Extracorporeal shockwave therapy (ESWT) in Achilles tendinopathy. A long-term follow-up observational study.
The etiology, pathogenesis and natural course of Achilles tendinopathy are not yet completely known. Various forms of therapies, either conservative or surgical, have been proposed for its treatment. In the last few years, extracorporeal shockwave therapy (ESWT) has been proposed in the treatment of these tendinopathies and has shown encouraging short-term results. The purpose of this type-C study was to evaluate the effectiveness of ESWT in the symptomatic treatment of Achilles tendinopathies over time. One hundred five patients (127 tendons) aged between 18 and 74 years (mean age 47.8) were enrolled in this study. All patients underwent clinical and instrumental diagnosis (ultrasonography, magnetic resonance imaging and X-rays) in order to identify presence, location and seriousness of the specific tendinopathy. The symptomatology was classified using the Visual Analogical Scale (VAS) and according to a five-stage clinical evaluation range. Shock wave treatment was applied with an electromagnetic shock wave generator. The protocol consisted in an average of four sessions (minimum three, maximum five), at a 2/7-day interval. In each session 1 500-2 500 impulses were administered with an energy varying between 0.08 and 0.40 mJ/mm2. All patients were evaluated before therapy and two months after the last ESWT session. Also, all patients were assessed and evaluated at medium-term (6 to 12 months), and 121 patients also at long-term (13 to 24 months). Authors obtained satisfactory results in 47.2% of cases (60 out of 127 tendons) at two-months follow-up, which increased to 73.2% at medium-term follow-up (93 out of 127 tendons), and then reaching 76% in the last evaluation (92 out of 121 tendons). The outcome of the described shock wave treatment appears to be satisfactory and confirms the role of this alternative treatment in the management of the tendon disorders.


Self-assembly of linear diblock copolymers in selective solvents: from single micelles to particles with tri-continuous inner structures.
Large-scale dissipative particle dynamics (DPD) simulations have been performed to investigate the self-assembly of over 20 000 linear diblock copolymer chains in a selective solvent. Specifically, we found that the transition from spherical to cylindrical vesicles and in turn to disk-like and onion-like vesicles, and finally to tri-continuous spherical particles is mainly due to the increase in the aggregation number. In addition, the structures with large aggregation numbers are formed through the fusion of smaller aggregates and the length of the corona block of the block copolymer plays a critical role in the resulting morphology. Furthermore, our simulations indicate that the very larger amount of polymer in our simulation is the key to the observation of a state of dynamic equilibrium between free chains and aggregates in solution, as well as the formation of more complex structures from linear diblock copolymers in selective solvents. Overall, this study paves the way for future coordinated experimental/computational studies on the formation of nanoparticles with complex morphologies from diblock copolymers, an area of great scientific and industrial interest.


Macrovascular disease is associated with increased plasma apolipoprotein A-IV levels in NIDDM.
Apolipoprotein A-IV (apoA-IV) might play an important role in lipoprotein metabolism, including modulation of triglyceride-rich lipoprotein catabolism, reverse cholesterol transport and cholesteryl ester transfer protein (CETP) activity. Increased apoA-IV levels have been reported in plasma from NIDDM patients. The aim of the present study was to look for a possible association between plasma apoA-IV level and prevalence of macrovascular disease in NIDDM. One hundred and thirty-six NIDDM patients were studied (71 men, 65 women). Macrovascular disease was assessed in each patient by a standardized questionnaire, physical examination, resting electrocardiogram (ECG), and laboratory evaluation (ankle/arm blood pressure ratio, continuous wave Doppler velocimetry). Moreover, patients without any history of coronary heart disease and showing a normal resting ECG underwent a bicycle exercise test or a dipyridamole thallium scintigraphy to detect possible silent myocardial ischemia. Among the 136 NIDDM patients, 56 had macrovascular disease. ApoA-IV levels were significantly higher in NIDDM patients with macrovascular disease than in NIDDM patients without macrovascular disease (20.9 +/- 8.6 vs. 13.3 +/- 5.3 mg/dl; P < 0.001). The influence of different factors, such as age, BMI, cigarette smoking, hypertension, total cholesterol, triglycerides, HDL cholesterol, apoA-IV level, apoA-IV phenotype, fasting glycemia, fasting C-peptide, and microalbuminuria, on the prevalence of macrovascular disease was analyzed using a logistic regression model. In the univariate analysis, apoA-IV level (P < 0.00001), age (P = 0.0087), hypertension (P = 0.012), microalbuminuria (P = 0.018), triglycerides (P = 0.02), and fasting C-peptide (P = 0.03) were positively associated with macrovascular disease. In the multivariate analysis, macrovascular disease was positively associated only with apoA-IV (P < 0.0001) and age (P = 0.003) and negatively associated with HDL cholesterol (P = 0.013). These results indicate that increased plasma apoA-IV level is associated with an increased prevalence of macrovascular disease in NIDDM. Moreover, apoA-IV, in NIDDM patients, appears to be a better marker for macrovascular disease than triglycerides.


[Five a day--ten years later].
Measures aimed at increasing fruit and vegetable consumption were implemented in the 1990ies. Official recommendations were published in 1996. The objective of this paper is to describe fruit and vegetable intake before and after introduction of the official recommendation. Data were obtained from Food Balance Sheets, household consumption surveys, the WHO's study "Health Behaviour in School-Aged Children" and market surveys. The development in fruit and vegetable consumption after 1996 is compared to that in previous years. Food supply and household consumption surveys show that fruit and vegetable consumption have increased the last 10 years. The increase after 1996 seems to be of the same relative magnitude as the years before. Pupils' fruit intake varied between 1993 and 2005, and vegetable intake increased between 1993 and 2005. The proportion of adults that had fruit or vegetables at least daily increased considerably between 1999 and 2005. It is difficult to give an unambiguous answer as to whether there has been an accelerating increase in consumption after 1996, representing a trend break. A large proportion of the population were still not having fruit or vegetables daily in 2005. Increased efforts are necessary to reach the target of at least five portions of fruit and vegetables daily.


The effect of floor type on the performance, cleanliness, carcass characteristics and meat quality of dairy origin bulls.
The aim of this study was to evaluate the effect of using different floor types to accommodate growing and finishing beef cattle on their performance, cleanliness, carcass characteristics and meat quality. In total, 80 dairy origin young bulls (mean initial live weight 224 kg (SD=28.4 kg)) were divided into 20 blocks with four animals each according to live weight. The total duration of the experimental period was 204 days. The first 101 days was defined as the growing period, with the remainder of the study defined as the finishing period. Cattle were randomly assigned within blocks to one of four floor type treatments, which included fully slatted flooring throughout the entire experimental period (CS); fully slatted flooring covered with rubber strips throughout the entire experimental period (RS); fully slatted flooring during the growing period and moved to a solid floor covered with straw bedding during the finishing period (CS-S) and fully slatted flooring during the growing period and moved to fully slatted flooring covered with rubber strips during the finishing period (CS-RS). Bulls were offered ad libitum grass silage supplemented with concentrates during the growing period. During the finishing period, bulls were offered concentrates supplemented with chopped barley straw. There was no significant effect of floor type on total dry matter intake (DMI), feed conversion ratio, daily live weight gain or back fat depth during the growing and finishing periods. Compared with bulls accommodated on CS, RS and CS-RS, bulls accommodated on CS-S had a significantly lower straw DMI (P<0.01). Although bulls accommodated on CS and CS-S were significantly dirtier compared with those accommodated on RS and CS-RS on days 50 (P<0.05) and 151 (P<0.01), there was no effect of floor type on the cleanliness of bulls at the end of the growing and finishing periods. There was also no significant effect of floor type on carcass characteristics or meat quality. However, bulls accommodated on CS-S had a tendency for less channel, cod and kidney fat (P=0.084) compared with those accommodated on CS, RS and CS-RS. Overall, floor type had no effect on the performance, cleanliness, carcass characteristics or meat quality of growing or finishing beef cattle.


PSRFlow: Probabilistic Super Resolution with Flow-Based Models for Scientific Data.
Although many deep-learning-based super-resolution approaches have been proposed in recent years, because no ground truth is available in the inference stage, few can quantify the errors and uncertainties of the super-resolved results. For scientific visualization applications, however, conveying uncertainties of the results to scientists is crucial to avoid generating misleading or incorrect information. In this paper, we propose PSRFlow, a novel normalizing flow-based generative model for scientific data superresolution that incorporates uncertainty quantification into the super-resolution process. PSRFlow learns the conditional distribution of the high-resolution data based on the low-resolution counterpart. By sampling from a Gaussian latent space that captures the missing information in the high-resolution data, one can generate different plausible super-resolution outputs. The efficient sampling in the Gaussian latent space allows our model to perform uncertainty quantification for the super-resolved results. During model training, we augment the training data with samples across various scales to make the model adaptable to data of different scales, achieving flexible super-resolution for a given input. Our results demonstrate superior performance and robust uncertainty quantification compared with existing methods such as interpolation and GAN-based super-resolution networks.


Hierarchical self-assembly of designed 2 x 2-alpha-helix bundle proteins on Au(111) surfaces.
Self-assembled monolayers of biomolecules on atomically planar surfaces offer the prospect of complex combinations of controlled properties, e.g., for bioelectronics. We have prepared a novel hemi-4-alpha-helix bundle protein by attaching two alpha-helical peptides to a cyclo-dithiothreitol (cyclo-DTT) template. The protein was de novo designed to self-assemble in solution to form a 4-alpha-helix bundle, whereas the disulfide moiety enables the formation of a self-assembled monolayer on a Au(111) surface by opening of the disulfide, thus giving rise to a two-step self-assembly process. The 2 x 2-alpha-helix bundle protein and its template were studied by X-ray photo electron spectroscopy (XPS), electrochemical methods, and electrochemical in situ scanning tunneling microscopy (in situ STM). XPS showed that the cyclo-DTT opens on adsorption to a gold surface with the integrity of the 2 x 2-alpha-helix bundle proteins retained. The surface properties of the DTT and 2 x 2-alpha-helix bundle protein adlayer were characterized by interfacial capacitance and impedance techniques. Reductive desorption was used to determine the coverage of the adlayers, giving values of 65 and 16 muC cm(-2) for DTT and 2 x 2-helix, respectively. The 2 x 2-alpha-helix bundle protein adlayers were imaged by in situ STM. The images indicated a dense monolayer according with the voltammetric data. No long-range order could be detected, but two clearly distinct STM contrasts were assigned to 2 x 2-alpha-helix bundle protein molecules oriented in parallel and antiparallel conformations. The template molecule DTT alone forms highly ordered 30-40 nm domains, giving an adlayer density which agreed well with the coverage determined by voltammetry. This could be exploited in STM imaging of mixed DTT/2 x 2-alpha-helix bundle protein monolayers, with clearly distinct STM patterns of the two components.


Floristic-functional variation of tree component along an altitudinal gradient in araucaria forest areas, in Southern Brazil.
We aimed to investigate the taxonomic and functional variations of tree component of Araucaria Forest (AF) areas located along an altitudinal gradient (700, 900 and 1,600 m asl), in the southern region of Brazil. The functional traits determined were leaf area, specific leaf area, wood density, maximum potential height and dispersal syndromes and deciduousness. The data were analyzed through a functional and taxonomic dissimilarity dendrograms, community-weighted mean trait values, parametric and nonparametric tests, and Principal Component Analysis. The largest floristic-structural similarity was observed between the lower altitude areas (700 and 900 m asl), whose Bray-Curtis distance was 0.63. The area at 700 m asl was characterized by a predominance of deciduous and semi-deciduous species, with a high number of self- and wind-dispersed species, whereas the area at 1,600 m asl exhibited a predominance of animal-dispersed and evergreen species. It was also observed that there were significant variations for leaf traits, basic wood density and maximum potential height. Over all altitudinal gradient, the ordinations indicated that there was no evidence of functional differentiation among dispersal and deciduousness groups. In conclusion, the evaluated Araucaria Forest areas presented high floristic-functional variation of the tree component along the altitudinal gradient.


Spinal cord injury: how can we improve the classification and quantification of its severity and prognosis?
The preservation of functional neural tissue after spinal cord injury (SCI) is the basis for spontaneous neurological recovery. Some injured patients in the acute phase have more potential for recovery than others. This fact is problematic for the construction of clinical trials because enrollment of subjects with variable recovery potential makes it difficult to detect effects, requires large sample sizes, and risks Type II errors. In addition, the current methods to assess injury and recovery are non-quantitative and not sensitive. It is likely that therapeutic combinations will be necessary to cause substantially improved function after SCI, thus we need highly sensitive techniques to evaluate changes in motor, sensory, autonomic and other functions. We review several emerging neurophysiological techniques with high sensitivity. Quantitative methods to evaluate residual tissue sparing after severe acute SCI have not entered widespread clinical use. This reduces the ability to correlate structural preservation with clinical outcome following SCI resulting in enrollment of subjects with varying patterns of tissue preservation and injury into clinical trials. We propose that the inclusion of additional measures of injury severity, pattern, and individual genetic characteristics may enable stratification in clinical trials to make the testing of therapeutic interventions more effective and efficient. New imaging techniques to assess tract injury and demyelination and methods to quantify tissue injury, inflammatory markers, and neuroglial biochemical changes may improve the evaluation of injury severity, and the correlation with neurological outcome, and measure the effects of treatment more robustly than is currently possible. The ability to test such a multimodality approach will require a high degree of collaboration between clinical and research centers and government research support. When the most informative of these assessments is determined, it may be possible to identify patients with substantial recovery potential, improve selection criteria and conduct more efficient clinical trials.


[The role of local immunity in chronic recurrent intraoral herpes].
Chronic recurrent herpetic stomatitis is an acute infectious disease caused by various types of herpes simplex virus. Patients showed various manifestations of immunodeficiency indicating that herpes infection as a disease of immune system. Our results confirm the influence of herpes on the state of the local immunity of the oral cavity. The correlation of the severity of chronic recurrent herpes sores and the amount of virus excreted allows determining the expected duration of the disease and treatment time.


Response of alanine metabolism in humans to manipulation of dietary protein and energy intakes.
Healthy young adult men were studied with 3 different series of dietary regimens: different levels of protein intake ranging from 1.5 to 0.0 g . kg-1 . day-1; different levels of dietary energy intake; and an excessive intake of protein (3.9 g . kg-1 . day-1). Under each dietary condition, subjects were infused postabsorptively with L-[1-13C]leucine, L-[15N]alanine, and L-[3,3,3-2H3]alanine to measure leucine and alanine kinetics. Leucine flux was significantly reduced when protein intake was restricted (maximum reduction = 24%), but changed insignificantly with dietary energy change or excessive protein intake. Alanine flux and de novo synthesis increased significantly when protein intake was restricted (maximum increase = 50%), changed proportionally with changes in dietary energy, and was significantly reduced with high protein intake. Stepwise regression showed that dietary carbohydrate intake, not protein intake, was the primary factor affecting alanine de novo synthesis. In addition, the alanine 2H tracer produced a 2.5-fold greater measure of alanine de novo synthesis than did the alanine 15N tracer.


[The important role of professor doctor Milovan Milovanovitsh in contemporary suicidology].
The paper deals with the important role of professor Milovan Milovanovitsh in contemporary suicidology. His monograph "Suicide", published in 1929, is a classical and excellent book in which medicolegal, psychosocial, statistical and preventive aspects of suicide are analyzed. His visionary ideas characterize this suicidologic manual, and many of his statements are widely accepted in modern science, e.g. definition of suicide, necessity of multidisciplinary approach in suicidological studies, analysis of suicidal predisposition and motives, concept of "appeal" phenomenon in suicidal behaviour, importance of suicidal announcements and attempts, characteristics of suicides in different periods and social conditions, making of the autopsy-anamnestic method for diagnosis of suicide, problems of prevention of suicide, etc. The work of Milovan Milovanovitsh was the important and primary basis for further suicidologic studies.


Polymorphisms of the farnesyl diphosphate synthase gene modulate bone changes in response to atorvastatin.
Although their primary therapeutic indications are different, aminobisphosphonates and statins target enzymes in the mevalonate pathway, which is critical for bone homeostasis. Previous studies have shown that some polymorphisms of the gene encoding farnesyl diphosphate synthase (FDPS), the main target of aminobisphosphonates, modulate the response to these drugs. In this study, we explored whether those single nucleotide polymorphisms (SNPs) also influence the changes in bone mineral density (BMD) following therapy with statins. Sixty-six patients with coronary heart disease were studied at baseline and after 1-year therapy with atorvastatin. BMD was measured by DXA. Three SNPs of the FDPS gene (rs2297480, rs11264359 and rs17367421) were analyzed by using Taqman assays. The results showed that there was no association between the SNPs and basal BMD. However, rs2297480 and rs11264359 alleles, which are in linkage disequilibrium, were associated with changes in hip BMD following atorvastatin therapy. Thus, patients with AA genotype at the rs2297480 locus had a 0.8 ± 0.8 % increase in BMD at the femoral neck, whereas in patients with AC/CC genotypes, BMD showed a 2.3 ± 0.8 % decrease (p = 0.02). Similar results were obtained regarding changes of BMD at the femoral trochanter and when alleles at the rs11264359 locus were analyzed. However, there was no association between BMD and rs17367421 alleles. In conclusion, these results suggest that polymorphisms of the FDPS gene may influence the bone response to various drugs targeting the mevalonate pathway, including not only aminobisphosphonates but also statins.


Whole-genome ChIP-chip analysis of Dorsal, Twist, and Snail suggests integration of diverse patterning processes in the Drosophila embryo.
Genetic studies have identified numerous sequence-specific transcription factors that control development, yet little is known about their in vivo distribution across animal genomes. We determined the genome-wide occupancy of the dorsoventral (DV) determinants Dorsal, Twist, and Snail in the Drosophila embryo using chromatin immunoprecipitation coupled with microarray analysis (ChIP-chip). The in vivo binding of these proteins correlate tightly with the limits of known enhancers. Our analysis predicts substantially more target genes than previous estimates, and includes Dpp signaling components and anteroposterior (AP) segmentation determinants. Thus, the ChIP-chip data uncover a much larger than expected regulatory network, which integrates diverse patterning processes during development.


Down-regulation of catalase activity allows transient accumulation of a hydrogen peroxide signal in Chlamydomonas reinhardtii.
In photosynthetic organisms, excess light is a stress that induces production of reactive oxygen species inside the chloroplasts. As a response, the capacity of antioxidative defence mechanisms increases. However, when cells of Chlamydomonas reinhardtii were shifted from dark to high light, a reversible partial inactivation of catalase activity was observed, which correlated with a transient increase in the level of H2 O2 in the 10 μm range. This concentration range seems to be necessary to activate H2 O2 -dependent signalling pathways stimulating the expression of H2 O2 responsive genes, such as the heat shock protein HSP22C. Catalase knock-down mutants had lost the transient accumulation of H2 O2 , suggesting that a decrease in catalase activity was the key element for establishing a transient H2 O2 burst. Catalase was inactivated by a one-electron event consistent with the reduction of a single cysteine. We propose that under high light intensity, the redox state of the photosynthetic electron transport chain is sensed and transmitted to the cytosol to regulate the catalase activity. This allows a transient accumulation of H2 O2 , inducing a signalling event that is transmitted to the nucleus to modulate the expression of chloroplast-directed protection enzymes.


Psoriatic skin molecular and histopathologic profiles after treatment with risankizumab versus ustekinumab.
IL-23 contributes to the activation, maintenance, and proliferation of TH17 cells and plays a major role in psoriasis pathophysiology. IL-23p19 inhibition with risankizumab resulted in superior clinical responses in patients with psoriasis compared with ustekinumab (dual IL-12/IL-23 inhibitor), but comparative molecular effects have not been established. We investigated the similarities and differences in molecular and histopathologic profiles in skin lesions from patients with psoriasis receiving risankizumab versus ustekinumab at an early time point. Lesional skin biopsy samples from 81 patients with moderate-to-severe plaque psoriasis participating in 2 different studies (a phase I risankizumab study and a phase II study of risankizumab vs ustekinumab) were analyzed by using histopathology, immunohistochemistry, and RNA sequencing. Risankizumab induced a rapid decrease in levels of proteins and transcriptomic biomarkers associated with the IL-23 pathway, which were maintained through 8 weeks. At week 4, risankizumab decreased histopathologic expression of biomarkers, including K16, Ki67, CD3, lipocalin-2, CD11c, dendritic cell lysosome-associated membrane glycoprotein, β-defensin 2, and S100A7; global histopathologic scoring revealed that 54% and 69% of patients treated with 90 or 180 mg of risankizumab, respectively, were graded as experiencing "excellent improvement" versus 29% of patients treated with ustekinumab. At week 4, there was a common decrease in expression of 2645 genes expressed in lesional skin between patients receiving risankizumab and ustekinumab and a significant decrease in 2682 genes unique to risankizumab treatment. Risankizumab more strongly downregulated expression of genes associated with keratinocytes, epidermal cells, and monocytes, versus ustekinumab. Risankizumab demonstrated more pronounced changes in the molecular and histopathologic profile of psoriatic skin lesions compared with ustekinumab at week 4.


Photopatterning of fluorescent host-guest carriers through pore activation of metal-organic framework single crystals.
Encoded fluorescent particles are fabricated through the selective uptake of dyes in photopatterned metal-organic framework single crystals. The concept is based on spatially controlled photochemical cleavage of pore-blocking pendant groups. Because of the crystalline and porous nature of the host, this approach enables guest uptake that is tunable and can be triggered though controlled irradiation.


Molecular mapping of the major epitopes of BP180 recognized by herpes gestationis autoantibodies.
Herpes gestationis (HG) is an autoantibody-mediated subepidermal bullous dermatosis associated with pregnancy. The primary target of HG autoantibodies is BP180, a 180-kDa hemidesmosomal glycoprotein. We previously showed that autoantibodies and autoimmune T lymphocytes from HG patients recognize the MCW-1 antigenic site (AA 507-520), which is located in the membrane-proximal noncollagenous domain (NC16A) of BP180. Here, we analyzed the sera of 37 HG patients to further define the sites on BP180 that are targeted by autoantibodies. All of the HG sera, but none of the control sera, were immunoreactive with sec180e, a 120-kDa recombinant protein encompassing the entire BP180 extracellular domain. HG sera depleted of reactivity to NC16A no longer reacted with sec180e, indicating that the major HG-associated epitopes on BP180 are restricted to the NC16A domain. The vast majority of the HG sera (34 of 37) reacted with a 7 amino acid peptide corresponding to the N-terminal half of MCW-1 (MCW-1A). Eleven HG sera (including the 3 that failed to react with MCW-1A) recognized one or more of three antigenic sites located within a 15 amino acid stretch immediately downstream of MCW-1A. In summary, we have identified four major HG-associated epitopes clustered within a 22 amino acid region of the BP180 ectodomain. These findings support the hypothesis that an autoimmune response to the BP180 NC16A domain is a crucial step in the pathogenesis of HG.


Classification of ovarian carcinomas based on pathology and molecular genetics.
Malignant epithelial tumours (carcinomas) are the most common ovarian cancers and the most lethal gynaecological malignancies. Based on light microscopy and molecular genetics, ovarian carcinomas are subdivided into at least five main subtypes that account for over 95% of cases and are inherently different diseases, as indicated by differences in epidemiological and genetic risk factors, precursor lesions, patterns of spread, molecular events during oncogenesis, response to chemotherapy and outcome. For successful subtype-specific treatment, reproducible pathological diagnosis of tumour cell type is critical. Recent investigations have also demonstrated that a significant number of cancers traditionally thought to be primary ovarian tumours (particularly serous, endometrioid and clear cell carcinomas) originate in the fallopian tube and the endometrium and involve the ovary secondarily. In this review we summarise recent advances in the molecular pathology, which have greatly improved our understanding of the biology of ovarian carcinoma and are also relevant to patient management.


Allergy and asthma.
Initiation and regulation of allergic inflammation is influenced by many factors, including cell type, membrane receptors, and mediators generated. Furthermore, the altered response of targeted tissues (ie, airway smooth muscle) becomes important to the eventual expression of asthma. Finally, the genetic regulation and association of genetic polymorphisms has enhanced our understanding of host susceptibility. In this review key findings published in 2004 issues of the Journal of Allergy and Clinical Immunology are highlighted to demonstrate recent advances in these areas.


Resistance to competitive neuromuscular blocking agents in burn patients: a review.
The quantitative and qualitative aspects of the phenomenon of resistance to competitive (non-depolarizing) neuromuscular blocking agents in burn patients are described. The correlates and temporal features of this resistance are discussed, in addition to therapeutic approaches and the possible mechanisms underlying the resistance.


Metabolic modulation of sympathetic vasoconstriction in exercising skeletal muscle.
The tight coupling of oxygen supply and utilization in exercising skeletal muscle is the result of complex interactions between local mechanisms that control muscle blood flow and substrate utilization and systemic mechanisms that control cardiac output and arterial pressure. The role of the sympathetic nervous system in the integration of these responses, specifically the interaction between sympathetic activation and local vasodilator mechanisms in exercising muscle, has been an active area of research for many years yet remains incompletely understood. The functional consequence of sympathetic activation in exercising skeletal muscle has been the subject of considerable debate. Previous studies in animals and humans have suggested that sympathetic vasoconstricton in active muscle is (a) well maintained and serves to limit active hyperaemia, thereby preventing muscle blood flow from outstripping cardiac output in order to preserve blood pressure and vital organ perfusion or (b) greatly attenuated in order to optimize muscle perfusion, a concept that has been termed 'functional sympatholysis'. Studies performed over the past 70 years have provided conflicting evidence regarding the relative importance of sympathetic vasoconstriction vs. functional sympatholysis in exercising skeletal muscle. The focus of this review is mainly on recent studies in anaesthetized animal preparations and in conscious humans that have provided evidence for the metabolic modulation of sympathetic vasoconstriction in contracting skeletal muscle and have identified a number of key underlying mechanisms that extend the initial concept of sympatholysis.


Glucose: a continuous risk factor for cardiovascular disease.
The glucose level that defines diabetes mellitus is that level above which patients have a high risk of eye, kidney, and neuronal disease. The risk of these complications rises as glucose levels increase, and decreases as therapy brings the glucose level down. Thus, in patients with diabetes, glucose is a continuous, modifiable risk factor for eye, kidney and peripheral nerve disease. Plasma glucose concentrations in the diabetic range are also a continuous risk factor for cardiovascular disease (CVD). Moreover, epidemiological evidence shows that the relationship between plasma glucose concentration and CVD extends well below the glucose level defined for diabetes and even impaired glucose tolerance. This continuous relationship between glucose and CVD exists in all people, not just in those with a defined metabolic disease, and is therefore similar to the relationship between cholesterol or blood pressure and CVD. It may be secondary to either a direct effect of elevated glucose or to some underlying metabolic abnormality that raises both glucose and cardiovascular risk. Whether interventions that lower glucose will also lower the risk of CVD is still unknown; the results of clinical trials are awaited.


Effects of group B Streptococcus on the responses to U46619, endothelin-1, and noradrenaline in isolated pulmonary and mesenteric arteries of piglets.
The release of endogenous vasoconstrictors together with changes in the vascular responses are central to the pathophysiology of sepsis. The effects of in vitro incubation for 20 h with heat-killed group B Streptococcus (GBS, 3 x 10(7) colony-forming units mL-1) on the vasoconstrictor responses to noradrenaline (NA, 10(-8) to 10(-4) M), the thromboxane A2 analog 9,11-dideoxy-11 alpha, 9 alpha-epoxymethanoprostaglandin F2 alpha (U46619; 10(-10) M to 10(-6) M) and endothelin-1 (ET-1, 10(-11) to 3 x 10(-9) M) were evaluated on isolated intrapulmonary and mesenteric arteries from 10-17-d-old piglets. The incubation with GBS reduced the maximal contractile response to NA and ET-1 (p < 0.01) in both arteries. The nitric oxide (NO) synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 10(-4) M) completely reversed this hyporesponsiveness. GBS-treated mesenteric arteries also showed a significant reduction of the maximal contractions induced by U46619 (p < 0.05) and this effect was inhibited by 10(-4) M L-NAME. In contrast, the maximal contractile responses to U46619 were similar in control and in GBS-treated pulmonary arteries. Addition of L-NAME did not modify the contractile responses to U46619 in GBS-treated pulmonary arteries. In conclusion, GBS-treated systemic arteries from neonatal piglets showed decreased responses to NA, U46619, and ET-1 due to enhanced NO release. GBS-treated pulmonary arteries also exhibited decreased responses to NA and ET-1 but not to U46619. Induction of NOS in vascular smooth muscle may play a key role in the hypotension and loss of systemic vascular responsiveness that occurs in GBS sepsis. The absence of pulmonary hyporesponsiveness to U46619 may partially explain the coexistence during sepsis of pulmonary hypertension and lung NOS induction.


Detached leaf and whole plant assays for soybean aphid resistance: differential responses among resistance sources and biotypes.
The soybean aphid, Aphis glycines Matsumura, is a pest of cultivated soybean, Glycine max (L.) Merr., in North America. Recent developments in host plant resistance studies have identified at least four soybean aphid resistance genes (Rag1-4) and two soybean aphid biotypes (biotype 1 and 2), defined by differential survivability on resistant soybean. Detached soybean leaves were tested as a more rapid and practical assay to assess host plant resistance and virulence. Two susceptible lines ('Wyandot' and 'Williams 82') and two resistant lines (PI 243540 and PI 567301B) were examined. Various life history characteristics were compared among aphids on whole plants and detached leaves. Results indicated that resistance to soybean aphid was lost using detached leaves of PI 567301B but retained with PI 243540. To test for aphid virulence, net fecundities were compared among biotype 1 and biotype 2 after rearing on detached leaves of the resistant 'Jackson' (to which biotype 2 is virulent). A significant difference was detected in net fecundities among biotypes on detached leaves of Jackson and used to predict growth rates and virulence from 30 field-collected individuals of unknown virulence. No field individuals matched biotype 2 predictions, but four individuals had higher net fecundities than biotype 2 predictions (13%) and could be considered moderately virulent. The results indicated that the retention of soybean aphid resistance in detached leaves is dependent on PI and resistant source, but if resistance is retained, detached leaves could be used to determine soybean aphid virulence.


Insulin resistance and obesity in childhood.
Childhood obesity is a significant health problem that has reached epidemic proportions around the world and is associated with several metabolic and cardiovascular complications. Insulin resistance is a common feature of childhood obesity and is considered to be an important link between adiposity and the associated risk of type 2 diabetes and cardiovascular disease. Insulin resistance is also a key component of the metabolic syndrome, and its prevalence in the paediatric population is increasing, particularly among obese children and adolescents. Several factors are implicated in the pathogenesis of obesity-related insulin resistance, such as increased free fatty acids and many hormones and cytokines released by adipose tissue. Valid and reliable methods are essential to assess the presence and the extent of insulin resistance, the associated risk factors and the effect of pharmacological and lifestyle interventions. The two most common tests to assess insulin resistance are the hyperinsulinemic euglycemic clamp and the frequently sampled i.v. glucose tolerance test utilizing the minimal model. However, both these tests are not easily accomplished, are time consuming, expensive and invasive. Simpler methods to assess insulin resistance based on surrogate markers derived from an oral glucose tolerance test or from fasting insulin and glucose levels have been validated in children and adolescents and widely used. Given the strong association between obesity, insulin resistance and the development of metabolic syndrome and cardiovascular disease, prevention and treatment of childhood obesity appear to be essential to prevent the development of insulin resistance and the associated complications.


Information content in fluorescence correlation spectroscopy: binary mixtures and detection volume distortion.
When properly implemented, fluorescence correlation spectroscopy (FCS) reveals numerous static and dynamic properties of molecules in solution. However, complications arise whenever the measurement scenario is complex. Specific limitations occur when the detection region does not match the ideal Gaussian geometry ubiquitously assumed by FCS theory, or when properties of multiple fluorescent species are assessed simultaneously. A simple binary solution of diffusers, where both mole fraction and diffusion constants are sought, can face interpretive difficulty. In order to better understand the limits of FCS, this study systematically explores the relationship between detection-volume distortion, diffusion constants, species mole fraction, and fitting methodology in analyses that utilize a two-component autocorrelation model. FCS measurements from solution mixtures of dye-labeled protein and free dye are compared to simulations, which predict the performance of FCS under a variety of experimental circumstances. The results reveal a range of conditions necessary for performing accurate measurements and describe experimental scenarios that should be avoided. The findings also provide guidelines for obtaining meaningful measurements when grossly distorted detection volumes are utilized and generally assess the latent information contained in FCS datasets.


Effects of a nutrient-enriched water on water intake and indices of hydration in healthy domestic cats fed a dry kibble diet.
OBJECTIVE To evaluate the effects of drinking nutrient-enriched water (NW) on water intake and indices of hydration in healthy domestic cats fed a dry kibble diet ad libitum. ANIMALS 18 domestic shorthair cats. PROCEDURES Group-housed cats were assigned to tap water (TW; n = 9) or NW (9) groups. All cats received TW at baseline (days -7 to -1). No changes were made to the food-water regimen for the TW group. The NW group received NW instead of TW from days 0 through 10, then received TW and NW in separate bowls (days 11 through 56). Food intake was measured through day 10; liquid consumed by drinking was measured throughout the study. Blood and urine samples were collected at predetermined times for analyses; 48-hour urine collection (days 28 through 30 or 31 through 33) was performed to assess output volume and aid endogenous creatinine-based glomerular filtration rate (GFR) determination. Data were analyzed with linear mixed-effects models. RESULTS Baseline TW and calorie intake were similar between groups. The NW treatment was significantly associated with increased liquid consumption during the treatment phase. Mean urine output was significantly higher in the NW group (15.2 mL/kg/d) than in the TW group (10.3 mL/kg/d). Mean GFR (1.75 vs 1.87 mL/min/kg, respectively) did not differ between groups. Effects of treatment and time were each significant for urine specific gravity and osmolality and urine creatinine, phosphate, and urea nitrogen concentrations, with lower values for the NW group. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that consumption of the NW can increase liquid intake and improve measures of hydration in healthy cats. These effects may offer health benefits to some cats in need of greater water consumption.


The role of antioxidant enzymes in the control of opossum sphincter of Oddi motility.
Superoxide rapidly oxidizes nitric oxide (NO) to form peroxynitrite, thus terminating the biological activity of NO. The aims of our study were to determine if superoxide alters the motor function of the sphincter of Oddi and to localize the antioxidant enzymes in the sphincter of Oddi. Immunostaining was performed and enzyme activities were measured in the sphincter of Oddi. In physiological experiments, force-displacement transducers recorded tension in the spontaneously contracting sphincter of Oddi and after electrical field stimulation (EFS) of precontracted sphincter of Oddi. Superoxide was generated by the addition of xanthine with xanthine oxidase, superoxide radicals were scavenged by the addition of superoxide dismutase (SOD), and catalase or SOD was inhibited by diethyldithiocarbamic acid. Immunostaining demonstrated SOD and catalase immunoreactivity in ganglia situated at the serosal surface of the circular muscle. Total SOD activity was 202 +/- 12 U/mg. Generation of superoxide or inhibition of SOD increased the contractile frequency and decreased relaxation after EFS. We conclude that superoxide alters sphincter of Oddi motor function, and the presence of superoxide scavenging enzymes in enteric plexuses suggests that they may regulate sphincter of Oddi neuromuscular function by clearing endogenous superoxide.


Financial Burdens of Cancer Treatment: A Systematic Review of Risk Factors and Outcomes.
Patients with cancer experience financial toxicity from the costs of treatment, as well as material and psychologic stress related to this burden. A synthesized understanding of predictors and outcomes of the financial burdens associated with cancer care is needed to underpin strategic responses in oncology care. This study systematically reviewed risk factors and outcomes associated with financial burdens related to cancer treatment. MEDLINE, Embase, PubMed, PsychINFO, and the Cochrane Library were searched from study inception through June 2018, and reference lists were scanned from studies of patient-level predictors and outcomes of financial burdens in US patients with cancer (aged ≥18 years). Two reviewers conducted screening, abstraction, and quality assessment. Variables associated with financial burdens were synthesized. When possible, pooled estimates of associations were calculated using random-effects models. A total of 74 observational studies of financial burdens in 598,751 patients with cancer were identified, among which 49% of patients reported material or psychologic financial burdens (95% CI, 41%-56%). Socioeconomic predictors of worse financial burdens with treatment were lack of health insurance, lower income, unemployment, and younger age at cancer diagnosis. Compared with patients with health insurance, those who were uninsured demonstrated twice the odds of financial burdens (pooled odds ratio [OR], 2.09; 95% CI, 1.33-3.30). Financial burdens were most severe early in cancer treatment, did not differ by disease site, and were associated with worse health-related quality of life (HRQoL) and nearly twice the odds of cancer medication nonadherence (pooled OR, 1.70; 95% CI, 1.13-2.56). Only a single study demonstrated an association with increased mortality. Studies assessing the comparative effectiveness of interventions to mitigate financial burdens in patients with cancer were lacking. Evidence showed that financial burdens are common, disproportionately impacting younger and socioeconomically disadvantaged patients with cancer, across disease sites, and are associated with worse treatment adherence and HRQoL. Available evidence helped identify vulnerable patients needing oncology provider engagement and response, but evidence is critically needed on the effectiveness of interventions designed to mitigate financial burden and impact.


Megakaryocyte interaction with subendothelial extracellular matrix is associated with adhesion, platelet-like shape change, and thromboxane A2 production.
We have examined the morphological and secretory behavior of rat and guinea pig megakaryocytes exposed for up to 24 hours to extracellular matrix produced by cultured bovine endothelial cells. By phase-contrast microscopy of living cells and in more detail by scanning electron microscopy, the megakaryocytes showed a nonreversible adherence, an extensive formation of filopodia around the periphery like the rays of the sun, and a tendency toward flattening. These filopodia were generally linear with attenuated tips and were larger than, but resembled the filopodia of, rat or guinea pig platelets exposed to this extracellular matrix. In contrast, isolated megakaryocytes on glass or on uncoated plastic surfaces did not show these responses; adherence, in the face of gentle agitation before fixation, was minimal, with rare filopodia and no flattening. Megakaryocytes that interacted with the extracellular matrix produced significant amounts of thromboxane A2, but this did not occur on uncoated surfaces and could not be attributed to other contaminating cells in the megakaryocyte suspensions. The appearance in megakaryocytes of these typical platelet responses indicates that megakaryocytes acquire the functional capabilities of platelets by the synthesis and assembly of platelet substances and organelles. Thromboxane production by megakaryocytes stimulated by the extracellular matrix is a readily quantifiable measure of this capacity.


Stroke care quality in China: Substantial improvement, and a huge challenge and opportunity.
Stroke is The first two authors contributed equally. the leading cause of death and adult disability in China. Although evidence-based clinical interventions have been identified to improve care and outcomes in stroke, significant gaps still exist between guideline recommendations and clinical practice in China. Regional and national stroke registries have been used to assess the benchmark of stroke care quality, provide feedback on compliance with evidence-based performance measures to health care providers, and continuously improve stroke care quality without increasing additional medical costs in the past several decades worldwide. In China, stroke care has become a national priority. A series of stroke care quality assessment and improvement actions was initiated by the Ministry of Health to increase the detection of high-risk populations with stroke, rate of adherence to evidence-based process performance measures of stroke care, and stroke care organization development, aiming to decrease the burden of stroke. China National Stroke Registries have been started in 2007, and they are conducted every 3 to 5 years. A carotid disease screen and intervention project for communities was initiated in 2009. The Chinese Stroke Association, founded in 2015, launched the Chinese Stroke Center Alliance to increase the stroke center design in the near future. In this article, we described these stroke care actions and progression, summarized the benchmark and improvement of stroke care quality, and outlined the future plans in China.


Investigation of Consensually Nonmonogamous Relationships.
We proposed that the premise that monogamy is the exemplary form of romantic partnership underlies much theory and research on relationship quality, and we addressed how this bias has prompted methodological issues that make it difficult to effectively address the quality of nonmonogamous relationships. Because the idea that consensually nonmonogamous (CNM) relationships are functional (i.e., satisfying and of high quality) is controversial, we included a basic study to assess, in a variety of ways, the quality of these relationships. In that study, we found few differences in relationship functioning between individuals engaged in monogamy and those in CNM relationships. We then considered how existing theories could help researchers to understand CNM relationships and how CNM relationships could shed light on relationship processes, and we proposed a model of how CNM and monogamous relationships differ. Finally, in a second study, we determined that even researchers who present data about CNM are affected by the stigma surrounding such relationships. That is, researchers presenting findings favoring polyamory were perceived as more biased than researchers presenting findings favoring monogamy.


Children eroticized by incest.
The assumption that children involved in incest are passive, unwilling victims is an oversimplification of a complex situation. Young children may find such relationships gratifying and, when exposed over time to intense genital and extragenital stimulation, they often become highly erotic. This hypermature responsiveness may be viewed as learned behavior; the behavior is self-reinforcing and may be difficult to modify. The author describes three children to illustrate their arousal, inability to differentiate sensual from affectionate touch, early gender discrimination, and stereotyped role modeling. Foster homes are neither trained nor supported in caring for these children, so serial placements are common.


GSH-triggered release of sulfur dioxide gas to regulate redox balance for enhanced photodynamic therapy.
Herein, a promising strategy is explored to regulate redox balance in tumor cells by simultaneously consuming GSH and releasing SO2 gas for enhanced photodynamic therapy. The photosensitizer is loaded with a carrier that releases SO2 gas in response to GSH overexpressed in the cell. SO2 was found not only to induce cell apoptosis but also increase the intercellular ROS level. Meanwhile, the loaded-photosensitizers could also generate ROS with light irradiation, resulting in apoptosis or necrosis of cells.


[Effect of carvedilol on blood levels of cytokines and symptoms of heart failure in patients with postinfarction cardiac dysfunction.].
Effect of 6 months treatment with carvedilol (25 mg/day) on blood levels of cytokines (interleukins 1alpha, 2, 6, 8, tumor necrosis factor alpha) and clinical symptoms of heart failure was studied in patients with cardiac dysfunction after myocardial infarction. Patients with NYHA class II heart failure, ejection fraction 50% and moderately lowered tolerance to physical exercise (n=21) initially had enhanced cytokine expression: blood content of interleukin (IL) 2 was 2.8 times, tumor necrosis factor (TNFalpha) 78%, IL-1alpha 60% above normal level. Therapy with carvedilol in this group was associated with decreases of Il-2 (-23.8%), TNFalpha (-16.7%), IL-1alpha (-12.5%) (p<0.05-0.01). This was accompanied by alleviation of clinical symptoms and improved exercise tolerance. Patients with NYHA class III heart failure (n=16) with low left ventricular ejection fraction (30+/-2.7%) and low exercise tolerance had high levels of all studied cytokines. Levels of IL-2, TNFalpha and IL-1alpha were most elevated (3.1, 2.8 and 2 times higher than normal values, respectively). Therapy with carvedilol was associated with improvement of clinical symptoms and exercise tolerance (+35%, p<0.05)), increase of ejection fraction (+15%, p<0.05), decrease of left ventricular end systolic volume (-17.5%, p<0.05), and lowering of blood levels of TNFalpha (-31%), IL-2 (-17.4%), IL-1alpha (-15.6%). However cytokine levels remained substantially elevated compared with normal values. Carvedilol was well tolerated, and did not cause negative metabolic effects or other complications.


Perinatal fluoxetine prevents the effect of pre-gestational maternal stress on 5-HT in the PFC, but maternal stress has enduring effects on mPFC synaptic structure in offspring.
Maternal affective disorders are frequently treated with selective serotonin reuptake inhibitor medications (SSRIs); with up to 10% of women being prescribed these medications during pregnancy. Infant development depends on the early serotonergic environment, which is altered by perinatal SSRIs, raising concern about how these medications affect neural outcomes. While clinical and preclinical research suggests an impact of SSRIs on the developing brain, more research is needed to determine the effects on neuroplasticity, the serotonergic system, and the hypothalamic-pituitary-adrenal axis in neural regions mediating behavior. The current work investigated the effects of the SSRI, fluoxetine, on the serotonergic system in the prefrontal cortex (PFC) during pre-adolescence, and changes to synaptic markers and glucocorticoid receptor density in the cingulate cortex (medial PFC) of pre-adolescent and adult Sprague-Dawley male and female rats. To model aspects of Perinatal Depression and maternal anxiety, pre-gestational maternal stress was used resulting in male and female offspring from 4 groups: 1) control, 2) perinatal fluoxetine exposed, 3) pre-gestational maternal stress exposed, and 4) pre-gestational maternal stress + fluoxetine. Perinatal fluoxetine prevented the effects of maternal stress on 5-HT levels and 5-HT turnover ratio in the PFC of pre-adolescent offspring, particularly in females. However, pre-gestational stress reduced synaptophysin and PSD-95 densities in the cingulate cortex, effects that were more pronounced in males. Interestingly, perinatal fluoxetine exposure reduced GR density in adult males in this same brain area. Together, results show differential effects of perinatal SSRIs and pre-gestational maternal stress on neurodevelopment in the PFC of males and females.


Effects of gamma radiation on solid trisodium citrate dihydrate: radical kinetics, radiosensitivity and dosimetry.
In the present work, radiosensitivity and dosimetric potential of solid trisodium citrate dihydrate (SC) were explored through a detailed electron spin resonance (ESR) study performed at various temperatures. Irradiated SC was observed to exhibit an ESR spectrum consisting of many intense and weak resonance lines spread over a magnetic field range of 7 mT and centered at g = 2.0039. An evaluation technique based on the variations of the characteristic resonance line intensities and the spectrum area under different experimental conditions was adopted, to determine the spectroscopic, kinetic and dosimetric features of radical species responsible for the observed experimental ESR spectrum. Radicals exhibiting similar ESR characteristics to those reported in the literature for irradiated tricarboxilic acids and their organic compounds were shown to be also produced in gamma-irradiated SC.


An unusual case of strychnine poisoning.
Strychnine-related death has been described since the 19th century. This alkaloid was discovered in 1818. Historically, strychnine was used by the South-East Asian autochthones on their arrows. However, its production was modified by legislation, which was used to protect people against accidental intoxications. Here, we present the case of a 69-year-old man who was found dead at home. During the autopsy, we found a blue substance in the stomach. Toxicological analysis measured strychnine at 0.29 μg/mL in the blood sample, which is a relatively low level in comparison with the results given in the literature. However, histologic examination and toxicological findings permitted the conclusion of strychnine poisoning.


Osteopathic primary care of patients with inflammatory bowel disease: a review.
Ulcerative colitis and Crohn disease are relatively common inflammatory diseases of the gastrointestinal tract that have unknown causes. A combination of abnormalities in genetics, the immune system, and the microbiome of the gut may cause inflammatory bowel disease (IBD). The majority of patients with IBD are in their late teens or early twenties. Most present to their primary care physician for a diagnosis. Although gastroenterologists and surgeons do most of the endoscopy and management of IBD, these patients require a great deal of health maintenance that many never receive. Osteopathic primary care physicians can play a pivotal role in the care of patients with IBD by understanding what areas of the body are affected by the disease and what screening and monitoring are needed to keep patients healthy with the highest quality of life possible.


[Heart rate variability in untrained young men under different power loading modes].
To study features of variability of a rhythm of heart at unexercised young men under the influence of power loadings in the conditions of appication of certain training modes in the course of long occupations by athleticism. 40 young men participated in ispections at the age of 19-20 years, not having contraindications for occupations with burdenings. Research of indicators training loading of both groups used by representatives in the course of occupations conducted a method of definition of an index of training loading in athleticism. For determination of values of indicators of the statistical and spectral analysis of a rhythm of Polar RS800CX cardiomonitor was used. Control of studied indicators at rest and after power loading carried out for 3months of occupations by athleticism with an interval in 1 month. Use in the course of occupations by athleticism of power loadings with large volume of work and low intensity considerably increases activity of the central mechanisms of neurohumoral regulation of a rhythm of heart due to decrease in panasympathetic activation of autonomous nervous system on sinusovy knot of heart, than loading of high intensity with a small volume of work. The result of long-term adaptation to occupations by athleticism, in the conditions of different modes of loading, is characterized by existence of an ekonomization of functioning of cardiovascular system of the unexercised contingent.


Regulation of B cell antigen receptor signal transduction and phosphorylation by CD45.
CD45 is a member of a family of membrane proteins that possess phosphotyrosine phosphatase activity, and is the source of much of the tyrosine phosphatase activity in lymphocytes. In view of its enzymatic activity and high copy number, it seems likely that CD45 functions in transmembrane signal transduction by lymphocyte receptors that are coupled to activation of tyrosine kinases. The B cell antigen receptor was found to transduce a Ca(2+)-mobilizing signal only if cells expressed CD45. Also, both membrane immunoglobulin M (mIgM) and CD45 were lost from the surface of cells treated with antibody to CD45, suggesting a physical interaction between these proteins. Finally, CD45 dephosphorylated a complex of mIg-associated proteins that appears to function in signal transduction by the antigen receptor. These data indicate that CD45 occurs as a component of a complex of proteins associated with the antigen receptor, and that CD45 may regulate signal transduction by modulating the phosphorylation state of the antigen receptor subunits.


Blood pressure reduction during treatment for alcohol dependence: results from the Combining Medications and Behavioral Interventions for Alcoholism (COMBINE) study.
Heavy drinking is associated with hypertension. This study evaluated blood pressure changes occurring during treatment for alcohol dependence. Subjects included 1383 people participating in the Combining Medications and Behavioral Interventions for Alcoholism (COMBINE) study, a large multi-center treatment study for alcohol dependence. Methods appropriate for repeated-measures data were used to assess the relationship of percentage of drinking days (PDD) to systolic and diastolic blood pressure over a 16-week treatment period. Modification of these associations by demographic and other variables was assessed. Blood pressure reduction was evident only in people who were above the median blood pressure at baseline. In this group, systolic blood pressure decreased by an average of 12 mmHg and diastolic blood pressure decreased by an average of 8 mmHg. Blood pressure reduction occurred during the first month of treatment. This effect was similar regardless of age, sex, body mass index, reported history of hypertension and use of anti-hypertensive medications. An observed association between blood pressure and PDD in Caucasians was not evident in African Americans due largely to their lower pre-treatment blood pressure. Reduction in alcohol consumption has a potent anti-hypertensive effect in alcoholics with higher blood pressure. For hypertensive, alcohol-dependent people, treatment for alcoholism should be considered a major component of anti-hypertensive therapy.


[Indications for the use of inosine in myocardial infarct (a clinical and experimental study)].
The effect of the nucleoside Inosie-F (inosin) on the intracardiac hemodynamics and the contraction and relaxation of a diseased myocardium was studied in the clinic and in experiments. An examination was made of 102 patients with macrofocal myocardial infarction (22 received inosin by intravenous drip in a single dose of 200 mg in the acute stage of infarction; 60 patients were given inosin pills in a daily dose of 800 mg in the restoration period for one month, and 20 patients were given placebo). Comparative appraisal of treatment in the period of rehabilitation showed prevailing improvement in the condition of individuals treated with inosin, positive ECG dynamics, increase of cardiac output and decrease of peripheral resistance. In experiments on 28 dogs with a model of acute myocardial ischemia a noticeable improvement in myocardial contraction and relaxation in the absence of negative ECG dynamics was recorded after intravenous infusion of inosin. Inosin achieves maximum effect by 60-90 mins after the beginning of infusion.


Qualities of caregiver-child interaction during daily activities of children born very low birth weight with and without white matter disorder.
The purpose of this study was to examine qualities of caregiver-child interactions during daily activities of healthy children born full-term and of children born prematurely and very low birth weight with and without white matter disorder. Three groups of 12 caregiver-child dyads, representing three levels of child biological risk, were matched on birth history, maternal education, ethnicity, and child gender. Ten expert clinicians used videotapes to rate behaviors of caregivers and their 30-month-old children engaging in dressing and snack activities. Correlations between ratings of three qualities were examined: caregiver directiveness, caregiver engagement, and child engagement. There were no significant differences between groups for the average caregiver and child ratings. However, correlations between caregiver directiveness and caregiver engagement ranged across the three groups from greatest to least biological risk (i.e., r= .63, .35, -.67, respectively). In the full-term group, correlations between the caregiver qualities of directiveness and engagement and child engagement were r= .62 and -.69, respectively. In contrast, the correlations between the caregiver and child qualities were small in the two very-low-birth-weight groups. Results suggest patterns of caregiver interactions during daily activities may vary according to the child's level of biological risk. Caregivers of children with the greatest risk (i.e., white matter disorder) were both engaging and directive of their children during the activities, whereas caregivers of full-term children were less engaging when directive. The findings suggest that caregivers may be adjusting the level of their social and emotional assistance during caregiver-child interactions to the level of their children's abilities.


Initiation of DNA synthesis by human papillomavirus E7 oncoproteins is resistant to p21-mediated inhibition of cyclin E-cdk2 activity.
The E6 and E7 proteins from the high-risk human papillomaviruses (HPVs) bind and inactivate the tumor suppressor proteins p53 and Rb, respectively. In HPV-positive cells, expression of E6 proteins from high-risk types results in increased turnover of p53, which leads to an abrogation of p21-mediated G1/S arrest in response to DNA-damaging agents. In contrast, keratinocytes which express E7 alone have increased levels of p53 but, interestingly, also fail to undergo a G1/S arrest. We investigated the mechanism by which E7 bypasses this p21 arrest by using both keratinocytes which stably express E7 as well as U20S cells which stably or transiently express E7. We observed that E7 does not affect the induction of p21 synthesis by p53. While glutathione S-transferase (GST)-E7 bound a low level of in vitro-translated p21, we were unable to detect E7 and p21 in the same complex by GST-E7 binding assays or immunoprecipitations from cell extracts. Furthermore, E7 did not prevent p21-mediated inhibition of cyclin E kinase activity. In keratinocytes expressing E7, increased levels of p53, p21, and cyclin E, as well as increased cyclin E kinase activity, were observed. To determine if this increase in cyclin E activity was necessary for E7's ability to overcome p21-mediated G1/S arrest, we examined U20S cells in which cyclin E levels are not increased in response to E7 expression. U20S cells which stably express E7 were found to initiate DNA synthesis in the presence of DNA-damaging agents despite the inhibition of cyclin E activity by p21. In transient assays, cotransfection of E7 or E2F-1 along with p21 into U20S cells rescued G1 arrest and resulted in S-phase entry, as measured by the ability to incorporate bromodeoxyuridine. These data indicate that E7 is able to overcome G1/S arrest without directly affecting p21 function and likely acts through deregulation of E2F activity.


Comparison of the boronic acid disk potentiation test and cefepime-clavulanic acid method for the detection of ESBL among AmpC-producing Enterobacteriaceae.
Extended spectrum β-lactamase (ESBL) and AmpC β-lactamase are important mechanisms of betalactam resistance among Enterobacteriaceae . The ESBL confirmation test described by Clinical Laboratory Standards Institute (CLSI) is in routine use. This method fails to detect ESBL in the presence of AmpC. Therefore, we compared two different ESBL detection methods against the CLSI confirmatory test. A total 200 consecutive clinical isolates of Enterobacteriaceae from various clinical samples were tested for ESBL production using (i) CLSI described phenotypic confirmatory test (PCT), (ii) boronic acid disk potentiation test and (iii) cefepime-CA disk potentiation method. AmpC confirmation was done by a modified three-dimensional test. Among total 200 Enterobacteriaceae isolates, 82 were only ESBL producers, 12 were only AmpC producers, 55 were combined ESBL and AmpC producers, 14 were inducible AmpC producers and 37 isolates did not harboured any enzymes. The CLSI described PCT detected ESBL-producing organisms correctly but failed to detect 36.3% of ESBLs among combined enzyme producers. The boronic acid disk potentiation test reliably detected all ESBL, AmpC, and combined enzyme producers correctly. The cefepime-CA method detected all ESBLs correctly but another method of AmpC detection has to be adopted. The use of boronic acid in disk diffusion testing along with the CLSI described PCT enhances ESBL detection in the presence of AmpC betalactamases.


NEP: web server for epitope prediction based on antibody neutralization of viral strains with diverse sequences.
Delineation of the antigenic site, or epitope, recognized by an antibody can provide clues about functional vulnerabilities and resistance mechanisms, and can therefore guide antibody optimization and epitope-based vaccine design. Previously, we developed an algorithm for antibody-epitope prediction based on antibody neutralization of viral strains with diverse sequences and validated the algorithm on a set of broadly neutralizing HIV-1 antibodies. Here we describe the implementation of this algorithm, NEP (Neutralization-based Epitope Prediction), as a web-based server. The users must supply as input: (i) an alignment of antigen sequences of diverse viral strains; (ii) neutralization data for the antibody of interest against the same set of antigen sequences; and (iii) (optional) a structure of the unbound antigen, for enhanced prediction accuracy. The prediction results can be downloaded or viewed interactively on the antigen structure (if supplied) from the web browser using a JSmol applet. Since neutralization experiments are typically performed as one of the first steps in the characterization of an antibody to determine its breadth and potency, the NEP server can be used to predict antibody-epitope information at no additional experimental costs. NEP can be accessed on the internet at http://exon.niaid.nih.gov/nep.


Sex-specific transcriptomic responses to changes in the nutritional environment.
Males and females typically pursue divergent reproductive strategies and accordingly require different dietary compositions to maximise their fitness. Here we move from identifying sex-specific optimal diets to understanding the molecular mechanisms that underlie male and female responses to dietary variation in Drosophila melanogaster. We examine male and female gene expression on male-optimal (carbohydrate-rich) and female-optimal (protein-rich) diets. We find that the sexes share a large core of metabolic genes that are concordantly regulated in response to dietary composition. However, we also observe smaller sets of genes with divergent and opposing regulation, most notably in reproductive genes which are over-expressed on each sex's optimal diet. Our results suggest that nutrient sensing output emanating from a shared metabolic machinery are reversed in males and females, leading to opposing diet-dependent regulation of reproduction in males and females. Further analysis and experiments suggest that this reverse regulation occurs within the IIS/TOR network.


Inhibition of mTOR or MAPK ameliorates vmhcl/myh7 cardiomyopathy in zebrafish.
Myosin heavy chain 7 (MYH7) is a major causative gene for hypertrophic cardiomyopathy, but the affected signaling pathways and therapeutics remain elusive. In this research, we identified ventricle myosin heavy chain like (vmhcl) as a zebrafish homolog of human MYH7, and we generated vmhcl frameshift mutants. We noted vmhcl-based embryonic cardiac dysfunction (VEC) in the vmhcl homozygous mutants and vmhcl-based adult cardiomyopathy (VAC) phenotypes in the vmhcl heterozygous mutants. Using the VEC model, we assessed 7 known cardiomyopathy signaling pathways pharmacologically and 11 candidate genes genetically via CRISPR/Cas9 genome editing technology based on microhomology-mediated end joining (MMEJ). Both studies converged on therapeutic benefits of mTOR or mitogen-activated protein kinase (MAPK) inhibition of VEC. While mTOR inhibition rescued the enlarged nuclear size of cardiomyocytes, MAPK inhibition restored the prolonged cell shape in the VEC model. The therapeutic effects of mTOR and MAPK inhibition were later validated in the VAC model. Together, vmhcl/myh7 loss of function is sufficient to induce cardiomyopathy in zebrafish. The VEC and VAC models in zebrafish are amenable to both efficient genetic and chemical genetic tools, offering a rapid in vivo platform for discovering candidate signaling pathways of MYH7 cardiomyopathy.


Distribution of gold Au 198 after intraperitoneal injection in animals.
The distribution of gold Au 198 after intraperitoneal administration in dogs and rats was determined by scans and tissue radioassays obtained 24 hours after injection. Relative activity and percent of injected radioisotope contained in different organs were calculated. The radioisotope was found to be heavily concentrated in mediastinal lymph nodes and liver, with liver uptake averaging 36.5% of the injected isotope 24 hours after injection. The use of therapeutic intracavitary radiocolloids should be reevaluated in light of possible excessive irradiation of the liver.


Livestock vaccination programme participation among smallholder farmers on the outskirts of National Parks and Tiger Reserves in the Indian states of Madhya Pradesh and Assam.
Effective livestock vaccination has the potential to raise prosperity and food security for the rural poor in low and middle income countries. To understand factors affecting access to vaccination services, and guide future policy, smallholder farmers in three locations in India were questioned about vaccination of their cattle and buffalo, with particular reference to foot and mouth disease (FMD), haemorrhagic septicaemia (HS) and blackquarter (BQ). In the three regions 51%, 50%, and 31% of respondents reported vaccinating their livestock; well below any threshold for effective population level disease control. However, within the third region, 65% of respondents in villages immediately surrounding the Kaziranga National Park reported vaccinating their cattle. The majority of respondents in all three regions were aware of FMD and HS, awareness of BQ was high in the Kanha and Bandhavgarh regions, but much lower in the Kaziranga region. The majority of respondents had positive attitudes to vaccination; understood vaccination protected their animals from specific diseases; and wished to immunise their livestock. There was no significant association between the age or gender of respondent and the immunisation of their livestock. Common barriers to immunisation were: negative attitudes to vaccination; lack of awareness of date and time of vaccination events; and difficulty presenting animals. Poor access to vaccination services was significantly associated with not vaccinating livestock. Fear of adverse reactions to vaccines was not significantly associated with not vaccinating livestock. Respondents who reported that vets or animal health workers (AHWs) were their main source of animal health knowledge were significantly more likely to have immunised their livestock in the last twelve months. Participants cited poor communication from vaccinators as problematic, both in publicising immunisation programmes, and explaining the purpose of vaccination. Where vaccinations were provided free of charge, farmers commonly displayed passive attitudes to accessing vaccination services, awaiting organised "immunisation drives" rather than seeking vaccination themselves. Based on these findings the following recommendations are made to improve participation and effectiveness of immunisation programmes. Programmes should be planned to integrate with annual cycles of: disease risk, agricultural activity, seasonal climate, social calendar of villages; and maximise efficiency for vaccinators. Dates and times of immunisation in each village must be well publicised, as respondents frequently reported missing the vaccinators. Relevant farmer education should precede immunisation programmes to mitigate against poor knowledge or negative attitudes. Immunisation drives must properly engage beneficiaries, particularly ensuring that services are accessible to female livestock keepers, and sharing some responsibilities with local farmers. Payment of a small monetary contribution by animal keepers could be considered to encourage responsibility for disease prevention, making vaccination an active process by farmers.


Integrated care clinic: Creating enhanced clinical pathways for integrated behavioral health care in a family medicine residency clinic serving a low-income, minority population.
Research examining the implementation and effectiveness of integrated behavioral health (BH) care in family medicine/primary care is growing. However, research identifying ways to consistently use integrated BH in busy family medicine/primary care settings with underserved populations is limited. This study describes 1 family medicine clinic's transformation into a fully integrated BH care clinic through the development of an Integrated Care Clinic (ICC) and enhanced clinical pathways to promote regular use of behavioral health clinicians (BHCs). We implemented the ICC at the Broadway Family Medicine Clinic serving a low-income (<$25,000 annual income/year) and minority population (>70% African American) in Minnesota. We conducted a pre- and postevaluation of the ICC during regular clinic activity. Pilot findings indicated that the creation of ICC and the use of enhanced clinical pathways (e.g., 5-2-1-0 obesity prevention messages, Transitional Care Management, postpartum depression screening visits, warm hand-offs) to facilitate regular use of integrated BH care resulted in 6 integrated care visits per BHC per clinic half-day. In addition, changes in the behavioral/mental health therapy appointment time slot (from 60 to 30 min) reduced therapy no-show rates. Transitional Care Management (TCM) visits also showed improved pre- and postchanges in patient and clinician satisfaction and reductions in patient hospital readmission rates. The transformation into a fully integrated BH family medicine clinic through the creation of ICC and enhanced clinical pathways to facilitate regular integrated BH care showed promising pilot results. Future research is needed to examine associations between ICC and patient outcomes (e.g., weight, depressive symptoms). (PsycINFO Database Record


Sublethal pesticide exposure influences behaviour, but not condition in a widespread Australian lizard.
Assessment of non-target impacts of pesticides used widely in agriculture and pest management rarely considers reptiles. Despite their integral role in all ecosystems, particularly arid ecosystems, reptiles are not included in risk assessments. Two pesticides used in agricultural pest management are fipronil and fenitrothion. Here, we used a field-based BACI design experiment in semi-arid Australia to investigate the impact of these pesticides on basic physiological and behavioural parameters of a common arid-zone lizard species, Pogona vitticeps. Fipronil and fenitrothion were applied at ecologically relevant doses via oral gavage. Before and after dosing, blood, physical activity and body condition parameters were assessed. We found that temperature significantly influenced lizard activity in the morning period of movement; however, fipronil-treated individuals moved at least 49% less than fenitrothion-treated and control lizards from 7 days after dosing through to the end of the experiment. Physiological measures did not change significantly before or after exposure to both pesticides; however, other indicators showed evidence of exposure, which remained for the entirety of our monitoring period. On average, cholinesterase inhibition was still >30% compared with control lizards at the end of 4 weeks, and fipronil sulfone blood residues remained at 0.219 μg/ml. Our study provides novel insights into the impacts that common pesticides have on widespread lizard species. We show that an ecologically relevant low dose of fipronil alters the behaviour of P. vitticeps, which has the potential to impact longer-term survivability. Persistence of both pesticides in the blood of all treatment lizards throughout the experiment indicates they are unable to clear these toxins within a month of being exposed. This may be significant for compounding exposure and latent toxicity. These findings highlight the susceptibility that reptiles have to a selection of common pesticides and the inherent need for higher prominence in wildlife ecotoxicological research.


The moral development of baccalaureate nursing students: understanding unethical behavior in classroom and clinical settings.
Unethical behavior in both classroom and clinical settings is a concern for nurse educators and has the potential to greatly influence the quality of patient care. A review of the literature suggests that students may view unethical clinical behaviors as different from unethical classroom behaviors because they recognize that clinical behaviors may have a direct effect on patient care. An overview of three moral theories, proposed by Kohlberg, Gilligan, and Rest, provides insight into the reasons for unethical behavior. These theories provide the foundation for strategies nurse educators can use to help reduce unethical behavior in both classroom and clinical settings in an attempt to ensure quality patient care.


A Vast Graveyard of Undead Theories: Publication Bias and Psychological Science's Aversion to the Null.
Publication bias remains a controversial issue in psychological science. The tendency of psychological science to avoid publishing null results produces a situation that limits the replicability assumption of science, as replication cannot be meaningful without the potential acknowledgment of failed replications. We argue that the field often constructs arguments to block the publication and interpretation of null results and that null results may be further extinguished through questionable researcher practices. Given that science is dependent on the process of falsification, we argue that these problems reduce psychological science's capability to have a proper mechanism for theory falsification, thus resulting in the promulgation of numerous "undead" theories that are ideologically popular but have little basis in fact.


Dual-Functional Surfaces Based on an Antifouling Polymer and a Natural Antibiofilm Molecule: Prevention of Biofilm Formation without Using Biocides.
Pathogenic biofilms formed on the surfaces of implantable medical devices and materials pose an urgent global healthcare problem. Although conventional antibacterial surfaces based on bacteria-repelling or bacteria-killing strategies can delay biofilm formation to some extent, they usually fail in long-term applications, and it remains challenging to eradicate recalcitrant biofilms once they are established and mature. From the viewpoint of microbiology, a promising strategy may be to target the middle stage of biofilm formation including the main biological processes involved in biofilm development. In this work, a dual-functional antibiofilm surface is developed based on copolymer brushes of 2-hydroxyethyl methacrylate (HEMA) and 3-(acrylamido)phenylboronic acid (APBA), with quercetin (Qe, a natural antibiofilm molecule) incorporated via acid-responsive boronate ester bonds. Due to the antifouling properties of the hydrophilic poly(HEMA) component, the resulting surface is able to suppress bacterial adhesion and aggregation in the early stages of contact. A few bacteria are eventually able to break through the protection of the anti-adhesion layer leading to bacterial colonization. In response to the resulting decrease in the pH of the microenvironment, the surface could then release Qe to interfere with the microbiological processes related to biofilm formation. Compared to bactericidal and anti-adhesive surfaces, this dual-functional surface showed significantly improved antibiofilm performance to prevent biofilm formation involving both Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus for up to 3 days. In addition, both the copolymer and Qe are negligibly cytotoxic, thereby avoiding possible harmful effects on adjacent normal cells and the risk of bacterial resistance. This dual-functional design approach addresses the different stages of biofilm formation, and (in accordance with the growth process of the biofilm) allows sequential activation of the functions without compromising the viability of adjacent normal cells. A simple and reliable solution may thus be provided to the problems associated with biofilms on surfaces in various biomedical applications.


Testing various scenarios to improve circulation in Golden Horn: A case study.
The Golden Horn (GH), as a consequence of heavy domestic and industrial discharges from Alibeykoy and Kagithane creeks, was heavily polluted for more than 50 years. As a result, the upstream area was filled with debris and organic solids, which produced unbearable odour in the past due to anaerobic decomposition of the organic matter in the sedimented zone. Istanbul Metropolitan Municipality (IBB) decided to develop new strategies of estuary management and pollution reduction. To this end, Golden Horn Environment Protection Project (GHEPP) was developed to transport 3m3/s of clean Black Sea water into GH through a diversion tunnel to keep circulation ongoing throughout the year. In this study, the performance of GHEPP is assessed by developing various scenarios. The relationship between Black Sea diversion flow (BSDF) and residence time is derived. The numerical tests highlight that BSDF is effective in reducing the residence time in the upstream, while in the downstream, exchange flows with the Bosphorus Strait (BS) is effective. Besides, the current patterns in the GH and exchange flow discharges with the BS are determined for three unique flow conditions occurring in the strait: (1) two-layer flow pattern, (2) one-layer flow patterns in the southern direction, and (3) one-layer flow pattern in the northern direction.


Effect of treatment with a topical ophthalmic preparation of 1% nalbuphine solution on corneal sensitivity in clinically normal horses.
To assess the effect of treatment with a topical ophthalmic preparation of 1.2% nalbuphine solution on corneal sensitivity in clinically normal horses. 8 horses. Baseline corneal touch threshold (CTT) was measured (defined as the mean filament length [mm] at which a consistent blink response was elicited) for both eyes of each horse by use of a Cochet-Bonnet aesthesiometer. Subsequently, 0.2 mL of 1.2% nalbuphine solution was instilled in 1 randomly selected eye of each horse, and 0.2 mL of artificial tears solution was instilled in the contralateral eye (control treatment). For all 8 horses, CTT of each eye was measured within 1 minute following nalbuphine or artificial tears administration and every 15 minutes thereafter for 60 minutes. For 5 of the 8 horses, CTT was also measured in both eyes at 120 minutes. Changes in CTT values from baseline over time were assessed, as were differences between treated and control eyes. At any time point, corneal sensitivity following nalbuphine treatment did not differ significantly from control treatment findings. Mean CTTs for nalbuphine-treated and control eyes were 38.8 and 37.9 mm, respectively. In both groups, CTT was significantly lower than baseline value at 15, 45, 60, and 120 minutes. No tearing or redness developed in any eye treated with nalbuphine. Topical administration of ophthalmic 1% nalbuphine solution had no effect on corneal sensitivity in clinically normal horses. The topical ocular treatment was not associated with local irritation.


Effect of grazing pastures with different botanical composition by lambs on rumen fatty acid metabolism and fatty acid pattern of longissimus muscle and subcutaneous fat.
In order to study the effect of grazing pastures with a different botanical composition on rumen and intramuscular fatty acid metabolism, 21 male lambs were assigned to three botanically different pastures: botanically diverse (BD) (consisting for 65% of a variety of grass species); Leguminosa rich (L) (consisting for 61% of Leguminosae) and intensive English ryegrass (IR) (with 69% Lolium perenne). Pastures were sampled weekly for 12 weeks for analysis of their fatty acid content and composition and on nine occasions to determine the botanical composition. Ruminal and abomasal contents were sampled at slaughter and muscle and subcutaneous fat 24 h after slaughter. All samples were prepared and analysed for fatty acid composition. The L pasture showed a higher fatty acid content (29.8 mg/g dry matter (DM) v. 18.5 and 25.5 mg/g DM, for BD and IR pastures, respectively), but the sum of the proportions of the major polyunsaturated fatty acids, C18:2 n-6 and C18:3 n-3, were similar for the three pastures (69.9, 69.4 and 71.1% of fatty acids methyl esters (FAME) for BD, L and IR pastures, respectively). The BD pasture was richer in C18:2 n-6 (18.2% of FAME), while IR pasture had a higher C18:3 n-3 content (57.2% of FAME). Rumen data showed that animals grazing the BD pasture presented higher proportions of biohydrogenation intermediates, mainly C18:1 t11, C18:2 t11c15 and CLA c9t11, suggesting an inhibition of biohydrogenation. These changes were associated with shifts in the rumen microbial population as indicated by differences in the rumen pattern of volatile fatty acids, microbial odd- and branched-chain fatty acids. In L pasture animals, the content of C18:2 n-6 and C18:3 n-3 in the abomasum and subcutaneous fat was higher. Finally, higher proportions of C20:4 n-6, C20:5 n-3 and C22:5 n-3 and higher indices for elongation and desaturation activity in the intramuscular fat of BD grazing animals suggest some stimulation of elongation and desaturation of long-chain fatty acids, although this also might have been provoked partially by reduced fat deposition (due to a lower growth rate of the animals).


Error analysis of the microradiographic determination of mineral content in mineralised tissue slices.
The microradiographic method, used to measure the mineral content in slices of mineralised tissues as a function of position, is analysed. The total error in the measured mineral content is split into systematic errors per microradiogram and random noise errors. These errors are measured quantitatively. Predominant contributions to systematic errors appear to be x-ray beam inhomogeneity, the determination of the step wedge thickness and stray light in the densitometer microscope, while noise errors are under the influence of the choice of film, the value of the optical film transmission of the microradiographic image and the area of the densitometer window. Optimisation criteria are given. We used these criteria, together with the requirement that the method be fast and easy, to build an optimised microradiographic system.


Serum sickness reaction to obinutuzumab in a patient with chronic lymphocytic leukaemia.
Serum sickness (SS) is a known phenomenon; however, it is commonly missed due to vague symptoms, and is usually confounded by other aetiologies that present similarly. Obinutuzumab is a novel anti-CD20 antibody agent that has been approved for chronic lymphocytic leukaemia (CLL) treatment. At the time of approval, it was not linked to SS; however, this phenomenon has been recognised with other anti-CD20 agents like rituximab. SS remains a rare entity, but it is important to be recognised accurately and quickly in the appropriate circumstances, so that effective treatment with corticosteroids can be initiated to alleviate inflammatory symptoms. Here we present a patient with CLL who developed maculopapular rash, fever and polyarthritis and elevated inflammatory markers consistent with serum sickness triggered by obinutuzumab and was effectively treated with corticosteroids.


[Treatment of multiple sclerosis and quality of life].
At the present time, the treatments available for multiple sclerosis (MS) are only partially effective, often expensive and with side-effects. This means that there are other variables in the use of drugs which may affect the quality of life. In this respect, some treatments may maintain the patient's quality of life rather than improving it. The quality of life test may serve as an instrument or tool to compare different treatments and permit suitable optimization of the equilibrium between risk and benefit, and the possible relation to the cost of the illness. There is no universally accepted test for quality of life in MS. We have tried to evaluate existing tests and find which best measures the specific aspects of quality of life in patients with MS.


Effects of endothelins on cardiac and vascular cells: new therapeutic target for the future?
The predominant isoform of the endothelin peptide family. endothelin-1 (ET-1) exerts various biological effects. These include effects on arterial smooth muscle cells causing intense vasoconstriction and stimulation of cardiac cells. ET-1 promotes changes in cardiomyocytes that are consistent with electrical remodelling such as changes in ionic current density and inhomogeneous prolongation of action potential duration resulting in increased dispersion. As for the underlying mechanisms, ET-1 was shown to suppress several cAMP-dependent ionic currents, such as ICa, IK and ICl in various mammalian cardiac preparations including human myocytes; however, the degree of suppression of these currents is different and highly dependent on experimental conditions. The proposed arrhythmogenic effects of ET-1 may also involve enhancement of Ca2+ release from intracellular stores, generation of IP3, and acidosis due to stimulation of the Na+/H+ exchange. Furthermore, ET-1 acts as the natural counterpart to endothelium-derived nitric oxide, which exerts vasodilator, antithrombotic and antiproliferative effects, and inhibits leukocyte adhesion to the vascular wall. Effects of ET-1 are mediated through interaction with two major types of cell surface receptors. ETA receptors have been associated with electrical remodelling, vasoconstriction and cell growth, while ETB receptors are involved in the clearance of ET-1, inhibition of endothelial apoptosis, release of NO and prostacyclins, and inhibition of the expression of ET-1 converting enzyme. The derangement of endothelial function in various cardiovascular diseases, such as cardiomyopathies, hypertension or arteriosclerosis, is a crucial element of the pathomechanism, thus ET receptors are considered as important therapeutic targets. Indeed, ET receptor antagonists may be able to preserve or restore endothelial integrity and may have antiarrhythmic properties; therefore, they are promising tools in cardiovascular medicine.


Significance of amino acid variation at human immunodeficiency virus type 1 reverse transcriptase residue 210 for zidovudine susceptibility.
Amino acid variation at reverse transcriptase (RT) codon 210 (generally Leu-210 to Trp [L210W], TTG-->TGG) is occasionally detected after the initiation of azidothymidine (AZT) therapy. The impact of this variation on AZT resistance and viral replication was addressed by four different approaches. The frequency and genetic background of the L210W mutation in vivo were assessed by analyzing sera of AZT-naive and AZT-experienced patients by RT-PCR and DNA sequencing. The degree of AZT resistance (50% infective concentration [IC50]) of recombinant viruses constructed by using the RT of 21 clinical isolates was stratified by the presence or absence of the 210 mutation. The AZT IC50S of a panel of mutant viruses (with or without W-210) constructed by site-directed mutagenesis in an HXB2 background were assayed by using a HeLa CD4 plaque reduction assay. Finally, the effect of the 210 mutation on viral replication was assessed by replication competition of an AZT-resistant virus, RTMN (L-41/Y-215), and RTMN with the W-210 mutation in the presence and in the absence of AZT. In AZT-naive patients, tryptophan at RT residue 210 was rare. After AZT exposure, W-210 appeared in a minority of those patients, most commonly in association with L-41 and Y-215. The presence of W-210 increased the AZTIC50 by two- to fourfold, as determined by both the recombinant virus assay and site-directed mutagenesis. A significant replication advantage in favor of the wild-type L-210 over W-210 was observed, although the selection against the 210 mutant was two- to threefold lower when the viruses were grown in the presence of 5 microM AZT. In summary, the L210W mutation appears to be of marginal significance, conferring approximately two- to fourfold-reduced sensitivity to AZT compared with similar AZT-resistant genomes with L-210. The selection pressure against W-210 may account for the modest proportion of patients in which W-210 appears in vivo.


Estimation of standardized phosphorus retention for corn, soybean meal, and corn-soybean meal diet in broilers.
Two experiments were conducted to estimate standardized phosphorus (P) retention (SPR) of corn, soybean meal (SBM), and corn-soybean meal (C-SBM) diet in broilers and verify the additivity of SPR for feed formulation of broilers. In total, ninety-six 22-d-old male broilers with similar BW were used in each experiment. After 3 d of acclimation, chicks were fasted for 24 h and then fed P-free, corn, SBM, or C-SBM diets, respectively for 4 h in experiment 1 or 72 h in experiment 2. In experiment 1, the results showed that the excreta collection time of 52 h (48 h after feed withdrawal) was adequate for the estimation of SPR. The basal endogenous P loss (EPL) of chicks fed the P-free diet was estimated to be 123±7 mg/52 h per bird. The values of SPR corrected by basal EPL were 37.6 and 50.5% for corn and SBM, respectively. The determined value of SPR of the C-SBM diet was very close (P>0.79) to the predicted summation of SPR from corn and SBM (44.4 vs. 43.5%). In experiment 2, the results showed that the excreta collection time of 96 h (24 h after feed withdrawal) was sufficient for the estimation of SPR. The basal EPL of chicks fed the P-free diet was estimated to be 85.4±4.0 mg/96 h per bird. The values of SPR corrected by basal EPL were 40.2 and 52.9% for corn and SBM, respectively. The determined value of SPR of the C-SBM diet was lower (P<0.001) than the predicted summation of SPR from corn and SBM (39.7 vs. 46.0%), which might be due to the effect of higher total P intake. The results from the current study demonstrated that the P-free diet could be used for measuring basal EPL in broilers and then estimating the SPR values of feedstuffs for broilers. However, the additivity of SPR in the diet formulation needs to be studied further.