Evaluating Trans-Benzocyclobutene-Fused Cyclooctene as a Monomer for Chemically Recyclable Polymer.
Chemically recyclable polymers offer a promising solution to address the issues associated with the unsustainable use of plastics by converting the traditional linear plastic economy into a circular one. Central to developing chemically recyclable polymers is to identify the appropriate monomers that enable practical conditions for polymerization and depolymerization and ensure useful stability and material properties. Our group has recently demonstrated that trans-cyclobutane-fused cyclooctene (tCBCO) meets the abovementioned requirements and is a promising candidate for developing chemically recyclable polymers. Herein, encouraged by the success with tCBCO, we investigate the thermodynamics of polymerization of a relevant system, trans-benzocyclobutene-fused-cyclooctene, which can be viewed as tCBCO with an additional benzene ring. The study shows that introducing an additional benzene ring favors polymerization and disfavors depolymerization, and the effect is predominantly entropic. The benzo-effect can be leveraged to fine-tune the thermodynamics of polymerization and depolymerization to facilitate the chemical recycling of polymers.


Theoretical model for gene-gene, gene-environment, and gene-sex interactions based on congenic-strain analysis of blood pressure in Dahl salt-sensitive rats.
There is a significant literature describing quantitative trait loci (QTL) controlling blood pressure (BP) in the Dahl salt-sensitive (S) rat. In studies to identify the genes underlying BP QTL it has been common practice to place chromosomal segments from low BP strains on the genetic background of the S rat and then reduce the congenic segments by substitution mapping. The present work suggests a model to simulate genetic interactions found using such congenic strains. The QTL are considered to be switches that can be either in series or in parallel represented by the logic operators AND or OR, respectively. The QTL switches can be on/off switches but are also allowed specific leak properties. The QTL switches are represented by a "universal" switch consisting of two molecules binding to form a complex. Genetic inputs enter the model as allelic products of one of the binding molecules and environmental variation (including dietary salt- and sex-related differences) enters as an influence on the concentration of the other binding molecule. The pairwise interactions of QTL are very well simulated and fall into recognizable patterns. There is, however, often more than one assumed model to predict a given pattern so that all patterns do not necessarily have a unique solution. Nevertheless, the models obtained provide a framework for placing the QTL in pathways relative to one another. Moreover, based on their leak properties pairs of QTL could be identified in which one QTL may alter the properties of the other QTL.


Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome.
In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), altered membrane excitability often occurs in exercising muscles demonstrating muscle dysfunction regardless of any psychiatric disorder. Increased oxidative stress is also present in many ME/CFS patients and could affect the membrane excitability of resting muscles. Seventy-two patients were examined at rest, during an incremental cycling exercise and during a 10-min post-exercise recovery period. All patients had at least four criteria leading to a diagnosis of ME/CFS. To explore muscle membrane excitability, M-waves were recorded during exercise (rectus femoris (RF) muscle) and at rest (flexor digitorum longus (FDL) muscle). Two plasma markers of oxidative stress (thiobarbituric acid reactive substance (TBARS) and oxidation-reduction potential (ORP)) were measured. Plasma potassium (K+) concentration was also measured at rest and at the end of exercise to explore K+ outflow. Thirty-nine patients had marked M-wave alterations in both the RF and FDL muscles during and after exercise while the resting values of plasma TBARS and ORP were increased and exercise-induced K+ outflow was decreased. In contrast, 33 other patients with a diagnosis of ME/CFS had no M-wave alterations and had lower baseline levels of TBARS and ORP. M-wave changes were inversely proportional to TBARS and ORP levels. Resting muscles of ME/CFS patients have altered muscle membrane excitability. However, our data reveal heterogeneity in some major biomarkers in ME/CFS patients. Measurement of ORP may help to improve the diagnosis of ME/CFS. Trial registration Ethics Committee "Ouest II" of Angers (May 17, 2019) RCB ID: number 2019-A00611-56.


Hairy-cell leukemia and alpha-interferon treatment: long-term responders.
In the 1980s alpha-interferon (alpha-IFN) dramatically improved the management of hairy cell leukemia (HCL), producing normalization of hematologic parameters including the disappearance of circulating hairy cells in the majority of treated patients, within 6 months. The quality and durability of the response depended on the duration of alpha-IFN treatment; progression of the disease consistently followed discontinuation of alpha-IFN. In this report, we examine the characteristics of long-term responders from our series of 44 HCL patients treated with alpha-IFN. We report follow-up data on 44 HCL patients who underwent alpha-IFN as first-line treatment between 1985 and 1990. The alpha-IFN dose was 3 x 10(6) U daily for 12-15 months, with 20 patients continuing to receive the same dose three times a week as maintenance treatment for an additional 6-12 months. Of the 44 patients, 8 achieved a CR, 28 a PR and 8 a MR, with an overall response rate of 82%. Thirty-eight (86%) of these patients showed disease progression and were retreated with alpha-IFN (2 pts), 2-chlorodeoxyadenosine (35 pts), or pentostatin (1 pt). So far, all 38 patients are alive and in good unmaintained second response, except for two patients who developed a second neoplasm. Six of the 8 first complete responders are alive and have not required further treatment after completing alpha-IFN. These long responders most often (5/6) presented a hairy cell index (HCI) < 0.50 at diagnosis; all 6 registered a significant reduction in bone marrow infiltration (HCI < 0.10) after induction therapy and underwent alpha-IFN maintenance treatment. These three parameters turned out to be statistically significant when the long-term responders were compared with the failure patients subset (p = 0.003 for HCI at diagnosis; p = 0.001 for HCI at the end of the induction phase; p = 0.003 for the maintenance phase). The median progression-free survival of these 6 long-term responders was 75 months (range, 62 to 78). Overall, alpha-IFN represents an excellent palliative treatment for most HCL patients. A small subset of these patients could become long-term responders following first-line alpha-IFN therapy alone.


Limitations of oxygen delivery to cells in culture: An underappreciated problem in basic and translational research.
Molecular oxygen is one of the most important variables in modern cell culture systems. Fluctuations in its concentration can affect cell growth, differentiation, signaling, and free radical production. In order to maintain culture viability, experimental validity, and reproducibility, it is imperative that oxygen levels be consistently maintained within physiological "normoxic" limits. Use of the term normoxia, however, is not consistent among scientists who experiment in cell culture. It is typically used to describe the atmospheric conditions of a standard incubator, not the true microenvironment to which the cells are exposed. This error may lead to the situation where cells grown in a standard "normoxic" oxygen concentration may actually be experiencing a wide range of conditions ranging from hyperoxia to near-anoxic conditions at the cellular level. This apparent paradox is created by oxygen's sluggish rate of diffusion through aqueous medium, and the generally underappreciated effects that cell density, media volume, and barometric pressure can have on pericellular oxygen concentration in a cell culture system. This review aims to provide an overview of this phenomenon we have termed "consumptive oxygen depletion" (COD), and includes a basic review of the physics, potential consequences, and alternative culture methods currently available to help circumvent this largely unrecognized problem.


Why are babies weaned early? Data from a prospective population based cohort study.
The recommended age of introduction of solids food to the diet of infants (weaning) has recently been increased in the UK to 6 months, but most babies are still weaned before the age of 4 months. To examine what predicts the age of weaning and how this relates to weight gain and morbidity using data from a population based cohort. Parents of 923 term infants born in a defined geographical area and recruited shortly after birth were studied prospectively using postal questionnaires, weaning diaries, and routinely collected weights, of whom 707 (77%) returned data on weaning. The median age of first weaning solids was 3.5 months, with 21% commencing before 3 months and only 6% after 4 months of age. Infants progressed quickly to regular solids with few reported difficulties, even when weaned early. Most parents did not perceive professional advice or written materials to be a major influence. The strongest independent predictors of earlier age at weaning were rapid weight gain to age 6 weeks, lower socioeconomic status, the parents' perception that their baby was hungry, and feeding mode. Weight gain after 6 weeks was unrelated to age of weaning. Babies weaned before 3 months, compared to after 4 months, had an increased risk of diarrhoea. Social factors had some influence on when weaning solids were introduced, but the great majority of all infants were established on solids before the previously recommended age of 4 months, without difficulty. Earlier weaning was associated with an increased rate of minor morbidity.


Modifiable factors associated with patient-reported pain during and after screening colonoscopy.
Pain associated with colonoscopy is a major burden for patients. We investigated modifiable factors associated with patient-reported pain during and after colonoscopy. This cross-sectional analysis included database records from 23 centres participating in a population-based colonoscopy screening programme in Poland. Colonoscopies were performed under three sedation modalities: none, benzodiazepine-opioid sedation or propofol sedation. We used Gastronet (a validated tool) to assess patients' pain during and after colonoscopy; pain was scored on a four-point scale (no, little, moderate or severe pain), with moderate to severe defined as painful. We used multivariate logistic regression models to estimate ORs for painful colonoscopy and calculated risk-adjusted ratios of painful colonoscopies per endoscopist and compared it to the mean rate. Of 35 216 screening colonoscopies in 2014 and 2015 included in our study, 22 725 (64.5%) patients returned valid Gastronet questionnaires. The proportion of examinations described as causing pain during (after) the procedure was 22.5% (14.2%) for unsedated, 19.9% (13.5%) for benzodiazepine-opioid sedation and 2.5% (7.5%) for propofol sedation. Propofol sedation, higher case volume of endoscopists, newest endoscope generation and adequate bowel preparation were significantly associated with lower odds of painful colonoscopy. Pain scores after colonoscopy showed similar associations. Adjusted pain rates during and after colonoscopy varied 11 and over 23-fold, respectively, between endoscopists. We identified several independent, modifiable factors associated with pain during and after colonoscopy, of which individual endoscopist was the most important. Dedicated training should be considered to decrease variability among endoscopists.


Genetically-predicted prefrontal DRD4 gene expression modulates differentiated brain responses to food cues in adolescent girls and boys.
The dopamine receptor 4 (DRD4) in the prefrontal cortex (PFC) acts to modulate behaviours including cognitive control and motivation, and has been implicated in behavioral inhibition and responsivity to food cues. Adolescence is a sensitive period for the development of habitual eating behaviors and obesity risk, with potential mediation by development of the PFC. We previously found that genetic variations influencing DRD4 function or expression were associated with measures of laboratory and real-world eating behavior in girls and boys. Here we investigated brain responses to high energy-density (ED) and low-ED food cues using an fMRI task conducted in the satiated state. We used the gene-based association method PrediXcan to estimate tissue-specific DRD4 gene expression in prefrontal brain areas from individual genotypes. Among girls, those with lower vs. higher predicted prefrontal DRD4 expression showed lesser activation to high-ED and low-ED vs. non-food cues in a distributed network of regions implicated in attention and sensorimotor processing including middle frontal gyrus, and lesser activation to low-ED vs non-food cues in key regions implicated in valuation including orbitofrontal cortex and ventromedial PFC. In contrast, males with lower vs. higher predicted prefrontal DRD4 expression showed minimal differences in food cue response, namely relatively greater activation to high-ED and low-ED vs. non-food cues in the inferior parietal lobule. Our data suggest sex-specific effects of prefrontal DRD4 on brain food responsiveness in adolescence, with modulation of distributed regions relevant to cognitive control and motivation observable in female adolescents.


Oregano: chemical analysis and evaluation of its antimalarial, antioxidant, and cytotoxic activities.
GC-FID and GC-MS analysis of essential oil from oregano leaves (Origanum compactum) resulted in the identification of 46 compounds, representing more than 98% of the total composition. Carvacrol was the predominant compound (36.46%), followed by thymol (29.74%) and p-cymene (24.31%). Serial extractions with petroleum ether, ethyl acetate, ethanol, and water were performed on aerials parts of Origanum compactum. In these extracts, different chemical families were characterized: polyphenols (gallic acid equivalent 21.2 to 858.3 g/kg), tannins (catechin equivalent 12.4 to 510.3 g/kg), anthocyanins (cyanidin equivalent 0.38 to 5.63 mg/kg), and flavonoids (quercetin equivalent 14.5 to 54.7 g/kg). The samples (essential oil and extracts) were subjected to a screening for antioxidant (DPPH and ABTS assays) and antimalarial activities and against human breast cancer cells. The essential oil showed a higher antioxidant activity with an IC50=2±0.1 mg/L. Among the extracts, the aqueous extract had the highest antioxidant activity with an IC50=4.8±0.2 mg/L (DPPH assay). Concerning antimalarial activity, Origanum compactum essential oil and ethyl acetate extract showed the best results with an IC50 of 34 and 33 mg/mL, respectively. In addition, ethyl acetate extract (30 mg/L) and ethanol extract (56 mg/L) showed activity against human breast cancer cells (MCF7). The oregano essential oil was considered to be nontoxic.


Alterations in membrane fluidity, lipid metabolism, mitochondrial activity, and lipophosphoglycan expression in pentamidine-resistant Leishmania.
Cytoplasmic and mitochondrial membranes were studied in wild-type promastigotes of Leishmania donovani and L. amazonensis treated with pentamidine and in the parasites resistant to this drug. Analyses by flow cytometry showed membrane fluidification in resistant cells and a modification of the lipidic metabolism in pentamidine-treated cells and in resistant clones as compared with wild-type ones. Pentamidine decreased the amounts of membrane polar lipids, i.e., phospholipids, and neutral lipidic droplets in the cytoplasm. Perturbation of lipid constituents did not induce modifications of membrane acid phosphatase and protease activities. Lipophosphoglycan, the major cell-surface glycoconjugate, was no longer detected by Western blotting in resistant cells. The use of rhodamine 123 showed a decrease in transmembrane mitochondrial potential in wild-type cells treated with pentamidine and in resistant parasites. In conclusion, cytoplasmic and mitochondrial membranes and lipidic metabolism are altered in pentamidine-resistant parasites.


Binge eating and weight control: the role of experiential avoidance.
Two thirds of the adults in the United States are overweight or obese. Binge eating is a barrier to treatment adherence and sustained weight loss, and can be seen as a form of experiential avoidance. The current study analyzed the impact of binge eating on weight reduction in a previously published study of a 1-day acceptance and commitment therapy (ACT) workshop (N = 83) and the psychological processes accounting for the binge-eating results. ACT participants reported less binge eating, which in turn significantly mediated changes in weight. Mediation analyses also showed that reductions in binge eating were mediated by changes in experiential avoidance. The study suggests that ACT and its targeted processes of change may be particularly relevant to binge eating, and that targeting binging is a possible pathway for improving weight management.


Evaluation of restriction endonuclease analysis of BRO beta-lactamases in clinical and carrier isolates of Moraxella catarrhalis.
A rapid increase in the prevalance of beta-lactamase producing M. catarrhalis isolates has highlighted its pathogenic potential. In this study, we aimed to detect the BRO beta-lactamases of our clinical (n = 32) and carrier (n =32) strains of Moraxella catarrhalis and compare the relationship of the enzyme type in assesment of MIC results of the antibiotics tested. BRO beta-lactamases were differentiated by restriction endonuclease analysis. Antibiotic susceptibility was performed by the agar dilution method recommended by NCCLS (M7A5). The clinical isolates produced 96.9%, whereas the carrier strains produced 90.6% beta-lactamase positivity by the restriction enzyme analysis. BRO-1 was isolated as 90.6% (n =29) while the BRO-2 and non-beta-lactamase producers (NBLP) were isolated as 6.3% (n =2) and 3.1% (n =1) respectively among clinical isolates. The rate of BRO-1 in the carrier strains was 75.0% (n =24), BRO-2 was 15.6% (n =5) and NBLP was 9.4%, (n =3). The beta-lactamase production with nitrocefin test was 96.9% (31/32) in clinical isolates and 90.6% (29/32) in carrier strains. M. catarrhalis needs a continous monitoring of antibiotic susceptibility; in this era restriction endonuclease analysis could be useful to screen BRO beta-lactamase genes.


Primary hybrid total hip replacement, performed with insertion of the acetabular component without cement and a precoat femoral component with cement. An average ten-year follow-up study.
One hundred and twenty-one primary hybrid total hip replacements were performed in 107 patients. A titanium, porous-coated, hemispherical acetabular component was fixed with screws, and a collared, chromium-cobalt femoral stem, with a roughened surface and a thin layer of methylmethacrylate on the proximal third, was inserted with contemporary cementing techniques (that is, use of a femoral medullary plug, a cement gun, and centrifugation and pressurization of the cement). Fifteen patients (fifteen hips) died before a minimum duration of follow-up of seven years, four patients (four hips) were too ill for a detailed follow-up examination at the time of the study, and two patients (two hips) refused to be evaluated at the time of the latest follow-up. None of these twenty-one hips had had a revision or a reoperation at the time of the latest follow-up. Eighty-six patients (100 hips) were available for clinical follow-up at an average of 120 months (range, eighty-four to 153 months) and for radiographic follow-up at an average of 118 months (range, eighty-four to 153 months). The average age of the patients at the time of the index arthroplasty was sixty-five years (range, forty-five to eighty-seven years). Three acetabular components were revised because of dissociation of the liner in association with a fracture of a locking tine. One well fixed acetabular component was revised because of pelvic osteolysis, and the femoral stem in the same patient was revised because of aseptic loosening. None of the ninety-six remaining acetabular components migrated, was classified as radiographically loose, or was revised because of aseptic loosening. Osteolytic lesions were identified adjacent to five acetabular components, and one of them was treated with bone-grafting around the well fixed acetabular shell. Two hips had a continuous radiolucent line at the interface between the acetabular implant and the bone. Three femoral stems had evidence of radiographic debonding (a radiolucent line that was one millimeter wide or less between the cement and the prosthesis), and they were classified as radiographically loose despite excellent clinical results. Seven hips had osteolytic areas located in the proximal aspect of the most proximal zones of Gruen et al., and five had small osteolytic regions in more distal areas. The Harris hip score for the eighty-two patients (ninety-six hips) who did not have a revision improved from 48 points (range, 22 to 70 points) preoperatively to 92 points (range, 53 to 100 points) at the most recent follow-up examination. Eighty-one patients had no, slight, or mild pain in the hip, and they were satisfied with the clinical result. In the present study, the hybrid total hip replacement with use of the Harris-Galante acetabular component and the Precoat femoral stem continued to provide an excellent result for most patients at an average of approximately ten years after the operation.


Immune Responses in Nucleus Basalis Magnocellularis-Lesioned Rats Exposed to Chronic Isolation Stress.
The present study was designed to establish the influence of chronic social isolation stress on humoral and cellular immunity in nucleus basalis magnocellularis (NBM)-lesioned rats. Therefore, ten days after bilateral electrolytic lesions of NBM, adult male Wistar rats were immunized with bovine serum albumin in complete Freund's adjuvant (BSA-CFA) and placed individually or in groups of five rats during 21 days. On days 10 and 21 after immunization, the Arthus and delayed hypersensitivity skin reactions to BSA as well as anti-BSA antibody production were determined. On day 10, the diameter and intensity of delayed hypersensitivity skin reaction to BSA were significantly higher in social-isolated rats in comparison with the group-reared ones. On day 21, the diameter and intensity of the Arthus skin reaction were significantly higher in social-isolated rats compared to group-reared rats. Between days 10 and 21, the diameter and intensity of the Arthus skin reaction significantly increased in social-isolated rats, while the diameter of delayed hypersensitivity skin reaction significantly decreased. In contrast to social-isolated rats, there were no significant differences in Arthus and delayed hypersensitivity skin reactions in group-reared rats, between days 10 and 21. Also there were no significant differences in the production of anti-BSA antibody between social-isolated and group-reared rats. The relative spleen weight was significantly lower in social-isolated rats. These data suggest that chronic isolation stress modify humoral and cellular immunity in NBM-lesioned rats.


The polypyrimidine tract binding protein (PTB) requirement for internal initiation of translation of cardiovirus RNAs is conditional rather than absolute.
Picornavirus RNAs are translated by an unusual mechanism of internal ribosome entry that requires a substantial segment of the viral 5'-untranslated region, generally known as the internal ribosome entry segment (IRES), and in some circumstances may require cellular trans-acting proteins, particularly polypyrimidine tract binding protein (PTB). It is shown here that for encephalomyocarditis virus (EMCV), the PTB dependence of IRES function in vitro is determined partly by the nature of the reporter cistron, and more especially by the size of an A-rich bulge in the IRES. With a wild-type EMCV IRES (which has a bulge of 6 As), translation is effectively independent of PTB provided the IRES is driving the synthesis of EMCV viral polyprotein. With an enlarged (7A) bulge and heterologous reporters, translation is highly dependent on PTB. Intermediate levels of PTB dependence are seen with a 7A bulge IRES driving viral polyprotein synthesis or a wild-type (6A) bulge IRES linked to a heterologous reporter. None of these parameters influenced the binding of PTB to the high-affinity site in the IRES. These results argue that PTB is not an essential and universal internal initiation factor, but, rather, that when it is required, its binding to the IRES helps to maintain the appropriate higher-order structure and to reverse distortions caused, for example, by an enlarged A-rich bulge.


Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains.
Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, and reductive aminations. The selectivity of the lead compound against other bromodomain family members was investigated using a thermal stability assay, which revealed some inhibition of the structurally related BET family members. To address the BET selectivity issue, X-ray crystal structures of the lead compound bound to the CREB binding protein (CBP) and the first bromodomain of BRD4 (BRD4(1)) were used to guide the design of more selective compounds. The crystal structures obtained revealed two distinct binding modes. By varying the aryl substitution pattern and developing conformationally constrained analogues, selectivity for CBP over BRD4(1) was increased. The optimized compound is highly potent (Kd = 21 nM) and selective, displaying 40-fold selectivity over BRD4(1). Cellular activity was demonstrated using fluorescence recovery after photo-bleaching (FRAP) and a p53 reporter assay. The optimized compounds are cell-active and have nanomolar affinity for CBP/p300; therefore, they should be useful in studies investigating the biological roles of CBP and p300 and to validate the CBP and p300 bromodomains as therapeutic targets.


The bioconcentration and bioaccumulation factors for molybdenum in the aquatic environment from natural environmental concentrations up to the toxicity boundary.
In a regulatory context, bioaccumulation or bioconcentration factors are used for considering secondary poisoning potential and assessing risks to human health via the food chain. In this paper, literature data on the bioaccumulation of molybdenum in the aquatic organisms are reviewed and assessed for relevance and reliability. The data available in the literature were generated at exposure concentrations below those recommended in the REACH registration dossiers for molybdenum compounds i.e. PNEC(freshwater) 12.7 mg Mo/L. To address possible environmental concerns at regulatorily-relevant molybdenum concentrations, both a field study and a laboratory study were conducted. In the field study, whole body and organ-specific molybdenum levels were evaluated in fish (eel, stickleback, perch, carp bream, roach) held in the discharge water collector tanks of a molybdenum processing plant, containing a mean measured molybdenum level of 1.03 mg Mo/L. In the laboratory study, rainbow trout were exposed to two different nominal molybdenum levels (1.0 and 12.7 mg Mo/L), for 60 days followed by a 60-day depuration period. Whole body concentrations in rainbow trout during the exposure period were between <0.20 and 0.53 mg Mo/L. Muscle tissue molybdenum concentrations in fish taken from both experiments remained below 0.2mg/kg dry wt. These studies show an inverse relationship between exposure concentration and bioconcentration or bioaccumulation factor for molybdenum. In aquatic organisms, and in fish in particular, internal molybdenum concentrations are maintained in the presence of variation in external molybdenum concentrations. These observations must be considered when evaluating potential risks associated with the bioconcentration and/or bioaccumulation of molybdenum in the aquatic environment.


Procalcitonin as a diagnostic and prognostic marker in diabetic foot infection. A current literature review.
Diabetic foot ulcers (DFUs) are a very common cause of mortality and morbidity. The distinction between infected and non-infected DFU remains a very challenging task for clinicians in everyday practice. Even when infection is documented, the spectrum of diabetic foot infection is wide, ranging from cellulitis and soft tissue infection to osteomyelitis. Procalcitonin (PCT), a well-established sepsis biomarker, has been used in the diagnosis of several infections including osteomyelitis in patients with diabetes mellitus. This review gathers and presents all the relevant data, up until now, regarding the use of PCT as an assessment tool in diabetic patients with foot infection. Current evidence suggests that PCT levels could aid clinicians in distinguishing infected from non-infected DFUs as well as in the distinction between soft tissue infection and bone involvement, but further and larger studies are warranted to confirm these findings.


Randomized Phase 2 Trial of Abiraterone Acetate Plus Prednisone, Degarelix, or the Combination in Men with Biochemically Recurrent Prostate Cancer After Radical Prostatectomy.
Phase 2 trial endpoints that can be utilized in high-risk biochemical recurrence (BCR) after prostatectomy as a way of more rapidly identifying treatments for phase 3 trials are urgently needed. The efficacy of abiraterone acetate plus prednisone (AAP) in BCR is unknown. To compare the rates of complete biochemical responses after testosterone recovery after 8 mo of AAP and degarelix, a gonadotropin-releasing hormone antagonist, alone or in combination. Patients with BCR (prostate-specific antigen [PSA] ≥1.0 ng/ml, PSA doubling time ≤9 mo, no metastases on standard imaging, and testosterone ≥150 ng/dl) after prostatectomy (with or without prior radiotherapy) were included in this study. Patients were randomized to AAP (arm 1), AAP with degarelix (arm 2), or degarelix (arm 3) for 8 mo, and monitored for 18 mo. The primary endpoint was undetectable PSA with testosterone >150 ng/dl at 18 mo. Secondary endpoints were undetectable PSA at 8 mo and time to testosterone recovery. For the 122 patients enrolled, no difference was found between treatments for the primary endpoint (arm 1: 5.1% [95% confidence interval {CI}: 1-17%], arm 2: 17.1% [95% CI: 7-32%], arm 3: 11.9% [95% CI: 4-26%]; arm 1 vs 2, p = 0.93; arm 2 vs 3, p = 0.36). AAP therapy showed the shortest median time to testosterone recovery (36.0 wk [95% CI: 35.9-36.1]) relative to degarelix (52.9 wk [95% CI: 49.0-56.0], p < 0.001). Rates of undetectable PSA at 8 mo differed between AAP with degarelix and degarelix alone (p = 0.04), but not between AAP alone and degarelix alone (p = 0.12). Limitations of this study include a lack of long-term follow-up. Rates of undetectable PSA levels with testosterone recovery were similar between arms, suggesting that increased androgen suppression with AAP and androgen deprivation therapy (ADT) is unlikely to eradicate recurrent disease compared with ADT alone. We evaluated the use of abiraterone acetate plus prednisone (AAP) and androgen deprivation therapy (ADT), AAP alone, or ADT alone in men with biochemically recurrent, nonmetastatic prostate cancer. While more men who received the combination had an undetectable prostate-specific antigen (PSA) level at 8 mo on treatment, once men came off treatment and testosterone level rose, there was no difference in the rates of undetectable PSA levels. This suggests that the combination is not able to eradicate disease any better than ADT alone.


Effects of alpha-difluoromethylornithine on the growth of 9L rat brain tumor multicellular spheroids and their response to 1,3-bis(2-chloroethyl)-1-nitrosourea.
9L rat brain tumor cell spheroids were treated with alpha-difluoromethylornithine (DFMO) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) alone and in combination. In contrast to results obtained with 9L monolayer culture cells, very low concentrations of DFMO killed spheroid cell within 0.5 day after the start of treatment; cell kill was maximum within 2 to 3 days. DFMO cytotoxicity could be prevented by adding putrescine (to a final concentration of 1 mM) to the culture medium. DFMO also significantly slowed and eventually stopped the growth of spheroids in a dose-dependent manner. Cells in all regions of DFMO-pretreated spheroids were sensitized to BCNU as measured by colony-forming efficiency; this sensitization was prevented when putrescine was added to culture medium before BCNU treatment. When used as single agents, either a 3-day treatment with 10 mM DFMO or a 1-hr treatment with BCNU (1.5 micrograms/ml) produced similar growth delay, but used in combination, the two agents produced a much longer growth delay than produced by either agent alone. Growth of spheroids treated continuously for up to 28 days with 10 mM DFMO ceased at approximately 7 times the volume at the time of treatment. When spheroid cells were treated for 1 hr with BCNU (1.5 micrograms/ml) and then were treated continuously with DFMO, growth plateaued at approximately 3.5 times the volume at the time of treatment; when spheroids were treated first with DFMO for 3 days, then with BCNU (1.5 micrograms/ml) for 1 hr, and then treated continuously with DFMO, growth plateaued at approximately 1.5 times the volume at the time of treatment. The number of clonogenic cells per spheroid that survived combination treatment also reflected the cytotoxic effects of the two drugs. Thus, the combined drug treatment was very effective in inhibiting the growth of spheroids and in preventing an increase in the number of clonogenic cells per spheroid.


Noncrossing quantile regression curve estimation.
Since quantile regression curves are estimated individually, the quantile curves can cross, leading to an invalid distribution for the response. A simple constrained version of quantile regression is proposed to avoid the crossing problem for both linear and nonparametric quantile curves. A simulation study and a reanalysis of tropical cyclone intensity data shows the usefulness of the procedure. Asymptotic properties of the estimator are equivalent to the typical approach under standard conditions, and the proposed estimator reduces to the classical one if there is no crossing. The performance of the constrained estimator has shown significant improvement by adding smoothing and stability across the quantile levels.


Expression of a specific variant surface glycoprotein has a major impact on suramin sensitivity and endocytosis in Trypanosoma brucei.
Suramin was introduced into the clinic a century ago and is still used to treat the first stage of acute human sleeping sickness. Due to its size and sixfold negative charge, uptake is mediated through endocytosis and the suramin receptor in trypanosomes is thought to be the invariant surface glycoprotein 75 (ISG75). Nevertheless, we recently identified a variant surface glycoprotein (VSGSur) that confers strong in vitro resistance to suramin in a Trypanosoma brucei rhodesiense line. In this study, we introduced VSGSur into the active bloodstream expression site of a T. b. brucei line. This caused suramin resistance and cross resistance to trypan blue. We quantified the endocytosis of different substrates by flow cytometry and showed that the expression of VSGSur strongly impairs the uptake of low-density lipoprotein (LDL) and transferrin, both imported by receptor-mediated endocytosis. However, bulk endocytosis and endocytosis of the trypanolytic factor were not affected, and the VSGSur -expressors did not exhibit a growth phenotype in the absence of suramin. Knockdown of ISG75 was synergistic with VSGSur expression, indicating that these two proteins are mediating distinct suramin resistance pathways. In conclusion, VSGSur causes suramin resistance in T. brucei bloodstream forms by decreasing specific, receptor-mediated endocytosis pathways.


Design and synthesis of fluorescent pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms.
Pilicides and curlicides are compounds that block the formation of the virulence factors pili and curli, respectively. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores. Several of the resulting fluorescent compounds had improved activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated with the bacteria with a heterogeneous distribution.


Traumatic brain injury among men in an urban homeless shelter: observational study of rates and mechanisms of injury.
Little empiric research has investigated the interrelationship between homelessness and traumatic brain injury. The objectives of this study were to determine the rate, mechanisms and associated outcomes of traumatic brain injury among men in an urban homeless shelter. We recruited participants from an urban men's shelter in Toronto, Ontario. Researchers administered the Brain Injury Screening Questionnaire, a semistructured interview screening tool for brain injury. Demographic information and detailed histories of brain injuries were obtained. Participants with positive and negative screening results were compared, and the rates and mechanisms of injury were analyzed by age group. A total of 111 men (mean age 54.2 ± standard deviation 11.5 yr; range 27-81 yr) participated. Nearly half (50 [45%]) of the respondents had a positive screening result for traumatic brain injury. Of these, 73% (35/48) reported experiencing their first injury before adulthood (< 18 yr), and 87% (40/46) reported a first injury before the onset of homelessness. Among those with a positive screening result, 33 (66%) reported sustaining at least one traumatic brain injury by assault, 22 (44%) by sports or another recreational activity, 21 (42%) by motor vehicle collision and 21 (42%) by a fall. A positive screening result was significantly associated with a lifetime history of arrest or mental illness and a parental history of substance abuse. Multiple mechanisms contributed to high rates of traumatic brain injury within a sample of homeless men. Assault was the most common mechanism, with sports and recreation, motor vehicle collisions and falls also being reported frequently by the participants. Injury commonly predated the onset of homelessness, with most participants experiencing their first injury in childhood. Additional research is needed to understand the complex interactions among homelessness, traumatic brain injury, mental illness and substance use.


Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension.
Clinical trials have failed to demonstrate an effective preventative or therapeutic strategy for bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disease in preterm infants frequently complicated by pulmonary hypertension (PH). Mesenchymal stem cells (MSCs) and their secreted components have been shown to prevent BPD and pulmonary fibrosis in rodent models. We hypothesized that treatment with conditioned media (CM) from cultured mouse bone marrow-derived MSCs could reverse hyperoxia-induced BPD and PH. Newborn mice were exposed to hyperoxia (FiO(2)=0.75) for two weeks, were then treated with one intravenous dose of CM from either MSCs or primary mouse lung fibroblasts (MLFs), and placed in room air for two to four weeks. Histological analysis of lungs harvested at four weeks of age was performed to determine the degree of alveolar injury, blood vessel number, and vascular remodeling. At age six weeks, pulmonary artery pressure (PA acceleration time) and right ventricular hypertrophy (RVH; RV wall thickness) were assessed by echocardiography, and pulmonary function tests were conducted. When compared to MLF-CM, a single dose of MSC-CM-treatment (1) reversed the hyperoxia-induced parenchymal fibrosis and peripheral PA devascularization (pruning), (2) partially reversed alveolar injury, (3) normalized lung function (airway resistance, dynamic lung compliance), (4) fully reversed the moderate PH and RVH, and (5) attenuated peripheral PA muscularization associated with hyperoxia-induced BPD. Reversal of key features of hyperoxia-induced BPD and its long-term adverse effects on lung function can be achieved by a single intravenous dose of MSC-CM, thereby pointing toward a new therapeutic intervention for chronic lung diseases.


Reduced exercise capacity in patients with tricuspid regurgitation after successful mitral valve replacement for rheumatic mitral valve disease.
To determine how severe tricuspid regurgitation influences exercise capacity and functional state in patients who have undergone successful mitral valve replacement for rheumatic mitral valve disease. 9 patients in whom clinically significant tricuspid regurgitation developed late after mitral valve replacement were compared with 9 patients with no clinical evidence of tricuspid regurgitation. The two groups were matched for preoperative clinical and haemodynamic variables. Patients were assessed by conventional echocardiography, Doppler echocardiography, and a maximal treadmill exercise test in which expired gas was monitored by mass spectrometry. University Hospital of Wales, Cardiff. 18 patients who had been reviewed regularly since mitral valve replacement. Objective indices of exercise performance including exercise duration, maximal oxygen consumption, anaerobic threshold, and ventilatory response to exercise. Mitral valve prosthetic function was normal in all patients and estimated pulmonary artery systolic pressure and left ventricular function were similar in the two groups. Right ventricular diameter (median (range) 5.0 (4.3-5.6) v 3.7 (3.0-5.4) cm, p less than 0.01) and the incidence of paradoxical septal motion (9/9 v 3/9, p less than 0.01) were greater in the group with severe tricuspid regurgitation. Exercise performance--assessed by exercise duration (6.3 (5.0-10.7) v 12.7 (7.2-16.0) min, p less than 0.01), maximum oxygen consumption (11.2 (7.3-17.8) v 17.7 (11.8-21.4) ml min-1 kg-1, p less than 0.01), and anaerobic threshold (8.3 (4.6-11.4) v 0.7 (7.3-15.5) ml min-1 kg-1, p less than 0.05)--was significantly reduced in the group with severe tricuspid regurgitation. The ventilatory response to exercise was greater in patients with tricuspid regurgitation (minute ventilation at the same minute carbon dioxide production (41.0 (29.9-59.5) v 33.6 (26.8-39.3) l/min, p less than 0.01). Clinically significant tricuspid regurgitation may develop late after successful mitral valve replacement and in the absence of residual pulmonary hypertension, prosthetic dysfunction, or significant left ventricular impairment. Patients in whom severe tricuspid regurgitation developed had a considerable reduction in exercise capacity caused by an impaired cardiac output response to exercise and therefore experienced a poor functional outcome. The extent to which this was attributable to the tricuspid regurgitation itself or alternatively to the consequences of right ventricular dysfunction was not clear and requires further investigation.


Contractile effects of bacterial cell walls, their enzymatic digests, and muramyl dipeptides on ileal strips from guinea pigs.
Cell walls isolated from four bacterial species (Streptococcus pyogenes, Lactobacillus plantarum, Streptomyces gardneri, and Nocardia corynebacteriodes), which exhibited the adjuvant effect of stimulating cellular and humoral immune responses against ovalbumin in guinea pigs, caused the slow-starting and long-lasting contraction of guinea pig ileal strips suspended in Tyrode solution. In contrast to these cell walls active in immunoadjuvancy, those isolated from five bacterial species (Micrococcus lysodeikticus, Staphylococcus epidermidis, Arthrobacter atrocyaneus, Corynebacterium insidiosum, and Ampullariella regularis), which lacked immunoadjuvancy at least in intact walls, caused no or very weak contraction of the ileal strips. Further study demonstrated that both a monomer and a polymer of disaccharide-stem peptides, which were obtained by enzymatic degradation of S. epidermis cell wall peptidoglycans, displayed similar contractile effects. It was finally revealed that guinea pig ileum strips showed a definite contractile response to N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and 6-O-stearoyl- and 6-O-(2-tetradecylhexadecanoyl)-MDPs, but not to their analogs, whose C-terminal amino acid was L-isoglutamine or D-isoasparagine in place of D-isoglutamine and which lacked adjuvancy. 6-O-(3-Hydroxy-2-docosylhexacosanoyl)-MDP, on the other hand, caused a slow and lasting relaxation of the ileum strips, but its L-isoglutamine and D-isoasparagine analogs did not.


Wetland management to reduce Baltic Sea eutrophication.
Seven regions with coastal eutrophication problems in the Baltic Sea, including the Kattegat, constitute the BERNET project (Baltic Eutrophication Regional Network). To counteract eutrophication and associated severe biological conditions the countries around this large brackish water body must all cooperate. The regions are characterized by large differences in land use, e.g. agricultural intensity, and losses of retention capacity in the catchments due to wetland reclamation. Initially it has been necessary to identify nutrient sources--especially nitrogen--and technical, economical and even administrative obstacles to initiate eutrophication management measures. Nitrogen retention in different types of wetlands in the Baltic Sea Region has been analysed. The wetlands generally have a positive effect on reduced nitrogen transport to aquatic environments and it is generally accepted that measures leading to decreased losses of nutrients to the aquatic environment must be combined with measures leading to increased retention of nutrients in catchments. Data analysed in the BERNET project show that the potential for such a measure is large. Therefore, conservation and restoration initiatives for wetlands is an essential part of the work in the BERNET project. Wetlands have been drained or totally eliminated due to intensive agriculture in some regions while large scale rehabilitation of wetlands occurs in regions with less intensive agriculture. Based on land use data from the seven regions, the working group for wetland management within the BERNET project has identified the possible use of wetlands as building blocks as a contribution to the management of the Baltic Sea eutrophication. Several recommendations are presented on the wise use of existing and constructed wetlands for water quality management in relation to non-point nutrient pollution.


Quantitative relationship between resting heart rate reduction and magnitude of clinical benefits in post-myocardial infarction: a meta-regression of randomized clinical trials.
The impact on mortality outcomes of beta-blockers and calcium blockers in post-myocardial infarction (MI) has been suggested to be related to resting heart rate (HR) reduction. A meta-regression of randomized clinical trials was carried out to assess this relationship using weighted meta-regression of logarithm of odds ratio against absolute HR reduction. Twenty-five controlled randomized trials (21 with beta-blockers and four with calcium channel blockers) involving a total of 30 904 patients meet eligibility criteria, but only 17 documented changes in resting HR (14 with beta-blockers and three with calcium channel blockers). A statistically significant relationship was found between resting HR reduction and the clinical benefit including reduction in cardiac death (P < 0.001), all-cause death (P = 0.008), sudden death (P = 0.015), and non-fatal MI recurrence (P = 0.024). Each 10 b.p.m. reduction in the HR is estimated to reduce the relative risk of cardiac death by 30%. The meta-regression of the randomized clinical trials strongly suggest that the beneficial effect of beta-blockers and calcium channel blockers in post-MI patients is proportionally related to resting HR reduction. Furthermore, the absence of residual heterogeneity indicated that resting HR reduction could be a major determinant of the clinical benefit.


Adherence to surgical care improvement project measures and the association with postoperative infections.
The Surgical Care Improvement Project (SCIP) aims to reduce surgical infectious complication rates through measurement and reporting of 6 infection-prevention process-of-care measures. However, an association between SCIP performance and clinical outcomes has not been demonstrated. To examine the relationship between SCIP infection-prevention process-of-care measures and postoperative infection rates. A retrospective cohort study, using Premier Inc's Perspective Database for discharges between July 1, 2006 and March 31, 2008, of 405 720 patients (69% white and 11% black; 46% Medicare patients; and 68% elective surgical cases) from 398 hospitals in the United States for whom SCIP performance was recorded and submitted for public report on the Hospital Compare Web site. Three original infection-prevention measures (S-INF-Core) and all 6 infection-prevention measures (S-INF) were aggregated into 2 separate all-or-none composite scores. Hierarchical logistical models were used to assess process-of-care relationships at the patient level while accounting for hospital characteristics. The ability of reported adherence to SCIP infection-prevention process-of-care measures (using the 2 composite scores of S-INF and S-INF-Core) to predict postoperative infections. There were 3996 documented postoperative infections. The S-INF composite process-of-care measure predicted a decrease in postoperative infection rates from 14.2 to 6.8 per 1000 discharges (adjusted odds ratio, 0.85; 95% confidence interval, 0.76-0.95). The S-INF-Core composite process-of-care measure predicted a decrease in postoperative infection rates from 11.5 to 5.3 per 1000 discharges (adjusted odds ratio, 0.86; 95% confidence interval, 0.74-1.01), which was not a statistically significantly lower probability of infection. None of the individual SCIP measures were significantly associated with a lower probability of infection. Among hospitals in the Premier Inc Perspective Database reporting SCIP performance, adherence measured through a global all-or-none composite infection-prevention score was associated with a lower probability of developing a postoperative infection. However, adherence reported on individual SCIP measures, which is the only form in which performance is publicly reported, was not associated with a significantly lower probability of infection.


CD40 ligand expressed on B cells in the BXSB mouse model of systemic lupus erythematosus.
Male BXSB mice, unlike female BXSB, develop a severe early onset lupus-like disease that has been linked to an intrinsic B cell defect. In investigating this B cell defect the present study showed that male, but not female, BXSB contained a higher percentage of large, activated splenic B cells that were more responsive to anti-CD40 mAb-induced proliferation. The hyperactivity of the large B cells from the male mice was also observed in the absence of anti-CD40 mAb or any other stimuli. In examining the mechanism of the B cell hyperactivity, it was found that 20% of unstimulated large B cells from male mice, unlike large B cells from female mice, expressed CD40 ligand (CD40L), a molecule normally expressed on activated CD4+ cells. The percentage of large B cells from the male BXSB that expressed CD40L was increased to 43% by stimulation with LPS. A functional role for CD40L expression on B cells was confirmed by showing that CD40-Ig blocked the spontaneous proliferation of the large B cells from male mice. In addition, the stimulatory capacity of the large B cells from the male mice was demonstrated by their ability to induce DNA synthesis in small B cells in a CD40L-dependent manner. These results demonstrated that large B cells from male BXSB expressed functionally active CD40L. It is likely that the B cell CD40L expression and increased susceptibility to CD40 signaling due to an intrinsic B cell hyperactivity promotes autoimmune disease in BXSB mice.


Isolation of self antigen-reactive cells from inflamed islets of nonobese diabetic mice using CD4high expression as a marker.
The low precursor frequency of Ag-reactive CD4+ T cells has been a barrier to the study of CD4+ T cell responses to conventional Ags as well as CD4+ T cell responses to autoantigens recognized during the course of an autoimmune disease. We have recently reported that all "conventional Ag" reactive CD4+ T cells are contained within the subpopulation expressing high levels of the CD4 molecule, termed CD4high. We have identified a CD4high population in the islets of Langerhans of prediabetic nonobese diabetic (NOD) mice that is extremely potent in transferring disease. As few as 500 CD4high islet-infiltrating CD4+ T cells transferred insulin-dependent diabetes mellitus to CD8 reconstituted NOD-SCID mice within 30 days of transfer. In contrast, CD4high T cells isolated from either NOD spleen or salivary glands did not transfer insulin-dependent diabetes mellitus into similar CD8-reconstituted NOD-SCID recipients. These data indicate that the precursor frequency of NOD islet-reactive, pathogenic CD4+ T cells is much higher in the prediabetic NOD pancreas than in these other organs. The islet-infiltrating CD4high T cells displayed selected memory markers, by cell surface analysis, and displayed a Th 1 phenotype by RNase protection assay, but had a marked decrease in IL-4 mRNA determined by quantitative real time PCR when compared with the less pathogenic CD4normal islet-infiltrating T cells. Use of the CD4high marker to select Ag activated T cells represents a tool to isolate and study pathogenic CD4+ T cells from autoimmune lesions in which the Ag has not been previously defined.


The general public's concerns about clinical risk in live kidney donation.
Difficulty in attracting live kidney donors may be related to fears regarding both the surgical procedure for kidney harvesting and future failure of the remaining kidney. We conducted a cross-sectional study of households in Maryland to identify public disincentives to living related kidney donation. In multivariate analyses, we assessed the independent effects of several factors on willingness to donate a kidney to a sibling. We also assessed thresholds for factors above which persons would not donate a kidney. Of 385 participants, 66% were extremely willing to donate to a sibling. After adjustment, those who considered the length of a hospital stay, out-of-pocket expenses, size and appearance of a scar, the time it takes to get to the transplant center, and the donor risk of developing kidney failure very important had 50-60% less odds of being extremely willing to donate. Median acceptable levels for risk of complications, hospital stay, compensated and uncompensated time from work, time requiring pain medications, and out-of-pocket expenses were greater than levels from clinical evidence regarding both laparoscopic and open nephrectomy. Unrealistic concerns among the general public regarding live donation may serve as potential disincentives to donation. Efforts to educate the public regarding live donation might help assuage fears and attract those who may not otherwise donate.


Results of multicenter registry for patients with inherited factor VII deficiency in Turkey.
Inherited factor VII (FVII) deficiency (FVIID) is the most common of inherited rare bleeding disorders. Other determinants of clinical severity apart from FVII level (FVIIL) include genetic and environmental factors. We aimed to identify the cut-off FVIILs for general and severe bleedings in patients with FVIID by using an online national registry system including clinical, laboratory, and demographic characteristics of patients. Demographic, clinical, and laboratory data of patients with FVIID extracted from the national database, constituted by the Turkish Society of Hematology, were examined. Bleeding phenotypes, general characteristics, and laboratory features were assessed in terms of FVIILs. Bleeding rates and prophylaxis during special procedures/interventions were also recorded. Data from 197 patients showed that 46.2% of patients had FVIIL< 10%. Most bleeds were of mucosal origin (67.7%), and severe bleeds tended to occur in younger patients (median age: 15 (IQR:6-29)). Cut-off FVIILs for all and severe bleeds were 16.5% and 7.5%, respectively. The major reason for long-term prophylaxis was observed as central nervous system bleeding (80%). Our data are consistent with most of the published literature in terms of cut-off FVIIL for bleeding, as well as reasons for prophylaxis, showing both an increased severity of bleeding and younger age at diagnosis with decreasing FVIIL. However, in order to offer a classification similar to that in Hemophilia A or B, data of a larger cohort with information about environmental and genetic factors are required.


The effect of cannabis laws on opioid use.
Many Americans rely on opioids at varying dosages to help ameliorate their suffering. However, empirical evidence is mounting that opioids are ineffective at controlling non-cancer related chronic pain, and many argue the strategies meant to relieve patient suffering are contributing to the growing opioid epidemic. Concurrently, several states now allow the use of medical cannabis to treat a variety of medical conditions, including chronic pain. Needing more exploration is the impact of cannabis laws on general opioid reliance and whether chronic pain sufferers are opting to use cannabis medicinally instead of opioids. This study investigates the effect of Medical Marijuana Laws (MML)s on opioid use and misuse controlling for a number of relevant factors using data from several years of the National Survey on Drug Use and Health and multivariate logistic regression and longitudinal analysis strategies. Results provide evidence that MMLs may be effective at reducing opioid reliance as survey respondents living in states with medical cannabis legislation are much less apt to report using opioid analgesics than people living in states without such laws, net other factors. Results further indicate that the presence of medicinal cannabis legislation appears to have no influence over opioid misuse. MMLs may ultimately serve to attenuate the consequences of opioid overreliance.


Two candidate genes (FTO and INSIG2) for fat accumulation in four canids: chromosome mapping, gene polymorphisms and association studies of body and skin weight of red foxes.
Fat accumulation is a polygenic trait which has a significant impact on human health and animal production. Obesity is also an increasingly serious problem in dog breeding. The FTO and INSIG2 are considered as candidate genes associated with predisposition for human obesity. In this report we present a comparative genomic analysis of these 2 genes in 4 species belonging to the family Canidae - the dog and 3 species which are kept in captivity for fur production, i.e. red fox, arctic fox and Chinese raccoon dog. We cytogenetically mapped these 2 loci by FISH and compared the entire coding sequence of INSIG2 and a fragment of the coding sequence of FTO. The FTO gene was assigned to the following chromosomes: CFA2q25 (dog), VVU2q21 (red fox), ALA8q25 (arctic fox) and NPP10q24-25 (Chinese raccoon dog), while the INSIG2 was mapped to CFA19q17, VVU5p14, ALA24q15 and NPP9q22, respectively. Altogether, 29 SNPs were identified (16 in INSIG2 and 13 in FTO) and among them 2 were missense substitutions in the dog (23C/T, Thr>Met in the FTO gene and 40C/A, Arg>Ser in INSIG2). The distribution of these 2 SNPs was studied in 14 dog breeds. Two synonymous SNPs, one in the FTO gene (-28T>C in the 5'-flanking region) and one in the INSIG2 (10175C>T in intron 2), were used for the association studies in red foxes (n = 390) and suggestive evidence was observed for their association with body weight (FTO, p < 0.08) and weight of raw skin (INSIG2, p < 0.05). These associations indicate that both genes are potential candidates for growth or adipose tissue accumulation in canids. We also suggest that the 2 missense substitutions found in dogs should be studied in terms of genetic predisposition to obesity.


Design of a high speed rat whiskers tracking and symmetry analysis system based on FPGA.
This paper presents a high-speed rat whisker tracking and symmetry analysis system based on FPGA. The system utilizes high-speed image sensors recording rat face videos at 120 and 1000 fps. The Xilinx Ultra96 single computer board is chosen as the platform to implement the system's processing system (PS) and the programmable logic (PL) part. The PL part is responsible for high-speed image processing and whisker tracking, while the PS part analyzes the symmetry of rat face using the tracking results from the PL part. With a processing speed FoM of 118.5 fps/GHz on the Xilinx Ultra96 single computer board and 275.47 fps/GHz on a laptop with Intel Core email@example.com, the presented system achieves excellent performance. The proposed whisker detection method has a precision of 98.2% when a threshold with a 4-degree error is selected, with an average error angle of 0.98 degrees across more than 10,000 video frames. Moreover, the proposed system is capable of local video processing within millisecond delays. These results demonstrate the feasibility of developing a high-speed, accurate, and efficient whisker tracking and symmetry analysis system for rat behavior research.


[Collagen powder dressing in the treatment of pressure ulcer. Multicenter comparative study assessing effectiveness and cost].
Pressure ulcers are lesions that usually occur to people to whom the social and economical repercusions are quite serious. Although present treatments with moisture cure dressings are efficient and have a lot of advantages than traditional cure, they do not solve the problem in a significant group of patients, whose ulcers do not heal or need a much longer treatment. Collagen dressings represent an important improvement, since collagen is a key element for wound scarring. We conducted a prospective, comparative and multicentrical study with Catrix, using as a control the same lesion. We compared pressure ulcers that had been previously treated on an average of 6 months without success with Catrix treatment within 7 weeks. We compared different variables, efficacy, opinion on the use of Catrix and economic cost. We included 104 pressure ulcers that fulfilled the inclusion requirements in the study. Three of them were excluded from the efficiency analysis because of a lack of data since they passed away 7 weeks later. We performed a statistical analysis on all the ulcers (GT) and we also analyzed the pressure ulcer subgroup (SG) included in this study because of a deterioration or a stagnation of the lesion despite previous treatments. Seven weeks after the beginning of the treatment with Catrix the healing or the stage change was observed in 73.3% of lesions of GT group and in 77.8% of lesions of SG group (p < 0.0001). The average material cost and nursing cost from all the lesions that scarred within 7 weeks (n = 39) with previous treatment was 17.234, 10 euros and 10.920 euros with Catrix. The average material cost per lesion used in the previous treatments was 441.9 euros and 280 euros with Catrix. These results prove that the treatment with Catrix significantly reduces the treatment length and therefore leads to a reduction of the sanitary cost in this kind of patients. Adding Catrix to the pressure ulcers treatment helps to increase significantly the scarring and improvement percentage of those pressure ulcers that do not respond to other treatments. It helps to improve patient's quality of life, and to reduce the costs of the treatment.


Modelling the VO2 kinetic response to heavy intensity exercise in children.
The purpose of this study was to apply a series of mathematical models in order to investigate the nature of the kinetic response to heavy intensity exercise with children and identify a suitable model with which to estimate parameters of the response. Sixty two children (35 male, 27 female aged 10-15 years) completed four transitions from baseline pedalling to 40% of the difference between their previously determined anaerobic threshold and peak VO2 on an electronically braked cycle ergometer. Initially three models were fitted to the averaged response profiles following the end of phase 1. and their residuals compared; 1, a single exponential with a delay term; 2, an exponential and linear term with independent delays; and 3, a double exponential with independent delays. Up to 95% of the response profiles were better fitted by either model 2 or 3 (p < 0.05), and model 3 was a statistically better fit (p < 0.05) than model 2 in 77% of cases. Residual inspection confirmed the superior fit by model 3. A fourth model which consisted of a single exponential with a delay term was fitted within the phase 2 fitting window. Estimated parameters (A1 and tau1), using model 4 were not significantly different from model 3, and model 4 was identified as the model of choice due to the wide confidence intervals in tau2 and A2 using model 3. It was concluded that the nature of the response to heavy intensity exercise in children is similar to that previously reported with adults and that the response should be modelled accordingly.


Near-euglycemia can be achieved safely in pediatric total pancreatectomy islet autotransplant recipients using an adapted intravenous insulin infusion protocol.
Children with severe chronic pancreatitis may undergo total pancreatectomy with islet autotransplantation (TPIAT) to relieve pain while minimizing the risk of postsurgical diabetes. Because overstimulation of transplanted islets by hyperglycemia can result in β-cell loss, we developed a specialized intravenous insulin infusion protocol (IIP) for pediatric TPIAT recipients to maintain euglycemia or near-euglycemia posttransplant. Our objective was to review glucose control using an IIP specific for TPIAT recipients at a single institution. We reviewed postoperative blood glucose (BG) levels for 32 children 4-18 years old with chronic pancreatitis who underwent TPIAT between July 2011 and June 2013. We analyzed the proportion of BG values in the range of 70-140 mg/dL, mean glucose, glucose variability, and occurrence of hypoglycemia during the IIP; we also evaluated the transition to subcutaneous therapy (first 72 h with multiple daily injections [MDI]). During IIP, the mean patient BG level was 116±27 mg/dL, with 83.1% of all values in the range of 70-140 mg/dL. Hypoglycemia was rare, with only 2.5% of values <70 mg/dL. The more recent era (n=16) had a lower mean BG and less variability than the early era (first 16 patients) (P≤0.004). Mean glucose level (116 vs. 128 mg/dL) and glucose variability were significantly lower during the IIP compared with MDI therapy (P<0.0001). Tight glycemic control without excessive severe hypoglycemia was achieved in children undergoing TPIAT using an IIP specifically designed for this population; the ability to maintain BG in target range improved with experience with the protocol.


From landing lights to mimicry: the molecular regulation of flower colouration and mechanisms for pigmentation patterning.
Flower colour is a key component for plant signaling to pollinators and a staggering variety of colour variations are found in nature. Patterning of flower colour, such as pigment spots or stripes, is common and is important in promoting pollination success. Developmentally programmed pigmentation patterns are of interest with respect to the evolution of specialised plant-pollinator associations and as models for dissecting regulatory signaling in plants. This article reviews the occurrence and function of flower colour patterns, as well as the molecular genetics of anthocyanin pigmentation regulation. The transcription factors controlling anthocyanin biosynthesis have been characterised for many species and an 'MBW' regulatory complex of R2R3MYB, bHLH and WD-Repeat proteins is of central importance. In particular, R2R3MYBs are key determinants of pigmentation intensity and patterning in plants. Progress is now being made on how environmental or developmental signal pathways may in turn control the production of the MBW components. Furthermore, additional regulatory proteins that interact with the MBW activation complex are being identified, including a range of proteins that repress complex formation or action, either directly or indirectly. This review discusses some of the recent data on the regulatory factors and presents models of how patterns may be determined.


Cerebral microbleeds are associated with nocturnal reverse dipping in hypertensive patients with ischemic stroke.
Abnormalities in nocturnal blood pressure dipping are well known for its relationship to cardiovascular diseases. Cerebral microbleeds are frequently observed in patients with hypertension and are known to be potent risk factors for stroke. However, there are scanty reports about the relationship between nocturnal dipping and cerebral microbleeds. We recruited consecutive patients with both hypertension and ischemic stroke within 7 days after symptom onset, and those with cardioembolism were excluded. We applied 24-hour ambulatory blood pressure monitoring two weeks after stroke onset, and we used brain MRI to detect cerebral microbleeds. Various blood pressure parameters such as mean 24-hour blood pressure, awake/sleep blood pressure, and morning surge were compared between cerebral microbleeds (+) vs. (-) groups. Subjects were further classified according to nocturnal dipping status and were analyzed by logistic regression to determine its association with cerebral microbleeds with adjustment for age, gender, and cardiovascular risk factors. A total of 162 patients (100 males, age 65.33 ± 10.32 years) were included. Cerebral microbleeds were detected in 65 patients (40.1%). Most ambulatory blood pressure parameters except morning surge were significantly higher in those who had cerebral microbleeds. After adjusting for the confounding factors, the reverse dippers were prone to have cerebral microbleeds (odds ratio, 3.81; 95% confidential interval, 1.36-10.65; p-value = 0.01). Cerebral microbleeds are independently associated with reverse dipping on ambulatory blood pressure monitoring in hypertensive stroke patients.


Aerobic granular sludge: a promising technology for decentralised wastewater treatment.
In order to evaluate the characteristics of aerobic granular sludge, a sequencing batch reactor, feeding with synthetic wastewater at the organic loading rate of 8 kg COD/m3 d, was employed on the laboratory scale. Granules occurred in the reactor within 1 week after the inoculation from conventional flocculent sludge. Aerobic granular sludge was characterised by the outstanding settling properties and considerable contaminates removal efficiencies. The SVI30 values were in the range of 20 to 40 ml g(-1). However, the sludge volume index of short settling time (e.g. SVI10--10 min) is suggested to describe the fast settling properties of aerobic granular sludge. The potential application in the decentralised system is evaluated from the point view of footprint and high bioactivity. The occurrence of sloughing, resulting from the outgrowth of filamentous organisms, would be responsible for the instability of aerobic granules. The starvation phase should therefore be carefully controlled for the maintenance and stability of aerobic granular sludge system.


Defect Chemistry, Sodium Diffusion and Doping Behaviour in NaFeO2 Polymorphs as Cathode Materials for Na-Ion Batteries: A Computational Study.
Minor metal-free sodium iron dioxide, NaFeO2, is a promising cathode material in sodium-ion batteries. Computational simulations based on the classical potentials were used to study the defects, sodium diffusion paths and cation doping behaviour in the α- and β-NaFeO2 polymorphs. The present simulations show good reproduction of both α- and β-NaFeO2. The most thermodynamically favourable defect is Na Frenkel, whereas the second most favourable defect is the cation antisite, in which Na and Fe exchange their positions. The migration energies suggest that there is a very small difference in intrinsic Na mobility between the two polymorphs but their migration paths are completely different. A variety of aliovalent and isovalent dopants were examined. Subvalent doping by Co and Zn on the Fe site is calculated to be energetically favourable in α- and β-NaFeO2, respectively, suggesting the interstitial Na concentration can be increased by using this defect engineering strategy. Conversely, doping by Ge on Fe in α-NaFeO2 and Si (or Ge) on Fe in β-NaFeO2 is energetically favourable to introduce a high concentration of Na vacancies that act as vehicles for the vacancy-assisted Na diffusion in NaFeO2. Electronic structure calculations by using density functional theory (DFT) reveal that favourable dopants lead to a reduction in the band gap.


EEG Signal Diversity Varies With Sleep Stage and Aspects of Dream Experience.
Several theories link consciousness to complex cortical dynamics, as suggested by comparison of brain signal diversity between conscious states and states where consciousness is lost or reduced. In particular, Lempel-Ziv complexity, amplitude coalition entropy and synchrony coalition entropy distinguish wakefulness and REM sleep from deep sleep and anesthesia, and are elevated in psychedelic states, reported to increase the range and vividness of conscious contents. Some studies have even found correlations between complexity measures and facets of self-reported experience. As suggested by integrated information theory and the entropic brain hypothesis, measures of differentiation and signal diversity may therefore be measurable correlates of consciousness and phenomenological richness. Inspired by these ideas, we tested three hypotheses about EEG signal diversity related to sleep and dreaming. First, diversity should decrease with successively deeper stages of non-REM sleep. Second, signal diversity within the same sleep stage should be higher for periods of dreaming vs. non-dreaming. Third, specific aspects of dream contents should correlate with signal diversity in corresponding cortical regions. We employed a repeated awakening paradigm in sleep deprived healthy volunteers, with immediate dream report and rating of dream content along a thought-perceptual axis, from exclusively thought-like to exclusively perceptual. Generalized linear mixed models were used to assess how signal diversity varied with sleep stage, dreaming and thought-perceptual rating. Signal diversity decreased with sleep depth, but was not significantly different between dreaming and non-dreaming, even though there was a significant positive correlation between Lempel-Ziv complexity of EEG recorded over the posterior cortex and thought-perceptual ratings of dream contents.


Motor control or graded activity exercises for chronic low back pain? A randomised controlled trial.
Chronic low back pain remains a major health problem in Australia and around the world. Unfortunately the majority of treatments for this condition produce small effects because not all patients respond to each treatment. It appears that only 25-50% of patients respond to exercise. The two most popular types of exercise for low back pain are graded activity and motor control exercises. At present however, there are no guidelines to help clinicians select the best treatment for a patient. As a result, time and money are wasted on treatments which ultimately fail to help the patient. This paper describes the protocol of a randomised clinical trial comparing the effects of motor control exercises with a graded activity program in the treatment of chronic non specific low back pain. Further analysis will identify clinical features that may predict a patient's response to each treatment. One hundred and seventy two participants will be randomly allocated to receive either a program of motor control exercises or graded activity. Measures of outcome will be obtained at 2, 6 and 12 months after randomisation. The primary outcomes are: pain (average pain intensity over the last week) and function (patient-specific functional scale) at 2 and 6 months. Potential treatment effect modifiers will be measured at baseline. This trial will not only evaluate which exercise approach is more effective in general for patients will chronic low back pain, but will also determine which exercise approach is best for an individual patient. ACTRN12607000432415.


Integral photoradiation therapy of multifocal bladder tumors.
Focal and diffuse hematoporphyrin derivative (HpD) photodynamic therapy was used for the treatment of resistant transitional cell carcinoma in situ (Tis) in 30 patients. Patients were given HpD intravenously followed by either focal light irradiation (630 nm) or diffuse bladder irradiation via a light bulb fiber. The light source was an argon ion pumped dye laser circulating rhodamine B dye. All patients were followed with periodic cystoscopic examinations, bladder biopsies, and urine cytologic examinations. All of the 15 patients who underwent focal therapy had biopsy and cytologic evidence of disappearance of the lesion in the treated area at the 3-month follow-up cystoscopic examination. Eight patients have experienced one or more recurrent lesions either in the treated area or in distant areas, and in each the recurrence was successfully treated with HpD photodynamic therapy. Eight of the 11 patients with diffuse Tis have returned for their 3-month follow-up evaluation, and all demonstrated disappearance of tumor (3 of these 8 patients have subsequently developed focal recurrent Tis). Four patients had diffuse Tis plus Ta lesions (2 patients) or T2 lesions (2 patients), and all had disappearance of the Tis, but persistence of the Ta or T2 disease. We conclude that HpD photodynamic therapy appears effective in the treatment of resistant Tis.


Higher risk for meningioma in women with uterine myoma: a nationwide population-based retrospective cohort study.
Evidence suggests that hormones play a role in modifying both uterine myoma (UM) and meningioma. A number of studies have observed the positive association between these diseases. The aim of the current population-based study was to determine if women with UM are at a higher risk for meningioma. The authors used data from the National Health Insurance system of Taiwan for the study. The UM cohort contained 281,244 women. Each woman was randomly frequency-matched with 4 women without UM, based on age, index year of diagnosis, occupation, urbanization (urbanization level was categorized by the population density of the residential area into 4 levels, with Level 1 as the most urbanized and Level 4 as the least urbanized), and comorbidity, to form the control cohort. Cox's proportional hazard regression analysis was conducted to estimate the influence of UM on the meningioma risk. Among women with UM, the risk of developing meningioma was significantly higher (45%) than among women without UM (95% CI 1.23-1.70). The same phenomenon was observed among most age groups, but a significant difference was only seen in the middle-age range. For women with UM, further analysis did not show a significant change after myomectomy. The cumulative incidence of meningioma between groups with and without UM differed over time. The nationwide population-based cohort study found that Taiwanese women with UM are at higher risk for developing meningioma.


[Influence of the anterior and posterior hypothalamus on the conditioned reflex activity and delayed responses of lower simians].
In 4 adult monkeys, electrical stimulation of the anterior hypothalamus followed by subsidence in the animal and the ECoG synchronization evoked also an impairment of conditioned reflex activity and a decrease in the test performance during delayed responses. Strong stimulation of the posterior hypothalamus followed by emotional arousal and desynchronization in the ECoG, on the contrary, improved the conditioned reflex activity and increased the level of the test performance. The hypothalamus is then supposed to play a certain role in memory as an emotiogenic structure.


Expression of ribosomal phosphoprotein PO is induced by antitumor agents and increased in Mer- human tumor cell lines.
We initiated this study to determine whether three structurally related bifunctional alkylating agents could induce the expression of a presumptive human DNA repair gene. The gene chosen for this study is known to encode the ribosomal phosphoprotein PO, but ironically may also share functions related to DNA repair. We now show by Northern analysis that PO is induced by L-phenylalanine mustard, 4-hydroperoxycyclophosphamide and mechlorethamine, which are DNA-damaging agents commonly used as chemotherapeutic antitumor agents. In further support of its involvement in DNA repair is the finding of a 30- to 50-fold constitutive overexpression of the PO gene in human tumor cell lines that are Mer-, cells which lack O6-methylguanine methyltransferase activity, when compared to Mer+ cell lines. This constitutively elevated level of PO in Mer- cell lines, which are thus DNA repair defective for O6-alkyguanine lesions, was not observed for other genes tested, including the human ribosomal gene S17 whose mRNA steady-state levels were uniformly the same in both Mer- and Mer+ cells. Taking these data together, it appears that increased levels of PO are somehow linked to DNA repair, and increased expression of PO may compensate for the decreased O6-methylguanine DNA methyltransferase activity in Mer- cells. Furthermore, the PO gene has also been shown to be overexpressed in colorectal tumors and polyps and the sera of some systemic lupus erythematosus patients contain antibodies against PO. The titer of the anti-PO antibodies rises significantly during lupus psychosis.


Cashew Nut Allergy: Clinical Relevance and Allergen Characterisation.
Cashew plant (Anacardium occidentale L.) is the most relevant species of the Anacardium genus. It presents high economic value since it is widely used in human nutrition and in several industrial applications. Cashew nut is a well-appreciated food (belongs to the tree nut group), being widely consumed as snacks and in processed foods by the majority of world's population. However, cashew nut is also classified as a potent allergenic food known to be responsible for triggering severe and systemic immune reactions (e.g. anaphylaxis) in sensitised/allergic individuals that often demand epinephrine treatment and hospitalisation. So far, three groups of allergenic proteins have been identified and characterised in cashew nut: Ana o 1 and Ana o 2 (cupin superfamily) and Ana o 3 (prolamin superfamily), which are all classified as major allergens. The prevalence of cashew nut allergy seems to be rising in industrialised countries with the increasing consumption of this nut. There is still no cure for cashew nut allergy, as well as for other food allergies; thus, the allergic patients are advised to eliminate it from their diets. Accordingly, when carefully choosing processed foods that are commercially available, the allergic consumers have to rely on proper food labelling. In this sense, the control of labelling compliance is much needed, which has prompted the development of proficient analytical methods for allergen analysis. In the recent years, significant research advances in cashew nut allergy have been accomplished, which are highlighted and discussed in this review.


The causes of falls: views of older people with visual impairment.
Sight impairment increases with age and, compared with the general older population, older people with sight impairment are more likely to fall. There is a growing body of evidence on the views and perceptions of older people about falls, but little is published on the views of older people with sight impairment. To explore what older people with sight impairment believe to be the causes of falls. A qualitative design was used, incorporating focus groups and interviews in which participants discussed falls and falls prevention. Framework analysis was employed to identify themes arising from participants' discussions of the causes of falls. Fifty-four community dwelling men and women with sight impairment, aged 65 and over, were recruited from across Greater Manchester, UK. Five types of factors were identified that were believed to cause falls: (i) health issues and changes in balance caused by ageing; (ii) cognitive and behavioural factors; (iii) the impact of sight impairment on getting around the home; (iv) the impact of sight impairment on negotiating the environment away from home; and (v) unexplained falls. Older people with sight impairment reported many researched risk factors previously identified by older people without sight impairment but also described many perceived risks unique to people with sight impairment. There are few interventions to prevent falls aimed at older people with sight impairment, and the results of this study allow further tailoring of such interventions based on views of older people with sight impairment.


Modeling Liquid Water by Climbing up Jacob's Ladder in Density Functional Theory Facilitated by Using Deep Neural Network Potentials.
Within the framework of Kohn-Sham density functional theory (DFT), the ability to provide good predictions of water properties by employing a strongly constrained and appropriately normed (SCAN) functional has been extensively demonstrated in recent years. Here, we further advance the modeling of water by building a more accurate model on the fourth rung of Jacob's ladder with the hybrid functional, SCAN0. In particular, we carry out both classical and Feynman path-integral molecular dynamics calculations of water with the SCAN0 functional and the isobaric-isothermal ensemble. To generate the equilibrated structure of water, a deep neural network potential is trained from the atomic potential energy surface based on ab initio data obtained from SCAN0 DFT calculations. For the electronic properties of water, a separate deep neural network potential is trained by using the Deep Wannier method based on the maximally localized Wannier functions of the equilibrated trajectory at the SCAN0 level. The structural, dynamic, and electric properties of water were analyzed. The hydrogen-bond structures, density, infrared spectra, diffusion coefficients, and dielectric constants of water, in the electronic ground state, are computed by using a large simulation box and long simulation time. For the properties involving electronic excitations, we apply the GW approximation within many-body perturbation theory to calculate the quasiparticle density of states and bandgap of water. Compared to the SCAN functional, mixing exact exchange mitigates the self-interaction error in the meta-generalized-gradient approximation and further softens liquid water toward the experimental direction. For most of the water properties, the SCAN0 functional shows a systematic improvement over the SCAN functional. However, some important discrepancies remain. The H-bond network predicted by the SCAN0 functional is still slightly overstructured compared to the experimental results.


Nanocrystalline High-Entropy Alloys: A New Paradigm in High-Temperature Strength and Stability.
Metals with nanometer-scale grains or nanocrystalline metals exhibit high strengths at ambient conditions, yet their strengths substantially decrease with increasing temperature, rendering them unsuitable for usage at high temperatures. Here, we show that a nanocrystalline high-entropy alloy (HEA) retains an extraordinarily high yield strength over 5 GPa up to 600 °C, 1 order of magnitude higher than that of its coarse-grained form and 5 times higher than that of its single-crystalline equivalent. As a result, such nanostructured HEAs reveal strengthening figures of merit-normalized strength by the shear modulus above 1/50 and strength-to-density ratios above 0.4 MJ/kg, which are substantially higher than any previously reported values for nanocrystalline metals in the same homologous temperature range, as well as low strain-rate sensitivity of ∼0.005. Nanocrystalline HEAs with these properties represent a new class of nanomaterials for high-stress and high-temperature applications in aerospace, civilian infrastructure, and energy sectors.


Immunosuppressive Therapy with Cyclosporin A of Severe Treatment Refractory Juvenile Rheumatoid Arthritis.
Rheumatoid arthritis is severe destructive inflammatory joint disease which usually leads to invalidisation of patient in spite of current therapies. The aim of the trial was to assess the effect of Cyclosporin A (Sandimmun (SIM), Sandos Pharma) in prevention of disability, reduction of inflammatory disease activity, tolerability, safety and suitability for a long treatment in severe treatment refractory juvenile rheumatoid arthritis (JRA). Fifteen patients of 7-15 years old (12 girls and 3 boys), of whom 6 had systemic seronegative and 9 had poliarticular seropositive severe JRA with anatomical stage 2-4 and functional capacities 2-3, were treated with Cyclosporin A in open self-controlled trial of 6 months duration for 15 patients and of 12 months duration for 7, All of them received non-steroid anti-inflammatory drugs and were regularly intra-articularly injected with corticosteroids and 6-prednisolone at a mean dose of 8.0 mg/day. Cyclosporin A was administrated in a dose of 3.5-4.5 mg/kg/day. Efficacy control was carried out according to dynamics of clinical and laboratory criteria of the disease activity, functional capacities and radiographic data. The results of the trial have shown that Cyclosporin A therapy led to statistically significant improvement in almost all clinical outcome variables (the number of swollen joints, p < 0.01, the number of painful joints, p < 0.001; pain score, p < 0.01; duration of morning stiffness, p < 0.001; volume of proximal interphalangeal joints, p < 0.001) and several laboratory parameters (ESR, p < 0.001; IgG level, p < 0.05; 6 seropositive patients became seronegative). All the patients exhibited significant increase in functional abilities and stabilization of joint destruction process. Response was considered as very good in 70% of patients and good in 20%, Prednisolone dose and the number of corticosteroid injections were reduced (p < 0.05). Adverse effects of Cyclosporin A included hypertrichosis, gingivitis, increase in appetite and weight, transitory increase in creatinin serum level of 30% over baseline, relapse of bacterial viral infection. These patients required temporal withdrawal of Cyclosporin A. It is concluded that Cyclosporin A therapy is effective in severe JRA, is well tolerated by patients, is suitable for a long-term treatment and has probable disease modifying effect in JRA.


Spinal cord blood flow decreases following microinjection of sodium nitroprusside into the nucleus tractus solitarii of anesthetized rats.
This study was undertaken to examine whether or not nitric oxide (NO) is involved in synaptic transmission in the nucleus tractus solitarius (NTS) during control of the spinal cord circulation. Employing urethane-anesthetized, paralyzed and artificially ventilated rats, sodium nitroprusside (SNP), which produces NO, was microinjected unilaterally into the NTS and the spinal cord blood flow (SCBF) was determined using labeled microspheres. Arterial blood pressure (ABP) was decreased by unilateral microinjection of SNP into the NTS, but its value was kept within the normotensive range by blood transfusion, in order to measure SCBF at normotension. After microinjection of SNP into the NTS, the SCBFs of the cervical, thoracic and lumbar cords decreased significantly from 63 +/- 8 (mean +/- S.E.M.) to 49 +/- 7 (P < 0.05), from 54 +/- 7 to 37 +/- 7 (P < 0.05), and from 77 +/- 9 to 58 +/- 8 (P < 0.05) ml/min/(100 g), respectively (n = 10). Prior microinjection of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of the formation of NO from L-arginine, into the NTS blocked the spinal cord vasoconstrictor response produced by microinjection of L-glutamate into the NTS (n = 10). Prior microinjection of NG-monomethyl-D-arginine (D-NMMA), which does not inhibit the formation of NO from L-arginine, did not block the spinal cord vasoconstrictor response elicited by microinjection of L-glutamate (n = 11). Unilateral microinjection of L-NMMA into the NTS exerted no effect on the spinal cord circulation (n = 9). These findings suggest that NO may be involved in the control of the spinal cord circulation in the NTS.


Visual functions following recovery from non-arteritic central retinal artery occlusion.
Visual acuity and other visual functions may improve following treatment of central retinal artery occlusion (CRAO). A prospective, noncomparative case series study was conducted to investigate patients' visual functions after treatment of non-arteritic CRAO. Eight consecutive patients whose visual acuity improved following successful systematic treatment protocol for non-arteritic CRAO of less than 48 hours (one of them with patent cilioretinal artery) were evaluated for visual functions. The visual acuity in seven patients ranged from no light perception to counting fingers at 3 feet on presentation and improved to 20/100 to 20/20 following treatment. The visual tests included: blue-yellow (Farnsworth D-15) and green-red (pseudoisochromatic Ishihara color plates) color discrimination, contrast sensitivity, and visual fields. The patients were also evaluated for subjective daily function following treatment. All tests were also performed in the fellow uninvolved eye as a control. The visual acuity following treatment improved from no light perception to counting fingers at 3 feet to an average of 20/65 (range, 20/20 to 20/100). Despite this improvement, six patients had dyschromatopsia to blue, green, or red whereas only two patients with a final visual acuity of 20/20 preserved their full color discrimination. All patients had decreased contrast sensitivity at mid-spatial frequency (6 cycles/min) or a more generalized decrease and visual field defects. All of the patients except one were satisfied with the visual outcome and daily function after treatment. Despite improvement in visual acuity after treatment for CRAO, all patients had residual visual function abnormalities. These abnormalities may be attributed to partial recanalization, conversion of CRAO to multiple branch retinal artery occlusions, or different retinal susceptibility for ischemia.


A propensity-matched study of hypertension and increased stroke-related hospitalization in chronic heart failure.
Hypertension is a risk factor for heart failure and stroke. However, the effect of hypertension on stroke in patients with heart failure has not been well studied. In the Digitalis Investigation Group trial, 3,674 (47%) of the 7,788 patients had a history of hypertension. Probability or propensity scores for a history of hypertension were calculated for each patient through use of a multivariable logistic regression model and were then used to match 2,386 pairs of patients with and without a history of hypertension. Kaplan-Meier and matched Cox regression analyses were used to estimate associations of a history of hypertension hospitalization for stroke during 37 months of median follow-up. After matching, patients without and with a history of hypertension had a mean systolic blood pressure of 127 mm Hg. Hospitalization for stroke occurred in 90 patients (rate, 129/10,000 person-years of follow-up) without a history of hypertension and 121 patients (rate, 178/10,000 person-years of follow-up) with a history of hypertension (hazard ratio when hypertension was compared with no hypertension=1.52; 95% confidence interval=1.11 to 2.08; p=0.010). This association was also observed among patients with baseline systolic blood pressure <140 mm Hg (hazard ratio=1.35; 95% confidence interval=1.01 to 1.81; p=0.044). In conclusion, a history of hypertension was associated with increased risk of hospitalization for stroke among patients with heart failure who were balanced in all measured baseline covariates, including blood pressure.


EMT6 solid tumor growth, DNA synthesis and DNA polymerase activity.
Serial DNA-polymerase-alpha and -beta enzyme level measurements were made during the growth of the EMT6 solid tumor. The determinations were correlated with DNA-synthesis in the tumor as measured by 3H-TdR labeling. The DNA-alpha polymerase levels were initially found to be low during early exponential growth phase, but to rise midgrowth to peak and to remain elevated thereafter until an advanced growth stage was reached. DNA-beta polymerase did not change during this entire observation period. DNA synthesis as measured by 3H-TdR uptake was greatest early in tumor growth and fell in midexponential growth phase. This pattern indicates that these two processes are not tightly coupled in the process of localized tumor growth.