Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity.
The worldwide diversity of dietary intakes of n-6 and n-3 fatty acids influences tissue compositions of n-3 long-chain fatty acids (LCFAs: eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids) and risks of cardiovascular and mental illnesses. We aimed to estimate healthy dietary allowances for n-3 LCFAs that would meet the nutrient requirements of 97-98% of the population. Deficiency in n-3 LCFAs was defined as attributable risk from 13 morbidity and mortality outcomes, including all causes, coronary heart disease, stroke, cardiovascular disease, homicide, bipolar disorder, and major and postpartum depressions. Dietary availability of n-3 LCFAs from commodities for 38 countries and tissue composition data were correlated by best fit to each illness in deficiency risk models. The potential attributable burden of disease ranged from 20.8% (all-cause mortality in men) to 99.9% (bipolar disorder). n-3 LCFA intake for Japan (0.37% of energy, or 750 mg/d) met criteria for uniformly protecting >98% of the populations worldwide. n-3 LCFA intakes needed to meet a tissue target representative of Japan (60% n-3 in LCFA) ranged from 278 mg/d (Philippines, with intakes of 0.8% of energy as linoleate, 0.08% of energy as alpha-linolenate, and 0.06% of energy as arachidonic acid) to 3667 mg/d (United States, with 8.91% of energy as linoleate, 1.06% of energy as alpha-linolenate, and 0.08% of energy as arachidonic acid). With caveats inherent for ecologic, nutrient disappearance analyses, a healthy dietary allowance for n-3 LCFAs for current US diets was estimated at 3.5 g/d for a 2000-kcal diet. This allowance for n-3 LCFAs can likely be reduced to one-tenth of that amount by consuming fewer n-6 fats.


[Nucleotide composition of RNA, synthesized by polynucleotide phosphorylase, in toluene-treated cells of Escherichia coli].
On incubation of cells of E. coli B and MRE 600 (logariphmic phase of growth), treated with toluene in presence of a mixture 14C-nucleoside-5'-diphosphates, Mg2+ or Mn2+ and tris HCl buffer pH 8.0, intracellular synthesis of heteropolyribonucleotide was observed. The synthesis was catalyzed by polynucleotide phosphorylase (PNPase, E. C. 188.8.131.52). An increase in GDP concentration in the medium distinctly decreased the incorporation of other NDP into the polymer (poly-AGUC). If the ratio of ADP, UDP, CDP, GDP in the medium was 1:1:1:0.2, the composition of nitrogenous bases in the heteropolymer produced reflected completely the NDP concentrations in the incubation mixture. Addition of different amino acids (1-lysine, 1-histidine, glycine, 1-phenylalanine) and their mixtures stimulated poly-AGUC synthesis markedly and caused an appreciable alteration in the nucleotide composition of the poly-AGUC synthesized. This phenomenon resembled the effect of amino acids on the activity of partially purified PNPase and on RNA synthesis, catalized by the enzyme in vitro. These data suggest that in bacterial cell, i. e. in vivo, PNPase synthesizes specific RNA polyribonucleotide sequences, participating in protein synthesis or in its regulation.


Rapid inactivation of plant aconitase by hydrogen peroxide.
Preincubation of potato (Solanum tuberosum) tuber mitochondria with 300 microM-H2O2 for 10 min nearly stopped the State 3 rate of citrate oxidation. Addition of isocitrate resulted in resumption of O2 uptake. The State 3 rates of succinate, external NADH and 2-oxoglutarate oxidation were unaffected by H2O2 over the dose range 50-500 microM. Preincubation of mitochondria with 300 microM-H2O2 for 5 min unmasked in the matrix space a paramagnetic signal with a peak at a g value of approx. 2.03. Aconitase was purified over 135-fold to a specific activity of 32 mumol/min per mg (with isocitrate as substrate) from the matrix of potato tuber mitochondria. The native enzyme was composed of a single polypeptide chain (molecular mass 90 kDa). Incubation of purified aconitase with small amounts of H2O2 caused the build up of a paramagnetic 3Fe cluster with a low-field maximum of g = 2.03 leading to a progressive inhibition of aconitase activity. The results show that aconitase present in the matrix space was the major intramitochondrial target for inactivation by H2O2.


Development and Validation of HPTLC Method for the Estimation of Clotrimazole in Bulk drug and Tablet Formulation.
A simple, precise, accurate and rapid high performance thin layer chromatographic method has been developed and validated for the determination of clotrimazole in bulk drug and tablet dosage form. The stationary phase used was precoated silica gel 60F(254). The mobile phase used was a mixture of cyclohexane:toluene:methanol:triethyleamine (8:2:0.5:0.2 v/v/v/v). The detection of spot was carried out at 262 nm. The method was validated in terms of linearity, accuracy, precision and specificity. The calibration curve was found to be linear between 200 to 1000 ng/spot for clotrimazole. The limit of detection and the limit of quantification for clotrimazole were found to be 50 ng/spot and 200 ng/spot, respectively. The proposed method can be successfully used to determine the drug content of bulk drug and marketed formulation of tablet.


A monoclonal antibody that detects expression of transferrin receptor in human erythroid precursor cells.
A monoclonal antibody, L5.1, obtained by immunizing a Balb/c mouse with HL60 human promyelocytic leukemia cells, was found to react with both HL60 cells and with the K562(S) cell line. This monoclonal antibody binds and immunoprecipitates a glycoprotein (Mr 87,000) present on the cell surface membrane of K562(S) as a disulfide bonded dimer. In competition experiments L5.1 competes with both transferrin and OKT9 (a known antitransferrin receptor antibody) for binding to target K562(S) erythroleukemia cells. Binding of both L5.1 and transferrin to the surface of K562(S) cells is inhibited by treatment with 12--O-tetradecanoyl-phorbol-13-acetate, and the extent and time course of inhibition is similar in both cases. Cell sorting analysis of normal human marrow cells incubated with L5.1 indicates that L5.1 reacts strongly with all the morphologically recognizable erythroid lineage precursors, from the pronormoblast to the orthochromatic normoblast, and with reticulocytes. Erythrocytes, myeloid elements, monocytes, megakaryocytes and platelets, peripheral blood B and T lymphocytes do not bind significantly with this antibody and only a small fraction of promyelocytes was reactive. Antibody L5.1 did not react with leukemic cells of patients with acute lymphoblastic, myeloblastic and promyelocytic leukemias, but it did react with some established B (1 of 5) and T (2 of 3) cell lines, and a myeloid (1 of 3) cell line, and with PHA-stimulated peripheral blood lymphocytes. The nonhemopoietic cell lines tested did not bind with L5.1 with the exception of a colorectal adenocarcinoma and a melanoma cell line, which were both strongly positive. The relationship of antibody L5.1 to other monoclonal antibodies that bind the transferrin receptor is discussed.


Self-management strategies used during flares of rheumatoid arthritis in an ethnically diverse population.
Effective management of flares of rheumatoid arthritis (RA) can improve symptoms and may delay disease progression. The practice of rheumatologists in managing a flare has been studied, but patients' experiences of, and responses to, disease flares remain poorly defined. This study aimed to address this issue. Semi-structured interviews were conducted with 21 patients from an ethnically diverse population who had suffered a recent RA flare. Open questions were asked regarding patients' definitions of a flare, causal attribution, self-management strategies, their triggers to consult health professionals, and the information they had received about RA flares from health professionals. Transcripts were studied using the grounded theory approach to identify themes. Flares were usually described as worsening joint pain and swelling. Over-use of joints was identified as the most common cause of a flare, and commonly used self-management strategies included rest, gentle exercise and warming the joints. There was some variation in causal attribution and self-management with ethnicity. This study identified a link between causal attribution of flares and the resultant self-management strategies. A perceived trigger of the flare in some patients formed a focus for their self-management strategies, whereas those who could not identify a cause aimed mainly to alleviate symptoms. A better understanding of patients' perspective in the context of disease flares will allow the development of educational programmes to facilitate more effective self-management of this important manifestation of disease.


Differential effects of periopathogens on host protease inhibitors SLPI, elafin, SCCA1, and SCCA2.
Secretory leukocyte peptidase inhibitors (SLPI), elafin, squamous cell carcinoma antigen 1 and 2 (SCCA1 and SCCA2) are specific endogenous serine protease inhibitors expressed by epithelial cells that prevent tissue damage from excessive proteolytic enzyme activity due to inflammation. To determine the effects of various periopathogens on these protease inhibitors, we utilized human gingival epithelial cells (GECs) challenged with cell-free bacteria supernatants of various periopathogens Porphyromonas gingivalis, Tannerella forsythia, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum. The gene expression and secretion of SLPI, elafin, SCCA1, and SCCA2 were determined using real-time PCR and ELISA, respectively. The direct effects of periopathogens and P. gingivalis gingipain mutants on these inhibitors were examined in vitro by Western Blot. The effect on the innate immune response of GECs was measured by expression of antimicrobial peptides: human beta-defenisin-2 (hBD2) and chemokine (C-C motif) ligand 20 (CCL20). We found that SLPI, SCCA2, elafin, hBD2, and CCL20 gene expression levels were significantly induced (p<0.001) in response to P. gingivalis, whose virulence factors include cysteine proteases, but not in response to stimulation by other bacteria. P. gingivalis reduced the secretion of SLPI and elafin significantly in GECs, and degraded recombinant SLPI, elafin, SCCA1, and SCCA2. Differential degradation patterns of SLPI, elafin, SCCA1, and SCCA2 were observed with different bacteria as well as P. gingivalis mutants associated with the loss of specific gingipains secreted by P. gingivalis. In addition, pretreatment of GECs with SLPI, SCCA1, or SCCA2 partially blocked hBD2 and CCL20 mRNA expression in response to P. gingivalis, suggesting a protective effect. Our results suggest that different periopathogens affect the host protease inhibitors in a different manner, suggesting host susceptibility may differ in the presence of these pathogens. The balance between cellular protease inhibitors and their degradation may be an important factor in susceptibility to periodontal infection.


Measuring voluntariness of consent to research: an instrument review.
The conceptual complexity of the term voluntariness has resulted in relatively few empirical studies of the voluntariness component of consent to research. As the call for a formal assessment of voluntariness to be incorporated into the consent process intensifies, more researchers are responding to the challenge of developing a valid and reliable measure of voluntariness. The purpose of this article was to summarize and describe the empirical literature on voluntariness of consent. As part of a broader study on the voluntariness of consent to research, existing empirical studies of voluntariness of consent to research were reviewed to establish how voluntariness of consent to research has been assessed to date. Fifteen studies using different voluntariness assessment instruments were identified and included in the review. The review found that little attempt has been made to systematically collect data on the reliability and validity of voluntariness assessment instruments. No two instruments reviewed were found to be based on a shared conceptualization of voluntary consent to research.


Genetics of dilated cardiomyopathy: practical implications for heart failure management.
Given the global burden of heart failure, strategies to understand the underlying cause or to provide prognostic information are critical to reducing the morbidity and mortality associated with this highly prevalent disease. Cardiomyopathies often have a genetic cause, and the field of heart failure genetics is progressing rapidly. Through a deliberate investigation, evaluation for a familial component of cardiomyopathy can lead to increased identification of pathogenic genetic variants. Much research has also been focused on identifying markers of risk in patients with cardiomyopathy with the use of genetic testing. Advances in our understanding of genetic variants have been slightly offset by an increased recognition of the heterogeneity of disease expression. Greater breadth of genetic testing can increase the likelihood of identifying a variant of uncertain significance, which is resolved only rarely by cellular functional validation and segregation analysis. To increase the use of genetics in heart failure clinics, increased availability of genetic counsellors and other providers with experience in genetics is necessary. Ultimately, through ongoing research and increased clinical experience in cardiomyopathy genetics, an improved understanding of the disease processes will facilitate better clinical decision-making about the therapies offered, exemplifying the implementation of precision medicine.


Training Performed Above Lactate Threshold Decreases p53 and Shelterin Expression in Mice.
Telomere shortening is associated to sarcopenia leading to functional impairment during aging. There are mechanisms associated with telomere attrition, as well to its protection and repair. Physical training is a factor that attenuates telomere shortening, but little is known about the effects of different exercise intensities on telomere biology. Thus, we evaluated the effects of exercise intensity (moderate vs. high-intensity domain) on gene expression of senescence markers Checkpoint kinase 2 and tumor suppressor (Chk2 and p53, respectively), shelterin telomere repeat binding 1 and 2 (Trf1/Trf2), DNA repair (Xrcc5), telomerase reverse transcriptase (mTERT) and telomere length in middle aged mice. Three groups were studied: a control group (CTL) and two groups submitted to swimming at intensities below the lactate threshold (LI group) and above the lactate threshold (HI group) for 40 and 20 min respectively, for 12 weeks. After training, the HI group showed reduction in p53 expression in the muscle, and decreased shelterin complex expression when compared to LI group. No differences were observed between groups for mTERT expression and telomere length. Thus, exercise training in high-intensity domain was more effective on reducing markers of senescence and apoptosis. The higher intensity exercise training also diminished shelterin expression, with no differences in telomere length and mTERT expression. Such results possibly indicate a more effective DNA protection for the higher-intensity exercise training.


Predictive variables for the successful treatment of trigeminal neuralgia with gamma knife radiosurgery.
Gamma Knife radiosurgery (GKRS) has been reported to be an effective modality to treat trigeminal neuralgia. To determine predictive factors for the successful treatment of trigeminal neuralgia with GKRS. Between 1999 and 2008, 777 GKRS procedures for patients with trigeminal neuralgia were performed at our institution. Evaluable follow-up data were obtained for 448 patients. Median follow-up time was 20.9 months (range, 3-86 months). The mean maximum prescribed dose was 88 Gy (range, 80-97 Gy). Dosimetric variables recorded included dorsal root entry zone dose, pons maximum dose, dose to the petrous dural ridge, and cisternal nerve length. By 3 months after GKRS, 86% of patients achieved Barrow Neurologic Institute I to III pain scores, with 43% of patients achieving a Barrow Neurologic Institute I pain score. Twenty-six percent of patients reported posttreatment facial numbness; 28% of patients reported a post-GKRS procedure for relapsed pain, and median time to next procedure was 4.4 years. Multivariate analysis revealed that the development of postsurgical numbness (odds ratio [OR], 2.76; P = .006) was the dominant factor predictive of efficacy. Longer cisternal nerve length (OR, 0.85; P = .005), prior radiofrequency ablation (OR, 0.35; P = .028), and diabetes mellitus (OR, 0.38; P = .013) predicted decreased efficacy. The mean dose delivered to the dorsal root entry zone dose in patients who developed facial numbness (57.6 Gy) was more than the mean dose (47.3 Gy) given to patients who did not develop numbness (P = .02). The development of post-GKRS facial numbness is a dominant factor that predicts for efficacy of GKRS. History of diabetes mellitus or previous radiofrequency ablation may portend worsened outcome.


Validation of the Intelligent Cognitive Assessment System (ICAS) for stroke survivors.
To investigate the internal consistency, test-re-test reliability of an Intelligent Cognitive Assessment System (ICAS) and its optimal cut-off score for stroke patients with or without cognitive impairment. A prospective cohort study design was adopted. Sixty-six post-stroke patients of aged 60 or above were recruited. They were screened by the Chinese version of Mini Mental State Examination (MMSE-CV) and assessed by the Intelligent Cognitive Assessment System (ICAS) consisting of 65 testing items which could be presented at a level according to stroke patient's response. It was administered to examine the internal consistency and test-re-test reliability (by repeating within a 7-day interval). The optimal cut-off score to screen stroke patients having cognitive impairment was determined by the receiver operating characteristics (ROC) curve. The internal consistency of the ICAS (Cronbach's alpha = 0.878) and its test-re-test reliability (rho = 0.789; p < 0.001) were demonstrated. The cut-off score for the ICAS to determine cognitive impairment was found to be 3.02, with a sensitivity of 80.5% and specificity of 96%. Preliminary results suggested that ICAS was a valid and reliable cognitive screening tool for stroke survivors. The ICAS can be further developed by studying its norms for stroke patients. It is also programmable for potential application to different countries by changing ICAS to other language versions and including other culturally relevant content.


Potential preventability of spontaneous bacterial peritonitis.
Antibiotic prophylaxis can reduce the incidence of the first episode and recurrent episodes of spontaneous bacterial peritonitis (SBP) in high-risk cirrhotic patients. However, recent data suggest that SBP prophylaxis may be underused. It is unclear how many cases of cirrhosis that develop SBP might actually be prevented with antibiotic prophylaxis. To determine the number of "preventable" cases of SBP and the adherence to standard guidelines for the use of antibiotic prophylaxis. A retrospective analysis of our patients diagnosed with SBP was performed. AASLD Guidelines (2004) for SBP prophylaxis include prior SBP, gastrointestinal (GI) hemorrhage, ascitic fluid (AF), protein ≤ 1 g/dl, or serum bilirubin ≥ 2.5 mg/dl. "Preventable (P) SBP" was defined as SBP occurring where prophylaxis was indicated but was not administered. "Non-preventable (NP) SBP" was defined as SBP that occurred despite proper adherence to the guidelines. "Inevitable (I) SBP" were those cases of SBP occurring in the absence of a documented indication for prophylaxis. A total of 259 patients with cirrhosis underwent paracentesis; 29 had confirmed SBP. Eighteen of the 29 patients (62%) had "P-SBP", one (3%) had "NP-SBP", and ten (34%) had "I-SBP". In the P-SBP cases, the overlooked indications for prophylaxis were GI hemorrhage (n, %) (8, 44%), serum bilirubin ≥ 2.5 mg/dl (6, 33%), prior SBP (2, 11%) and AF protein ≤ 1 g/dl (2, 11%). Of the P-SBP, 78% were community-acquired; 22% were nosocomial. In-hospital mortality in the P-SBP was 16% (n = 3). Only one-third of patients who survived SBP received long-term outpatient prophylaxis after discharge. Many cases of SBP could be prevented by adhering to the AASLD guidelines. GI hemorrhage is the most frequently overlooked indication for SBP prophylaxis. Studies identifying the reasons for non-adherence to guidelines and developing interventions to increase utilization are warranted.


Endothelial-dependent and -independent responses in the thoracic aorta during endotoxic shock.
Endotoxic shock is characterized by a variety of hemodynamic disturbances which result in tissue hypoperfusion. There is some evidence for endothelial damage caused by endotoxin. The present study addressed the hypothesis that vascular responsiveness to endothelial-dependent vasodilators is altered in endotoxic shock. Dose-response relationships for an endothelial-dependent vasodilator, acetylcholine, and an endothelial-independent vasodilator, adenosine, were determined in guinea pig aortic rings. Rings were examined from either control (untreated) animals or from animals given Escherichia coli endotoxin (4 mg/kg, i.p.) 16 hr prior to functional studies. Dose-response relationships to adenosine were similar in aortic rings from control and shocked animals. However, response to acetylcholine were attenuated by 30% (P less than .05) in the shocked group. To distinguish between a direct, acute effect of endotoxin versus effects produced by systemic changes that occur during shock, rings were isolated from untreated animals and incubated with endotoxin in vitro for 30 min prior to and during dose-response measurements. Incubation with endotoxin caused no change in aortic responses to adenosine or acetylcholine. Electron microscopy revealed a separation of the endothelium from the internal elastic lamina and an increase in inter-endothelial gaps in rings isolated from shocked animals. These structural changes were not observed in rings from untreated animals or in rings incubated with endotoxin in vitro. We conclude that endothelial-dependent vasodilation is attenuated during endotoxic shock. The functional changes are correlated with ultrastructural alterations of the endothelium.


Jello Shot Consumption among Underage Youths in the United States.
We sought, for the first time, to identify the extent of jello shot consumption among underage youth. We conducted a study among a national sample of 1,031 youth, aged 13 to 20, using a pre-recruited internet panel maintained by GfK Knowledge Networks to assess past 30-day consumption of jello shots. Nearly one-fifth of underage youth have consumed jello shots in the past 30 days and jello shots make up an average of nearly 20% of their overall alcohol intake. Jello shot users in our sample were approximately 1.5 times more likely to binge drink, consumed approximately 1.6 times as many drinks per month, and were 1.7 times more likely to have been in a physical fight related to their alcohol use as drinkers in general. Ascertainment of jello shot use should become a standard part of youth alcohol surveillance and states should consider banning the sale of these products.


Cryptosporidium species and subtypes and clinical manifestations in children, Peru.
To determine whether clinical manifestations are associated with genotypes or subtypes of Cryptosporidium spp., we studied a 4-year longitudinal birth cohort of 533 children in Peru. A total of 156 infection episodes were found in 109 children. Data from first infections showed that C. hominis was associated with diarrhea, nausea, vomiting, general malaise, and increased oocyst shedding intensity and duration. In contrast, C. parvum, C. meleagridis, C. canis, and C. felis were associated with diarrhea only. C. hominis subtype families were identified (Ia, Ib, Id, and Ie); all were associated with diarrhea. Ib was also associated with nausea, vomiting, and general malaise. All C. parvum specimens belonged to subtype family IIc. Analysis of risk factors did not show associations with specific Cryptosporidium spp. genotypes or subtypes. These findings strongly suggest that Cryptosporidium spp. and subtypes are linked to different clinical manifestations in children.


Relation between earthquakes, weather, and soil tilt.
Two years of local earthquake, temperature, and rainfall data taken near a tiltmeter site were used in a study of the numerical relation between these phenomena and the recorded tilt response. A least-squares shaping and predictive error filter approach was used. The relations were ranked in part according to the root mean square (r.m.s.) error of fit across the entire sample space. The tilt data with an annual range of tilt of approximately 10 microradians were fitted to the combined weather data of temperature and rainfall with a 0.75-microradian r.m.s. error. The best fit of earthquakes to these same tilt data is the subclass of events with magnitude (M) > 2.5 within 30 kilometers of the tilt site. The filter that mapped earthquakes to tilt yielded a 1.03-microradian r.m.s. error. The most unusual tilt anomaly over the entire 2-year period has the best fit of rainfall to the data for any single month of the entire data set. This unusual anomaly was the basis of an erroneously predicted earthquake (M approximately 5). These data indicate that if there are premonitory earthquake signals, they are buried in local meteorlogical noise. Separating an earthquake anomaly from the response to surface phenomena becomes more difficult as the earthquake anomaly lead time approaches the rise time of the soil to weather and seasonal variations.


Dynamic structures in Escherichia coli: spontaneous formation of MinE rings and MinD polar zones.
In Escherichia coli, division site selection is regulated in part by the Min-protein system. Oscillations of the Min proteins from pole to pole every approximately 40 sec have been revealed by in vivo studies of GFP fusions. The dynamic oscillatory structures produced by the Min proteins, including a ring of MinE protein, compact polar zones of MinD, and zebra-striped oscillations in filamentous cells, remain unexplained. We show that the Min oscillations, including mutant phenotypes, can be accounted for by in vitro-observed interactions involving MinD and MinE, with a crucial role played by the rate of nucleotide exchange. Recent discoveries suggest that protein oscillations may play a general role in proper chromosome and plasmid partitioning.


Relatedness of Macrophomina phaseolina isolates from tallgrass prairie, maize, soybean and sorghum.
Agricultural and wild ecosystems may interact through shared pathogens such as Macrophomina phaseolina, a generalist clonal fungus with more than 284 plant hosts that is likely to become more important under climate change scenarios of increased heat and drought stress. To evaluate the degree of subdivision in populations of M. phaseolina in Kansas agriculture and wildlands, we compared 143 isolates from maize fields adjacent to tallgrass prairie, nearby sorghum fields, widely dispersed soybean fields and isolates from eight plant species in tallgrass prairie. Isolate growth phenotypes were evaluated on a medium containing chlorate. Genetic characteristics were analysed based on amplified fragment length polymorphisms and the sequence of the rDNA-internal transcribed spacer (ITS) region. The average genetic similarity was 58% among isolates in the tallgrass prairie, 71% in the maize fields, 75% in the sorghum fields and 80% in the dispersed soybean fields. The isolates were divided into four clusters: one containing most of the isolates from maize and soybean, two others containing isolates from wild plants and sorghum, and a fourth containing a single isolate recovered from Solidago canadensis in the tallgrass prairie. Most of the sorghum isolates had the dense phenotype on media containing chlorate, while those from other hosts had either feathery or restricted phenotypes. These results suggest that the tallgrass prairie supports a more diverse population of M. phaseolina per area than do any of the crop species. Subpopulations show incomplete specialization by host. These results also suggest that inoculum produced in agriculture may influence tallgrass prairie communities, and conversely that different pathogen subpopulations in tallgrass prairie can interact there to generate 'hybrids' with novel genetic profiles and pathogenic capabilities.


Determination of antimicrobial activity of sorrel (Hibiscus sabdariffa) on Escherichia coli O157:H7 isolated from food, veterinary, and clinical samples.
The use of medicinal plants as natural antimicrobial agents is gaining popularity. Sorrel (Hibiscus sabdariffa) is widely used for the treatment of diseases. The objective of this study was to investigate the antimicrobial activity of sorrel on Escherichia coli O157:H7 isolates from food, veterinary, and clinical samples. Phenolics of the calyces were extracted from 10 g of ground, freeze-dried samples using 100 mL of 80% aqueous methanol. Concentrations of 10%, 5%, and 2.5% methanol extract of sorrel were investigated for its antimicrobial activity. Inhibition zones were indicated by a lack of microbial growth due to inhibitory concentrations of sorrel diffused into semisolid culture medium beneath the sorrel-impregnated disk. The results of this experiment showed that the most potent sorrel concentration was 10%, then 5%, and finally 2.5%. The overall mean zone of inhibition for the sorrel extract was 12.66 mm for 10%, 10.75 mm for 5%, and 8.9 mm for 2.5%. The highest inhibition zones (11.16 mm) were observed in veterinary samples, and the lowest (10.57 mm) in the food samples. There were significant (P<.05) differences among mean zones of inhibition found in the food, veterinary, and clinical sources. Based on the source of samples and concentration of sorrel extract, the lowest mean inhibition was 7.00±0.04 mm from clinical samples, and the highest was 15.37±0.61 mm from a food source. These findings indicated that sorrel was effective at all levels in inhibiting E. coli O157:H7; thus it possesses antimicrobial activity and hold great promise as an antimicrobial agent.


Group sequential designs with prospectively planned rules for subpopulation enrichment.
We propose a class of randomized trial designs aimed at gaining the advantages of wider generalizability and faster recruitment while mitigating the risks of including a population for which there is greater a priori uncertainty. We focus on testing null hypotheses for the overall population and a predefined subpopulation. Our designs have preplanned rules for modifying enrollment criteria based on data accrued at interim analyses. For example, enrollment can be restricted if the participants from a predefined subpopulation are not benefiting from the new treatment. Our designs have the following features: the multiple testing procedure fully leverages the correlation among statistics for different populations; the asymptotic familywise Type I error rate is strongly controlled; for outcomes that are binary or normally distributed, the decision rule and multiple testing procedure are functions of the data only through minimal sufficient statistics. Our designs incorporate standard group sequential boundaries for each population of interest; this may be helpful in communicating the designs, because many clinical investigators are familiar with such boundaries, which can be summarized succinctly in a single table or graph. We demonstrate these designs through simulations of a Phase III trial of a new treatment for stroke. User-friendly, free software implementing these designs is described. Copyright © 2016 John Wiley & Sons, Ltd.


Murine endoglin-specific single-chain Fv fragments for the analysis of vascular targeting strategies in mice.
Endoglin has been identified as a promising cell surface antigen for vascular targeting approaches in cancer therapy, e.g. employing antibody molecules as targeting moieties. However, in vivo analysis of such strategies in mouse models requires antibodies recognizing endoglin on mouse endothelial cells. Here we describe the isolation of single-chain Fv fragments (scFvs) from phage display libraries, which bind to the extracellular region of mouse endoglin. One of these clones, scFv mE12, showed strong (K(d)=11 nM) and selective binding to purified endoglin and also to the endoglin-expressing mouse endothelioma cell line eEnd.2. This antibody recognized a linear epitope located in the N-terminal region (aa 27-361) of endoglin. Cell binding was further increased by generating a bivalent scFv-Fc fusion protein composed of scFv mE12 and the human gamma1 Fc part. Moreover, scFv mE12 was endowed with an additional cysteine residue in the linker region and applied for the generation of anti-endoglin scFv immunoliposomes capable of selectively binding to endoglin-expressing cells. Thus, anti-mouse endoglin scFv mE12 should be useful to analyze vascular targeting strategies in mice.


A possible structure of the rabbit reticulocyte ribosome. An exercise in model building.
It is suggested that the location of each of the diverse ribosomal proteins in the ribosome, or in the ribosomal subparticles in their native or derived forms, is determined by the nucleotide sequence of the 16s and 23-30s RNA moieties, i.e. that the 16s and 23-30s RNA species provide a unique binding site for each species of ribosomal protein. The ways of assembling such a thread into a ribosome-like structure appear limited if the ribosome is largely stabilized by protein-protein interactions. The nucleoprotein thread was built into a structure, having the general features of a hollow cylinder, that is consistent with the known dimensions and properties of the rabbit reticulocyte ribosome. It appears possible to test the model by experiment.


The path to Australia's tobacco health warnings.
Australia introduced new health warnings and contents labelling on cigarettes and other tobacco products from January 1995. The changes were based on recommendations emerging from research commissioned for that purpose. The research demonstrated the need for changes that changes could increase the noticeability of the warnings and contribute to an increase in relevant knowledge, and that the changes were acceptable to the public. The tobacco industry fought the changes and some modifications resulted, but new stronger warnings with elaborations on the back of the pack, an information number to call and elaborated contents labelling have been implemented.


[General pharmacological action of 4-(o-benzylphenoxy)-N-methylamine hydrochloride (bifemelane hydrochloride, MCI-2016)--influence on the central nervous system].
General pharmacological action of 4-(o-Benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane hydrochloride, MCI-2016) was examined with regard to the effects mainly on the central nervous system. MCI-2016, at 30-100 mg/kg, p.o., only showed a weak sleep prolongation effect (mice), anti-convulsant action (mice) and a moderate facilitation of exploratory behavior, but produced no remarkable behavioral changes. Above the doses of 200 to 300 mg/kg, p.o., MCI-2016 produced a decrease in muscle or body tone, mydriasis and a slight decrease of locomotor activity. The drug, however, showed little influence on exploratory behavior, conditioned avoidance response and normal body temperature (rats). Normal body temperature in rabbits was also little affected by MCI-2016. Effects on EEG was characterized by moderate activation of spontaneous EEG and potentiation of arousal response by stimulation of the midbrain reticular formation (1.5-5 mg/kg, i.v.). The drug, however, did not significantly change the sleep-wakefulness cycle and REM-sleep in rats. MCI-2016 also showed little influence on spinal reflex potentials and neuromuscular junction at high doses (10 mg/kg, i.v.). These results may indicate that MCI-2016 has slight influence on overall behavioral and motor changes. Effects of MCI-2016 on acetic acid-induced writhing, carrageenin edema and corneal reflex were also examined. MCI-2016 showed moderate analgesic and anti-inflammatory actions at 50-100 mg/kg, p.o., and also showed local anesthetic action. The duration of local anesthetic action was relatively long but the drug produced no local damage.


Interspecies comparative genome hybridization and interspecies representational difference analysis reveal gross DNA differences between humans and great apes.
Comparative chromosome G-/R-banding, comparative gene mapping and chromosome painting techniques have demonstrated that only few chromosomal rearrangements occurred during great ape and human evolution. Interspecies comparative genome hybridization (CGH), used here in this study, between human, gorilla and pygmy chimpanzee revealed species-specific regions in all three species. In contrast to the human, a far more complex distribution of species-specific blocks was detected with CGH in gorilla and pygmy chimpanzee. Most of these blocks coincide with already described heterochromatic regions on gorilla and chimpanzee chromosomes. Representational difference analysis (RDA) was used to subtract the complex genome of gorilla against human in order to enrich gorilla-specific DNA sequences. Gorilla-specific clones isolated with this technique revealed a 32-bp repeat unit. These clones were mapped by fluorescence in situ hybridization (FISH) to the telomeric regions of gorilla chromosomes that had been shown by interspecies CGH to contain species-specific sequences.


Involvement of alpha noradrenergic receptors in mediation of brain polyphosphoinositides metabolism in vivo.
The acute effects of norepinephrine (NE) on polyphosphoinositide (PPI) metabolism were examined in regions of rat brain in vivo with the techniques of intracisternal injection and microwave irradiation fixation. NE (80 nmol/g of brain) increased PPI incorporation of both [32P] orthophosphate and [3H] inositol by 50 to 100% within 5 min of the simultaneous intracisternal administration of both drug and radiolabel. These effects of NE were more pronounced in the brainstem and cerebellum than in the cerebral cortex, and were greater for triphosphoinositide than for diphosphoinositide. The increases were blocked by phentolamine and phenoxybenzamine but not by propranolol or atropine, suggesting that alpha noradrenergic receptors mediated the effect. Similar metabolic responses were observed with PPI precursors, phosphatidic acid and monophosphoinositide. However, no other phospholipid was altered in response to the agents administered in these studies (data not shown). Increased incorporation of radiolabels into PPI was never accompanied by detectable increases in endogenous PPI concentrations, suggesting that head group turnover was stimulated rather than whole molecule synthesis. Also, the increase in PPI phosphate radiolabel incorporation was not due to NE effects on the specific activity of phosphate donor precursors (nucleotides). The present data suggest that the PPI may be involved in the membrane processes that result from stimulation of alpha noradrenergic receptors in brain.


Ultrasonographical diagnosis of acute gynaecological pain.
Acute pelvic pain is a common presentation in women. There are a myriad of causes, both gynaecological and non-gynaecological in origin. Ultrasonography is well-established as the primary initial investigation of choice. Familiarity with the imaging features of the commonly-associated conditions aids in the rapid diagnosis, and immediate management of the patient. This article provides a pictorial review of the common gynaecological causes of pelvic pain.


Assessing individual variability of the entorhinal subfields in health and disease.
Investigating interindividual variability is a major field of interest in neuroscience. The entorhinal cortex (EC) is essential for memory and affected early in the progression of Alzheimer's disease (AD). We combined histology ground-truth data with ultrahigh-resolution 7T ex vivo MRI to analyze EC interindividual variability in 3D. Further, we characterized (1) entorhinal shape as a whole, (2) entorhinal subfield range and midpoints, and (3) subfield architectural location and tau burden derived from 3D probability maps. Our results indicated that EC shape varied but was not related to demographic or disease factors at this preclinical stage. The medial intermediate subfield showed the highest degree of location variability in the probability maps. However, individual subfields did not display the same level of variability across dimensions and outcome measure, each providing a different perspective. For example, the olfactory subfield showed low variability in midpoint location in the superior-inferior dimension but high variability in anterior-posterior, and the subfield entorhinal intermediate showed a large variability in volumetric measures but a low variability in location derived from the 3D probability maps. These findings suggest that interindividual variability within the entorhinal subfields requires a 3D approach incorporating multiple outcome measures. This study provides 3D probability maps of the individual entorhinal subfields and respective tau pathology in the preclinical stage (Braak I and II) of AD. These probability maps illustrate the subfield average and may serve as a checkpoint for future modeling.


Multi-stringency wash of partially hybridized 60-mer probes reveals that the stringency along the probe decreases with distance from the microarray surface.
Here, we describe a multi-parametric study of DNA hybridization to probes with 20-70% G + C content. Probes were designed towards 71 different sites/mutations in the phenylalanine hydroxylase gene. Seven probe lengths, three spacer lengths and six stringencies were systematically varied. The three spacer lengths were obtained by placing the gene-specific sequence in discrete steps along the 60-mer probes. The study was performed using Agilent 8 x 15 000 probes custom-made arrays and a home-built array washer providing different stringencies to each of the eight sub-arrays on the slides. Investigation of hybridization signals, specificity and dissociation curves indicated that probes close to the surface were influenced by an additional stringency provided by the microarray surface. Consistent with this, probes close to the surface required 4 x SSC, while probes placed away from the surface required 0.35 x SSC wash buffers in order to give accurate genotyping results. Multiple step dissociation was frequently observed for probes placed furthest away from surface, but not for probes placed proximal to the surface, which is consistent with the hypothesis that there is different stringency along the 60-mer. The results have impact on design of probes for genotyping, gene expression and comparative genome hybridization analysis.


Structural and Thermodynamic Understandings in Mn-Based Sodium Layered Oxides during Anionic Redox.
A breakthrough utilizing an anionic redox reaction (O2-/On-) for charge compensation has led to the development of high-energy cathode materials in sodium-ion batteries. However, its reaction results in a large voltage hysteresis due to the structural degradation arising from an oxygen loss. Herein, an interesting P2-type Mn-based compound exhibits a distinct two-phase behavior preserving a high-potential anionic redox (≈4.2 V vs Na+/Na) even during the subsequent cycling. Through a systematic series of experimental characterizations and theoretical calculations, the anionic redox reaction originating from O 2p-electron and the reversible unmixing of Na-rich and Na-poor phases are confirmed in detail. In light of the combined study, a critical role of the anion-redox-induced two-phase reaction in the positive-negative point of view is demonstrated, suggesting a rational design principle considering the phase separation and lattice mismatch. Furthermore, these results provide an exciting approach for utilizing the high-voltage feature in Mn-based layered cathode materials that are charge-compensated by an anionic redox reaction.


GPCR functional selectivity has therapeutic impact.
Many in vitro data show that some ligands can cause the differential activation of signaling pathways mediated by a single receptor (termed 'functional selectivity'). It remains unclear, however, whether functionally selective properties are meaningful in vivo. Data obtained with experimental compounds that are functionally selective at the dopamine D2L receptor in vitro suggest that these properties might predict atypical behavioral actions. Moreover, the antipsychotic drug aripiprazole is commonly thought to be a D2 partial agonist, but data clearly show that aripiprazole is functionally selective in vitro. It is proposed that the effects of aripiprazole in animal models and humans can be reconciled only with its functionally selective D2 properties, not its partial D2 agonism. Together, these data provide support for the hypothesis that compounds with functionally selective properties in vitro are likely to have novel actions in vivo, opening doors to new avenues of drug discovery.


Longitudinal associations among family environment, neural cognitive control, and social competence among adolescents.
During adolescence, prefrontal cortex regions, important in cognitive control, undergo maturation to adapt to changing environmental demands. Ways through which social-ecological factors contribute to adolescent neural cognitive control have not been thoroughly examined. We hypothesize that household chaos is a context that may modulate the associations among parental control, adolescent neural cognitive control, and developmental changes in social competence. The sample involved 167 adolescents (ages 13-14 at Time 1, 53% male). Parental control and household chaos were measured using adolescents' questionnaire data, and cognitive control was assessed via behavioral performance and brain imaging at Time 1. Adolescent social competence was reported by adolescents at Time 1 and at Time 2 (one year later). Structural equation modeling analyses indicated that higher parental control predicted better neural cognitive control only among adolescents living in low-chaos households. The association between poor neural cognitive control at Time 1 and social competence at Time 2 (after controlling for social competence at Time 1) was significant only among adolescents living in high-chaos households. Household chaos may undermine the positive association of parental control with adolescent neural cognitive control and exacerbate the detrimental association of poor neural cognitive control with disrupted social competence development.


A finite element approach for gastrointestinal tissue mechanics.
The biomechanical properties of gastrointestinal (GI) tissue play a significant role in the normal functioning of the organ. GI soft tissues exhibit a highly nonlinear rate- and time-dependent stress-strain behaviour. In recent years, many constitutive relations have been proposed to characterize these properties. However, a constitutive relation is not sufficient to analyse the biomechanics at the organ level with complex loading and boundary conditions. Hence, for a refined mechanical analysis, a finite element (FE) implementation of the constitutive relation is needed. Here, we propose an FE implementation of a finite nonlinear hyperviscoelastic model suitable for soft biological tissues. The FE model has been validated at first by comparing its results with the analytical solutions of a standard linear solid, and then it has been used to recreate experimental observations performed on tissue strips obtained from different animals. We have also proposed a method, in this work, to construct a residually stressed FE model so that the consequences of residual stresses on GI mechanics can be examined. Our FE formulation was able to capture the nonlinear soft tissue properties and also demonstrated that the addition of residual stresses reduces stress concentrations and the stress gradient in the GI wall.


Super-Resolution Fluorescence Microscopy Methods for Assessing Mouse Biology.
Super-resolution (diffraction unlimited) microscopy was developed 15 years ago; the developers were awarded the Nobel Prize in Chemistry in recognition of their work in 2014. Super-resolution microscopy is increasingly being applied to diverse scientific fields, from single molecules to cell organelles, viruses, bacteria, plants, and animals, especially the mammalian model organism Mus musculus. In this review, we explain how super-resolution microscopy, along with fluorescence microscopy from which it grew, has aided the renaissance of the light microscope. We cover experiment planning and specimen preparation and explain structured illumination microscopy, super-resolution radial fluctuations, stimulated emission depletion microscopy, single-molecule localization microscopy, and super-resolution imaging by pixel reassignment. The final section of this review discusses the strengths and weaknesses of each super-resolution technique and how to choose the best approach for your research. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC.


Effectiveness and predictors of outcome in routine out-patient mental health care for older adults.
ABSTRACT Background: Meta-analyses show efficacy of several psychological and pharmacological interventions for late-life psychiatric disorders, but generalization of effects to routine mental health care for older people remains unknown. Aim of this study is to investigate the improvement of functioning within one year of referral to an outpatient mental health clinic for older adults. Methods: Pre-post measurement of the Health of Nations Outcome Scale 65+ (HoNOS 65+) in 704 older people referred for psychiatric problems (no dementia) to any of the seven participating mental health care organizations. Results: The pre-post-test Cohen's d effect size was 1.08 in the total group and 1.23 in depressed patients, the largest subgroup. Linear regression identified better functioning at baseline, comorbid personality disorder, somatic comorbidity and life events during treatment as determinants of a worse outcome. Conclusions: Functioning of older persons with psychiatric problems largely improves after treatment in routine mental health care.


The effects of mysid grazing on kelp zoospore survival and settlement.
Recent studies have indicated that long-distance dispersal by kelp zoospores may play an important role in the colonization of newly exposed rocky habitats and in the recovery of recently disturbed kelp forests. This may be facilitated by the vertical transport of zoospores into the shallower portions of the water column where they are exposed to greater alongshore currents that increase their dispersal potential. However, this vertical transport can also expose them to elevated irradiances and enhanced grazing by zooplankton, both of which negatively impact zoospore survival and settlement. In this study, we used plankton tows to show that zooplankton (mysids) were at least seven times more abundant in the surface waters than near the benthos along the edge of a large kelp forest at the time of our spring sampling. We then used feeding experiments and epifluorescence microscopy to verify that these mysids grazed on kelp zoospores. Finally, we conducted laboratory experiments to show that grazing by these mysids over a 12 h period reduced kelp zoospore settlement by at least 50% relative to treatments without grazing. Together with previous studies that have revealed the impacts of high irradiance on zoospore survival and settlement, our study indicates that the vertical transport of kelp zoospores into the shallower portions of the water can also expose them to significantly increased mortality from mysid grazing. Thus, if these patterns are consistent over broader temporal and geographic scales, vertical transport may not be a viable method for sustained long-distance zoospore dispersal.


Analysis of Keloid Response to 5-Fluorouracil Treatment and Long-Term Prevention of Keloid Recurrence.
Keloids are benign fibroproliferative skin tumors that can cause disfigurement and disability. Although they frequently recur after excision or medical management and can affect 6 to 16 percent of African Americans, there is no gold standard therapy. Keloids are challenging to study because there are no animal or in vitro models of this disorder. This makes it very difficult to validate data from treated tissue samples or cells and develop targeted therapies for this disease. In this study, the authors demonstrate that intralesional 5-fluorouracil injection after keloid excision prevents recurrence for 2 years, with no reported adverse events. The authors analyze the expression of treated and untreated biopsy specimens of the same keloids in their native context to capture insights that may be missed by in vitro cell culture models and correct for intrakeloid variability. Random forest analysis of the microarray data dramatically increased the statistical power of the authors' results, permitting hypothesis-free creation of a gene expression profile of 5-fluorouracil-treated keloids. Through this analysis, the authors found a set of genes, including YAP1 and CCL-2, whose expression changes predict 5-fluorouracil therapy status and include genes that have not previously been associated with keloid biology and are of unknown function. The authors further describe keloid heterogeneity for the first time using multidimensional analysis of their microarray results. The methods and tools the authors developed in this research may overcome some of the challenges in studying keloids and developing effective treatments for this disease. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Therapeutic, V.


Exergy and Exergoeconomic Analysis of a Cogeneration Hybrid Solar Organic Rankine Cycle with Ejector.
Solar energy is utilized in a combined ejector refrigeration system with an organic Rankine cycle (ORC) to produce a cooling effect and generate electrical power. This study aims at increasing the utilized share of the collected solar thermal energy by inserting an ORC into the system. As the ejector refrigeration cycle reaches its maximum coefficient of performance (COP), the ORC starts working and generating electrical power. This electricity is used to run the circulating pumps and the control system, which makes the system autonomous. For the ejector refrigeration system, R134a refrigerant is selected as the working fluid for its performance characteristics and environmentally friendly nature. The COP of 0.53 was obtained for the ejector refrigeration cycle. The combined cycle of the solar ejector refrigeration and ORC is modeled in EBSILON Professional. Different parameters like generator temperature and pressure, condenser temperature and pressure, and entrainment ratio are studied, and the effect of these parameters on the cycle COP is investigated. Exergy, economic, and exergoeconomic analyses of the hybrid system are carried out to identify the thermodynamic and cost inefficiencies present in various components of the system.


Limited immunogenicity of HIV CD8+ T-cell epitopes in acute Clade C virus infection.
Human immunodeficiency virus type 1 (HIV-1)-specific CD8(+) responses contribute to the decline in acute peak viremia following infection. However, data on the relative immunogenicity of CD8(+) T-cell epitopes during and after acute viremia are lacking. We characterized CD8(+) T-cell responses in 20 acutely infected, antiretroviral-naive individuals with HIV-1 subtype C infection using the interferon-γ enzyme-linked immunosorbent spot assay. Eleven of these had not fully seroconverted at the time of analysis. Viruses from plasma were sequenced within defined cytotoxic T-lymphocyte (CTL) cell epitopes for selected subjects. At approximately 28 days after estimated initial infection, CD8(+) T-cell responses were directed against an average of 3 of the 410 peptides tested (range, 0-6); 2 individuals had no detectable responses at this time. At 18 weeks, the average number of peptides targeted had increased to 5 (range 0-11). Of the 56 optimal Gag CTL epitopes sequenced, 31 were wild-type in the infecting viruses, but only 11 of 31 elicited measurable CD8(+) T-cell responses. These data demonstrate that the majority of CD8(+) responses are not elicited during acute HIV infection despite the presence of the cognate epitope in the infecting strain. There is a need to define factors that influence lack of induction of effective immune responses and the parameters that dictate immunodominance in acute infection.


The patient centered medical home. A systematic review.
The patient-centered medical home (PCMH) describes mechanisms for organizing primary care to provide high quality care across the full range of individuals' health care needs.It is being widely implemented by provider organizations and third party payers. To describe approaches for PCMH implementation and summarize evidence for effects on patient and staff experiences,process of care, and clinical and economic outcomes. PubMed (through 6 December 2011), Cumulative Index to Nursing & Allied Health Literature, and the Cochrane Database of Systematic Reviews (through 29 June 2012). English-language trials and longitudinal observational studies that met criteria for the PCMH, as defined by the Agency for Healthcare Research and Quality, and included populations with multiple conditions. Information on study design, populations, interventions,comparators, financial models, implementation methods,outcomes, and risk of bias were abstracted by 1 investigator and verified by another. In 19 comparative studies, PCMH interventions had a small positive effect on patient experiences and small to moderate positive effects on the delivery of preventive care services(moderate strength of evidence). Staff experiences were also improved by a small to moderate degree (low strength of evidence).Evidence suggested a reduction in emergency department visits(risk ratio [RR], 0.81 [95% CI, 0.67 to 0.98]) but not in hospital admissions (RR, 0.96 [CI, 0.84 to 1.10]) in older adults (low strength of evidence). There was no evidence for overall cost savings. Systematic review is challenging because of a lack of consistent definitions and nomenclature for PCMH. The PCMH holds promise for improving the experiences of patients and staff and potentially for improving care processes,but current evidence is insufficient to determine effects on clinical and most economic outcomes


Initial neuro-ophthalmological manifestations in Churg-Strauss syndrome.
Churg-Strauss syndrome (CSS) is a systemic vasculitis with frequent respiratory tract involvement. It can also affect the nervous system, notably the optic tract. The present work reports the case of a 65-year-old man diagnosed as having CSS in the context of several acute onset neurological symptoms including muscle weakness and signs of temporal arteritis, including bilateral anterior ischaemic optic neuropathy (ON). Electroretinograms (ERGs) and visual evoked potentials (VEPs) were performed. Flash ERGs were normal whereas VEPs were highly abnormal, showing a dramatic voltage reduction, thus confirming the ON. The vision outcome was poor. Ophthalmological presentations of CSS have rarely been reported, but no previous case of sudden blindness documented by combined ERG and VEP investigations were found in the literature. The present case strongly suggests that the occurrence of visual loss in the context of systemic inflammation with hypereosinophilia should lead to considering the diagnosis of CSS.


Granulomatous lobular mastitis: a complex diagnostic and therapeutic problem.
Granulomatous lobular mastitis is a rare chronic inflammatory disease of the breast. Clinical and radiological features may mimic breast carcinoma. Since this entity was first described, several clinical and pathologic features of the disease have been reported, but diagnostic features and treatment alternatives are still unclear. The purpose of this study is to evaluate diagnostic difficulties and discuss the outcome of surgical treatment in a series of 21 patients with granulomatous lobular mastitis. A retrospective review of 21 patients with histologically confirmed granulomatous lobular mastitis treated in our center between January 1995 and May 2005 was analyzed to identify issues in the diagnosis and treatment of this rare condition. The most common presenting symptoms were a mass in the breast and pain. Four patients had no significant mammographic findings (MMG), but on ultrasound (US), 2 had irregular hypoechoic mass, and 2 hypoechoic nodular structures had abnormalities-one parenchymal distortion and 1 mass formation in 2 of these 4 patients' magnetic resonance imaging (MRI). In recurrent cases, limited excision under local anesthesia was performed, as the clinical examination suggested carcinoma. Although some findings on MMG and US are suggestive of benign breast disease, these modalities do not rule out malignancy. MRI may be helpful in patients who do not have significant pathology at MMG or US. Fine-needle aspiration cytology may be useful in some cases but diagnosis is potentially difficult because of its cytologic characteristics. Wide excision, particularly under general anesthesia, can be therapeutic as well as useful in providing an exact diagnosis.


Structural insights into DNA binding domain of vancomycin-resistance-associated response regulator in complex with its promoter DNA from Staphylococcus aureus.
In Staphylococcus aureus, vancomycin-resistance-associated response regulator (VraR) is a part of the VraSR two-component system, which is responsible for activating a cell wall-stress stimulon in response to an antibiotic that inhibits cell wall formation. Two VraR-binding sites have been identified: R1 and R2 in the vraSR operon control region. However, the binding of VraR to a promoter DNA enhancing downstream gene expression remains unclear. VraR contains a conserved N-terminal receiver domain (VraRN ) connected to a C-terminal DNA binding domain (VraRC ) with a flexible linker. Here, we present the crystal structure of VraRC alone and in complex with R1-DNA in 1.87- and 2.0-Å resolution, respectively. VraRC consisting of four α-helices forms a dimer when interacting with R1-DNA. In the VraRC -DNA complex structure, Mg2+ ion is bound to Asp194. Biolayer interferometry experiments revealed that the addition of Mg2+ to VraRC enhanced its DNA binding affinity by eightfold. In addition, interpretation of NMR titrations between VraRC with R1- and R2-DNA revealed the essential residues that might play a crucial role in interacting with DNA of the vraSR operon. The structural information could help in designing and screening potential therapeutics/inhibitors to deal with antibiotic-resistant S. aureus via targeting VraR.


Does a corporate worksite physical activity program reach those who are inactive? Findings from an evaluation of the Global Corporate Challenge.
Workplace physical activity programs can motivate inactive target groups to increase daily activity levels, but it is important to determine their reach and impact. The Global Corporate Challenge (GCC) is a team-based program promoting pedometer-based self-monitoring to reach 10000 steps per day. Participants (n = 587) from an Australian university were recruited and recorded their daily step counts. Demographic, anthropometric, behavioural, self-reported physical activity and sitting time data were collected at baseline and following the 16-week program. On average, participants self-estimated 11 638 daily steps in Week 1, increasing to measured estimates of 13 787 daily steps in Week 16 (P < 0.001). At baseline, 92% of survey completers were already meeting the physical activity recommendations, increasing to 98% (P = 0.059) at follow-up. Four month improvements in objectively assessed anthropometric measures showed small, non-significant reductions in weight (-0.12 kg; P = 0.416), body mass index (-0.06 kg/m2; P = 0.314) and waist circumference (-0.43 cm; P = 0.082). Sitting time during work decreased significantly by 21 min per day (P < 0.001) and participants with initially low levels of sitting time at work were more likely to increase their step counts during the GCC (adjusted odds ratio 1.90, 95% confidence interval 1.03-3.50). Although this pedometer-based program resulted in increases in physical activity and reductions in occupational sedentary behaviour, most participants were already meeting physical activity recommendations at baseline. SO WHAT? Workplace interventions need to be better targeted to reach inactive employees to have population-level impacts on chronic disease risk factors.


Disulphide reduction alters the immunoreactivity and increases the affinity of insulin-like growth-factor-I receptors in human placenta.
We previously identified two forms of the insulin-like growth-factor-I (IGF-I) receptor in human placenta: a lower-affinity form reactive with an autoantiserum (B-2) to the insulin receptor and a higher-affinity non-immunoreactive form [Jonas & Harrison (1985) J. Biol. Chem. 260, 2288-2294]. Evidence is now presented that the lower-affinity immunoreactive forms are convertible into higher-affinity non-immunoreactive forms via reduction of receptor disulphide bonds. Treatment of placental membranes with increasing concentrations of dithiothreitol (DTT): (1) converted native Mr-290 000 heterotetrameric IGF-I receptors into Mr-180 000 dimers (determined by chemical cross-linking of 125I-IGF-I with disuccinimidyl suberate); (2) increased 125I-IGF-I binding, owing to an increase in receptor affinity; and (3) abolished the reactivity of Triton-solubilized IGF-I receptors with antiserum B-2 and transformed the curvilinear plot of IGF-I binding to a linear form. In isolated complexes between receptor and B-2 antibody, DTT increased 125I-IGF-I binding and released a single class of higher affinity IGF-I receptors of Mr 180,000. Thus DTT-treated IGF-I receptors have similar properties to the higher-affinity non-immunoreactive forms of the native receptor, except that reduced dimeric forms are not detected by cross-linking of 125I-IGF-I to native membranes. Cleavage of the inter-dimeric disulphide bonds is therefore not a prerequisite for higher-affinity binding or loss of immunoreactivity. These observations suggest that the thiol redox state of the IGF-I receptor in vivo is an important determinant of receptor conformation and therefore of the biological responses to IGF-I.


Preponderance of postsystolic period in the positive inotropic effects of increases in (Ca++).
If the frequency of stimulation of isolated kitten right ventricular papillary muscles is progressively reduced, the size of contractions decreases until a frequency is reached (rested state rate) where further reduction produces no change (rested state contraction, Koch-Weser and Blinks, 1963). At 30 degrees C and 2.25 mM Ca++, the rested state rate was about one per 2-5 min, the peak tension of 0.2-0.6 g/mm2 was about 5-15% of the tension of 20/min beats, and times to peak tension and 80% repolarization about doubled. Sudden calcium increases in the perfusion fluid, [Ca++]p, from 2.25 to 6.75 mM were produced at random during intervals between rested state contractions, and time and amplitude of peak isometric tension, max +/- dT/dt of subsequent beats were studied. The greatest positive inotropic response of the initial beats following increments in [Ca++]p resulted when [Ca++]p was increased immediately after a rested state contraction: as the postsystolic interval before the [Ca++]p increment was increased, the positive inotropic effects decreased approximately exponentially, attaining a plateau level in about 30 sec. This plateau was then maintained until the period prior to the initial test beat in high calcium was less than the approximately 2-min diffusion equilibrium time between [Ca++]p and the interior of the fiber.


No Interference of H9 Extract on Trastuzumab Pharmacokinetics in Their Combinations.
Trastuzumab is used to treat breast cancer patients overexpressing human epidermal growth factor receptor 2, but resistance and toxicity limit its uses, leading to attention to trastuzumab combinations. Recently, the synergistic effect of trastuzumab and H9 extract (H9) combination against breast cancer has been reported. Because drug exposure determines its efficacy and toxicity, the question of whether H9 changes trastuzumab exposure in the body has been raised. Therefore, this study aimed to characterize trastuzumab pharmacokinetics and elucidate the effect of H9 on trastuzumab pharmacokinetics at a combination dose that shows synergism in mice. As a result, trastuzumab showed linear pharmacokinetics after its intravenous administration from 1 to 10 mg/kg. In the combination of trastuzumab and H9, single and 2-week treatments of oral H9 (500 mg/kg) did not influence trastuzumab pharmacokinetics. In the multiple-combination treatments of trastuzumab and H9 showing their synergistic effect (3 weeks of trastuzumab with 2 weeks of H9), the pharmacokinetic profile of trastuzumab was comparable to that of 3 weeks of trastuzumab alone. In tissue distribution, the tissue to plasma ratios of trastuzumab below 1.0 indicated its limited distributions within the tissues, and these patterns were unaffected by H9. These results suggest that the systemic and local exposures of trastuzumab are unchanged by single and multiple-combination treatments of H9.


Cytokine regulation of periportal fibrosis in humans infected with Schistosoma mansoni: IFN-gamma is associated with protection against fibrosis and TNF-alpha with aggravation of disease.
Hepatic periportal fibrosis, which affects 5-10% of subjects infected by Schistosoma mansoni, is caused by the T cell-dependent granuloma that develop around schistosome eggs. Experimental models of infection have shown that granuloma and fibrosis are tightly regulated by cytokines. However, it is unknown why advanced periportal fibrosis occurs only in certain subjects. The goal of the present study was to evaluate the cytokine response of S. mansoni-infected subjects with advanced liver disease in an attempt to relate susceptibility to periportal fibrosis with an abnormal production of cytokines that regulate granuloma and fibrosis. Fibrosis was evaluated by ultrasound on 795 inhabitants of a Sudanese village in which S. mansoni is endemic: advanced periportal fibrosis was observed in 12% of the population; 35% of the affected subjects exhibited signs of portal hypertension. Age (odds ratio (OR), 11.5), gender (OR, 4.2), and infection levels (OR, 2.2) were significantly (p < or = 0.01) associated with hepatic fibrosis. Cytokines produced by egg-stimulated blood mononuclear cells from 99 subjects were measured (75 with no or mild fibrosis; 24 subjects with advanced fibrosis). Multivariate analysis of cytokine levels showed that high IFN-gamma levels were associated with a marked reduction of the risk of fibrosis (p = 0.01; OR, 0.1); in contrast, high TNF-alpha levels were associated with an increased risk (p = 0.05; OR, 4.6) of periportal fibrosis. Moreover, infection levels were negatively associated with IFN-gamma production. These results with observations in experimental models strongly suggest that IFN-gamma plays a key role in the protection of S. mansoni-infected patients against periportal fibrosis, whereas TNF-alpha may aggravate the disease.


In vitro and in vivo evaluation of a moisture treatment cream containing three critical elements of natural skin moisturization.
To evaluate skin barrier and hydration effects of a new rebalancing moisture treatment (TRMT) and to assess efficacy and tolerability in subjects with photodamaged skin. In an epidermal skin model, tissues (n = 5/group) were topically treated with 25 µL of TRMT, 25 µL of a market-leading moisturizer (MLM), or untreated for 60 minutes. Hydration was measured at 0, 15, and 30 minutes. Tissues were harvested for gene expression analysis of markers associated with skin barrier and hydration: Claudin (CLD), Aquaporin (AQP), Hyaluronic Acid Syntheses (HAS), and Hyaluronidase (HYAL). A clinical study evaluated twice-daily application of TRMT, assessing changes in fine lines/wrinkles, brightness, texture, erythema, and tolerability from baseline through week 8. Hydration was measured using electrical impedance. TRMT and MLM demonstrated significant increases in hydration vs untreated tissue at each timepoint (P < .005), with greater hydration effects observed for TRMT vs MLM. TRMT-treated tissues demonstrated greater expression of CLD, AQP, and HA, and reduced expression of HYAL vs untreated and MLM-treated tissues. Twice-daily application of TRMT demonstrated significant improvements at 2 weeks in fine lines/wrinkles (P < .001), brightness (P < .0001), texture (P < .0004), and hydration (P < .004). At 8 weeks, statistically significant improvements were achieved in all categories. In an epidermal skin model, TRMT demonstrated significant increases in hydration, greater hydration effects, and expression of key markers associated with skin barrier and hydration vs a MLM. Twice-daily application of TRMT was well tolerated and resulted in early, significant improvements in hydration and visible improvements in skin brightness, texture, fine lines/wrinkles, and erythema at 8 weeks.


Device-associated infection rates in 398 intensive care units in Shanghai, China: International Nosocomial Infection Control Consortium (INICC) findings.
To determine device-associated healthcare-associated infection (DA-HAI) rates and the microorganism profile in 398 intensive care units (ICUs) of 70 hospitals in Shanghai, China. An open-label, prospective, cohort, active DA-HAI surveillance study was conducted on patients admitted to 398 tertiary-care ICUs in China from September 2004 to December 2009, implementing the methodology developed by the International Nosocomial Infection Control Consortium (INICC). The data were collected in the participating ICUs, and uploaded and analyzed at the INICC headquarters on proprietary software. DA-HAI rates were registered by applying the definitions of the US Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN). We analyzed the rates of DAI-HAI, ventilator-associated pneumonia (VAP), central line-associated bloodstream infection (CLABSI), and catheter-associated urinary tract infection (CAUTI), and their microorganism profiles. During the 5 years and 4 months of the study, 391 527 patients hospitalized in an ICU for an aggregate of 3,245,244 days, acquired 20,866 DA-HAIs, an overall rate of 5.3% (95% confidence interval (CI) 5.3-5.4) and 6.4 (95% CI 6.3-6.5) infections per 1000 ICU-days. VAP posed the greatest risk (20.8 per 1000 ventilator-days, 95% CI 20.4-21.1), followed by CAUTI (6.4 per 1000 catheter-days, 95% CI 6.3-6.6) and CLABSI (3.1 per 1000 catheter-days, 95% CI 3.0-3.2). The most common isolated microorganism was Acinetobacter baumannii (19.1%), followed by Pseudomonas aeruginosa (17.2%), Klebsiella pneumoniae (11.9%), and Staphylococcus aureus (11.9%). DA-HAIs in the ICUs of Shanghai pose a far greater threat to patient safety than in ICUs in the USA. This is particularly the case for the VAP rate, which is much higher than the rates found in developed countries. Active infection control programs that carry out infection surveillance and implement prevention guidelines can improve patient safety and must become a priority.


An evaluation of Irish cattle herds with inconclusive serological evidence of bovine brucellosis.
Since 1998, there has been a steady decline in herd restrictions and de-populations in Ireland due to bovine brucellosis. There is concern that the interpretation of laboratory results may become increasingly problematic, as brucellosis prevalence falls in Ireland. Therefore, the purpose of the current study was to evaluate the infection status of Irish herds and animals with inconclusive serological evidence of bovine brucellosis. During 12 months from September 1, 2004, laboratory and observational epidemiological data were collected from all Irish herds where animal testing identified at least one animal with a complement fixation test (CFT) reading greater than zero and/or a positive result to the indirect enzyme-linked immunosorbent assay (iELISA). Due to the observational nature of the study, we have robust estimates of the relative, but not the absolute, performance of the CFT, iELISA and brucellin skin test (BST). Herds were divided into three categories (Group A, B or C) on the basis of test results at initial assessment. A total of 639 herds were enrolled into the study, and observed for at least two years following enrolment. A rising CFT titre, with a CFT reading of 111 International CFT Units (IU) or greater at the subsequent blood test, was generally associated with herds where other evidence of infection was also available. Knowledge of the CFT reading at the initial and a subsequent blood test proved useful in distinguishing false-positive and true-positive brucellosis results. There was poor correlation between the CFT and iELISA results, and between the CFT and BST results. As a result of this study, national policy has been modified to include re-sampling of all animals with CFT readings of 20 IU or greater. This project has also led to a reduction in the number of herds restricted, as well as restriction duration. It has also contributed to a reduction in the number of herds listed for contiguous tests, and therefore the potential for contiguity testing of false positive results.


Masochism, the ego ideal, and the psychology of women.
Psychoanalytic advances have led to refinement and reformulation of early models of female personality development. Masochism was taken as a point of departure for a study of the psychology of women and earlier hypotheses of a masochistic and inferior female psychic structure. Masochism is a residue of unresolved infantile conflict and is neither essentially feminine nor a valuable component of mature female function and character. Though the female might be more predisposed to masochism, there is no evidence of particular female pleasure in pain. It is important to distinguish between masochistic suffering as a goal in itself, and tolerance for a discomfort or deprivation in the service of the ego or ego ideal. Initial hypotheses of a diminished female libido, ego tendencies toward arrest and rigidity, relative inability to sublimate, and a deficient superego are incomplete and obsolete theoretical propositions. The female ego and superego are different from but not inferior to the male. Female development cannot be described in a simple reductionism and overgeneralization. Femininity cannot be predominantly derived from a primary masculinity, disappointed maleness, masochistic resignation to fantasied inferiority, or compensation for fantasied castration and narcissistic injury. Castration reactions and penis envy contribute to feminine character, but penis envy is not the major determinant of femininity. Penis envy variously impedes and fosters femininity but penis envy is more closely related to the girl's bisexual masculinity. The female Oedipus complex is central to feminine development, but has significant normative roots in primary and positive feminine identifications and individuation. Contemporary contributions to the psychology of women have emphasized concepts of gender and sexual identity, body image and self-representation, psychosexual response and empathic motherliness, etc. The female superego includes an ego ideal with feminine ideals and values and regulates feminine interests. The maternal ego ideal consolidates overdetermined maternal attitudes, guides the formation and integration of maternal attitudes, and directs the developmental achievement of "the ordinary devoted mother." Conflicts between the maternal ego ideal and infanticidal impulses are ubiquitous and clinically significant. Current theoretical amendments conceptualize mature female autonomy, pride, and self-esteem. Female creativity may be exemplified in many and new forms in addition to motherhood. The capacity to sublimate and to foster sublimation in children is a prerequisite for normal motherhood. Femininity evolves under the influence of parents and culture, with unique developmental challenges and transformations, and a universal psychobiological core linked to functions and roles that should be neither idealized nor devalued.


Amino acid profiles and muscle protein composition in rats with a reduced renal mass in the fed state.
In severe chronic renal failure (CRF) with associated metabolic acidosis, abnormalities in protein metabolism and amino acid (AA) profiles in the fed state are well described. To evaluate the effect of early uraemia and the influence of acid-base status on protein metabolism and AA profiles, three groups of pair-fed rats were studied: group I - rats with 1+ 1/2 nephrectomy; group II - rats with 1+ 1/2 nephrectomy receiving NaHCO3 supplementation, and group III - sham-operated rats with NaHCO3 supplementation. After 4 weeks, serum creatinine values were similar in groups I and II (111 +/- 5 and 119 +/- 4 mumol/l) and higher than in group III (51 +/- 5 mumol/l, p < 0.0001); HCO-3 was reduced only in group I (22.4 +/- 0.8 mmol/l) compared to group II (28.3 +/- 0.6 mmol/l, p < 0.001) and group III (28.2 +/- 1.3 mmol/l, p < 0.001). In the uraemic animals (groups I and II) arterial AA profiles showed increased levels of phenylalanine, glycine, glutamate, proline and alanine. The marked increase of threonine in group I was corrected by NaHCO3 supplementation in group II. The total nonessential AA were higher both in group I (1,832 +/- 53 mumol/l, p < 0.05) and group II (1,788 +/- 103 mumol/l, p < 0.05) than in group III (1,542 +/- 54 mumol/l). These results are similar to those described in the fed state of uraemic patients. Intracellular AA changes were detected, especially in group II namely increased glycine and a decrease in threonine and serine levels. No signs of malnutrition or changes in alkali-soluble protein (ASP) or ASP/DNA ratio in liver and muscle were observed. These results show that AA abnormalities in the fed state occur early in the course of CRF, and that the marked increase of threonine is corrected by NaHCO3 supplementation. These data suggest that either an impaired utilization of the ingested proteins might occur before the appearance of major alterations in endogenous protein metabolism or acid-base status might alter AA metabolic rate per se.


T cell targeting in cancer therapy.
Targeting of immune cells by bispecific antibodies has proven a powerful tool for the investigation of cellular cytotoxicity, lymphocyte activation and induction of cytokine production, as well as to represent an innovative form of immunotherapy for the treatment of cancer. The hallmark of this approach is the use of the specificity of monoclonal antibodies to join target and immune cells by virtue of the dual specificity of bispecific antibodies for the two entities. More precisely the bispecific antibody has two different binding sites, which are capable of recognizing tumor associated antigens on the one hand and lymphocyte activation sites on the other. This process of crosslinking results in the activation of the lymphocyte and triggering of its lytic machinery, as well as lymphokine production. A major advantage of this therapeutic modality is, that use is made of the normal cellular immune defence system and therefore is only associated with minor toxicity. The distinct lymphocyte populations, which can be used for adoptive immunotherapy and the various bispecific antibody preparations, as well as the chimeric immunoglobulin/T cell receptor construction are the major topics of this review.


Association between Diet and Lifestyle Habits and Irritable Bowel Syndrome: A Case-Control Study.
Recent papers have highlighted the role of diet and lifestyle habits in irritable bowel syndrome (IBS), but very few population-based studies have evaluated this association in developing countries. The aim of this study was to evaluate the association between diet and lifestyle habits and IBS. A food frequency and lifestyle habits questionnaire was used to record the diet and lifestyle habits of 78 IBS subjects and 79 healthy subjects. Cross-tabulation analysis and logistic regression were used to reveal any association among lifestyle habits, eating habits, food consumption frequency, and other associated conditions. The results from logistic regression analysis indicated that IBS was associated with irregular eating (odds ratio [OR], 3.257), physical inactivity (OR, 3.588), and good quality sleep (OR, 0.132). IBS subjects ate fruit (OR, 3.082) vegetables (OR, 3.778), and legumes (OR, 2.111) and drank tea (OR, 2.221) significantly more frequently than the control subjects. After adjusting for age and sex, irregular eating (OR, 3.963), physical inactivity (OR, 6.297), eating vegetables (OR, 7.904), legumes (OR, 2.674), drinking tea (OR, 3.421) and good quality sleep (OR, 0.054) were independent predictors of IBS. This study reveals a possible association between diet and lifestyle habits and IBS.


Osteonecrosis of the Jaw and Antiresorptive Agents in Benign and Malignant Diseases: A Critical Review Organized by the ECTS.
Antiresorptive therapy significantly reduces fracture risk in patients with benign bone disease and skeletal-related events (SREs) in patients with bone metastases (BM). Osteonecrosis of the jaw (ONJ) is a rare but severe condition manifested as necrotic bone lesion or lesions of the jaws. ONJ has been linked to the use of potent antiresorptive agents, termed medication-related ONJ (MRONJ). We aimed to identify the differences various aspects of MRONJ among distinct patient categories and provide recommendations on how to mitigate the risk and optimally manage MRONJ in each of them. A working group of the European Calcified Tissue Society (ECTS) and 2 experts performed an updated detailed review of existing literature on MRONJ incidence, characteristics, and treatment applied in bone diseases with variable severity of skeletal insult, ranging from osteoporosis to prevention of cancer treatment-induced bone loss and SREs in cancer patients with BM. The risk for MRONJ is much higher in patients with advanced malignancies compared to those with benign bone diseases because of the higher doses and more frequent administration of antiresorptive agents in individuals with compromised general health, along with coadministration of other medications that predispose to MRONJ. The overall risk for MRONJ is considerably lower than the benefits in all categories of patients. The risk for MRONJ largely depends on the underlying bone disease and the relevant antiresorptive regimen applied. Physicians and dentists should keep in mind that the benefits of antiresorptive therapy far outweigh the risk for MRONJ development.


Self-reported management among people with rotator cuff related shoulder pain: An observational study.
Rotator cuff related shoulder pain is the most common cause of shoulder pain. Whilst guidelines recommend conservative management prior to imaging, injection or surgical management, recent findings suggest that patients experience management contrary to guideline recommendations. The aim of this study was to investigate self-reported management among people with rotator cuff related shoulder pain (RCRSP) and their beliefs towards management. Cross-sectional survey of people with RCRSP recruited when referred for imaging (n = 120). Electronic survey about demographic factors, management people had had (including imaging, injections, surgery, exercise, adjuncts), and beliefs about treatments. The frequency of various treatments was reported (separately for each cohort and traumatic onset) as well as the timing of interventions related to first-line care. Most people had tried exercise (99/120, 82.5%) but only one in five people reported exercise was helpful, and one in six reported it was unhelpful or made their symptoms worse. Approximately a third of the cohort reported not receiving activity modification advice (34.2%, 41/120), those that did received inconsistent information. People with both traumatic (imaging 31/43, 72.1%; injections 13/24, 54.2%, surgery 8/21, 38.1%) and atraumatic onset pain (imaging 43/77, 55.8%; injections 31/51, 60.8%, surgery 4/19, 21.1%) had similarly high rates of intervention prior to trialling conservative management. Patient beliefs in regards to management showed trends towards interventionalist care. Patient reported management of RCRSP is often inconsistent with guideline recommended management.


Pd-Catalyzed Substitution of the OH Group of Nonderivatized Allylic Alcohols by Phenols.
Nonactivated phenols have been employed as nucleophiles in the allylation of nonderivatized allylic alcohols to generate allylated phenolic ethers with water as the only byproduct. A Pd[BiPhePhos] catalyst was found to be reactive to give the O-allylated phenols in good to excellent yields in the presence of molecular sieves. The reactions are chemoselective in which the kinetically favored O-allylated products are formed exclusively over the thermodynamically favored C-allylated products.


Atg17/FIP200 localizes to perilysosomal Ref(2)P aggregates and promotes autophagy by activation of Atg1 in Drosophila.
Phagophore-derived autophagosomes deliver cytoplasmic material to lysosomes for degradation and reuse. Autophagy mediated by the incompletely characterized actions of Atg proteins is involved in numerous physiological and pathological settings including stress resistance, immunity, aging, cancer, and neurodegenerative diseases. Here we characterized Atg17/FIP200, the Drosophila ortholog of mammalian RB1CC1/FIP200, a proposed functional equivalent of yeast Atg17. Atg17 disruption inhibits basal, starvation-induced and developmental autophagy, and interferes with the programmed elimination of larval salivary glands and midgut during metamorphosis. Upon starvation, Atg17-positive structures appear at aggregates of the selective cargo Ref(2)P/p62 near lysosomes. This location may be similar to the perivacuolar PAS (phagophore assembly site) described in yeast. Drosophila Atg17 is a member of the Atg1 kinase complex as in mammals, and we showed that it binds to the other subunits including Atg1, Atg13, and Atg101 (C12orf44 in humans, 9430023L20Rik in mice and RGD1359310 in rats). Atg17 is required for the kinase activity of endogenous Atg1 in vivo, as loss of Atg17 prevents the Atg1-dependent shift of endogenous Atg13 to hyperphosphorylated forms, and also blocks punctate Atg1 localization during starvation. Finally, we found that Atg1 overexpression induces autophagy and reduces cell size in Atg17-null mutant fat body cells, and that overexpression of Atg17 promotes endogenous Atg13 phosphorylation and enhances autophagy in an Atg1-dependent manner in the fat body. We propose a model according to which the relative activity of Atg1, estimated by the ratio of hyper- to hypophosphorylated Atg13, contributes to setting low (basal) vs. high (starvation-induced) autophagy levels in Drosophila.


The relationship between cognitive function and body mass index in multiple sclerosis patients.
Many patients with multiple sclerosis (MS) endure cognitive impairment, which affects their everyday life and lowers their life quality. It has been demonstrated that obesity can result in poor cognitive performance in healthy individuals through various mechanisms. Therefore, we aimed at assessing the association between body mass index (BMI) and cognitive function in MS patients, using minimal assessment of cognitive functions in MS (MACFIMS) battery. This study included eighty-one patients with relapsing-remitting MS (RRMS). After collecting the demographic data, patients' height and weight were measured in order to calculate BMI. Then, MACFIMS battery was administered in one session, after obtaining information using expanded disability status scale (EDSS). Paced Auditory Serial Addition Test (PASAT) and Symbol Digit Modalities Test (SDMT) scores were negatively correlated with BMI (P values are equal to 0.005 and 0.037, respectively). PASAT score correlated with BMI after controlling for sex, age, and EDSS, but SDMT score did not correlate. Nevertheless, no significant variation was observed in the BMI level among individuals having MS with or without cognitive deficit. We have shown that, BMI is associated with poor cognitive performance in some tests which, MACFIMS battery was included. This could suggest that obesity might be an important factor, which have effect on the cognitive performance.


Biocontrol capacity of bacteria isolated from sawdust of the dairy cattle production environment.
This research paper aimed to find endemic bacteria from the cattle production system to control the growth of mastitis pathogens. Bacteria were isolated from compost barn sawdust of two dairy cattle systems and later tested to verify their ability to control the growth of Staphylococcus aureus isolates obtained from cattle with mastitis. Bacterial isolates from these systems were tested to verify biocontrol capacity using the double-layer method. A total of 189 isolates were obtained from all samples by considering the morphology of the different bacterial colonies, with 30 isolates showing positive results for the growth control of at least one S. aureus strain and 19 isolates showing the ability to control more than one pathogen strain. The ability to control more than one pathogen and present a significant halo of inhibition in our isolates represents positive traits in the search for cattle mastitis biocontrol microorganisms. Thus, the results obtained represent the range of bacteria capable of controlling the pathogens without the use of antibiotics.


Estimating changes in hydration status from changes in body mass: considerations regarding metabolic water and glycogen storage.
The potential for imprecision in the estimation of hydration status from changes in body mass has been outlined previously but the equations derived from these derivations appear inconsistent. Reconciliation of body mass loss in terms of sweat loss and effective body water loss is possible from specific equation sets provided that gains and losses of both body mass and water used in the derivation of sweat loss and to derive effective body water loss are in inclusive equation sets. This is obligatory so that mass and water changes as quantifiable determinants are consistent with both internal processes and external gains and losses. Thus, body mass loss, substrate oxidation, metabolic water, and all the terms used in simultaneous equation sets have to be reconciled not only as identical variables but mathematically balance exactly. The revised equation for effective body water loss given here is different from that originally proposed. Metabolic water is part of body mass loss corrected for substrate oxidation, fluid ingestion, and respiratory water to derive sweat loss and it may not be justified to also include water associated with glycogen as releasable bound water. Accordingly, our calculated effective body water loss is substantially a greater loss than originally supposed but clearly still less than the simple balance between mass loss and fluid ingested.


Role of staging laparoscopy in peri-pancreatic and hepatobiliary malignancy.
Even after extensive preoperative assessment, staging laparoscopy may allow avoidance of non-therapeutic laparotomy in patients with radiographically occult metastatic or locally unresectable disease. Staging laparoscopy is associated with decreased postoperative pain, a shorter hospital stay and a higher likelihood of receiving systemic therapy compared to laparotomy but its yield has decreased with improvements in imaging techniques. Current uses of staging laparoscopy include the following: (1) In the staging of pancreatic adenocarcinoma, laparoscopic staging allows for the identification of sub-radiographic metastatic disease in locally advanced cancer in approximately 30% of patients and, in radiographically resectable cancer, may identify metastatic disease in 10%-15% of cases; (2) In colorectal liver metastases, selective use of laparoscopic staging in patients with a clinical risk score of over 2 identifies unresectable disease in approximately 20% of patients; (3) In hepatocellular carcinoma, laparoscopic staging could be selectively used in high-risk patients such as those with clinically apparent liver cirrhosis and in patients with major vascular invasion or bilobar tumors; and (4) In biliary tract malignancy, staging laparoscopy may be used in all patients with potentially resectable primary gallbladder cancer and in selected patients with T2/T3 hilar cholangiocarcinoma. Because of the decreasing yield of SL secondary to improvements in imaging techniques, staging laparoscopy should be used selectively for patients with pancreatic and hepatobiliary malignancy to avoid unnecessary non-therapeutic laparotomy and to improve resource utilization. Each individual surgeon should apply his or her threshold as to whether staging laparoscopy is indicated according to the quality of preoperative imaging studies and the availability of resources at their own institution.


RESTORE: Robust intEnSiTy nORmalization mEthod for multiplexed imaging.
Recent advances in multiplexed imaging technologies promise to improve the understanding of the functional states of individual cells and the interactions between the cells in tissues. This often requires compilation of results from multiple samples. However, quantitative integration of information between samples is complicated by variations in staining intensity and background fluorescence that obscure biological variations. Failure to remove these unwanted artifacts will complicate downstream analysis and diminish the value of multiplexed imaging for clinical applications. Here, to compensate for unwanted variations, we automatically identify negative control cells for each marker within the same tissue and use their expression levels to infer background signal level. The intensity profile is normalized by the inferred level of the negative control cells to remove between-sample variation. Using a tissue microarray data and a pair of longitudinal biopsy samples, we demonstrated that the proposed approach can remove unwanted variations effectively and shows robust performance.