Effects of licorice on relief and recurrence of menopausal hot flashes.
Vasomotor hot flash is the most common and distressful complication of menopausal women. Its treatment is the most frequent clinical challenge. As a result, an effective and harmless therapy is needed. This double-blind controlled clinical trial was conducted to determine the effects of licorice roots on the relief and recurrence of hot flash in menopausal women referring to the healthcare centers affiliated to Shahid Beheshti Medical University in 2010. Ninety menopausal women complaining of hot flash were selected by reviewing their records in healthcare centers and randomly divided into 2 licorices (3 capsules daily containing 330 mg licorice abstract) and placebo (3 capsules daily containing 330 mg starch) groups over the 8 weeks of intervention and 4 weeks of follow-up. Two weeks prior to the intervention, the severity as well as frequency of hot flashes and the foods taken were asked and documented with questionnaires and data sheets. Data within and between the groups were analyzed by ANOVA with repeated measurements and t-test respectively. Means of age and body mass index (BMI) of the subjects in licorice and placebo groups were 53 ± 3.2, 52.69 ± 2.8, 24.71 ± 3.2 and 23.61 ± 3.3, respectively. The groups were similar in terms of intervening variables. The frequency of hot flash decreased significantly in the experimental (than the placebo group) and this lasted for 2 weeks after the administration of the capsules. The severity of hot flash decreased in the licorice group as well. This decrease was also seen in the placebo group in the first week of the intervention. Decreased hot flash in the placebo group was only significant after the 1(st) week of intervention compared to the previous period. Recurrence of frequency and severity of hot flashes occurred 2 weeks after the termination of therapy. The significant decrease in the placebo group after the 1(st) week of the intervention may be attributed to the psychological effects of placebo. Licorice roots decreased the frequency and severity of hot flashes. The administration of this harmless, inexpensive herb well accepted by the menopausal women together with the appropriate and continuous physical activities and consumption of dairy products are recommended for relieving this complication.


Occurrence of Halogenated Pollutants in Domestic and Occupational Indoor Dust.
The occurrence of halogenated organic pollutants in indoor dust can be high due to the presence of textile, electronic devices, furniture, and building materials treated with these chemicals. In this explorative study, we focused on emerging organic pollutants, such as novel brominated flame retardants (nBFRs) and some perfluoroalkyl substances, together with legacy polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (BDEs) in settled dust collected in houses and workplaces such as one office and two electrotechnical and mechanical workshops. The total contribution of the investigated pollutants was lower in house and in office dusts except for few nBFRs (such as bis (2-ethylhexyl)-3,4,5,6-tetrabromo-phthalate at a concentration of 464.5 ng/g in a house and hexachlorocyclopentadienyldibromocyclooctane at 40.4 ng/g in the office), whereas in electrotechnical and mechanical workshops a high incidence of PCBs, BDEs, and nBFRs occurred (for example, BDE 209 at a concentration of 2368.0 ng/g and tetrabromobisphenol A at 32,320.1 ng/g in electrotechnical and mechanical workshops). Estimated daily intakes were also calculated, showing that domestic and occupational environments can lead to a similar contribution in terms of human exposure. The higher exposure contribution was associated to nBFRs, whose EDIs were in the range of 3968.2-555,694.2 pg/kg bw/day. To provide a complete view about the indoor contamination, in this investigation, we also included polycyclic aromatic hydrocarbons (PAHs) and their oxygenated and nitrated derivatives. Definitely, dust collection represents a simple, fast, and cost-effective sampling and dust contamination level can be a useful indicator of environment healthiness. Besides, the presented method can be a smart tool to provide a time and money saving technique to characterize 99 pollutants thanks to a single sample treatment.


[The sequelae of Hansen's disease. (Pathologic viewpoint of etiologies, morphologies and countermeasures)].
The proportion of glomerulonephritis, often a sequence of arteriolitis, among the sequelae of Hansen's disease after the introduction of chemotherapy increased markedly in Japan and nullified that of once prevalent tuberculosis after 1960s. However, most significant aftermath of the disease for numbers of years in the past have been peripheral nerve injuries worldwide for which effective countermeasures are yet to be developed. In this brief autopsy cases study from 1960s to 1990s, we confirmed the presence of cases in which arteriolitis and resulted infarction of peripheral nerves and not M. leprae itself were shown to be the major cause of axonal damages. There were also cases in which the accumulation of the bacilli without vascular changes did not damage the axons. The cases as these could not be solitary but should be rather common in this time of chemotherapy. If so, the methods to reconstruct nerves and blood vessels by promoting those regeneration should be developed to cope with the situation for surgeon, assisted by pathologists.


Ribosomal DNA structure in Aedes mosquitoes (Diptera: Culicidae) and their cell lines.
The molecular organization of the ribosomal DNA repeat unit in laboratory colonies of Aedes albopictus (Skuse) and Aedes aegypti (L.) and in continuous cell lines derived from these species was examined using restriction enzyme mapping and Southern blotting techniques. In the rRNA coding regions, restriction enzyme sites were conserved in Ae. aegypti and Ae. albopictus. In particular, sites that had been mapped in rDNA cloned from the Mauritius strain of Ae. albopictus mosquitoes were confirmed in cloned DNA from cultured Ae. alboptictus cells. The intergenic spacer region of the ribosomal DNA repeat unit in Ae. albopictus was longer than that in Ae. aegypti; contained multiple recognition sites for AluI, SstI, PvuI, and XhoI; and was more heterogeneous in DNA from cultured cells than in DNA from inbred laboratory mosquitoes. The rDNA copy number was 3- to 4-fold lower in cell lines from both Ae. albopictus and Ae. aegypti than in the corresponding adult mosquitoes.


The D2/D3 agonist PD128907 (R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol) inhibits stimulated pyloric relaxation and spontaneous gastric emptying.
Enteric neuronal dopamine (DA) inhibits acetylcholine release and gastric motility; this has been thought to be mediated via neuronal dopamine-2 receptor (D2R). The aim of this study was to investigate the modulation of gastric motility by the dopamine-3 receptor (D3R). Adult Sprague-Dawley rats were used. Pyloric relaxation in response to electrical field stimulation (EFS) was assessed in an organ bath in the presence of varying concentrations of a selective D3R agonist, PD128907. Gastric emptying was assessed by the phenol red method after rats were treated with varying doses of PD128907 or DA with and without a selective D3R antagonist, L-nafadotride. Immunoblotting and immunohistochemistry confirmed the presence of D3R in the myenteric neurons in the rat pylorus. D3R activation reduced EFS-induced relaxation of pyloric strips in a dose-dependent manner and significantly delayed gastric emptying compared with vehicle. The D3R antagonist partially reversed the effect of DA on gastric emptying. Our data suggest a novel role for D3R in regulation of gastric motility. D3R activation delays gastric emptying, an effect that may be due to impairment of pyloric relaxation. D3R antagonists therefore hold promise as useful agents for treatment of gastric motility disorders.


[Explanation and prediction of the kinetics of degradation in a Rusitec fermentor of nitrogenous vegetable matter after cell wall fractionation].
The relation between nitrogen solubility in Van Soest detergents and in vitro nitrogen degradation was studied on 11 substrates with degradation process calculations in digestive trials and an artificial semi-continuous flow (Rusitec) rumen. The kinetics of plant protein degradation in Rusitec, especially the maximum degradation values, were rather similar to those calculated from literature data obtained in situ. In the exponential model used to describe the protein degradation, the maximum disappearance (a + b) was negatively correlated with the percentage of acid detergent insoluble nitrogen in the Van Soest (ADIN/Total N). In the foods tested, the non degradable fraction corresponds to a quantity which is equivalent to approximately 76% of the ADIN fraction. The instantaneously degraded nitrogen (a) was rather well explained by the percentage of neutral detergent insoluble nitrogen in the Van Soest (NDIN/Total N). The rate of disappearance (c) of the slowly degraded fraction was inversely correlated with the proportion of ADF in the NDF, which demonstrates the latter's resistance to degradation. This type of fractionation could be used in predicting nitrogenous value of feed stuffs for ruminants.


Cyclic AMP changes in guinea pig mammary gland and milk.
Cyclic AMP was measured in guinea pig mammary gland biopsies from midpregnancy through lactation and in daily milk samples throughout lactation. The results indicate that mammary gland cAMP levels rise sharply in late pregnancy to a prepartum peak and then drop abruptly at partus. This is similar to the pattern observed by others in rat and mouse although the guinea pig does not undergo a prepartum progesterone withdrawal. In animals with a 3-wk lactation period, milk cAMP concentration decreases approximately 40% between days 10 and 20, whereas the mammary gland level increases 22% per unit wet tissue weight. Although milk concentrations of lactose and cAMP are weakly correlated, a strong correlation exists between the total collected daily outputs of these two substances. The results suggest that, as lactation proceeds, mammary gland cAMP levels gradually increase, whereas milk cAMP levels decrease. Concurrently, lactose output decreases as lactation proceeds. These observations are consistent with first, a milk secretory route for regulating mammary gland cAMP levels (in addition to synthesis and hydrolysis), and second, an inhibitory action of cAMP on lactose synthesis.


[A combined approach to the treatment of paranasal and nasopharyngeal inflammation in childhood].
105 patients with chronic purulent sinusitis and chronic adenoiditis were divided into two groups. 85 patients of the study group before adenotomy were subjected to non-puncture cleansing of the nasal cavity and paranasal sinuses using [symbol: see text] sinus catheter. 20 patients of the control group underwent adenotomy without prior cleansing. Adenotomy in patients of the study group was not associated with any complications, 25 of them required no surgery. 5 controls developed abnormal intraoperative bleeding, 10 controls had high temperature for 3 days. Complications of adenotomy were registered in 3 controls.


Client-therapist congruence in session-helpfulness ratings and its association with therapy outcomes.
Objective: The present study aimed to explore client-therapist congruence in helpfulness evaluations session-by-session and its association with therapy outcomes. As suggested by West and Kenny's truth and bias model, we constructed congruence as both temporal congruence (i.e., the correlation between therapists' and clients' helpfulness judgments over time) and directional discrepancy (i.e., the average difference between therapists' and clients' helpfulness judgments).Method: Seventy-eight clients were treated by 22 experienced therapists within a 12-session course of integrative psychotherapy. At the end of each session, clients and therapists rated their perceptions of session helpfulness and, at the beginning of the next session, clients rated their own psychological functioning.Results: Therapists' and clients' helpfulness judgments were temporally congruent across treatment, and therapists' judgments were lower than those of their clients. Moreover, we found that therapists' negative directional discrepancy, but not temporal congruence, was associated with improvement in clients' psychological functioning as well as with clients' global treatment evaluations.Conclusion: Our results highlight the importance of therapists' vigilant assessment of session helpfulness in a course of brief integrative psychotherapy. As such, they strengthen the importance of further research regarding client-therapist congruence (in different aspects of the therapeutic process) and its association with therapy outcomes.Clinical or methodological significance of this article In this study, we found that therapists' tendency to provide lower session-helpfulness assessments than did their clients was associated with better therapeutic outcomes. These results may highlight the importance of therapists' cautious and humble stance when assessing their perception of session helpfulness across treatment.


Random graphs: structural-contextual dichotomy.
A formal definition of random graphs is introduced which is applicable to graphical pattern recognition problems. The definition is used to formulate rigorously the structural-contextual dichotomy of random graphs. The probability of outcome graphs is expressed as the product of two terms, one due to the statistical variability of structure among the outcome graphs and the other due to their contextual variability. Expressions are obtained to estimate the various probability, typicality, and entropy measures. The members in an ensemble of signed digraphs are interpreted as outcome graphs of a random graph. The synthesized random graph is used to quantify the structural, contextual, and overall typicality of the outcome graphs with respect to the random graph.


Proteolysis in Manchego-type cheese salted by brine vacuum impregnation.
A new salting procedure based on the brine vacuum impregnation of porous products was tested on Manchego-type cheese and compared with conventional brine immersion. Its effect on cheese proteolysis throughout a 90-d ripening period was determined. Three cheese regions were evaluated (the rind, the middle, and the internal regions). The parameters analyzed were total N, water-soluble N, soluble N in trichloroacetic acid and soluble N in phosphotungstic acid by using the Kjeldahl method, casein profile by urea-PAGE, and peptide profile of the water soluble nitrogen extract by reverse-phase HPLC. Free amino acid formation was monitored with a spectrophotometric method by using a Cd-ninhydrin reagent. Globally, proteolysis was significantly affected by ripening stage (increasing throughout all the maturation period studied) and cheese region (rind showed a proteolysis pattern different from the middle and internal regions). The salting procedure only affected cheese proteolysis in the rind, whereas conventional brine-salted cheeses showed lower proteolysis than vacuum-impregnated cheeses.


Radiation and smoking effects on lung cancer incidence among atomic bomb survivors.
While radiation increases the risk of lung cancer among members of the Life Span Study (LSS) cohort of atomic bomb survivors, there are still important questions about the nature of its interaction with smoking, the predominant cause of lung cancer. Among 105,404 LSS subjects, 1,803 primary lung cancer incident cases were identified for the period 1958-1999. Individual smoking history information and the latest radiation dose estimates were used to investigate the joint effects of radiation and smoking on lung cancer rates using Poisson grouped survival regression methods. Relative to never-smokers, lung cancer risks increased with the amount and duration of smoking and decreased with time since quitting smoking at any level of radiation exposure. Models assuming generalized interactions of smoking and radiation fit markedly better than simple additive or multiplicative interaction models. The joint effect appeared to be super-multiplicative for light/moderate smokers, with a rapid increase in excess risk with smoking intensity up to about 10 cigarettes per day, but additive or sub-additive for heavy smokers smoking a pack or more per day, with little indication of any radiation-associated excess risk. The gender-averaged excess relative risk per Gy of lung cancer (at age 70 after radiation exposure at 30) was estimated as 0.59 (95% confidence interval: 0.31-1.00) for nonsmokers with a female : male ratio of 3.1. About one-third of the lung cancer cases in this cohort were estimated to be attributable to smoking while about 7% were associated with radiation. The joint effect of smoking and radiation on lung cancer in the LSS is dependent on smoking intensity and is best described by the generalized interaction model rather than a simple additive or multiplicative model.


Characterization of a phosphodiesterase capable of hydrolyzing EA 2192, the most toxic degradation product of the nerve agent VX.
Glycerophosphodiesterase (GpdQ) from Enterobacter aerogenes is a nonspecific diesterase that enables Escherichia coli to utilize alkyl phosphodiesters, such as diethyl phosphate, as the sole phosphorus source. The catalytic properties of GpdQ were determined, and the best substrate found was bis(p-nitrophenyl) phosphate with a kcat/Km value of 6.7 x 10(3) M-1 s-1. In addition, the E. aerogenes diesterase was tested as a catalyst for the hydrolysis of a series of phosphonate monoesters which are the hydrolysis products of the highly toxic organophosphonate nerve agents sarin, soman, GF, VX, and rVX. Among the phosphonate monoesters tested, the hydrolysis product of rVX, isobutyl methyl phosphonate, was the best substrate with a kcat/Km value of 33 M-1 s-1. The ability of GpdQ to hydrolyze the phosphonate monoesters provides an alternative selection strategy in the search of enhanced variants of the bacterial phosphotriesterase (PTE) for the hydrolysis of organophosphonate nerve agents. This investigation demonstrated that the previously reported activity of GpdQ toward the hydrolysis of methyl demeton-S is due to the presence of a diester contaminant in the commercial material. Furthermore, it was shown that GpdQ is capable of hydrolyzing a close analogue of EA 2192, the most toxic and persistent degradation product of the nerve agent VX.


Effectiveness of fetal cystoscopy as a diagnostic and therapeutic intervention for lower urinary tract obstruction: a systematic review.
To determine the effectiveness of fetal cystoscopy in the prenatal diagnosis of and intervention for congenital lower urinary tract obstruction. This study was a literature search using MEDLINE, Embase, Cochrane Library, MEDION, Web of Science reference lists and contact with experts. All studies reporting on fetal cystoscopy in lower urinary tract obstruction with data for a 2 × 2 table were selected for review. No language restrictions were applied. There was independent selection of studies, data extraction and quality assessment by two reviewers. Peto odds ratios were calculated as a summary measure of effect. A total of 2071 citations were identified and 66 papers selected for detailed evaluation, from which four papers with a total of 63 patients were selected for inclusion. Two papers had results for the use of cystoscopy in diagnosis, showing that fetal cystoscopy altered the ultrasound diagnosis of the underlying pathology in 36.4 and 25.0% of fetuses, respectively. Compared to no treatment, fetal cystoscopic intervention demonstrated an odds ratio for improved perinatal survival of 20.51 (95% CI, 3.87-108.69). However, comparing vesicoamniotic shunt (VAS) with fetal cystoscopy there appeared to be no significant improvement in the perinatal survival odds ratio of 1.49 (95% CI, 0.13-16.97). These results had wide CIs and for cystoscopy vs. VAS, all results crossed the line of no effect. There is little published evidence for the effectiveness of therapeutic fetal cystoscopy as an intervention for congenital lower urinary tract obstruction and the quality of this evidence is poor. It should thus be considered to be an 'experimental intervention' and subjected to further investigation.


Noncontact Evaluation Method for Autonomic Nervous System Activity during Exercise Using RGB Camera.
For efficient exercise, motor functions, heart rate, oxygen uptake (which are controlled by autonomic nervous system activity), heat acclimation-related functions, such as sweating, and thermoregulation must work properly during exercise. In this research, a noncontact method of measuring capillary contraction and dilation, one of the autonomic nervous system activities, using only a commercial web camera was developed. The absorption rate by haemoglobin in blood differs for each wavelength of light. When the capillaries in the face contract or dilate, the colour component of the light reflected from the face changes. The focus of this study was on the changes in the green and blue values of the face image. Green light reaches the dermis, where capillaries are located, while blue light reaches only the epidermis. The G/B ratio, the green value divided by the blue value, shows the changes in capillary contraction and dilation. An experiment was conducted to validate the G/B ratio method. Ten subjects (23 ± 1.6 years of age) participated in the experiment, and face movement and heart rate were measured during an aerobic bike exercise test. The results showed that, when the heart rate increased, the G/B ratio decreased immediately after the start of exercise. After the exercise stopped, the heart rate decreased immediately, and the G/B ratio increased. The G/B ratio revealed that the sympathetic nervous system became dominant during exercise, causing facial capillaries to dilate, and that the parasympathetic nervous system became dominant after exercise, causing facial capillaries to constrict.


Catchments of general practice in different countries--a literature review.
The purpose of this paper is to review the current research on catchment areas of private general practices in different developed countries because healthcare reform, including primary health care, has featured prominently as an important political issue in a number of developed countries. The debates around health reform have had a significant health geographic focus. Conceptually, GP catchments describe the distribution, composition and profile of patients who access a general practitioner or a general practice (i.e. a site or facility comprising one or more general practitioners). Therefore, GP catchments provide important information into the geographic variation of access rates, utilisation of services and health outcomes by all of the population or different population groups in a defined area or aggregated area.This review highlights a wide range of diversity in the literature as to how GP catchments can be described, the indicators and measures used to frame the scale of catchments. Patient access to general practice health care services should be considered from a range of locational concepts, and not necessarily constrained by their place of residence. An analysis of catchment patterns of general practitioners should be considered as dynamic and multi-perspective. Geographic information systems provide opportunities to contribute valuable methodologies to study these relationships. However, researchers acknowledge that a conceptual framework for the analysis of GP catchments requires access to real world data. Recent studies have shown promising developments in the use of real world data, especially from studies in the UK. Understanding the catchment profiles of individual GP surgeries is important if governments are serious about patient choice being a key part of proposed primary health reforms. Future health planning should incorporate models of GP catchments as planning tools, at the micro level as well as the macro level, to assist policies on the allocation of resources so that opportunities for good health outcomes for all groups within society, especially those who have been systematically denied equitable access, are maximised.


Multimodal imaging reveals structural and functional heterogeneity in different bone marrow compartments: functional implications on hematopoietic stem cells.
Intravital microscopy of the calvarium is the only noninvasive method for high-resolution imaging of the bone marrow (BM) and hematopoietic stem cell (HSC) niches. However, it is unclear if the calvarium is representative of all BM compartments. Using the combination of whole body optical imaging, intravital microscopy, and "in vivo fluorescence trapping," a thorough comparison of HSCs and putative HSC niches in the calvaria, epiphyses, and diaphyses, at steady state or after HSC transplantation, can be made. We report substantial heterogeneity between different BM compartments in terms of bone-remodeling activity (BRA), blood volume fraction (BVF), and hypoxia. Although BVF is high in all BM compartments, including areas adjacent to the endosteum, we found that compartments displaying the highest BVF and BRA were preferentially seeded and engrafted upon HSC transplantation. Unexpectedly, the macroanatomical distribution of HSCs at steady state is homogeneous across these 3 areas and independent of these 2 parameters and suggests the existence of "reconstituting niches," which are distinct from "homeostatic niches." Both types of niches were observed in the calvarium, indicating that endochondral ossification, the process needed for the formation of HSC niches during embryogenesis, is dispensable for the formation of HSC niches during adulthood.


The human cytomegalovirus IE2 and UL112-113 proteins accumulate in viral DNA replication compartments that initiate from the periphery of promyelocytic leukemia protein-associated nuclear bodies (PODs or ND10).
During human cytomegalovirus (HCMV) infection, the periphery of promyelocytic leukemia protein (PML)-associated nuclear bodies (also known as PML oncogenic domains [PODs] or ND10) are sites for both input viral genome deposition and immediate-early (IE) gene transcription. At very early times after infection, the IE1 protein localizes to and subsequently disrupts PODs, whereas the IE2 protein localizes within or adjacent to PODs. This process appears to be required for efficient viral gene expression and DNA replication. We have investigated the initiation of viral DNA replication compartment formation by studying the localization of viral IE proteins, DNA replication proteins, and the PML protein during productive infection. Localization of IE2 adjacent to PODs between 2 and 6 h after infection was confirmed by confocal microscopy of human fibroblasts (HF cells) infected with both wild-type HCMV(Towne) and with an IE1-deletion mutant HCMV(CR208) that fails to disrupt PODs. In HCMV(Towne)-infected HF cells at 24 to 48 h, IE2 also accumulated in newly formed viral DNA replication compartments containing the polymerase processivity factor (UL44), the single-stranded DNA binding protein (SSB; UL57), the UL112-113 accessory protein, and newly incorporated bromodeoxyuridine (BrdU). Double labeling of the HCMV(CR208)-infected HF cells demonstrated that formation of viral DNA replication compartments initiates within granular structures that bud from the periphery of some of the PODs and subsequently coalesce into larger structures that are flanked by PODs. In transient DNA transfection assays, both the N terminus (codons 136 to 290) and the C terminus (codons 379 to 579) of IE2 exon 5, but not the central region between them, were found to be necessary for both the punctate distribution of IE2 and its association with PODs. Like IE2, the UL112-113 accessory replication protein was also distributed in a POD-associated pattern in both DNA-transfected and virus-infected cells beginning at 6 h. Furthermore, when all six replication core machinery proteins (polymerase complex, SSB, and helicase-primase complex) were expressed together in the presence of UL112-113, they also accumulated at POD-associated sites, suggesting that the UL112-113 protein (but not IE2) may play a role in recruitment of viral replication fork proteins into the periphery of PODs. These results show that (i) subsequent to accumulating at the periphery of PODs, IE2 is incorporated together with the core proteins into viral DNA replication compartments that initiate from the periphery of PODs and then grow to fill the space between groups of PODs, and (ii) the UL112-113 protein appears to have a key role in assembling and recruiting the core replication machinery proteins in the initial stages of viral replication compartment formation.


DNA sequence variation in the mitochondrial control region of subterranean mole rats, Spalax ehrenbergi superspecies, in Israel.
The complete mitochondrial control region was sequenced for 60 individuals representing different populations for each of the four species of the subterranean mole rat Spalax ehrenbergi superspecies in Israel: Spalax galili (2n = 52), S. golani (2n = 54), S. carmeli (2n = 58), and S. judaei (2n = 60). The control region of all species and populations is very similar both in length (979 to 983 bp) and in base composition. As in agreement with previous surveys on mitochondrial control regions on mammals, the mole rat control region can be divided into a central domain and two flanking domains, ETAS (extended termination associated sequences) and CSB (conserved sequence blocks). Along with the common conserved blocks found in these domains (ETAS1, ETAS2, CSB1, CSB2, and CSB3), we have also detected in all individuals an ETAS1-like and a CSB1-like element, both in the ETAS domain. The most conserved region was the central domain, followed by the CSB and ETAS domains, showing important differences in the four species analyzed. Phylogenetic analysis supported the existence of two clades. One clade contained individuals belonging to Spalax galili (2n = 52) and S. golani (2n = 54), separated in two different branches depending on the species. The other clade contained individuals belonging to S. carmeli (2n = 58) and S. judaei (2n = 60) mixed together, suggesting a more recent event of speciation. Within species we have observed a southward trend of increasing variability. These results have been explained as a consequence of the adaptation of the species to ecological factors such as aridity and temperature stresses.


Assessment of cytochrome P450 fluorometric substrates with rainbow trout and killifish exposed to dexamethasone, pregnenolone-16alpha-carbonitrile, rifampicin, and beta-naphthoflavone.
Cytochrome P450s (CYPs) are important xenobiotic metabolizing proteins. While their functions are well understood in mammals, CYP function in non-mammalian vertebrate systems is much less defined, with function often inferred from mammalian data, assuming similar function across vertebrate species. In this study, we investigate whether in vivo treatment with known mammalian CYP inducers can alter the in vitro catalytic activity of fish microsomes using eleven fluorescent CYP-mediated substrates. We investigate the basal metabolism and induction potential for hepatic CYPs in two fish species, rainbow trout (Oncorhynchus mykiss) and killifish (Fundulus heteroclitus). Species differences were found in the baseline metabolism of these substrates. Killifish have significantly higher metabolic rates for all tested substrates except 7-benzyloxyquinoline and 7-benzyloxy-4-trifluoromethylcoumarin (both mammalian CYP3A substrates); significant differences were also seen between male and female killifish. Treatment with dexamethasone, pregnenolone-16alpha-carbonitrile, and rifampicin did not cause broad, measurable CYP induction in either fish species. In trout, dexamethasone (100 mg kg(-1)) significantly induced 3-cyano-7-ethoxycoumarin metabolism and rifampicin (100 mg kg(-1)) induced the dealkylation of 7-methoxyresorufin, although both were highly variable. Female killifish exposed to pregnenolone-16alpha-carbonitrile (100 mg kg(-1)) showed significantly higher metabolism of 7-pentoxyresorufin. Overall, dexamethasone, pregnenolone-16alpha-carbonitrile and rifampicin did not appear to consistently increase CYP activity in fish. Trout treated with 10 or 50 mg kg(-1) beta-naphthoflavone (BNF), a CYP1A inducer, showed significantly induced activity across almost all substrates tested, exceptions being 7-benzyloxyquinoline, 7-benzyloxy-4-trifluoromethylcoumarin and dibenzylfluorescein. 7-Methoxy-4-(aminomethyl)coumarin, a typical CYP2D substrate in mammals, was not metabolized by untreated fish liver microsomes; however, treatment with BNF significantly induced the metabolism of this substrate in trout. Induced substrate metabolism in BNF-treated microsomes was only correlated across selective substrates, suggesting that BNF induces multiple CYPs in fish liver. These include the known BNF inducible CYP1s plus a number of as yet unidentified fish CYPs. Overall, many of these catalytic assays could be valuable tools for identification of the function of specific CYP subfamilies and individual isoforms in fish.


Role of the USF1 transcription factor in diabetic kidney disease.
The predominant transcription factors regulating key genes in diabetic kidney disease have not been established. The transcription factor upstream stimulatory factor 1 (USF1) is an important regulator of glucose-mediated transforming growth factor (TGF)-β1 expression in mesangial cells; however, its role in the development of diabetic kidney disease has not been evaluated. In the present study, wild-type (WT; USF1 +/+), heterozygous (USF1 +/-), and homozygous (USF1 -/-) knockout mice were intercrossed with Akita mice (Ins2/Akita) to induce type 1 diabetes. Mice were studied up to 36 wk of age. The degree of hyperglycemia and kidney hypertrophy were similar in all groups of diabetic mice; however, the USF1 -/- diabetic mice had significantly less albuminuria and mesangial matrix expansion than the WT diabetic mice. TGF-β1 and renin gene expression and protein were substantially increased in the WT diabetic mice but not in USF1 -/- diabetic mice. The underlying pathway by which USF1 is regulated by high glucose was investigated in mesangial cell culture. High glucose inhibited AMP-activated protein kinase (AMPK) activity and increased USF1 nuclear translocation. Activation of AMPK with AICAR stimulated AMPK activity and reduced nuclear accumulation of USF1. We thus conclude that USF1 is a critical transcription factor regulating diabetic kidney disease and plays a critical role in albuminuria, mesangial matrix accumulation, and TGF-β1 and renin stimulation in diabetic kidney disease. AMPK activity may play a key role in high glucose-induced regulation of USF1.


ROCA - An ArcGIS toolbox for road alignment identification and horizontal curve radii computation.
We present the ROCA (ROad Curvature Analyst) software, in the form of an ESRI ArcGIS Toolbox, intended for vector line data processing. The software segments road network data into tangents and horizontal curves. Horizontal curve radii and azimuth of tangents are then automatically computed. Simultaneously, additional frequently used road section characteristics are calculated, such as the sinuosity of a road section (detour ratio), the number of turns along an individual road section and the average cumulative angle for a road section. The identification of curves is based on the naïve Bayes classifier and users are allowed to prepare their own training data files. We applied ROCA software to secondary roads within the Czech road network (9,980 km). The data processing took less than ten minutes. Approximately 43% of the road network in question consists of 42,752 horizontal curves. The ROCA software outperforms other existing automatic methods by 26% with respect to the percentage of correctly identified curves. The segmented secondary roads within the Czech road network can be viewed on the roca.cdvgis.cz/czechia web-map application. We combined data on road geometry with road crashes database to develop the crash modification factors for horizontal curves with various radii. We determined that horizontal curves with radii of 50 m are approximately 3.7 times more hazardous than horizontal curves with radii accounting for 1000 m. ROCA software can be freely downloaded for noncommercial use from https://roca.cdvinfo.cz/ website.


Subpopulations of B lymphocytes and the carriage of immunological memory.
Thoracic duct lymphocytes from rats primed with DNP-BGG confer on irradiated, syngeneic recipients the ability to mount a large, IgG anti-DNP response after challenge with the immunizing conjugate. An analysis of this adoptive response lead to the following conclusions. the B memory cells which generate the IgG response carry IgG on their surface and are present in a subpopulation amounting to less than l0% of all B cells in thoracic duct lymph. The view that memory cells carry exclusively IgD is untenable. The majority of B lymphocytes in thoracic duct lymph are recirculating cells which carry surface IgM...


The structure and interactions of SpoIISA and SpoIISB, a toxin-antitoxin system in Bacillus subtilis.
Spore formation in Bacillus subtilis begins with an asymmetric cell division, following which differential gene expression is established by alternative compartment-specific RNA polymerase σ factors. The spoIISAB operon of B. subtilis was identified as a locus whose mutation leads to increased activity of the first sporulation-specific sigma factor, σ(F). Inappropriate spoIISA expression causes lysis of vegetatively growing B. subtilis cells and Escherichia coli cells when expressed heterologously, effects that are countered by co-expression of spoIISB, identifying SpoIISA-SpoIISB as a toxin-antitoxin system. SpoIISA has three putative membrane-spanning segments and a cytoplasmic domain. Here, the crystal structure of a cytoplasmic fragment of SpoIISA (CSpoIISA) in complex with SpoIISB has been determined by selenomethionine-multiwavelength anomalous dispersion phasing to 2.5 Å spacing, revealing a CSpoIISA(2)·SpoIISB(2) heterotetramer. CSpoIISA has a single domain α/β structure resembling a GAF domain with an extended α-helix at its N terminus. The two CSpoIISA protomers form extensive interactions through an intermolecular four-helix bundle. Each SpoIISB chain is highly extended and lacking tertiary structure. The SpoIISB chains wrap around the CSpoIISA dimer, forming extensive interactions with both CSpoIISA protomers. CD spectroscopy experiments indicate that SpoIISB is a natively disordered protein that adopts structure only in the presence of CSpoIISA, whereas surface plasmon resonance experiments revealed that the CSpoIISA·SpoIISB complex is stable with a dissociation constant in the nanomolar range. The results are interpreted in relation to sequence conservation and mutational data, and possible mechanisms of cell killing by SpoIISA are discussed.


Lipophilization of ascorbic acid: a monolayer study and biological and antileishmanial activities.
Ascorbyl lipophilic derivatives (Asc-C2 to Asc-C(18:1)) were synthesized in a good yield using lipase from Staphylococcus xylosus produced in our laboratory and immobilized onto silica aerogel. Results showed that esterification had little effect on radical-scavenging capacity of purified ascorbyl esters using DPPH assay in ethanol. However, long chain fatty acid esters displayed higher protection of target lipids from oxidation. Moreover, compared to ascorbic acid, synthesized derivatives exhibited an antibacterial effect. Furthermore, ascorbyl derivatives were evaluated, for the first time, for their antileishmanial effects against visceral (Leishmania infantum) and cutaneous parasites (Leishmania major). Among all the tested compounds, only Asc-C10, Asc-C12, and Asc-C(18:1) exhibited antileishmanial activities. The interaction of ascorbyl esters with a phospholipid monolayer showed that only medium and unsaturated long chain (Asc-C10 to Asc-C(18:1)) derivative esters were found to interact efficiently with mimetic membrane of leishmania. These properties would make ascorbyl derivatives good candidates to be used in cosmetic and pharmaceutical lipophilic formulations.


The amino-terminal part of PRELP binds to heparin and heparan sulfate.
PRELP (proline, arginine-rich end leucine-rich repeat protein) is an extracellular matrix leucine-rich repeat protein. The amino-terminal region of PRELP differs from that of other leucine-rich repeat proteins in containing a high number of proline and arginine residues. The clustered proline and basic residues are conserved in rat, bovine, and human PRELP. Although the function of PRELP is not yet known, the clustered arginine residues suggest a heparan sulfate/heparin-binding capacity. We show here that PRELP indeed binds heparin and heparan sulfate. Truncated PRELP without the amino-terminal region does not bind heparin. The dissociation constant for the interaction of PRELP with heparin was determined by an in solution binding assay and by surface plasmon resonance analysis to be in the range of 10-30 nm. A 6-mer heparin oligosaccharide was the smallest size showing binding to PRELP. The binding increased with increasing length up to an 18-mer and depended on the degree of sulfation of heparin as well as heparan sulfate. Sulfate groups at all positions were shown to be of importance for the binding. Fibroblasts bind PRELP, and this interaction is inhibited with heparin, suggesting a function for PRELP as a linker between the matrix and cell surface proteoglycans.


POPISK: T-cell reactivity prediction using support vector machines and string kernels.
Accurate prediction of peptide immunogenicity and characterization of relation between peptide sequences and peptide immunogenicity will be greatly helpful for vaccine designs and understanding of the immune system. In contrast to the prediction of antigen processing and presentation pathway, the prediction of subsequent T-cell reactivity is a much harder topic. Previous studies of identifying T-cell receptor (TCR) recognition positions were based on small-scale analyses using only a few peptides and concluded different recognition positions such as positions 4, 6 and 8 of peptides with length 9. Large-scale analyses are necessary to better characterize the effect of peptide sequence variations on T-cell reactivity and design predictors of a peptide's T-cell reactivity (and thus immunogenicity). The identification and characterization of important positions influencing T-cell reactivity will provide insights into the underlying mechanism of immunogenicity. This work establishes a large dataset by collecting immunogenicity data from three major immunology databases. In order to consider the effect of MHC restriction, peptides are classified by their associated MHC alleles. Subsequently, a computational method (named POPISK) using support vector machine with a weighted degree string kernel is proposed to predict T-cell reactivity and identify important recognition positions. POPISK yields a mean 10-fold cross-validation accuracy of 68% in predicting T-cell reactivity of HLA-A2-binding peptides. POPISK is capable of predicting immunogenicity with scores that can also correctly predict the change in T-cell reactivity related to point mutations in epitopes reported in previous studies using crystal structures. Thorough analyses of the prediction results identify the important positions 4, 6, 8 and 9, and yield insights into the molecular basis for TCR recognition. Finally, we relate this finding to physicochemical properties and structural features of the MHC-peptide-TCR interaction. A computational method POPISK is proposed to predict immunogenicity with scores which are useful for predicting immunogenicity changes made by single-residue modifications. The web server of POPISK is freely available at http://iclab.life.nctu.edu.tw/POPISK.


Development and in vitro evaluation of an artificial spinal disc loading cell.
One of the common diseases for chronic low back pain is Disc Degeneration Disease (DDD). In this disease, spinal intervertebral disc loses its ability to safely handle the mechanical stresses. The knowledge of the in-vivo loading on the spinal disk is of great importance in the understanding of low back pain. In this study a loading cell has been developed utilizing an artificial spinal disc which was loaded with strain gauges and piezoresistive sensors in an effort to investigate the behavior of the sensors during in vitro loading of the disc. The artificial disc with all sensors was loaded in a laboratory environment. The in vitro loading produced reliable and repeatable results and therefore suggesting that such approach might aid in the development of an artificial intelligent disc which will contribute in the better understanding of the in vivo loading of the human spine.


Cartilage-like tribological performance of charged double network hydrogels.
A synthetic hydrogel material may offer utility as a cartilage replacement if it is able to maintain low friction in different sliding environments and achieve bulk mechanical properties to withstand the severe environment of the joint. In this work, we compared the tribological behavior of four double network (DN) hydrogels to that of fresh porcine cartilage in both water and fetal bovine serum (FBS). The DN hydrogels were comprised of a negatively charged 1st network and a 2nd network wherein comonomers of varying charge (i.e. neutral, positive, negative, and zwitterionic) were introduced at 10 wt% to an otherwise neutral network. A steel ball probe was used to perform microindentation tests to determine the surface elastic modulus of the samples and estimate their contact areas during sliding. Friction tests using a stationary probe with a stage that reciprocated at a range of speeds were performed to develop lubrication curves in both water and FBS. We found that the DN hydrogels with a neutral or zwitterionic 2nd network had the lowest friction and shear stresses, notably below that of cartilage. The differences in charge and structure of the samples were more evident in water than in FBS, as the lubrication responses for all the hydrogels spanned a wider range of values. In FBS, the lubrication responses were pushed towards elasto-hydrodynamics with nearly all friction coefficient values falling below 0.3. This indicates that the FBS interacts with the hydrogels and cartilage samples in a similar manner as that of cartilage by maintaining a robust layer of solution at the interface during sliding. These DN hydrogels prove to fulfill, and in some cases surpass, the lubrication demands for cartilage replacement in load bearing joints.


A randomized double-blind placebo-controlled clinical study on the effects of gabapentin premedication on hemodynamic stability during laparoscopic cholecystectomy.
Carbon dioxide pneumoperitoneum for laparoscopic surgery increases arterial pressures, heart rate, and systemic vascular resistance. In this randomized double-blind placebo-controlled clinical study, we investigated the efficacy of gabapentin premedication to provide perioperative hemodynamic stability in patients undergoing laparoscopic cholecystectomy. Sixty patients, of either sex (18-65 years of age) undergoing elective laparoscopic cholecystectomy were randomly allocated to two groups of 30 patients each. Patients of group G received oral gabapentin 900 mg 2 h before induction of anesthesia, while patients in group P received placebo at the same time. Mean arterial pressure in patients of group G were significantly lower (P < 0.05) after tracheal intubation and pneumoperitoneum and remained lower, as compared to group P, throughout the pneumoperitoneum. Similarly, heart rate in group G was significantly lower (P < 0.05) after tracheal intubation and pneumoperitoneum and remained lower, in comparison to group P, throughout the peumoperitoneum. Intravenous labetalol was required, to control intraoperative hypertension, in 33.3% (10 out of 30) patients in group P. There was no significant difference in the incidence of adverse effects between the two groups. Gabapentin premedication provided perioperative hemodynamic stability during laparoscopic surgery.


Novel functional assay for spindle-assembly checkpoint by cyclin-dependent kinase activity to predict taxane chemosensitivity in breast tumor patient.
Taxanes are among the drugs most commonly used for preoperative chemotherapy for breast cancer. Taxanes induce mitotic arrest and subsequent apoptosis. The spindle-assembly checkpoint (SAC) is known to be activated during mitosis, along with cyclin-dependent kinase-1 (CDK1), and is required for taxane-induced cell death. We hypothesized that CDK1 activity predicts response to taxane-containing chemotherapy. This study included breast cancer patients who received preoperative chemotherapy- taxane-containing treatment followed by anthracycline-based treatment-and then underwent surgery. Before starting taxane-containing chemotherapy, patients underwent fine-needle aspiration biopsy, and the biopsy samples were incubated in paclitaxel solution to measure CDK activity. Clinical were evaluated after taxane therapy, and pathological resposes were evaluated after completion of all preoperative chemotherapy. Thirty five patients were eligible for analysis of clinical response to taxane-containing therapy. Twenty-six patients had taxane-sensitive and 9 taxane-resistant tumors. Using a cut-off of CDK activity determined by the ROC analysis, patients were classified into SAC function and dysfunction groups. Univariate logistic regression analysis with clinicopathologic parameters showed that only CDK-based SAC functionality was significantly correlated with clinical response (P =0.017). No significant correlation was observed between SAC functionality and pathologic response. CDK-based SAC functionality significantly predicted clinical response (P =.0072, overall agreement = 71.4%), and this is a unique mechanism-based marker for predicting taxane chemosensitivity. Further, large prospective study is needed to determine CDK-based SAC functionality could be developed as a predictive biomarker.


Gender Differences in Behçet's Disease Associated Uveitis.
Behçet's disease is a systemic vasculitis of unknown etiology, characterized by oral and genital ulceration, skin lesions, and uveitis as well as vascular, central nervous system, and gastrointestinal system involvement. It is prevalent in the Middle East, Mediterranean, and Eastern Asia. The aim of this review is to evaluate the gender differences in clinical manifestations of Behçet's disease, treatment responses, mortality, and morbidity. Behçet's disease has been reported to be more prevalent in males from certain geographic regions and particular ethnic groups; however, recent reports indicate more even gender distribution across the world. There are gender differences in clinical manifestations and severity of the disease. Ocular manifestations, vascular involvement, and neurologic symptoms are more frequently reported in male patients whereas oral and genital ulcers, skin lesions, and arthritis occur more frequently in female patients. The disease can have a more severe course in males, and overall mortality rate is significantly higher among young male patients.


Assessing the Impact of a Serious Game (MedSMARxT: Adventures in PharmaCity) in Improving Opioid Safety Awareness Among Adolescents and Parents: Quantitative Study.
The opioid crisis continues to worsen across the United States, affecting people of all demographics. Few evidence-based interventions exist for educating families, particularly those with adolescents, about opioid prescription safety. Serious games have demonstrated impacts in improving medication-related outcomes for various health conditions. The characterizing goal of this serious game is to improve opioid safety knowledge and awareness among adolescents and their families. This study evaluated the impact of a serious game, MedSMARxT: Adventures in PharmaCity, designed to foster opioid safety awareness among adolescents and their parents. A national sample of parents and their adolescent children was recruited through Qualtrics research panels, social media, listservs, and snowball sampling. Eligible participants were adolescents aged between 12 and 18 years and their parents. Study participants were required to reside in the United States; speak, read, and understand English; and have access to a computer with a webcam. Parent-child dyads completed pregame and postgame surveys and participated in gameplay for up to 30 minutes. Primary outcome scales have been previously evaluated by the study team. A total of 60 adolescent participants and 68 parent participants met full attention criteria for inclusion in this study. Statistical analysis confirmed that both adolescents' and parents' concept scores improved from baseline regarding opioid safety self-efficacy (adolescent: mean 0.35, SD 0.60; P<.001; parent: mean 0.28, SD 0.42; P<.001), perceived knowledge (adolescent: mean 1.08, SD 1.04; P<.001; parent: mean 0.56, SD 0.55; P<.001), behavioral intent (adolescent: mean 0.26, SD 0.39; P<.001; parent: mean 0.25, SD 0.32; P<.001), safe storage (adolescent: mean 0.12, SD 0.27; P<.001; parent: mean 0.03, SD 0.11; P=.03), disposal knowledge (adolescent: mean 0.10, SD 0.27; P=.006; parent: mean 0.07, SD 0.16; P<.001), and knowledge about misuse behavior (adolescent: mean 0.05, SD 0.14; P=.002; parent: mean 0.04, SD 0.10; P<.001). Participant groups, stratified by who completed and who did not complete gameplay, improved their knowledge and awareness, with no significant differences between subgroups. The use of this serious game to improve opioid prescription safety practices among parents and adolescents was supported by the study findings. MedSMARxT: Adventures in PharmaCity is an intervention with the capability of teaching parents and adolescents about safe opioid prescription practices. Further studies and game refinement are needed to demonstrate the effectiveness of a game-based intervention in clinical settings and community pharmacies.


Anti-microbial, anti-biofilm activities and cell selectivity of the NRC-16 peptide derived from witch flounder, Glyptocephalus cynoglossus.
Previous studies had identified novel antimicrobial peptides derived from witch flounder. In this work, we extended the search for the activity of peptide that showed antibacterial activity on clinically isolated bacterial cells and bacterial biofilm. Pseudomonas aeruginosa was obtained from otitis media and cholelithiasis patients, while Staphylococcus aureus was isolated from otitis media patients. We found that synthetic peptide NRC-16 displays antimicrobial activity and is not sensitive to salt during its bactericidal activity. Interestingly, this peptide also led to significant inhibition of biofilm formation at a concentration of 4-16 μM. NRC-16 peptide is able to block biofilm formation at concentrations just above its minimum inhibitory concentration while conventional antibiotics did not inhibit the biofilm formation except ciprofloxacin and piperacillin. It did not cause significant lysis of human RBC, and is not cytotoxic to HaCaT cells and RAW264.7 cells, thereby indicating its selective antimicrobial activity. In addition, the peptide's binding and permeation activities were assessed by tryptophan fluorescence, calcein leakage and circular dichroism using model mammalian membranes composed of phosphatidylcholine (PC), PC/cholesterol (CH) and PC/sphingomyelin (SM). These experiments confirmed that NRC-16 does not interact with any of the liposomes but the control peptide melittin did. Taken together, we found that NRC-16 has potent antimicrobial and antibiofilm activities with less cytotoxicity, and thus can be considered for treatment of microbial infection in the future.


Operative treatment of chondral defects in the hip joint: a systematic review.
Young patients with cartilage defects in the hip present a complex problem for the treating physician with limited treatment modalities available. Cartilage repair/replacement techniques have shown promising results in other joints, however, the literature regarding the hip joint is limited. The purpose of the current study is to conduct a systematic review of clinical outcomes following various treatments for chondral lesions of the hip and define the techniques for the treatment of these cartilage defects. The full manuscripts of 15 studies were reviewed for this systematic review including case studies, case series, and clinical studies. A variety of techniques have been reported for the treatment of symptomatic chondral lesions in the hip. Microfracture, cartilage repair, autologous chondrocyte implantation, mosaicplasty, and osteochondral allografting have all been used in very limited case series. Although good results have been reported, most studies lack both a control group and a large number of patients. However, the reported results in this article do provide a good foundation for treatments and stimulant for further study in an inherently difficult to treat young patient population with articular cartilage defects in the hip.


Is Same-Day Discharge Following Minimally Invasive Sacrocolpopexy Safe and Feasible? A National Contemporary Database Analysis.
The aim of this study was to investigate trends and outcomes of ambulatory minimally invasive sacrocolpopexy (MISC) using data from a contemporary multicenter nationwide cohort. We used the American College of Surgeons National Surgical Quality Improvement Program database to identify women who underwent nonemergent MISC (laparoscopic and robotic) from 2012 to 2018. Exclusion criteria were age <18 or ≥90 years, rectal prolapse, postoperative discharge day ≥3, and concomitant hysterectomy, transvaginal mesh repair, colpocleisis, and/or colorectal surgery. Baseline demographics and 30-day outcomes were compared between patients who underwent same-day discharge (SDD; discharge on postoperative day [POD] 0) and those discharged on POD 1-2 using Kruskal-Wallis, Fisher exact, and Pearson χ2 tests. A 2-sided Cochran-Armitage trend test assessed SDD over time, and person-years methodology was used to assess readmission rates. Multivariable logistic regression and Cox proportional hazards modeling evaluated associations between SDD and postoperative outcomes. We hypothesized that SDD increased over the study time frame and is not associated with adverse outcomes. Of 2,928 women, 362 (12.4%) were SDD, and 2,566 (87.6%) were discharged POD 1-2. The proportion of SDD nearly quadrupled over time (5.6% [2012], 20.6% [2018]; P < 0.001). The SDD group was younger (mean age, 61.9 vs 63.6; P = 0.04), with lower proportion of American Society of Anesthesiologists class III or higher (21.8% vs 27.5%; P = 0.02) and hypertension (37.3% vs.46.5%; P < 0.001), shorter total operation time (median, 142 vs 172 minutes; P < 0.001), and fewer concomitant slings (21.5% vs 33.0%; P < 0.001). Outcomes were similar for SDD: 30-day overall complications (3.0% vs 4.4%; P = 0.23), readmissions (1.1% vs 2.0%; P = 0.28), and reoperations (1.1% vs 0.9%; P = 0.55) and persisted with multivariable analysis. Ambulatory MISC significantly increased during the study period and appears safe and feasible in select patients.


Leadership and Teamwork in Trauma and Resuscitation.
Leadership skills are described by the American College of Surgeons' Advanced Trauma Life Support (ATLS) course as necessary to provide care for patients during resuscitations. However, leadership is a complex concept, and the tools used to assess the quality of leadership are poorly described, inadequately validated, and infrequently used. Despite its importance, dedicated leadership education is rarely part of physician training programs. The goals of this investigation were the following: 1. Describe how leadership and leadership style affect patient care; 2. Describe how effective leadership is measured; and 3. Describe how to train future physician leaders. We searched the PubMed database using the keywords "leadership" and then either "trauma" or "resuscitation" as title search terms, and an expert in emergency medicine and trauma then identified prospective observational and randomized controlled studies measuring leadership and teamwork quality. Study results were categorized as follows: 1) how leadership affects patient care; 2) which tools are available to measure leadership; and 3) methods to train physicians to become better leaders. We included 16 relevant studies in this review. Overall, these studies showed that strong leadership improves processes of care in trauma resuscitation including speed and completion of the primary and secondary surveys. The optimal style and structure of leadership are influenced by patient characteristics and team composition. Directive leadership is most effective when Injury Severity Score (ISS) is high or teams are inexperienced, while empowering leadership is most effective when ISS is low or teams more experienced. Many scales were employed to measure leadership. The Leader Behavior Description Questionnaire (LBDQ) was the only scale used in more than one study. Seven studies described methods for training leaders. Leadership training programs included didactic teaching followed by simulations. Although programs differed in length, intensity, and training level of participants, all programs demonstrated improved team performance. Despite the relative paucity of literature on leadership in resuscitations, this review found leadership improves processes of care in trauma and can be enhanced through dedicated training. Future research is needed to validate leadership assessment scales, develop optimal training mechanisms, and demonstrate leadership's effect on patient-level outcome.


Toward delineating the structure and function of the particulate methane monooxygenase from methanotrophic bacteria.
The particulate methane monooxygenase (pMMO) is a complex membrane protein complex that has been difficult to isolate and purify for biochemical and biophysical characterization because of its instability in detergents used to solubilize the enzyme. In this perspective, we summarize the progress recently made toward obtaining a purified pMMO-detergent complex and characterizing the enzyme in pMMO-enriched membranes. The purified pMMO is a multi-copper protein, with ca. 15 copper ions sequestered into five trinuclear copper clusters: two for dioxygen chemistry and alkane hydroxylation (catalytic or C-clusters) and three to provide a buffer of reducing equivalents to re-reduce the C-clusters following turnover (electron transfer or E-clusters). The enzyme is functional when all the copper ions are reduced. When the protein is purified under ambient aerobic conditions in the absence of a hydrocarbon substrate, only the C-clusters are oxidized; there is an apparent kinetic barrier for electron transfer from the E-cluster copper ions to the C-clusters under these conditions. Evidence is provided in support of both C-clusters participating in the dioxygen chemistry, but only one C-cluster supporting alkane hydroxylation. Acetylene modification of the latter C-cluster in the hydrophobic pocket of the active site lowers or removes the kinetic barrier for electron transfer from the E-clusters to the C-clusters so that all the copper ions could be fully oxidized by dioxygen. A model for the hydroxylation chemistry when a hydrocarbon substrate is bound to the active site of the hydroxylation C-cluster is presented. Unlike soluble methane monooxygenase (sMMO), pMMO exhibits limited substrate specificity, but the hydroxylation chemistry is highly regioselective and stereoselective. In addition, the hydroxylation occurs with total retention of configuration of the carbon center that is oxidized. These results are consistent with a concerted mechanism involving direct side-on insertion of an active singlet "oxene" from the activated copper cluster across the "C-H" bond in the active site. Finally, in our hands, both the purified pMMO-detergent complex and pMMO-enriched membranes exhibit high NADH-sensitive as well as duroquinol-sensitive specific activity. A possible role for the two reductants in the turnover of the enzyme is proposed.


SARS-CoV-2 testing and its role in understanding the evolving landscape of the pandemic in Bangladesh.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is readily transmitted from person to person. We evaluated the emerging landscape of SARS-CoV-2 variants in Bangladesh from a retrospective study of nasopharyngeal swabs collected from 130 SARS-CoV-2-positive cases randomly selected over 6 months. Mutation analysis of whole-genome sequencing of 130 SARS-CoV-2 variants revealed 528 unique coding mutations, of which 102 were deletions, 6 were premature stop codons, and the remaining were substitutions. The most common mutation in the cohort was ORF1b:P314L, with a frequency of 98.5%. A total of 132 unique coding mutations were observed in the spike protein gene. Fourteen mutations were mapped to the spike protein receptor binding domain (RBD). These mutations increase the affinity between the spike protein and its human receptor, angiotensin converting enzyme 2 (ACE2), thereby increasing SARS-CoV-2 transmissibility. This study will help understand the SARS-CoV-2 virus and ultimately aid in monitoring and combatting the COVID-19 pandemic by furthering research on appropriate therapies. Analysis of age revealed closer association of the Delta variant with older populations and of the Omicron variant with younger populations. This may have important implications on how we monitor infections, distribute vaccines, and treat patients based on their ages.


Fasting-induced adipose factor identified as a key adipokine that is up-regulated in white adipose tissue during pregnancy and lactation in the rat.
Adipokines, which are expressed and secreted from white adipose tissue (WAT), are potential factors that could contribute to the changes in energy homeostasis that occurs in pregnancy and lactation to meet the nutrient demands of fetal growth and milk production. The aim was to identify adipokines that could be involved by measuring the pattern of their mRNA expression in adipose tissue. Adipokine mRNAs were measured by quantitative RT-PCR in RNA isolated from white and brown adipose tissue (BAT) of rats at days 7, 14 and 21 of pregnancy, day 7 of lactation and virgin at dioestrus phase. The results for leptin, adiponectin and resistin expression in WAT essentially confirmed previous studies and it is unlikely that they are directly involved in the metabolic adaptations. The relative amounts of the mRNAs of the adipokines in BAT were comparable with those in WAT, but the patterns of expression did not follow those in WAT, except for apelin. Visfatin mRNA in WAT was elevated 2.5-fold only at day 21 of pregnancy. Apelin mRNA in WAT was increased 2.2-fold at day 7 of pregnancy. Retinol-binding protein 4 mRNA in WAT decreased to 46% of control at day 14 of pregnancy. Fasting-induced adipose factor (FIAF) mRNA in WAT was 2.2- to 2.5-fold higher throughout pregnancy and lactation. The marked induction of FIAF identifies this adipokine as a potential regulator of the metabolic adaptations that occur during pregnancy and lactation.


Kin relationships in cultural species of the marine realm: case study of a matrilineal social group of sperm whales off Mauritius island, Indian Ocean.
Understanding the organization and dynamics of social groups of marine mammals through the study of kin relationships is particularly challenging. Here, we studied a stable social group of sperm whales off Mauritius, using underwater observations, individual-specific identification, non-invasive sampling and genetic analyses based on mitochondrial sequencing and microsatellite profiling. Twenty-four sperm whales were sampled between 2017 and 2019. All individuals except one adult female shared the same mitochondrial DNA (mtDNA) haplotype-one that is rare in the western Indian Ocean-thus confirming with near certainty the matrilineality of the group. All probable first- and second-degree kin relationships were depicted in the sperm whale social group: 13 first-degree and 27 second-degree relationships were identified. Notably, we highlight the likely case of an unrelated female having been integrated into a social unit, in that she presented a distinct mtDNA haplotype and no close relationships with any members of the group. Investigating the possible matrilineality of sperm whale cultural units (i.e. vocal clans) is the next step in our research programme to elucidate and better apprehend the complex organization of sperm whale social groups.


1/f 2 Characteristics and isotropy in the fourier power spectra of visual art, cartoons, comics, mangas, and different categories of photographs.
Art images and natural scenes have in common that their radially averaged (1D) Fourier spectral power falls according to a power-law with increasing spatial frequency (1/f(2) characteristics), which implies that the power spectra have scale-invariant properties. In the present study, we show that other categories of man-made images, cartoons and graphic novels (comics and mangas), have similar properties. Further on, we extend our investigations to 2D power spectra. In order to determine whether the Fourier power spectra of man-made images differed from those of other categories of images (photographs of natural scenes, objects, faces and plants and scientific illustrations), we analyzed their 2D power spectra by principal component analysis. Results indicated that the first fifteen principal components allowed a partial separation of the different image categories. The differences between the image categories were studied in more detail by analyzing whether the mean power and the slope of the power gradients from low to high spatial frequencies varied across orientations in the power spectra. Mean power was generally higher in cardinal orientations both in real-world photographs and artworks, with no systematic difference between the two types of images. However, the slope of the power gradients showed a lower degree of mean variability across spectral orientations (i.e., more isotropy) in art images, cartoons and graphic novels than in photographs of comparable subject matters. Taken together, these results indicate that art images, cartoons and graphic novels possess relatively uniform 1/f(2) characteristics across all orientations. In conclusion, the man-made stimuli studied, which were presumably produced to evoke pleasant and/or enjoyable visual perception in human observers, form a subset of all images and share statistical properties in their Fourier power spectra. Whether these properties are necessary or sufficient to induce aesthetic perception remains to be investigated.


Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice.
Adoptive transfer of T cells genetically engineered with a chimeric antigen receptor (CAR) has successfully been used to treat both chronic and acute lymphocytic leukemia as well as other hematological cancers. Experimental therapy with CAR-engineered T cells has also shown promising results on solid tumors. The prostate stem cell antigen (PSCA) is a protein expressed on the surface of prostate epithelial cells as well as in primary and metastatic prostate cancer cells and therefore a promising target for immunotherapy of prostate cancer. We developed a third-generation CAR against PSCA including the CD28, OX-40 and CD3 ζ signaling domains. T cells were transduced with a lentivirus encoding the PSCA-CAR and evaluated for cytokine production (paired Student's t-test), proliferation (paired Student's t-test), CD107a expression (paired Student's t-test) and target cell killing in vitro and tumor growth and survival in vivo (Log-rank test comparing Kaplan-Meier survival curves). PSCA-CAR T cells exhibit specific interferon (IFN)-γ and interleukin (IL)-2 secretion and specific proliferation in response to PSCA-expressing target cells. Furthermore, the PSCA-CAR-engineered T cells efficiently kill PSCA-expressing tumor cells in vitro and systemic treatment with PSCA-CAR-engineered T cells significantly delays subcutaneous tumor growth and prolongs survival of mice. Our data confirms that PSCA-CAR T cells may be developed for treatment of prostate cancer.


Application of the empirical mode decomposition to the extraction of features from EEG signals for mental task classification.
In this work, it is proposed a technique for the feature extraction of electroencephalographic (EEG) signals for classification of mental tasks which is an important part in the development of Brain Computer Interfaces (BCI). The Empirical Mode Decomposition (EMD) is a method capable to process nonstationary and nonlinear signals as the EEG. This technique was applied in EEG signals of 7 subjects performing 5 mental tasks. For each mode obtained from the EMD and each EEG channel were computed six features: Root Mean Square (RMS), Variance, Shannon Entropy, Lempel-Ziv Complexity Value, and Central and Maximum Frequencies, obtaining a feature vector of 180 components. The Wilks' lambda parameter was applied for the selection of the most important variables reducing the dimensionality of the feature vector. The classification of mental tasks was performed using Linear Discriminate Analysis (LD) and Neural Networks (NN). With this method, the average classification over all subjects in database was 91+/-5% and 87+/-5% using LD and NN, respectively. It was concluded that the EMD allows getting better performances in the classification of mental tasks than the obtained with other traditional methods, like spectral analysis.


Removal of N-linked carbohydrates decreases the infectivity of herpes simplex virus type 1.
Purified preparations of herpes simplex virus type 1 Angelotti were digested with the exoglycosidases sialidase, beta-galactosidase, N-acetyl-beta-D-glucosaminidase and alpha-mannosidase, and with the endoglycosidases Endo-H and Endo-F. It was found that treatment of virions with Endo-F specifically decreased viral infectivity by a factor of 10. This reduction in titre was not associated with any measurable differences in virus adsorption, suggesting a role of N-linked complex type oligosaccharide chains in penetration. In contrast, a reduction in titre observed upon digestion of virions with exoglycosidases could be attributed to a proteolytic contamination in these enzyme preparations. Treatment of virions with Endo-H, demonstrated to be free of proteolytic contamination, did not reduce viral infectivity. Analysis of endoglycosidase-digested virions by monospecific antibodies and immunoblotting revealed a susceptibility of all four major glycoproteins (gC, gB, gE and gD) to Endo-F, but only gB was susceptible to Endo-H treatment. In contrast, of all the exoglycosidases used only sialidase was found to be active towards native viral glycoproteins. Upon analysis of endoglycosidase-digested virions we could not find any evidence for proteolysis, degradation or altered protein composition of viral envelopes. In contrast, vigorous inhibition of glycoprotein glycosylation by tunicamycin led to the formation of physically intact virions almost completely lacking all major glycoproteins. These data show that digestion of intact virions with glycosidases allows an analysis of the functional relevance of carbohydrate residues without any obvious alterations in the virion glycoprotein composition.


The Impact of Mortality Salience on Intergenerational Altruism and the Perceived Importance of Sustainable Development Goals.
The Sustainable Development Goals (SDGs), consisting of 17 specific goals such as ending poverty, reducing inequality, and combating climate change, were proposed by the UN member states in 2014 for the ongoing UN agenda until 2030. These goals articulate the growing need for the international community to build a sustainable future. To progress and build a truly sustainable future requires not only the immediate support of individuals for the current SDGs, but also their personal long-term commitment to the needs of future generations (i.e., intergenerational altruism). Reminders of death can influence attitudes, motivation, and behavior in various aspects of our lives. In the current research, we thus explored whether reminding individuals of their own death will influence their intergenerational altruism and perceived importance of the SDGs. Using a three-condition (mortality salience vs. dentist visit vs. neutral) randomized experiment, we found that mortality salience led participants to place a higher priority on the needs of future generations only when compared to the neutral condition. Further, we conducted a factor analysis that generated two SDGs factors (socially related SDGs and ecologically related SDGs). We found that mortality salience reduced participants' perceived importance of the socially related SDGs when compared to both the dentist visit and the neutral conditions, and mortality salience decreased participants' perceived importance of the ecologically related SDGs only when compared to the neutral condition.


Antibody to H(+) V-ATPase subunit E colocalizes with portasomes in alkaline larval midgut of a freshwater mosquito (Aedes aegypti).
The pH profile, gross structure, ultrastructure and immunolabeling of the mosquito (Aedes aegypti) larval midgut are described as a first step in analyzing the role of plasma membrane H(+ )V-ATPase in the alkalization of the gut, nutrient uptake and ionic regulation. Binding of an antibody to H(+ )V-ATPase subunit E colocalizes with 'portasomes' (approximately 10 nm in diameter), which are thought to correspond to the V(1) part of the H(+) V-ATPase. In gastric caeca (pH 8), both antibody-binding sites and portasomes are located apically; in the anterior midgut (pH 10-11), they are located basally; and in the posterior midgut (pH approximately equal to 8) they are again located apically. The hypothesis that the energization of alkalization is mediated by an H(+) V-ATPase is supported by the inability of larvae to maintain the high pH after 72 h in 10 (micro)M bafilomycin B1. Confirming earlier reports, the two principal epithelial cell types are designated as 'columnar' and 'cuboidal' cells. The apical plasma membranes (microvilli) of epithelial cells in the gastric caeca and basal infoldings of anterior midgut are invaded by mitochondria that lie within approximately 20 nm of the portasome-studded plasma membranes. The colocalization of V-ATPase-immunolabeling sites and portasomes to specific plasma membranes within so-called 'mitochondria-rich' cells of gastric caeca and anterior midgut suggests that midgut alkalization in mosquitoes is achieved by molecular mechanisms similar to those that have been described in caterpillars, even though the gross structure of the midgut and the localization of the V-ATPase are dissimilar in the two species. In caterpillars, the high alkalinity is thought to break down dietary tannins, which block nutrient absorption; it may play a similar role in plant-detritus-feeding mosquito larvae. The colocalization of immunolabeling sites and portasomes, together with the presence of long, 'absorptive-type' microvilli in the posterior midgut, suggest that the V-ATPase energizes nutrient uptake there.


Mechanism of inhibition of immunoglobulin G-mediated phagocytosis by monoclonal antibodies that recognize the Mac-1 antigen.
We have investigated the effects of the monoclonal antibodies against the cell surface molecule Mac-1 on C3bi-mediated rosetting and IgG-mediated rosetting and phagocytosis by human peripheral blood monocytes. Highly purified M1/70 F(ab')2, used in the fluid phase, inhibited both monocyte functions. Half-maximal C3bi rosette inhibition occurred at a concentration of 2 nM F(ab')2 M1/70. An equivalent decrease in IgG-mediated rosetting required 10 nM M1/70 F(ab')2, and 50% inhibition of IgG-mediated phagocytosis required 7 nM antibody. Mo-1 F(ab')2 inhibited EC3bi binding with an ID50 of 0.3 nM, whereas 50% decrease in IgG-mediated rosetting required 70 nM of this antibody. OKM1 did not inhibit rosettes of sheep erythrocytes opsonized with IgG antibody (EA) at all. F(ab')2 M1/70 did not affect the binding of monomeric human IgG to monocytes, but did substantially decrease the binding of IgG aggregates. Half-maximal inhibition of aggregated IgG binding at 0 degrees C occurred at 8 nM F(ab')2 M1/70, very close to the concentration that caused equivalent inhibition of IgG-mediated phagocytosis. Aggregated IgG inhibited the binding of radiolabeled M1/70 to monocytes by approximately 40%, suggesting that some, but not all Mac-1 molecules were associated with IgG receptors under these conditions. When cells were allowed to adhere to surfaces coated with M1/70 or Mo-1 F(ab')2, C3bi-mediated rosetting was inhibited, but IgG mediated-phagocytosis was unaffected. Moreover, the dose response of inhibition of phagocytosis by fluid-phase F(ab')2, of anti-Mac-1 monoclonals was similar on monocytes adherent to albumin-coated and antibody-coated surfaces. Kinetic experiments showed that even prolonged incubation of monocytes on M1/70 coated surfaces did not lead to inhibition of EA binding nor did these incubations alter the dose response for inhibition of EA binding by fluid-phase M1/70 F(ab')2. This suggested that not all molecules recognized by M1/70 are freely mobile in the plasma membrane. Indeed, only approximately 60% of 125I-M1/70-biding sites were lost even after 4 h when monocytes were adherent to M1/70-coated surfaces. We conclude that some anti-Mac-1 antibodies can inhibit EA binding because of their epitope specificity, independent of any direct interaction with monocyte Fc receptors. This interference with IgG-Fc receptor-mediated binding and ingestion apparently occurs because of antibody binding to a subpopulation of Mac-1 molecules which are associated with IgG Fc receptors and remain on the apical membrane of monocytes adherent to anti-Mac-1-coated surfaces. We suggest that there may be two functionally distinct molecules on human monocytes recognized by M1/70 and Mo-1 that can be distinguished by their mobility in the plane of the monocyte membrane. The more mobile form of Mac-1 is involved in C3bi rosettes, and does not affect IgG-mediated phagocytosis. The other antigen recognized by M1/70 does not diffuse within the plane of the membrane; ligation of the latter molecule by antibody is associated with inhibition of IgG-mediated phagocytosis.


Relationship of skin autofluorescence to cardiovascular disease in Japanese hemodialysis patients.
Advanced glycation end products (AGE) are significantly increased in end-stage renal disease patients and it has been suggested that AGE accumulation is related to the progression of cardiovascular disease. An autofluorescence reader non-invasively assesses AGE accumulation using skin autofluorescence under ultraviolet light. Skin autofluorescence has been reported to be an independent predictor of mortality in Caucasian hemodialysis patients. The aim of this study was to assess whether skin autofluorescence in Japanese hemodialysis patients is related to the presence of cardiovascular disease. In this cross-sectional study, patients on maintenance hemodialysis (N = 128; 59 men, 69 women) were included. AGE accumulation was assessed by skin autofluorescence using an autofluorescence reader. Associations between skin autofluorescence, cardiovascular disease, and other parameters were studied. Skin autofluorescence correlated with age (r = 0.32, P < 0.01), diabetes (r = 0.21, P = 0.02), carotid intima-media thickness (IMT) (r = 0.23, P = 0.02), high-sensitivity C-reactive protein (hsCRP) (r = 0.20, P = 0.03), and plasma pentosidine (r = 0.20, P = 0.03). Each parameter was compared in patients with and without cardiovascular disease; the gender distribution, age, carotid IMT, high-density lipoprotein cholesterol, hsCRP, and skin autofluorescence were significantly related to the presence of cardiovascular disease. Multiple logistic regression analysis identified carotid IMT (OR 6.76), hsCRP (OR 1.41), and skin autofluorescence (OR 2.29) as significant factors for the presence of cardiovascular disease. Increased skin autofluorescence was related to the presence of cardiovascular disease in Asian (non-Caucasian) hemodialysis patients, and therefore an autofluorescence reader might have the potential to be a useful assessment of cardiovascular risk in these patients.


Analyzing Unstructured Communication in a Computer-Mediated Environment for Adults With Type 2 Diabetes: A Research Protocol.
Individuals with type 2 diabetes have an increased risk for comorbidities such as heart disease, lower limb amputations, stroke, and renal failure. Multiple factors influence development of complications in a person living with type 2 diabetes; however, an individual's self-management behaviors may delay the onset of, or lessen the severity of, these complications. Social support provides personal, informal advice and knowledge that helps individuals initiate and sustain self-management and adherence. Our aim was to gain an understanding of type 2 diabetes social interaction in a virtual environment, one type of computer-mediated environment (CME), and the social support characteristics that increase and sustain self-management in adults living with chronic illness. This study is a secondary analysis of longitudinal data collected in a CME study, Second Life Impacts Diabetes Education & Self-Management (1R21-LM010727-01). This virtual environment replicated a real-life community where 6 months of naturalistic synchronous voice conversations, emails, and text chats were recorded among participants and providers. This analysis uses a mixed-methods approach to explore and compare qualitative and quantitative findings. This analysis is guided by two theories: Strong/Weak Ties Theory and Social Penetration Theory. Qualitative data will be analyzed using content analysis, and we will complete descriptive statistics on the quantified variables (eg, average number of ties). Institutional review board approval was obtained in June 2016. This study is in progress. Interventions provided through virtual environments are a promising solution to increasing self-management practices. However, little is known of the depth, breadth, and quality of social support that is exchanged and how interaction supports self-management and relates to health outcomes. This study will provide knowledge that will help guide clinical practice and policy to enhance social support for chronic illness via the Internet.


Impact of Prosthesis Length on Tympanic Membrane's and Annular Ligament's Stiffness and the Resulting Middle Ear Sound Transmission.
Prosthesis' length creates tension in ossicular reconstructions, which directly effects the middle ear sound transmission. Relatively long prostheses are often used to stabilize the middle ear reconstruction to prevent dislocation. Thereby, tension on the flexible components such as the tympanic membrane (TM) and the annular ligament (AL) is increased. Only little is known on the amount of displacement-related stiffening of the TM and AL, as well as the consecutive reduction in middle ear transfer function (METF). An expandable total ossicular replacement prosthesis was tensionfree inserted in nine cadaveric temporal bones between the malleus handle and the stapes footplate. Upon heat activation the prosthesis was lengthened, thus inducing tension on the reconstruction. The METF was assessed before and after elongation. TM's and AL's stiffness were determined by measuring their force-displacement characteristics. Upon activation the prostheses were elongated between 50 and 200 μm. A frequency-dependent METF reduction was measured with a decrease of 5 to 25 dB below 1.0 kHz. At frequencies >2.0 kHz the reduction was less prominent or the METF showed even an improvement of up to 10 dB. TM's stiffness remained constant during the elongation-induced displacement, whereas the AL's stiffness increased. The METF reduction below 1.0 kHz correlated with the increasing AL's stiffness. Tension has a significant impact on the METF after middle ear reconstruction. As little tension as possible should be used to enable best sound transmission. Stabilization of prosthesis should be achieved with dislocation devices to ensure secure coupling to the ossicular remnants without creating additional tension.


[Changes attributed to a program based on the action-training of health agents. What do the associations say?]
Interventions aimed at improving health must take into account the health inequalities and the target the population in need. The mihsalud program (Women, Children and Men creating health) promotes health in vulnerable populations through engaging and collaborating with the local third sector. The objective of the study was to describe the changes attributed to the mihsalud programme and the process of action-training of community-based health volunteers (ASBC in Spanish) as perceived by the local organizations where they work or volunteer. Qualitative descriptive study through semi-structured interviews with representatives of organizations that trained ASBC during 2012 in Valencia. Twelve semi-structured interviews were conducted with representatives of organizations which had trained some of their volunteers to become ASBC during the 2012 action-training session. The interviews were transcribed verbatim and analysed with the programme for qualitative analysis Nvivo. Themathic analysis was performed: transcripts were coded line by line from an inductive perspective. Three main categories were identified: 1) The role of the ASBC: The associations recognise the role of the ASBC among their peers and the importance of the training received in the program; 2) Perceived changes: The associations recognize having a broader vision of health, identify the role of the figure ASBC that coordinates with health professionals in their health area and networking with other associations that were previously unknown; 3) Challenges and opportunities: Lack of support for the continuity of projects with ASBC due to the precariousness of small organisations and coordination with services, recognition at the local level and promotion of participation and interculturality through ASBC and their peers. The organizations recognize that the program and ASBC have made collaboration with health sector possible, have promoted health among their peers and have encouraged networking with other organizations and areas.


T cell costimulatory pathways: promising novel targets for immunosuppression and tolerance induction.
It is now accepted that T cells need two signals for full activation. The first is the foreign antigen itself presented by self-major histocompatibility complex and thus provides antigen specificity to the immune response. The second is a "costimulatory" signal, the best-characterized of which is provided through the T cell accessory molecule CD28. In vitro, the blockade of costimulatory signals inhibits T cell activation and induces a state of antigen-specific unresponsiveness. In vivo, agents that block CD28-mediated costimulation have proved extremely effective in inhibiting the immune response in experimental models of transplantation and autoimmune disease, providing novel strategies for use in clinical trials in the near future.


Botulinum toxin with and without casting in ambulant children with spastic diplegia: a clinical and functional assessment.
This study compared clinical and functional outcomes after treatment with botulinum toxin A (BTX-A) and BTX-A with casting in children with dynamic equinus foot. Ten children (seven males, three females; mean age 6 years 4 months, SD 2 years 7 months; range 4 to 11 years) with mild spastic diplegia and independent walking were divided into two groups: group 1, BTX-A and group 2, BTX-A plus casting. BTX-A was injected in the triceps surae bilaterally at multiple sites while the children were sedated with mask anaesthesia. Dysport toxin was used, 15 to 20 IU/kg in each muscle. Immediately after injection an ankle-foot orthosis was applied to children in group 1 and a cast to children in group 2. Clinical assessment using the Ashworth scale, Gross Motor Function Measure (GMFM), range of movement measurement, and gait analysis was performed before treatment and 1, 4, and 12 months after treatment. Spasticity decreased significantly at 1-month examination in both groups (p = 0.002), at 4-month examinations (Wilcoxon test p = 0.003), and 12 month (p = 0.052) examinations in group 2. GMFM highlighted a significant improvement in group 2 at the 4-month examination (p = 0.052 for standing,p = 0.007 for walking). Gait analysis showed a significant increase in the walking speed in group 2 (p = 0.04). No change was detected in ankle kinematics and kinetics or in muscular activity during the gait cycle. We confirmed that BTX-A reduces spasticity and improves functional performance in standing and walking; association with casting provides more marked and enduring results.


Full Factorial Design for Development and Validation of a Stability-Indicating RP-HPLC Method for the Estimation of Timolol Maleate in Surfactant-Based Elastic Nano-Vesicular Systems.
A novel isocratic stability-indicating chromatographic method was developed, optimized and validated using Design-Expert® following ICH guidelines for the quantification of Timolol maleate (TM). The intrinsic stability of TM was assessed by force degradation studies, which concluded no extensive degradation except under alkaline and oxidative conditions. TM was quantified accurately in the surfactant-based elastic vesicular system by separating it on Hypersil BDS C8 column using triethylamine in H2O (0.15%v/v; pH 3.0) and acetonitrile (ACN; 65:35%v/v). The influence of variable factors like mobile phase pH, injection volume (μL), flow rate (mL/min) and ACN content (%) on method responses were assessed using a full factorial design. The method was linear between 0.05 and 10 μg/mL with an R2 value of 0.9993. Limit of detection and limit of quantification were found to be 0.90 and 27.2 ng/mL. The method was specific, with recovery in plain drug solution of 89-92% and elastic nanovesicles of 90-93%. The experimental model was significant (P < 0.0001) as indicated by deliberate changes in the method analyzed through analysis of variance. The total drug content in elastic nanovesicles was estimated to be 9.53 ± 0.01 mg/20-mL dispersion and entrapment efficiency was 44.52 ± 0.73%. The developed method was rapid, economic and precise for the quantification of TM in bulk and vesicular system.


Are we getting any better at staying better? The long view on relapse and recovery in first episode nonaffective psychosis and schizophrenia.
Relapse in, and recovery from, schizophrenia has been acknowledged since the disease was first described. In this review the authors summarize the long-term (>100 years) data on relapse and recovery in schizophrenia by reviewing the extant older and modern relevant literature. The authors systematically question the utility of pharmacological and nonpharmacological interventions, with an emphasis on first episode nonaffective psychosis. The method used is a narrative review of earlier meta-analytic and systematic reviews. Antipsychotic medication discontinuation studies suggest a role for prophylactic maintenance treatment in the majority of people with schizophrenia, despite recent debate on this subject. The authors conclude that long-term outcomes, including relapse and recovery rates, have improved in the last 100 years, though prospectively identifying those people who do not require long-term antipsychotic treatment has not yet been possible. Data also suggests that interventions and outcomes during the first 5 years of the disease can influence the long-term schizophrenia trajectory.


Development of a microsimulation of melanoma mortality for evaluating the effectiveness of population-based skin cancer screening.
A nationwide skin cancer screening (SCS) was implemented in Germany in 2008. It aims at improving early detection of melanoma in order to reduce melanoma mortality. While the idea of early detection is compelling, demonstrating the effectiveness of melanoma screening is crucial. Since it is not feasible to conduct epidemiological studies to investigate the impact of factors such as screening interval or targeted age groups, we developed a microsimulation model that is able to predict melanoma mortality in Germany under several SCS conditions. Using German cancer registry data, population data, and other published data on melanoma progression and screening participation, we developed a stochastic microsimulation model. With this model, 10,000 populations of 100,000 persons and their melanoma-related life histories were simulated separately for women and for men and calibrated to observed melanoma incidence. In a second step, life histories of melanoma were changed by an SCS. Compared with a nonscreening scenario (age-standardized mortality rate: 1.6 and 2.9 per 100,000 for women and men), a biennial SCS of the 35- to 85-year-old population with a participation probability of 20% for each screening-eligible individual and a test sensitivity of 80% reduced mortality by up to 0.7 and 1.4 deaths per 100,000 person-years for women and men, respectively, corresponding to a relative reduction of melanoma mortality by 45% in women and men. We developed a microsimulation model of melanoma mortality that can be used to evaluate the effectiveness of population-based skin cancer screening. The simulation provided plausible melanoma mortality predictions and is a tool for comparing different SCS scenarios. However, it does not provide estimates on total costs of SCS.