[The neuronal organization of the amygdala-visceral reflex arch].
The paper summarizes the histomorphic, histochemical, autoradiographic, immune-histochemical and electrophysiological data on the structural-functional organization of the amygdalar complexes. While discussing the problem of neuron organization of the afferent and efferent groups in the amygdala-visceral arch the authors present their data of microelectrophysiological studies of the specific amygdala neuron reactions in response to stimulation of the vagus, ventric, and sciatic nerves, and of the second somatic sensor cortex zone. It was observed that interoceptive impulsation reaching the polysensor neurons of the central, corticomedial, and basolateral groups of the amygdala complex nuclei have no significant qualitative differences. A series of experiments demonstrated that the polysensor convergent amygdala neurons are also polyeffectoral. Comparative studies of the sympathetic discharges in the white connecting branches produced by stimulation of the above nuclear amygdala groups, confirmed absence of a clear topographic localization of the sympatho-activating structures within an amygdala. Comparative exploration of the parasympathetic discharges in the pelvis nerve discovered a discharge of complex configuration in response to simulation of the pelvis nerve nuclei. There was no notable topographic localization of the amygdala parasympathoactivating structures. The system's arterial pressure was studied in response to stimulation of various amygdala structures. Low-frequency stimulation (5 Hertz) of all amygdala structures produces depressor reactions, high-frequency stimulation (100 Hertz) produces pressor reactions. Microelectrophysiological data are provided on the specific reactions of the inspiration and expiration neurons of the bulbar respiratory centre under frequency stimulation of various amygdala structures. The authors have concluded that the bulbar-spinal mechanisms regulating the vegetative functions are implemented by polysensoral-polyeffectoral integrative amygdala neurons of the convergent-divergent type. Consequently, there are no separate populations of the sympatho-activating and parasympathoactivation neurons and of the selective structures regulating the respiratory and the cardiovascular functions.


Machine Learning-Enabled Pipeline for Large-Scale Virtual Drug Screening.
Virtual screening is receiving renewed attention in drug discovery, but progress is hampered by challenges on two fronts: handling the ever-increasing sizes of libraries of drug-like compounds and separating true positives from false positives. Here, we developed a machine learning-enabled pipeline for large-scale virtual screening that promises breakthroughs on both fronts. By clustering compounds according to molecular properties and limited docking against a drug target, the full library was trimmed by 10-fold; the remaining compounds were then screened individually by docking; and finally, a dense neural network was trained to classify the hits into true and false positives. As illustration, we screened for inhibitors against RPN11, the deubiquitinase subunit of the proteasome, and a drug target for breast cancer.


In situ synthesis of magnetite nanoparticles in carrageenan gels.
Magnetite nanoparticles have been successfully synthesized in the presence of carrageenan polysaccharides using an in situ coprecipitation method. Iron coordination to the sulfate groups of the polysaccharide was confirmed by FTIR. The polysaccharide type (kappa, iota, or lambda) and concentration have been varied and their effects on particle morphology and chemical stability of the resultant nanocomposite investigated. The presence of carrageenan induces the formation of smaller particles, compared to those formed in the absence of polymer, and their average size depends on the nature and concentration of the polysaccharide used. The chemical stability of magnetite nanoparticles toward oxidation was also seen to depend on biopolymer type with magnetite formed in iota-carrageenan showing the highest chemical stability. A general tendency toward lower stability is observed as the polysaccharide concentration is increased. It is suggested that magnetite chemical stability in the carrageenan composites is determined by a fine balance between particle size and gel strength, the latter determining oxygen diffusion rates through the medium.


Cellular remodeling in heart failure disrupts K(ATP) channel-dependent stress tolerance.
ATP-sensitive potassium (K(ATP)) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K(ATP) channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor alpha induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K(ATP) channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K(ATP) channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by K(ATP) channel openers. Thus, disease-induced K(ATP) channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy.


The efficacy of Trauma Management Therapy: A controlled pilot investigation of a three-week intensive outpatient program for combat-related PTSD.
Despite the 8-18.5% of returning Operation Iraqi Freedom (OIF), Operation Enduring Freedom (OEF) and Operation New Dawn (OND) veterans who are suffering from posttraumatic stress disorder (PTSD), few receive empirically supported treatments. Among those that do, the dropout rate is high and more than 50% retain their diagnosis after treatment. This study evaluated the efficacy of Trauma Management Therapy (TMT), delivered in a 3-week intensive outpatient (IOP) format. TMT combines virtual-reality augmented individual exposure therapy with a group intervention to address social isolation, anger, and depression. One hundred twelve (112) OIF/OEF/OND veterans and active duty personnel participated. Assessment included measures of PTSD, sleep, depression, anger, guilt, and social isolation, administered at post-treatment, 3-month, and 6-month follow-up. The effect size for TMT delivered in an IOP format was 2.06, with 65.9% no longer meeting diagnostic criteria for PTSD. There were similar positive effects in other domains and treatment gains were maintained at 6-month follow-up. The results are discussed regarding the need for efficacious, multi-component interventions that can be delivered safely and rapidly, and the potential of this approach towards that end.


Unifying model for the electrokinetic and phase behavior of aqueous suspensions containing short and long amphiphiles.
Aqueous suspensions containing oppositely charged colloidal particles and amphiphilic molecules can form fluid dispersions, foams, and percolating gel networks, depending on the initial concentration of amphiphiles. While models have been proposed to explain the electrokinetic and flotation behavior of particles in the presence of long amphiphilic molecules, the effect of amphiphiles with less than six carbons in the hydrocarbon tail on the electrokinetic, rheological, and foaming behavior of aqueous suspensions remains unclear. Unlike conventional long amphiphiles (≥10 carbons), short amphiphiles do not exhibit increased adsorption on the particle surface when the number of carbons in the molecule tail is increased. On the basis of classical electrical double layer theory and the formerly proposed hemimicelle concept, we put forward a new predictive model that reconciles the adsorption and electrokinetic behavior of colloidal particles in the presence of long and short amphiphiles. By introducing in the classical Gouy-Chapman theory an energy term associated with hydrophobic interactions between the amphiphile hydrocarbon tails, we show that amphiphilic electrolytes lead to a stronger compression of the diffuse part of the electrical double layer in comparison to hydrophilic electrolytes. Scaling relationships derived from this model provide a quantitative description of the rich phase behavior of the investigated suspensions, correctly accounting for the effect of the alkyl chain length of short and long amphiphiles on the electrokinetics of such colloidal systems. The proposed model contributes to our understanding of the stabilization mechanisms of particle-stabilized foams and emulsions and might provide new insights into the physicochemical processes involved in mineral flotation.


Monomeric C-reactive protein modulates classic complement activation on necrotic cells.
The acute-phase protein C-reactive protein (CRP) recruits C1q to the surface of damaged cells and thereby initiates complement activation. However, CRP also recruits complement inhibitors, such as C4b-binding protein (C4bp) and factor H, which both block complement progression at the level of C3 and inhibits inflammation. To define how CRP modulates the classic complement pathway, we studied the interaction of CRP with the classic pathway inhibitor C4bp. Monomeric CRP (mCRP), but not pentameric CRP (pCRP), binds C4bp and enhances degradation of C4b and C3b. Both C1q, the initiator, and C4bp, the inhibitor of the classic pathway, compete for mCRP binding, and this competition adjusts the local balance of activation and inhibition. After attachment of pCRP to the surface of necrotic rat myocytes, generation of mCRP was demonstrated over a period of 18 h. Similarly, a biological role for mCRP, C1q, and C4bp in the disease setting of acute myocardial infarction was revealed. In this inflamed tissue, mCRP, pCRP, C4bp, C1q, and C4d were detected in acetone-fixed and in unfixed tissue. Protein levels were enhanced 6 h to 5 d after infarction. Thus, mCRP bound to damaged cardiomyocytes recruits C1q to activate and also C4bp to control the classic complement pathway.


Hepatitis C virus infection in Italian kidney graft recipients. Changing risk factors and hepatitis C virus genotypes.
The risk for hepatitis C virus infection in kidney transplant recipients has been reduced by the introduction of accurate diagnostic tests. Little is known, however, of the current risk factors and the molecular genetics of hepatitis C virus infection in Italy. We studied 101 Italian kidney allograft recipients, transplanted between 1975 and 1995, in Italy or abroad. Sera were assayed for biochemistry, presence of HBsAg, anti-hepatitis C virus antibodies, hepatitis C virus-RNA (by reverse transcription nested PCR) and hepatitis C virus genotyping. HBsAg was found in 4 sera and anti-Hepatitis C Virus antibodies in 33 (33%). The duration of pre-transplant dialysis was longer in anti-hepatitis C virus positive than in anti-hepatitis C virus negative patients (5.9 +/- 4.3 vs 2.8 +/- 1.9 years, p = 0.0004). Anti-hepatitis C virus seropositivity was more frequent among patients grafted before than after 1990 (50% vs 27%, p = 0.04) and varied depending on the country of transplantation (25% in Italy; 56% in other European countries; and 40% in non-European developing countries). Twenty-seven sera were hepatitis C virus-RNA positive, including 5 without anti-hepatitis C virus antibodies. Hepatitis C virus genotype 1b was found in 13 (48%) patients, the remainder being infected with genotypes 1a (6 cases), 2a, 2c, 3a and 4. Genotype 1b was largely predominant among patients grafted in Europe but never found in those transplanted in developing countries. All but one patient without a sustained antibody response were infected by non-1b genotypes. Hepatitis C virus-RNA seropositivity was associated (p = 0.03) with a higher dose of prednisone (p = 0.03) and a lower dose of cyclosporine (p = 0.05) used as immunosuppressants. Current risk factors for hepatitis C virus infection in Italian kidney graft recipients include the duration of haemodialysis, transplantation in developing countries and the level of post-transplant immunosuppression. The pattern of hepatitis C virus genotypes is changing from predominantly 1b to non-1b genotypes and the latter infection often occurs without a sustained antibody response. Few patients develop clinical liver disease.


Purification and characterization of streptomycin 6-kinase, an enzyme implicated in self-protection of a streptomycin-producing micro-organism.
Streptomycin 6-kinase of the streptomycin-producing strain Streptomyces griseus HUT 6037 was purified by fractionation with (NH4)2SO4 and chromatography on DEAE-Sephadex A-25, hydroxyapatite and Sephadex G-100. After PAGE of the final fraction, a protein band corresponding to streptomycin 6-kinase was detected, together with a less intense band having no enzyme activity. Molecular weights determined by SDS-PAGE and by Sephadex G-100 chromatography were about 36000 and 38000, respectively, suggesting that the enzyme was a monomer. The isoelectric point of the enzyme was pH 6.6. Among the nucleoside 5'-triphosphates tested, ATP was the preferred phosphoryl donor. The Km values for streptomycin and ATP were 3.5 mM and 0.4 mM, respectively. The enzyme activity was strongly inhibited by EDTA and AgNO3. It was shown by using an in vitro protein-synthesizing system that purified streptomycin 6-kinase could protect polyphenylalanine synthesis of the streptomycin-susceptible S. griseus strain KSN from inhibition by streptomycin.


Effects of a substance P analogue with antagonist properties ([D-Arg1, D-Trp7,9, Leu11]substance P) on spontaneous activity of the adrenal sympathetic nerve and its evoked reflex discharges in response to somatic afferent stimulation.
The present study was designed to test the effect of a substance P (SP) antagonist, [D-Arg1, D-Trp7,9, Leu11]substance P (Spantide), on spontaneous efferent activity of adrenal sympathetic nerve and the two A- and C-sympathetic reflex components evoked in adrenal sympathetic nerve by stimulation of myelinated A- and unmyelinated C-afferent nerve fibers of a hindlimb nerve, respectively, in anesthetized rats. The spontaneous adrenal nerve activity and both of the A- and C-sympathetic reflex components were proportionally reduced by intrathecal application of the SP antagonist (0.038-0.76 nmol), although the same doses did not affect A- and C-somatic reflex components. These data suggest that the SP antagonist has a greater effect on SP-containing neurons related to the generation of spontaneous activity of sympathetic neurons and somato-sympathetic reflex pathways than on SP-containing primary somatic afferent nerves and somato-somatic reflex pathways.


Drug transport across the blood-brain barrier and the impact of breast cancer resistance protein (ABCG2).
With the discovery of novel therapeutic targets within the central nervous system (CNS), there has been a significant effort to synthesize a multitude of drug molecules with increasing potency and selectivity. However, the impact of the blood-brain barrier (BBB) in limiting effective concentrations of drug candidate from reaching the brain parenchyma is often ignored, resulting in a lack of efficacy when administered to animal models or humans. Intercellular drug transport across the BBB is negligible due to the impermeable tight junctions formed by interconnecting endothelial cells. Furthermore, drug permeability via the transcellular route cannot be assumed for all molecules due to the high expression of drug efflux transport proteins, which effectively extrude compounds from the brain endothelial cell back into the cerebral vasculature. In addition to the extensively-studied P-glycoprotein (P-gp, ABCB1), the brain endothelial cells also express multidrug resistance associated proteins (MRP, ABCC) and breast cancer resistance protein (BCRP, ABCG2), amongst other efflux transporters. While more research has focussed on the impact of P-gp and MRP on drug transport across the BBB, the role of ABCG2 in limiting exposure of drug molecules to the CNS is now becoming more clearly understood. The purpose of this review, therefore, is to summarise the findings of the various studies assessing the expression profile of ABCG2 at the BBB, to provide an overview on the current research being undertaken to identify specific ABCG2 inhibitors with therapeutic benefit, and to critically assess the functional role of ABCG2 on drug transport across the BBB.


Adrenoleukodystrophy: abnormality of "tightly bound" fatty acids in the erythrocyte membrane proteins.
"Tightly bound" and "loosely bound" fatty acids in erythrocyte membranes were analyzed in three patients with adrenoleukodystrophy, three probable carriers, and eight controls. The ratios of C28:0 or C26:0 to C22:0 or C20:0 in the tightly bound fatty acids of three patients were significantly higher than those of controls, and the ratios in two of three probable carriers were higher than those in controls. The ratios of C26:0 to C22:0 or C20:0 in the loosely bound fatty acids of three patients and three probable carriers were also significantly higher than those of controls. Since tightly bound fatty acids in membrane proteins are found not only in erythrocyte membranes but also in myelin proteins, the abnormality of tightly bound fatty acids may be related to the demyelination in adrenoleukodystrophy.


Role of hypothalamic melanocortin system in adaptation of food intake to food protein increase in mice.
The hypothalamic melanocortin system--the melanocortin receptor of type 4 (MC4R) and its ligands: α-melanin-stimulating hormone (α-MSH, agonist, inducing hypophagia), and agouti-related protein (AgRP, antagonist, inducing hyperphagia)--is considered to play a central role in the control of food intake. We tested its implication in the mediation of the hunger-curbing effects of protein-enriched diets (PED) in mice. Whereas there was a 20% decrease in food intake in mice fed on the PED, compared to mice fed on an isocaloric starch-enriched diet, there was a paradoxical decrease in expression of the hypothalamic proopiomelanocortin gene, precursor of α-MSH, and increase in expression of the gene encoding AgRP. The hypophagia effect of PED took place in mice with invalidation of either MC4R or POMC, and was even strengthened in mice with ablation of the AgRP-expressing neurons. These data strongly suggest that the hypothalamic melanocortin system does not mediate the hunger-curbing effects induced by changes in the macronutrient composition of food. Rather, the role of this system might be to defend the body against the variations in food intake generated by the nutritional environment.


Free L-Lysine and Its Methyl Ester React with Glyoxal and Methylglyoxal in Phosphate Buffer (100 mM, pH 7.4) to Form Nε-Carboxymethyl-Lysine, Nε-Carboxyethyl-Lysine and Nε-Hydroxymethyl-Lysine.
Glyoxal (GO) and methylglyoxal (MGO) are highly reactive species formed in carbohydrate metabolism. Nε-Carboxymethyllysine (CML) and Nε-carboxyethyllysine (CEL) are considered to be the advanced glycation end-products (AGEs) of L-lysine (Lys) with GO and MGO, respectively. Here, we investigated the reaction of free L-lysine (Lys) with GO and MGO in phosphate buffer (pH 7.4) at 37 °C and 80 °C in detail in the absence of any other chemicals which are widely used to reduce Schiff bases. The concentrations of Lys, GO and MGO used in the experiments were 0.5, 2.5, 5.0, 7.5 and 10 mM. The reaction time ranged between 0 and 240 min. Experiments were performed in triplicate. The concentrations of remaining Lys and of CML and CEL formed in the reaction mixtures were measured by stable-isotope dilution gas chromatography-mass spectrometry (GC-MS). Our experiments showed that CML and CEL were formed at higher concentrations at 80 °C compared to 37 °C. CML was found to be the major reaction product. In mixtures of GO and MGO, MGO inhibited the formation of CML from Lys (5 mM) in a concentration-dependent manner. The highest CML concentration was about 300 µM corresponding to a reaction yield of 6% with respect to Lys. An addition of Lys to GO, MGO and their mixtures resulted in strong reversible decreases in the Lys concentration up to 50%. It is assumed that free Lys reacts rapidly with GO and MGO to form many not yet identified reaction products. Reaction mixtures of Lys and MGO were stronger colored than those of Lys and GO, notably at 80 °C, indicating higher reactivity of MGO towards Lys that leads to polymeric colored MGO species. We have a strong indication of the formation of Nε-(hydroxymethyl)-lysine (HML) as a novel reaction product of Lys methyl ester with MGO. A mechanism is proposed for the formation of HML from Lys and MGO. This mechanism may explain why Lys and GO do not react to form a related product. Preliminary analyses show that HML is formed at higher concentrations than CEL from Lys methyl ester and MGO. No Schiff bases or their hydroxylic precursors were identified as reaction products. In their reactions with Lys, GO and MGO are likely to act both as chemical oxidants on the terminal aldehyde group to a carboxylic group (i.e., R-CHO to R-COOH) and as chemical reductors on labile Schiff bases (R-CH=N-R to R-CH2-NH-R) presumably via disproportionation and hydride transfer. Our study shows that free non-proteinic Lys reacts with GO and MGO to form CML, CEL and HML in very low yield. Whether proteinic Lys also reacts with MGO to form HML residues in proteins remains to be investigated. The physiological occurrence and concentration of HML in biological fluids and tissues and its relation to CML and CEL are elusive and warrant further investigations in health and disease. Chemical synthesis and structural characterization of HML are expected to advance and accelerate the scientific research in this topic.


Magnetic resonance imaging procedure for pelvic fracture urethral injuries and recto urethral fistulas: A simplified protocol.
The urethral gap in pelvic fracture urethral injury (PFUI) is traditionally assessed using voiding cystourethrogram (VCUG) and retrograde urethrogram (RGU). Magnetic resonance imaging (MRI) is performed in complex cases. We assessed the refined "Joshi" MRI protocol to evaluate complex urethral defects after PFUI. A prospective study was conducted at our center from January 2018 to January 2020, involving patients aged >18 years with PFUI, suitable for MRI, and those who gave consent to perform standard RGU, VCUG, and MRI using standard and "Joshi" protocol. Forty men were included in the study. Distance between urethral/prostatic stumps was measured. Image quality was scored by four radiologists and four urologists. The surgical approach and type of PFUI repair were noted. We also established the need for inferior pubectomy by assessing the position of the posterior urethra (membranous) in relation to a horizontal line drawn from the lower edge of the pubic bone anteriorly to the rectum posteriorly in a sagittal image. The mean age was 30 years (SD, 5.25; range, 21-43), and the time from injury to imaging was 4 months (3-10 months); 40% of the men underwent crural separation, 57.5%, inferior pubectomy, and 2.5%, crural rerouting. There was a difference of 0.3 to 1.1 cm in the urethral gap measurements between MR images using the standard versus "Joshi" technique. MRI identified complex injuries such as rectourethral fistula, the need for inferior pubectomy, and the orientation of the posterior urethra. Urologists' and radiologists' satisfaction scores for the MR images were satisfactory to excellent. If the posterior urethra was over the defined mark, there was a 100% likelihood of inferior pubectomy (23/40 patients). MR image acquisition using the "Joshi" protocol provided high-quality anatomical information in PFUI cases to assist with surgical planning.


An experience with application of human leucocyte interferon for cervical cancer treatment.
Interferon was injected intracervically as the first stage of combination treatment in 125 cases of histologically verified squamous Ca in situ and invasive cervical carcinoma. Colpomicroscopic, cytological and histological examination was carried out before and after treatment. The pronounced effect of interferon as an antitumor agent was established. Post-treatment histological examination failed to detect any tumor cells in 36 out of 125 patients (28.8%). Widening the scope of indications for preservative operations in patients with preinvasive and microinvasive cervical carcinoma after preliminary interferon therapy was suggested.


Fatal Pulmonary Embolism following Achilles Tendon Repair: A Case Report and a Review of the Literature.
Deep venous thrombosis (DVT) is a significant source of morbidity in orthopaedic surgery. It can progress to a pulmonary embolism, a significant source of mortality. Up to date, patients with Achilles tendon rupture routinely do not receive DVT chemical prophylaxis. We are presenting a case of fatal pulmonary embolism after a surgically treated Achilles tendon rupture in a forty-two-year-old male healthy patient. In the current body of the literature, the reported incidence of DVT after Achilles tendon rupture is highly variable ranging from less than 1% to 34%, and there is a disagreement in the international guidelines regarding the need of chemical DVT prophylaxis with this type of injury. Further research needs to be conducted to investigate the risks and benefits of chemical DVT prophylaxis following Achilles tendon rupture. For low-risk patients, the use of milder forms of prophylaxis such as aspirin should also be explored.


Searching for help online: An analysis of peer-to-peer posts on a male-only infertility forum.
Men's experiences of infertility help seeking are under-researched and thus less widely understood than women's experiences, with men's needs for support often missing from reproductive research knowledge. This article presents a thematic analysis of peer-to-peer posts within the context of a UK men-only online infertility forum. The key themes demonstrate that men value male support from those with experience, and that masculinity influences help-seeking requests and men's accounts more broadly. We highlight the value of such online communities in offering support to men in need while recognising the importance of further research across other online settings in order to inform practice around supporting men in the reproductive realm.


Airway obstruction due to bilateral vocal cord paralysis as a complication of stroke.
In two patients with unilateral cortical stroke, bilateral vocal cord paralysis resulted in airway obstruction. Realization of this potential complication can lead to vigilant monitoring and early tracheostomy if needed.


Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma.
Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m(2) per 5 days) or dose-intensified (DI) TMZ (100 mg/m(2) per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3(+) T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T(Reg); P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI(95): 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI(95): 11.0-18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI(95): 18.5-33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.


Plasma-derived extracellular vesicles from Plasmodium vivax patients signal spleen fibroblasts via NF-kB facilitating parasite cytoadherence.
Plasmodium vivax is the most widely distributed human malaria parasite. Previous studies have shown that circulating microparticles during P. vivax acute attacks are indirectly associated with severity. Extracellular vesicles (EVs) are therefore major components of circulating plasma holding insights into pathological processes. Here, we demonstrate that plasma-derived EVs from Plasmodium vivax patients (PvEVs) are preferentially uptaken by human spleen fibroblasts (hSFs) as compared to the uptake of EVs from healthy individuals. Moreover, this uptake induces specific upregulation of ICAM-1 associated with the translocation of NF-kB to the nucleus. After this uptake, P. vivax-infected reticulocytes obtained from patients show specific adhesion properties to hSFs, reversed by inhibiting NF-kB translocation to the nucleus. Together, these data provide physiological EV-based insights into the mechanisms of human malaria pathology and support the existence of P. vivax-adherent parasite subpopulations in the microvasculature of the human spleen.


Interventions to Improve Quality of Life, Well-Being, and Care in Latino Cancer Survivors: A Systematic Literature Review.
Hispanic/Latino cancer survivors are at risk for increased psychosocial burden, in part, because of lower survival rates and lower quality of life (QOL) when compared with other populations. Despite this, very few interventional studies have been conducted in this population. This review synthesizes research on supportive care interventions to improve QOL, well-being, and cancer care in Hispanic/Latino cancer survivors. . Data sources included MEDLINE®, CINAHL®, and PsycINFO®. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline was employed. . This review includes studies conducted with cancer survivors from diagnosis to survivorship and addresses any type of intervention for Hispanic/Latino survivors of all cancer types and sites. Studies were written in English and had a sample of at least 25% Hispanics/Latinos. Key study attributes were extracted and tabled. . Of the 15 studies reviewed, types of interventions included were psychosocial (n = 6), educational (n = 4), exercise/diet (n = 4), and navigational (n = 1). Most studies were pilot and feasibility studies, and nine were randomized, controlled trials (RCTs). . Interventional studies for Hispanic/Latino cancer survivors are at the very early stages of scientific development and are feasible and accepted by the Hispanic/Latino population. Culturally relevant psychosocial support and educational, exercise, and navigational interventions are beneficial for this population. . To advance the science, as the Hispanic/Latino population rapidly increases, a great need exists for additional research in this area. A theoretical basis for interventions is needed for development of additional research. Efficacy of culturally relevant supportive care interventions needs to be tested through RCTs, replication, and multisite studies. A need exists for these developing interventions to be translated into practice to improve QOL and well-being for Hispanic/Latino cancer survivors.


Structure-Based Insight into the Asymmetric Bioreduction of the C=C Double Bond of alpha,beta-Unsaturated Nitroalkenes by Pentaerythritol Tetranitrate Reductase.
Biocatalytic reduction of alpha- or beta-alkyl-beta-arylnitroalkenes provides a convenient and efficient method to prepare chiral substituted nitroalkanes. Pentaerythritol tetranitrate reductase (PETN reductase) from Enterobacter cloacae st. PB2 catalyses the reduction of nitroolefins such as 1-nitrocyclohexene (1) with steady state and rapid reaction kinetics comparable to other old yellow enzyme homologues. Furthermore, it reduces 2-aryl-1-nitropropenes (4a-d) to their equivalent (S)-nitropropanes 9a-d. The enzyme shows a preference for the (Z)-isomer of substrates 4a-d, providing almost pure enantiomeric products 9a-d (ees up to > 99%) in quantitative yield, whereas the respective (E)-isomers are reduced with lower enantioselectivity (63-89% ee) and lower product yields. 1-Aryl-2-nitropropenes (5a, b) are also reduced efficiently, but the products (R)-10 have lower optical purities. The structure of the enzyme complex with 1-nitrocyclohexene (1) was determined by X-ray crystallography, revealing two substrate-binding modes, with only one compatible with hydride transfer. Models of nitropropenes 4 and 5 in the active site of PETN reductase predicted that the enantioselectivity of the reaction was dependent on the orientation of binding of the (E)- and (Z)-substrates. This work provides a structural basis for understanding the mechanism of asymmetric bioreduction of nitroalkenes by PETN reductase.


Ion channels in yeast.
Voltage-dependent ion channels have been found in the plasma membrane of the yeast Saccharomyces cerevisiae. Ion channel activities were recorded from spheroplasts or patches of plasma membrane with the patch-clamp technique. The most prominent activities came from a set of potassium channels with the properties of activation by positive but not negative voltages, high selectivity for potassium over sodium ion, unit conductance of 20 picosiemens, inhibition by tetraethylammonium or barium ions, and bursting kinetics.


Continuous glucose monitoring and intensive treatment of type 1 diabetes.
The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined. In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks. The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference. Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.)


Effects of Physical Activity on Mobile Phone Addiction Among College Students: The Chain-Based Mediating Role of Negative Emotion and E-Health Literacy.
Smartphones have become an important tool for college students' study and life, but mobile phone addiction caused by excessive dependence use of cell phones can have serious negative impacts on college students' mental health, life behaviors, and so on. It is urgent to explore the causes and influence mechanisms of college students' cell phone addiction. The purpose of this study was to investigate the relationship between physical exercise and mobile phone addiction among Chinese college students and the mediating role of negative affect and e-health literacy between the two. The stratified sampling method was used to investigate the physical activity, mobile phone addiction, negative emotion and e-health literacy of 4621 university students in Jiangsu Province using the Physical Activity Rating scale, Mobile Phone Addiction scale, Depression-anxiety-stress scale and E-Health Literacy scale, Thus the data were statistically analysed using SPSS 26.0 and AMOS 23.0. (1) Physical exercise was significantly negatively correlated with mobile phone addiction and negative emotion among college students (r=-.713, P<0.01; r=-.571, P<0.01), and physical exercise was significantly positively correlated with e-health literacy (r=0.616, P<0.01); (2) Negative emotion and e-health literacy played independent mediating roles between physical exercise and mobile phone addiction, respectively; (3) Negative emotion and e-health literacy played chain mediating roles between physical exercise and mobile phone addiction. This study explored the potential mechanisms of cell phone addiction in college students and found that physical activity can influence Internet addiction through the independent mediating effect including the chain mediating effect of negative emotions and e-health literacy. This study further reveals the mechanism of action of physical exercise affecting college students' cell phone addiction, and provides some reference value for the prevention and intervention of college students cell phone addiction.


Cognition and attitudes of hospice care among healthcare providers: a case study of Sichuan Province.
Under the background of the increasing aging population and cancer burden in China, the role of hospice care has become increasingly prominent. The government has paid more attention to the development of hospice care and set up pilot hospitals to promote hospice care. Moreover, healthcare providers play a leading role in hospice care services. To improve the quality of hospice care, the National Health Commission of the People's Republic of China proposed to set up hospice care training bases in municipal or above-level hospitals with hospice care or relevant work foundations, and train healthcare providers on hospice care. This study aimed to investigate the current situation of cognition and attitudes about hospice care among healthcare providers and provide a theoretical basis for hospital training. We used a quantitative design. A questionnaire survey was conducted among 1591 healthcare providers from August 2022 to November 2022. SPSS 22.0 software was used to analyze the data. As a significant way of continuing education for healthcare providers, hospital training hasn't been effectively exploited in hospice care education. The average score of hospice care knowledge among participants was (7.74 ± 2.242) and the average score of hospice care attitudes among participants was (4.55 ± 1.503). According to multivariate linear regression analysis, sex (p < 0.001), education levels (p < 0.001), and professional titles (p = 0.018) of participants had significant difference on the score of hospice care knowledge; education levels (p = 0.009) and professional titles (p = 0.016) of participants had significant difference on the score of hospice care attitudes. There were some misunderstandings about hospice care among healthcare providers and their attitudes towards hospice care were inactive. It's suggested that hospitals should carry out professional and systematic education courses to help healthcare providers understand hospice care correctly, and participate in hospice care services actively.


Body mass index and dietary intake among Head Start children and caregivers.
The US Head Start program serves low-income preschoolers and their caregivers and provides an opportunity for assessment and intervention on obesity. We sought to determine the prevalence of obesity among children and their caregivers and to identify variables that are associated with child body mass index (BMI) z scores and caregiver BMI. Cross-sectional data on diet and BMI from 770 caregiver-child dyads recruited from 57 Head Start centers in Alabama and Texas. Height and weight of each caregiver and child were measured using standardized protocols. Dietary intakes of caregiver-child dyads were collected using three 24-hour dietary recalls and Block food frequency questionnaires. Data were collected between September 2004 and November 2005. The larger Food Pyramid categories were divided into 17 food consumption groups and tested for their association with child BMI z scores. Analysis of variance was used to test if food groups were significantly associated with child BMI z score. The prevalence of obesity among children was 18.4%, 24.3%, and 37.3% among black, Hispanic, and white children, respectively (P<0.0001), whereas it was 58.3%, 41.4%, and 41.6% among black, Hispanic, and white caregivers, respectively (P<0.0001). Child BMI z scores and caregiver BMIs were correlated (r=0.16, P<0.0001). In multivariable models, children were 1.90 (95% confidence interval 1.31-2.74) times more likely to have BMI ≥95th percentile if their caregiver was obese. Five variables (fruits, unsweetened beverages, low-fat dairy, race, and caregiver's BMI) were significantly associated with child BMI z scores. Fruits were inversely related, whereas unsweetened beverages, low-fat dairy, and caregiver's BMI were positively associated with child BMI z score (P<0.03). Compared to whites, black and Hispanic children had lower BMI z scores (P<0.05). The high prevalence of obesity in this population together with the observed inverse association between fruit consumption and BMI, if replicated in other studies, suggests that interventions that promote fruit consumption could have beneficial effects on child BMI.


Percutaneous Screw Fixation of Lateral Condylar Humeral Fractures.
Lateral condylar humeral fractures are the second most common elbow injury in children and commonly occur between the ages of 5 and 10 years. There are several systems for classification of this fracture, including those of Milch (fracture line location) and Jakob et al. (displacement). Although nonoperative management is indicated for nondisplaced or minimally displaced fractures (<2 mm), operative fixation is indicated for greater displacement. Traditionally, open reduction and internal fixation has been the method used to ensure adequate reduction. However, closed reduction and internal fixation techniques for displaced fractures have been receiving increasing attention, with recent studies showing promising results. Several constructs (multiple smooth pins, a single lag screw, and threaded pins) for closed reduction and internal fixation have been described. Smooth-pin fixation has the advantage of a small diameter and easy removal, whereas threaded pins combine a small diameter with compressive properties. Compression of these small, articular fractures is important, and the optimal mode of fixation for maintaining fracture reduction is debated. Fixation with a partially threaded lag screw works by achieving metaphyseal compression, preventing loss of reduction of the distal fragment. In our experience, the compressive abilities of smooth and threaded pins are limited in the soft osteocartilaginous lateral condyle. Partially threaded lag screw fixation is indicated for pediatric patients with a substantially displaced (Jakob type-II or III) lateral condylar fracture. The major steps of the procedure are (1) preoperative planning with anteroposterior, lateral, and oblique radiographs; (2) supine positioning of the patient with the shoulder in abduction; (3) closed reduction with manual pressure; (4) guide-pin insertion through the lateral column of the distal part of the humerus; and (5) exchange of the guide pin with a lag screw. Postoperatively, the elbow is immobilized with a bivalved long-arm fiberglass cast or a posterior splint. The cast or splint is removed after interval healing is demonstrated on radiographs, and the lag screw is removed after complete fracture union is demonstrated. Complications are rare, and patients are expected to have decreased infection and open-reduction rates compared those treated with pin fixation.


High prevalence of antibodies reacting to mimotopes of Simian virus 40 large T antigen, the oncoprotein, in serum samples of patients affected by non-Hodgkin lymphoma.
A new immunological investigation was carried out to study the association between non-Hodgkin lymphoma and Simian virus 40 (SV40). To this end, a new indirect ELISA was employed with two mimotopes from SV40 large T antigen (Tag), the viral oncoprotein, to analyse for specific reactions to antibodies in sera from non-Hodgkin lymphoma patients and controls, represented by healthy subjects (HS) and breast carcinoma (BC) patients. This study allowed us to assay a new sera collection from non-Hodgkin lymphoma patients (NHL, n = 254). To verify the association between NHL and SV40 Tag, two totally independent cohorts were analysed: NHL1 n = 150 and NHL2 n = 104. The epidemiological survey included sera from HS1, n = 150; HS2, n = 104 and BC, n = 78. This new indirect ELISA revealed that antibodies against SV40 Tag mimotopes are detectable in NHL1 and NHL2 sera with a prevalence of 37 and 36%, respectively. The prevalence of SV40-antibodies detected in both NHL1 and NHL2 cohorts differs statistically from controls, at 19% for HS1 (p < 0.01), HS2 (p < 0.05) and BC patients (p < 0.05). This study, carried out with an immunological assay with specific Tag oncoprotein mimotopes of Simian virus 40, reports the presence of IgG antibodies against the large Tumour antigen in non-Hodgkin lymphomas for the first time. Our immunological data with two independent NHL cohorts show a statistically significant association between Simian virus 40 Tag and non-Hodgkin lymphoma. These results suggest that SV40-positive non-Hodgkin lymphomas could be treated differently from those tested SV40-negative.


Inulinase production and mathematical modeling from carob extract by using Aspergillus niger.
The main objectives of the study were to produce inulinase from carob extract by Aspergillus niger A42 (ATCC 204447) and to model the inulinase fermentation in the optimum carob extract-based medium. In the study, carob extract was used as a novel and renewable carbon source in the production of A. niger inulinase. For medium optimization, eight different variables including initial sugar concentration (°Bx), (NH4 )2 HPO4 , MgSO4 .7H2 O, KH2 PO4 , NH4 NO3 , yeast extract, peptone, and ZnSO4 .7H2 O were employed. After fermentations, optimum medium composition contained 1% yeast extract in 5°Bx carob extract. As a result of the fermentation, the maximum inulinase activity, maximum invertase-type activity, I/S ratio, maximum inulinase- and invertase-type activity rates, maximum sugar consumption rate, and sugar utilization yield were 1507.03 U/ml, 1552.86 U/ml, 0.97, 175.82 and 323.76 U/ml/day, 13.26 g/L/day, and 98.52%, respectively. Regarding mathematical modeling, the actual inulinase production and sugar consumption data were successfully predicted by Baranyi and Cone models based on the model evaluation and validation results and the predicted kinetic values, respectively. Consequently, this was the first report in which carob extract was used in the production of inulinase as a carbon source. Additionally, the best-selected models can serve as universal equations in modeling the inulinase production and sugar consumption in shake flask fermentation with carob extract medium.


Managing for the unexpected: Building resilient forest landscapes to cope with global change.
Natural disturbances exacerbated by novel climate regimes are increasing worldwide, threatening the ability of forest ecosystems to mitigate global warming through carbon sequestration and to provide other key ecosystem services. One way to cope with unknown disturbance events is to promote the ecological resilience of the forest by increasing both functional trait and structural diversity and by fostering functional connectivity of the landscape to ensure a rapid and efficient self-reorganization of the system. We investigated how expected and unexpected variations in climate and biotic disturbances affect ecological resilience and carbon storage in a forested region in southeastern Canada. Using a process-based forest landscape model (LANDIS-II), we simulated ecosystem responses to climate change and insect outbreaks under different forest policy scenarios-including a novel approach based on functional diversification and network analysis-and tested how the potentially most damaging insect pests interact with changes in forest composition and structure due to changing climate and management. We found that climate warming, lengthening the vegetation season, will increase forest productivity and carbon storage, but unexpected impacts of drought and insect outbreaks will drastically reduce such variables. Generalist, non-native insects feeding on hardwood are the most damaging biotic agents for our region, and their monitoring and early detection should be a priority for forest authorities. Higher forest diversity driven by climate-smart management and fostered by climate change that promotes warm-adapted species, might increase disturbance severity. However, alternative forest policy scenarios led to a higher functional and structural diversity as well as functional connectivity-and thus to higher ecological resilience-than conventional management. Our results demonstrate that adopting a landscape-scale perspective by planning interventions strategically in space and adopting a functional trait approach to diversify forests is promising for enhancing ecological resilience under unexpected global change stressors.


Role of Personality Functioning in the Quality of Life of Patients with Depression.
Depression is associated with reduced quality of life (QoL), and personality pathology is associated with higher impairment and poorer treatment outcomes in patients with depression. This study aims to analyze the effects of personality functioning on the QoL of patients with depression. Severity of depressive symptoms (Beck Depression Inventory), level of personality functioning (Operationalized Psychodynamic Diagnosis Structure Questionnaire), and QoL (Medical Outcome Study 36-item Short-Form) were assessed in a sample of 84 depressive outpatients. Personality functioning showed main effects on both the mental and physical components of QoL. A moderating effect of personality functioning on the relationship between depressive symptoms and QoL was tested but not confirmed. Severity of depressive symptoms was found to mediate the effect of personality functioning on the mental component of QoL. These results suggest that the effect of personality functioning on the QoL of patients with depression may be related to the higher severity of depressive symptoms found in patients with lower levels of personality functioning.


Case 261: Thymoma Embedded in Thymus with Pleural Implant in Myasthenia Gravis Lambert-Eaton Overlap Syndrome.
History A 29-year-old woman presented with a 6-month history of progressive general fatigue, fluctuating limb weakness, and difficulty climbing stairs. She initially experienced occasional episodes of transient diplopia that developed while reading in the evening. She subsequently started to experience dry eyes and mouth, difficulty chewing, and mild dysphagia that worsened throughout the day. Her medical history included hypothyroidism from Hashimoto thyroiditis and pneumonia with left pleural effusion. She had no smoking history, and her body mass index was normal (23.8 kg/m2). No medication use was reported at admission. Physical examination revealed mild bilateral ptosis, reduced muscle tone and strength that worsened in proximal leg muscles, and decreased deep tendon reflexes. An edrophonium test revealed improvement in muscle strength and eyelid ptosis. Repetitive nerve stimulation revealed low amplitude of compound muscle action potential at rest (0.21 mV), with a marked increase (700%; normal increase, <60%) at high-rate stimulation (50 Hz). Laboratory work-up was unremarkable except for detection of acetylcholine receptor antibodies in the serum (21.30 nmol/L) and P/Q-type voltage-gated calcium channel antibodies (220 pmol/L). Recent MRI of the brain and spine at an outside hospital showed no abnormal findings. At admission, the patient underwent CT of the chest, abdomen, and pelvis followed by thoracic MRI to further evaluate CT findings.


Comparison of active and passive coronary perfusion in off-pump coronary artery bypass grafting.
The myocardial protective effects of active and passive coronary perfusion were compared during off-pump coronary artery bypass grafting (OPCAB) in coronary stenosis model. An internal shunt tube was placed in the proximal left anterior descending arteries of adult dogs to produce a 75% coronary stenosis model. In 10 animals passive coronary perfusion was performed using an internal shunt tube placed in a pseudo-anastomotic site, and active coronary perfusion was performed through an external shunt tube. Ischemia was examined at normal and low blood pressure, based on hemodynamics, regional myocardial blood flow, and oxygen and lactate extraction in the perfused area. With passive perfusion, regional myocardial blood flow decreased and oxygen extraction and regional lactate production increased at normal blood pressure, indicating myocardial ischemia. Regional myocardial blood flow further decreased at low blood pressure. In contrast, regional myocardial blood flow with active perfusion did not change at normal or low blood pressure, and oxygen and lactate extraction were unchanged, indicating prevention of myocardial ischemia. Myocardial ischemia can occur with passive perfusion even at normal blood pressure. Active coronary perfusion that provides sufficient regional perfusion prevents myocardial ischemia during coronary artery anastomosis in OPCAB.


Minimizing factor requirements for surgery without increased risk.
The most common type of surgical procedure in patients with haemophilia is orthopaedic surgery on the lower limb. These procedures are of great importance for the improvement of the function and quality of life of patients with haemophilia, but in many countries resources are lacking to provide the factor concentrates needed for these operations. We have attempted to reduce the level of replacement during and after total hip or total knee replacement without jeopardizing the outcome of the procedures. The results from 30 operations in 27 patients are presented. Steady-state levels down to 0.5 IU mL(-1) did not appear to increase the amount of blood loss or cause an increased incidence of complications, compared with higher levels. In addition, we review the possibilities to reduce the amount of factor concentrate by performing a combination of orthopaedic procedures and using local haemostatic agents or antifibrinolytic agents.


Molecular predictors of drug-induced prolongation of the QT interval.
One of the most common causes of drug withdrawal from the market is the prolongation of the QT interval associated with polymorphic ventricular tachycardia or torsade de pointes (TdP) that can degenerate into ventricular fibrillation and sudden cardiac death. Cardiac and non-cardiac drugs prolong the QT interval and cause TdP by blocking cardiac K+ channels in general, and selectively blocking the rapidly activating delayed rectifier channel IKr. Co-assembly of HERG (human-ether-a-go-go-related gene) alpha-subunits and MiRP1 (MinK-related peptide 1) beta-subunits recapitulate the behavior of native human IKr, and the majority of mutations of HERG and MiRP1 decrease the repolarizing current, delay ventricular repolarization and prolong the QT. Thus, drug-induced QT prolongation and TdP might represent an iatrogenic reproduction of the congenital long-QT syndrome (LQTS). Current evidence suggests that 5 to 10% of persons in whom TdP develops on exposure to QT-interval prolonging drugs harbor mutations associated with the LQTS and can therefore be viewed as having a subclinical form of the congenital syndrome. This clinical observation is entirely consistent with the concept of reduced repolarization reserve arising from a mutation in an ion-channel gene, which predisposes the carrier to drug-induced TdP. This review centers on the possible molecular mechanisms underlying drug-induced QT prolongation and TdP, the description of specific drugs and risk factors facilitating the development of TdP, and the recommendations for preventing and treating this potentially fatal arrhythmia.


Plasma and liver lipidomics response to an intervention of rimonabant in ApoE*3Leiden.CETP transgenic mice.
Lipids are known to play crucial roles in the development of life-style related risk factors such as obesity, dyslipoproteinemia, hypertension and diabetes. The first selective cannabinoid-1 receptor blocker rimonabant, an anorectic anti-obesity drug, was frequently used in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m(2) with associated risk factors such as type II diabetes and dyslipidaemia in the past. Less is known about the impact of this drug on the regulation of lipid metabolism in plasma and liver in the early stage of obesity. We designed a four-week parallel controlled intervention on apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) transgenic mice with mild overweight and hypercholesterolemia. A liquid chromatography-linear ion trap-Fourier transform ion cyclotron resonance-mass spectrometric approach was employed to investigate plasma and liver lipid responses to the rimonabant intervention. Rimonabant was found to induce a significant body weight loss (9.4%, p<0.05) and a significant plasma total cholesterol reduction (24%, p<0.05). Six plasma and three liver lipids in ApoE*3Leiden.CETP transgenic mice were detected to most significantly respond to rimonabant treatment. Distinct lipid patterns between the mice were observed for both plasma and liver samples in rimonabant treatment vs. non-treated controls. This study successfully applied, for the first time, systems biology based lipidomics approaches to evaluate treatment effects of rimonabant in the early stage of obesity. The effects of rimonabant on lipid metabolism and body weight reduction in the early stage obesity were shown to be moderate in ApoE*3Leiden.CETP mice on high-fat diet.


Serum cholesterol, MTHFR methylation, and symptoms of depression in children.
Depression is associated with dietary factors and epigenetics. Serum cholesterol, which is prone to dietary influences, has been linked to symptoms of depression. This relationship may be (in part) due to altered epigenetic regulation of Methylenetetrahydrofolate Reductase (MTHFR). MTHFR codes for the MTHFR enzyme, which has diverse metabolic functions, and has recently been linked individually with diet, serum cholesterol levels and depressive symptoms. In 514 mother-child pairs, we examined prospective relationships between maternal (pregnancy) and child (7 years) serum cholesterol, MTHFR DNA methylation (DNAm; birth, 7 years), and development of depression symptoms from 8-15 years. After adjusting for potential confounding, we had three main findings. First, higher prenatal cholesterol associated (at a small effect size) with higher MTHFR DNAm at birth. Second, there was small effect size continuity for MTHFR DNAm between birth and age 7. Third, higher age 7 MTHFR DNAm associated with higher initial symptoms of depression symptoms at age 8, again at a small effect size. Overall, our findings provide preliminary evidence for a relationship between prenatal cholesterol, MTHFR DNAm, and symptoms of depression in children. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Developing, implementing and evaluating the effectiveness of a sleep health educational module for pharmacy students.
Pharmacists need sleep health knowledge and management skills to deliver evidence-based treatments to patients with sleep disorders/disturbance. The aim of this study was to develop, implement and evaluate a pedagogically informed-interactive sleep health educational module for pharmacy students. An educational module utilising a flipped classroom approach, with an interactive lecture, student self-reflection of sleep patterns, case discussions and pharmacist-patient role-play scenarios, was designed and implemented. A questionnaire assessing pre-/post-module changes in knowledge about and attitudes towards sleep health as well as post-module learning satisfaction, was administered to all participating 2nd year pharmacy students at an Australian university. Mean total knowledge scores for participating students (n=125, 70.4% females) improved significantly, from a baseline of 11.1 ± 3.8 to 17.1 ± 3.5 post-module (range: 0 - 25). Attitudes towards sleep health were moderately high at baseline (28.8 ± 3.2) and improved marginally post-module (29.4 ± 3.8) (range: 10 - 50); however, this increase was insignificant. Participants expressed high satisfaction with the module through subjective feedback, and post-module reflective statements indicated plans for changing sleep behaviours. The results of this study have shown that a targeted educational module for pharmacy students improved sleep health knowledge. It appeared that positive attitudes towards sleep health were not significantly increased which may reflect a ceiling effect. Future modules should focus on attitudinal aspects of positive sleep health to enhance pharmacists' skills in providing clinically related sleep health care in patients with sleep disturbance.


[Detection of the ermB gene associated with macrolide resistance in Campylobacter strains isolated from chickens marketed in Lima, PeruDetecção do gene ermB associado à resistência a macrolídeos em cepas de Campylobacter isoladas de frangos comercializados em Lima, no Peru].
To detect the presence of the ermB gene associated with macrolide resistance in Campylobacter spp. strains isolated from chickens marketed in Lima, Peru. 120 samples of chicken skin from three markets in the districts of San Martin de Porres (n = 30), Santa Anita (n = 20), and Independencia (n = 70), located in the Province of Lima, Peru, were analyzed. Microbiological analysis of the samples was carried out according to ISO standard 10272-1:2017. For the polymerase chain reaction (PCR) confirmation of genus and species, 16-rRNA and GlyA and hipO primers, respectively, were used. For the evaluation of antibiotic sensitivity, the Müller-Hinton agar with 5% blood, with sensi-discs for azithromycin (15 µg) and erythromycin (15 µg), was used. For detection of the ermB gene in strains with resistant phenotypes, conventional PCR was used. A total of 117 positive samples (97.5%) were obtained; of these, 100% were compatible with Campylobacter coli (negative hippurate test) and confirmed by PCR. The plate-based assessment of antibiotic resistance to azithromycin and erythromycin resulted in 100% of strains with a phenotype that is resistant to these macrolides, while the PCR to detect the ermB gene indicated a total of 62 positives (53%), which were confirmed through sequencing. These results demonstrate that the chicken carcasses sold in markets in Lima present contamination by C. coli with high resistance to macrolides, which can be attributed to the presence of the ermB gene.


Objective Assessment of Listening Effort: Coregistration of Pupillometry and EEG.
Listening to speech in noise is effortful, particularly for people with hearing impairment. While it is known that effort is related to a complex interplay between bottom-up and top-down processes, the cognitive and neurophysiological mechanisms contributing to effortful listening remain unknown. Therefore, a reliable physiological measure to assess effort remains elusive. This study aimed to determine whether pupil dilation and alpha power change, two physiological measures suggested to index listening effort, assess similar processes. Listening effort was manipulated by parametrically varying spectral resolution (16- and 6-channel noise vocoding) and speech reception thresholds (SRT; 50% and 80%) while 19 young, normal-hearing adults performed a speech recognition task in noise. Results of off-line sentence scoring showed discrepancies between the target SRTs and the true performance obtained during the speech recognition task. For example, in the SRT80% condition, participants scored an average of 64.7%. Participants' true performance levels were therefore used for subsequent statistical modelling. Results showed that both measures appeared to be sensitive to changes in spectral resolution (channel vocoding), while pupil dilation only was also significantly related to their true performance levels (%) and task accuracy (i.e., whether the response was correctly or partially recalled). The two measures were not correlated, suggesting they each may reflect different cognitive processes involved in listening effort. This combination of findings contributes to a growing body of research aiming to develop an objective measure of listening effort.


Local differentiation amidst extensive allele sharing in Oryza nivara and O. rufipogon.
Genetic variation patterns within and between species may change along geographic gradients and at different spatial scales. This was revealed by microsatellite data at 29 loci obtained from 119 accessions of three Oryza series Sativae species in Asia Pacific: Oryza nivara Sharma and Shastry, O. rufipogon Griff., and O. meridionalis Ng. Genetic similarities between O. nivara and O. rufipogon across their distribution are evident in the clustering and ordination results and in the large proportion of shared alleles between these taxa. However, local-level species separation is recognized by Bayesian clustering and neighbor-joining analyses. At the regional scale, the two species seem more differentiated in South Asia than in Southeast Asia as revealed by F ST analysis. The presence of strong gene flow barriers in smaller spatial units is also suggested in the analysis of molecular variance (AMOVA) results where 64% of the genetic variation is contained among populations (as compared to 26% within populations and 10% among species). Oryza nivara (H E = 0.67) exhibits slightly lower diversity and greater population differentiation than O. rufipogon (H E = 0.70). Bayesian inference identified four, and at a finer structural level eight, genetically distinct population groups that correspond to geographic populations within the three taxa. Oryza meridionalis and the Nepalese O. nivara seemed diverged from all the population groups of the series, whereas the Australasian O. rufipogon appeared distinct from the rest of the species.


[Level, structure and dynamics of combined forms of occupational diseases among coal miners of Donetsk region].
The authors presented data on levels, structure and dynamics of combined occupational diseases in coal miners of Donetsk region in Ukraine, analyzed possible mechanisms of such diseases.


Lectin binding to common epithelial tumors of the ovaries.
Binding sites of peanut agglutinin (PNA), Ulex europaeus (UEA-1), wheat germ agglutinin, concanavalin A, and Ricinus communis were localized in 46 common epithelial ovarian tumors. Binding pattern of serous cystadenomas showed significant similarity with the pattern seen in the epithelium of fallopian tubes. Lectin affinity of endometriosis and endometrioid tumors was similar to normal endometrium in secretory phase. Binding pattern of clear cell carcinomas was similar to gestational endometrium, with PNA and UEA-1 showing strong affinity. This pattern is in contrast to clear cell carcinomas of the kidney, that do not bind PNA and UEA-1. Mucinous cystadenomas exhibited binding patterns identical with cervical epithelium. Malignant counterparts of the described tumors were characterized by the partial loss of lectin binding and uneven distribution of the binding reaction.


Inhibition of Neisseria gonorrhoeae by a bacteriocin from Pseudomonas aeruginosa.
Supernatants from broth-grown cultures of Pseudomonas aeruginosa PA 103 exhibited bactericidal activity against Neisseria gonorrhoeae. The concentration of the bactericidal substance increased significantly after induction by mitomycin C. Purification was effected by salt fractionation, chromatography on diethylaminoethyl-cellulose, and sedimentation by centrifugation at 100,000 x g for 90 min. Electron microscopy of this purified preparation revealed structures resembling R-type pyocins in both the contracted and uncontracted state. Pyocins in the contracted state were observed in association with the gonococcal cell surface. No loss of bactericidal activity was observed after treatment with proteolytic enzymes. Standard pyocin typing procedures identified the pyocin pattern as 611 131. The bactericidal activity of this pyocin was examined on various species of Neisseria. Out of 56 strains of N. gonorrhoeae from disseminated and nondisseminated infections, all were susceptible to pyocin 611 131. However, only 3 of 20 strains of N. meningitidis and 5 of 16 strains of N. lactamica were susceptible. The bactericidal activity that pyocin 611 131 has for N. gonorrhoeae and other species of Neisseria is significant because it departs from the expected specificity that heretofore has distinguished bacteriocins from most "classical" antibiotics.


Immunomodulatory activities of whey fractions in efferent prefemoral lymph of sheep.
Studies on the immunomodulatory activities of ruminant milk and colostral whey fractions were undertaken. By comparing with boiled colostral whey in a preliminary experiment, a putative heat-labile immunostimulatory factor for antibody responses was found to be present in ovine colostral whey. Studies were then undertaken in sheep in which the efferent prefemoral lymphatic ducts were cannulated bilaterally, and immune responses in the node were measured following subcutaneous injection in the flank fold of whey protein preparations of various purities. A significant sustained decline of efferent lymphocyte output was observed following injection with autologous crude milk whey or colostral whey preparations, but no changes were observed in interferon-gamma levels in lymph plasma. Two bovine milk whey fractions (lactoperoxidase and lactoferrin) of high purity were compared in bilaterally cannulated sheep. A transient decline over the first 6 h was seen in the efferent lymphocyte output and lymph flow rate after injection of both fractions. A significant difference was seen between the two fractions in interferon-gamma levels in lymph at 6 h after injection. However, no significant changes in the proportion of the various efferent lymphocyte phenotypes were seen following either treatment. Whereas both fractions showed a significant inhibitory effect in a dose-dependent manner on the proliferative response of T lymphocytes, but not B lymphocytes, to mitogenic stimulation in vitro, no similar changes were seen following in vivo stimulation with these two fractions.


Bioimaging using bipolar electrochemical microscopy with improved spatial resolution.
In this study, we developed bipolar electrochemical microscopy (BEM) using a closed bipolar electrode (cBPE) array with an electrochemiluminescence (ECL) detecting system. Because cBPEs are not directly connected to a detector, high spatio-temporal resolution imaging can be achieved by fabricating a microelectrode array in which each electrode point is arranged in a short interval. A cBPE array with individual cBPEs arranged in 41 μm intervals was successfully fabricated by depositing gold in the pores of a track-etched membrane using electroless plating. Using BEM with the cBPE array, which has a higher density of electrode points than the conventional multi-electrode array, we effectively demonstrated the imaging of [Fe(CN)6]3- diffusion and the respiratory activity of MCF-7 spheroids with high spatio-temporal resolution.


All-optical microdisk switch using EIT.
We present theoretical results of a low-loss all-optical switch based on electromagnetically induced transparency and the quantum Zeno effect in a microdisk resonator. We show that a control beam can modify the atomic absorption of the evanescent field which suppresses the cavity field buildup and alters the path of a weak signal beam. We predict more than 35 dB of switching contrast with less than 0.1 dB loss using just 2 μW of control-beam power for signal beams with less than single photon intensities inside the cavity.


SynergyFinder: a web application for analyzing drug combination dose-response matrix data.
Rational design of drug combinations has become a promising strategy to tackle the drug sensitivity and resistance problem in cancer treatment. To systematically evaluate the pre-clinical significance of pairwise drug combinations, functional screening assays that probe combination effects in a dose-response matrix assay are commonly used. To facilitate the analysis of such drug combination experiments, we implemented a web application that uses key functions of R-package SynergyFinder, and provides not only the flexibility of using multiple synergy scoring models, but also a user-friendly interface for visualizing the drug combination landscapes in an interactive manner. The SynergyFinder web application is freely accessible at https://synergyfinder.fimm.fi ; The R-package and its source-code are freely available at http://bioconductor.org/packages/release/bioc/html/synergyfinder.html . firstname.lastname@example.com.


Impact of Biometric Patient Data, Probiotic Supplementation, and Selected Gut Microorganisms on Calprotectin, Zonulin, and sIgA Concentrations in the Stool of Adults Aged 18-74 Years.
Alterations to the intestinal barrier may be involved in the pathogenesis of various chronic diseases. The diagnosis of mucosal barrier disruption has become a new therapeutic target for disease prevention. The aim of this study was to determine whether various patient demographic and biometric data, often not included in diagnostic analyses, may affect calprotectin, zonulin, and sIgA biomarker values. Stool markers' levels in 160 samples were measured colorimetrically. The analysis of twenty key bacteria (15 genera and 5 species) was carried out on the basis of diagnostic tests, including cultures and molecular tests. The concentrations of selected markers were within reference ranges for most patients. The sIgA level was significantly lower in participants declaring probiotics supplementation (p = 0.0464). We did not observe differences in gastrointestinal discomfort in participants. We found significant differences in the sIgA level between the 29-55 years and >55 years age-related intervals groups (p = 0.0191), together with a significant decreasing trend (p = 0.0337) in age-dependent sIgA concentration. We observed complex interdependencies and relationships between their microbiota and the analyzed biomarkers. For correct clinical application, standardized values of calprotectin and sIgA should be determined, especially in elderly patients. We observed a correlation between the composition of the gut community and biomarker levels, although it requires further in-depth analysis.


Sialic acid binding sites: role in hemagglutination by Mycoplasma gallisepticum.
Hemagglutination of turkey erythrocytes by Mycoplasma gallisepticum was inhibited by mucoproteins containing sialic acid, by sialic acid itself, and by treatment of the erythrocytes with neuraminidase. Neuraminidase treatment of the mucoprotein-rich inhibitors reduced or abolished their inhibitory activity. The findings indicate that sialic acid on the erythrocyte surface provides binding sites for Mycoplasma gallisepticum.


DNA damage and cytotoxicity induced by minor groove binding methyl sulfonate esters.
Minor groove specific DNA equilibrium binding peptides (lex) based on N-methylpyrrole-carboxamide and/or N-methylimidazolecarboxamide subunits have been modified with an O-methyl sulfonate ester functionality to target DNA methylation in the minor groove at Ade/Thy- and/or Gua/Cyt-rich sequences. HPLC and sequencing gel analyses show that the Me-lex compounds all selectively react with DNA to afford N3-alkyladenine as a major adduct. The formation of the N3-alkyladenine lesions is sequence-dependent based on the equilibrium binding preferences of the different lex peptides. In addition to the reaction at adenine, the molecules designed to target Gua/Cyt sequences also generate lesions at guanine; however, the methylation is not sequence dependent and takes places in the major groove at the N7-position. To determine if and how the level of the different DNA adducts and the sequence selectivity for their formation affects cytotoxicity, the Me-lex analogues were tested in wild type Escherichia coli and in mutant strains defective in base excision repair (tag and/or alkA or apn). The results demonstrate the importance of 3-methyladenine, and in some cases 3-methylguanine, lesions in cellular toxicity, and the dominant protective role of the DNA glycosylases. There is no evidence that the sequence specificity is related to toxicity.


Identification of the triazine receptor protein as a chloroplast gene product.
The triazine herbicides inhibit photosynthesis by blocking electron transport at the second stable electron acceptor of photosystem II. This electron transport component of chloroplast thylakoid membranes is a protein-plastoquinone complex termed "B." The polypeptide that is believed to be a component of the B complex has recently been identified as a 32- to 34-kilo-dalton polypeptide by using a photoaffinity labeling probe, azido-[(14)C]atrazine. A 34-kilodalton polypeptide of pea chloroplasts rapidly incorporates [(35)S]methionine in vivo and is also a rapidly labeled product of chloroplast-directed protein synthesis. Trypsin treatment of membranes tagged with azido-[(14)C]atrazine, [(35)S]methionine in vivo, or [(35)S]methionine in isolated intact chloroplasts results in identical, sequential alterations of the 34-kilo-dalton polypeptide to species of 32, then 18 and 16 kilodaltons. From the identical pattern of susceptibility to trypsin we conclude that the rapidly synthesized 34-kilodalton polypeptide that is a product of chloroplast-directed protein synthesis is identical to the triazine herbicide-binding protein of photosystem II. Chloroplasts of both triazine-susceptible and triazine-resistant biotypes of Amaranthus hybridus synthesize the 34-kilodalton polypeptide, but that of the resistant biotype does not bind the herbicide.


Effects of prazosin, clonidine, and propranolol on the elevations in brain reward thresholds and somatic signs associated with nicotine withdrawal in rats.
Tobacco withdrawal is characterized by a negative mood state and relatively mild somatic symptoms. Increased noradrenergic transmission has been reported to play an important role in opioid withdrawal, but little is known about the role of noradrenergic transmission in nicotine withdrawal. The aim of these experiments was to investigate the effects of prazosin, clonidine, and propranolol on the negative mood state and somatic signs associated with nicotine withdrawal in rats. A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective state of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all the experiments, the nicotinic acetylcholine receptor antagonist mecamylamine (3 mg/kg) elevated the brain reward thresholds of the nicotine-treated rats and did not affect those of the control rats. The α1-adrenergic receptor antagonist prazosin (0.0625 and 0.125 mg/kg) dose-dependently attenuated the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. The α2-adrenergic receptor agonist clonidine (10-40 μg/kg) and the nonselective β-adrenergic receptor antagonist propranolol (2.5-10 mg/kg) did not attenuate the elevations in brain reward thresholds associated with nicotine withdrawal. Furthermore, mecamylamine (2 mg/kg) induced more somatic signs in the nicotine-treated rats than in the control rats. Clonidine and propranolol, but not prazosin, decreased the total number of somatic signs associated with nicotine withdrawal. Blockade of α1-adrenergic receptors attenuates the deficit in brain reward function associated with nicotine withdrawal. Antagonism of β-adrenergic receptors or stimulation of α2-adrenergic receptors attenuates the somatic symptoms of nicotine withdrawal.


Immunological substrates of depressive symptoms in patients with severe obesity: An exploratory study.
In this pilot study, we explored the immune phenotype of patients with severe obesity and comorbid depressive symptoms compared to non-depressed patients with obesity and normal-weight controls. Immune cell subsets were analysed by flow cytometry and depressive symptoms assessed using the Patient Health Questionnaire (PHQ-9). Cell frequencies were correlated with depressive symptom scores and waist-to-hip ratio (WHR). Patients with obesity and comorbid depression showed significantly lower numbers of circulating cytotoxic natural killer cells, dendritic cells and CD8+ effector memory T cells, compared to normal-weight controls. Regulatory T cells and CD4+ central memory T cells were increased compared to non-depressed patients with obesity and compared to normal-weight controls, respectively. Frequencies of cytotoxic natural killer cells and CD4+ central memory T cells significantly correlated with PHQ-9 scores, but not with WHR. Reduced numbers of dendritic cells were observed in both patient groups with obesity and correlated with PHQ-9 scores and WHR. These findings provide evidence for an altered immune composition in comorbid obesity and depression, supporting a pathobiological overlap between the two disorders.


Endurance with partnership: a preliminary conceptual framework for couples undergoing in vitro fertilisation treatment.
Infertility affects both women and men in the physical, emotional, existential, and interpersonal realms. When couples seek in vitro fertilisation (IVF) treatment, they further suffer from the difficulties of the treatment and the uncertainty of its outcome. The aim of this study was to develop a preliminary conceptual framework for couples undergoing IVF treatment to give health professionals a better understanding of the experiences of such couples, and to guide the development of an intervention. The process of identifying frameworks adopted in intervention studies confirmed that there is no established framework for infertile couples undergoing IVF treatment. A skeletal framework identified from previous studies provides an internal structure for the proposed framework for couples undergoing IVF treatment, filled out with concepts drawn from a concept analysis and a qualitative study, knitting the structure together. This preliminary framework is the Endurance with Partnership Conceptual Framework (P-EPCF). It consists of four domains: the impacts of infertility and stressors, dyadic mediators, dyadic moderators and dyadic outcomes. According to the P-EPCF, the impacts of infertility and IVF treatment can be mediated by the couples' partnership and dyadic coping. Improvements in the psychological well-being and marital functioning of IVF couples can then be expected. The P-EPCF would be potentially valuable in guiding the development of a complex, couple-based intervention, which could focus on enhancing the partnership of couples and their coping strategies.


Structural mapping of the active site specificity determinants of human tissue-type plasminogen activator. Implications for the design of low molecular weight substrates and inhibitors.
The recent structure determination of the catalytic domain of tissue-type plasminogen activator (tPA) suggested residue Arg174 could play a role in P3/P4 substrate specificity. Six synthetic chromogenic tPA substrates of the type R-Xaa-Gly-Arg-p-nitroanilide, in which R is an N-terminal protection group, were synthesized to test this property. Although changing the residue Xaa (in its L or D form) at position P3 from the hydrophobic Phe to an acidic residue, Asp or Glu, gave no improvement in catalytic efficiency, comparative analysis of the substrates indicated a preference for an acidic substituent occupying the S3 site when the S4 site contains a hydrophobic or basic moiety. The 2.9 A structure determination of the catalytic domain of human tPA in complex with the bis-benzamidine inhibitor 2, 7-bis-(4-amidinobenzylidene)-cycloheptan-1-one reveals a three-site interaction, salt bridge formation of the proximal amidino group of the inhibitor with Asp189 in the primary specificity pocket, extensive hydrophobic surface burial, and a weak electrostatic interaction between the distal amidino group of the inhibitor and two carbonyl oxygens of the protein. The latter position was previously occupied by the guanidino group of Arg174, which swings out to form the western edge of the S3 pocket. These data suggest that the side chain of Arg174 is flexible, and does not play a major role in the S4 specificity of tPA. On the other hand, this residue would modulate S3 specificity, and may be exploited to fine tune the specificity and selectivity of tPA substrates and inhibitors.


[Light-induced changes in activity of Na, K-ATPase from the retinal photoreceptors of vertebrates: possible mechanism].
The mechanism of light-induced changes in the activity of Na,K-ATPase from plasma membranes (PM) of photoreceptor cells was studied in vitro. Illumination resulted in inhibition of the ATPase activity and an increase of 18O exchange between water and Pi. The maximum light effect was revealed when the PM contained both the inner segments of the rods (RIS) and rod outer segments (ROS) of the photoreceptor cells. Lipid peroxidation stimulated by the FeSO4+ascorbate system induced a decrease of the ATPase activity. Antioxidants (ionol, Na2SeO3, vitamin E) prevented the effect of the lipid peroxidation products on NA,K-ATPase and the photoinduced changes of the enzyme activity. It is supposed that the photoinduced changes of the Na,K-ATPase activity in vitro are due to lipid peroxidation of photoreceptor PM.


Dynamics of Interferon System State Parameters during the Immune Therapy of Multiple Sclerosis: Individual Analysis.
Three patients with obvious multiple sclerosis (MS) were observed in a dynamics of immune therapy based on administration of rIFN-beta preparation. The ability to produce IFN-alpha and IFN-gamma by stimulated peripheral blood leukocytes (PBL) of the patients was tested simultaneously with detection of PBL response to the in vitro IFN-beta priming action on the every 10th day of observation. It has been shown that positive clinical effect of recombinant IFN-beta therapy was associated with a partial restoration of initially decreased IFN-beta and IFN-beta production by PBL, and paralleled by reducing the cell IFN-beta sensitivity. On the other hand, increase of PBL response to the in vitro IFN-beta action was related with diminishing IFN-alpha and IFN-gamma production, and did precede the following MS exacerbation. Mechanisms of IFN-beta therapeutical action in patients with MS in a context of changing relations between the parameters of IFN system functioning are discussed. Possibility is underlined to use the IFN system state parameters, combined with the cell IFN sensitivity determination, for prognosis of disease progression.


Competitive enzymatic interactions determine the relative amounts of prostaglandins E2 and D2.
Prostaglandins (PGs) are a family of cellular messengers exerting diverse homeostatic and pathophysiologic effects. Recently, several studies reported significant increases of PGI(2) and PGF(2α) after the inhibition of microsomal PGE synthase-1 (mPGES-1) expression, which indicated that PGH(2) metabolism might be redistributed when the PGE(2) pathway is blocked. To address the determinants that govern the relative amounts of PGs, we developed an in vitro cell-free method, based on liquid chromatography-tandem mass spectrometry, to measure the exact amounts of these PGs formed in response to the addition of recombinant isomerases and their selective inhibitors. Our in vitro cell-free assay results were confirmed in cells using bone marrow-derived macrophage. Initially, we determined the in vitro stability of PGH(2) and noted that there was spontaneous nonenzymatic conversion to PGD(2) and PGE(2). mPGES-1 markedly increased the conversion to PGE(2) and decreased conversion to PGD(2). Reciprocally, the addition of hematopoietic or lipocalin PGD synthase resulted in a relative increase of PGD(2) and decrease of PGE(2). A detailed titration study showed that the ratio of PGE(2)/PGD(2) was closely correlated with the ratio of PGE synthase/PGD synthase. Our redistribution results also provide the foundation for understanding how PGH(2) metabolism is redistributed by the presence of distal isomerases or by blocking the major metabolic outlet, which could determine the relative benefits and risks resulting from interdiction in nonrated-limiting components of PG synthesis pathways.


Ureaplasma parvum lipoproteins, including MB antigen, activate NF-{kappa}B through TLR1, TLR2 and TLR6.
Ureaplasma species (Ureaplasma parvum and Ureaplasma urealyticum) are commonly isolated pathogens from the female reproductive tract and are associated with perinatal diseases in humans. Inappropriate induction of inflammatory responses may be involved in the occurrence of such diseases; however, pathogenic agents that induce the inflammatory response have not been identified in ureaplasmas. In this study, we examined the involvement of Toll-like receptors (TLRs) in the activation of the immune response by U. parvum lipoproteins, as well as the U. parvum components responsible for nuclear factor kappaB (NF-kappaB) activation. The Triton X-114 (TX-114) detergent phase of U. parvum was found to induce NF-kappaB through TLR2. The active components of the TX-114 detergent phase were lipoproteins, such as multiple banded (MB) antigen, UU012 and UU016 of U. parvum. The activation of NF-kappaB by these lipoproteins was inhibited by dominant negative (DN) constructs of TLR1 and DN TLR6. Thus, the lipoproteins from U. parvum were found to activate NF-kappaB through TLR1, TLR2 and TLR6. Furthermore, these lipoproteins possessed an ability to induce tumour necrosis factor-alpha (TNF-alpha) in mouse peritoneal macrophages.


The pathology of rotavirus-associated deaths, using new molecular diagnostics.
Rotavirus, the most common cause of severe, dehydrating gastroenteritis among children worldwide, annually causes approximately 500,000 deaths among children aged <5 years. The primary site of rotavirus infection is the small intestine. Pathologic investigations of patients who died of rotavirus infection are limited to data from a few reported autopsies, and dehydration with electrolyte imbalance is believed to be the major cause of death. Several recent reports suggest that children who died during a rotavirus illness were viremic before death, because rotavirus was detected at several extraintestinal sites. We report 3 rotavirus-associated deaths among children, 2 of whom had evidence of rotavirus genome in extraintestinal tissues detected by use of novel molecular diagnostic methods. The part played by rotavirus in fatal cases is unclear and requires additional investigation of diarrhea-associated deaths, because a better understanding might alter the approach to treatment and the need for antiviral therapy.


Biomechanical Comparison of Tape Versus Suture in Simulated Achilles Tendon Midsubstance Rupture.
As sutures have progressed in strength, increasing evidence supports the suture tendon interface as the site where most tendon repairs fail. We hypothesized that suture tape would have a higher load to failure versus polyblend suture due to its larger surface area. Eleven matched pairs of cadaveric Achilles tendons were sutured with 2 mm wide braided ultrahigh molecular weight polyethylene tape (Tape) or 2 mm wide braided ultrahigh molecular weight polyethylene suture (Suture) using a Krackow repair method. All Achilles repair constructs were cyclically loaded, after which they were loaded to failure. Change in suture footprint height, clinical and ultimate load to failure, and location of failure was recorded. Clinical loads to failure for Tape and Suture were 290.4 ± 74.8 and 231.7 ± 70.4 Newtons, respectively (p= .01). Ultimate loads to failure for Tape and Suture were 352.9 ± 108.1 and 289.8 ± 53.7 Newtons, respectively (p = .11). Cyclic testing resulted in significant changes in footprint height for both Tape and Suture, but the 2 sutures did not differ in terms of the magnitude of change in footprint height (p = .52). The suture tendon interface was the most common site of failure for both Tape and Suture. Our results suggest that Tape may provide added repair strength in vivo for Achilles midsubstance rupture.


Hematologic toxicity in patients undergoing radical anti- cancer therapy: a cross-sectional analysis of patients in an oncology ward in India.
Burden of cancer is progressively increasing in developing countries like India which has also led to a steep rise in toxicity due to anti-cancer therapy. A cross-sectional analysis was here conducted for patients with different malignancies (except leukaemia) who while undergoing radical anti-cancer therapy were admitted to our oncology ward from January-July 2013. In a total of 280 patients, the total number of toxicity events was 473. Nine patients expired over this time period. Among the events, grade 2 anaemia the most common (n=189) while the most common grades of neutropenia and thrombocytopenia were grade 4 (n=114) and grade 2 (n=48), respectively. Among the tracable microbial etiologies, gram negative bacteria were the most commonly found pathogens. Treatment interruptions took place in 240 patients (median duration=8.8 days). Prolonged hospital admission, intensive care and artificial ventilation support was needed to be given in 48, 7 and 13 patients respectively. Advanced NSCLC, KPS <70, pancytopenia and artificial ventilation requirement were found to have a significant impact on death. Such studies show the prevailing practice from institutes of our country and may guide us formulating a guideline for managing such toxicities for this part of the world.


Ethical issues in cluster randomized trials conducted in low- and middle-income countries: an analysis of two case studies.
Cluster randomized trials are common in health research in low- and middle-income countries raising issues that challenge interpretation of standard ethical guidelines. While the Ottawa Statement on the ethical design and conduct of cluster randomized trials provides guidance for researchers and research ethics committees, it does not explicitly focus on low- and middle-income settings. In this paper, we use the lens of the Ottawa Statement to analyze two cluster randomized trials conducted in low- and middle-income settings in order to identify gaps or ethical issues requiring further analysis and guidance. The PolyIran trial was a parallel-arm, cluster trial examining the effectiveness of a polypill for prevention of cardiovascular disease in Golestan province, Iran. The PASTAL trial was an adaptive, multistage, parallel-arm, cluster trial evaluating the effect of incentives for human immunodeficiency virus self-testing and follow-up on male partners of pregnant women in Malawi. Through an in-depth case analysis of these two studies we highlight several issues in need of further exploration. First, standards for verbal consent and waivers of consent require methods for operationalization if they are to be employed consistently. Second, the appropriate choice of a control arm remains contentious. Particularly in the case of implementation interventions, locally available care is required as the comparator to address questions of comparative effectiveness. However, locally available care might be lower than standards set out in national guidelines. Third, while the need for access to effective interventions post-trial is widely recognized, it is often not possible to guarantee this upfront. Clarity on what is required of researchers and sponsors is needed. Fourth, there is a pressing need for ethics education and capacity building regarding cluster randomized trials in these settings. We identify four issues in cluster randomized trials conducted in low- and middle-income countries for which further ethical analysis and guidance is required.