Antimutagenic and Antioxidant Activities of Thai Rice Brans.
Rice bran is the outer layer of the rice grain, and contains high amounts of bioactive phytochemicals. Here, we investigated and compared chemopreventive properties of purple and white rice bran extracts. Rice bran was extracted with dichloromethane and methanol. Chemical constituents in the extracts were analyzed by colorimetric assay and high performance liquid chromatography. The mutagenicity and antimutagenicity of the extracts were determined via the Salmonella mutation assay. The anticarcinogenic enzyme induction and antioxidant activities of the extracts were examined using Hepa1c1c7 cells and 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay, respectively. The methanol extracts of rice bran contained high amounts of phenolic acids, flavonoids, anthocyanins, and phytic acid, whereas large amounts of γ-oryzanol and vitamin E were presented in the dichloromethane extract. None of the extracts were mutagenic to Salmonella typhimurium. All rice bran extracts had strong antimutagenic effects against aflatoxin B1- and 2-amino-3,4-dimethylimidazo [4,5-f]quinoline-induced mutagenesis. The inhibitory effect against 2-aminofluorene-induced mutagenesis was found in the dichloromethane extract, while only the methanol extract of purple rice bran exhibited antimutagenic effects against benzo(a)pyrene. None of the extracts induced quinone reductase activity in Hepa1c1c7 cells. Additionally, the greatest antioxidant capacity was found in the methanol extract of purple rice bran. The methanol extract of purple rice bran containing high amount of phenolic acids, flavonoids, anthocyanins, and phytic acid showed the most effective antioxidant and antimutagenic activities by inhibiting mutagenic metabolizing enzymes and/or scavenging free radicals. These results demonstrate the nutritional and medical value of Thai rice for cancer prevention.


Caspases playing in the field of neuroinflammation: old and new players.
Neuroinflammation is a complex immune response against the harmful effects of diverse stimuli within the central nervous system. Caspases are a family of intracellular cysteine proteases that mediate proteolytic events indispensable for transduction of signaling pathway-controlling biological phenomena such as apoptosis and inflammation. To date, 14 players have been identified in mammals. For many years, caspases were simply divided into 'apoptotic' and 'proinflammatory' caspases and this classification remains useful to some extent. However, increasing evidence indicates that many of these so-called apoptotic caspases also exert nonapoptotic functions. In addition, the role of certain members of the supposed inflammatory caspases in the inflammatory process per se has also been discussed. In this review, we highlight the role for 'apoptotic' and 'proinflammatory' caspases in the regulation of the inflammation response with a special focus on the central nervous system.


Primary immunodeficiencies in Switzerland: first report of the national registry in adults and children.
This first report of a Swiss registry includes 313 patients with primary immunodeficiency syndromes (PIDS) who were observed between January 1975 and January 1985. Diagnosis of specific PIDS was made according to WHO criteria. The most frequent disorders were IgA deficiency (33%) and common variable immunodeficiency (22%), followed by selective deficiency of other immunoglobulin isotypes (9%), severe combined immunodeficiency (9%), infantile sex-linked agammaglobulinemia (7%), and Wiskott-Aldrich syndrome (6%). Frequencies of other types of PIDS varied between 0.3 and 4%. Half of the patients were in the pediatric age group. Male patients predominated (63%). In addition to respiratory and urogenital tract infections, autoimmune disorders were observed in 14 patients with IgA deficiency or common variable immunodeficiency. IgA deficiency was, furthermore, associated with atopic and neurological disorders. A comparison with other national registries revealed some differences: the frequency of severe combined immunodeficiency was high (incidence, 24.3 cases per 10(6) live births), and that of ataxia teleangiectasia was particularly low (1.4 per 10(6) live births) in Switzerland. Frequencies of the three major PIDS groups of (i) predominantly antibody defects, (ii) predominantly cell-mediated defects, and (iii) PIDS associated with other major defects agreed with those reported in the other European studies.


Central presynaptic alpha 2-autoreceptors are involved in the blood pressure-lowering effect of moxonidine.
The alpha-adrenoceptor-mediated effects of the newly developed antihypertensive drug moxonidine and of clonidine were compared in four in vitro models and in anesthetized rabbits. Inhibition of the electrically induced twitch response in the isolated rat vas deferens by moxonidine and clonidine (pEC50 values 7.8 and 8.5) was counteracted by yohimbine. The maximum degree of inhibition obtained with both drugs was identical. The contractile response of the rat anococcygeal muscle to moxonidine and clonidine (pEC50 6.2 and 6.9) was antagonized by prazosin. The maximum degree of contraction obtained with moxonidine was similar in degree to that of phenylephrine, whereas that of clonidine was lower. Moxonidine and clonidine inhibited the electrically evoked [3H]norepinephrine (NE) overflow in strips of rabbit pulmonary artery (pEC50 7.1 and 6.6) and in rat brain cortex slices (pEC50 6.9 and 7.7); the effect of moxonidine was counteracted by rauwolscine. After intracisternal injection in anesthetized rabbits, moxonidine lowered blood pressure (BP) more potently than did clonidine. Intracisternal pretreatment of rabbits with 6-hydroxydopamine strongly attenuated the hypotensive effect of moxonidine without affecting that of clonidine. The hypotensive effect of moxonidine was abolished by pretreatment with reserpine and alpha-methyl-p-tyrosine (alpha-MPT). In conclusion, in isolated tissues of the rat, moxonidine is as selective as clonidine as an alpha-adrenoceptor agonist. The hypotensive effect of moxonidine, unlike that of clonidine, appears to involve central presynaptic alpha 2-autoreceptors in large part.


Acute renal failure in general surgery.
The high mortality and morbidity can be significantly reduced by three cardinal steps: 1. Early diagnosis of intrinsic renal failure 2. Early institution of fluid restriction and dialysis 3. The identification of patients who are likely to be at high risk from acute renal failure, and the careful planning and institution of available therapeutic measures to prevent it.


Temporal trends in the surgical outcomes of patients with breast cancer.
The incidence of breast cancer has been increasing in Japan over the past three decades, and it is the currently the most common malignancy in Japan. This study investigated the temporal trends of the surgical outcomes in patients with breast cancer. We evaluated 543 consecutive patients who underwent breast-cancer resection between 1980 and 2009. The temporal trends in the surgical outcome and clinicopathological features were evaluated separately for the periods covering 1980 to 1989, 1990 to 1999, and 2000 to 2009. The number of patients who underwent resection during these three respective periods were 133, 176, and 234, respectively. All patients were women. The percentage of patients at stages 0 or 1 was 63.2%, 58.5%, and 43.6%, respectively, during the three periods. The mean diameter of tumors in each period was 38, 29, and 30 mm, respectively. The percentage of tumors with positive ER expression was 62.5%, 64.3%, and 69.7%, respectively. In terms of surgical procedures, the use of Halsted's radical mastectomy decreased during each period: from 40.6% of cases to 8.5% and then to 0.4%, while the proportion of breast-conserving therapies increased, from 0% to 12.5%, and finally to 35.9%. The postoperative 10-year survival rates during the three periods were 75.9%, 83.5%, and 84.9%, respectively. The 10-year survival rates of patients with stage II disease during the three periods were 66.2%, 75.7%, and 90.7%, respectively. The prognosis of stage III disease in the three periods also showed a tendency toward improvement, increasing from 37.8% to 64.2%, and finally to 84.5%. The survival of patients with stage II and III disease has improved during the past 30 years. Along with the recent advances in drug therapy, the surgical treatment has become less invasive, often because of drug therapy-related modifications.


The construction of movement with behavior-specific and behavior-independent modules.
Growing evidence suggests that different forms of complex motor acts are constructed through flexible combinations of a small number of modules in interneuronal networks. It remains to be established, however, whether a module simply controls groups of muscles and functions as a computational unit for use in multiple behaviors (behavior independent) or whether a module controls multiple salient features that define one behavior and is used primarily for that behavior (behavior specific). We used the Aplysia feeding motor network to examine the two proposals by studying the functions of identifiable interneurons. We identified three types of motor programs that resemble three types of behaviors that Aplysia produce: biting, swallowing, and rejection. Two ingestive programs (biting, swallowing) are defined by two movement parameters of the feeding apparatus (the radula): one is the same in both programs (phasing of radula closure motoneurons relative to radula protraction-retraction), whereas the other parameter (protraction duration) is different in the two programs. In each program, these two parameters were specified together by an individual neuron, but the neurons in each were different (B40 for biting, B30 for swallowing). These findings support the existence of behavior-specific modules. Furthermore, neuron B51 was found to mediate a phase that can be flexibly added on to both ingestive and egestive-rejection programs, suggesting that B51 may be a behavior-independent module. The functional interpretation of the role played by these modules is supported by the patterns of synaptic connectivity that they make. Thus, both behavior-specific and behavior-independent modules are used to construct complex behaviors.


Estimating Vehicle Fuel Consumption and Emissions Using GPS Big Data.
The energy consumption and emissions from vehicles adversely affect human health and urban sustainability. Analysis of GPS big data collected from vehicles can provide useful insights about the quantity and distribution of such energy consumption and emissions. Previous studies, which estimated fuel consumption/emissions from traffic based on GPS sampled data, have not sufficiently considered vehicle activities and may have led to erroneous estimations. By adopting the analytical construct of the space-time path in time geography, this study proposes methods that more accurately estimate and visualize vehicle energy consumption/emissions based on analysis of vehicles' mobile activities (MA) and stationary activities (SA). First, we build space-time paths of individual vehicles, extract moving parameters, and identify MA and SA from each space-time path segment (STPS). Then we present an N-Dimensional framework for estimating and visualizing fuel consumption/emissions. For each STPS, fuel consumption, hot emissions, and cold start emissions are estimated based on activity type, i.e., MA, SA with engine-on and SA with engine-off. In the case study, fuel consumption and emissions of a single vehicle and a road network are estimated and visualized with GPS data. The estimation accuracy of the proposed approach is 88.6%. We also analyze the types of activities that produced fuel consumption on each road segment to explore the patterns and mechanisms of fuel consumption in the study area. The results not only show the effectiveness of the proposed approaches in estimating fuel consumption/emissions but also indicate their advantages for uncovering the relationships between fuel consumption and vehicles' activities in road networks.


Effect of iloprost on serum creatine kinase and lactate dehydrogenase isoenzymes after isoprenaline-induced cardiac damage in rats.
The effect of iloprost was investigated in an experimental model of cardiac damage in rats after isoprenaline (isoproterenol) treatment. Iloprost was administered by continuous subcutaneous infusion at a dose of 0.44 micrograms/kg body weight (b.w.)/min over a total period of 9 days. On day 8, 5 mg isoprenaline/kg b.w. was applied subcutaneously to induce the cardiac damage. The determinations of creatine kinase (CK, EC 220.127.116.11) and CK isoenzymes, lactate dehydrogenase (LDH, EC 220.127.116.11) and LDH isoenzymes as well as a-hydroxybutyrate dehydrogenase (a-HBDH, no EC) were performed 2, 6 and 24 h after isoprenaline application. Immediately after the last blood sampling, the animals were sacrificed and the hearts were examined histologically. Iloprost-pretreated animals showed a reduction in the rise in heart-specific isoenzymes CK-MB and LDH1-3 in the serum after isoprenaline application. A decrease in isoenzymes CK-BB and LDH4-5 in the serum was also observed in iloprost-pretreated rats. However, no difference could be detected histologically in the extent of myocardial necrosis between animals treated with isoprenaline alone or in combination with iloprost. These results suggest a biochemical cardioprotective effect of iloprost in this rat model after isoprenaline application and the lack of correlation with histological findings is discussed.


[Optomechanical device for radiotherapy planning with the computer tomograph].
An opto-mechanical device is described allowing to register in computed tomography the displacements of the patient relative to the table plane. Furthermore, the transmission of the irradiation plan to simulator and therapy unit can be checked by means of this device.


Association of genetic variants in the Rho guanine nucleotide exchange factor AKAP13 with familial breast cancer.
The A-kinase anchor protein 13 (AKAP13, alias BRX and lbc) tethers cAMP-dependent protein kinase to its subcellular environment and catalyses Rho GTPases activity as a guanine nucleotide exchange factor. The crucial role of members of the Rho family of GTPases in carcinogenesis is well established and targeting Rho proteins with antineoplastic compounds has become a major effort in the fight against cancer. Thus, genetic alterations within the candidate cancer susceptibility gene AKAP13 would be expected to provoke a constitutive Rho signalling, thereby facilitating the development of cancer. Here, we analysed the potential impact of four polymorphic non-conservative amino acid exchanges (Arg494Trp, Lys526Gln, Asn1086Asp and Gly2461Ser) in AKAP13 on familial breast cancer. We performed a case-control study using genomic DNA of BRCA1/2 mutation-negative German female index patients from 601 unrelated families, among a subset of 356 high-risk families, and 1053 German female unrelated controls. The newfound Lys526Gln polymorphism revealed a significant association with familial breast cancer (OR = 1.58, 95% CI = 1.07-2.35) and an even stronger association with high-risk familial breast cancer (OR = 1.85, 95% CI = 1.19-2.88). Haplotype analyses were in line with genotype results displaying a similar significance as analyses of individual polymorphisms. Due to the pivotal role of AKAP13 in the Rho GTPases signalling network, this variant might affect the susceptibility to other cancers as well.


The inhibition of calcium oxalate monohydrate crystal growth by maleic acid copolymers.
The crystallization of calcium oxalate monohydrate (COM) was investigated at conditions of constant supersaturation both in the absence and in the presence of synthetic maleic acid copolymers at 37C, 0.15 M NaCl. The dependence of the rates of COM crystallization in the absence of inhibitors was found to be second order at low and first order at higher supersaturations suggesting a surface diffusion controlled mechanism. The presence of all copolymers tested at concentration levels up to 5 ppm retarded the rates of COM crystal growth up to 90%. The decrease of the COM crystal growth rates by the polymers depended on the nature of the comonomer polymerized with maleic acid and the order of inhibition was found to be vinyl acetate > N-vinylpyrrolidone > styrene. Taking into consideration kinetics data published in the literature concerning the inhibition of COM crystal growth, it is suggested that molecular weight also plays a role, with more inhibition at higher molecular weights. The morphology of the COM crystals grown was unaffected yet the crystals growing at lower rates in the presence of the copolymers were larger and their size more uniform. It is concluded that maleic acid copolymers are strong inhibitors of the crystallization of COM, the inhibitory activity being more pronounced in the case of the linear copolymers.


SEXUAL SELECTION THROUGH FEMALE CHOICE IN LAWES' PAROTIA, A LEK-MATING BIRD OF PARADISE.
We studied sexual selection in Lawes' Parotia, a lek-mating bird of paradise, during 1981-1983 in Papua New Guinea. There was a high variance in mating success among males, with fewer than half of the individuals mating in any one year. This variance was independent of male-male interactions and disruptions. A role of female choice in sexual selection was suggested by the patterns of female visitation to courts and statistical correlations across males between phenotypic traits and mating success. Females repeatedly visited most males in their home ranges and began visiting males up to six weeks before mating. In one or more years, six aspects of male behavior and one morphological variable were positively correlated with mating success, but the probability values were not significant using a simultaneous inference test. Calculation of combined probability values across all three years revealed that one aspect of male display behavior, the probability of display, positively and significantly influenced mating status. The probability of display was also significantly correlated with relative mating success among males. Females showed strong fidelity to mates, both within and between seasons. Display sites of male Lawes' Parotia are variably dispersed, but mating success did not differ for grouped and solitary males. These data confirm an important role of female choice in sexual selection in birds of paradise but also suggest that female choice may be unrelated to the process of lek-initiation in this species.


Stability of Methadone Hydrochloride for Injection in Saline Solution.
Until October 2014, methadone hydrochloride for injection (10 mg/mL) was available in Canada through Health Canada's Special Access Programme. Diluted to 5 mg/mL in saline, it was used in pediatrics for acute and cancer-related pain. More recently, the department of pharmacy of the Centre hospitalier universitaire Sainte-Justine in Montréal, Quebec, proposed compounding a solution of methadone hydrochloride for injection (5 mg/mL) from bulk powder and saline solution for pediatric administration. To assess the stability of the proposed compounded preparation. Solutions of methadone hydrochloride in saline were prepared from bulk powder and stored in clear glass vials for up to 180 days at room temperature (25 °C) or with refrigeration (5 °C), with testing on days 0, 7, 14, 30, 60, 90, and 180. The appearance of the solutions and presence of particulate matter were assessed. A stability-indicating high-performance liquid chromatography (HPLC) method was developed to assay the concentration of methadone over time. No notable changes in appearance of the methadone solution were observed, particle counts did not exceed limits specified by the United States Pharmacopeia, and no microbial growth was observed. The HPLC analysis showed that the concentration of methadone remained above 90% on all study days. Methadone hydrochloride for injection prepared from bulk powder in saline solution at a concentration of 5 mg/mL remained chemically stable for at least 180 days when stored in clear glass vials at 5 °C and at 25 °C.


Tanshinone IIA inhibits cell viability and promotes PUMA-mediated apoptosis of oral squamous cell carcinoma.
Apoptosis alteration is responsible for tumorigenesis and tumor resistance to therapies. The natural product Tanshinone IIA (Tan IIA) exhibits potent inhibitory effects against various tumors. However, the effect of Tan IIA on apoptosis and its underlying mechanism remains elusive in oral squamous cell carcinoma (OSCC). Here, we demonstrated that Tan IIA dose-dependently suppressed cell viability and colony formation in CAL27, SCC4, and SCC25 cells. Moreover, Tan IIA inhibited Akt activation from inducing Foxo3a dephosphorylation and PUMA-mediated apoptosis. PUMA or Foxo3a knockdown compromised the inhibitory effect of Tan IIA on OSCC cells. Tan IIA administration inhibited CAL27-deprived xenograft tumor growth and increased PUMA expression in vivo. Tan IIA synergistically intensified the efficacy of CDDP/5-FU-based chemotherapy on OSCC cells. Overall, our results revealed that Tan IIA exerted potent antitumor effects via promoting PUMA-mediated apoptosis in OSCC cells.


Hsp70 - a master regulator in protein degradation.
Proteostasis, the controlled balance of protein synthesis, folding, assembly, trafficking and degradation, is a paramount necessity for cell homeostasis. Impaired proteostasis is a hallmark of ageing and of many human diseases. Molecular chaperones are essential for proteostasis in eukaryotic cells, and their function has traditionally been linked to protein folding, assembly and disaggregation. More recent findings suggest that chaperones also contribute to key steps in protein degradation. In particular, Hsp70 has an essential role in substrate degradation through the ubiquitin-proteasome system, as well as through different autophagy pathways. Accumulated knowledge suggests that the fate of an Hsp70 substrate is dictated by the combination of partners (cochaperones and other chaperones) that interact with Hsp70 in a given cell context.


Beta-adrenoceptors, but not alpha-adrenoceptors, stimulate AMP-activated protein kinase in brown adipocytes independently of uncoupling protein-1.
Brown adipocytes provide a potentially important model system for understanding AMP-activated protein kinase (AMPK) regulation, where adrenergic stimulation leads to mitochondrial uncoupling through uncoupling protein-1 (UCP1) activity. AMPK is a sensor of energy homeostasis and has been implicated in glucose and lipid metabolism in several insulin-sensitive tissues. The aim of this study was to characterise the potential role of AMPK in adrenergically mediated glucose uptake and to find out whether UCP1 is involved in the adrenergic activation of AMPK. We used primary brown adipocytes differentiated in culture and measured AMPK phosphorylation and glucose uptake following adrenergic activation. Treatment of adipocytes with noradrenaline (norepinephrine) caused phosphorylation of AMPK via beta-adrenoceptors and not alpha(1)- or alpha(2)-adrenoceptors. This effect was not beta(3)-adrenoceptor specific, since responses remained intact in adipocytes from beta(3)-adrenoceptor knock-out mice. These effects were also mimicked by forskolin and cAMP analogues. Treatment of cells with adenine 8-beta-D-arabinofuranoside, an AMPK inhibitor, partially blocked beta-adrenoceptor-mediated increases in glucose uptake. Brown adipocytes are characterised by the production of UCP1, which can uncouple the mitochondria. Using adipocytes from Ucp1(+/+) and Ucp1(-/-) mice, we showed that noradrenaline-mediated phosphorylation of AMPK does not require the presence or activity of UCP1. These results suggest a pathway where increases in cAMP mediated by beta-adrenoceptors leads to activation of AMPK in brown adipocytes, which contributes in part to beta-adrenoceptor-mediated increases in glucose uptake, an effect independent of the presence or function of UCP1.


The influence of carbohydrate-protein co-ingestion following endurance exercise on myofibrillar and mitochondrial protein synthesis.
The aim of the present study was to determine mitochondrial and myofibrillar muscle protein synthesis (MPS) when carbohydrate (CHO) or carbohydrate plus protein (C+P) beverages were ingested following prolonged cycling exercise. The intracellular mechanisms thought to regulate MPS were also investigated. In a single-blind, cross-over study, 10 trained cyclists (age 29 ± 6 years, VO2max 66.5 ± 5.1 ml kg(−1) min(−1)) completed two trials in a randomized order. Subjects cycled for 90 min at 77 ± 1% VO2max before ingesting a CHO (25 g of carbohydrate) or C+P (25 g carbohydrate + 10 g whey protein) beverage immediately and 30 min post-exercise. A primed constant infusion of L-[ring-(13)C6]phenylalanine began 1.5 h prior to exercise and continued until 4 h post-exercise. Muscle biopsy samples were obtained to determine myofibrillar and mitochondrial MPS and the phosphorylation of intracellular signalling proteins. Arterialized blood samples were obtained throughout the protocol. Plasma amino acid and urea concentrations increased following ingestion of C+P only. Serum insulin concentration increased more for C+P than CHO. Myofibrillar MPS was ∼35% greater for C+P compared with CHO (0.087 ± 0.007 and 0.057 ± 0.006% h(−1), respectively; P = 0.025). Mitochondrial MPS rates were similar for C+P and CHO (0.082 ± 0.011 and 0.086 ± 0.018% h(−1), respectively). mTOR(Ser2448) phosphorylation was greater for C+P compared with CHO at 4 h post-exercise (P < 0.05). p70S6K(Thr389) phosphorylation increased at 4 h post-exercise for C+P (P < 0.05), whilst eEF2(Thr56) phosphorylation increased by ∼40% at 4 h post-exercise for CHO only (P < 0.01). The present study demonstrates that the ingestion of protein in addition to carbohydrate stimulates an increase in myofibrillar, but not mitochondrial, MPS following prolonged cycling. These data indicate that the increase in myofibrillar MPS for C+P could, potentially, be mediated through p70S6K, downstream of mTOR, which in turn may suppress the rise in eEF2 on translation elongation.


Safety of allergen immunotherapy in children.
The current review discusses allergen immunotherapy (AIT) safety in children. AIT is a well tolerated and effective treatment for pediatric allergic conditions. While mostly well tolerated, severe reactions and near fatal reactions may occur with subcutaneous immunotherapy (SCIT) once in every 160 000 visits. Sublingual immunotherapy (SLIT) is associated more with local side effects, but severe systemic reactions, including anaphylaxis, have been rarely reported. Providing informed consent, recognizing risk factors for severe systemic reactions, such as severe or uncontrolled asthma, and mitigating the risk of severe reactions are important components to improving the safety of AIT. Overall, AIT is well tolerated in children, and data suggest that the incidence of systemic reactions in children receiving SCIT is no less than mixed populations of adult and pediatric patients. SLIT carries less risk for systemic reactions, and local oral site-application reactions are usually mild and resolve within 15 days of treatment.


Beta-endorphin-sensitive opioid receptors in the rat tail artery.
Isolated tail arteries of rats were perfused and field-stimulated every 2 min with 2 pulses at 1 Hz. Different opioid peptides depressed the contractile responses to stimulation; their concentration-response curves showed a maximum at about 40% inhibition. The rank order of potency of the peptides was beta-endorphin (IC50 = 97 nmol/l) approximately equal to BAM-22P greater than FK-33824 greater than DAGO greater than [D-Ala2,D-Leu5]-enkephalin greater than or equal to metorphamide greater than dynorphin A-(1-13) approximately equal to [Met5]enkephalin. All these substances have in common a certain activity at opioid mu-receptors, although the enkephalins are preferential delta-, and the dynorphins preferential kappa-agonists. However, the selective delta-agonist [D-Pen2,L-Pen5]enkephalin was ineffective at up to 10 mumol/l, and the kappa-agonists ethylketocyclazocine and U-50488 acted only at concentrations higher than 3 mumol/l. Whereas the effects of beta-endorphin, DAGO and [D-Ala2,D-Leu5]enkephalin could be reduced by the mu-preferential antagonist naloxone, the effects of ethylketocyclazocine and U-50488 were not changed. The delta-selective antagonist ICI 174864 did not influence the action of [D-Ala2,D-Leu5]enkephalin. Naloxone in a concentration (1 mumol/l) which nearly abolished the effect of DAGO 3 mumol/l, slightly enhanced responses to stimulation. Neither beta-endorphin nor DAGO influenced vasoconstriction evoked by the application of noradrenaline or adenosine triphosphate; U-50488 reduced it. In arteries preincubated with [3H]noradrenaline DAGO depressed, whereas naloxone enhanced the tritium overflow and vasoconstriction evoked by field stimulation (0.4 Hz, 24 pulses every 14 min). In addition, naloxone antagonized the effect of DAGO.(ABSTRACT TRUNCATED AT 250 WORDS)


Estimation in flexible two stage designs.
Adaptive test designs for clinical trials allow for a wide range of data driven design adaptations using all information gathered until an interim analysis. The basic principle is to use a test statistics which is invariant with respect to the design adaptations under the null hypothesis. This allows for a control of the type I error rate for the primary hypothesis even for adaptations not specified a priori in the study protocol. Estimation is usually another important part of a clinical trial, however, is more difficult in adaptive designs. In this research paper we give an overview of point and interval estimates for flexible designs and compare methods for typical sample size rules. We also make some proposals for confidence intervals which have nominal coverage probability also after an unforeseen design adaptation and which contain the maximum likelihood estimate and the usual unadjusted confidence interval.


Evaluation of treatment outcomes of early-stage endometrial cancer radiotherapy: a single center experience.
Postoperative adjuvant radiotherapy (RT) in the management of early stage endometrial cancer (EC) is still controversial. Here we report our institutional experience with patients who received postoperative RT for stage I-II EC over a period of 35 years and assess potential predictors of local recurrence (LR), distant metastasis (DM), and overall survival (OS). A total of 188 patients undergoing postoperative RT for stage IA-II EC between 1977 and 2012 were evaluated. Some 96 received median 46 Gy whole pelvic radiotherapy (WPRT) (range: 40-60 Gy), 37 were given WPRT with vaginal cuff therapy (VCT), and 55 received only VCT either with brachytherapy (BT) or stereotactic body radiotherapy (SBRT). Chemotherapy was given to 5 patients with uterine papillary serous carcinoma (UPSC). Logistic regression analysis was used to assess the effect of clinicopathological factors on LR, DM, and OS. Median follow-up time was 11 years (range: 1-35 years). At the time of analysis, 34 patients were not alive. Of the 15 patients with LR, 7 (46.7%) recurred in the vaginal stump, 5 (33.3%) in the pelvic region, and 3 (20%) in the paraaortic nodal region, while 12 had distant metastasis. UPSC histology (p=0.027), sole VCT (p=0.041), high histologic grade (p=0.034), and age≥71 (p=0.04) were poor prognostic factors on univariate analysis. In our patients receiving radiotherapy for early-stage EC, grade III disease and age≥71 were associated with shorter OS whereas UPSC histology was an independent predictor for both LR and DM.


In vivo efficacy study of milk thistle extract (ETHIS-094™) in STAM™ model of nonalcoholic steatohepatitis.
A subcategory of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is characterized by accumulation of fat accompanied by inflammatory infiltration and hepatocellular damage. The active complex of milk thistle is a lipophilic extract from its seeds, comprising three isomers, collectively known as silymarin. Silymarin has demonstrated antioxidant, anti-inflammatory, and antifibrotic properties, and has been extensively studied in the treatment of liver diseases. The majority of published clinical research on silymarin has used Legalon(®) (Rottapharm/Madaus), containing the patented extract of milk thistle ETHIS-094™ (Euromed). The current study was undertaken to examine the effects of ETHIS-094™ in the Stelic Animal Model (STAM™), a validated and widely used animal model for NASH. After 4 h fasting from 4 to 8 weeks of age, 15 male mice in whom NASH had been induced were orally administered, once daily, either (1) vehicle (saline) at a volume of 10 mL/kg, (2) vehicle supplemented with milk thistle at a dose of 500 mg/kg, or (3) vehicle supplemented with milk thistle at a dose of 1,000 mg/kg. Mean liver weight and the liver-to-body weight ratio were significantly (P < 0.01) decreased in the milk thistle high-dose group compared with the vehicle group. NAFLD activity score (NAS) tended to decrease in the milk thistle treatment groups compared with vehicle group, as did steatosis scores. Milk thistle extract administration induced a decreasing trend in NAS compared with the vehicle group. Milk thistle induced a numerical decrease of the steatosis score compared with vehicle, and this was accompanied by a statistically significant decrease in liver weight and the liver-to-body weight ratio, implying a potential anti-steatosis effect of milk thistle.


Precise and efficient C-to-U RNA base editing with SNAP-CDAR-S.
Site-directed RNA base editing enables the transient and dosable change of genetic information and represents a recent strategy to manipulate cellular processes, paving ways to novel therapeutic modalities. While tools to introduce adenosine-to-inosine changes have been explored quite intensively, the engineering of precise and programmable tools for cytidine-to-uridine editing is somewhat lacking behind. Here we demonstrate that the cytidine deaminase domain evolved from the ADAR2 adenosine deaminase, taken from the RESCUE-S tool, provides very efficient and highly programmable editing when changing the RNA targeting mechanism from Cas13-based to SNAP-tag-based. Optimization of the guide RNA chemistry further allowed to dramatically improve editing yields in the difficult-to-edit 5'-CCN sequence context thus improving the substrate scope of the tool. Regarding editing efficiency, SNAP-CDAR-S outcompeted the RESCUE-S tool clearly on all tested targets, and was highly superior in perturbing the β-catenin pathway. NGS analysis showed similar, moderate global off-target A-to-I and C-to-U editing for both tools.


A hepatic antimicrobial peptide, hepcidin from Indian major carp, Catla catla: molecular identification and functional characterization.
Increase of antibiotic resistance in pathogenic microbes necessitated novel molecules for curing infection. Antimicrobial peptides (AMPs) are the gene-encoded evolutionarily conserved small molecules with therapeutic value. AMPs are considered as an alternative drug for conventional antibiotics. Hepcidin, the cysteine-rich antimicrobial peptide, is an important component in innate immune response. In this study, we identified and characterized hepcidin gene from the fish, Catla catla (Indian major carp) and termed it as Cc-Hep. Open reading frame of Cc-Hep consists of 261 base pair that encodes 87 amino acids. Cc-Hep is synthesized as a prepropeptide consisting of 24 amino acid signal peptide, 36 amino acid propeptide, and 26 amino acid mature peptide. Sequence analysis revealed that Cc-Hep shared sequence similarity with hepcidin from Sorsogona tuberculata. Phylogenetic analysis indicated that Cc-Hep was grouped with HAMP2 family. Structure analysis of mature Cc-Hep identified two antiparallel beta sheets stabilized by four disulphide bonds and a random coil. The mature peptide region of Cc-Hep has a charge of + 2, isoelectric value 8.23 and molecular weight 2.73 kDa. Functional characterization predicted antibacterial, antioxidant, and anticancer potential of Cc-Hep, which can be explored in aquaculture or human health care.


Variation in uterus position prior to brachytherapy of the cervix: A case report.
Rationale: brachytherapy is administered in the treatment of patients with locally advanced cervical cancer following chemoradiotherapy. Lack of local anatomy evaluation prior to this procedure might lead to the selection of an inappropriate brachytherapy applicator, increasing the risk of side effects (e.g. uterus perforation, painful procedure ...). Objective: To assess the movement of the uterus and cervix prior to brachytherapy in patients with gynecological cancer, in order to select the proper type of brachytherapy applicator. Also we wanted to promote the replacement of the plain X-ray brachytherapy with the image-guided procedure. Methods and results: We presented the case of a 41-year-old female diagnosed with a biopsy that was proven cervical cancer stage IIIB. At diagnosis, the imaging studies identified an anteverted uterus. The patient underwent preoperative chemoradiotherapy. Prior to brachytherapy, the patient underwent a pelvic magnetic resonance imaging (MRI), which identified a displacement of the uterus in the retroverted position. Discussion: A great variety of brachytherapy applicators is available nowadays. Major changes in uterus position and lack of evaluation prior to brachytherapy might lead to a higher rate of incidents during this procedure. Also, by using orthogonal simulation and bidimensional (2D) treatment planning, brachytherapy would undoubtedly fail to treat the remaining tumoral tissue. This is the reason why we proposed the implementation of a prior imaging of the uterus and computed tomography (CT)/ MRI-based simulation in the brachytherapy procedure. Abbreviations: MRI = magnetic resonance imaging, CT = computed tomography, CTV = clinical target volume, DVH = dose-volume histogram, EBRT = external beam radiotherapy, GTV = gross tumor volume, Gy = Gray (unit), ICRU = International Commission of Radiation Units, IGRT = image guided radiotherapy, IM = internal margin, IMRT = image modulated radiotherapy, ITV = internal target volume, MRI = magnetic resonance imaging, OAR = organs at risk, PTV = planning target volume, QUANTEC = Quantitative Analyses of Normal Tissue Effects in the Clinic.


[The Rubino reaction. Criterion for inactivation in lepromatous patients].
Approximately 55% of active lepromatous patients respond positively to the Rubino reaction. With arrested cases this rate of positivity lowers considerably to about 15%. In an effort to associate this reaction with the presence of bacilli, a study of 796 cases was undertaken. The patients were divided into: a control group, active tuberculoid cases, arrested tuberculoid cases, active borderline cases, arrested borderline cases, active lepromatous cases, and arrested lepromatous cases. The patients were submitted to the following tests: Rubino reaction, presence of cryoglobulins, and VDRL and PCR positivity. By the results obtained we may conclude that: a) A positive Rubino reaction may be present in all the forms of leprosy studied, this reaction having an inverse relationship with the organism's resistance to "M. leprae". b) The Rubino reaction has specificity to leprosy. c) This reaction does not depend on the number of bacilli present in the host. d) A positive Rubino reaction is not related to the presence of cryoglobulins in the serum, nor to VDRL or PCR positivity, nor to the length of time the patient's disease has been arrested. The authors present these findings and suggest that this reaction be used as one of the criteria for determining cure.


Assessing the Mental Wellbeing and Help-Seeking Behaviors of Pre-Veterinary Undergraduates at a Land-Grant Institution.
Recent research conducted within the veterinary profession has reported higher rates of depression and stress than the general US population. While this decline in mental wellbeing has been documented in Doctor of Veterinary Medicine (DVM) students and veterinary professionals, there is a lack of research on the mental wellbeing of the pre-veterinary population. This gap led the authors to conduct a survey in the fall of 2021 utilizing the DASS-21 and ATSPPH-sf inventories to assess the levels of depression, anxiety, stress, and help-seeking stigma in pre-veterinary students to better understand when the decline in veterinary mental wellbeing begins. A pre-test survey was completed by 233 pre-veterinary students in September, and an identical post-test survey was completed by 184 pre-veterinary students in November. From the pre- and post-test data, depression, anxiety, and stress scores increased as students advanced in academic status during their undergraduate degree. Juniors reported the highest averages of depression, anxiety, and stress compared to their peers. In the post-test, sophomores and juniors exhibited higher rates of depression than freshmen, and juniors and seniors exhibited higher rates of stress than freshmen. Current VMCAS applicants exhibited higher levels of stress than non-VMCAS applicants in the pre-test, and lower levels of stress in the post-test. In both the pre-test and post-test data, respondents averaged a neutral attitude toward help-seeking. Based on these results, a decline in pre-veterinary mental wellbeing occurs as students' progress in their undergraduate career and should be further studied to assess its impact on Doctor of Veterinary Medicine and veterinary professional wellbeing.


Comparison the efficacy of phonophoresis and ultrasound therapy in myofascial pain syndrome.
The aim of this study is to compare the effect of phonophoresis, ultrasound and placebo ultrasound therapies in the treatment of myofascial pain syndrome (MPS). This is a randomized, double-blind placebo controlled study. Sixty patients (48 women, 12 men, mean age 37.9 ± 12.2 years) with MPS were included in this study. Patients were allocated into three groups. Group 1(n = 20) was received diclofenac phonophoresis, group 2(n = 20) was received ultrasound and group 3(n = 20) was received placebo ultrasound therapies over trigger points, 10 min a day for 15 session during 3 weeks (1 MHz-1,5 watt/cm²). Additionally, all patients were given neck exercise program including isotonic, isometric and stretching. Patients were assessed by means of pain, range of motion (ROM) of neck, number of trigger points (NTP), algometric measurement and disability. Pain severity was measured by visual analog scale (VAS) and Likert scale. The neck pain disability index (NPDI) was used for assessing disability. Measurements were taken before and after treatment. After treatment, there were statistically significant improvements in pain severity, NTP, pressure pain threshold (PPT), ROM and NPDI scores both in phonophoresis and in ultrasound therapy groups (P < 0.05). Statistically significant increase in cervical lateral flexion and rotation was observed in the placebo US group. While there was no statistically significant improvement in the cervical flexion-extension joint movement, pain levels, number of trigger points and NPDI score, pressure pain threshold (P > 0.05), also there were no significant differences in all parameters between group 1 and 2 (P = 0.05). Both diclofenac phonophoresis and ultrasound therapy were effective in the treatment of patients with MPS. Phonophoresis was not found to be superior over ultrasound therapy.


Compressive femoral neuropathy caused by anticoagulant therapy induced retroperitoneal hematoma: A case report.
Spontaneous retroperitoneal hematomas due to anticoagulant therapy rarely occur. Retroperitoneal hematomas can cause severe pain in the groin, quadriceps femoris muscle weakness, hemodynamic instability, and abdominal distension. They rarely cause compressive neuropathy of the femoral nerve transversing the iliacus muscle. Differential diagnosis is not easy because they have similar clinical features to retroperitoneal hematomas. A 72-year-old female patient whose right arm was stuck in a bookshelf for 5 days developed right cephalic vein thrombosis. After 5 days of intravenous heparin therapy for venous thrombosis, she presented with sudden right groin pain, right leg paresis, hemodynamic instability, and abdominal distension. Emergency abdominal and pelvic CT showed a large number of hematomas in the bilateral retroperitoneal space with active bleeding of the right lumbar artery. An electrodiagnostic study was performed 2 weeks later to check for neuromuscular damage in the right lower extremity, and right compressive femoral neuropathy was confirmed. Heparin therapy was discontinued; emergency embolization of the lumbar artery was performed. After 2 weeks, the patient started receiving physical, occupational, and transcutaneous electrical stimulation therapies. She became hemodynamically stable after arterial embolization; a significant decrease in hematoma and patency of the femoral nerve was confirmed on follow-up pelvic MRI. After 2 months of comprehensive rehabilitation, the muscle strength of the right leg significantly improved, and the pain disappeared. Although rare, spontaneous retroperitoneal hematomas may occur in patients receiving anticoagulant medications. They may even occur in patients receiving emergency anticoagulant therapy. Compressive femoral neuropathy due to retroperitoneal hematomas should be considered if muscle weakness and groin pain are observed. Early diagnosis and appropriate treatment plan of compressive femoral neuropathy due to retroperitoneal hematoma are helpful for a good prognosis.


Association between polymorphisms in IL17F and male asthma in a Chinese population.
Interleukin (IL) 17F is a marker of type 17 helper T cells and has a proinflammatory role in asthma.The aim of the present study was to assess the possible association between asthma and polymorphisms in the IL17F gene in a Chinese population. A total of 318 asthmatic patients and 352 nonasthmatic controls were recruited. Two single-nucleotide polymorphisms in IL17F (rs763780 and rs13209590) were detected using GenomeLab SNPstream. Logistic regression methods were used to analyze data. A significantly lower frequency of the C allele in rs763780 was observed in the control group (P = .0148). The rs763780 TC heterozygote was associated with an increased risk of asthma, and a similar trend was observed assuming a codominant genotype effect (adjusted OR, 1.58; 95% CI, 1.06-2.36; P = .0148; adjusted OR, 1.64; 95% CI, 1.10-2.45; P = .0217). Furthermore, a novel finding of the present study was that this association was exclusive to males (adjusted OR, 1.79; 95% CI, 1.06-3.05; P = .0308) and patients with higher immunoglobulin E levels (> or = 1.85 IU/mL) (adjusted OR, 1.88; 95% CI, 1.10-3.22; P = .0213). We also found that the haplotype with minor alleles for rs763780 was associated with an increased risk of asthma (adjusted OR, 1.62; 95% CI, 1.11-2.35; P = .0115). Our findings indicated that polymorphisms might play a role in susceptibility to asthma.


Plasma levels of salicylate and aspirin in healthy volunteers: relevance to drug interaction on platelet function.
Salicylate can prevent the inhibitory effect of aspirin on platelet cyclooxygenase activity. We investigated whether salicylate and aspirin interact in platelets in humans at doses and plasma levels of clinical relevance. In our first experiment in healthy volunteers, the lowest dose of intravenously administered aspirin that suppressed arachidonate-induced platelet aggregation and serum immunoreactive thromboxane B2 generation was 40 mg. In our second experiment, volunteers given oral doses of sodium salicylate (250 or 1000 mg) had peak plasma salicylate levels averaging 20 and 76 micrograms/ml, respectively. Neither platelet aggregation or thromboxane B2 formation was modified by either salicylate treatment. Forty minutes later, all six volunteers received 40 mg of aspirin intravenously. Aspirin levels were not affected by previous salicylate ingestion, but inhibition by aspirin of both platelet aggregation and thromboxane B2 generation was significantly prevented by the higher salicylate dose. In our last experiment, peak plasma levels of aspirin and salicylate were measured in healthy volunteers after ingestion of either 320 mg of compressed or 800 mg of enteric-coated aspirin. Salicylate levels averaged 19 and 51 micrograms/ml, respectively, after the lower and higher doses of aspirin, whereas aspirin averaged 3 micrograms/ml after either dose. Serum thromboxane B2 generation was almost completely inhibited 1 hour after either aspirin dose.(ABSTRACT TRUNCATED AT 250 WORDS)


multiHiCcompare: joint normalization and comparative analysis of complex Hi-C experiments.
With the development of chromatin conformation capture technology and its high-throughput derivative Hi-C sequencing, studies of the three-dimensional interactome of the genome that involve multiple Hi-C datasets are becoming available. To account for the technology-driven biases unique to each dataset, there is a distinct need for methods to jointly normalize multiple Hi-C datasets. Previous attempts at removing biases from Hi-C data have made use of techniques which normalize individual Hi-C datasets, or, at best, jointly normalize two datasets. Here, we present multiHiCcompare, a cyclic loess regression-based joint normalization technique for removing biases across multiple Hi-C datasets. In contrast to other normalization techniques, it properly handles the Hi-C-specific decay of chromatin interaction frequencies with the increasing distance between interacting regions. multiHiCcompare uses the general linear model framework for comparative analysis of multiple Hi-C datasets, adapted for the Hi-C-specific decay of chromatin interaction frequencies. multiHiCcompare outperforms other methods when detecting a priori known chromatin interaction differences from jointly normalized datasets. Applied to the analysis of auxin-treated versus untreated experiments, and CTCF depletion experiments, multiHiCcompare was able to recover the expected epigenetic and gene expression signatures of loss of chromatin interactions and reveal novel insights. multiHiCcompare is freely available on GitHub and as a Bioconductor R package https://bioconductor.org/packages/multiHiCcompare. Supplementary data are available at Bioinformatics online.


CHROMOSOMAL ANALYSIS OF HEAT-SHOCK TOLERANCE IN DROSOPHILA MELANOGASTER EVOLVING AT DIFFERENT TEMPERATURES IN THE LABORATORY.
We investigated the heat tolerance of adults of three replicated lines of Drosophila melanogaster that have been evolving independently by laboratory natural selection for 15 yr at "nonextreme" temperatures (18°C, 25°C, or 28°C). These lines are known to have diverged in body size and in the thermal dependence of several life-history traits. Here we show that they differ also in tolerance of extreme high temperature as well as in induced thermotolerance ("heat hardening"). For example, the 28°C flies had the highest probability of surviving a heat shock, whereas the 18°C flies generally had the lowest probability. A short heat pretreatment increased the heat tolerance of the 18°C and 25°C lines, and the threshold temperature necessary to induce thermotolerance was lower for the 18°C line than for the 25°C line. However, neither heat pretreatment nor acclimation to different temperatures influenced heat tolerance of the 28°C line, suggesting the loss of capacity for induced thermotolerance and for acclimation. Thus, patterns of tolerance of extreme heat, of acclimation, and of induced thermotolerance have evolved as correlated responses to natural selection at nonextreme temperatures. A genetic analysis of heat tolerance of a representative replicate population each from the 18°C and 28°C lines indicates that chromosomes 1, 2, and 3 have significant effects on heat tolerance. However, the cytoplasm has little influence, contrary to findings in an earlier study of other stocks that had been evolving for 7 yr at 14°C versus 25°C. Because genes for heat stress proteins (hsps) are concentrated on chromosome 3, the potential role of hsps in the heat tolerance and of induced thermotolerance in these naturally selected lines is currently unclear. In any case, species of Drosophila possess considerable genetic variation in thermal sensitivity and thus have the potential to evolve rapidly in response to climate change; but predicting that response may be difficult.


[Analysis of rare earth elements in pu'er tea of Yunnan by ICP-AES].
The 150 samples of pu'er tea collected from the main producing area of Yunnan were detected by ICP-AES method, to investigate the current safety status of pu'er tea rare earth elements. The rare earth elements contents were found to be in the range 0.26-4.07 mg x kg(-1) in all detected samples, with the 43.0% samples exceeding the maximum levels of contaminants of 2 mg x kg(-1) set by GB 2762-2005 "Maximum levels of contaminants in foods". There was a significant difference between ripened tea rare earth elements and raw tea's from the same sources, which affected some ripened tea quality at last. There was a significant difference among the rare earth elements contents of the pu'er tea main producing areas, and the condition of pu'er tea quality and safety controlling was not optimistic at individual producing areas.


Will the addition of pentoxifylline reduce proteinuria in patients with diabetic glomerulosclerosis refractory to maximal doses of both an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker?
While interruption of angiotensin synthesis and angiotensin blockade are well know to reduce proteinuria and preserve renal function in patients with diabetic glomerulosclerosis, many patients still have significant proteinuria after having reached maximal doses of those medications. We chose to examine the effect of the addition of pentoxifylline to the therapeutic regimen of patients with significant proteinuria and chronic renal insufficiency who had reached maximal does of an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin receptor blocker (ARB), on the reduction of proteinuria and the preservation of renal function. Seven male patients with diabetic glomerulosclerosis with proteinuria of at least 1.5 g/24 hours and a creatinine clearance of at least 15 ml/min despite maximal doses of an ACEI and an ARB for over 12 months were treated with pentoxifylline adjusted for creatinine clearance. They were then compared with 7 similar patients matched for age, duration of medications, proteinuria, creatinine clearance and mean arterial pressure. The groups were compared for any significant differences on at baseline and at 12 months. Although proteinuria decreased in the pentoxifylline group (5.657 +/- 3.5227 to 3.799 +/- 3.647 g/24 hours) there was no significant difference from the control group (4.743 +/- 2.320 to 4.986 +/- 2.941 g/24 hours). Similarly both groups lost creatinine clearance (41.0 +/- 27.44 to 29.33 +/- 22.21 ml/min with pentoxifylline and 45.57 +/- 21.854 to 27.33 +/- 27.105 ml/min in controls), but there was no significant difference in either clearance or mean arterial pressure. Although there was a trend toward the reduction of proteinuria, we found no statistical benefit in proteinuria reduction or preservation of renal function by the addition of pentoxifylline to maximal doses of ACEIs and ARBs.


[A new opportunistic infection: microsporidiosis].
Microsporidiosis is a recently identified opportunistic infection in patients with AIDS. Microsporidie usually induce chronic diarrhoeas, cachexia, and cholangitis. Disseminated infection with pulmonary or renal involvement and sinusitis has also been described. Rarely, conjunctivitis can occur. Diagnosis now relies on direct identification of microsporidial spores in faeces. Treatment remains essentially symptomatic, although cure can be obtained in some cases.


Hydroxychloroquine-induced hyperpigmentation in systemic diseases: prevalence, clinical features and risk factors: a cross-sectional study of 41 cases.
Introduction Hydroxychloroquine is an antimalarial agent widely prescribed in internal medicine, rheumatology and dermatology. Its use can be complicated by various side effects including skin pigmentation. Objectives The aim of the study is to review epidemiological, clinical features and risk factors of hydroxychloroquine-induced pigmentation. Materials and methods We performed a cross-sectional study conducted over a period of 5 months. During this period, patients who had been treated with hydroxychloroquine for over 6 months, in the internal medicine department, underwent a complete dermatological examination. All patients completed a structured questionnaire to collect demographic data, dosage and treatment duration of hydroxychloroquine, other drug intake, hydroxychloroquine indication, and presence of pigmentary changes on the skin, nail, hair, and mucosa. Results A total of 41 patients (38 women and 3 men) were included in the study. The mean age was 39.2 ± 15.4 years. The hydroxychloroquine was indicated for systemic lupus erythematosus in 73.2%, dermatomyositis in 12.2%, rheumatoid arthritis in 9.8%, actinic lichen and sarcoidosis each in 2.4%. Cutaneous pigmented lesions were found in 21 cases (51%), mucous pigmentation in 5 cases (12%) and nail pigmentation in 1 case (2.5%). In 12 of 41 (29%) of the hydroxychloroquine users, we conclude a hydroxychloroquine-induced pigmentation. There were 11 women and one man with a mean age of 43 years and all of them were systemic lupus erythematosus patients. Pigmented lesions were located on the lower limbs in seven cases, the face in two cases, lips in two cases and the gum in two cases. Pigmentation appeared after a median duration of hydroxychloroquine treatment of 32 months with a median cumulative dose of 361 g. Overall, two patients reported that the appearance of pigmented lesions was preceded by the occurrence of ecchymotic areas following microtrauma. Significant association was found between hydroxychloroquine-induced pigmentation and treatment with oral anticoagulants and/or antiplatelet agents ( p = 0.03). Conclusion Our systematic examination of patients demonstrated that hydroxychloroquine-induced pigmentation is not rare. The imputability of hydroxychloroquine in the genesis of this discoloration is difficult to establish. Our study supports the hypothesis that ecchymosis, platelet antiaggregants and oral anticoagulants may be the main predisposing factors to hydroxychloroquine-induced pigmentation.


Accurate Nonlinearity and Temperature Compensation Method for Piezoresistive Pressure Sensors Based on Data Generation.
Piezoresistive pressure sensors exhibit inherent nonlinearity and sensitivity to ambient temperature, requiring multidimensional compensation to achieve accurate measurements. However, recent studies on software compensation mainly focused on developing advanced and intricate algorithms while neglecting the importance of calibration data and the limitation of computing resources. This paper aims to present a novel compensation method which generates more data by learning the calibration process of pressure sensors and uses a larger dataset instead of more complex models to improve the compensation effect. This method is performed by the proposed aquila optimizer optimized mixed polynomial kernel extreme learning machine (AO-MPKELM) algorithm. We conducted a detailed calibration experiment to assess the quality of the generated data and evaluate the performance of the proposed method through ablation analysis. The results demonstrate a high level of consistency between the generated and real data, with a maximum voltage deviation of only 0.71 millivolts. When using a bilinear interpolation algorithm for compensation, extra generated data can help reduce measurement errors by 78.95%, ultimately achieving 0.03% full-scale (FS) accuracy. These findings prove the proposed method is valid for high-accuracy measurements and has superior engineering applicability.


[Proteolytic activity control in fish silage].
Microbial fish silage was produced from ground low commercial fish species added with 15% mollase and stored at 35 degrees C. Experiment were conducted to evaluate the effect of the addition of a commercial preparation of bromeline (0.20-0.90%) to the fish silage. Liquefaction was evaluated measuring both the product consistency and its non protein nitrogen content. Results indicate that bromeline addition (0.7 or higher), increases dramatically the rate of proteolysis and decreases the time required for liquefaction from 15 days (no enzyme control) to only 12 hours. Therefore, the use of the commercial preparation of bromeline is highly recommended for silage production.


Electrochemically Assisted Self-Assembly Technique for the Fabrication of Mesoporous Metal-Organic Framework Thin Films: Composition of 3D Hexagonally Packed Crystals with 2D Honeycomb-like Mesopores.
In this work, we introduce a novel and general strategy for the environmentally friendly fabrication of mesoporous metal-organic framework (mMOF) thin films via the electrochemically assisted self-assembly (EASA) technique. Implementation of this procedure as a one-step, additive-free, and versatile protocol leads to the in situ simultaneous synthesis and deposition of mesoporous architectures of MOFs at room temperature under green conditions without the need for any base, pretreatment, or chemical modification of the underlying surface. Our procedure provides a controllable method for the synthesis of mMOF thin films (modified electrodes) consisting of hollow three-dimensional hexagonally packed crystals with two-dimensional honeycomb-like mesopores in the walls of the cavities, which grow perpendicularly onto any of the conducting surface. The resulting modified electrodes show enhanced electron transfer properties and better mass transfer performance along with the appropriate signal suitable for electrochemical sensing applications. This work can be a breakthrough and provide a new perspective for the modification and functionalization of the surface with any type of mMOF by the electrochemically driven cooperative (soft-templating) mechanism.


Applying mode-of-action and pharmacokinetic considerations in contemporary cancer risk assessments: an example with trichloroethylene.
The guidelines for carcinogen risk assessment recently proposed by the U.S. Environmental Protection Agency (U.S. EPA) provide an increased opportunity for the consideration of pharmacokinetic and mechanistic data in the risk assessment process. However, the greater flexibility of the new guidelines can also make their actual implementation for a particular chemical highly problematic. To illuminate the process of performing a cancer risk assessment under the new guidelines, the rationale for a state-of-the-science risk assessment for trichloroethylene (TCE) is presented. For TCE, there is evidence of increased cell proliferation due to receptor interaction or cytotoxicity in every instance in which tumors are observed, and most tumors represent an increase in the incidence of a commonly observed, species-specific lesion. A physiologically based pharmacokinetic (PBPK) model was applied to estimate target tissue doses for the three principal animal tumors associated with TCE exposure: liver, lung, and kidney. The lowest points of departure (lower bound estimates of the exposure associated with 10% tumor incidence) for lifetime human exposure to TCE were obtained for mouse liver tumors, assuming a mode of action primarily involving the mitogenicity of the metabolite trichloroacetic acid (TCA). The associated linear unit risk estimates for mouse liver tumors are 1.5 x 10(-6) for lifetime exposure to 1 microg TCE per cubic meter in air and 0.4 x 10(-6) for lifetime exposure to 1 microg TCE per liter in drinking water. However, these risk estimates ignore the evidence that the human is likely to be much less responsive than the mouse to the carcinogenic effects of TCA in the liver and that the carcinogenic effects of TCE are unlikely to occur at low environmental exposures. Based on consideration of the most plausible carcinogenic modes of action of TCE, a margin-of-exposure (MOE) approach would appear to be more appropriate. Applying an MOE of 1000, environmental exposures below 66 microg TCE per cubic meter in air and 265 microg TCE per liter in drinking water are considered unlikely to present a carcinogenic hazard to human health.


Single-turnover kinetics of helicase-catalyzed DNA unwinding monitored continuously by fluorescence energy transfer.
We describe a fluorescence assay that can be used to monitor helicase-catalyzed unwinding of duplex DNA continuously in real time. The assay is based on the observation that fluorescence resonance energy transfer (FRET) occurs between donor (fluorescein) and acceptor (hexachlorofluorescein) fluorophores that are in close proximity due to their covalent attachment to the 3' and 5' ends of the complementary strands of a duplex oligodeoxynucleotide. FRET results in a reduction in the fluorescence emission intensity of fluorescein in the duplex DNA substrate relative to that observed for fluorescein-labeled single stranded DNA. Therefore, an enhancement of fluorescein fluorescence (lambda ex = 492 nm; lambda em = 520 nm) occurs upon helicase-catalyzed unwinding of the duplex DNA and separation of the complementary strands. The fluorescence assay is extremely sensitive, allowing DNA unwinding reactions to be monitored continuously at DNA concentrations as low as 1 nM in a fluorescence stopped-flow experiment. We demonstrate the use of this DNA substrate in pre-steady state, single turnover studies of duplex DNA unwinding catalyzed by the Escherichia coli Rep helicase, monitored by fluorescence stopped flow. We show that the fluorescence enhancement monitors Rep-catalyzed DNA unwinding by comparisons with identical kinetic studies carried out using rapid chemical quench-flow techniques. Single turnover kinetic studies performed at 1 nM DNA as a function of excess Rep concentration show that Rep-catalyzed unwinding of an 18 base pair duplex containing a 3'-ss-(dT)20 tail is biphasic and can be described by the sum of two exponential terms. The observed rate constant of the first phase is independent of [Rep] (20-300 nM) and measures the rapid single turnover, unwinding of the duplex DNA by Rep dimers bound in productive complexes (1.3 +/- 0.2 s-1; 23 +/- 3 base pairs s-1 at 25.0 degrees C). The observed rate constant for the second phase increases linearly with [Rep], reflecting DNA unwinding that is limited by a Rep binding event occurring with a bimolecular rate constant of (1.8 +/- 0.1) x 10(5) M-1 s-1, which may reflect the rate constant for Rep dimerization on DNA. Kinetic competition studies indicate that both Rep subunits are bound stably to the DNA substrate in the productive complex that is unwound in the fast phase. The results of these kinetic studies are consistent with an active, rolling mechanism for Rep-catalyzed unwinding of DNA [Wong, I., & Lohman, T. M., (1992) Science 256, 350].(ABSTRACT TRUNCATED AT 400 WORDS)


Women's roles and illness episodes: a prospective study.
As more women enter the labor force, their roles proliferate. The purpose of this study was to determine whether proliferation of roles would have a deleterious effect on the women's health. A group of 96 women completed a family health diary for 3 weeks which included an estimate of stress level typical of the family on each day, the measures taken by the family to maintain health, an estimate of how each family member felt, whether or not behavior restriction was necessary, and any symptoms or complaints. An illness episode was considered to be any continued sequence of days during which health complaints were recorded in the health diary. The mean number of illness episodes for the 3-week diary-keeping period was 3.23 (SD = 1.50). Role proliferation did not correlate with the number of illness episodes (Spearman's rho = -.115 p < .132). The variables that best explained the variance in the number of illness episodes were the number of children and role reinforcement, both of which had modest negative effects on number of illness episodes; together they explained 11.3% of the variance. It was concluded that the number of episodes of illness women experience is a function of the compatibility of a woman's other roles with being ill and with the support available to her performing her roles.


On the benefits of transient attention across the visual field.
There are well-known differences in resolution and performance across the visual field with performance generally better for the lower than the upper visual hemifield. Here we attempted to assess how transient attention summoned by a peripheral precue affects performance across the visual field. Four different attentional precueing tasks were used, varying in difficulty and attentional load. When a single discrimination target was presented (experiments 1 and 2), precues that summon transient attention had very little, if any, effect upon performance. However, when the target was presented among distractors (experiments 3 and 4), the precue had a substantial effect upon discrimination performance. The results showed that asymmetries in visual resolution between the upper and lower hemifields become more pronounced with increasing eccentricity. Furthermore, when the observers performed a precued acuity task with distractors, involving the judgment of the relative position of a small disk within a larger one, there was an asymmetry in the transient attentional effect on discrimination performance; the benefits of transient attention were larger in the upper than in the lower hemifield. Areas in the visual field where visual performance is generally worse thus appear to receive the largest attentional boost when needed. Possible ecological explanations for this are discussed.


Prestroke factors associated with poststroke mortality and recovery in older women in the Women's Health Initiative.
To examine prestroke lifestyle factors associated with poststroke mortality and recovery in older women. Longitudinal prospective cohort study. The Women's Health Initiative (WHI, clinical trials and observational study), 40 clinical centers in the United States. WHI participants, women aged 50 to 79, who were stroke-free at baseline (1993/98), with incident stroke before 2005. Participants were followed for mortality through 2010. Prestroke characteristics were from the last examination before the stroke event. Annual follow-up for clinical events ascertained hospitalization for stroke that was subsequently physician adjudicated with medical records. Multivariable regression models were used to analyze factors associated with poststroke mortality and poststroke recovery at hospital discharge (poststroke Glasgow score), adjusting for stroke type. Of 3,173 women with incident stroke, 1,111 (35%) died. Individuals who were overweight or obese before stroke had lower poststroke mortality than those who were normal weight (obese: hazard ratio (HR) = 0.69, 95% confidence interval (CI) = 0.53-0.88; overweight: HR = 0.72, 95% CI = 0.58-0.90); individuals who were underweight before stroke had nonsignificantly greater poststroke mortality (HR = 2.02, 95% CI = 0.98-4.16, P = .06). Other prestroke factors associated with poststroke mortality included diabetes mellitus (HR = 1.28, 95% CI = 1.01-1.64), current smoking (vs nonsmoker, HR = 2.13, 95% CI = 1.53-3.00), physical inactivity (vs >150 min of exercise per week, HR = 1.39, 95% CI = 1.09-1.78), and lowest physical function quartile (vs highest, HR = 1.54, 95% CI = 1.18-2.02). Prestroke diabetes mellitus was associated with lower odds of good recovery after stroke (odds ratio (OR) = 0.60, 95% CI = 0.44-0.82). Current hormone use before stroke was associated with greater odds of moderate than of severe disability after stroke (OR = 1.29, 95% CI = 1.00-1.66). Potentially modifiable factors before stroke, including smoking, diabetes mellitus, and being underweight, were associated with greater poststroke mortality in older women. Being overweight or obese and physical activity before stroke were associated with lower poststroke mortality in older women.


Telaprevir-based therapy in patients coinfected with chronic hepatitis C virus infection and HIV: INSIGHT study.
INSIGHT (ClinicalTrials.gov NCT01513941) evaluated the efficacy, safety and pharmacokinetics of telaprevir-based therapy and specific antiretroviral agents in hepatitis C virus genotype 1 (HCV-1)/HIV-1-coinfected patients. Open-label, Phase IIIb, multicentre study of telaprevir with pegylated-IFN (Peg-IFN) α2a and ribavirin in treatment-naive or -experienced HCV-1/HIV-1-coinfected patients on stable HIV HAART comprising efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir, etravirine or rilpivirine with two nucleos(t)ide analogues. Patients received 750 mg telaprevir (1125 mg, if on efavirenz) every 8 h plus 180 μg/week Peg-IFNα2a and 800 mg/day ribavirin for 12 weeks, followed by Peg-IFNα2a and ribavirin alone for 12 weeks (HCV treatment naive and relapsers without cirrhosis, with extended rapid virological response) or 36 weeks (all others). Overall, 162 patients (median age of 46 years, 78% male, 92% Caucasian and mean CD4 count of 687 cells/mm(3)) were treated; 13% had cirrhosis. One-hundred-and-thirty-two patients (81%) completed telaprevir; 14 (9%) discontinued due to an adverse event (AE). Sustained virological response (SVR) 12 rates (<25 IU/mL HCV RNA 12 weeks after the last planned treatment dose) in treatment-naive patients, relapsers and non-responders were 64% (41 of 64), 62% (18 of 29) and 49% (34 of 69), respectively. SVR12 rates ranged from 51% (33 of 65) (patients receiving efavirenz) to 77% (13 of 17) (patients receiving raltegravir). Most frequently reported AEs during telaprevir treatment were pruritus (43%) and rash (34%) special search categories. Anaemia special search category occurred in 15% of patients; 6% of patients reported a serious AE. In treatment-naive/-experienced HCV-1/HIV-1 patients there were significantly higher SVR rates with telaprevir-based therapy compared with pre-specified historical controls, and safety comparable to that in HCV-monoinfected patients.


Nano/microplastics in water and wastewater treatment processes - Origin, impact and potential solutions.
The presence of nano and microplastics in water has increasingly become a major environmental challenge. A key challenge in their detection resides in the relatively inadequate analytical techniques available preventing deep understanding of the fate of nano/microplastics in water. The occurrence of nano/microplastics in water and wastewater treatment plants poses a concern for the quality of the treated water. Due to their broad but small size and diverse chemical natures, nano/microplastics may travel easily along water and wastewater treatment processes infiltrating remediation processes at various levels, representing operational and process stability challenges. This review aims at presenting the current understanding of the fate and impact of nano/microplastics through water and wastewater treatment plants. The formation and fragmentation mechanisms, physical-chemical properties and occurrence of nano/microplastics in water are correlated to the interactions of nano/microplastics with water and wastewater treatment plant processes and potential solutions to limit these interactions are comprehensively reviewed. This critical analysis offers new strategies to limit the number of nano/microplastics in water and wastewater to keep water quality up to the required standards and reduce threats on our ecosystems.


Repurposing Suzuki Coupling Reagents as a Directed Fragment Library Targeting Serine Hydrolases and Related Enzymes.
Serine hydrolases are susceptible to potent reversible inhibition by boronic acids. Large collections of chemically diverse boronic acid fragments are commercially available because of their utility in coupling chemistry. We repurposed the approximately 650 boronic acid reagents in our collection as a directed fragment library targeting serine hydrolases and related enzymes. Highly efficient hits (LE > 0.6) often result. The utility of the approach is illustrated with the results against autotaxin, a phospholipase implicated in cardiovascular disease.


Graphene sustained nonlinear modes in dielectric waveguides.
We discuss the existence of nonlinear modes sustained by graphene layers in dielectric waveguides. Taking advantage of the almost two dimensional nature of graphene, we introduce the nonlinear effect as a parameter in the continuity equations. We then apply our modeling to a simple slab waveguide to enlighten how graphene can be used to induce huge nonlinear phase shifts at easily accessible power levels.


Reduced MLH1 expression after chemotherapy is an indicator for poor prognosis in esophageal cancers.
Loss of function or expression of the mismatch repair gene MLH1 has been implicated in experimentally acquired resistance to cisplatin (CDDP) and other anticancer agents. The clinical significance of MLH1 expression was evaluated in advanced thoracic squamous cell carcinoma of the esophagus (ESCC) treated by neoadjuvant chemotherapy. We investigated MLH1 and P53 expression by immunohistochemistry in the surgical specimens of 107 patients who had undergone preoperative chemotherapy using CDDP along with 5-FU and ADM. These findings were correlated with the clinical outcome for this treatment. Biopsy samples before chemotherapy in 20 of these patients, and another 43 surgical specimens without chemotherapy, were also examined as control samples. In surgical specimens of ESCC, low MLH1 expression was not frequent without chemotherapy, whereas it was commonly observed after chemotherapy (14 versus 37%, P = 0.0057). Comparison between samples before and after chemotherapy revealed that MLH1 expression was unchanged during chemotherapy in 12 of 20 patients (60%) but was from high to low in 8 of 20 patients (40%). In the surgical specimen after neoadjuvant chemotherapy, MLH1 expression was not correlated with any clinicopathological factors, including the response to chemotherapy. However, low MLH1 showed poorer prognosis than high MLH1 (5-year survival 40.6 versus 19.3%, P = 0.0393), and in multivariate analysis, MLH1 was an independent prognostic factor for this multimodal treatment, following lymph node metastasis and clinical response to chemotherapy. Positive p53 expression, which was not affected by chemotherapy, was weakly associated with a poor response and clinical outcome, although this trend was not significant. In advanced ESCC, expression of MLH1 is reduced during CDDP-based chemotherapy, and this may partly account for poor postoperative survival.


Detection of Nocturnal Elevation in Intraocular Pressure Using a Home Tonometer in a Patient With Iridocorneal Endothelial Syndrome.
We report on a patient with iridocorneal endothelial (ICE) syndrome in whom intraocular pressure (IOP) elevation during the night was detected using a home tonometer. A 44-year-old woman was diagnosed with ICE syndrome in the left eye. Angle-closure attack-like symptoms, including blurred vision and headache, appeared and spontaneously resolved irregularly at bedtime. Daytime examination indicated normal IOP and no obvious signs of glaucoma such as visual field defects or fundus abnormalities. However, nocturnal IOP measurements using a home tonometer revealed temporary high IOP at the time of symptom onset. A home tonometer may be a useful tool to detect transient IOP elevation at night, even if the IOP is normal during daytime examinations.


Induction of Proteasome Subunit Low Molecular Weight Protein (LMP)-2 Is Required to Induce Active Remodeling in Adult Rat Ventricular Cardiomyocytes.
Isolated adult rat ventricular cardiomyocytes (ARVC) adapt to the two-dimensional surface of culture dishes once they are isolated from the three-dimensional heart tissue. This process mimics aspects of cardiac adaptation to pressure overload and requires an initial breakdown of sarcomeric structures. The present study therefore aimed to identify key steps in this remodeling process. ARVC were cultured under serum-free or serum-supplemented conditions and their sizes and shapes were analyzed as well as apoptosis and the ability to disintegrate their sarcomeres. ARVC require serum-factors in order to adapt to cell culture conditions. More ARVC survived if they were able to breakdown their sarcomeres and mononucleated ARVC, which were smaller than binucleated ARVC, had a better chance to adapt. During the early phase of adaptation, proteasome subunit low molecular weight protein (LMP)-2 was induced. Inhibition of LMP-2 up-regulation by siRNA attenuated the process of successful adaptation. In vivo, LMP-2 was induced in the left ventricle of spontaneously hypertensive rats during the early phase of adaptation to pressure overload. In conclusion, the data suggest that breakdown of pre-existing sarcomeres is optimized by induction of LMP-2 and that it is required for cardiac remodeling processes, for example, occurring during pressure overload.


Angioid streaks in a case of Camurati-Engelmann disease.
Camurati-Engelmann disease (CED) is a rare autosomal dominant disease with various phenotypic expressions. The hallmark of the disease is bilateral symmetric diaphyseal hyperostosis of the long bones with progressive involvement of the metaphysis. Ocular manifestations occur rarely and mainly result from bony overgrowth of the orbit and optic canal stenosis. We report a case of CED showing angioid streaks (ASs) in both fundi with no macular involvement and discuss the possible theories of the pathogenesis of AS in this disease.


Case Report: Dysfunction of the Paraventricular Hypothalamic Nucleus Area Induces Hypersomnia in Patients.
Hypersomnia is a common and highly impairing symptom marked by pathological excessive sleepiness, which induces suboptimal functioning and poor quality of life. Hypersomnia can be both a primary (e.g., hypersomnolence disorder) and secondary (e.g., tumors, and head trauma) symptom of disorders. However, its underlying mechanisms remain largely unknown. We report that three clinical cases with lesions around the paraventricular nucleus of the hypothalamus (PVH) area showed excessive daytime sleepiness and a prolonged nocturnal sleep lasting more than 20 h per day. Sleep architecture and subjective daytime sleepiness were examined by polysomnography. These cases were presented with stroke, myelin oligodendrocyte glycoprotein (MOG) antibody associated disorders and neuromyelitis optical spectrum disorder (NMOSD), respectively. Magnetic resonance imaging (MRI) showed lesions around the PVH area in all these three patients. After treatment of their primary disorders, their excessive sleep decreased as the PVH area recovered. Our findings suggest that the PVH may play an essential role in the occurrence of hypersomnia.


Host factors involved in resistance to retroviral infection.
Viral replication requires the help of host cell factors, whose species specificity may affect viral tropism. On the other hand, there exist host factors that restrict viral replication. The anti-viral system mediated by some of these restriction factors, which is termed intrinsic immunity and is distinguished from conventional innate and adaptive immunity, has been described as playing an important role in making species-specific barriers against viral infection. Here, we describe the current progress in understanding of such restriction factors against retroviral replication, focusing on TRIM5alpha and APOBEC, whose anti-retroviral effects have recently been recognized. Additionally, we mention cyclophilin A, which is essential for HIV-1 replication in human cells and may affect viral tropism. Understanding of these host factors would contribute to identification of the determinants for viral tropism.


Simplified CRISPR tools for efficient genome editing and streamlined protocols for their delivery into mammalian cells and mouse zygotes.
Genome editing using the CRISPR/Cas9 system requires the presence of guide RNAs bound to the Cas9 endonuclease as a ribonucleoprotein (RNP) complex in cells, which cleaves the host cell genome at sites specified by the guide RNAs. New genetic material may be introduced during repair of the double-stranded break via homology dependent repair (HDR) if suitable DNA templates are delivered with the CRISPR components. Early methods used plasmid or viral vectors to make these components in the host cell, however newer approaches using recombinant Cas9 protein with synthetic guide RNAs introduced directly as an RNP complex into cells shows faster onset of action with fewer off-target effects. This approach also enables use of chemically modified synthetic guide RNAs that have improved nuclease stability and reduces the risk of triggering an innate immune response in the host cell. This article provides detailed methods for genome editing using the RNP approach with synthetic guide RNAs using lipofection or electroporation in mammalian cells or using microinjection in murine zygotes, with or without addition of a single-stranded HDR template DNA.


Investigating interventions to increase uptake of HIV testing and linkage into care or prevention for male partners of pregnant women in antenatal clinics in Blantyre, Malawi: study protocol for a cluster randomised trial.
Despite large-scale efforts to diagnose people living with HIV, 54% remain undiagnosed in sub-Saharan Africa. The gap in knowledge of HIV status and uptake of follow-on services remains wide with much lower rates of HIV testing among men compared to women. Here, we design a study to investigate the effect on uptake of HIV testing and linkage into care or prevention of partner-delivered HIV self-testing alone or with an additional intervention among male partners of pregnant women. A phase II, adaptive, multi-arm, multi-stage cluster randomised trial, randomising antenatal clinic (ANC) days to six different trial arms. Pregnant women accessing ANC in urban Malawi for the first time will be recruited into either the standard of care (SOC) arm (invitation letter to the male partner offering HIV testing) or one of five intervention arms offering oral HIV self-test kits. Three of the five intervention arms will additionally offer the male partner a financial incentive (fixed or lottery amount) conditional on linkage after self-testing with one arm testing phone call reminders. Assuming that 25% of male partners link to care or prevention in the SOC arm, six clinic days, with a harmonic mean of 21 eligible participants, per arm will provide 80% power to detect a 0.15 absolute difference in the primary outcome. Cluster proportions will be analysed by a cluster summaries approach with adjustment for clustering and multiplicity. This trial applies adaptive methods which are novel and efficient designs. The methodology and lessons learned here will be important as proof of concept of how to design and conduct similar studies in the future. Although small, this trial will potentially present good evidence on the type of effective interventions for improving linkage into ART or prevention. The trial results will also have important policy implications on how to implement HIVST targeting male partners of pregnant women who are accessing ANC for the first time while paying particular attention to safety concerns. Contamination may occur if women in the intervention arms share their self-test kits with women in the SOC arm. ISRCTN, ID: 18421340 . Registered on 31 March 2016.


Nanotechnology in combating biofilm: A smart and promising therapeutic strategy.
Since the birth of civilization, people have recognized that infectious microbes cause serious and often fatal diseases in humans. One of the most dangerous characteristics of microorganisms is their propensity to form biofilms. It is linked to the development of long-lasting infections and more severe illness. An obstacle to eliminating such intricate structures is their resistance to the drugs now utilized in clinical practice (biofilms). Finding new compounds with anti-biofilm effect is, thus, essential. Infections caused by bacterial biofilms are something that nanotechnology has lately shown promise in treating. More and more studies are being conducted to determine whether nanoparticles (NPs) are useful in the fight against bacterial infections. While there have been a small number of clinical trials, there have been several in vitro outcomes examining the effects of antimicrobial NPs. Nanotechnology provides secure delivery platforms for targeted treatments to combat the wide range of microbial infections caused by biofilms. The increase in pharmaceuticals' bioactive potential is one of the many ways in which nanotechnology has been applied to drug delivery. The current research details the utilization of several nanoparticles in the targeted medication delivery strategy for managing microbial biofilms, including metal and metal oxide nanoparticles, liposomes, micro-, and nanoemulsions, solid lipid nanoparticles, and polymeric nanoparticles. Our understanding of how these nanosystems aid in the fight against biofilms has been expanded through their use.


Favoured conformations of methyl isopropyl, ethyl isopropyl, methyl tert-butyl, and ethyl tert-butyl 2-(triphenylphosphoranylidene)malonate.
The conformations of organic compounds determined in the solid state are important because they can be compared with those in solution and/or from theoretical calculations. In this work, the crystal and molecular structures of four closely related diesters, namely methyl isopropyl 2-(triphenylphosphoranylidene)malonate, C(25)H(25)O(4)P, ethyl isopropyl 2-(triphenylphosphoranylidene)malonate, C(26)H(27)O(4)P, methyl tert-butyl 2-(triphenylphosphoranylidene)malonate, C(26)H(27)O(4)P, and ethyl tert-butyl 2-(triphenylphosphoranylidene)malonate, C(27)H(29)O(4)P, have been analysed as a preliminary step for such comparative studies. As a result of extensive electronic delocalization, as well as intra- and intermolecular interactions, a remarkably similar pattern of preferred conformations in the crystal structures results, viz. a syn-anti conformation of the acyl groups with respect to the P atom, with the bulkier alkoxy groups oriented towards the P atom. The crystal structures are controlled by nonconventional hydrogen-bonding and intramolecular interactions between cationoid P and acyl and alkoxy O atoms in syn positions.


Mouse Models to Examine Differentiated Thyroid Cancer Pathogenesis: Recent Updates.
Although the overall prognosis of differentiated thyroid cancer (DTC), the most common endocrine malignancy, is favorable, a subset of patients exhibits aggressive features. Therefore, preclinical models that can be utilized to investigate DTC pathogenesis and novel treatments are necessary. Various mouse models have been developed based on advances in thyroid cancer genetics. This review focuses on recent progress in mouse models that have been developed to elucidate the molecular pathogenesis of DTC.


Mycosis fungoides--a retrospective study of 40 cases in Hong Kong.
Mycosis fungoides is rare in Hong Kong and oriental data on the disease are lacking. This is a multiclinic, 13-year, retrospective study to determine the clinicopathologic characteristics, treatment, and disease outcomes of 40 patients with mycosis fungoides/Sézary syndrome seen in the Social Hygiene Service, Hong Kong. There were 27 males and 13 females with a mean age at diagnosis of 56.4 years. Based on figures in the Social Hygiene Service alone, the incidence in Hong Kong was estimated to be 0.044 per 100,000. Eighty-five per cent of patients presented with skin-limited disease, and pruritus was absent in 40% of patients. A mean of 1.48 biopsies was needed to establish the diagnosis, and only 58% of the mycosis fungoides skin biopsies were reported to be histologically diagnostic of the disease. Atypical lymphocytes, epidermotropism, interface changes, and Pautrier's microabscesses were the four most frequently encountered features that attained statistical significance. Sixty-nine per cent of patients were treated with psoralen-UVA as their initial therapy, and the complete response and relapse rates were 78.3% and 66.6%, respectively. Disease progression to more advanced stages was only seen in 15% of patients. The 5-year survival rates for the whole group and for stage IA and IB patients were 88.8% and 100%, respectively. Mycosis fungoides is rare amongst Hong Kong Chinese and the majority present with skin-limited nonprogressive disease.


A Canadian perspective on bendamustine for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma.
Despite the success of standard treatments in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), patients are often unable to tolerate aggressive regimens, and they require effective alternatives. Bendamustine is a bifunctional alkylator with unique properties that significantly distinguish it from other agents in its class. In untreated CLL, bendamustine has demonstrated rates of response and progression-free survival (PFS) that are superior to those with chlorambucil, with an acceptable toxicity profile. In the relapsed setting, combination treatment with bendamustine-rituximab (BR) has demonstrated promising activity in high-risk patients such as those refractory to fludarabine or alkylating agents. In untreated patients with indolent NHL and mantle cell lymphoma, BR has demonstrated a PFS significantly longer than that achieved with R-CHOP (rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone), with significantly reduced toxicity. In the relapsed setting, br has demonstrated rates of response and PFS superior to those with fludarabine-rituximab, with comparable toxicity. In the United States and Europe, bendamustine has been approved for the treatment of CLL and indolent NHL; its approval in Canada is pending and eagerly awaited. Once available, bendamustine will benefit many Canadian patients with NHL and CLL.


The effects of endotoxin on the splanchnic metabolism of glutamine and related substrates.
The effects of endotoxemia on glutamine metabolism by the splanchnic bed was studied in vivo in adult rats 12 hours following administration of E. coli LPS. Glutamine uptake by the portal-drained viscera fell in the endotoxin-treated animals while glucose uptake doubled. Simultaneously, hepatic glutamine uptake increased ten-fold owing to both an increase in hepatic blood flow and glutamine extraction from the bloodstream. Hepatic alanine uptake, oxygen consumption, and glucose release were also accelerated in endotoxemic rats. The increase in liver glutamine utilization was associated with increases in parenchymal DNA and glutathione levels and an increase in glutathione and urea release into the systemic circulation. This marked increase in metabolic activity occurred in animals with chemical evidence of hepatocellular injury and histologic evidence of hepatocyte necrosis. During endotoxemia the liver becomes the major organ of glutamine consumption. This accelerated utilization provides carbons for energy and gluconeogenesis, nitrogen for ureagenesis, and substrate for nucleotide and glutathione biosynthesis in order to support cell repair and detoxification reactions.


Exploring the relationship of second-trimester corticotropin releasing hormone, chronic stress and preterm delivery.
We examined the impact of chronic stress on the relationship between second-trimester serum corticotropin releasing hormone (CRH) concentrations and preterm delivery (PTD) in working women. Birth records from mothers of 364 PTD and 730 controls in Southern California were linked to stored mid-pregnancy maternal serum analysed for CRH. Association of CRH with stressors reported in post-partum interviews was examined in cases and controls separately. Stratified multivariable logistic regression analyses examined moderating influence of seven chronic stressors on CRH in predicting PTD. Mean log CRH was lower among women with chronic stressors. Chronic stressors were not related to an increased risk of PTD, but did strengthen the association of CRH with PTD. Adjusted for confounders, the odds of PTD were 1.5-times higher per unit increase in log CRH in the overall study population, but were two-to-three times higher in subjects who reported unfulfilling jobs, little sleep or strong anger in the second trimester. The relation of CRH with PTD is moderated by exposure to chronic stressors during pregnancy.


Characteristics and Prognosis of Pacemaker-Identified New-Onset Atrial Fibrillation in Japanese People.
The characteristics and prognosis of implanted pacemaker-identified new-onset atrial fibrillation (AF) in Japanese people has not been well evaluated.Methods and Results:A total of 395 consecutive patients with newly implanted pacemakers were retrospectively analyzed between January 2010 and December 2015 at Yokohama City University Hospital. Patients with a prior history of AF, VVI mode pacemaker, congenital heart disease, severe valvular heart disease, and cardiovascular surgery before pacemaker implantation were excluded. Among the remaining patients, 44 (21.3%) developed new AF during follow-up (mean follow-up, 1,115±651 days; range, 9-2,176 days). Patients with new-onset AF had a significantly higher CHADS2score (2.09±1.27 vs. 1.31±1.08, P<0.001) and CHA2DS2-VASc score (3.00±1.39 vs. 2.26±1.19, P<0.001) compared with those without new-onset AF. On Cox regression analysis only age at implantation was significantly correlated with new-onset AF. Interestingly, the incidence of hospitalization due to heart failure was significantly higher in the new-onset AF than in the without new-onset AF group. A total of 21.3% of pacemaker-implanted patients with high CHADS2and CHA2DS2-VASc scores developed new-onset AF during a mean follow-up of 3.1 years; and pacemaker-identified AF was associated with an increased risk of worsening heart failure.