Superior efficacy of olanzapine over haloperidol: analysis of patients with schizophrenia from a multicenter international trial.
Previously, a double-blind, 6-week, parallel-group trial compared the therapeutic profiles of olanzapine (5-20 mg/day; N = 1,336) and haloperidol (5-20 mg/day; N = 660) in 1996 patients with DSM-III-R schizophrenia (83.1%) or schizophreniform (1.9%) or schizoaffective disorders (15.0%) and showed olanzapine to have a superior, broader spectrum of efficacy as well as a more favorable adverse event profile. The present post hoc analysis examined the efficacy of olanzapine compared with haloperidol in the schizophrenic cohort of that study and in subgroups of schizophrenic patients defined by baseline symptom profile and course of illness. A total of 1,658 patients were included. Patients were included in analyses of change if they had both a baseline and at least 1 postbaseline measurement (N = 1,622; 1,096 olanzapine-treated patients, 526 haloperidol-treated patients). An analysis of variance was used to compare treatment effects on efficacy measurements including the Brief Psychiatric Rating Scale (BPRS; scored 0-6) and the Positive and Negative Syndrome Scale (total, positive subscale, and negative subscale scores). Olanzapine-treated patients exhibited statistically significantly greater improvements from baseline (last observation carried forward) on all efficacy measurements. Olanzapine-treated patients with predominantly positive, predominantly negative, or mixed symptoms had statistically significantly greater improvements in BPRS total scores compared with similar haloperidol-treated patients. Patients with primarily chronic negative symptoms and patients with chronic or subchronic courses of illness had statistically significantly greater mean improvements from baseline on the BPRS total with olanzapine compared with haloperidol. Furthermore, within the olanzapine treatment group, patients with a subchronic course of illness had greater mean improvements than patients with a chronic course of illness. Olanzapine was more effective than haloperidol in treating a varied spectrum of patients with schizophrenia, including patients with positive, negative, or mixed symptom profiles and either a chronic or subchronic course of illness.


RASPD+: Fast Protein-Ligand Binding Free Energy Prediction Using Simplified Physicochemical Features.
The virtual screening of large numbers of compounds against target protein binding sites has become an integral component of drug discovery workflows. This screening is often done by computationally docking ligands into a protein binding site of interest, but this has the drawback of a large number of poses that must be evaluated to obtain accurate estimates of protein-ligand binding affinity. We here introduce a fast pre-filtering method for ligand prioritization that is based on a set of machine learning models and uses simple pose-invariant physicochemical descriptors of the ligands and the protein binding pocket. Our method, Rapid Screening with Physicochemical Descriptors + machine learning (RASPD+), is trained on PDBbind data and achieves a regression performance that is better than that of the original RASPD method and traditional scoring functions on a range of different test sets without the need for generating ligand poses. Additionally, we use RASPD+ to identify molecular features important for binding affinity and assess the ability of RASPD+ to enrich active molecules from decoys.


Time to abandon electroconvulsion as a treatment in modern psychiatry.
This review examines the evidence for the current use of electroconvulsive therapy (ECT) in psychiatry. The history of ECT is discussed because ECT emerged with no scientific evidence, and the absence of other suitable therapy for psychiatric illness was decisive in its adoption as a treatment. Evidence for the current recommendation of ECT in psychiatry is reconsidered. We suggest that ECT is an unscientific treatment and a symbol of authority of the old psychiatry. ECT is not necessary as a treatment modality in the modern practice of psychiatry.


Flexible and Fast Spatial Return Level Estimation Via a Spatially Fused Penalty.
Spatial extremes are common for climate data as the observations are usually referenced by geographic locations and dependent when they are nearby. An important goal of extremes modeling is to estimate the T-year return level. Among the methods suitable for modeling spatial extremes, perhaps the simplest and fastest approach is the spatial generalized extreme value (GEV) distribution and the spatial generalized Pareto distribution (GPD) that assume marginal independence and only account for dependence through the parameters. Despite the simplicity, simulations have shown that return level estimation using the spatial GEV and spatial GPD still provides satisfactory results compared to max-stable processes, which are asymptotically justified models capable of representing spatial dependence among extremes. However, the linear functions used to model the spatially varying coefficients are restrictive and may be violated. We propose a flexible and fast approach based on the spatial GEV and spatial GPD by introducing fused lasso and fused ridge penalty for parameter regularization. This enables improved return level estimation for large spatial extremes compared to the existing methods.


Growth and ethanol fermentation ability on hexose and pentose sugars and glucose effect under various conditions in thermotolerant yeast Kluyveromyces marxianus.
Ethanol fermentation ability of the thermotolerant yeast Kluyveromyces marxianus, which is able to utilize various sugars including glucose, mannose, galactose, xylose, and arabinose, was examined under shaking and static conditions at high temperatures. The yeast was found to produce ethanol from all of these sugars except for arabinose under a shaking condition but only from hexose sugars under a static condition. Growth and sugar utilization rate under a static condition were slower than those under a shaking condition, but maximum ethanol yield was slightly higher. Even at 40°C, a level of ethanol production similar to that at 30°C was observed except for galactose under a static condition. Glucose repression on utilization of other sugars was observed, and it was more evident at elevated temperatures. Consistent results were obtained by the addition of 2-deoxyglucose. The glucose effect was further examined at a transcription level, and it was found that KmGAL1 for galactokinase and KmXYL1 for xylose reductase for galactose and xylose/arabinose utilization, respectively, were repressed by glucose at low and high temperatures, but KmHXK2 for hexokinase was not repressed. We discuss the possible mechanism of glucose repression and the potential for utilization of K. marxianus in high-temperature fermentation with mixed sugars containing glucose.


Porous hydroxyapatite ceramics for tissue engineering.
We have determined the biocompatibility of high porosity (92%) sintered hydroxyapatite (HA) foams prepared using a novel ceramic foaming system. The ability of human osteoblast-like cells to grow within the HA foam was investigated in vitro using human osteosarcoma cells seeded directly on the ceramic surfaces to determine the bioactivity. Scanning electron microscopy showed evidence of attachment of numerous cells to the surface. Significant proliferation was observed and the pattern was comparable to that of the tissue culture control, Thermanox TM . There was an increase in cell proliferation and retention of phenotype for the period studied. This hydroxyapaptite foam which has the advantage of being easily fashioned by surgeons, shows potential as a bone substitute scaffold for tissue engineering and future development for clinical application.


[Comparison of morphological and biochemical indicators of prostatic growth and function in castrated rats receiving separately and simultaneously 5 alpha-dihydrotestosterone and 5 alpha-androstane-3 beta, 17 beta-diol].
Experiments in vito showed that indicators of prostatic growth (organ mass, protein content, DNA) and function (acid phosphatase activity) of castrated rats regenerated under the influence of 5 alpha-dihydrotestosterone. The morphological structure of this organ showed a pronounced activation of the glandular epithelium proliferation by this metabolite without a significant effect on the connective tissue. The other testosterone metabolite 5 alpha-androstan-3 beta, 17 beta-diol did not influence biochemical indicators but according to the morphological data it stimulated the secretory activity of the glandular epithelium and connective tissue formation. As a result of a combined effect of the metabolites the influence of 5 alpha-dihydrotestosterone on the proliferative processes in the prostate was limited, and the response of the connective tissue to 5 alpha-androstan-3 beta, 17 beta-diol preserved. The results obtained were not in accord with a hypothesis that 5 alpha-dihydrotestosterone is the only physiologically active testosterone metabolite in the rat pancreas, and confirmed the idea of androgen functional interrelationship.


Vision-Related Quality of Life in Danish Patients with Albinism and the Impact of an Updated Optical Rehabilitation.
(1) Background: Albinism is characterized by a lack of pigment in eyes, hair, and skin and developmental changes in the eye such as foveal hypoplasia. Patients require optical rehabilitation due to low vision, refractive errors, and photosensitivity. We aimed to assess vision-related quality of life in patients with albinism and to evaluate how this was affected by optical rehabilitation. (2) Methods: Patients with ocular or oculocutaneous albinism were invited for the study. Free-of-charge optical rehabilitation was provided as needed, including filters, glasses for near or distance, contact lenses, magnifiers or binoculars. Vision-related quality of life was assessed prior to and after optical rehabilitation using the visual function questionnaire (VFQ39) and the effect of optical rehabilitation was evaluated after accounting for age, gender, and visual acuity. (3) Results: Seventy-eight patients filled out the VFQ39 at the initial visit. Fifty patients (64.1%) returned the questionnaire 3-6 months after optical rehabilitation. The mean age of included patients was 35.9 years (standard deviation 16.6), and their best corrected distance visual acuity was 56 ETDRS letters (range 3-81). The VFQ39 composite score improved significantly from a median of 62.5 (range 14.2-77.0) to 76.5 (20.6-99.6). Significant improvements were seen for ocular pain, social functioning, mental health, role difficulties, and dependency, whereas self-assessed distance or near visual functions did not change. (4) Conclusions: Optical rehabilitation improved the self-reported vision-related quality of life in Danish patients with albinism on a number of parameters related to leading an independent and worry-free life, whereas visual improvement for distance and near tasks was likely limited by the nature of the disease and by the fact that most patients already had access to some optical aids prior to the study.


EEG based emotion recognition by hierarchical bayesian spectral regression framework.
Spectral regression (SR), a graph-based learning regression model, can be used to extract features from graphs to realize efficient dimensionality reduction. However, due to the SR method remains a regularized least squares problem and being defined in L2-norm space, the effect of artifacts in EEG signals cannot be efficiently resisted. In this work, to further improve the robustness of the graph-based regression models, we propose to utilize the prior distribution estimation in the Bayesian framework and develop a robust hierarchical Bayesian spectral regression framework (named HB-SR), which is designed with the hierarchical Bayesian ensemble strategies. In the proposed HB-SR, the impact of noises can be effectively reduced by the adaptive adjustment approach in model parameters with the data-driven manner. Specifically, in the current work, three different distributions have been elaborately designed to enhance the universality of the proposed HB-SR, i.e., Gaussian distribution, Laplace distribution, and Student-t distribution. To objectively evaluate the performance of the HB-SR framework, we conducted both simulation studies and emotion recognition experiments based on emotional EEG signals. Experimental results have consistently indicated that compared with other existing spectral regression methods, the proposed HB-SR can effectively suppress the influence of noises and achieve robust EEG emotion recognition.


In vivo, continuous and automatic monitoring of extracellular ascorbic acid by microdialysis and on-line liquid chromatography.
A system for in vivo, automatic, continuous monitoring of organ extracellular ascorbic acid in anesthetized rat is described. This system involves microdialysis perfusion and a LC system equipped with an electrochemical detector. Microdialysate, eluted from a microdialysis probe implanted in the brain cortex or in the left ventricular myocardium of anesthetized rats was collected in the sample loop of an on-line injector for direct injection onto the LC system. This automated method provides a shortened sample processing time. This system was utilized to investigate the effect of cerebral ischemia on cortex extracellular ascorbic acid and the effect of myocardial ischemia on left ventricular myocardium extracellular ascorbic acid in anesthetized rats. Basal ascorbic acid concentrations in the cortex and left ventricular myocardium ranged from 9.7 to 15.4 microM (mean +/- S.D., 12.7 +/- 2.5 microM from the results of eight rats) and from 9.3 to 36.0 microM (mean +/- S.D., 24.3 +/- 8.9 microM from the results of twelve rats), respectively. Cerebral ischemia significantly elevated ascorbic acid levels in the cortex extracellular space, while myocardial ischemia did not significantly alter ascorbic acid levels in the left ventricular myocardium extracellular space.


Comparison of transperitoneal laparoscopic access techniques: Optiview visualizing trocar and Veress needle.
We retrospectively compared the safety, efficacy, and relative indications of the Optiview visualizing trocar and the Veress needle for obtaining transperitoneal laparoscopic access. Of 100 consecutive transperitoneal laparoscopic procedures performed by a single surgeon, the Veress needle was used initially in 96 patients. The Optiview was used on 26 occasions: in 4 patients as the initial access attempt, and in 22 patients after the Veress needle had failed. Patient characteristics (age, body mass index [BMI], American Society of Anesthesiologists [ASA] score, and history of abdominal surgery), success rates, and complications were compared. Access was obtained successfully with the Optiview in 25 of 26 cases (96%), whereas the Veress needle was successful in 72 of 96 (75%; P = 0.02). The Hasson cannula was used successfully after two of the Veress needle failures and the single Optiview failure. Age, BMI, ASA score, and history of abdominal surgery were not associated with access failure. There were no Optiview-related complications. Use of the Hasson cannula was not associated with any complications, but it was difficult to place, leaked gas, or both in two of the three patients. There were four Veress-related access complications (all minor): one colon insufflation, two retroperitoneal hematomas, and one liver laceration. As an alternative to the Hasson cannula, the Optiview visualizing trocar is a safe and highly effective method of obtaining transperitoneal laparoscopic access, particularly in those patients in whom difficulty is encountered with the Veress needle. However, the needle is less expensive and, in our experience, has not been associated with significant complications. Because we were unable to determine objective patient characteristics that increase the risk for Veress needle failure, we continue to use it for the first attempts at transperitoneal access in most patients.


About the σA estimate.
The resolution parameter σ(A) is currently used for evaluating the degree of similarity between a model and the target structure. Here, quasi-Wilson distributions are used to represent the local statistics of the normalized amplitudes both for the target and for the model structure. The study uses the joint probability distribution approach to provide (i) a description of the statistical properties of the σ(A) parameter; (ii) a deeper insight into the role, for the σ(A) estimate, of the high-order moments of the target and of the model structure-factor distributions; and (iii) new statistical formulas for estimating σ(A). The theoretical results have been checked using test proteins.


Microenvironmental regulation of hematopoietic stem cells and its implications in leukemogenesis.
Hematopoietic stem cells (HSCs) are a population of cells in the bone marrow which can self-renew, differentiate into late lineage progenitors, or remain quiescent. HSCs exist alongside several cell types in the bone marrow microenvironment that comprise the stem cell niche. These cells regulate HSC function and can contribute to leukemogenesis. In this review we will discuss recent advances in this field. In the vascular niche, arteriolar and sinusoidal zones appear to play distinct roles in HSC function. Endothelial cells modulate HSC function via Notch and other signaling pathways. In the endosteal niche multiple cell types regulate HSCs. Osteoblasts promote HSC quiescence via secreted factors and possibly physical interactions, whereas adipocytes may oppose HSC quiescence. The balance of these opposing factors depends on metabolic cues. Feedback from HSC-derived cells, including macrophages and megakaryocytes also appears to regulate HSC quiescence. Dysfunction of the bone marrow microenvironment, including mesenchymal stem cell-derived stromal cells and the sympathetic nervous system can induce or alter the progression of hematologic malignancies. Many cell types in the bone marrow microenvironment affect HSC function and contribute to malignancy. Further understanding how HSCs are regulated by the microenvironment has clinical implications for stem cell transplantation and other therapies for hematologic malignancies.


Assessing the effect of estimation error on risk-adjusted CUSUM chart performance.
Risk-adjusted control charts have become popular for monitoring processes that involve the management and treatment of patients in hospitals or other healthcare institutions. However, to date, the effect of estimation error on risk-adjusted control charts has not been studied. We studied the effect of estimation error on risk-adjusted binary cumulative sum (CUSUM) performance using actual and simulated data on patients undergoing coronary artery bypass surgery and assessed for mortality up to 30 days post-surgery. The effect of estimation error was indicated by the variability of the 'true' average run lengths (ARLs) obtained using repeated sampling of the observed data under various realistic scenarios. Results showed that estimation error can have a substantial effect on risk-adjusted CUSUM chart performance in terms of variation of true ARLs. Moreover, the performance was highly dependent on the number of events used to derive the control chart parameters and the specified ARL for an in-control process (ARL(0)). However, the results suggest that it is the uncertainty in the overall adverse event rate that is the main component of estimation error. When designing a control chart, the effect of estimation error could be taken into account by generating a number of bootstrap samples of the available Phase I data and then determining the control limit needed to obtain an ARL(0) of a pre-specified level 95% of the time. If limited Phase I data are available, it may be advisable to continue to update model parameters even after prospective patient monitoring is implemented.


Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency.
Hereditary angioedema (HAE), type I and II, is an autosomal dominant disease with deficiency of functional C1 inhibitor protein causing episodic swellings of skin, mucosa and viscera. HAE is a genetically heterogeneous disease with more than 200 different mutations in the SERPING1 gene. A genotype-phenotype relationship does not seem to exist in HAE, although the polymorphism c.-21T>C of exon 2 has been reported to be associated with a more severe phenotype. We aimed to establish the mutational spectrum of C1 inhibitor deficiency in Denmark and investigate the possible disease-aggravating effect of the c.-21T>C polymorphism. Hereditary angioedema was diagnosed based on clinical features and C1 inhibitor deficiency. A general severity score ranging from 0 to 10 was developed based on age at disease onset, clinical manifestations and treatment experiences. SERPING1 gene investigation was performed by exon sequencing followed by multiplex ligation-dependent probe amplification genomic rearrangement analysis in all known Danish HAE families. Fifty-nine patients with HAE from 26 families were included in this study. The mean disease severity score was 7.12 [1-10], and the mean C1 inhibitor function was 26% [20-46%]. The sensitivity of the mutational screening was 96%, and 13 new mutations were found in this Danish patient cohort. Nine patients (15%) carried the c.-21T>C polymorphism, but they didn't have a more severe phenotype. Thirteen new mutations were identified in the Danish HAE population. No correlation between the c.-21T>C polymorphism, the biochemical values of C1 inhibitor function and the clinical severity score was found.


University of Malaya dental students' attitudes towards communication skills learning: implications for dental education.
The Ministry of Higher Education in Malaysia has called for the implementation of a soft skills module in all public universities in Malaysia. In response to this and as part of curriculum development efforts for a new integrated program for 2011, a study was undertaken to improve the University of Malaya (UM) Faculty of Dentistry's communication skills course. One of the study objectives was to investigate dental students' attitudes towards communication skills learning and the association between their attitudes and demographic and education-related characteristics. A cross-sectional survey--using a self-administered twenty-four-item adapted Communication Skills Attitude Scale (CSAS) that contained both positive (PAS) and negative (NAS) attitude subscales--was carried out targeting all final-year dental students at the UM and the Universiti Kebangsaan Malaysia (UKM). A total of 148 students completed the survey, yielding a response rate of 88.1 percent. Overall, UKM students had significantly more positive attitudes towards communication skills learning (PAS score: mean=48.69, SD=4.48, p<0.001) than UM students (mean=46.03, SD=4.22). There was no statistically significant difference in negative attitudes between the two groups. UKM students with more positive attitudes tended to be female (p<0.05). UM students with more negative attitudes perceived themselves as poor communicators (p<0.05), and UKM students with more negative attitudes tended to have poor English proficiency (p<0.05). This study found that both UM and UKM final-year dental students have positive and negative attitudes towards learning communication skills. These attitudes were significantly associated with certain background and education-related attributes. Outcomes of this study served as a valuable guide in strengthening the communication skills course for the UM's new, integrated dental curriculum.


[Lactate dehydrogenase in the esophageal mucosa of patients with different types of esophagitis].
Total lactate dehydrogenase (LDH) activity and its isozymic spectrum were examined in esophageal tissue biopsy specimens from 56 patients with various esophagitides. For control esophageal mucosa specimens from 30 subjects dead in accidents were examined. The findings evidence a significant increase of the total LDH activity in the patients with erosive esophagitis and more so in those with the ulcerative condition. Increased share of the fifth fraction parallelled by a drop of the first LDH fraction were detected in the esophageal mucosa of the patients suffering from erosive and ulcerative esophagitides. The detected disorders of redistribution of LDH isoform activities in erosive and ulcerative esophagitides are less manifest than in malignant tumors but show the same tendency.


Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp130 resistance in cardiovascular system in rat treated with cardiotrophin-1 in vivo.
CIS (cytokine-inducible SH2 protein), SOCS (suppressor of cytokine signaling), or SSI (signal transducers and activators of transcription [STAT]-induced STAT inhibitor) proteins are a family of cytokine-inducible negative regulators of cytokine signaling via Janus kinase (JAK)-STAT pathways. Given the evidence that the JAK-STAT pathway plays a critical role in the cardiovascular system, the primary objective of this study was to assess the effects of the CIS family on JAK-STAT signaling in the cardiovascular system in rats treated with cardiotrophin-1 (CT-1), an interleukin-6 family of cytokines. Intravenous injection of 20 microgram/kg body weight of CT-1 induced a transient, marked increase in STAT3 activation in various tissues, including heart and lung, and subsequent upregulation of 2 members of the CIS family, JAK-binding protein (JAB)/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3, in the same tissues. It was also observed that CIS3 was directly associated with JAK2 in vivo. Pretreatment with the same dose of CT-1 60 minutes before significantly attenuated the STAT3 activation induced by a second injection of CT-1. We previously reported that intravenous injection of CT-1 results in the nitric oxide (NO)-dependent hypotension accompanied by the induction of inducible NO synthase mRNA. In rats pretreated with CT-1, the induction of inducible NO synthase mRNA or hypotension by subsequent CT-1 injection was not observed. Forced expression of JAB or CIS3, but not other CISs, directly blocked CT-1-induced STAT3 activation in 293 cells. These results suggest that JAB and CIS3 serve as endogenous inhibitors of CT-1-mediated JAK-STAT signaling in the cardiovascular system in vivo.


Myocardial cytochrome c oxidase activity in Swedish moose (Alces alces L.) affected by molybdenosis.
Since the mid-1980s, a 'mysterious' wasting disease has been afflicting the moose (Alces alces L.) population of south-western Sweden. In 1994, molybdenosis combined with copper deficiency was suggested as the cause of this complex syndrome of clinical signs, diversity of necropsy findings and changes in trace element concentrations. These findings were corroborated by scientists in many countries by similar observations in other ruminants, particularly cattle and sheep, and also by changes in trace element concentrations and clinical chemical findings in our model experiments with goats. The biochemistry of copper is dependent on a number of copper-dependent enzymes in the animal organism. An important example is cytochrome c oxidase (COX), responsible for oxidative phosphorylation and energy production within the cell. In the present study, COX activity and trace element concentrations were determined in myocardium from affected and healthy moose. Citrate synthase (CS) activity was also measured for use as a mitochondrial marker. COX activity had decreased by 45% and the COX/CS ratio by 37%, while Mo and Na were found to have increased by 140% and 25%, respectively. The increase in Na was indicative of the frequently reported oedematous changes in 'flabby' moose heart. The concentrations of the elements Cu, Mg, Mn, P and Zn had decreased by 20%, 20%, 35%, 7% and 19%, respectively. The simultaneous decrease in COX activity and Cu concentration and the increase in Mo further support the hypothesis that molybdenosis is the cause of the moose disease.


Mini Heme-Proteins: Designability of Structure and Diversity of Functions.
Natural heme proteins may have heme bound to poly-peptide chain as a cofactor via noncovalent forces or heme as a prosthetic group may be covalently bound to the proteins. Nature has used porphyrins in diverse functions like electron transfer, oxidation, reduction, ligand binding, photosynthesis, signaling, etc. by modulating its properties through diverse protein matrices. Synthetic chemists have tried to utilize these molecules in equally diverse industrial and medical applications due to their versatile electro-chemical and optical properties. The heme iron has catalytic activity which can be modulated and enhanced for specific applications by protein matrix around it. Heme proteins can be designed into novel enzymes for sterio specific catalysis ranging from oxidation to reduction. These designed heme-proteins can have applications in industrial catalysis and biosensing. A peptide folds around heme easily due to hydrophobic effect of the large aromatic ring of heme. The directional property of co-ordinate bonding between peptide and metal ion in heme further specifies the structure. Therefore heme proteins can be easily designed for targeted structure and catalytic activity. The central aromatic chemical entity in heme viz. porphyrin is a very ancient molecule. Its presence in the prebiotic soup and in all forms of life suggests that it has played a vital role in the origin and progressive evolution of living organisms. Porphyrin macrocycles are highly conjugated systems composed of four modified pyrrole subunits interconnected at their α -carbon atoms via methine (=CH-) bridges. Initial minimalist models of hemoproteins focused on effect of heme-ligand co-ordinate bonding on chemical reactivity, spectroscopy, electrochemistry and magnetic properties of heme. The great sensitivity of these spectroscopic features of heme to its surrounding makes them extremely useful in structural elucidation of designed heme-peptide complexes. Therefore heme proteins are easier to work on for designing novel proteins for industrial and medical applications.


Awareness & knowledge of AIDS & HIV risk among women attending STD clinics in Pune, India.
The present study attempts to understand the awareness, knowledge and risk to HIV/AIDS among two groups of women: one reporting sex-work (FSW) and second reporting other work (FOW) from two clinics in Pune. The patients are screened for HIV and enrolled in the study. This paper includes 711 women covered between May 1993 and April 1995, 409 FSW and 302 FOW women, who differed by several characteristics. The FSW are older, less educated, unmarried, staying away from home, speak Kannada with 60 per cent using condoms for preventing pregnancy. FOW are ever-married women and among Family Planning method users only 7 per cent used condoms and 84 per cent had tubal ligation. At enrollment 47 per cent FSW and 14 per cent FOW were HIV positive with less than one third of all the women reporting AIDS knowledge. Among the knowledgeable women, 82 per cent understood the sexual route, half knew of transmission by blood and a third understood the vertical route of transmission; 77 per cent FSW and 48 per cent FOW knew that condom was protective. FSW reporting consistent condom use in past three months had greater knowledge of AIDS transmission, were more likely to have used condoms as contraceptive or had tubal ligation and less likely to have history of STD. This suggests the HIV/AIDS awareness and educational programs are having a limited effect specially among the married women who do not perceive of the risk of STD/HIV from their spouses and requires urgent preventive measures through innovative approaches that focus on female controlled methods. It is of critical importance that family planning and STD/HIV programs be integrated.


Inflammation alters iron distribution in bone and spleen in mice.
Anemia of inflammation (or inflammation-associated anemia) decreases the quality of life in billions of patients suffering from various inflammatory diseases, such as infection, autoimmune diseases, and cancer, associated with a prolonged state of immune activation. While proper utilization of iron, a nutrient metal essential for erythropoiesis, is important for the prevention of anemia, the alteration of body iron homeostasis upon inflammation, which can contribute to the development of anemia, is not completely understood. Thus, we sought to examine temporal and spatial changes in the distribution of iron and iron-associated molecules during inflammation in mice. To induce inflammation, C57BL/6J mice were injected with turpentine oil weekly for 3 weeks, which resulted in anemia, decreased protein expression of ferroportin, a cellular iron exporter, in the spleen, duodenum, and liver, and increased iron stores in the duodenum and spleen. Tracer kinetic studies after oral administration of 59Fe revealed that more iron was found in the spleen and less in the femur bone in turpentine oil-injected mice compared to the saline-injected mice, indicating tissue-specific abnormalities in iron distribution during inflammation. However, there was no difference in the utilization of iron for red blood cell production after turpentine oil injection; instead, serum hemopexin level and lactate dehydrogenase activity were increased, suggesting increased red blood cell destruction upon inflammation. Our findings provide an improved understanding of temporal and spatial changes in the distribution and utilization of iron during inflammation.


An Ontario-wide study of vitamin B12, serum folate, and red cell folate levels in relation to plasma homocysteine: is a preventable public health issue on the rise?.
Plasma homocysteine has been reported to be useful in the evaluation of patients with suspected vitamin B12 or folate deficiency. In November 1998, Canada began its mandatory fortification of all flour, and some corn and rice products, with folic acid. We evaluated the status of folate and vitamin B12 in Ontario since this fortification program began, and also studied the role of plasma homocysteine in the assessment of vitamin B12 deficiency since that time. A retrospective cross-sectional study design was performed using a community database of all Ontario samples analyzed by MDS Laboratories, a major provider of diagnostic laboratory services in Canada. All consecutive single-patient fasting samples for plasma homocysteine collected between January 1 and September 30, 1999 were included, as well as corresponding red cell folate and serum B12 concentrations. Data for serum folate were included when available. Descriptive statistics included the arithmetic and geometric means for each measure, as well as the lower and upper centile values. After excluding cases with a concomitant serum creatinine > 120 micromol/L or red cell folate < 215 nmol/L, we established the test properties of a plasma homocyteine level of 15 micromol/L or greater for the diagnosis of "low" (< 120 pmol/L) or "indeterminate" (i.e., between 120 and 150 pmol/L) serum vitamin B12 concentrations. The mean age of all subjects was 58.4 years (95% CI 57.4 to 59.4). Plasma homocysteine samples were obtained from 403 males (56.7%) and 308 females. The geometric mean homocysteine concentration for the entire population was 8.3 micromol/L, and was significantly higher among males (9.3 micromol/L) than females (8.3 micromol/L) (unpaired t-test: 2-p < 0.0001). The geometric mean serum folate concentration was significantly higher in females (35.8 nmol/L) than males (33.6 nmol/L) (2-p < 0.0001), as were the mean red cell folate levels (females 966.8 nmol/L, males 949.3 nmol/L; 2-p < 0.0001). Serum vitamin B12 concentrations were available for 692 subjects, with a geometric mean of 322.0 pmol/L. Again, mean vitamin B12 was higher in females (332.5 pmol/L) than males (314.3 pmol/L) (2-p < 0.0001). The fifth centile for vitamin B12 was 134.6 pmol/L. A plasma homocysteine concentration > 15 micromol/L did not discriminate between cobalamin concentrations below versus above 120 pmol/L (positive and negative predictive values 7.4% and 97.2%, respectively), nor did it discriminate "indeterminate" B12 levels between 120 and 150 pmol/L (positive and negative predictive values 6.3% and 94.0%, respectively). In a large select group of Ontarians, serum and red cell folate concentrations appear to be higher than expected, possibly due to a recent national folate fortification programme; cobalamin levels are no higher than expected. Given our inability to detect mild B12 deficiency using such indicators as plasma homocysteine, and considering the substantial growth in the elderly segment of the Canadian population, occult cobalamin deficiency could become a common disorder. Accordingly, we recommend either consideration of the addition of vitamin B12 to the current folate fortification programme, and/or the development of better methods for the detection of cobalamin deficiency.


Heart and heart-lung transplantation: program, development, organization, and initiation.
Since the initiation of cardiac transplantation in 1967, more than 1,000 procedures have been done worldwide. A high percentage of these transplant procedures have been completed in the past few years. In 1983, II centers in the United States performed 173 transplant procedures; by 1984, there were more than 30 heart transplant centers. This sudden increase is due primarily to increasing survival of transplant recipients since the introduction of cyclosporine. However, most transplant surgeons believe that the use of this drug alone will not result in survival results and rehabilitation similar to those obtained in experienced transplant centers. Institutional commitment, adequate resources, attention to detail and most importantly, a dedicated transplant team, are important elements to ensure success. This manuscript will define guidelines for the establishment of a new transplant program and eludicate the organizational details necessary to implement such a program, based on our experience at the Johns Hopkins Hospital over the past two years.


[Analysis of 83 urethroplasties for urethral stenosis].
To determine the appropriate technique for each case of urethral stricture, according to its length, depth, localization, etiology and age of the patient. 83 urethroplasties for urethral stricture performed from 1992-1998 were reviewed. The strictures involved different levels of the urethra. The techniques utilized were analyzed (substitution urethroplasty with pedicle skin graft and free grafts using buccal mucosa and extragenital skin, excision and anastomotic repair, regeneration techniques with internal urethrotomy and placement of intraluminal prosthesis, and two-stage repair procedures). The overall functional results were good in 93% of the cases (78 good, 5 poor), but the morphological results demonstrated by the radiological findings were not as good in 24% of the cases, which corresponded to those that had received preputial pedicle grafts and buccal mucosa free grafts. Using the appropriate urethroplasty technique is essential to achieve good functional results. The substitution techniques require well-vascularized grafts and/or recipient sites. The foregoing must be taken into account in the selection of the appropriate graft and deciding on the stricture length and localization.


The development and application of pseudoviruses: assessment of SARS-CoV-2 pseudoviruses.
Although most Coronavirus disease (COVID-19) patients can recover fully, the disease remains a significant cause of morbidity and mortality. In addition to the consequences of acute infection, a proportion of the population experiences long-term adverse effects associated with SARS-CoV-2. Therefore, it is still critical to comprehend the virus's characteristics and how it interacts with its host to develop effective drugs and vaccines against COVID-19. SARS-CoV-2 pseudovirus, a replication-deficient recombinant glycoprotein chimeric viral particle, enables investigations of highly pathogenic viruses to be conducted without the constraint of high-level biosafety facilities, considerably advancing virology and being extensively employed in the study of SARS-CoV-2. This review summarizes three methods of establishing SARS-CoV-2 pseudovirus and current knowledge in vaccine development, neutralizing antibody research, and antiviral drug screening, as well as recent progress in virus entry mechanism and susceptible cell screening. We also discuss the potential advantages and disadvantages.


[New genovariantes of Chlamydia trachomatis serovar L2 proctitis causing].
Lymphogranuloma venereum (LGV) is a chronic disease of the lymphatic system that is transmitted sexually and whose etiologic agents are L1, L2 and L3 serotypes of Chlamydia trachomatis. Since 2003 in Europe, USA, Canada and Australia have had outbreaks of L2 serotype infection that develops proctitis in place of LGV in men who have sex with men. It appears that these strains are a new genovariant of L2 serotype (L2b) that is developing a different pathology to LGV. However, the analysis of L2b genome not differs significantly to L2 genome (L2/434 UB) for which L2b is considered as a classic L2 strain. Despite this, new genovariantes of L2 and L2b are appearing, which develop or not LGV or proctitis so we need to do an analysis of its genome to identify genetic changes that these strains shown.


Exposure and Recovery from Environmentally Relevant Levels of Waterborne Polycyclic Aromatic Hydrocarbons from Deepwater Horizon Oil: Effects on the Gulf Toadfish Stress Axis.
There is evidence that the combination of polycyclic aromatic hydrocarbons (PAHs) released in the Deepwater Horizon oil spill impairs the glucocorticoid stress response of vertebrates in the Gulf of Mexico, but the mechanisms are unclear. We hypothesized that inhibition of cortisol release may be due to 1) overstimulation of the hypothalamic-pituitary-inter-renal (HPI) axis, or 2) an inhibition of cortisol biosynthesis through PAH activation of the aryl hydrocarbon receptor (AhR). Using a flow-through system, Gulf toadfish (Opsanus beta) were continuously exposed to control conditions or one of 3 environmentally relevant concentrations of PAHs from Deepwater Horizon oil (∑PAH50 = 0-3 μg L-1 ) for up to 7 d. One group of toadfish was then exposed to a recovery period for up to 7 d. No changes in corticotrophin-releasing factor mRNA expression, adrenocorticotropic hormone (ACTH), or pituitary mass suggested that overstimulation of the HPI axis was not a factor. The AhR activation was measured by an elevation of cytochrome P4501A1 (CYP1A) mRNA expression within the HPI axis in fish exposed to high PAH concentrations; however, CYP1A was no longer induced after 3 d of recovery in any of the tissues. At 7 d of recovery, there was an impairment of cortisol release in response to an additional simulated predator chase that does not appear to be due to changes in the mRNA expression of the kidney steroidogenic pathway proteins steroidogenic acute regulatory protein, cytochrome P450 side chain cleavage, and 11β-hydroxylase. Future analyses are needed to determine whether the stress response impairment is due to cholesterol availability and/or down-regulation of the melanocortin 2 receptor. Environ Toxicol Chem 2021;40:1062-1074. © 2020 SETAC.


Differential expression of BAFF and its receptors in discoid lupus erythematosus patients.
B-cell activating factor of the TNF family (BAFF) promotes the maturation and survival of B cells. Because BAFF levels are elevated in systemic lupus erythematosus (SLE) patients, BAFF has been the target of emerging therapies for SLE, such as belimumab. Levels of BAFF and its receptors in discoid lupus erythematosus (DLE) patients are unknown. To compare skin and blood mRNA and protein levels of BAFF and its receptors BAFF-R, TACI, and BCMA in DLE subjects with (DLE+/SLE+ (N=28)) and without SLE (DLE+/SLE- (N=35)), psoriasis subjects (N=11), and normal subjects (N=42). We used quantitative real-time PCR to measure blood and skin BAFF, BAFF-R, TACI, and BCMA mRNA, sandwich ELISAs to measure sera BAFF, and immunohistochemistry to evaluate BAFF and BAFF-R skin protein expression. BAFF mRNA and protein levels were highest in DLE+/SLE+blood, followed by DLE+/SLE-, psoriasis, and normal blood. BAFF protein also correlated with anti-nuclear antibodies, and autoantibodies against double-stranded DNA, single-stranded DNA, and ribonucleoprotein, and Systemic Lupus Erythematosus Disease Activity Index scores in DLE patients. While showing no difference between DLE+/SLE+ and DLE+/SLE- skin, BAFF and its receptors mRNA were up-regulated in DLE skin vs. normal and psoriasis skin. DLE skin had higher percentages of BAFF-R⁺ inflammatory cells, likely T cells and macrophages, than psoriasis and normal skin. BAFF may be a serologic marker of systemic disease in DLE patients. BAFF and its receptors are elevated in DLE skin, suggesting that targeted therapies against these proteins could treat refractory DLE patients.


Combining median electroencephalography frequency and sympathetic activity in an index to evaluate opioid detoxification in patients.
During rapid opioid detoxification, increased sympathetic activity and a greater median frequency (MF) of activity on electroencephalography (EEG) have been reported. The purpose of this study was to evaluate a new index for detoxification that combines sympathetic activity and MF data. After informed consent was obtained, eight patients were sedated with propofol. The MF of EEG activity derived from frontal electrodes was determined. Heart rate variability was evaluated in 256-second segments by power spectral analysis, and sympathetic activity was determined by the low frequency component. The Hoffman Index for narcotic detoxification was weighted 70% to sympathetic activity and 30% to MF to normalize the difference in scales and to provide adequate weight to the sympathetic component. Opioid detoxification was produced by infusion of 25 mg naloxone for 30 minutes, followed by a 24-hour infusion of 1 mg per hour. The MF showed a rapid increase during high-dose infusion of naloxone, but the peak response occurred 1 to 2 hours later. Sympathetic activation and the Hoffman Index increased more slowly after the start of naloxone infusion, but peak increases in all components occurred at approximately the same time. The peak increases in Hoffman Index (110% of baseline), MF (260%), and sympathetic activity (304%) during administration of naloxone were significant and correlated with respect to time (r = 0.89-0.94). The Hoffman Index showed an early increase related to MF and a well-defined peak response indicative of sympathetic and MF activity. The behavior of the Hoffman Index in relation to the MF and sympathetic activity more clearly indicated the onset of opioid detoxification and the maximum response to opioid reversal than did MF or sympathetic activity alone.


[Use of a new Indis computer program to analyze the results of lacrimal scintigraphy].
To study the diagnostic importance of a new Indis software package for the postprocessing of the results of radionuclude examinations (Center for Information and Diagnostic Systems, St. Petersburg, Russia) when analyzing the results of lacrimal scintigraphy. Dynamic lacrimal scintigraphy was carried out in 6 volunteers (12 eyes) and 20 patients (32 years) with dacryostenosis. The examined Indis program and the known Syngo program (Siemens, Germany) were used to calculate the elimination half-life of a radiopharmaceutical from the interest region corresponding to the whole ocular surface. The time taken to postprocess the results of the examination was also determined. When calculations were made using the Indis program and the Syngo system, the elimination half-lives of a tracer in the volunteers was 6.57 ± 2.46 and 7.54 ± 3.21 min, respectively. These in the patents with dacryostenosis were 69.39 ± 65.52 and 74.85 ± 64.59 min. With these programs, the times taken for postprocessing were 12.3 ± 4.2 and 26.3 ± 7.9 min, respectively. The investigation showed the practical significance of the Indis software package in processing the data of lacrimal scintigraphy. The calculations made with the Indis program correspond to those made with the known Syngo program. The convenience and ergonomics of the program can precisely identify the region of interest. The economic justification of the system is associated with the shorter time taken to postprocess and interpret the results of lacrimal scintigraphy. The Indis software package may be recommended for use in the examination and treatment monitoring in patients with abnormal lacrimaton.


Activation of 5-HT1A receptors in the rat dorsomedial hypothalamus inhibits stress-induced activation of the hypothalamic-pituitary-adrenal axis.
Acute activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of corticosteroid hormones into the circulation, is an adaptive response to perceived threats. Persistent activation of the HPA axis can lead to impaired physiological or behavioral function with maladaptive consequences. Thus, efficient control and termination of stress responses is essential for well-being. However, inhibitory control mechanisms governing the HPA axis are poorly understood. Previous studies suggest that serotonergic systems, acting within the medial hypothalamus, play an important role in inhibitory control of stress-induced HPA axis activity. To test this hypothesis, we surgically implanted chronic jugular cannulae in adult male rats and conducted bilateral microinjection of vehicle or the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT; 8 nmol, 0.2 μL, 0.1 μL/min, per side) into the dorsomedial hypothalamus (DMH) immediately prior to a 40 min period of restraint stress. Repeated blood sampling was conducted using an automated blood sampling system and plasma corticosterone concentrations were determined using enzyme-linked immunosorbent assay. Bilateral intra-DMH microinjections of 8-OH-DPAT suppressed stress-induced increases in plasma corticosterone within 10 min of the onset of handling prior to restraint and, as measured by area-under-the-curve analysis of plasma corticosterone concentrations, during the 40 min period of restraint. These data support an inhibitory role for serotonergic systems, acting within the DMH, on stress-induced activation of the HPA axis. Lay summary: Inhibitory control of the hypothalamic-pituitary-adrenal (HPA) stress hormone response is important for well-being. One neurochemical implicated in inhibitory control of the HPA axis is serotonin. In this study we show that activation of serotonin receptors, specifically inhibitory 5-HT1A receptors in the dorsomedial hypothalamus, is sufficient to inhibit stress-induced HPA axis activity in rats.


Non-canonical Hedgehog signaling regulates spinal cord and muscle regeneration in Xenopus laevis larvae.
Inducing regeneration in injured spinal cord represents one of modern medicine's greatest challenges. Research from a variety of model organisms indicates that Hedgehog (Hh) signaling may be a useful target to drive regeneration. However, the mechanisms of Hh signaling-mediated tissue regeneration remain unclear. Here, we examined Hh signaling during post-amputation tail regeneration in Xenopus laevis larvae. We found that while Smoothened (Smo) activity is essential for proper spinal cord and skeletal muscle regeneration, transcriptional activity of the canonical Hh effector Gli is repressed immediately following amputation, and inhibition of Gli1/2 expression or transcriptional activity has minimal effects on regeneration. In contrast, we demonstrate that protein kinase A is necessary for regeneration of both muscle and spinal cord, in concert with and independent of Smo, respectively, and that its downstream effector CREB is activated in spinal cord following amputation in a Smo-dependent manner. Our findings indicate that non-canonical mechanisms of Hh signaling are necessary for spinal cord and muscle regeneration.


Silicon Oxycarbide-Tin Nanocomposite as a High-Power-Density Anode for Li-Ion Batteries.
Tin-based materials are an emerging class of Li-ion anodes with considerable potential for use in high-energy-density Li-ion batteries. However, the long-lasting electrochemical performance of Sn remains a formidable challenge due to the large volume changes occurring upon its lithiation. The prevailing approaches toward stabilization of such electrodes involve embedding Sn in the form of nanoparticles (NPs) in an active/inactive matrix. The matrix helps to buffer the volume changes of Sn, impart better electronic connectivity and prevent particle aggregation upon lithiation/delithiation. Herein, facile synthesis of Sn NPs embedded in a SiOC matrix via the pyrolysis of a preceramic polymer as a single-source precursor is reported. This polymer contains Sn 2-ethyl-hexanoate (Sn(Oct)2) and poly(methylhydrosiloxane) as sources of Sn and Si, respectively. Upon functionalization with apolar divinyl benzene sidechains, the polymer is rendered compatible with Sn(Oct)2. This approach yields a homogeneous dispersion of Sn NPs in a SiOC matrix with sizes on the order of 5-30 nm. Anodes of the SiOC/Sn nanocomposite demonstrate high capacities of 644 and 553 mAh g-1 at current densities of 74.4 and 2232 mA g-1 (C/5 and 6C rates for graphite), respectively, and show superior rate capability with only 14% capacity decay at high currents.


Retinoic acid-binding protein in normal tissues and experimental tumors.
The tissue distribution of retinoic acid-binding protein (RABP) has been determined for tissues of chick embryos and young and adult rats and mice and has been compared with other published data. Although no species variability has been detected with tissue distribution of RABP, relatively more of the protein is detected in the tissues of young animals than in those of adult ones. This protein is below the limits of detection in the adult rat or mouse brains, whereas it was present in abundance in the embryonic and young brains. RABP is present in the epithelial cells but not in the connective tissue of skin. Besides brain, skin, testis, and eye, RABP is also detected in small quantities in the bladder prostate, uterus, trachea, and mammary glands of rats and mice. Although RABP could not be detected in normal lungs, this protein is found to be present in Lewis lung tumors and in lungs with metastatic Lewis lung foci. Of four chemically induced transplantable colon tumors of mice, two highly metastatic ones contained RABP, whereas the two nonmetastatic lines as well as normal colon did not.


Rationale and evidence for the incorporation of heparin into the diclofenac epolamine medicated plaster.
The nonsteroidal anti-inflammatory drug (NSAID) diclofenac epolamine (DHEP) formulated as a topical patch has demonstrated efficacy and safety in the localized treatment of acute pain from minor strains, sprains and contusions, and for epicondylitis and knee osteoarthritis. The glycosaminoglycan heparin enhances the activity of topical NSAIDs formulated as a medicated plaster, even in the absence of any significant release of heparin. Therefore, DHEP plus, a new formulation of the DHEP medicated plaster containing a small amount of heparin sodium as excipient, has been developed. We reviewed the pivotal and supportive studies of the clinical development program of the new patch and evaluated the role of heparin as an enhancer in the treatment of localized pain/inflammation of musculoskeletal structures, associated with post-traumatic and/or rheumatic conditions. The data was consistent with the concept that heparin increased the clinical activity of the DHEP plus medicated plaster versus the reference DHEP medicated plaster through improved bioavailability due to enhanced movement of diclofenac from the plaster. Both DHEP formulations have the same dissolution profile, indicating that heparin does not change the physical and chemical characteristics of the plaster. Permeation testing showed that heparin is not released from the DHEP plus medicated plaster. Efficacy studies showed that the DHEP plus medicated plaster was significantly more effective in reducing pain than the reference marketed DHEP medicated plaster. The benefit/risk assessment of DHEP plus 180 mg medicated plaster is favorable, with a safety profile equal to placebo and improved efficacy over the reference marketed DHEP medicated plaster.


Treatment of cryptosporidiosis: do we know what we think we know?
The management of cryptosporidiosis is fraught with controversies. New research on diagnostics and medications has reached the field in recent years. Therefore, familiarity with key features of current management tools is important. We discuss diagnostic and therapeutic aspects of cryptosporidiosis focusing on evidence behind the medications available to date. Molecular methods provide a clearer understanding of cryptosporidiosis epidemiology. The major determinants of severity still are host immune status and parasite species. Children and immunosuppressed individuals, especially with HIV/AIDS, are disproportionately affected. Nitazoxanide is an important advance in treatment of HIV negative patients. However, recent research confirms the limited effectiveness of antiparasitic drugs to treat cryptosporidiosis in AIDS. Questions remain about using partially active drugs paromomycin and nitazoxanide for treatment. Potent antiretroviral combinations modify disease epidemiology and are key components of therapy in AIDS. However, it is unclear whether this is due solely to immune reconstitution or due in part to antiparasitic effects of HIV protease inhibitors. Newer candidate drugs are in development. There is better understanding of the epidemiology of cryptosporidiosis and promising new diagnostic methods. There are significant challenges in terms of control and treatment of cryptosporidiosis among the groups at risk.


[Lymphocyte depletion through experimental anastomosis of the thoracic duct and cervical esophagus].
In 25 dogs, a short segment of the left subclavian vein, adjacent to the connection of the thoracic duct, was dissected free with its jugular branch and ligated. An end-to-side anastomosis, using interrupted sutures was performed in two layers, between the side of the cervical esophagus and the proximal part of the jugular vein. This vein, acting as a reservoir, remains connected to the thoracic duct by the isolated segment of the subclavian vein. The original aspect, of our technique is the use of a catheter placed into a branch of the vein near the site of the anastomosis and through which a saline solution with heparin (1 mg/kg) and penicillin (40.000 U/kg) is injected daily. The catheter emerged on top of the dog's neck, and continuous perfusion was provided by a chronofusor. The catheter was removed after one month. In 30% of the dogs, the anastomosis was found patent after more than 6 weeks. This has been proved by fibro-esophagoscopy after injection of a solution of patent blue in the jugular catheter ; lymphangiograms obtained by direct injection of radio-opaque material through the jugular catheter, and a decrease in lymphocyte counts to 4% of the total white blood cell count, compared to 30% in the controls. There was no significant loss of weight in the surviving dogs.


Differential diagnostic yield of lumbar puncture in investigation of suspected subarachnoid haemorrhage: a retrospective study.
The diagnostic algorithm of computerized tomography (CT) and lumbar puncture (LP) for suspected subarachnoid haemorrhage (SAH) has lately been challenged by the advancement of radiological techniques, such as higher resolution offered by newer generation CT-scanners and increased availability of CT-angiography. A purely radiological workup of suspected SAH offers great advantages for both patients and the health care system, but the risks of abandoning LP in this setting are not well investigated. We have characterized the differential diagnostic yield of LP in the investigation of suspected SAH by a retrospective study. From the hospital laboratory database, we analyzed the medical records of all patients who had undergone CSF-analysis in search of subarachnoid bleeding during 2009-2011. A total of 453 patients were included. In 14 patients (3%) the LP resulted in an alternative diagnosis, the most common being aseptic meningitis. Two patients (0.5%) received treatment for herpes meningitis. Five patients (1%) with subarachnoid haemorrhages were identified. Among these, the four patients presenting with thunderclap headache had non-aneurysmal bleedings and did not require surgical intervention. We conclude that the differential diagnostic yield of LP in investigation of suspected SAH is low, which indicates that alternative diagnoses is not a reason to keep LP in the workup when a purely radiological strategy has been validated. However, algorithms should be developed to increase the recognition of aseptic meningitis. One hundred and fifty-three patients (34%) were admitted to undergo LP, which estimates the number of hospital beds that might be made available by a radiological diagnostic algorithm.


Septic shock attributed to Candida infection: importance of empiric therapy and source control.
Delayed treatment of candidemia has previously been shown to be an important determinant of patient outcome. However, septic shock attributed to Candida infection and its determinants of outcome have not been previously evaluated in a large patient population. A retrospective cohort study of hospitalized patients with septic shock and blood cultures positive for Candida species was conducted at Barnes-Jewish Hospital, a 1250-bed urban teaching hospital (January 2002-December 2010). Two hundred twenty-four consecutive patients with septic shock and a positive blood culture for Candida species were identified. Death during hospitalization occurred among 155 (63.5%) patients. The hospital mortality rate for patients having adequate source control and antifungal therapy administered within 24 hours of the onset of shock was 52.8% (n = 142), compared to a mortality rate of 97.6% (n = 82) in patients who did not have these goals attained (P < .001). Multivariate logistic regression analysis demonstrated that delayed antifungal treatment (adjusted odds ratio [AOR], 33.75; 95% confidence interval [CI], 9.65-118.04; P = .005) and failure to achieve timely source control (AOR, 77.40; 95% CI, 21.52-278.38; P = .001) were independently associated with a greater risk of hospital mortality. The risk of death is exceptionally high among patients with septic shock attributed to Candida infection. Efforts aimed at timely source control and antifungal treatment are likely to be associated with improved clinical outcomes.


An architecture for non-linear discovery of aggregated multimedia document web search results.
The recent proliferation of multimedia information on the web enhances user information need from simple textual lookup to multi-modal exploration activities. The current search engines act as major gateways to access the immense amount of multimedia data. However, access to the multimedia content is provided by aggregating disjoint multimedia search verticals. The aggregation of the multimedia search results cannot consider relationships in them and are partially blended. Additionally, the search results' presentation is via linear lists, which cannot support the users' non-linear navigation patterns to explore the multimedia search results. Contrarily, users' are demanding more services from search engines. It includes adequate access to navigate, explore, and discover multimedia information. Our discovery approach allow users to explore and discover multimedia information by semantically aggregating disjoint verticals using sentence embeddings and transforming snippets into conceptually similar multimedia document groups. The proposed aggregation approach retains the relationship in the retrieved multimedia search results. A non-linear graph is instantiated to augment the users' non-linear information navigation and exploration patterns, which leads to discovering new and interesting search results at various aggregated granularity levels. Our method's empirical evaluation results achieve 99% accuracy in the aggregation of disjoint search results at different aggregated search granularity levels. Our approach provides a standard baseline for the exploration of multimedia aggregation search results.


[Concentrations of free and bound 4-aminobutyric acid in human serum: reference values].
A rapid and sensitive procedure is described for the quantification of gamma-aminobutyric acid in human plasma, using ion-exchange fluorescence. Analytical values for gamma-aminobutyric acid vary according to the method of deproteinization, storage conditions and sample treatment. A practicable and precise method for the evaluation of free and bound gamma-aminobutyric acid is presented. The mean concentration of the free neurotransmitter in neurologically normal control subjects was 142.4 +/- 13.1 nmol/l (n = 30). The mean concentration of the bound form was 438.6 +/- 51.1 nmol/l in the same subgroup.


Synergistic effects of microplastic and lead trigger physiological and biochemical impairment in a mangrove crab.
Microplastics (MP) are vectors for other environmental contaminants, such as metals, being a considerable problem, especially in the aquatic ecosystem. To investigate the combined effects of MP (high density polyethylene) with lead (Pb), we exposed the mangrove fiddler crab Minuca vocator to Pb (50 mg L-1), and MP (25 mg L-1) alone and in mixture, for 5 days. We aimed to determine Pb and MP bioaccumulation, as well as physiological (oxygen consumption and hemolymph osmolality) and biochemical (superoxide dismutase, catalase, glutathione peroxidase, and lipid peroxidation) traits effects. Co-exposure of MP and Pb significantly increased the bioaccumulation of Pb, but reduced MP tissue accumulation. Regarding the physiological traits, increasing osmolality and oxygen consumption rates compared to the control were observed, particularly in the combined Pb and MP exposure. As to biochemical traits, the combination of Pb and MP induced the most significant responses in the enzymatic profile antioxidant enzyme activity. The catalase (CAT), glutathione peroxidase (GPx), and dismutase superoxide (SOD) decreased compared to individual exposure effects; the combination of MP and Pb had a synergistic effect on promoting lipid peroxidation (LPO). The co-exposure of MP and Pb acted synergistically when compared to the effects of the isolated compounds. Due to the increasing MP contamination in mangroves, more severe physiological and biochemical effects can be expected on mangrove crabs exposed to metal contamination.


Antioxidant vitamins E and C and risk of Alzheimer's disease.
Age-related neurodegenerative disorders are increasing rapidly. Alzheimer's disease is the most common cause of dementia associated with aging. A recent study has examined the role of vitamins E and C in a prospective epidemiologic cohort study and suggested that they might protect against Alzheimer's disease.


A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin lymphoma.
Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. Rituximab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with rituximab was performed in patients with CD20+ lymphoma. Cohorts of 3-4 patients were given infusions of rituximab (375 mg/m2) weekly for 4 weeks with escalating doses of rhIL-18 as a 2-hour intravenous infusion weekly for 12 consecutive weeks. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic studies. Nineteen patients with CD20+ B-cell non-Hodgkin lymphoma were given rituximab in combination with rhIL-18 at doses of 1, 3, 10, 20, 30, and 100 μg/kg. Common side effects included chills, fever, headache, and nausea. Common laboratory abnormalities included transient, asymptomatic lymphopenia, hyperglycemia, anemia, hypoalbuminemia, and bilirubin and liver enzyme elevations. No dose-limiting toxicities were observed. Biologic effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, GM-CSF, and chemokines were observed after dosing. Objective tumor responses were seen in 5 patients, including 2 complete and 3 partial responses. rhIL-18 can be given in biologically active doses by weekly infusions in combination with rituximab to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus rituximab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B-cell malignancies are warranted.


Natural interferon-beta plus ribavirin therapy led to sustained virological response after seven unsuccessful courses of anti-viral treatment in a chronic hepatitis C patient.
We describe a patient infected with hepatitis C virus (HCV) genotype 1 who failed to respond to interferon with or without ribavirin seven times but who then achieved sustained virological response by the combination of interferon-beta plus ribavirin treatment for 48 weeks. He did not respond to stronger treatment such as prolonged peginterferon plus ribavirin treatment for 87 weeks. It might be rare to treat a patient with interferon 8 times considering the cost and time, since patients failing interferon treatment several times are regarded to be refractory to interferon. It is possible that the difference in biological effects between interferon-alfa and interferon-beta might have resulted in a different outcome in our patient. Interferon-beta plus ribavirin therapy might be one of the treatment options for certain patients chronically infected with HCV who do not respond to standard care treatment.


Isolation and characterisation of a class of carbohydrate oxidases from higher plants, with a role in active defence.
In a search for novel plant-derived antimicrobial proteins, we screened extracts from salicylic acid (SA)-treated lettuce and sunflower leaves. These extracts displayed very potent antimicrobial activity against a set of phytopathogens. Characterisation of these extracts revealed that in both extracts, proteins of approximately 60 kDa were responsible for the antimicrobial activity. Further characterisation of these proteins and cloning of the respective cDNAs revealed close homology to a range of (plant) oxidases. Dissection of the enzymatic activity of both proteins revealed them to be carbohydrate oxidases (Helianthus annuus carbohydrate oxidase (Ha-CHOX) and Lactuca sativa carbohydrate oxidase (Ls-CHOX)) with broad substrate specificity and with hydrogen peroxide (H(2)O(2)) as one of the reaction products. The sunflower transcript, in addition to being SA inducible, was also inducible by fungal pathogens but not by ethylene and jasmonate. To determine whether Ha-CHOX plays a role in pathogen defence, it was transformed into tobacco and the effect of resistance to Pectobacterium carotovorum ssp. carotovorum was examined. Transgenic plants overexpressing Ha-CHOX displayed enhanced resistance to infection by this pathogen, and the resistance level was proportional to enzyme expression.


A Case of Neonatal Heart Failure Caused by Left Ventricular Diverticulum: Successful ECMO Support Application.
Congenital left ventricular diverticulum is a rare cardiac anomaly. During the newborn period, symptomatic patients are diagnosed with heart failure findings. We present a 23-day-old male newborn with congenital left ventricular diverticulum diagnosed during fetal echocardiographic examination. After the birth, the patient had heart failure symptoms and his echocardiographic examination showed low cardiac ejection fraction. Diverticulum was operated with endoventricular circular patch plasty (DOR) technique, and after, cardiopulmonary bypass venoarterial extracorporeal membrane oxygenation (ECMO) support was performed because of low cardiac output syndrome. On postoperative day 17, he was discharged with no problem.


How does electronic cigarette smoking affect sinonasal symptoms and nasal mucociliary clearance?
is to evaluate the sinonasal symptom scores and mucociliary clearance (MCC) after starting to use electronic cigarette METHODOLGY: This prospective randomized single-blind clinical trial was conducted between March 2013 and November 2013. Patients (n=98) admitted to smoking cessation clinic were divided into two groups; Electronic cigarette smokers (group 1) and non-electronic cigarette smokers (group 2). SNOT-22 and saccharin transit time for MCC were evaluated before starting electronic cigarettes and after the third months. SNOT-22 scores and MCC time were evaluated between groups and within groups after 3 months. SNOT 22 scores and MCC measurements showed no difference between groups before the cessation of cigarette smoking (p >0.05). SNOT 22 results of both groups revealed statistically significantly lower scores after the three months (p < 0.05). However, SNOT-22 scores of group 2 was significantly better than group 1 (p > 0.05). Comparison of MCC results of group 2 revealed statistically significantly lower scores after the three months (p < 0.05). However, group 1 did not show any significant difference after three months (p > 0.05). There was a significant difference between the groups at the third month measurements (p < 0.05). Although EC is widely used as a method of quitting smoking, it has negative effects on the sinonasal symptoms and MCC.


Fibroblast growth factor-2 represses platelet-derived growth factor receptor-alpha (PDGFR-alpha) transcription via ERK1/2-dependent Sp1 phosphorylation and an atypical cis-acting element in the proximal PDGFR-alpha promoter.
Platelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant for vascular smooth muscle cells (SMCs) whose biological activity is mediated via its high affinity interaction with specific cell surface receptors. The molecular mechanisms governing the expression of PDGF receptor-alpha (PDGFR-alpha) are poorly understood. Here we demonstrate that PDGFR-alpha protein and transcriptional regulation in SMCs is under the positive regulatory influence of the zinc finger nuclear protein, Sp1. Electrophoretic mobility shift, competition, and supershift analysis revealed the existence of an atypical G-rich Sp1-binding element located in the PDGFR-alpha promoter -61 to -52 bp upstream of the transcriptional start site. Mutation of this sequence ablated endogenous Sp1 binding and activation of the PDGFR-alpha promoter. PDGFR-alpha transcription, mRNA, and protein expression were repressed in SMCs exposed to fibroblast growth factor-2 (FGF-2). This inhibition was rescued by the blockade of extracellular signal-regulated kinase-1/2 (ERK1/2). FGF-2 repression of PDGFR-alpha transcription was abrogated upon mutation of this Sp1-response element. FGF-2 stimulated Sp1 phosphorylation in an ERK1/2- but not p38-dependent manner, the growth factor enhancing Sp1 interaction with the PDGFR-alpha promoter. Mutation of residues Thr(453) and Thr(739) in Sp1 (amino acids phosphorylated by ERK) blocked FGF-2 repression of PDGFR-alpha transcription. These findings, taken together, demonstrate that FGF-2 stimulates ERK1/2-dependent Sp1 phosphorylation, thereby repressing PDGFR-alpha transcription via the -61/-52 element in the PDGFR-alpha promoter. Phosphorylation triggered by FGF-2 switches Sp1 from an activator to a repressor of PDGFR-alpha transcription, a finding previously unreported in any Sp1-dependent gene.


Submicron Metal 3D Printing by Ultrafast Laser Heating and Induced Ligand Transformation of Nanocrystals.
Currently, light-based three-dimensional (3D) printing with submicron features is mainly developed based on photosensitive polymers or inorganic-polymer composite materials. To eliminate polymer/organic additives, a strategy for direct 3D assembly and printing of metallic nanocrystals without additives is presented. Ultrafast laser with intensity in the range of 1 × 1010 to 1 × 1012 W/cm2 is used to nonequilibrium heat nanocrystals and induce ligand transformation, which triggers the spontaneous fusion and localized assembly of nanocrystals. The process is due to the operation of hot electrons as confirmed by a strong dependence of the printing rate on laser pulse duration varied in the range of electron-phonon relaxation time. Using the developed laser-induced ligand transformation (LILT) process, direct printing of 3D metallic structures at micro and submicron scales is demonstrated. Facile integration with other microscale additive manufacturing for printing 3D devices containing multiscale features is also demonstrated.


The clinical significance of whole blood viscosity in (cardio)vascular medicine.
Whole blood is a non-Newtonian fluid, which means that its viscosity depends on shear rate. At low shear, blood cells aggregate, which induces a sharp increase in viscosity, whereas at higher shear blood cells disaggregate, deform and align in the direction of flow. Other important determinants of blood viscosity are the haematocrit, the presence of macro-molecules in the medium, temperature and, especially at high shear, the deformability of red blood cells. At the sites of severe atherosclerotic obstructions or at vasospastic locations, when change of vessel diameter is limited, blood viscosity contributes to stenotic resistance thereby jeopardising tissue perfusion. However, blood viscosity plays its most important role in the microcirculation where it contributes significantly to peripheral resistance and may cause sludging in the postcapillary venules. Apart from the direct haemodynamic significance, an increase in blood viscosity at low shear by red blood cell aggregation is also associated with increased thrombotic risk, as has been demonstrated in atrial fibrillation. Furthermore, as increased red blood cell aggregation is a reflection of inflammation, hyperviscosity has been shown to be a marker of inflammatory activity. Thus, because of its potential role in haemodynamics, thrombosis and inflammation, determination of whole blood viscosity could provide useful information for diagnostics and therapy of (cardio)vascular disease.


Causes and outcome of seizures in liver transplant recipients.
Previous studies found that seizures in orthotopic liver transplantation (OLT) herald a catastrophic neurologic event, but the studies were done of patients who later died and came to autopsy. We studied 630 OLT patients. Laboratory values, electroencephalography, neuroimaging, and levels of cyclosporine or FK506 were reviewed. Neurotoxicity from immunosuppression was considered a trigger for seizures when toxic blood level or increases > or = to 100% were documented, or when white matter lesions or confusional state or tremors were present. Generalized tonic-clonic seizures occurred in 28 of 630 patients (4%). In 7 patients seizures were part of an agonal event (central nervous system infection [n = 3], anoxic encephalopathy [n = 1], cerebral edema with fulminant hepatic failure [n = 1], intracranial hemorrhage [n = 1], and sepsis [n = 1]. In 17 patients cyclosporine (n = 11) or FK506 (n = 6) could be implicated. Remaining causes were acute uremia (n = 1), meningioma (n = 1), and unknown (n = 2). All patients were initially treated with anticonvulsants. Median follow-up of 2 years did not reveal seizure recurrence after discontinuation of anticonvulsants. We conclude that the majority of new-onset seizures after OLT are not indicative of a poor prognosis. Immunosuppression neurotoxicity is the most frequent cause. Anticonvulsant therapy is not necessary for favorable long-term outcome.


Micro-fabricated fluorescence-activated cell sorter.
We demonstrate a high sensitivity, high throughput microfabricated cell sorting device with the integrated piezoelectric actuator and optofluidic waveguide on a chip. For automated sorting, field-programmable-gate-array (FPGA) embedded real time control loop system is built. The sorting is performed under high flow rate ( approximately 10 cm/sec), and the sorting system can achieve a high throughput (> 1kHz) with high purity. Moreover, to enhance its sensitivity, Teflon AF coated liquid core waveguide (LCW) structure is demonstrated. Teflon AF has a lower refractive index (n=1.31) than water (n=1.33) and forms the cladding layer of the LCW. Incident light is confined and guided along the Teflon AF coated fluidic channel, and interact with samples flowing along the same channel. This enables flexible device design and gives high sensitivity to the fluorescence detection system. The preliminary results demonstrate sorting fluorescent beads at a sorting efficiency of approximately 70% with no false sorting.


High resolution implantable microsystem and probe design for retinal prosthesis.
By a retinal prosthesis, the researchers have been able to stimulate a limited number of neurons (around 100) by biphasic current stimulus to reproduce an image spatially by multiplexing technique. For functional restoration of sight (visual acuity 20/80), we are to stimulate at least 2500 neurons/mm². We are far behind that target. The time required by biphasic current stimulus, the sequential stimulation by multiplexing technique, and the conventional probes used for stimulation limits our ability to stimulate large number of neurons and maintains the persistence of vision. To address this problem, we have designed high resolution donut probes and used them in designing neural implant chip (NIC) applying parallel multiplexing technique, which helped us stimulate large number of neurons. This paper presents the design of a donut probe and an implantable CMOS-based 5x5 array NIC to demonstrate that idea. This 5x5 array NIC is scalable to any larger array. It uses external clock, which makes it suitable for any data rate. The programmable biphasic width controller (BWC) used in this design is capable of generating various kinds of stimulus for stimulation. NIC doesn't need address to route the pixels, which reduces the data transmission overhead. 0.5 microm CMOS technology is used to fabricate NIC with donut probes. Test results verify our technique of increasing the resolution.


Developing Cutoff Scores for the Inventory of Callous-Unemotional Traits (ICU) in Justice-Involved and Community Samples.
Objective: The recent addition of the callous-unemotional (CU) traits specifier, "with Limited Prosocial Emotions (LPE)," to major classification systems has prompted the need for assessment tools that aid in the identification of elevations on these traits for diagnostic purposes. The goal of the current study was to use and evaluate multiple methods for establishing cutoff scores for the multi-informant questionnaire, the Inventory of Callous-Unemotional Traits (ICU).Method: The present study compared the clinical utility of various proposed cutoff methods and scores (i.e., empirically derived cutoffs using receiver operating characteristic (ROC), normative cutoffs, and rational scoring approximations of LPE criteria) in both a longitudinal sample of justice-involved male adolescents (N = 1,216; Mage = 15.29, SD = 1.29) and a cross-sectional sample of school children (N = 289; Mage = 11.47 years; SD = 2.26).Results: Methods resulted in a range of cutoff scores with substantial diagnostic overlap and validity. Specifically, they designated justice-involved adolescents at risk for later delinquency, aggression, and rearrests, and they designated school children more likely to be rated by parents and teacher as having conduct problems and rated by peers as being rejected and mean.Conclusions: The results lead to ranges of ICU scores that have support for their validity and can help to guide clinical decisions about children and adolescents who may be elevated on CU traits.


Measurements of pre- and postpubertal human larynx: a cadaver study.
This study investigates the differences in proportion and structure of the larynx in both children and adults, as well as changes which the larynx undergoes during puberty and adolescence. Furthermore, we have tried to answer the question on the existence of laryngeal sexual dismorphism in pre-pubertal (or pubertal) children. Larynges of 20 adults (10 men and 10 women) and 34 larynges of children not more than 12 years of age were acquired from the Forensic Medicine Department of the Medical University of Warsaw, Poland. Methods used are based on (1) anatomical preparation, (2) anatomical description and (3) measurements performed with the use of a digital camera and a computer-aided system MULTISCAN. Statistics, the Student's test and Pearson's linear correlation coefficient were calculated. Results show that proportions of the larynx depend on the age of the individual. The younger the individual is the more slender the larynx would be. However, proportion is not gender-related and hence is about the same in both males and females of any given age-group. Nevertheless, basic parameters were larger in males.


Glutamate-containing parenteral nutrition doubles plasma glutamate: a risk factor in neurosurgical patients with blood-brain barrier damage?
Animal studies have shown that the elevation of plasma glutamate levels increase cerebral edema formation whenever the blood-brain barrier is disturbed. Therefore, changes in plasma glutamate levels as influenced by the administration of a glutamate-containing amino acid solution were investigated in neurosurgical patients. Prospective, descriptive study. Eight-bed neurosurgical intensive care unit in a university hospital. Twenty-three neurosurgical patients requiring parenteral nutrition. Parenteral nutrition was begun 24 hrs after craniotomy. Patients receiving a glutamate-containing amino acid solution (3.75 g/L glutamate) were compared with patients infused with a glutamate-free solution. Arterial plasma and urine amino acids were analyzed using high-performance liquid chromatography. Administration of a glutamate-containing solution doubled plasma glutamate levels in neurosurgical patients (from 53.3 +/- 9.8 microM [preinfusion] to 98.5 +/- 18.7 microM [after 4 hrs of infusion]; p < 0.001), whereas no elevation was seen when infusing a glutamate-free solution (from 52.3 +/- 7.3 [1 hr of infusion] to 53.6 +/- 6.4 microM [4 hrs of infusion]). Upon terminating the glutamate-containing infusion, arterial plasma glutamate levels decreased immediately (from 120 +/- 13.2 microM to 81.2 +/- 19.5 microM). Glutamate as infused in excess appears to exceed a renal threshold and is eliminated renally. As shown in animal models, administration of a glutamate-containing amino acid solution significantly increased plasma glutamate levels. Because such an increase in plasma glutamate levels could aggravate cerebral edema formation, glutamate-containing amino acid solutions cannot be recommended for patients with a disturbed blood-brain barrier.


Cloning, sequencing and disruption of a bromoperoxidase-catalase gene in Streptomyces venezuelae: evidence that it is not required for chlorination in chloramphenicol biosynthesis.
Genomic DNA libraries of Streptomyces venezuelae ISP5230 and of a mutant blocked at the chlorination step of chloramphenicol biosynthesis were probed by hybridization with a synthetic oligonucleotide corresponding to the N-terminal amino acid sequence of a bromoperoxidase-catalase purified from the wild-type strain. Hybridizing fragments obtained from the two strains were cloned and sequenced. Analysis of the nucleotide sequences demonstrated that the fragments contained the same 1449 bp open reading frame with no differences in nucleotide sequence. The deduced polypeptide encoded 483 amino acids with a calculated M(r) of 54,200; the N-terminal sequence was identical to that of the bromoperoxidase-catalase purified from wild-type S. venezuelae. Comparison of the amino acid sequence predicted for the cloned bromoperoxidase-catalase gene (bca) with database protein sequences showed a significant similarity to a group of prokaryotic and eukaryotic catalases, but none to other peroxidases or haloperoxidases. Replacement of the bca gene in the wild-type strain of S. venezuelae with a copy disrupted by insertion of a DNA fragment encoding apramycin resistance did not prevent chloramphenicol production. The results suggest that the role of the enzyme in S. venezuelae is related to its activity as a catalase rather than as a halogenating agent.


Evaluation of an oral preventive protocol in children with acute lymphoblastic leukemia.
This study was designed to assess the effectiveness of a preventive oral protocol in children receiving antineoplastic treatment for acute lymphoblastic leukemia (ALL) before initiating a larger intervention study. During a seven month period, fourteen children from two to ten years old with a diagnosis of ALL were evaluated. Patients with ALL who received a 0.12% chlorhexidine mouth rinse (seven children) were compared to a control group of patients who were not given the same preventive treatment (seven children) as to the occurrence of oral mucosal complications. Children in both groups received daily oral hygiene care, and were examined daily by the pediatric dentistry team until discharge. A significant decrease in the incidence of oral mucositis and ulceration was observed in the children who received a 0.12% chlorhexidine mouth rinse (p < 0.05 by Fisher's exact test). The findings obtained in the present trial are encouraging, and suggest that the systematic application of a preventive protocol reduces the incidence of oral complications in children with ALL receiving chemotherapy.


Characterization of age-related gene expression profiling in bone marrow and epididymal adipocytes.
While an increase in bone marrow adiposity is associated with age-related bone disease, the function of bone marrow adipocytes has not been studied. The aim of this study was to characterize and compare the age-related gene expression profiles in bone marrow adipocytes and epididymal adipocytes. A total of 3918 (13.7%) genes were differentially expressed in bone marrow adipocytes compared to epididymal adipocytes. Bone marrow adipocytes revealed a distinct gene profile with low expression of adipocyte-specific genes peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid binding protein 4 (FABP4), perilipin (Plin1), adipsin (CFD) and high expression of genes associated with early adipocyte differentiation (CCAAT/enhancer binding protein beta (C/EBPβ), regulator of G-protein signaling 2 (RGS2). In addition, a number of genes including secreted frizzled related protein 4 (SFRP4), tumor necrosis factor α (TNFα), transforming growth factor beta 1(TGFβ1), G-protein coupled receptor 109A (GPR109A) and interleukin 6 (IL-6), that could affect adipose-derived signaling to bone are markedly increased in bone marrow adipocytes. Age had a substantial effect on genes associated with mitochondria function and inflammation in bone marrow adipocytes. Twenty seven genes were significantly changed with age in both adipocyte depots. Among these genes, IL6 and GPR109A were significantly reduced with age in both adipocyte depots. Overall, gene profiling reveals a unique phenotype for primary bone marrow adipocytes characterized by low adipose-specific gene expression and high expression of inflammatory response genes. Bone marrow and epididymal adipocytes share a common pathway in response to aging in mice, but age has a greater impact on global gene expression in epididymal than in bone marrow adipocytes. Genes that are differentially expressed at greater levels in the bone marrow are highly regulated with age.


Interleukin 6 is not a crucial regulator in an animal model of tumour necrosis factor-mediated bilateral sacroiliitis.
To evaluate the role of interleukin 6 (IL-6) in the pathogenesis of bilateral erosive sacroiliitis in human tumour necrosis factor transgenic (hTNFtg) mice, an animal model of ankylosing spondylitis (AS). Histological sections of the sacroiliac joints from hTNFtg and IL-6(-/-)hTNFtg mice were evaluated, and wild type and IL-6(-/-)mice served as controls. mRNA levels of inflammation and tissue degradation related genes isolated from sacroiliac joints were also evaluated by quantitative PCR. Severe, erosive bilateral sacroiliitis in 14-week-old hTNFtg animals was accompanied by an upregulation of mRNAs related to tissue inflammation such as matrix metalloproteinase 3 (MMP3), MMP9 and MMP13 or osteoclast activation such as cathepsin K and tartrate-resistant acid phosphatase. In addition, IL-6 was increased in the sera and in the sacroiliac joints of hTNFtg animals. However, high expression of these marker genes in sacroiliac joints from IL-6(-/-)hTNFtg mice was also found. Moreover, absence of IL-6 in these animals did not alter bilateral, erosive sacroiliitis when compared to hTNFtg littermates. IL-6 is not a crucial regulator in an animal model of TNF-mediated bilateral, erosive sacroiliitis. This finding questions the potential of IL-6 blockade as a new treatment in patients with AS.


Desialylation of insulin receptors and IGF-1 receptors by neuraminidase-1 controls the net proliferative response of L6 myoblasts to insulin.
We recently established that the subunit of cell surface-residing elastin receptor, neuraminidase-1 (Neu1), can desialylate adjacent insulin-like growth factor 1 receptors (IGF-1R) of arterial smooth muscle cells, thereby quenching their proliferative response to insulin-like growth factor II. In this study, we explored whether Neu1 would also desialylate the insulin receptors (IR), as well as the IGF-1R on rat skeletal L6 myoblasts, and whether desialylation of IR and IGF-1R would affect a net proliferative effect of insulin. First, we found that physiological (0.5-1 nM) and high therapeutic (10 nM) insulin concentrations induced a modest increase in proliferation rate of cultured L6 myoblasts. While IR kinase inhibitor could abolish the mitogenic effect of these insulin concentrations, the observed more pronounced proliferative response to supraphysiological concentration (100 nM) of insulin could be eliminated only by specific inhibition of IGF-1R. Then, we found that treatment of L6 cells with mouse-derived Neu1 or with Clostridium perfringens neuraminidase caused desialylation of IR, which coincided with a significant increase of their proliferative response to lower (0.5-10 nM) concentrations of insulin. In contrast, experimental desialylation of IGF-1R coincided with elimination of the heightened proliferative response of L6 myoblasts to 100 nM insulin. Importantly, we also found that inhibition of endogenous Neu1 abolished the increase in proliferation of L6 cells induced by 1 and 10 nM of insulin, but amplified the proliferative effect of 100 nM insulin. We therefore conclude that desialylation of both IR and IGF-1R by Neu1 controls the net proliferative response of skeletal myoblasts to insulin.


The pharmacokinetics of co-administered lisinopril and hydrochlorothiazide.
Co-administration of drugs with complementary action is a rational approach to the treatment of hypertension provided that the drugs are free of mutual pharmacokinetic interactions. The pharmacokinetics of single doses of lisinopril 10 mg alone, hydrochlorothiazide 12.5 mg alone, both drugs given concomitantly, and both given in a fixed combination tablet were studied in 24 healthy volunteers (including four women) using a randomized four-way crossover design with each treatment separated by 2 weeks. Timed blood and urine samples were collected for measurement of peak serum levels, area under the concentration vs time curve (AUC) and urinary recovery of lisinopril and hydrochlorothiazide. When given alone, peak serum levels of lisinopril (attained 6-8 hours post dose) were 44 ng/ml. Urinary recovery was 17.6% of the dose. Mean values after treatment with the combination tablet were only 2-6% lower, and co-administration with hydrochlorothiazide in free combination gave mean values 7% higher than the fixed-dose combination. Time to peak serum levels did not vary between treatments. Dosing with hydrochlorothiazide alone resulted in a mean peak serum concentration of 53 ng/ml, 2-6 hours post dose. The combination tablet resulted in a peak serum level and AUC for hydrochlorothiazide about 10% lower. The corresponding values for the free combination were only about 7% lower. The results indicate no clinically relevant pharmacokinetic interaction between the two components when administered in a single tablet.


ICAM-1 induced rearrangements of capsid and genome prime rhinovirus 14 for activation and uncoating.
Most rhinoviruses, which are the leading cause of the common cold, utilize intercellular adhesion molecule-1 (ICAM-1) as a receptor to infect cells. To release their genomes, rhinoviruses convert to activated particles that contain pores in the capsid, lack minor capsid protein VP4, and have an altered genome organization. The binding of rhinoviruses to ICAM-1 promotes virus activation; however, the molecular details of the process remain unknown. Here, we present the structures of virion of rhinovirus 14 and its complex with ICAM-1 determined to resolutions of 2.6 and 2.4 Å, respectively. The cryo-electron microscopy reconstruction of rhinovirus 14 virions contains the resolved density of octanucleotide segments from the RNA genome that interact with VP2 subunits. We show that the binding of ICAM-1 to rhinovirus 14 is required to prime the virus for activation and genome release at acidic pH. Formation of the rhinovirus 14-ICAM-1 complex induces conformational changes to the rhinovirus 14 capsid, including translocation of the C termini of VP4 subunits, which become poised for release through pores that open in the capsids of activated particles. VP4 subunits with altered conformation block the RNA-VP2 interactions and expose patches of positively charged residues. The conformational changes to the capsid induce the redistribution of the virus genome by altering the capsid-RNA interactions. The restructuring of the rhinovirus 14 capsid and genome prepares the virions for conversion to activated particles. The high-resolution structure of rhinovirus 14 in complex with ICAM-1 explains how the binding of uncoating receptors enables enterovirus genome release.