Reaction pattern of photosystem II: oxidative water cleavage and protein flexibility.
This short communication addresses three topics of photosynthetic water cleavage in Photosystem II (PS II): (a) effect of protonation in the acidic range on the extent of the 'fast' ns kinetics of P680+. reduction by YZ, (b) mechanism of O-O bond formation and (c) role of protein flexibility in the functional integrity of PS II. Based on measurements of light-induced absorption changes and quasielastic neutron scattering in combination with mechanistic considerations, evidence is presented for the protein acting as a functionally active constituent of the water cleavage machinery, in particular, for directed local proton transfer. A specific flexibility emerging above a threshold of about 230 K is an indispensable prerequisite for oxygen evolution and plastoquinol formation.


Hepatitis C virus antibodies in a long-term follow-up of beta-thalassaemic children with acute and chronic non-A non-B hepatitis.
The presence of antibodies toward hepatitis C virus (HCV) was examined in 78 polytransfused beta-thalassaemic children. The anti-HCV status was correlated with acute and chronic non-A non-B (NANB) hepatitis that developed during a follow up of about 13 years. Anti-HCV was present in 83.3% of children with acute NANB hepatitis and in 82.9% of those with chronic NANB hepatitis. The percentage of chronic evolution was 56.7% for acute anti-HCV positive NANB hepatitis and 50.0% for anti-HCV negative NANB hepatitis. The long-term persistence of anti-HCV antibodies did not correlate with chronic evolution of liver infection in thalassaemic patients. Histological features of chronic hepatitis showed little or no difference between HCV associated or non-associated liver disease. The multifactorial liver injury in beta-thalassaemic children explains the high prevalence of cirrhosis (about 30%) observed in these patients with NANB hepatitis. On the other hand, independent of liver disease, some patients never seroconverted during the follow up in spite of the high number of transfusions suggesting the existence of "non-responders".


Mating studies, new species, and new reports of Marasmius from northern Thailand.
The mating systems operating in seven species of Marasmius collected recently in northern Thailand were determined. Marasmius cremeus belonging to sect. Sicci subsect. Siccini ser. Leonini, and Marasmius straminiceps belonging to sect. Marasmius subsect. Sicciformes are described as new species. Five members of sect. Marasmius were tetrapolar (bifactorial), viz. M. apatelius, M. guyanensis, M. nigrobrunneus, M. ruforotula, and M. straminiceps. Two members of sect. Sicci were bipolar (unifactorial), viz., M. corneri (syn. M. incarnatus) and M. cremeus. Our data support the hypothesis that the mating system is consistent within infrageneric taxa. The seven species that are herein described, illustrated, and compared with phenetically similar species represent the first reports for this genus in Thailand.


Separation of keto-enol tautomers of chlortetracycline and 4-epichlortetracycline by liquid chromatography on poly(styrene-divinylbenzene)copolymer.
Keto and enol tautomers of chlortetracycline and 4-epichlortetracycline were successfully separated by low temperature high-performance liquid chromatography on poly(styrene-divinylbenzene)copolymer. The keto-enol tautomerism occurs between C-11a and C-12. The elucidation of the chemical structure of the tautomers was realized with the help of on-line and off-line UV-spectrophotometry and of 13C and 1H NMR spectrometry. The kinetics of the equilibrium reaction were investigated.


DigiTag assay for multiplex single nucleotide polymorphism typing with high success rate.
As a consequence of Human Genome Project and single nucleotide polymorphism (SNP) discovery projects, several millions of SNPs, which include possible susceptibility SNPs for multifactorial diseases, have been revealed. Accordingly, there has been a strong drive to perform the investigation with all candidate SNPs for a certain disease without decreasing the number of analyzed SNPs. We developed DigiTag assay, which uses well-designed oligonucleotides called DNA coded numbers (DCNs) in multiplex SNP genotype analysis. During the analysis, the information of a genotype is converted to one of the DCNs in a one to one manner using oligonucleotide ligation assay (encoding). After the encoding reaction, only the DCNs regions and not the SNP specific regions are amplified using the universal primers and then SNP genotype is read out using DNA capillary arrays. DigiTag assay was found to be successful in SNP genotyping, giving a high success rate (24 of 27 SNPs) for randomly chosen SNPs. Moreover, this assay has the potential to analyze almost all kinds of the target SNPs by applying mismatch-induced probes and redesigned primer pairs at a low-cost.


Matted nodes: poor prognostic marker in oropharyngeal squamous cell carcinoma independent of HPV and EGFR status.
Despite better prognosis, there is a group of oropharyngeal squamous cell carcinoma (SCC) human papillomavirus (HPV)+ patients who experience treatment failure and succumb to distant metastasis. Seventy-eight previously untreated patients nested in a concurrent chemoradiation protocol were reviewed to correlate patterns of local-regional tumor extent to distant metastasis. Biomarker assessment was: HPV in situ hybridization and epidermal growth factor receptor (EGFR) immunointensity. The 3-year disease-specific survival (DSS) for patients presenting with and without matted nodes was 69% and 94%, respectively (p = .003). Matted nodes were a poor prognostic factor independent of T classification, HPV, EGFR, and smoking status. For patients who were HPV+, 7 of 11 died of distant metastasis and 6 of 7 with distant metastasis had matted nodes. Matted nodes are a novel marker of poor prognosis in oropharyngeal SCC independent of established prognostic factors. Matted nodes may identify patients at risk for the development of distant metastasis who could benefit from systemic therapy, whereas patients without matted nodes may be candidates for de-escalation of therapy.


Role of kinases and G-proteins in the hyposmotic stimulation of cardiac IKs.
Exposure of cardiac myocytes to hyposmotic solution stimulates slowly-activating delayed-rectifying K(+) current (I(Ks)) via unknown mechanisms. In the present study, I(Ks) was measured in guinea-pig ventricular myocytes that were pretreated with modulators of cell signaling processes, and then exposed to hyposmotic solution. Pretreatment with compounds that (i) inhibit serine/threonine kinase activity (10-100 microM H89; 200 microM H8; 50 microM H7; 1 microM bisindolylmaleimide I; 10 microM LY294002; 50 microM PD98059), (ii) stimulate serine/threonine kinase activity (1-5 microM forskolin; 0.1 microM phorbol-12-myristate-13-acetate; 10 microM acetylcholine; 0.1 microM angiotensin II; 20 microM ATP), (iii) suppress G-protein activation (10 mM GDPbetaS), or (iv) disrupt the cytoskeleton (10 microM cytochalasin D), had little effect on the stimulation of I(Ks) by hyposmotic solution. In marked contrast, pretreatment with tyrosine kinase inhibitor tyrphostin A25 (20 microM) strongly attenuated both the hyposmotic stimulation of I(Ks) in myocytes and the hyposmotic stimulation of current in BHK cells co-expressing Ks channel subunits KCNQ1 and KCNE1. Since attenuation of hyposmotic stimulation was not observed in myocytes and cells pretreated with inactive tyrphostin A1, we conclude that TK has an important role in the response of cardiac Ks channels to hyposmotic solution.


Assessment of tobacco heating product THP1.0. Part 5: In vitro dosimetric and cytotoxic assessment.
Tobacco heating products (THPs) represent a subset of the next-generation nicotine and tobacco product category, in which tobacco is typically heated at temperatures of 250-350 °C, thereby avoiding many of the harmful combustion-related toxicant emissions of conventional cigarettes. In this study, we have assessed aerosol generation and cytotoxicity from two commercially available THPs, THP1.0 and THS, relative to tobacco smoke from 3R4F reference cigarettes, using an adapted Borgwaldt RM20S Smoking Machine. Quantification of nicotine in the exposed cell-culture media showed greater delivery of nicotine from both THPs than from the cigarette. Using Neutral Red Uptake assay, THPs demonstrated reduced in vitro cytotoxicity in H292 human bronchial epithelial cells as compared with 3R4F cigarette exposure at the air-liquid interface (p < 0.0001). Both THPs demonstrated a statistically similar reduction in biological response, with >87% viability relative to 3R4F at a common aerosol dilution (1:40, aerosol:air). A similar response was observed when plotted against nicotine; a statistical difference between 3R4F and THPs (p < 0.0001) and no difference between the THPs (p = 0.0186). This pre-clinical in vitro biological testing forms part of a larger package of data to help assess the safety and risk reduction potential of next-generation tobacco products relative to cigarettes, using a weight of evidence approach.


Taenia crassiceps: basic mechanisms of endocytosis in the cysticercus.
The effects of glucose, yeast extract, fetal bovine serum albumin, and ruthenium red on endocytosis of smooth micropinocytotic vesicles (pinosomes) in the tegument of the cysticercus of Taenia crassiceps have been investigated stereologically. Glucose has been shown to stimulate pinocytosis, whether it was used alone or in combination with yeast extract or bovine serum albumin. Yeast extract was a stimulant of endocytosis. Bovine serum albumin was the most potent stimulant of all the substances investigated in this study. Although the time of incubation in ruthenium red was the same for all incubation experiments, varied numbers of ruthenium red-containing pinosomes were observed in different experiments. The role of ruthenium red as a stimulant and/or initiator of endocytosis and the possible explanations for differences in ruthenium red uptake are discussed.


QSAR with experimental and predictive distributions: an information theoretic approach for assessing model quality.
We propose that quantitative structure-activity relationship (QSAR) predictions should be explicitly represented as predictive (probability) distributions. If both predictions and experimental measurements are treated as probability distributions, the quality of a set of predictive distributions output by a model can be assessed with Kullback-Leibler (KL) divergence: a widely used information theoretic measure of the distance between two probability distributions. We have assessed a range of different machine learning algorithms and error estimation methods for producing predictive distributions with an analysis against three of AstraZeneca's global DMPK datasets. Using the KL-divergence framework, we have identified a few combinations of algorithms that produce accurate and valid compound-specific predictive distributions. These methods use reliability indices to assign predictive distributions to the predictions output by QSAR models so that reliable predictions have tight distributions and vice versa. Finally we show how valid predictive distributions can be used to estimate the probability that a test compound has properties that hit single- or multi- objective target profiles.


Native and oxidized low-density lipoproteins have different inhibitory effects on endothelium-derived relaxing factor in the rabbit aorta.
1. The effect of native low-density lipoproteins (LDL) and oxidized LDL (OXLDL) on the relaxations to endothelium-derived relaxing factor (EDRF) in isolated, intact aortic rings of the rabbit were investigated. 2. Native LDL induced a concentration-dependent reversible inhibition of the relaxations elicited by acetylcholine (ACh) or A23187, in rings pre-contracted by noradrenaline (NA), adrenaline (Ad) and 5-hydroxytryptamine (5-HT), but not phenylephrine (PE), which was not influenced by indomethacin. 3. The inhibition was surmountable in the rings pre-contracted with NA and Ad and only partially in those pre-contracted with 5-HT. 4. OXLDL induced an inhibition of the relaxations elicited by ACh and A23187 which was independent of the contractile agonist. The extent of inhibition and its reversibility varied with the LDL from individual donors, but was unaffected by indomethacin. 5. Native and oxidized LDL inhibited relaxations evoked by exogenous nitric oxide (NO) to the same extent. Higher concentrations of NO overcame the inhibition. The inhibition was independent of the contractile agonist and the preparation of LDL from individual donors. 6. Only OXLDL inhibited reversibly relaxations evoked by glyceryl trinitrate (GTN) and the inhibition was independent of the LDL preparation from individual donors. 7. This study demonstrates that native and OXLDL influence the response to EDRF in isolated aorta. We suggest that these lipoproteins may contribute to the attenuation of responses to EDRF found in isolated arteries from hypercholesterolaemic and atherosclerotic animals.


Adverse reactions to isotretinoin. A report from the Adverse Drug Reaction Reporting System.
Between October 1982 and June 1985 the Adverse Drug Reaction Reporting System received reports of 104 suspected adverse reactions occurring in 93 patients who took isotretinoin. Adverse reactions involving the skin and mucous membranes (29 reports), central nervous system (23), musculoskeletal system (12), pregnancy (11), and eyes (8) were most commonly reported. Severe headache was the most frequently reported adverse reaction (15 reports). In four cases headaches were attributed to pseudotumor cerebri. Some of the reported reactions, for example, a disulfiram (Antabuse)-like reaction and oculogyric crisis, have not been described previously in the literature. Other reports, such as congenital malformations, serve to emphasize some of the serious reactions that are known to occur. These spontaneous reports of adverse reactions associated with isotretinoin use, together with the literature we review, may help alert physicians to the diverse spectrum of adverse reactions that may develop in patients taking isotretinoin.


Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported.


ESTs library from embryonic stages reveals tubulin and reflectin diversity in Sepia officinalis (Mollusca — Cephalopoda).
New molecular resources regarding the so-called "non-standard models" in biology extend the present knowledge and are essential for molecular evolution and diversity studies (especially during the development) and evolutionary inferences about these zoological groups, or more practically for their fruitful management. Sepia officinalis, an economically important cephalopod species, is emerging as a new lophotrochozoan developmental model. We developed a large set of expressed sequence tags (ESTs) from embryonic stages of S. officinalis, yielding 19,780 non-redundant sequences (NRS). Around 75% of these sequences have no homologs in existing available databases. This set is the first developmental ESTs library in cephalopods. By exploring these NRS for tubulin, a generic protein family, and reflectin, a cephalopod specific protein family,we point out for both families a striking molecular diversity in S. officinalis.


Effect of ageing on the murine venous circulation.
The effect of ageing on the morphology of veins, venous valves and arteries was investigated in male wild-type mice using an adapted procedure with injection of a silicone polymer Microfil(®) that preserves morphology of the vasculature. Throughout the hind limb the arterial, but not the venous, lumen area and wall thickness were significantly greater in 24-month as compared to 10-week-old C57BL/6 mice. Venous valves were most frequently located at the sapheno-femoral vein junction in the lower extremities, and appeared thicker at the base supported by structurally intact collagen fibers, and thinner towards the proximal end of the valve leaflet, with less organized collagen. Overall, valves were less supported by structurally intact collagen at 24 months as compared to 10 weeks. Endothelial expression of CD31, endothelial protein C receptor or von Willebrand factor (VWF) was not affected by age, while thrombomodulin expression was lower in aged versus young arteries. At both ages, expression of VWF was lower at venous valves versus veins. Evaluation of the blood coagulation profile revealed that aged mice had shortened prothrombin time, elevated plasma levels of factor (F)VII, FVIII and VWF and increased neutrophil and platelet counts. Thus, our data indicate that in mice with ageing, venous valves become more fragile, in association with a procoagulant and inflammatory blood phenotype. Taken together, we found that the procoagulant state in ageing, is accompanied by mild vascular changes.


De novo assembly and annotation of the transcriptome of Astyanax lacustris liver unveil candidate genes to monitor response to environmental stress.
Astyanax lacustris is a freshwater characid fish species that inhabits small streams, lakes and rivers in South America. These fish are abundant in the wild and highly adaptable in captive, being considered a good model for ecotoxicological studies. Nevertheless, there are only shortcoming gene sequence information available in public databases, which hinder their use in more comprehensive investigations that employ sensitivity molecular biology techniques to assess gene expression profile for biomarker identification. In this study, we report the first de novo transcriptome of A. lacustris liver with the aim of improving gene sequence data available for this fish species. Illumina sequencing generated 79,102,610 raw reads, which were filtered in 62,041,259 high-quality transcripts. De novo assembly resulted in 93,888 unigenes and 120,674 isoforms of an average length of 909.12 and 1046.50 bp, respectively. 60,495 isoforms (50.13%) were functionally annotated against seven databases, retrieving homology queries for about 46% of all isoforms. Therefore, in this study we provide information of relevant genes associated to environmental stress and contamination of A. lacustris, enabling future ecotoxicological researches and other molecular studies using this fish species as model.


Preparation of activated carbon from coconut shell chars in pilot-scale microwave heating equipment at 60 kW.
Experiments to prepare activated carbon by microwave heating indicated that microwave energy can decrease reaction temperature, save the energy and shorten processing time remarkably compared to conventional heating, owing to its internal and volumetric heating effects. The above results were based on the laboratory-scale experiments. It is desirable to develop a pilot-scale microwave heating equipment and investigate the parameters with the aim of technological industrialization. In the present study, the components and features of the self-invented equipment were introduced. The temperature rise curves of the chars were obtained. Iodine numbers of the activated carbons all exceed the state standard of China under the following conditions: 25 kg/h charging rate, 0.42 rev/min turning rate of ceramic tube, flow rate of steam at pressure of 0.01 MPa and 40 kW microwave heating power after 60 kW pre-activation for 30 min. Pore structure of the sample obtained at a time point of 46 h, which contained BET surface area, and pore size distributions of micropores and total pores, was tested by nitrogen adsorption at 77K.


Repeatability of long intracortical inhibition in healthy subjects.
Transcranial magnetic stimulation (TMS) is widely used to assess cortical excitability. To detect changes in excitability with longitudinal studies, it is important to validate the repeatability of excitability measures within a subject between different sessions. Repeatability studies on long intracortical inhibition (LICI) are limited and reported agreement ranges from poor to good. This study aims to evaluate the repeatability of LICI in healthy subjects using paired pulse TMS. In addition, it investigates whether LICI repeatability differs for manual and robot-guided coil positioning. Thirty healthy subjects (10 males, mean age 28.4 ± 8.2 years) were studied twice, approximately one week apart. Both motor cortices were stimulated with 50 paired pulses (intensity 120% of resting motor threshold) at interstimulus intervals (ISIs): 50, 100, 150, 200, 250 and 300 ms. In twenty subjects a figure-of-eight coil was positioned and held in place manually during both sessions, while in ten subjects a robot-navigated arm was used. LICI repeatability was assessed using the intraclass correlation coefficient (ICC). For manual and robot-guided coil positioning we found a large variation in repeatability at the subject level and ISI level, ranging from poor to good agreement. On a group level, we found good repeatability for averaged LICI curves (manual: ICC = 0.91, robot-guided: ICC = 0.95), which decreased when individual curves were correlated between sessions (manual: ICC = 0.76, robot-guided: ICC = 0.84). For a correct interpretation of longitudinal study outcomes it is important to know the subject specific LICI repeatability and to analyze each ISI individually. Furthermore, the added value of robot-guided coil positioning for paired pulse TMS seems limited. The large variation in LICI repeatability at the subject level and ISI level should be taken into account in longitudinal studies, while robot-guided coil positioning seems unnecessary.


Contamination with multiple heavy metals decreases microbial diversity and favors generalists as the keystones in microbial occurrence networks.
Soil contamination with multiple heavy metals poses threats to human health and ecosystem functioning. Using the Nemerow pollution index, which considers the effects of multiple heavy metals, we compared the diversity and composition of bacteria, fungi and protists and their potential interactions in response to a multi-metal contamination gradient. Multi-metal contamination significantly altered the community composition of bacteria, fungi and protists, and the degree of alteration increased with increasing severity of contamination. The alpha-diversity of bacteria, fungi and protists significantly decreased with increasing contamination level. The dominant generalists, found in all soil samples, were Gammaproteobacteria, Chloroflexi and Bacillus sp, whereas the dominant specialists were Anaerolineaceae, Entoloma sp. and Sandonidae_X sp. The relative abundances of generalists were positively correlated, whereas those of specialists were negatively correlated, with the Nemerow pollution index. In addition, the complexity of the microbial co-occurrence network increased with increasing contamination level. Generalists, rather than specialists, were the keystones in the microbial co-occurrence network and played a crucial role in adaptation to multi-metal contamination through enhanced potential interactions within the entire microbiome. Our results provide insights into the ecological effects of multi-metal contamination on the soil microbiome and will help to develop bio-remediation technologies for contaminated soils.


Molecular-scale origins of wettability at petroleum-brine-carbonate interfaces.
Wettability control of carbonates is a central concept for enhanced petroleum recovery, but a mechanistic understanding of the associated molecular-scale chemical processes remains unclear. We directly probe the interface of calcium carbonate (calcite) with natural petroleum oil, synthetic petroleum analogues, and aqueous brines to understand the molecular scale behavior at this interface. The calcite-petroleum interface structure is similar whether or not calcite was previously exposed to an aqueous brine, and is characterized by an adsorbed interfacial layer, significant structural changes within the calcite surface, and increased surface roughness. No evidence for an often-assumed thin-brine wetting layer at the calcite-petroleum interface is observed. These features differ from those observed at the calcite-brine interface, and for parallel measurements using model synthetic petroleum mixtures (consisting of representative components, including dodecane, toluene, and asphaltene). Changes to the interface after petroleum displacement by aqueous brines are also discussed.


Towards gene therapy for the central nervous system.
Gene therapy has generated enormous scientific, medical and public interest over the last decade. Clinical trials involving approximately 2000 patients worldwide have targeted simple genetic diseases such as cystic fibrosis, muscular dystrophy, adenosine deaminase deficiency, Gaucher's disease and familial hypercholesterolemia, as well as complex acquired diseases such as cancer and AIDS. The central nervous system is a new and particularly exciting target for gene therapy because its unique properties prevent the successful treatment of many neurological disorders by conventional means. This review discusses the potential applications of in vivo gene therapy to neurological disorders that have the greatest potential for genetic treatments.


Effect of extrusion parameters on the interaction between rice starch and glutelin in the preparation of reconstituted rice.
Reconstituted rice produced by extrusion has been attracted attention due to nutritional fortification and convenient production. Nevertheless, how to achieve desirable qualities and physicochemical properties of reconstituted rice nearly to natural rice by regulating extrusion process parameters is difficult. Herein, rice starch/glutelin mixture as raw material of reconstituted rice was extruded at varying extrusion conditions. Specific mechanical energy (SME) and sectional expansion index (SEI) dropped with rise in density (R2 = 0.9117 and 0.8207). Solubility was enhanced with increase in product temperature (R2 = 0.9085), color darkened and shifted to reddish and yellowish as extrusion temperature increased (R2 = 0.8577). These trends were well fitted by sigmoid models. Furthermore, SME enhanced hydrophobic and electrostatic interactions between rice starch and glutelin and caused the reduction in crystallinity and thermal stability, promoting the formation of a bi-continuous matrix of protein aggregates with rice starch. The obtained results can be applied to guide the production of reconstituted rice with desirable qualities.


Contemplative practices: The body as therapeutic site linking health and place.
During times of upheaval, supporting stability, health and wellbeing on all levels is essential. While literature regarding 'therapeutic landscapes' has burgeoned over the last 30 years, to date no studies have considered the therapeutic potential of embodied contemplative practices (CP), such as yoga and meditation, within the most accessible, ordinary environment - the body at home. Equally, the field of mobilities appears to have overlooked the spiritual and political nature of these deliberately immobilising acts of resistance. Our paper draws on narrative data collected over the course of three months of daily CP. We interpret the resulting autoethnography through thematic analysis. We conclude that within a fast-paced, hyper-connected world, CPs can be a therapeutic counterpoint, connecting health and place by nurturing an appreciation for the immaterial, interdependent aspects of life.


Window of Opportunity Clinical Trials to Evaluate Novel Therapies for Brain Tumors.
Despite significant improvement in understanding of molecular underpinnings driving glioblastoma, there is minimal improvement in overall survival of patients. This poor outcome is caused in part by traditional designs of early phase clinical trials, which focus on clinical assessments of drug toxicity and response. Window of opportunity trials overcome this shortcoming by assessing drug-induced on-target molecular alterations in post-treatment human tumor specimens. This article provides an overview of window of opportunity trials, including novel designs for incorporating biologic end points into early stage trials in context of brain tumors, and examples of successfully executed window of opportunity trials for glioblastoma.


Interactions in vitro between sporozoites of Eimeria tenella and host peritoneal exudate cells: electron microscopal observations.
The interactions of sporozoites of Eimeria tenella with peritoneal cells from normal and from immunized chickens were examined in vitro. Although the uptake of sporozoites by cells from immunized birds was greater than by cells from susceptible birds, no differences were apparent in their appearance in electron micrographs. Entry into both macrophages and heterophils (comparable to mammalian neutrophils) was by phagocytosis. The findings are discussed.


Lymphoma cells protected from apoptosis by dysregulated bcl-2 continue to bind annexin V in response to B-cell receptor engagement: a cautionary tale.
Translocation of phosphatidylserine (PS) from the inner to outer leaflet of the surface membrane lipid bilayer, a characteristic early event of cells entering the apoptotic program, is routinely assessed by the Ca(2+)-dependent binding of Annexin V (AV). Here, we show that lymphoma cells protected from apoptosis by expression of a bcl-2 transgene or by virtue of the t(14;18)(q32;q21) translocation continue to register enhanced AV binding in response to BCR crosslinking. Induced AV binding appeared BCR-selective in that it did not proceed in Bcl-2(high) cells in response to calcium ionophore or the antidepressant fluoxetine, each of which activate the full apoptotic program in Bcl-2(low) equivalents. AV-positive cells did increase on crosslinking the BCR co-receptor CD19, despite it being a completely non-apoptotic signal. These findings advise caution when interpreting studies where Annexin V binding is used as a sole, or major, indicator of apoptotic death among lymphoma B cells.


Comparison of rosiglitazone and metformin for treating HIV lipodystrophy: a randomized trial.
The use of antiretroviral combination therapy in HIV has been associated with lipodystrophy and cardiovascular risk factors. To compare the effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone and metformin for treating HIV lipodystrophy. An open, randomized, 6-month clinical trial. University Medical Center, Utrecht, the Netherlands. 39 HIV-infected men with lipodystrophy. Rosiglitazone, 8 g/d, or metformin, 2 g/d [DOSAGE ERROR CORRECTED] Insulin sensitivity estimated by the oral glucose tolerance test, subcutaneous and visceral abdominal fat measured by single-slice computed tomography, endothelial function measured by flow-mediated vasodilation, and fasting plasma measurements. Two patients in the metformin group withdrew from the study. Complete case analysis was performed. Compared with metformin, rosiglitazone increased subcutaneous abdominal fat (between-treatment change from baseline, 27 cm2 [95% CI, 7 cm2 to 46 cm2]) and visceral abdominal fat (between-treatment change from baseline, 24 cm2 [CI, 6 cm2 to 51 cm2]). The area under the curve for insulin after the oral glucose tolerance test decreased similarly with both agents, but only rosiglitazone increased adiponectin levels. Metformin showed greater benefits on fasting lipid profile than rosiglitazone. Flow-mediated vasodilation statistically significantly increased with metformin (mean change, 1.5% [CI, 0.4% to 3.3%]) and not with rosiglitazone (mean change, 0.7% [CI, -1.1% to 2.7%]). The metformin versus rosiglitazone increases did not statistically differ. Rosiglitazone and metformin did not change C-reactive protein levels. This small trial was not blinded or placebo-controlled and did not measure clinical outcomes. The findings emphasize the importance of individualized care in HIV-infected patients. Although rosiglitazone may partly correct lipoatrophy, metformin improves visceral fat accumulation, fasting lipid profile, and endothelial function.


Smooth muscle sphincteroplasty in colostomy.
The present work elaborated on Schmidt's idea of an effective smooth muscle sphincteroplasty. The aim of the study was to analyze the effects on the patients with a lower quadrant colostomy constructed after abdominoperineal extirpation of a modified smooth muscle sphincteroplasty combined with colon irrigations. Seventy-two rectal cancer patients (39 men and 33 women, median age, 54.5 years) with smooth muscle sphincteroplasty and 20 controls with conventional colostomy using colon irrigations (11 men and 9 women, median age, 63.2 years) were examined. A modified smooth muscle wrap of the colostomy with a free graft of a 4-cm-long colon segment without mucosa was applied. In this precolostomy segment a high intraluminal pressure was achieved. The functional capacity and anatomic integrity of the transplanted smooth muscle graft were examined manometrically, electromyographically, and histomorphologically. The functional activity of the colostomy was assessed by periodic recording of the number of "spontaneous" and "directed" defecations.RESULTS. In the patients with smooth muscle sphincteroplasty, the basal intraluminal pressure of the precolostomy segment two years after operation measured 29.7 mmHg. After dilatation of the transplant, these pressures reached up to 43 mmHg ( P < 0.001). The weekly "spontaneous" stools were 3 to 5 times less frequent than in the controls ( P < 0.001). The modified smooth muscle sphincteroplasty offers operative-technical opportunities for increasing intraluminal pressure in the precolostomy colon segment. Its combination with colonic irrigations facilitates control of the evacuatory rhythm and "spontaneous" stools in colostomy patients, thus improving their quality of life.


A new hypothalamic polypeptide is a regulator of myelopoiesis.
The effect of hypothalamic proline-rich polypeptide (PRP) against Pseudomonas aeruginosa infection in BALB/c mice with leukopenia was investigated. Mice were treated with cyclophosphamide (CPA) and were then injected with PRP 24 h after CPA treatment. The lethal doses of P. aeruginosa were injected to mice when the number of peripheral blood leukocytes reached a nadir on day 5 after CPA administration. The administration of PRP significantly increased the survival of infected mice, and had a pronounced protective effect during the period of development of the infection. The number of bacteria in internal organs of PRP-treated mice was significantly lower than that in control mice. In PRP-treated mice, the neutrophil levels in peripheral blood started to increase 7 days after CPA administration and were consistently higher, and they were more mature than those in controls. Our results may indicate the ability of PRP to stimulate recovery of myelopoiesis and enhance mature neutrophil function.


Estimating the combined effect of several disease precursors in health risk appraisal.
Health risk appraisal is an attractive health education technique but suffers from methodologic weaknesses. Many of the problems center on the formula that is usually used to estimate the combined effects of different disease precursors. The formula does not reflect current models of disease causation, underestimates the effects of protective factors, and confounds the effects of different precursors. We suggest a modification that resolves these problems by estimating the prevalence and associated composite relative risk for each combination of precursors before calculating the numerical estimate of combined risk. This method can be applied to the many diseases for which the data needed to support a multivariate approach are not available. We recommend its incorporation into existing appraisal instruments.


Evaluation of a handheld device for measurement of β-hydroxybutyrate concentration to identify prepartum dairy cattle at risk of developing postpartum hyperketonemia.
To evaluate the use of a handheld device for measurement of β-hydroxybutyrate (BHBA) concentration to identify prepartum dairy cattle at risk of developing hyperketonemia during the first week after parturition. Cross-sectional study. Animals-210 prepartum dairy cows from 6 herds. A blood sample was collected from each cow 3 to 9 days before its expected calving date. β-Hydroxybutyrate concentration was immediately measured with a handheld device. Serum was harvested from the remaining sample and submitted to a laboratory for measurement of BHBA and nonesterified fatty acid (NEFA) concentrations. β-Hydroxybutyrate concentration determined with the handheld device was compared with that determined by laboratory methods. The association between prepartum BHBA concentration and the development of hyperketonemia (BHBA concentration, ≥ 1.2 mmol/L) during the first week after parturition was determined. The agreement between prepartum BHBA and NEFA concentrations for identification of cows at risk of developing postpartum hyperketonemia was evaluated. β-Hydroxybutyrate concentration determined by the handheld device was moderately correlated with that determined by laboratory methods. Cows with a prepartum BHBA concentration ≥ 0.6 mmol/L were 2.2 times as likely to develop hyperketonemia within 1 week after parturition as were cows with a prepartum BHBA concentration < 0.6 mmol/L. There was substantial agreement between prepartum BHBA and NEFA concentrations for identification of cows at risk of developing postpartum hyperketonemia. Results indicated the handheld device was a valid tool for measurement of BHBA concentration in prepartum dairy cattle, and measurement of prepartum BHBA concentration may be helpful for identifying cows at risk of developing postpartum hyperketonemia.


Tissue distribution of fentanyl and alfentanil in the rat cannot be described by a blood flow limited model.
Traditionally, physiological pharmacokinetic models assume that arterial blood flow to tissue is the rate-limiting step in the transfer of drug into tissue parenchyma. When this assumption is made the tissue can be described as a well-stirred single compartment. This study presents the tissue washout concentration curves of the two opioid analgesics fentanyl and alfentanil after simultaneous 1-min iv infusions in the rat and explores the feasibility of characterizing their tissue pharmacokinetics, modeling each of the 12 tissues separately, by means of either a one-compartment model or a unit disposition function. The tissue and blood concentrations of the two opioids were measured by gas-liquid chromatography. The well-stirred one-compartment tissue model could reasonably predict the concentration-time course of fentanyl in the heart, pancreas, testes, muscle, and fat, and of alfentanil in the brain and heart only. In most other tissues, the initial uptake of the opioids was considerably lower than predicted by this model. The unit disposition functions of the opioids in each tissue could be estimated by nonparametric numerical deconvolution, using the arterial concentration times tissue blood flow as the input and measured tissue concentrations as the response function. The observed zero-time intercepts of the unit disposition functions were below the theoretical value of one, and were invariably lower for alfentanil than for fentanyl. These findings can be explained by the existence of diffusion barriers within the tissues and they also indicate that alfentanil is less efficiently extracted by the tissue parenchyma than the more lipophilic compound fentanyl. The individual unit disposition functions obtained for fentanyl and alfentanil in 12 rat tissues provide a starting point for the development of models of intratissue kinetics of these opioids. These submodels can then be assembled into full physiological models of drug disposition.


The impact of oxidative stress in thiamine deficiency: a multifactorial targeting issue.
Thiamine (vitamin B1) deficiency, the underlying cause of Wernicke-Korsakoff syndrome, is associated with the development of focal neuronal loss in vulnerable areas of the brain. Although the actual mechanism(s) that lead to the selective histological lesions characteristic of this disorder remain unresolved, oxidative stress has been shown to play a major role in its pathophysiology. In this review, the multifactorial influence of oxidative stress on a variety of processes known to take part in the development of structural lesions in TD including excitotoxicity, neuroinflammation, blood-brain barrier integrity, mitochondrial integrity, apoptosis, nucleic acid function, and neural stem cells will be discussed, and therapeutic strategies undertaken for treating neurodegeneration examined which may have an impact on the future treatment of this important vitamin deficiency.


Spatiotemporal Dynamic Assembly/Disassembly of Organelle-Mimics Based on Intrinsically Disordered Protein-Polymer Conjugates.
Design of reversible organelle-like microcompartments formed by liquid-liquid phase separation in cell-mimicking entities has significantly advanced the bottom-up construction of artificial eukaryotic cells. However, organizing the formation of artificial organelle architectures in a spatiotemporal manner within complex primitive compartments remains scarcely explored. In this work, thermoresponsive hybrid polypeptide-polymer conjugates are rationally engineered and synthesized, resulting from the conjugation of an intrinsically disordered synthetic protein (IDP), namely elastin-like polypeptide, and synthetic polymers (poly(ethylene glycol) and dextran) that are widely used as macromolecular crowding agents. Cell-like constructs are built using droplet-based microfluidics that are filled with such bioconjugates and an artificial cytoplasm system that is composed of specific polymers conjugated to the IDP. The distinct spatial organizations of two polypeptide-polymer conjugates and the dynamic assembly and disassembly of polypeptide-polymer coacervate droplets in response to temperature are studied in the cytomimetic protocells. Furthermore, a monoblock IDP with longer length is concurrently included with bioconjugates individually inside cytomimetic compartments. Both bioconjugates exhibit an identical surfactant-like property, compartmentalizing the monoblock IDP coacervates via temperature control. These findings lay the foundation for developing hierarchically structured synthetic cells with interior organelle-like structures which could be designed to localize in desired phase-separated subcompartments.


Mean-Field Limits: From Particle Descriptions to Macroscopic Equations.
We rigorously derive pressureless Euler-type equations with nonlocal dissipative terms in velocity and aggregation equations with nonlocal velocity fields from Newton-type particle descriptions of swarming models with alignment interactions. Crucially, we make use of a discrete version of a modulated kinetic energy together with the bounded Lipschitz distance for measures in order to control terms in its time derivative due to the nonlocal interactions.


Chemical effects in high-resolution nickel Kalpha X-ray fluorescence spectra.
The nickel Kalpha spectra of oxides, halides (NiF2, K2NiF6, NiCl2, NiBr2), complex compounds, and metal are measured with two different double-crystal X-ray fluorescence spectrometers. The peak shifts and line width changes due to the changes in the chemical states are reported. High reproducibility has been shown for the chemical shift and line width measurements. The DV-Xalpha molecular orbital calculation at the ground and the 1s(-1) hole states was performed to prove that the chemical effect originats from the charge-transfer mechanism.


[Determination of estradiol-17 beta receptors in tumorous breast tissue as an index of the hormonal dependence of the tumor].
To judge the hormone-dependence of mammary tumors the technic of tissue sections was employed, which were examined for the presence of oestradiol-17 beta receptors. Under examination were 192 patients, 78 of them being in their reproductive age and 14 menopausal patients. Oestradiol-17 beta receptors were found in the tumor material from 42.7% of patients.


Behavior of antithrombin III isoforms on immobilized heparins. Evidence that the isoforms bind to different numbers of low-affinity heparin sites.
Antithrombin III exists in plasma as major and minor isoforms differing in affinity for heparin. The nature of the binding of each purified isoform to immobilized heparins was investigated. Unfractionated, mixed-affinity heparin bound each isoform with both high affinity and concentration-dependent low affinity. The isoforms were resolved when filtered through low-affinity heparin (heparin repeatedly passed over immobilized antithrombin III) columns. Following chemical modification of a specific tryptophan residue required for heparin binding, each isoform failed to bind to either low-affinity or mixed-affinity heparin-agarose, but elution of the modified higher-affinity isoform was retarded on both gels. Because the modified lower-affinity isoform eluted with the similarly sized bovine serum albumin in these experiments, the difference in isoform affinity for heparin appears to be the result of a unique, secondary heparin-binding site in the higher-affinity isoform that can bind a heparin site with low affinity for antithrombin III. This interpretation was supported by the chromatographic behavior of the isoforms on mixed-affinity agarose during reverse gradient elution. Two other populations of each of the tryptophan-modified isoforms were identified. Since these isoforms bound tightly to mixed-affinity heparin-agarose but eluted at lower salt concentrations than the corresponding unmodified isoforms, both isoforms may contain additional secondary sites that interact weakly with heparin. A general model of heparin-antithrombin III interaction is proposed in which a high-affinity heparin site initially interacts with a primary site on antithrombin III. The subsequent conformational change leads to a cooperative, entropy-driven association between secondary sites on the protein and low-affinity sites on heparin, stabilizing antithrombin III in its activated form.


Sex influences on shared risk factors for bulimia nervosa and other psychiatric disorders.
The examination of opposite-sex and same-sex dizygotic twins allows us to explore the sex-specific comorbidity of psychiatric disorders. To date, this question has not been explored in eating disorders. To determine whether sex influences shared risk factors between bulimia nervosa (BN) and other forms of psychopathology. The study examines associations between BN and other forms of psychopathology in twin pairs using interview and survey reports. Twins from the Virginia population-based twin registry. Male-female dizygotic twins (N = 1192 pairs), mean (SD) age 36.6 (8.9) years, and female-female dizygotic twins (N = 467 pairs), mean (SD) age 36.0 (7.6) years. Lifetime psychiatric disorders as diagnosed by a structured psychiatric interview, including major depression, anxiety disorders, and substance abuse and dependence. Also, continuous measures of body mass index and personality, including neuroticism and novelty seeking. Significant within-person associations existed for women between BN and higher body mass index, neuroticism, novelty seeking, and all lifetime psychopathology. Results from this study suggest the presence of either familial or nonfamilial shared risk factors between BN and generalized anxiety disorder, neuroticism, psychoactive substance use, novelty seeking, major depression, and panic disorder. The shared risk factors between BN and generalized anxiety disorder and BN and novelty seeking were only present in men. Evidence supports the existence of a sex-specific manifestation of familial liability with respect to BN and generalized anxiety disorder and BN and novelty seeking.


Hydranencephaly in CENPJ-related Seckel syndrome.
Pathogenic variants in CENPJ have been first identified in consanguineous Pakistani families with Hereditary Primary Microcephaly type 6 (MCPH6). In addition to primary microcephaly, the CENPJ-related phenotypic spectrum lately included also distinctive and peculiar 'bird-like' craniofacial dysmorphisms, intrauterine and/or postnatal growth retardation, and moderate to severe intellectual disability (ID). These features are also part of the clinical spectrum of Seckel syndrome (SCKL) a genetically heterogeneous neurodevelopmental condition caused by mutations in different genes involved in cell cycle progression. Among these, CENPJ is responsible for type 4 Seckel syndrome (SCKL4). The literature reports two individuals affected by SCKL4 suffering from seizures and other two individuals with other brain malformations in addition to microcephaly. However, neither epilepsy nor brain malformations are described in detail and genotype-phenotype information remains limited. We describe the first Caucasian affected with SCKL4 and harboring a novel, homozygous mutation in CENPJ. We detail the clinical and neuroradiological findings including structural focal epilepsy and a severe brain malformation (i.e., hydranencephaly) that was never associated with SCKL4 to date.


Production of antibodies and development of an immunoassay for the anticoagulant, diphacinone.
Diphacinone, a commonly used anticoagulant rodenticide, was coupled to protein via an (O-carboxymethyl) oxime bridge. Immunization in rabbits produced antibodies with good ability to recognize the hapten as demonstrated by indirect EIA and affinity column adsorption. A competitive EIA was developed which clearly measured 10 micrograms/L diphacinone concentrations showing the sensitivity of the assay. Cross-reactivity study with chlorophacinone showed that the antisera possessed a high degree of diphacinone specificity.


Evidence that local non-NMDA receptors contribute to functional deficits in contusive spinal cord injury.
To investigate the role of non-N-methyl-D-aspartate (non-NMDA) types of excitatory amino acid (EAA) receptors in traumatic spinal cord injury, we administered 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX), a potent and specific antagonist of non-NMDA receptors, to rats with a standardized contusive spinal cord injury. Focal infusion of NBQX into the injury site significantly reduced long-term hindlimb functional deficits as well as decreasing the time required for the rats to establish a reflex bladder. The results suggest that non-NMDA receptors at or near the injury site are involved in producing a portion of the functional deficits that result from contusive spinal cord injury.


Enhanced Doula Support to Improve Pregnancy Outcomes Among African American Women With Disabilities.
This article is a meta-analysis of studies examining the influence of doula support on birth outcomes among African American women with disabilities. While an estimated 11% of women in their childbearing years are impacted by some type of disability, mothers with disabilities are faced with risks during pregnancy. When risks in addition to maternal disability are present, mothers may encounter extra barriers that impede receipt of effective care. A meta-analysis of studies revealed women with disabilities are at risk for poor birth outcomes. Specifically, women of color living in poverty-stricken areas are at a greater risk for adverse birth outcomes. As a result of adverse experiences related to birth, mothers may experience levels of traumatic stress. To advocate for better pregnancy and birth outcomes, the intervention of doula support is emphasized. There is a widely recognized need to promote better pregnancy outcomes among African American women to address disproportionate birth outcomes. Strategies to enhance doula support among African American women with disabilities are offered. Implications include future research surrounding the development of a training program for doulas specific to disability, trauma-informed care, and maternal mental health.


What are cancer patients willing to pay for prophylactic epoetin alfa? A cost-benefit analysis.
Anemia, one of the most common complications of cancer chemotherapy, has been managed with red blood cell (RBC) transfusions. As an alternative, the agent epoetin alfa has the potential to reduce the transfusion requirements of patients receiving cancer chemotherapy. To estimate the value that cancer patients place on the drug, an economic analysis using the concept of willingness to pay (WTP) was conducted. The method of WTP was used within the framework of a classical cost-benefit analysis to estimate the net cost or benefit of administering prophylactic epoetin alfa to cancer patients. This estimate included the direct cost of epoetin alfa administration and savings secondary to reduced RBC transfusions. A cohort of 100 cancer patients who received or were scheduled to receive cisplatin or noncisplatin chemotherapy (50 per group) were then interviewed to measure the maximum WTP (net benefit) that they experienced with epoetin alfa. Regarding the benefits they would experience after 3 months of epoetin alfa administration, patients receiving cisplatin and noncisplatin therapy stated that they would be willing to pay an average of 587 U.S. dollars (U.S.$587) (95%CI: $300-$875) and U.S.$613 (95%CI: $324-$902), respectively. These benefits were then subtracted from the total cost of the drug when administered to patients receiving cisplatin (U.S.$3530) and noncisplatin (U.S.$3653) therapy. This produced a net incremental treatment cost of U.S.$2943 (95%CI: $2655-$3230) and U.S.$3039 (95%CI: $2750-$3328) for the respective treatment groups. The results of the current study suggest that the routine administration of epoetin alfa to cancer patients receiving myelosuppressive chemotherapy is a highly resource-intensive treatment policy with modest benefit to patients. Additional research is required to identify high risk patient subgroups who would benefit most from the drug. [See editorial on pages 2427-9, this issue.]


Kinetic analysis of DNA compaction by mycobacterial integration host factor at the single-molecule level.
Nucleoid-associated proteins (NAPs) play an important role on chromosome condensation and organization. Mycobacterial integration host factor (mIHF) is one of the few mycobacterial NAPs identified so far. mIHF has the ability to stimulate mycobacteriophage L5 integration and compact DNA into nucleoid-like or higher order filamentous structures by atomic force microscopy observation. In this study, M. smegmatis IHF (MsIHF), which possesses the sequence essential for mIHF's functions, binds 30-bp dsDNA fragments in a sequence-independent manner and displays sensitivity to ion strength in bio-layer interferometry (BLI) experiments. The DNA compaction process of MsIHF was observed at the single-molecule level using the total internal reflection fluorescence microscopy (TIRFM). MsIHF efficiently compacted λ DNA into a highly condensed structure with the concentration of 0.25 and 1.0 μM, and the packing ratios were higher than 10. Further kinetic analysis revealed MsIHF compacts DNA in a three-step mechanism, which consists of two compaction steps with different compacting rates separated by a lag step. This study would help us better understand the mechanisms of chromosomal DNA organization in mycobacteria.


Hereditary angioedema and aortitis.
A 28-year-old male with hereditary angioedema died of an extensive stroke. Autopsy revealed cicatricial aortitis with narrowing of the coronary ostia, myocardial infarctions, and a left ventricular mural thrombus. There was neither acute inflammation of the aorta nor systemic vasculitis. A possible association of the aortitis with the hereditary angioedema is discussed.


Predictability of drug release from cochlear implants.
A simplified mathematical theory is presented allowing for in silico simulation of the effects of key parameters of miniaturized implants (size and composition) on the resulting drug release kinetics. Such devices offer a great potential, especially for local drug treatments, e.g. of the inner ear. However, the preparation and characterization of these systems is highly challenging, due to the small system dimensions. The presented mathematical theory is based on Fick's second law of diffusion. Importantly, theoretical predictions do not require the knowledge of many system-specific parameters: Only the "apparent" diffusion coefficient of the drug within the implant matrix is needed. This parameter can be easily determined via drug release measurements from thin, macroscopic films. The validity of the theoretical model predictions was evaluated by comparison with experimental results obtained with a cochlear implant. The latter consisted of miniaturized electrodes, which were embedded in a silicone matrix loaded with various amounts of dexamethasone. Importantly, independent experimental results confirmed the theoretical predictions. Thus, the presented simplified theory can help to significantly speed up the optimization of this type of controlled drug delivery systems, especially if long release periods are targeted (e.g., several months or years). Straightforward experiments with thin, macroscopic films and computer simulations can allow for rapid identification of optimal system design.


STD program activity in state policy processes, 1995 and 2000.
Generating state policy support for sexually transmitted disease (STD) prevention is crucial; however, little is known about policy activity by STD programs. The goals of the study were to identify state-level policy behaviors by state STD programs and to examine the association between policy behavior and selected state characteristics. Information was gathered through a survey of STD directors in 2001. Policy activities were recalled for 1995 and 2000 and compared with several state characteristics. A majority of state STD programs reported at least one policy behavior in the state policy process for 1995 and for 2000. An increase was observed with the provision of state legislative testimony, participation in STD coalitions, and dissemination of information to policy-makers by STD programs. Reported policy activity may be evidence of an emerging environment enabling state STD directors to engage in public policy activity. An opportunity exists to improve state and local support for STD prevention.


[Exceptionally good response to sodium valproate in patients with recurrent Sydenham's chorea].
Sydenham's chorea is the most common acquired cause of chorea in the third world. We report a case of recurrent chorea successfully treated with sodium valproate. Miss A.C, aged 16, with a history of recurrent angina reported an episode of choreic movements 2 years before requiring treatment with haloperidol and prevention of rheumatic fever. The patient interrupted her treatment with occurrence of a relapse a few months later. Brain MRI and transthoracic ultrasound were normal. Preventive treatment with extencilline and haloperidol was restarted without any improvement, hence the treatment with sodium valproate. The patient responded very well after 2 months of treatment, without recurrence at 3 years' follow-up. The treatment of Sydenham's chorea was based on neuroleptics. Recent studies advocate the use of other more effective and better tolerated molecules.


Imaging in Tumor Immunology.
Recent advances in immune modulation have made impressive progress in cancer immunotherapy. Because dynamic nature of the immune response often makes it difficult to evaluate therapeutic outcomes, innovative imaging technologies have been developed to enable non-invasive visualization of immune cells and tumors in their microenvironment. This review summarizes the current tumor immunology and describes new innovative imaging methods with great potential to obtain non-invasive real-time insights into the complex functions of the immune system and into the management of cancer immunotherapy.


Hepatitis B virus whole-X and X protein play distinct roles in HBV-related hepatocellular carcinoma progression.
The role of HBV X protein (HBx) in the development of hepatocellular carcinoma (HCC) has been well studied. However, little is known about the molecular functions of HBV whole-X protein (HBwx), a protein fused with HBx and upstream 56 amino acid, in HCC. In current study, the molecular functions of HBwx in HCC pathogenesis has been investigated, as well as comparison between HBwx and HBx. Expression of HBwx and HBx in 50 HCC tissues was examined by immunohistochemistry. Their tumor-forming abilities were evaluated by an animal model and colony formation assay. Migration and invasion were detected by transwell assay and subcellular localization was tracked by GFP fluorescence. Cell proliferation, cell cycle and apoptosis were detected by CCK8 and FCM. Protein level was determined by Western blotting. HBwx was present in 72 % (36/50) of the liver tumor tissues and mainly expressed in the nucleus and deposited in the cytoplasm surrounding karyotheca. HBwx showed a promoting effect on tumorigenesis and growth in vivo and in vitro as well as cell migration and invasion, whilst such effect is compromised compared with that of HBx. Further analysis demonstrated differences in cell proliferation, cell cycle and cell apoptosis between cells expressing HBwx and those expressing HBx. Additionally, it was confirmed that RKIP-p-ERK pathway was involved in HBwx-related tumor formation. HBwx, with the extra 56 amino acids, is closely related with hepatocarcinogenesis, while displays different biological functions from HBx.


Retrospective analysis of high-intensity focused electromagnetic procedure synchronized with radiofrequency energy for visceral fat reduction.
Visceral adipose tissue (VAT), present in the abdominal cavity, oftentimes contributes to an unpleasant aesthetic appearance and can be correlated with serious health issues. High-intensity focused electromagnetic field (HIFEM) technology with synchronized radiofrequency (RF) was recently used for abdominal body shaping through subcutaneous fat reduction and muscle growth. This study aimed to assess the effect of HIFEM + RF technology on VAT tissue. Data of 16 men and 24 women (22-62 years, 21.2-34.3 kg/cm2 ) from the original study were retrospectively reviewed. All subjects received three 30-min HIFEM + RF abdominal treatments once weekly for three consecutive weeks. The VAT area was measured in the axial plane of MRI scans at two levels: L4-L5 vertebrae and 5 cm above this level. The VAT was identified, segmented, and calculated, yielding total area in square centimeters per scan at both specified levels. By thoughtful review of the subject's post-treatment MRI scans, no other changes in the abdominal cavity were found except for VAT. The evaluation showed a VAT reduction of 17.8% (p < 0.001) on average at 3-month follow-up, maintaining the results up to 6 months (-17.3%). Averaging the values obtained from both measured levels, the VAT, occupied an area of 100.2 ± 73.3 cm2 at the baseline. At the 3-month follow-up, the subjects achieved an average reduction of 17.9 cm2 , preserving the results at 6 months (-17.6 ± 17.3 cm). This retrospective analysis of MRI images objectively documented the effect of HIFEM + RF abdominal therapy on VAT. The data indicates considerable VAT reduction without serious adverse events following the HIFEM + RF procedure.


Creatine and cyclocreatine treatment of human colon adenocarcinoma xenografts: 31P and 1H magnetic resonance spectroscopic studies.
Creatine (Cr) and cyclocreatine (cyCr) have been shown to inhibit the growth of a variety of human and murine tumours. The purpose of this study was to evaluate the anti-tumour effect of these molecules in relation to drug accumulation, energy metabolism, tumour water accumulation and toxicity. Nude mice carrying a human colon adenocarcinoma (LS174T) with a creatine kinase (CK) activity of 2.12 units mg(-1) protein were fed Cr (2.5% or 5%) or cyCr (0.025%, 0.1% or 0.5%) for 2 weeks and compared with controls fed standard diet. Cr concentrations of 2.5% and 5% significantly inhibited tumour growth, as did 0.1% and 0.5% cyCr. In vivo 31P magnetic resonance spectroscopy (MRS) after 2 weeks of treatment showed an increase in [phosphocreatine (PCr)+phosphocyclocreatine (PcyCr)]/nucleoside triphosphate (NTP) with increasing concentrations of dietary Cr and cyCr, without changes in absolute NTP contents. The antiproliferative effect of the substrates of CK was not related to energy deficiency but was associated with acidosis. Intratumoral substrate concentrations (measured by 1H-MRS) of 4.8 micromol g(-1) wet weight Cr (mice fed 2.5% Cr) and 6.2 micromol g(-1) cyCr (mice fed 0.1% cyCr) induced a similar decrease in growth rate, indicating that both substrates were equally potent in tumour growth inhibition. The best correlant of growth inhibition was the total Cr or (cyCr+Cr) concentrations in the tissue. In vivo, these agents did not induce excessive water accumulation and had no systemic effects on the mice (weight loss, hypoglycaemia) that may have caused growth inhibition.


Engineering CAR-T cells to activate small-molecule drugs in situ.
Chimeric antigen receptor (CAR)-T cells represent a major breakthrough in cancer therapy, wherein a patient's own T cells are engineered to recognize a tumor antigen, resulting in activation of a local cytotoxic immune response. However, CAR-T cell therapies are currently limited to the treatment of B cell cancers and their effectiveness is hindered by resistance from antigen-negative tumor cells, immunosuppression in the tumor microenvironment, eventual exhaustion of T cell immunologic functions and frequent severe toxicities. To overcome these problems, we have developed a novel class of CAR-T cells engineered to express an enzyme that activates a systemically administered small-molecule prodrug in situ at a tumor site. We show that these synthetic enzyme-armed killer (SEAKER) cells exhibit enhanced anticancer activity with small-molecule prodrugs, both in vitro and in vivo in mouse tumor models. This modular platform enables combined targeting of cellular and small-molecule therapies to treat cancers and potentially a variety of other diseases.


Expression and Localization of Connexins in the Outer Retina of the Mouse.
The identification of the proteins that make up the gap junction channels between rods and cones is of crucial importance to understand the functional role of photoreceptor coupling within the retinal network. In vertebrates, connexin proteins constitute the structural components of gap junction channels. Connexin36 is known to be expressed in cones whereas extensive investigations have failed to identify the corresponding connexin expressed in rods. Using immunoelectron microscopy, we demonstrate that connexin36 (Cx36) is present in gap junctions of cone but not rod photoreceptors in the mouse retina. To identify the rod connexin, we used nested reverse transcriptase polymerase chain reaction and tested retina and photoreceptor samples for messenger RNA (mRNA) expression of all known connexin genes. In addition to connexin36, we detected transcripts for connexin32, connexin43, connexin45, connexin50, and connexin57 in photoreceptor samples. Immunohistochemistry showed that connexin43, connexin45, connexin50, and connexin57 proteins are expressed in the outer plexiform layer. However, none of these connexins was detected at gap junctions between rods and cones as a counterpart of connexin36. Therefore, the sought-after rod protein must be either an unknown connexin sequence, a connexin36 splice product not detected by our antibodies, or a protein from a further gap junction protein family.


Are COPD patients with nocturnal REM sleep-related desaturations more prone to developing chronic respiratory failure requiring long-term oxygen therapy?
Nocturnal oxygen desaturations (NOD), especially during REM sleep, have been described in patients with COPD. However, the role of NOD in the evolution of COPD to chronic respiratory failure has not been well studied. The aim of our study was to evaluate whether NOD is a risk factor for the development of chronic respiratory failure in COPD patients. We studied 34 consecutive COPD patients with a stable daytime PaO(2) >60 mm Hg over a period of 42 months. We classified patients as desaturators (NOD) when episodic desaturations were found mainly during REM sleep, independently of baseline SaO(2) values. At enrollment 19 patients (55.8%) had NOD. Over the follow-up period, 10 patients (29.4%) were included in a long-term oxygen therapy (LTOT) programme (9 were desaturators). The LTOT was initiated a median time of 22 +/- 6.8 months after enrollment. Patients who were subsequently prescribed LTOT had lower values of FEV(1) at enrollment, with a higher degree of NOD and PaCO(2). Stable respiratory failure developed earlier in patients with NOD: the two enrollment curves for LTOT differed significantly (log-rank test 2.56, p = 0.005). PaCO(2), NOD and FEV(1) were statistically significantly associated, both in univariate and multivariate Cox proportional hazards analyses, with an increased risk of entering a LTOT programme. We conclude that NOD may represent an independent risk factor for the development of chronic respiratory failure in COPD patients with daytime PaO(2) >60 mm Hg. A larger study is needed to confirm the role of NOD in the natural history of COPD and subsequently to identify the most appropriate therapeutic approach.


OUTBREAK OF SALMONELLA FOOD POISONING AT HIGH ALTITUDE.
An outbreak of food poisoning occurred among soldiers of an army unit located at high altitude (3300m) in western Himalayas. A total of 78 of the 103 soldiers who had consumed the incriminated meal suffered from the illness. Sixteen of the 78 had symptoms severe enough to warrant admission to hospital. The symptoms consisted of diarrhoea, vomiting, fever, headache, vertigo and abdominal cramps of varying intensity. Salmonella enteritidis was isolated from 6 stool samples and in one blood sample. Epidemiologically, frozen fowl was traced as the probable incriminating food agent responsible for the outbreak. This is probably the first such outbreak being reported from high altitude. It is of significance for the Indian Armed Forces, as the cause of the food poisoning was traced to an inherent shortcoming in the supply of food items to the troops located in far flung and isolated regions and in the cooking practices being followed.


HPV vaccination coverage in French girls attending middle and high schools: a declarative cross sectional study in the department of Côte d'Or.
To assess human papillomavirus prophylactic vaccine coverage among a representative population of French girls, aged 14 years and above, attending middle and high schools, and to determine factors associated with the initiation and completion of the vaccination protocol. This cross-sectional study, designed with cluster sampling, was conducted from October 2010 to May 2011, in 29 schools in the department of Côte d'Or, France. The schools were randomized according to their status (public or private) and location (rural or urban). Two classes per level were then included. All analyses were stratified on age. 948 questionnaires were collected (87.9% participation). Mean age was 15.2 years (SD=1.3), ranging between 14 and 19. Only 31.7% of 14-year-old girls and 61.4% of girls aged 15 and above initiated vaccination (one dose), and 7.8% of 14-year-old girls and 48.5% of girls aged 15 and above completed it (three doses). An urban school location and a physician's recommendation were independently associated with vaccination initiation in girls aged 14. In girls aged 15 and above, the parents' socioeconomic status, the family composition and a recommendation by a physician were independently associated with vaccination initiation. Once vaccination had been initiated, girls who attended private school, who belonged to families with higher outcomes, who lived with a single parent or who smoked were less likely to complete the vaccination protocol. HPV prophylactic vaccine coverage in girls attending school in Côte d'Or appears to be low. Physicians play a major role in vaccine acceptance.


Increased carbon monoxide production in patients with cirrhosis with and without spontaneous bacterial peritonitis.
Carbon monoxide, a product of the heme-oxygenase (HO) pathway, is an important endogenous vasoactive substance. Production of CO has not been assessed in human cirrhosis. The aim of this study was to assess production of CO in patients with cirrhosis with and without spontaneous bacterial peritonitis (SBP). CO concentration in the exhaled air and blood carboxyhemoglobin (COHb) levels, as estimates of total HO activity, were determined in 16 healthy subjects, 32 noninfected cirrhotic patients (20 with ascites), and 19 patients with SBP, all nonsmokers. Noninfected cirrhotic patients had a CO concentration in the exhaled air and COHb levels significantly higher compared with values of healthy subjects (2.3 +/- 0.2 ppm vs. 0.7 +/- 0.1 ppm and 1.0% +/- 0.1% vs. 0.6% +/- 0.1%, respectively; P <.05 for both). Patients with ascites had the highest values. Both CO concentration in the exhaled air and COHb levels were very high in patients with SBP (5.6 +/- 0.6 ppm and 1.9% +/- 0.2%; P <.01 vs. the other 2 groups) and decreased slowly after resolution of the infection, reaching values similar to those of noninfected patients 1 month after SBP. In patients with SBP, there was a significantly direct correlation between CO and plasma renin activity (PRA) (r = 0.71, P <.001). In conclusion, these results support the existence of increased CO production in human cirrhosis, which further increases in the setting of SBP. Increased CO production may participate in the disturbance of circulatory function that occurs during severe bacterial infections in cirrhosis.


Transcriptomic analysis of loss of Gli1 in neural stem cells responding to demyelination in the mouse brain.
In the adult mammalian brain, Gli1 expressing neural stem cells reside in the subventricular zone and their progeny are recruited to sites of demyelination in the white matter where they generate new oligodendrocytes, the myelin forming cells. Remarkably, genetic loss or pharmacologic inhibition of Gli1 enhances the efficacy of remyelination by these neural stem cells. To understand the molecular mechanisms involved, we performed a transcriptomic analysis of this Gli1-pool of neural stem cells. We compared murine NSCs with either intact or deficient Gli1 expression from adult mice on a control diet or on a cuprizone diet which induces widespread demyelination. These data will be a valuable resource for identifying therapeutic targets for enhancing remyelination in demyelinating diseases like multiple sclerosis.


Chylomicron synthesis by intestinal cells in vitro and in vivo.
Synthesis and secretion of chylomicrons by the intestine is essential to transport dietary fats in the circulation and to deliver these fats to the appropriate peripheral tissues. The assembly of chylomicrons within the enterocyte and the subsequent secretion of these lipoprotein particles into the lymph is a complex, multi-step process that includes absorption of lipids by the enterocytes, cellular lipid (re)synthesis and translocation of cellular lipid pools, synthesis and post-translational modification of various apolipoproteins and, finally, the assembly of lipid and lipoprotein components into a chylomicron. The key process in chylomicron synthesis is the intracellular association of apolipoprotein (apo)B48, the structural protein of chylomicrons, with lipids.


Computationally designed antibody-drug conjugates self-assembled via affinity ligands.
Antibody-drug conjugates (ADCs) combine the high specificity of antibodies with cytotoxic payloads. However, the present strategies for the synthesis of ADCs either yield unstable or heterogeneous products or involve complex processes. Here, we report a computational approach that leverages molecular docking and molecular dynamics simulations to design ADCs that self-assemble through the non-covalent binding of the antibody to a payload that we designed to act as an affinity ligand for specific conserved amino acid residues in the antibody. This method does not require modifications to the antibody structure and yields homogenous ADCs that form in less than 8 min. We show that two conjugates, which consist of hydrophilic and hydrophobic payloads conjugated to two different antibodies, retain the structure and binding properties of the antibody and its biological specificity, are stable in plasma and improve anti-tumour efficacy in mice with non-small cell lung tumour xenografts. The relative simplicity of the approach may facilitate the production of ADCs for the targeted delivery of cytotoxic payloads.


Utility of 3D T1-weighted turbo spin echo black blood sequence for the diagnosis of cerebral venous thrombosis.
Accurate assessment of dural sinus, deep and cortical venous thrombosis on MR imaging is challenging. The aim of this study is to evaluate the accuracy of 3D-T1 turbo spin echo (T1S), sequences in detecting venous thrombosis and comparing it with susceptibility-weighted imaging (SWI), magnetic resonance venography (MRV) and post contrast T1 magnetization-prepared rapid acquisition gradient echo (T1C). A blinded retrospective observational analysis of 71 consecutive patients evaluated for cerebral venous thrombosis (CVT) and 30 control patients was performed. Multimodality reference standard adopted included T1C, SWI with MRV. Sub-analyses in superficial, deep and cortical venous segments were performed in addition to correlation of signal intensity of thrombus with the clinical stage. A total of 2222 segments in 101 complete MRI examinations were evaluated. Sensitivity/specificity/positive predictive value/negative predictive value/accuracy and precision of T1S for detection of cortical vein thrombosis was 0.994/1/1/0.967/0.995/1, 1/0.874/0.949/1/0.963/0.950 for detection of superficial venous sinus thrombosis and 1/1/1/1/1/1 for deep venous thrombosis. The AUC yield for T1S was 0.997 for cortical, 1 for deep and 0.988 for superficial venous segments. T1S paralleled the accuracy of conventional sequences in the overall detection of CVT but showed superior accuracy in the detection of cortical venous thrombosis. It makes a fitting addition to the CVT MRI protocol in scenarios demanding negation of gadolinium administration.


Effects of Lag Time on Performance on ARRT's Primary Certification and Registration Exams.
To investigate how lag time between graduation from an education program and exam date influenced candidates' performance on the American Registry of Radiologic Technologists (ARRT) certification and registration exams for radiography, nuclear medicine technology, radiation therapy, and magnetic resonance imaging. Data for this quasi-experimental study were obtained for 39 898 candidates taking the 4 certification and registration exams from January 1, 2017, to December 31, 2019. Comparisons were made between candidates who took their certification exam within 8 weeks of graduation and candidates who waited 9 to 16 weeks after program completion. All 4 exams had a significant decrease in their total scaled scores and content category-scaled scores on 4 exams from the first 8 weeks after program completion to the subsequent 8 weeks. These results should encourage students to take their ARRT certification and registration exam as soon as possible after program completion, ideally within 8 weeks. Taking certification and registration exams soon after program completion can benefit students as well as the education programs from which they graduated because specialized-accredited programs must document ARRT pass rates with a minimum 5-year average of 75% or higher.


Oral malodour--a review.
Halitosis is a very common condition which may affect up to 30% of the population. In most cases the aetiology of the condition is from local oral causes (oral malodour). Oral malodour is the result of the action of anaerobic bacteria in producing a range of malodorous molecular species including volatile sulphur compounds. Whilst malodour is often associated with the presence of periodontitis, in many cases there is no such link, and the evidence points to the importance of these anaerobic bacteria in tongue coatings which results in the clinical presentation of oral malodour. Management of oral malodour is directed at managing and reducing the bacterial load both in periodontitis and in tongue coatings by instituting proper oral hygiene measures, control of tongue flora by brushing or scraping, and possibly the adjunctive use of antiseptic agents. Treatments have also been proposed to neutralise malodorous compounds by chemical agents to mask the presence of the condition. Further evidence is required to demonstrate the long-term efficacy of therapies for this troublesome condition.


Machine learning model for anti-cancer drug combinations: Analysis, prediction, and validation.
Drug combination therapy is a highly effective approach for enhancing the therapeutic efficacy of anti-cancer drugs and overcoming drug resistance. However, the innumerable possible drug combinations make it impractical to screen all synergistic drug pairs. Moreover, biological insights into synergistic drug pairs are still lacking. To address this challenge, we systematically analyzed drug combination datasets curated from multiple databases to identify drug pairs more likely to show synergy. We classified drug pairs based on their MoA and discovered that 110 MoA pairs were significantly enriched in synergy in at least one type of cancer. To improve the accuracy of predicting synergistic effects of drug pairs, we developed a suite of machine learning models that achieve better predictive performance. Unlike most previous methods that were rarely validated by wet-lab experiments, our models were validated using two-dimensional cell lines and three-dimensional tumor slice culture (3D-TSC) models, implying their practical utility. Our prediction and validation results indicated that the combination of the RTK inhibitors Lapatinib and Pazopanib exhibited a strong therapeutic effect in breast cancer by blocking the downstream PI3K/AKT/mTOR signaling pathway. Furthermore, we incorporated molecular features to identify potential biomarkers for synergistic drug pairs, and almost all potential biomarkers found connections between drug targets and corresponding molecular features using protein-protein interaction network. Overall, this study provides valuable insights to complement and guide rational efforts to develop drug combination treatments.


[Modern surgery of meningiomas affecting anterior visual pathways].
Meningiomas are the most common form of primary intracranial tumors. If the anterior visual pathways are affected clinical visual compromise, visual field defects, oculomotor nerve disturbances or propotosis are predominant. Meningiomas of the anterior visual pathway remain therapeutically challenging due to the direct anatomical relationship to the circulus arteriosus cerebri, the cavernous sinus and cranial nerves. The therapy of choice is microsurgical resection. In many cases a curative approach can be achieved with modern surgical techniques and simultaneously maintaining patient quality of life. Problematic are cases in which resection would be associated with the risk of clinical impairment and in these cases radiotherapy is an important therapeutic option. In cases involving complex invasiveness an interdisciplinary treatment to control local clinical symptoms is favored.


Expanding the valorization of waste mushroom substrates in agricultural production: progress and challenges.
Waste mushroom substrate (WMS) generated in large quantities from mushroom production process has caused severe environmental pollution. As a sustainable resource, the valorization of WMS in the agricultural field has attracted attention due to the abundant active components. A comprehensive review of valorization of WMS in agricultural production is meaningful to promote the further utilization of this resource. This paper provided an overview of the valorization in sustainable agricultural production using WMS, including animal and crop farming improvement, and agricultural environmental restoration. Moreover, the limitations and the possible development directions of WMS in agricultural production were discussed. Different sustainable cycle models for WMS in agricultural production were proposed. The aim of this review is to provide a feasible solution for the favorable treatment of WMS and improvement of agricultural production quality.


Insomnia symptoms and daytime function in stable heart failure.
To evaluate insomnia symptoms and the extent to which they are associated with clinical and demographic patient characteristics, daytime symptoms, and functional performance in patients with stable heart failure (HF). Cross-sectional, observational. Five structured HF disease management programs in the Northeastern U.S. 173 stable chronic HF patients N/A. Full polysomnography was obtained for one night in participants' homes. Participants completed the six-minute walk test, Medical Outcomes Study SF-36, Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Multi-Dimensional Assessment of Fatigue Scale, Centers for the Epidemiological Studies of Depression Scale, and questionnaire items eliciting insomnia symptoms (self-reported difficulty initiating and maintaining sleep and waking too early in the morning). Over half of HF patients reported insomnia symptoms. These were associated with increased daytime symptoms (depression, fatigue), excessive daytime sleepiness, and functional performance in models that statistically controlled for clinical and demographic covariates. These relationships were not explained by sleep disordered breathing. Insomnia symptoms are common in patients with stable heart failure and are associated with daytime symptoms and decrements in functional performance.


[The "chapeau-claque" mechanism. Biomechanical aspects of roentgen diagnosis of vertebral fractures].
During follow-up examinations of patients with fractures of the spine at the Inner City Surgical Clinic in Munich, particular attention was paid to the problem of the diagnosis of fractures of the dorsal edges of vertebral bodies. Repeatedly we found a kind of a deformation resembling collapse or folding up of a "chapeau claque" top hat.


[Community-acquired methicillin resistant Staphylococcus aureus skin and soft tissue infections in Madrid: prevalence study].
Since it was first described in the 1990s, Methicillin-Resistant Staphylococcus aureus infection among people with no contact with a hospital setting or with no traditional risk factors, has spread worldwide and is now an important epidemiological and public health problem. The present prospective and observational study was carried out from April to November 2010. All adult patients with community-acquired suppurative skin and soft tissue infection (SSTI) attending the Emergency Department were enrolled. Clinical, microbiological and epidemiological features of the infection were assessed. A total of 59 samples were collected from 59 patients and CA-MRSA was isolated in 13 of them. Prevalence of CA-MRSA in patients with suppurative SSTI seen in the emergency department was 22.03%, and was 33.3% in patients with staphylococcal infection. Is worth noting the greater presence of necrosis detected in CA-MRSA lesions. Only 3 patients required hospital admission. Eleven of the 13 strains were Panton-Valentine leucocidin producers, and 5 were resistant to non-betalactam antibiotics. CA MRSA infection is still more frequent in the immigrant population. Data on CA-MRSA prevalence in Spain are sparse. This study aims to emphasise the current importance of this emergent pathogen in our area. About one third of suppurative staphylococcal SSTI presenting in our emergency department are caused by this agent, confirming a rapid spread in our country. Some clinical features, such as the high presence of necrosis, are closely related to CA-MRSA.


Fading time of retinally-stabilized images as a function of background luminance and target width.
Fading time of a retinally-stabilized difference-of-Gaussian (DOG) stimulus depends on the background luminance, contrast and spatial frequency content of the stimulus. A model of the visual system including a nonlinear multiplicative, non-local and fast process followed by a linear subtractive, local and slower process accounts for these effects. Analysis of the fading time data allows us to estimate the spatiotemporal characteristics of the proposed adaptation processes. The model is consistent with recent models of normal light adaptation from the probe-flash paradigm.


HHV-6 and seizure: A systematic review and meta-analysis.
Human herpesvirus-6 (HHV-6) is a common infection in childhood. This systematic review aims to assess the relationship between HHV-6 infection and seizure disorders based on available literature. MEDLINE database was searched using a search strategy. We included studies that were published after 1993 in English, and described patients with HHV-6 infection and accompanying seizure or status epilepticus. We identified 503 articles, and included 147 studies. Meta-analysis results showed a 0.21 detection rate of HHV-6 in febrile seizure patients. In the febrile seizure group (110 cases), 76 patients had simple and 34 had complex febrile seizures. Patients with "HHV-6 infection and status epilepticus" had a mean age of 16.24 months. In children with febrile illnesses, a higher index of clinical suspicion for HHV-6 infection may be required. Further studies including CSF and brain tissue may be needed to validate relationships between HHV6 infection and epilepsy. J. Med. Virol. 89:161-169, 2017. © 2016 Wiley Periodicals, Inc.


Batch control system vaccines: BCSV : A new man machine interface for bioreactors.
The Batch Control System for Vaccines (BCSV), a new Man Machine Interface (MMI) for the control of cultivations in bioreactors, was developed according to SP-88. SP-88 is the ISA standard for Batch Control Systems. Among others, SP-88 supplied the concept of recipes, which organize and specify the monitoring and control requirements for manufacturing. Process optimisation and compliance to GMP rules and regulations were the main objectives for this development.The most important features of the BCSV interface include: - implementation at production, pilot and R & D scale to assure easy transfer of knowledge and experience at the various stage of process development; - independency of underlying hardware to ensure similar "look and feel" for different pieces of equipment; - in-house development and maintenance of recipes to have maximum control over applications; - interactive communication between operator and BCSV during recipe execution. GMP compliance was assured not only by considering governing sets of GMP regulations, but also by taking up the interface in a overall Information & Automation strategy and by setting up a QA strategy for the entire life cycle of the system.


Correlation between hematological profile and theileriosis in Bali cattle from Muara Bulian, Jambi, Indonesia.
Theileriosis is a parasitic disease caused by the hemoprotozoan Theileria spp. The main transmission route of this disease is through tick vector bite. Theileriosis causes economic losses in livestock such as Bali cattle. This study aims to analyze the prevalence of theileriosis and its correlation with the hematological profile of Bali cattle from the subdistrict of Muara Bulian, Batang Hari, Jambi, Indonesia. Ninety-four blood samples were collected through jugular vein of Bali cattle. The presence of Theileria spp. was determined using blood smear. Routine blood tests and double-staining immunohistochemistry against CD4+ and CD8+ lymphocytes were conducted on all blood samples. A total of 34.04% of the samples were infected by Theileria spp. Theileriosis affected only hemoglobin level (p<0.05); it did not affect the other parameters of the hematological profile (p>0.05). However, it also decreased CD4+ and CD4+/CD8+ ratio (p<0.05), besides increasing CD8+ (p<0.05). Theileriosis does not change the hematological profile of Bali cattle except for the hemoglobin levels. Moreover, it promotes T-cell depletion.


Fluorescent redox-dependent labeling of lipid droplets in cultured cells by reduced phenazine methosulfate.
Natural and synthetic phenazines are widely used in biomedical sciences. In dehydrogenase histochemistry, phenazine methosulfate (PMS) is applied as a redox reagent for coupling reduced coenzymes to the reduction of tetrazolium salts into colored formazans. PMS is also currently used for cytotoxicity and viability assays of cell cultures using sulfonated tetrazoliums. Under UV (340 nm) excitation, aqueous solutions of the cationic PMS show green fluorescence (λem: 526 nm), whereas the reduced hydrophobic derivative (methyl-phenazine, MPH) shows blue fluorescence (λem: 465 nm). Under UV (365 nm) excitation, cultured cells (LM2, IGROV-1, BGC-1, and 3T3-L1 adipocytes) treated with PMS (5 μg/mL, 30 min) showed cytoplasmic granules with bright blue fluorescence, which correspond to lipid droplets labeled by the lipophilic methyl-phenazine. After formaldehyde fixation blue-fluorescing droplets could be stained with oil red O. Interestingly, PMS-treated 3T3-L1 adipocytes observed under UV excitation 24 h after labeling showed large lipid droplets with a weak green emission within a diffuse pale blue-fluorescing cytoplasm, whereas a strong green emission was observed in small lipid droplets. This fluorescence change from blue to green indicates that reoxidation of methyl-phenazine to PMS can occur. Regarding cell uptake and labeling mechanisms, QSAR models predict that the hydrophilic PMS is not significantly membrane-permeant, so most PMS reduction is expected to be extracellular and associated with a plasma membrane NAD(P)H reductase. Once formed, the lipophilic and blue-fluorescing methyl-phenazine enters live cells and mainly accumulates in lipid droplets. Overall, the results reported here indicate that PMS is an excellent fluorescent probe to investigate labeling and redox dynamics of lipid droplets in cultured cells.


First molecular detection of Leishmania major within naturally infected Phlebotomus salehi from a zoonotic cutaneous leishmaniasis focus in southern Iran.
Human cutaneous leishmaniasis (CL) is a major notifiable public health problem in many parts of Iran. It is often caused by the zooflagellate parasite Leishmania major which is mainly transmitted by the bites of female phlebotomine sandflies belonging to the genus Phlebotomus (Diptera: Psychodidae). The annual incidence of CL in Fars province, southern Iran, was about 108-144 in 2007. The leishmanial infections of wild sandflies that may act as vectors were thus investigated at an endemic focus in this province. In all 330 female Phlebotomus sandflies were screened for the detection of Leishmania-specific kinetoplast DNA (kDNA) by polymerase chain reaction (PCR) methods. A two stage nested PCR protocol was used to establish the identity of Leishmania major species in naturally infected sandflies. The L. major kDNA was detected in 18 (5.5%) individual sandflies which belonged to four different Phlebotomus species (Phlebotomus papatasi, Phlebotomus salehi, Phlebotomus sergenti and P. major group). For the first time, one naturally infected P. salehi specimen contained the kDNA of the protozoan parasite, L. major, with a main band of 560 base pairs identified using the nested PCR method. It seems most likely therefore that P. salehi is potentially a rare sylvatic vector of L. major parasites in parts of this province. This is the first combined morphological and molecular studies of P. salehi in Iran.


[Experimental study of the effect of the association of hyperthermia and BCNU on solid sarcoma 180 in C3H mice. Development of tumor volume, survival and rate of cure].
The authors describe the experimental results of administering BCNU combined with hyperthermia upon the growth of sarcoma 180 of the mouse. Best results were obtained employing the combined therapy than using BCNU or hyperthermia alone, and hyperthermia was necessary in all cases where a curative effect was attained.