggest that PV+ interneurons, but not CR+ interneurons, are prominent synaptic targets of dopaminergic terminals in the BLC.