Enterogyrus spp. (Monogenea: Ancyrocephalinae) and Aeromonas jandaei co-infection associated with high mortality following transport stress in cultured Nile tilapia.
Monogenean infection of the internal organs is extremely rare when compared to external infections. This study describes mass mortality of Nile tilapia (Oreochromis niloticus L.) originating from co-infection with Enterogyrus spp. and Aeromonas jandaei following transport stress. The first fish deaths occurred on day 1 post-transport, while cumulative mortality reached approximately 90% by day 10 post-stocking. An atypical amount of pale (whitish) faeces floating on the surface of the water as well as typical clinical signs of motile Aeromonas septicemia, were reported. Adult monogeneans and countless eggs of monogeneans were found in the stomachs and the intestines of both moribund and dead fish, respectively. Two strains of A. jandaei were isolated from the kidneys. Scanning electron microscope microphotographs of the stomach revealed the presence of numerous monogeneans penetrating deep into the gastric tissue, and diffuse lesions filled with bacilliform bacteria. Histopathological examination showed multifocal eosinophilic infiltrate, gastric gland and epithelial necrosis with sloughed necrotic debris in the lumen. This is the first report of co-infection by Enterogyrus spp. and A. jandaei in Nile tilapia and the first report of Enterogyrus coronatus, Enterogyrus foratus, and Enterogyrus malbergi parasitizing tilapia in Brazil. These findings indicate that synergic co-infection by Monogenean stomach parasites (E. coronatus, E. foratus, and E. malbergi) and A. jandaei may induce high mortalities in tilapia following transport stress.


Lessons from in vitro studies and a related intracellular angiotensin II transgenic mouse model.
In the classical renin-angiotensin system, circulating ANG II mediates growth stimulatory and hemodynamic effects through the plasma membrane ANG II type I receptor, AT1. ANG II also exists in the intracellular space in some native cells, and tissues and can be upregulated in diseases, including hypertension and diabetes. Moreover, intracellular AT1 receptors can be found associated with endosomes, nuclei, and mitochondria. Intracellular ANG II can function in a canonical fashion through the native receptor and also in a noncanonical fashion through interaction with alternative proteins. Likewise, the receptor and proteolytic fragments of the receptor can function independently of ANG II. Participation of the receptor and ligand in alternative intracellular pathways may serve to amplify events that are initiated at the plasma membrane. We review historical and current literature relevant to ANG II, compared with other intracrines, in tissue culture and transgenic models. In particular, we describe a new transgenic mouse model, which demonstrates that intracellular ANG II is linked to high blood pressure. Appreciation of the diverse, pleiotropic intracellular effects of components of the renin-angiotensin system should lead to alternative disease treatment targets and new therapies.


Incitement, genocide, genocidal terror, and the upstream role of indoctrination: can epidemiologic models predict and prevent?
We apply the models and tools of epidemiology and public health to propose a unified field theory showing the role of ideologies, indoctrination, and incitement, in genocide, genocidal terror, and terror by groups or individuals. We examine the effects of indoctrination and incitement as exposures and risks in relation to genocide and genocidal terror. Incitement has been recognized as a trigger to these outcomes but indoctrination is upstream to incitement. Population-wide exposure to indoctrination increases susceptibility to the effects of incitement. These relationships have been seen in all major genocides and genocidal terror in the late twentieth and twenty-first centuries. There is some insight into the relationship between ideology, incitement, and genocidal acts of violence from the so-called localized genocides in Bosnia, Rwanda, Darfur, Syria, and most recently, among the Rohingya in Myanmar. There is a need to recognize the upstream role of ideologies of hate in order to determine the degree to which indoctrination posed, and continues to pose, a contributing factor. Epidemiologic models, such as the iceberg model of exposure and disease and the concept of "sick individuals" and "sick populations," guide our understanding of the content and spread of indoctrination and incitement and can provide essential insights for prevention. The hateful indoctrination and ideologies behind genocidal violence must be countered and replaced by positive ideologies and role models that emphasize respect for life and human dignity for all.


Endobronchial embolization for life-threatening hemoptysis with Endobronchial Watanabe Spigot.
Massive hemoptysis is a common encounter in respiratory medicine. Bronchoscopy plays an important role in localizing the origin of bleeding, as well as endoscopic treatment of centrally located lesions. Endobronchial embolization is a novel technique enabling the management of hemoptysis arising even from peripheral lesions, via occlusion of the culprit bronchus, thereby securing the airway. Endobronchial Watanabe Spigot had been advocate in the treatment of bronchopleural fistula and the use of this novel technique had since then been expanded into the management of massive hemoptysis. To the best of our knowledge, this is the first reported case in Malaysia. 78-year-old lady who presented with life-threatening hemoptysis leading rapidly to cardiac arrest upon arrival. Spontaneous circulation was restored after resuscitation with an urgent thoracic computed tomography angiogram revealed bleeding likely from the posterior basal segment of left lower lobe, with bronchiectatic changes. Urgent flexible bronchoscopy revealed airway flooding, with bleeding originating from the lingular and posterior-basal segment of the left lower lobe. Airway toileting was performed and two 7 mm Endobronchial Watanabe Spigots were plugged into the culprit bronchi. Urgent bronchial artery embolization was then attempted, but was unsuccessful. She was managed conservatively, as surgical resection was deemed high risk. The spigots were removed 4 days later uneventfully. There was no recurrence of hemoptysis, and patient remained well during 1-month follow up. The utmost priority in managing life-threatening hemoptysis is to prevent airway flooding. Endobronchial embolization with Endobronchial Watanabe Spigot is useful as a temporary measure before definitive therapy, or can itself be the main therapeutic player in the hemoptysis armament for high-risk patients.


[Localization of the primary action of amino acids leading to the stimulation of gastric secretion].
An attempt has been made to specify whether the stimulant action of amino acids on gastric secretion is related to their direct effect on the structures of the central nervous system or to the influence on certain peripheral receptor formations followed by information transmission to the nervous centres. Acute experiments on dogs were performed to compare the effect of amino acids injected to the carotid artery and to the peripheral vein. It was established that amino acids injected to the carotid artery produced a more rapidly developing and more pronounced secretory reaction of the gastric glands than amino acids injected to the peripheral vein. This fact may strongly indicate that the above effect of amino acids is linked with their direct action on brain structures.


Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community.
Wounds that exhibit delayed healing add extraordinary clinical, economic, and personal burdens to patients, as well as to increasing financial costs to health systems. New interventions designed to ease such burdens for patients with cancer, renal, or ophthalmologic conditions are often cleared for approval by the U.S. Food and Drug Administration (FDA) using multiple endpoints but the requirement of complete healing as a primary endpoint for wound products impedes FDA clearance of interventions that can provide other clinical or patient-centered benefits for persons with wounds. A multidisciplinary group of wound experts undertook an initiative, in collaboration with the FDA, to identify and content validate supporting FDA criteria for qualifying wound endpoints relevant to clinical practice (CP) and patient-centered outcomes (PCO) as primary outcomes in clinical trials. As part of the initiative, a research study was conducted involving 628 multidisciplinary expert wound clinicians and researchers from 4 different groups: the interdisciplinary core advisory team; attendees of the Spring 2015 Symposium on Advanced Wound Care (SAWC); clinicians employed by a national network of specialty clinics focused on comprehensive wound care; and Association for the Advancement of Wound Care (AAWC) and Wound Healing Society (WHS) members who had not previously completed the survey. The online survey assessed 28 literature-based wound care endpoints for their relevance and importance to clinical practice and clinical research. Fifteen of the endpoints were evaluated for their relevance to improving quality of life. Twenty-two endpoints had content validity indexes (CVI) ≥ 0.75, and 15 were selected as meriting potential inclusion as additional endpoints for FDA approval of future wound care interventions. This study represents an important first step in identifying and validating new measurable wound care endpoints for clinical research and practice and for regulatory evaluation.


The Saccharomyces cerevisiae quinone oxidoreductase Lot6p: stability, inhibition and cooperativity.
Lot6p (EC 188.8.131.52; Ylr011wp) is the sole quinone oxidoreductase in the budding yeast, Saccharomyces cerevisiae. Using hexahistidine tagged, recombinant Lot6p, we determined the steady-state enzyme kinetic parameters with both NADH and NADPH as electron donors; no cooperativity was observed with these substrates. The NQO1 inhibitor curcumin, the NQO2 inhibitor resveratrol, the bacterial nitroreductase inhibitor nicotinamide and the phosphate mimic vanadate all stabilise the enzyme towards thermal denaturation as judged by differential scanning fluorimetry. All except vanadate have no observable effect on the chemical cross-linking of the two subunits of the Lot6p dimer. These compounds all inhibit Lot6p's oxidoreductase activity, and all except nicotinamide exhibit negative cooperativity. Molecular modelling suggests that curcumin, resveratrol and nicotinamide all bind over the isoalloxazine ring of the FMN cofactor in Lot6p. Resveratrol was predicted to contact an α-helix that links the two active sites. Mutation of Gly-142 (which forms part of this helix) to serine does not greatly affect the thermal stability of the enzyme. However, this variant shows less cooperativity towards resveratrol than the wild type. This suggests a plausible hypothesis for the transmission of information between the subunits and, thus, the molecular mechanism of negative cooperativity in Lot6p.


E-cigarette attitudes and behaviours amongst 15-30-year-olds in the UK.
The use of e-cigarettes has been rising in the UK, particularly by young people. This study investigated behaviours, attitudes and beliefs about e-cigarettes amongst 15-30-year-olds in the UK. An online survey was administered to a sample of 1009 15-30-year-olds in the UK. About one in five participants currently used e-cigarettes at least monthly, with 1 in 10 using them daily. Amongst those using e-cigarettes at least monthly, 90% had used e-cigarettes containing nicotine. E-cigarettes were mainly obtained from vape shops and used at home. Having friends who used e-cigarettes and using them to help quit/reduce smoking were the most common reasons for vaping. About half of participants had been exposed to e-cigarette advertising, especially online, and warning labels on e-cigarettes. Most participants agreed that e-cigarettes are addictive (75%), help people quitting smoking (64%) and are bad for health (63%). Previous or current tobacco smokers were 9 and 22 times more likely to use e-cigarettes than never smokers, respectively. Perceiving e-cigarettes as harmful was associated with a 40% lower likelihood of use. Raising awareness on the uncertain long-term consequences of vaping and regulation of marketing and sales are crucial to protect young people in the UK.


The GLN1 locus of Saccharomyces cerevisiae encodes glutamine synthetase.
Among 41 yeast glutamine auxotrophs, complementation analysis defined a single gene, GLN1, on chromosome 16 between MAK3 and MAK6. Half of the alleles fell into two intragenic complementation classes. No clustering of complementing alleles was found in a fine structure map. Altered glutamine synthetase subunits, including nonsense fragments and charge variants, were identified in several of the mutants, indicating that GLN1 is the structural gene for this enzyme. Negative complementation was observed for almost every allele associated with a protein product and all gln1/+ heterozygotes displayed reduced susceptibility to ammonia repression of the remaining glutamine synthetase activity. This latter observation is explained by the hypothesis that ammonia represses the enzyme only through its metabolism to glutamine. A basis for the two gln1 complementation classes is proposed.


The influence of spirituality and religiousness on suicide risk and mental health of patients undergoing hemodialysis.
Despite the large amount of literature assessing how spiritual and religious beliefs have an impact on mental health and suicide risk in various groups of patients, few studies have investigated patients with chronic kidney disease (CKD). The purpose of this study is to investigate whether spirituality and religiousness (S/R) are associated with the presence of suicide risk as well as whether those beliefs are also associated with the presence of mental health problems in patients undergoing hemodialysis. Cross-sectional study carried out in three Brazilian dialysis units involving hemodialysis patients. The study assessed religiousness (Duke Religion Index); spiritual well-being (FACIT-Sp 12); mental health - depression and anxiety (Mini International Neuropsychiatric Interview-MINI); and risk of suicide (MINI). For analysis, adjusted logistic regression models were applied. A total of 264 (80.7%) patients were included, 17.8% presented suicide risk, 14.0% presented current major depressive episode, and 14.7% presented generalized anxiety disorder. Concerning spiritual well-being (FACIT-Sp 12), the subscale of "Meaning" was associated with lower risk of suicide, depression, and anxiety. The subscale "Peace" was associated with lower depression and anxiety, whereas the subscale "Faith" was associated with lower suicide risk and depression. Religiousness measures were not associated with the study outcomes. Spiritual beliefs were associated with lower suicide risk and better mental health among hemodialysis patients. Factors related to spiritual well-being, such as "meaning", "peace" and "faith" were more associated with the outcomes studied than religious involvement. Further studies are needed to replicate our findings in different cultural and religious settings.


Clinical correlations between ethanol intake and fetal alcohol syndrome.
Fetal alcohol syndrome (FAS) is a cluster of features observed in some offspring of women who abuse alcohol in pregnancy. The defining features include intrauterine growth retardation, specific craniofacial dysmorphology, and central nervous system dysfunction. FAS is a full expression of a continuum of fetal alcohol effects. The assessment of alcohol abuse is one of several major problems in the study of the topic. Research findings are reviewed under a hypothesis of increasing effect in ordered categories: lethal effects, adverse obstetrical outcomes, malformations, growth retardation, reduced head circumference, and neuropsychological effects. Evidence of fetal alcohol effects may be found for each outcome category. The evidence across studies is not consistent nor is there any clear support for an effect order. The risk for psychological deficit may depend on the presence of dysmorphic effects.


Role of SOX family of transcription factors in central nervous system tumors.
SOX genes are developmental regulators with functions in the instruction of cell fate and maintenance of progenitor's identity during embryogenesis. They play additional roles during tissue homeostasis and regeneration in adults particularly in the Central Nervous System (CNS). In the last years a growing number of evidences has shown that mutations and dysfunction of SOX factors are implicated in several human diseases, including a variety of cancers. In this review, we will summarize the current knowledge about SOX family in CNS tumors and their role in the origin and maintenance of the subpopulation of cancer stem cells in these tumors.


Cavity-enhanced sum-frequency generation of blue light with near-unity conversion efficiency.
We report on double-resonant highly efficient sum-frequency generation in the blue range. The system consists of a 10-mm-long periodically poled KTP crystal placed in a double-resonant bow-tie cavity and pumped by a fiber laser at 1064.5 nm and a Ti:sapphire laser at 849.2 nm. An optical power of 375 mW at 472.4 nm in a TEM00 mode was generated with pump powers of 250 mW at 849.2 nm and 200 mW at 1064.5 nm coupled into the double-resonant ring resonator with 88% mode-matching. The resulting internal conversion efficiency of 95(±3)% of the photons mode-matched to the cavity constitutes, to the best of our knowledge, the highest overall achieved quantum conversion efficiency using continuous-wave pumping. Very high conversion efficiency is rendered possible due to very low intracavity loss on the level of 0.3% and high nonlinear conversion coefficient up to 0.045(0.015) W-1. Power stability measurements performed over one hour show a stability of 0.8%. The generated blue light can be tuned within 5 nm around the center wavelength of 472.4 nm, limited by the phase-matching of our nonlinear crystal. This can however be expanded to cover the entire blue spectrum (420 nm to 510 nm) by proper choice of nonlinear crystals and pump lasers. Our experimental results agree very well with analytical and numerical simulations taking into account cavity impedance matching and depletion of the pump fields.


Polyhydramnios: Causes, Diagnosis and Therapy.
Polyhydramnios is defined as a pathological increase of amniotic fluid volume in pregnancy and is associated with increased perinatal morbidity and mortality. Common causes of polyhydramnios include gestational diabetes, fetal anomalies with disturbed fetal swallowing of amniotic fluid, fetal infections and other, rarer causes. The diagnosis is obtained by ultrasound. The prognosis of polyhydramnios depends on its cause and severity. Typical symptoms of polyhydramnios include maternal dyspnea, preterm labor, premature rupture of membranes (PPROM), abnormal fetal presentation, cord prolapse and postpartum hemorrhage. Due to its common etiology with gestational diabetes, polyhydramnios is often associated with fetal macrosomia. To prevent the above complications, there are two methods of prenatal treatment: amnioreduction and pharmacological treatment with non-steroidal anti-inflammatory drugs (NSAIDs). However, prenatal administration of NSAIDs to reduce amniotic fluid volumes has not been approved in Germany. In addition to conventional management, experimental therapies which would alter fetal diuresis are being considered.


Assessing Reality Testing in Mice Through Dopamine-Dependent Associatively Evoked Processing of Absent Gustatory Stimuli.
Impairments in reality testing are core features of numerous neuropsychiatric conditions. However, relatively few animal models have been developed to assess this critical facet of neuropsychiatric illness, thus impeding our understanding of the underlying central systems and circuits. Using mice in which dominant-negative Disrupted-in-Schizophrenia-1 is expressed throughout central nervous system circuitry (DN-DISC1-PrP), the capacity for an auditory conditioned stimulus (CS) to evoke perceptual processing of an absent sucrose solution was examined. At test, during CS presentations, DN-DISC1-PrP mice consumed more water and displayed a licking profile that is more typically revealed while ingesting a sweet-tasting solution. DN-DISC1-PrP mice also displayed greater c-fos expression in the insular (gustatory) cortex when consuming water in the presence of the CS. This capacity for the CS to more readily substitute for the taste features of the absent sucrose solution in DN-DISC1-PrP mice was attenuated following systemic treatment with the antipsychotic haloperidol. Conversely, social isolation during adolescence promoted the manifestation of these effects. These results provide strong validation for using associative learning procedures to examine dopamine-mediated reality testing associated with insular cortex activation.


Developing Reflective Thinking through Poetry Writing: Views from Students and Educators.
Aims and Objectives To explore student nurse and educator perspectives on the use of poetry writing as a way to reflect on important nursing practice issues. Background Reflective practice is a well-established method of learning in pre-registration nurse education although student nurses can find reflection a challenging process. Design An exploratory descriptive approach. Methods Data were extracted from unstructured interviews with students and educators (n = 12) from one university in the North-West region of England, United Kingdom (UK). Data were thematically analysed. Results Poetry writing supports a meaningful exploration of events, which have the potential to lead to changes in perspective. Careful planning of the poetry writing process is required, to ensure the potential of this approach is realised. Conclusion Poetry writing is an effective way to reflect on clinical practice. This work has relevance and transferability to a wide range of professional disciplines, where reflective practice is encouraged.


Helping people in a minimally conscious state develop responding and stimulation control through a microswitch-aided program.
Postcoma persons in a minimally conscious state (MCS) and with extensive motor impairment cannot independently access and control environmental stimulation. Assessing the effects of a microswitch-aided program aimed at helping MCS persons develop responding and stimulation control and conducting a social validation/evaluation of the program. A single-subject ABAB design was used for each participant to determine the impact of the program on his or her responding. Staff interviews were used for the social validation/evaluation of the program. Rehabilitation and care facilities that the participants attended. Eleven MCS persons with extensive motor impairment and lack of speech or any other functional communication. For each participant, baseline (A) phases were alternated with intervention (B) phases during which the program was used. The program relied on microswitches to monitor participants' specific responses (e.g., prolonged eyelid closures) and on a computer system to enable those responses to control stimulation. In practice, the participants could use a simple response such as prolonged eyelid closure to generate a new stimulation input. Sixty-six staff people took part in the social validation of the program. They were to compare the program to basic and elaborate forms of externally controlled stimulation, scoring each of them on a six-item questionnaire. All participants showed increased response frequencies (and thus higher levels of independent stimulation input/control) during the B phases of the study. Their frequencies for each intervention phase more than doubled their frequencies for the preceding baseline phase with the difference between the two being clearly significant (P<0.01). Staff involved in the social validation procedure provided significantly higher scoring (P<0.01) for the program on five of the six questionnaire items. A microswitch-aided program can be an effective and socially acceptable tool in the work with MCS persons. The participants and staff's data can be taken as an encouragement for the use of a microswitch-aided program within care and rehabilitation settings for MCS persons.


Microinfarct disruption of white matter structure: a longitudinal diffusion tensor analysis.
To evaluate the local effect of small asymptomatic infarctions detected by diffusion-weighted imaging (DWI) on white matter microstructure using longitudinal structural and diffusion tensor imaging (DTI). Nine acute to subacute DWI lesions were identified in 6 subjects with probable cerebral amyloid angiopathy who had undergone high-resolution MRI both before and after DWI lesion detection. Regions of interest (ROIs) corresponding to the site of the DWI lesion (lesion ROI) and corresponding site in the nonlesioned contralateral hemisphere (control ROI) were coregistered to the pre- and postlesional scans. DTI tractography was additionally performed to reconstruct the white matter tracts containing the ROIs. DTI parameters (fractional anisotropy [FA], mean diffusivity [MD]) were quantified within each ROI, the 6-mm lesion-containing tract segments, and the entire lesion-containing tract bundle. Lesion/control FA and MD ratios were compared across time points. The postlesional scans (performed a mean 7.1 ± 4.7 months after DWI lesion detection) demonstrated a decrease in median FA lesion/control ROI ratio (1.08 to 0.93, p = 0.038) and increase in median MD lesion/control ROI ratio (0.97 to 1.17, p = 0.015) relative to the prelesional scans. There were no visible changes on postlesional high-resolution T1-weighted and fluid-attenuated inversion recovery images in 4 of 9 lesion ROIs and small (2-5 mm) T1 hypointensities in the remaining 5. No postlesional changes in FA or MD ratios were detected in the 6-mm lesion-containing tract segments or full tract bundles. Asymptomatic DWI lesions produce chronic local microstructural injury. The cumulative effects of these widely distributed lesions may directly contribute to small-vessel-related vascular cognitive impairment.


Fractional protein synthesis rates are similar when measured by intraperitoneal or intravenous flooding doses of L-[ring-2H5]phenylalanine in combination with a rapid regimen of sampling in piglets.
Fractional protein synthesis rates (FSR) are widely measured by the flooding dose technique via either an i.g. or an i.v. route. This study was conducted to compare differences in tracer incorporation and FSR in organs and tissues of fed piglets. The piglets were surgically implanted with catheters and randomly assigned to receive a flooding dose of Phe (1.5 mmol/kg body weight, 40 percent molar enrichment with [(2)H(5)]Phe) in saline administered via an i.p. or an i.v. route. [(2)H(5)]Phe free-pool enrichment in plasma increased logarithmically (P < 0.05) from 0 to 25% in the i.p. group, whereas it rose to a peak level within 3 min of the tracer injection and then decreased linearly (P < 0.05) in the i.v. group. Intracellular free-pool tracer enrichments in organs and tissues were within the range of the values measured for the plasma-free pool (25-27%), reaching the flooding status. Administration of the tracer via the i.p. and i.v. routes induced a logarithmical pattern (P < 0.05) of a surge in plasma cortisol concentrations within 30 min. Measurements of FSR in plasma, cardiac muscle, and skeletal muscles were lower (P < 0.05) in the i.p. than in the i.v. group due to the adverse effect of cortisol surge being more dramatic (P < 0.05) in the i.p. than in the i.v. group at 30 min of the post-tracer administration. We conclude that FSR may be measured by the flooding dose through an i.p. or an i.v. route and the i.p. route may underestimate FSR by the flooding dose for plasma, cardiac muscle, and skeletal muscles. This concern may be addressed by a fast regimen of sampling to be completed within 12-20 min after an i.p. route of tracer injection.


Testosterone treatment promotes tubular damage in experimental diabetes in prepubertal rats.
Puberty unmasks or accelerates progressive kidney diseases, including diabetes mellitus (DM), perhaps through effects of sex steroids. To test the hypothesis that rising androgen levels at puberty permit diabetic kidney damage, we studied four groups of male rats with and without streptozocin-induced DM: adult onset (A), adult onset after castration (AC), juvenile onset (J), and juvenile onset with testosterone treatment (JT). Profibrotic markers were measured after 6 wk with blood glucose levels 300-450 mg/dl. JT permitted increased expression of mRNA for two isoforms of transforming growth factor-beta and connective tissue growth factor compared with J animals with DM; prior castration did not provide protection in adult-onset DM. JT also permitted greater tubular staining for alpha-smooth muscle actin and fibroblast-specific protein, two markers of cell damage and potential epithelial mesenchymal transition. Once again, castration was not protective for these effects of DM in the AC group. These data indicate that puberty permits detrimental effects in the tubulointerstitium in the diabetic kidney, an effect mimicked by testosterone treatment of juvenile animals and partially blunted by castration of adults, but damage does not correlate with testosterone levels, suggesting a less direct mechanism.


Novel Vasopressors in the Treatment of Vasodilatory Shock: A Systematic Review of Angiotensin II, Selepressin, and Terlipressin.
Vasodilatory shock is the most common type of shock. Catecholamine vasopressors are the cornerstone of hemodynamic therapy but carry risks. Angiotensin II (AT2) was recently approved, and other novel agents (selepressin and terlipressin) are under investigation and used outside the United States (terlipressin). We performed a systematic review to summarize the efficacy and safety of these novel vasopressors and to offer guidance on their appropriate use. Systematic review of controlled trials. Numerous databases were searched using terms related to angiotensin II, selepressin, terlipressin, vasopressor, and shock. Twenty-one citations, including 16 prospective comparative trials and 5 post hoc analyses reporting effects of AT2, selepressin, and terlipressin, were reviewed for data on outcomes related to hemodynamic measures, mortality, severity and duration of illness, concomitant vasopressor utilization, and adverse effects. Findings from eligible literature are described qualitatively using Cochrane methods. Fourteen controlled trials were assessed after exclusion of 2 dated trials of a distinct AT2 formulation. Trials are limited for AT2 (n = 2) and selepressin (n = 1), while terlipressin was investigated in 11 small trials. Overall, the trials have an unclear risk of bias. Most report mean arterial pressure (MAP) as primary end point, and all indicate novel vasopressors increase MAP compared to placebo and to a similar degree as with catecholamine vasopressors. Mortality findings are preliminary, as they have been limited to specific subgroups in trials of terlipressin and post hoc analyses of one trial of AT2. Trials reported safety concerns for each agent including thromboembolism with AT2 and ischemia with terlipressin/selepressin. In this systematic review, controlled trials of novel vasopressors in treatment of vasodilatory shock were limited and of low quality. Angiotensin II, selepressin, and terlipressin appear to significantly increase MAP, but further study is required, particularly for selepressin, to determine their safety, efficacy, and role in treatment of vasodilatory shock.


Usefulness of MALDI-TOF MS as a Diagnostic Tool for the Identification of Streptococcus Species Recovered from Clinical Specimens of Pigs.
The application of MALDI-TOF MS for identifying streptococcal isolates recovered from clinical specimens of diseased pigs was evaluated. For this proposal, the MALDI BDAL Database (Bruker Daltoniks, Germany) was supplemented with the main spectrum profiles (MSP) of the reference strains of S. porci, S. porcorum and S. plurextorum associated with pneumonia and septicemia. Although these three species showed similar MALDI profiles, several peaks were recognized that can be useful for their differentiation: S. porci (4113, 6133, 7975 and 8228 m/z Da), S. plurextorum (3979, 4078, 4665, 6164, 6491, 6812, 7959 and 9330 m/z Da) and S. porcorum (3385, 3954, 4190, 6772, 7908, and 8381 m/z Da). After adding these MSPs, an evaluation was conducted to determine the accuracy of MALDI-TOF MS for the identification of streptococci from diseased pigs using 74 field isolates. Isolates were identified as S. suis, S. porcinus, S. dysgalactiae, S. hyovaginalis, S. porcorum, S. alactolyticus, S. hyointestinalis and S. orisratti. This is the first time that the latter three species have been reported from clinical specimens of pigs. Overall, there was good concordance (95.9%) between the results obtained from MALDI-TOF MS identification (best hint) and those from genotyping. Our results demonstrate the good performance of MALDI-TOF MS (100% sensitivity and specificity) for identifying most of the species of streptococci that can frequently be isolated from diseased pigs. However, conflicting results were observed in the correct identification of some isolates of S. dysgalactiae and S. alactolyticus.


Comparing transmission potential networks based on social network surveys, close contacts and environmental overlap in rural Madagascar.
Social and spatial network analysis is an important approach for investigating infectious disease transmission, especially for pathogens transmitted directly between individuals or via environmental reservoirs. Given the diversity of ways to construct networks, however, it remains unclear how well networks constructed from different data types effectively capture transmission potential. We used empirical networks from a population in rural Madagascar to compare social network survey and spatial data-based networks of the same individuals. Close contact and environmental pathogen transmission pathways were modelled with the spatial data. We found that naming social partners during the surveys predicted higher close-contact rates and the proportion of environmental overlap on the spatial data-based networks. The spatial networks captured many strong and weak connections that were missed using social network surveys alone. Across networks, we found weak correlations among centrality measures (a proxy for superspreading potential). We conclude that social network surveys provide important scaffolding for understanding disease transmission pathways but miss contact-specific heterogeneities revealed by spatial data. Our analyses also highlight that the superspreading potential of individuals may vary across transmission modes. We provide detailed methods to construct networks for close-contact transmission pathogens when not all individuals simultaneously wear GPS trackers.


[Dosage of anesthetics--a tricky question].
The optimal dosage of anaesthetic agents may be difficult. Not only does the intensity of surgical stimuli vary during a surgical procedure, but drug sensitivity varies between subjects exposed to comparable stimuli. Moreover, clinically monitored body reactions do not always reflect the balance between central nervous system effects of the surgical stimuli and of the anaesthetic agent. Therefore, the specialist in anaesthesiology requires access to additional methods of monitoring to enable dosage to be optimised for each patient, minute by minute, thus improving the chances of maintaining an appropriate depth of anaesthesia. Two electro-encephalographic techniques are presented in the article, and aspects of under- and over-dosage of anaesthetic agents are discussed.


Bioethics: power and injustice: IAB presidential address.
A major focus within the modern bioethics debate has been on reshaping power relationships within the doctor-patient relationship. Empowerment of the vulnerable has been achieved through an emphasis on human rights and respect for individual dignity. However, power imbalances remain pervasive within healthcare. To a considerable extent this relates to insufficient attention to social injustice. Such power imbalances together with the development of new forms of power, for example through new genetic biotechnology, raise the spectre of increasing social injustice. Attention will be drawn to the need to extend the bioethics debate to include ethical considerations regarding public health. Changes in political philosophy will also be required to reshape international power relations and improve population health.


Intimal hyperplasia in autogenous veins used for arterial replacement.
This study compares the effects on intimal hyperplasia of different methods of manipulating a vein graft before using it as an arterial substitute. Grafts that were denuded of endothelium showed the most intimal hyperplasia, while those that were washed with saline, dilated with saline or crushed did not differ appreciably from each other with respect to the degree of intimal hyperplasia. The hyperplasia was well developed and stabilized at 3 weeks, which coincided with restoration of the endothelial surface. The similarity between the last three methods of graft manipulation suggests that minor endothelial disruption produced at the time of harvesting the vein is equalized after insertion of the vein into the arterial circulation.


[The meaning of PSA progression after radical prostatectomy. Preliminary results].
To report our findings regarding to the natural history of prostate cancer (PCa) that shows recurrence after radical prostatectomy (RP), in terms of time to development of metastatic disease and death from PCa. To identify independent predictors of PSA recurrence. Retrospective analysis of 227 patients with clinically localized PCa who underwent RP. The event PSA recurrence was defined as the presence of a postoperative PSA level of 0,2 ng/ml or higher at least 3 months after surgery. Hence, cases with shorter follow-up time were excluded from analysis. No adjuvant therapy (radiotherapy or hormonal therapy) was performed in the included population. Recurrence free survival was calculated during the follow-up period (Kaplan-Meier analysis). Uni and multivariate study was performed in order to assess the ability of factors as preoperative PSA level, Gleason score in surgical specimen, capsular penetration, positive surgical margins (excluding urethral), extracapsular extension, positive pelvic lymph nodes, and seminal vesicle invasion, to predict PSA recurrence. Finally, we selected the group of patients with PSA recurrence and calculated the probability of being free from distant metastatic disease during the follow-up period. Also, function of disease-specific survival was calculated. A total of 208 records were finally included in the study. Median age was 61 years. A total of 47 (22.6%) presented with extracapsular extension. Median follow-up time was 35.8 months, and 49 (23.6%) developed PSA recurrence. Recurrence free survival was 79.9% and 67.4% at 2 and 5 years, respectively. Only three factors were identified with the aid of multivariate analysis as independent predictors of recurrence: preoperative PSA >= 10 ng/ml (hazard ratio--HR--3.03), Gleason score in surgical specimen 8 or higher (HR 3.42), and the finding of capsular penetration (HR 2.17). When only patients with PSA recurrence were considered, 16.3% developed distant metastasis. Probabilities of being free from distant disease after PSA recurrence were 97.7% and 86.9% at 2 and 5 years respectively (actuarial median time 110.8 months). Only 2 patients died from PCa, therefore disease-specific mortality analysis was not performed. Although an important proportion of patients present with PSA recurrence after RP in our setting, the prognosis in term of development of metastatic disease is acceptable in the short-medium term. Anyway, further analysis will be needed to ascertain the evolution of these patients in the long term.


First reported cases of gyrate atrophy of the choroid from Nepal.
Two sisters previously diagnosed as having retinitis pigmentosa presented with complaints of frequent change of glasses. On ocular examination, the fundus showed the appearance of confluent arcuate equatorial full thickness lesions of the choroid and retina, sparing some of the large choroidal vessels, and separated from one another by thin margins of pigment, in both the sisters. Serum analysis was done for ornithine levels, which showed hyperornithinaemia (741 and 462 µmol/l in the elder and younger sister, respectively) consistent with gyrate atrophy (GA) of the choroid. Both the sisters were prescribed vitamin B(6) and a restricted protein diet to which they responded very well. This case highlights the importance of correct diagnosis and prompt management in diagnosed cases. These are the first reported cases of GA of choroid from Nepal.


Postoperative morbidity after simultaneous versus staged resection of synchronous colorectal liver metastases: Impact of hepatic tumor burden.
We sought to characterize the risk of postoperative complications relative to the surgical approach and overall synchronous colorectal liver metastases tumor burden score. Patients with synchronous colorectal liver metastases who underwent curative-intent resection between 2000 and 2020 were identified from an international multi-institutional database. Propensity score matching was employed to control for heterogeneity between the 2 groups. A virtual twins analysis was performed to identify potential subgroups of patients who might benefit more from staged versus simultaneous resection. Among 976 patients who underwent liver resection for synchronous colorectal liver metastases, 589 patients (60.3%) had a staged approach, whereas 387 (39.7%) patients underwent simultaneous resection of the primary tumor and synchronous colorectal liver metastases. After propensity score matching, 295 patients who underwent each surgical approach were analyzed. Overall, the incidence of postoperative complications was 34.1% (n = 201). Among patients with high tumor burden scores, the surgical approach was associated with a higher incidence of postoperative complications; in contrast, among patients with low or medium tumor burden scores, the likelihood of complications did not differ based on the surgical approach. Virtual twins analysis demonstrated that preoperative tumor burden score was important to identify which subgroup of patients benefited most from staged versus simultaneous resection. Simultaneous resection was associated with better outcomes among patients with a tumor burden score <9 and a node-negative right-sided primary tumor; in contrast, staged resection was associated with better outcomes among patients with node-positive left-sided primary tumors and higher tumor burden score. Among patients with high tumor burden scores, simultaneous resection of the primary tumor and liver metastases was associated with an increased incidence of postoperative complications.


Enhanced visible-light photocatalytic activity of g-C3N4/TiO2 films.
Enhanced photocatalytic degradation of methylene blue (MB) using graphitic carbon nitride/titanium dioxide (g-C3N4/TiO2) catalyst films has been demonstrated in this present work. The g-C3N4/TiO2 composites were prepared by directly heating the mixture of melamine and pre-synthesized TiO2 nanoparticles in Ar gas flow. The g-C3N4 contents in the g-C3N4/TiO2 composites were varied as 0, 20, 50 and 70 wt%. It was found that the visible-light-induced photocatalytic degradation of MB was remarkably increased upon coupling TiO2 with g-C3N4 and the best degradation performance of ~70% was obtained from 50 wt% g-C3N4 loading content. Results from UV-vis absorption study, Electron microscopy, Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy suggest that the improved photoactivity is due to a decrease in band gap energy, an increased light absorption in visible light region and possibly an enhanced electron-hole separation efficiency as a result of effective interfacial electron transfer between TiO2 and g-C3N4 of the g-C3N4/TiO2 composite film. Based on the obtained results, the possible MB degradation mechanism is ascribed mainly to the generation of active species induced by the photogenerated electrons.


OCA-B is a functional analog of VP16 but targets a separate surface of the Oct-1 POU domain.
OCA-B is a B-cell-specific coregulator of the broadly expressed POU domain transcription factor Oct-1. OCA-B associates with the Oct-1 POU domain, a bipartite DNA-binding structure containing a POU-specific (POU[S]) domain joined by a flexible linker to a POU homeodomain (POU[H]). Here, we show that OCA-B alters the activity of Oct-1 in two ways. It provides a transcriptional activation domain which, unlike Oct-1, activates an mRNA-type promoter effectively, and it stabilizes Oct-1 on the Oct-1-responsive octamer sequence ATGCAAAT. These properties of OCA-B parallel those displayed by the herpes simplex virus Oct-1 coregulator VP16. OCA-B, however, interacts with a different surface of the DNA-bound Oct-1 POU domain, interacting with both the POU(S) and POU(H) domains and the center of the ATGCAAAT octamer sequence. The OCA-B and VP16 interactions with the Oct-1 POU domain are sufficiently different to permit OCA-B and VP16 to bind the Oct-1 POU domain simultaneously. These results emphasize the structural versatility of the Oct-1 POU domain in its interaction with coregulators.


Communicating vaccine safety in the context of immunization programs in low resource settings.
Vaccines are effective in preventing infectious diseases and their complications, hence reducing morbidity and infectious disease mortaity. Successful immunization programs, however, depend on high vaccine acceptance and coverage rates. In recent years there has been an increased level of public concern towards real or perceived adverse events associated with immunizations, leading to many people in high- as well as low-resource settings to refuse vaccines. Health care workers therefore must be able to provide parents and guardians of children with the most current and accurate information about the benefits and risks of vaccination. Communicating vaccine safety using appropriate channels plays a crucial role in maintaining public trust and confidence in vaccination programs. Several factors render this endeavor especially challenging in low-resource settings where literacy rates are low and access to information is often limited. Many languages are spoken in most countries in low-resource settings, making the provision of appropriate information difficult. Poor infrastructure often results in inadequate logistics. Recently, some concerned consumer groups have been able to propagate misinformation and rumors. To successfully communicate vaccine safety in a resource limited setting it is crucial to use a mix of communication channels that are both culturally acceptable and effective. Social mobilization through cultural, administrative and political leaders, the media or text messages (SMS) as well as the adoption of the Village Health Team (VHT) strategy whereby trained community members (Community Health Workers (CHWs)) are providing primary healthcare, can all be effective in increasing the demand for immunization.


Antihyperalgesic Activity of Atomoxetine on Diabetes-Induced Neuropathic Pain: Contribution of Noradrenergic and Dopaminergic Systems.
Atomoxetine is a selective noradrenaline reuptake inhibitor drug. Based on the knowledge that agents increasing monoamine levels in the central nervous system have therapeutic potential for neuropathic pain, it is planned to investigate the possible efficacy of atomoxetine on diabetes-induced hyperalgesia, in this study. Randall-Selitto (mechanical noxious stimuli) and Hargreaves (thermal noxious stimuli) tests were used to evaluate nociceptive perception of rats. Obtained data indicated that streptozotocin-induced diabetes causes significant decreases in the paw withdrawal threshold and paw withdrawal latency values of the animals, respectively. However, atomoxetine administered at 3 mg/kg/day for 7 and 14 days improved these diabetes-induced hyperalgesia responses. Furthermore, antihyperalgesic activity was antagonized with α-methyl-para-tyrosine methyl ester, phentolamine, propranolol, and sulpiride pre-treatments. The same effect was not reversed, however, by SCH 23390. These findings demonstrated, for the first time, that atomoxetine possesses significant antihyperalgesic activity on diabetes-induced neuropathic pain and this effect seems to be mediated by α- and β-adrenergic and D₂/D₃ dopaminergic receptors. Results of this present study seem to offer a new indication for an old drug; atomoxetine, but these preclinical data should first be confirmed with further well-designed clinical trials.


Natural Language Processing for Mimicking Clinical Trial Recruitment in Critical Care: A Semi-Automated Simulation Based on the LeoPARDS Trial.
Clinical trials often fail to recruit an adequate number of appropriate patients. Identifying eligible trial participants is resource-intensive when relying on manual review of clinical notes, particularly in critical care settings where the time window is short. Automated review of electronic health records (EHR) may help, but much of the information is in free text rather than a computable form. We applied natural language processing (NLP) to free text EHR data using the CogStack platform to simulate recruitment into the LeoPARDS study, a clinical trial aiming to reduce organ dysfunction in septic shock. We applied an algorithm to identify eligible patients using a moving 1-hour time window, and compared patients identified by our approach with those actually screened and recruited for the trial, for the time period that data were available. We manually reviewed records of a random sample of patients identified by the algorithm but not screened in the original trial. Our method identified 376 patients, including 34 patients with EHR data available who were actually recruited to LeoPARDS in our centre. The sensitivity of CogStack for identifying patients screened was 90% (95% CI 85%, 93%). Of the 203 patients identified by both manual screening and CogStack, the index date matched in 95 (47%) and CogStack was earlier in 94 (47%). In conclusion, analysis of EHR data using NLP could effectively replicate recruitment in a critical care trial, and identify some eligible patients at an earlier stage, potentially improving trial recruitment if implemented in real time.


Biophotons: New Experimental Data and Analysis.
Biophotons are an ultra-weak emission of photons in the visible energy range from living matter. In this work, we study the emission from germinating seeds using an experimental technique designed to detect light of extremely small intensity. The emission from lentil seeds and single bean was analyzed during the whole germination process in terms of the different spectral components through low pass filters and the different count distributions in the various stages of the germination process. Although the shape of the emission spectrum appears to be very similar in the two samples used in our experiment, our analysis can highlight the differences present in the two cases. In this way, it was possible to correlate the various types of emissions to the degree of development of the seed during germination.


Indicator foods for vitamin A assessment.
Epidemiological interview studies examining the association between vitamin A and cancer at various sites have been hampered by restricted time available for interview; consequently, studies have included varying lists of food items or broad food groups, thus making comparability of results difficult. To identify a standardized list of indicator foods that adequately assess total vitamin A intake, we examined the 24-hour dietary recall of 13,201 adults who participated in the First National Health and Nutrition Examination Survey (NHANES I) from 1971 to 1974. Food items reportedly consumed were ranked by contribution to overall (aggregated) intake in various subpopulations by an index of vitamin A contribution, which reflected the frequency of consumption, portion size, and vitamin A concentration (IUs/100 g). A comparison of these ranks identified certain food items that had a relative contribution to vitamin A intake which varied by sex/race group, season of interview, age, or region of the country; income level had little effect on the food rankings. The top-ranking 50 foods were sufficient to correctly classify 80%-90% of the individuals into low-, moderate-, and high-consumer categories. The major contributing foods for any subpopulation examined included both retinol (e.g., dairy products, liver) and carotenoid sources of vitamin A (e.g., certain fruits and vegetables) in addition to items (e.g., mixed tomato and cheese dishes) not included in earlier questionnaire studies. Recommendations are made for future questionnaires designed to assess vitamin A.


Overexpression of AtGRDP2, a novel glycine-rich domain protein, accelerates plant growth and improves stress tolerance.
Proteins with glycine-rich signatures have been reported in a wide variety of organisms including plants, mammalians, fungi, and bacteria. Plant glycine-rich protein genes exhibit developmental and tissue-specific expression patterns. Herein, we present the characterization of the AtGRDP2 gene using Arabidopsis null and knockdown mutants and, Arabidopsis and lettuce over-expression lines. AtGRDP2 encodes a short glycine-rich domain protein, containing a DUF1399 domain and a putative RNA recognition motif (RRM). AtGRDP2 transcript is mainly expressed in Arabidopsis floral organs, and its deregulation in Arabidopsis Atgrdp2 mutants and 35S::AtGRDP2 over-expression lines produces alterations in development. The 35S::AtGRDP2 over-expression lines grow faster than the WT, while the Atgrdp2 mutants have a delay in growth and development. The over-expression lines accumulate higher levels of indole-3-acetic acid and, have alterations in the expression pattern of ARF6, ARF8, and miR167 regulators of floral development and auxin signaling. Under salt stress conditions, 35S::AtGRDP2 over-expression lines displayed higher tolerance and increased expression of stress marker genes. Likewise, transgenic lettuce plants over-expressing the AtGRDP2 gene manifest increased growth rate and early flowering time. Our data reveal an important role for AtGRDP2 in Arabidopsis development and stress response, and suggest a connection between AtGRDP2 and auxin signaling.


Repeat-Specific Functions for the C-Terminal Domain of RNA Polymerase II in Budding Yeast.
The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII) is required to regulate transcription and to integrate it with other essential cellular processes. In the budding yeast Saccharomyces cerevisiae, the CTD of Rpb1p consists of 26 conserved heptad repeats that are post-translationally modified to orchestrate protein factor binding at different stages of the transcription cycle. A long-standing question in the study of the CTD is if there are any functional differences between the 26 repeats. In this study, we present evidence that repeats of identical sequence have different functions based on their position within the CTD. We assembled plasmids expressing Rpb1p with serine to alanine substitutions in three defined regions of the CTD and measured a range of phenotypes for yeast expressing these constructs. Mutations in the beginning and middle regions of the CTD had drastic, and region-specific effects, while mutating the distal region had no observable phenotype. Further mutational analysis determined that Ser5 within the first region of repeats was solely responsible for the observed growth differences and sequencing fast-growing suppressors allowed us to further define the functional regions of the CTD. This mutational analysis is consistent with current structural models for how the RNAPII holoenzyme and the CTD specifically would reside in complex with Mediator and establishes a foundation for studying regioselective binding along the repetitive RNAPII CTD.


Nanomechanics of the endothelial glycocalyx contribute to Na+-induced vascular inflammation.
High dietary salt (NaCl) is a known risk factor for cardiovascular pathologies and inflammation. High plasma Na+ concentrations (high Na+) have been shown to stiffen the endothelial cortex and decrease nitric oxide (NO) release, a hallmark of endothelial dysfunction. Here we report that chronic high Na+ damages the endothelial glycocalyx (eGC), induces release of inflammatory cytokines from the endothelium and promotes monocyte adhesion. Single cell force spectroscopy reveals that high Na+ enhances vascular adhesion protein-1 (VCAM-1)-dependent adhesion forces between monocytes and endothelial surface, giving rise to increased numbers of adherent monocytes on the endothelial surface. Mineralocorticoid receptor antagonism with spironolactone prevents high Na+-induced eGC deterioration, decreases monocyte-endothelium interactions, and restores endothelial function, indicated by increased release of NO. Whereas high Na+ decreases NO release, it induces endothelial release of the pro-inflammatory cytokines IL-1ß and TNFα. However, in contrast to chronic salt load (hours), in vivo and in vitro, an acute salt challenge (minutes) does not impair eGC function. This study identifies the eGC as important mediator of inflammatory processes and might further explain how dietary salt contributes to endothelialitis and cardiovascular pathologies by linking endothelial nanomechanics with vascular inflammation.


Familial Parkinsonism and early onset Parkinson's disease in a Brazilian movement disorders clinic: phenotypic characterization and frequency of SNCA, PRKN, PINK1, and LRRK2 mutations.
The aim of the study was to evaluate the frequency and to perform phenotypic and genotypic characterization of familial Parkinsonism and early onset Parkinson's disease (EOPD) in a Brazilian movement disorder unit. We performed a standardized clinical assessment of patients followed by sequencing of PRKN, PINK1 in EOPD cases and SNCA, LRRK2 in familial Parkinsonism individuals. During the period of study (January through December, 2006), we examined 575 consecutive patients of whom 226 (39.3%) met the diagnosis of Parkinsonism and idiopathic Parkinson's disease (IPD) was diagnosed in 202 of the latter. Of the IPD cases, 45 (22.3%) had EOPD. The age at onset in the EOPD cases (n = 45) was 34.8 +/- 5.4 years (mean +/- standard deviation). The age at onset in the familial late-onset PD patients (n = 8) was 52.3 +/- 12.2 years. In the early onset cases, we identified five known mutations in PRKN, two single heterozygous and three compound heterozygous (P153R, T240M, 255Adel, W54R, V3I); in addition, we identified one novel mutation in PINK1 (homozygous deletion of exon 7). In the familial cases (late onset), 1 patient had a novel LRRK2 variant, Q923H, but no SNCA mutations were identified. We have demonstrated that EOPD accounts for a high frequency of IPD cases in our tertiary referral center. PRKN was the most commonly mutated gene, but we also identified a novel mutation in PINK1 and a novel variant in LRRK2.


Phase diagram and structures in mixtures of poly(styrenesulfonate anion) and alkyltrimethylammonium cations in water: significance of specific hydrophobic interaction.
Mixtures of polyelectrolytes and oppositely charged surfactants show very rich phase behavior that is influenced by surfactant-ion and polyion properties and by water content. A general feature is associative phase separation as a result of strong electrostatic interactions, whereas the effect of eventual more specific interactions (e.g., hydrophobic) has not been thoroughly investigated. In this paper, we report a detailed study on phase behavior and structures in poly(styrenesulfonate anion) (PSS(-))-cetyltrimethylammonium cation (CTA(+))-water mixtures that are characterized by a hydrophobic interaction between the styrene groups of PSS(-) and the micelle interior. Structures of various phases were determined by small-angle X-ray scattering, and results indicated the presence of a disordered micellar and an ordered hexagonal phase; no cubic phase was found. The general conclusion is that the highlighted hydrophobic interaction promotes dissolution of CTAPSS when the polyion salt is added and provides further stabilization of the dense phase when the surfactant salt is added.


γ-[Glu]n-Trp ameliorates anxiety/depression-like behaviors and its anti-inflammatory effect in an animal model of anxiety/depression.
This study compared the abilities of γ-[Glu]n-Trp (EW) and whey protein hydrolysate (WPH) with a high ratio of Trp : 5 large neutral amino acids (5LNAAs) to reverse chronic restraint stress-corticosterone injection induced anxiety/depression-like behaviors in C57BL/6 male mice. EW was synthesized using l-glutaminase from Bacillus amyloliquefaciens. Acid protease, trypsin, pancreatin or flavorzyme was used to produce WPHs. The WPH with the highest Trp/5LNAAs ratio (17.38%; by trypsin) was selected for animal trials. EW (dose 2.0, 5.0 or 10.0 mg kg-1 d-1) and WPH (dose 0.5, 1.0 or 2.0 mg g-1 d-1) reversed behavioral dysfunctions, suppressed serum inflammatory cytokines (TNF-α, IL-6, IL-1β and IFN-γ), and reduced the activity of indoleamine 2,3-dioxygenase (key rate-limiting enzyme of the kynurenine pathway) while increasing the activity of tryptophan hydroxylase (key rate-limiting enzyme of the serotonin pathway) in the hypothalamus, hippocampus and prefrontal cortex, with EW acting more effectively. EW could also increase body weight gain and might act more effectively via the kynurenine pathway. These findings are of significance to promote the future practical application of kokumi γ-[Glu]n-Trp peptides.


Nonexpression of the human serum amyloid A three (SAA3) gene.
Serum amyloid A (SAA) is a major acute-phase plasma protein synthesized by the liver. In addition to the two major plasma isoforms described in humans (SAA1 and SAA2), a third form (SAA3) has been demonstrated in several other species and is distinguished by predominant extrahepatic expression. Two clones, Ch11g5-1-1 and HDg1-1, containing the human SAA3 gene are described in this report. The human SAA3 gene is comparable in organization to the SAA1 and SAA2 genes and shares with them 87% nucleotide identity in the region spanning exon 3 through exon 4. Sequences 5' to exon 3, however, are strikingly different from those in the SAA1 and SAA2 genes. For instance, the sequence deduced for amino acids 1-12 (exon 2) has only 25% identity with human SAA1 and SAA2; it most closely resembles that of rabbit SAA3 isolated from synovial fibroblast cultures (75% identity). Although rabbit SAA3 induces collagenase production in an autocrine fashion the human SAA3 gene is not expressed. This is shown by: (i) a single base insertion in the sequence corresponding to codon 31, (ii) the inability of a 918-bp fragment immediately upstream from SAA3 exon sequences to direct transcription of a chloramphenicol acetyltransferase reporter gene, and (iii) the absence of detectable human SAA3 in mRNA.


F-BAR Cdc15 Promotes Cdc42 Activation During Cytokinesis and Cell Polarization in Schizosaccharomyces pombe.
Cdc42, a Rho-family GTPase, is a master regulator of cell polarity. Recently, it has been shown that Cdc42 also facilitates proper cytokinesis in the fission yeast Schizosaccharomyces pombe Cdc42 is activated by two partially redundant GEFs, Gef1 and Scd1. Although both GEFs activate Cdc42, their deletion mutants display distinct phenotypes, indicating that they are differentially regulated by an unknown mechanism. During cytokinesis, Gef1 localizes to the division site and activates Cdc42 to initiate ring constriction and septum ingression. Here, we report that the F-BAR protein Cdc15 promotes Gef1 localization to its functional sites. We show that cdc15 promotes Gef1 association with cortical puncta at the incipient division site to activate Cdc42 during ring assembly. Moreover, cdc15 phospho-mutants phenocopy the polarity phenotypes of gef1 mutants. In a hypermorphic cdc15 mutant, Gef1 localizes precociously to the division site and is readily detected at the cortical patches and the cell cortex. Correspondingly, the hypermorphic cdc15 mutant shows increased bipolarity during interphase and precocious Cdc42 activation at the division site during cytokinesis. Finally, loss of gef1 in hypermorphic cdc15 mutants abrogates the increased bipolarity and precocious Cdc42 activation phenotype. We did not see any change in the localization of the other GEF Scd1 in a Cdc15-dependent manner. Our data indicate that Cdc15 facilitates Cdc42 activation at the division site during cytokinesis at the cell cortex to promote bipolarity and this is mediated by promoting Gef1 localization to these sites.


Outcome expectations, expectancy accessibility, and exercise in endometrial cancer survivors.
Studies have shown that expectations about exercise outcomes are associated with exercise behavior. Outcome expectations can be assessed by self-report questionnaires, but a new method-the expectancy accessibility task-may convey unique information about outcome expectations that is less subject to respondent biases. This method involves measuring the reaction time to endorse or reject an outcome We examined the relationship of self-reported outcome expectations and expectancy accessibility tasks in a pilot study of sedentary endometrial cancer survivors (N = 20). After measuring outcome expectations and expectancy accessibility, participants were given an exercise program and asked to monitor exercise for 7 days using diaries and accelerometers. Analyses revealed no relationship between outcome expectation scores and exercise, but shorter response times to endorse positive exercise outcomes was related to more exercise in the next week (p = .02).


Self-rated health status transition and long-term care need, of the oldest Chinese.
The objectives of this paper are: (1) to estimate the transition probabilities among self-rated health status for the oldest Chinese aged 80 and above; (2) to project the future need of long-term care due to changes in demography and health status among the oldest Chinese. Self-rated health data collected in Chinese Longitudinal Healthy Longevity Survey conducted in 1998, 2000 and 2002 were used to estimate the self-rated health status transition probabilities, and to project future long-term care need by calculating the number of unhealthy person-years. The majority of the oldest Chinese's health status remains unchanged or worsens within 2 years. The number of unhealthy person-years rises regardless of gender, and the absolute number and increase rate of females are higher than those of males. Under the assumption that average care expenditure is 15 US dollars per hour in 2010, the long-term care expenditure will increase from 8352 million dollars in 2010 to 42,530 million dollars in 2050, a growth of more than 400% over the next 40 years. Long-term care need for the oldest Chinese will rise rapidly in the next decades, which should stimulate increased governmental and public awareness of their need.


Predictive Accuracy of the American College of Surgeons Risk Calculator in Patients Undergoing Major Lower Extremity Amputation.
The American College of Surgeons Risk Calculator (ACS-RC) provides an assessment of a patient's risk of 30-day postoperative complications. The Surgeon Adjusted Risk (SAR) parameter of the calculator allows for ad hoc adjustment of risk based on risk factors not considered by the model. This study aims to evaluate the predictive accuracy of the ACS-RC in vascular surgery patients undergoing major lower-extremity amputation (LEA) and identify additional risk factors that warrant use of the SAR parameter. This is a retrospective study of 298 sequential amputations at a single institution. At the population level, the mean of predicted 30-day outcomes from the ACS-RC with a SAR score of 1 (no adjustment necessary) and 2 (risk somewhat higher than estimate) were compared to the rate of observed outcomes. Predictive accuracy at the individual level was completed using receiver operating curve area under the curve (AUC). Logistic regression with respect to mortality was performed over variables not considered by the ACS-RC. Efficacy of selectively utilizing the SAR parameter in predicting mortality was analyzed with a stratified analysis in which patients with risk factors significant for mortality were assigned increased risk. At the population level, ACS-RC grossly underpredicted serious complications, SSI, VTE, and unplanned RTOR, while overpredicting mortality and cardiac complications. At the individual level, SAR1 was more predictive for serious complications (AUC = 0.624), SSI (AUC = 0.610), and unplanned RTOR (AUC = 0.541). Conversely, SAR2 was more predictive for mortality (AUC = 0.709), cardiac complications (AUC = 0.561), and VTE (AUC = 0.539). Logistic regression identified history of CVA with a residual deficit (OR = 4.61, P = 0.033) and ischemic rest pain without tissue loss (OR = 4.497, P = 0.047) as independent risk factors for postoperative mortality. Stratified analysis with utilization of the SAR2 based on the 2 independent risk factors improved AUC in predicting mortality (AUC 0.792 from 0.709). Major LEAs are associated with high perioperative morbidity and mortality. In a veteran population, the ACS-RC showed mixed predictability at the population level and fair predictability at the individual level with regards to postoperative outcomes. Rest pain without tissue loss and history of CVA with residual deficit were identified as risk factors for postoperative mortality. Although ad hoc adjustment with the subjective SAR modifier based on the presence of these 2 risk factors increased the calculator's accuracy, this study highlights some potential limitations of the ACS-RC when applied to vascular surgery patients undergoing major LEA.


Imaging of Intestinal and Multivisceral Transplantation.
Intestinal transplantation has evolved from its experimental origins in the mid-20th century to its status today as an established treatment option for patients with end-stage intestinal failure who cannot be sustained with total parenteral nutrition. The most common source of intestinal failure in both adults and children is short-bowel syndrome, but a host of other disease processes can lead to this common end-point. The development of intestinal transplantation has presented multiple hurdles for the transplant community, including technical challenges, immunologic pitfalls, and infectious complications. Despite these hurdles, the success rate has climbed over the past decades owing to achievements that include improved surgical techniques, new immunosuppressive regimens, and more effective strategies for posttransplant surveillance and management. Nearly 2800 intestinal transplants have been performed worldwide, and current patient and graft survival rates are now comparable to those of other types of solid organ transplantations. As their population continues to increase, it will be increasingly likely that intestinal-transplant patients will seek imaging at sites other than transplant centers. Therefore, it is important that diagnostic and interventional radiologists be familiar with the procedure, its common variations, and the spectrum of postoperative complications. In this article, the authors provide an overview of intestinal transplantation, including the indications, variations, expected postoperative anatomy, and range of potential complications. ©RSNA, 2018.


[Optimizing antibiotics use policy in the Netherlands. I. The Netherlands Antibiotics Policy Foundation (SWAB)].
The worldwide problem of antibiotic resistance of bacteria is a point of concern in the Netherlands as well. Responsible use of existing antibiotics was the incentive to establish a foundation, with the acronym SWAB, the primary goal of which is to optimize the use of antibiotics in the Netherlands in order to diminish the development of antibiotic resistance. One of the SWAB projects is the development of national guidelines for the use of antibiotics in hospitals. These guidelines are prepared by a committee of experts and reviewed by external consultants: infectious disease specialists, medical microbiologists and pharmacists. The revised version of the guidelines is submitted for publication in this journal. The SWAB hopes that these guidelines will make the prevention of antibiotic resistance a major factor in the choice of the antibiotic. Streamlining antibiotic therapy is an important tool in this respect.


Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment.
Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo. We therefore used different combinations of maternal and embryo SERT Ala56 genotypes to examine effects on blood, placenta and embryo serotonin levels and neurodevelopment at embryonic day E14.5, when peripheral sources of 5-HT predominate, and E18.5, when midbrain 5-HT projections have reached the forebrain. Maternal SERT Ala56 genotype was associated with decreased placenta and embryonic forebrain 5-HT levels at E14.5. Low 5-HT in the placenta persisted, but forebrain levels normalized by E18.5. Maternal SERT Ala56 genotype effects on forebrain 5-HT levels were accompanied by a broadening of 5-HT-sensitive thalamocortical axon projections. In contrast, no effect of embryo genotype was seen in concepti from heterozygous dams. Blood 5-HT levels were dynamic across pregnancy and were increased in SERT Ala56 dams at E14.5. Placenta RNA sequencing data at E14.5 indicated substantial impact of maternal SERT Ala56 genotype, with alterations in immune and metabolic-related pathways. Collectively, these findings indicate that maternal SERT function impacts offspring placental 5-HT levels, forebrain 5-HT levels, and neurodevelopment.


Ultrasonographic evaulation of breast masses.
B-mode ultrasonic contact scanning should be performed in conjunction with mammography in any patient with a palpable breast mass that is 1 cm or larger in diameter. Patients with masses that appear cystic on the sonogram should undergo needle aspiration of their masses. The fluid should then be cytologically examined for confirmation of its benign nature and repeat sonograms obtained to ensure that the mass has completely disappeared. Patients with masses appearing either solid or complex ultrasonographically should undergo surgical biopsy.


DNA methylation of HOX genes and its clinical implications in cancer.
Homeobox (HOX) genes encode highly conserved transcription factors that play vital roles in embryonic development. DNA methylation is a pivotal regulatory epigenetic signaling mark responsible for regulating gene expression. Abnormal DNA methylation is largely associated with the aberrant expression of HOX genes, which is implicated in a broad range of human diseases, including cancer. Numerous studies have clarified the mechanisms of DNA methylation in both physiological and pathological processes. In this review, we focus on how DNA methylation regulates HOX genes and briefly discuss drug development approaches targeting these mechanisms.


Molecular and expression analysis of a family of the Amblyomma americanum tick Lospins.
Serine proteinase inhibitors (serpins) are a family of structurally similar but functionally diverse proteins that regulate several important proteolytic cascades in most branches of life. We have characterized 17 Amblyomma americanum serpin cDNAs here named as ;Lospins' (L; an acronym for Lone Star tick serpin) that possess three beta-sheets, eight alpha-helices and a reactive center loop consistent with the consensus serpin superfamily secondary structures. Visual inspection of deduced amino acid sequences revealed two patterns of basic residues: (i) (86)DKSRVLKAYKRL(97) in L5 and L13-16 and (ii) (158)VRDKTRGKI(166) in all Lospins, which are similar to consensus glycosaminoglycan (GAG) binding sites (XBnXmBX, where X and B are non-basic and basic residues, n=1 or 2 and m=1, 2 or 3). On three-dimensional models, the two putative GAG binding sites mapped onto alpha-helices D and F, respectively, with calculation of electrostatic surface potentials revealing basic patches on L5 and L13-16 models that are comparable to the heparin-binding site on antithrombin. RT-PCR expression analysis of 15 selected genes showed that the majority (11/15) of the Lospins were ubiquitously expressed in the midgut, ovary and salivary glands. On a neighbor-joining phylogeny guide tree, 15 serpins from other ticks and 17 Lospins from this study, a total of 32 tick serpin sequences, segregated into five groups with Lospins in groups A and D being conserved across tick species. The discovery of Lospins in this study sets the framework for future studies to understand the role of serpins in tick physiology.


A brief history of British military experiences with infectious and tropical diseases.
Infectious and tropical diseases have been a problem for British expeditionary forces ever since the Crusades. Outbreaks were especially common on Navy ships from the 16th to 18th centuries due to poor living conditions and travel to the tropics. However, since these occurred in small, isolated and controlled environments it meant that naval medical practitioners were able to keep detailed records and develop empirical approaches for their prevention. The first Royal Naval Hospitals were established in response to these diseases and Royal Navy doctors made valuable early contributions towards understanding them. Even larger outbreaks of infectious and tropical diseases occurred in the Army during the Napoleonic, Crimean and Boer Wars and throughout the colonial era, which strongly influenced the formation of the Army Medical Services including provision for teaching and research. The establishment of germ theory led to a golden era of discovery regarding these diseases and British Army doctors made numerous important contributions. Subsequent improvements in prevention, diagnosis and treatment reduced the mortality from infectious and tropical diseases during the World Wars, but they remained a significant problem in the non-European campaigns and also the numerous 'small wars' that followed. Even in the 21st century some of these diseases still cause outbreaks with significant morbidity and impact on deployments, but the military clinical and academic resources to deal with them are now much reduced. Preventive measures such as hygiene, sanitation, infection control, vaccination and chemoprophylaxis are invaluable, but history shows that these can become neglected over time and disrupted or overwhelmed during the early or most intense stages of military operations. This is why military specialists in infectious diseases, tropical medicine, sexual health, medical microbiology and communicable diseases control are still required.


[Alterations of gait parameters under external cueing in schizophrenic patients: a switch study].
Schizophrenic disorders as well as neuroleptic treatment can affect locomotion. The study assessed the influence of neuroleptic treatment on externally triggered gait on a treadmill at three different velocities via ultrasonic topometric gait analysis. Spatial and temporal gait parameters were assessed in two groups of schizophrenic patients either under treatment with conventional neuroleptics (n = 12) or without neuroleptic treatment (n = 10) and re-assessed after treatment change to the atypical neuroleptic olanzapine in a repeated measures design. After switch from conventional neuroleptics to olanzapine patients showed an increase of step length and decrease of cadence at the low (p </= 0.01) and the intermediately low treadmill velocity (p </= 0.05), whereas the parameters remained stable at the normal gait velocity. Significant differences between the untreated state and treatment with olanzapine were not detectable. We conclude that conventional neuroleptic treatment impairs the regulation of gait parameters and that this effect can be reversed at slow gait velocities by external stimulation via treadmill walking.


Occupational Therapy Practice Guidelines for Adults With Traumatic Brain Injury.
Occupational therapy practitioners are uniquely qualified to address the occupational needs of people with traumatic brain injury (TBI) and their caregivers to maximize participation, health, and well-being. These Practice Guidelines are informed by systematic reviews of the effectiveness of interventions that address impairments and skills to improve the occupational performance of people with TBI, as well as interventions for caregivers of people with TBI. The purpose of these guidelines is to summarize the current evidence available to assist clinicians' clinical decision-making in providing interventions for people with TBI and their caregivers. We reviewed six systematic reviews and synthesized the results into clinical recommendations to be used in occupational therapy clinical practice. Sixty-two articles served as the basis for the clinical recommendations. Strong to moderate evidence supports multimodal sensory stimulation, unimodal auditory stimulation, physical activity, virtual reality, cognitive interventions, vision therapy, goal-focused interventions, individual and group training and education, and caregiver supports. Occupational therapy practitioners should incorporate these interventions into individual and group sessions to maximize recovery and promote occupational participation. Additional interventions are also available, based on emerging evidence and expert opinion, including prevention approaches, complexity of injury, and the use of occupation-based performance assessments. What This Article Adds: These Practice Guidelines provide a summary of evidence in clinical recommendations tables supporting occupational therapy interventions that address impairments resulting from and skills to improve occupational performance after TBI. The guidelines also include case study examples and evidence graphics for practitioners to use to support clinical reasoning when selecting interventions that address the goals of the person with TBI and their caregiver's needs.


Clinical outcome and gut development after insulin-like growth factor-1 supplementation to preterm pigs.
Elevation of circulating insulin-like growth factor-1 (IGF-1) within normal physiological levels may alleviate several morbidities in preterm infants but safety and efficacy remain unclear. We hypothesized that IGF-1 supplementation during the first 1-2 weeks after preterm birth improves clinical outcomes and gut development, using preterm pigs as a model for infants. Preterm pigs were given vehicle or recombinant human IGF-1/binding protein-3 (rhIGF-1, 2.25 mg/kg/d) by subcutaneous injections for 8 days (Experiment 1, n = 34), or by systemic infusion for 4 days (Experiment 2, n = 19), before collection of blood and organs for analyses. In both experiments, rhIGF-1 treatment increased plasma IGF-1 levels 3-4 fold, reaching the values reported for term suckling piglets. In Experiment 1, rhIGF-1 treatment increased spleen and intestinal weights without affecting clinical outcomes like growth, blood biochemistry (except increased sodium and gamma-glutamyltransferase levels), hematology (e.g., red and white blood cell populations), glucose homeostasis (e.g., basal and glucose-stimulated insulin and glucose levels) or systemic immunity variables (e.g., T cell subsets, neutrophil phagocytosis, LPS stimulation, bacterial translocation to bone marrow). The rhIGF-1 treatment increased gut protein synthesis (+11%, p < 0.05) and reduced the combined incidence of all-cause mortality and severe necrotizing enterocolitis (NEC, p < 0.05), but had limited effects on intestinal morphology, cell proliferation, cell apoptosis, brush-border enzyme activities, permeability and levels of cytokines (IL-1β, IL-6, IL-8). In Experiment 2, rhIGF-1 treated pigs had reduced blood creatine kinase, creatinine, potassium and aspartate aminotransferase levels, with no effects on organ weights (except increased spleen weight), blood chemistry values, clinical variables or NEC. Physiological elevation of systemic IGF-1 levels for 8 days after preterm birth increased intestinal weight and protein synthesis, spleen weight and potential overall viability of pigs, without any apparent negative effects on recorded clinical parameters. The results add further preclinical support for safety and efficacy of supplemental IGF-1 to hospitalized very preterm infants.


The role of interindividual variation in human carcinogenesis.
The process of chemical carcinogenesis is a complex multistage process initiated by DNA damage in growth control genes. Carcinogens enter the body from a variety of sources, but most require metabolic activation before they can damage DNA. There are multiple protective processes that include detoxification and conjugation, DNA repair and programmed cell death. Most of these functions exhibit wide interindividual variation in the population and thus are thought to affect cancer risk. The role of gene-environment interactions is being explored, and current data indicate that genetic susceptibilities can modify carcinogen exposures from the diet and tobacco smoking, although much more data exist for the latter. This review addresses the relationships of human carcinogenesis to these interindividual differences of phase I, phase II and DNA repair enzymes.


Worsened punch sticking by external lubrication with magnesium stearate.
External lubrication of tooling with magnesium stearate (MgSt) is a common strategy to eliminate punch sticking when compressing powders with a high sticking propensity, such as many pure active pharmaceutical ingredients (APIs). We found that it actually led to aggravated punch sticking at low compaction pressures. This counterintuitive phenomenon was explained based on interplay of forces among the punch tip, MgSt, and API. The explanation is supported by the observed effects of pressure and mechanical properties of APIs on this phenomenon.


Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma.
Neuroblastoma is a childhood cancer that is fatal in almost half of patients despite intense multimodality treatment. This cancer is derived from neuroendocrine tissue located in the sympathetic nervous system. Glypican-2 (GPC2) is a cell surface heparan sulfate proteoglycan that is important for neuronal cell adhesion and neurite outgrowth. In this study, we find that GPC2 protein is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival compared with patients with low GPC2 expression. We demonstrate that silencing of GPC2 by CRISPR-Cas9 or siRNA results in the inhibition of neuroblastoma tumor cell growth. GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of the target gene N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. We have isolated human single-domain antibodies specific for GPC2 by phage display technology and found that the single-domain antibodies can inhibit active β-catenin signaling by disrupting the interaction of GPC2 and Wnt3a. To explore GPC2 as a potential target in neuroblastoma, we have developed two forms of antibody therapeutics, immunotoxins and chimeric antigen receptor (CAR) T cells. Immunotoxin treatment was demonstrated to inhibit neuroblastoma growth in mice. CAR T cells targeting GPC2 eliminated tumors in a disseminated neuroblastoma mouse model where tumor metastasis had spread to multiple clinically relevant sites, including spine, skull, legs, and pelvis. This study suggests GPC2 as a promising therapeutic target in neuroblastoma.


Interventional psychiatry in the management of behavioural and psychological symptoms of dementia: a qualitative review.
"Behavioural and psychological symptoms of dementia" (BPSD) refers to a heterogeneous group of clinical manifestations related to dementia, including apathy, depression, anxiety, delusions, hallucinations, sexual or social disinhibition, sleep-wake cycle disturbances, aggression, agitation and other behaviours considered inappropriate. Because of the complexity and heterogeneity of BPSD, as well as the fragility and multimorbidity of the elderly, pharmacological treatment appears to be limited in terms of safety and efficacy, and nonpharmacological therapies are today considered the first choice. There is growing evidence that interventional approaches such as electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS) could be safe and efficient options for several psychiatric illnesses in a population presenting resistance to and/or intolerance of pharmacotherapy. The aim of the present work is to provide a qualitative review of the state of the art in interventional psychiatry in the treatment of BPSD. A particular focus will be on depression and agitation, which represent major stressors on caregivers and a primary cause of institutionalisation. ECT is probably the most promising interventional procedure needing further investigation in order to obtain specific protocols and a consensus on indications. Preliminary data on rTMS, tDCS, and VNS are encouraging although randomised controlled trials to investigate and compare their efficacy in the treatment of BPSD are still lacking. Their feasibility profile could represent an important advantage over ECT. DBS could represent a very effective therapy for behavioural disorders, but knowledge of the precise neuroanatomical targets for BPSD is currently too limited to justify this invasive approach.


Expanding the knowledge frontier of mitoviruses in Cannabis sativa.
Mitoviruses were initially known for their presence in the mitochondria of fungi and were considered exclusive to these organisms. However, recent studies have shown that they are also present in a large number of plant species. Despite the potential impact that mitoviruses might have on the mitochondria of plant cells, there is a lack of information about these ancient RNA viruses, especially within the Cannabaceae family. Cannabis sativa has been in the spotlight in recent years due to the growing industrial applications of plant derivatives, such as fiber and secondary metabolites. Given the importance of Cannabis in today's agriculture, our study aimed to expand the knowledge frontier of Mitoviruses in C. sativa by increasing the number of reference genomes of CasaMV1 available in public databases and representing a larger number of crops in countries where its industrial-scale growth is legalized. To achieve this goal, we used transcriptomics to sequence the first mitoviral genomes of Colombian crops and analyzed RNA-seq datasets available in the SRA databank. Additionally, the evolutionary analysis performed using the mitovirus genomes revealed two main lineages of CasaMV1, termed CasaMV1_L1 and CasaMV1_L2. These mitoviral lineages showed strong clustering based on the geographic location of the crops and differential expression intensities.


[Quality of life in rheumatoid arthritis patients].
To study quality of life (QL) in patients with rheumatoid arthritis (RA). Questionnaire survey (MCA, BIPQ, AIMS, MHAQ) covered 190 RA patients (mean age 47.7 +/- 1.4 years). Many of them were group II invalids. All the patients had slow-progressive polyarthritis, articular and seronegative RA prevailed. Most of the patients had articular and seronegative RA with first-degree activity, x-ray stage II and third-degree deficiency of the articular function. It is shown that RA patients have subnormal quality of life. Its deterioration was related to clinical parameters: duration of the disease and its activity, invalidity, X-ray stage, articular and locomotor functions, psychological status. Hypochondriac, apathical and neurastenic reactions to the disease occurred most frequently. Euphoric reaction to the disease was a positive factor for QL. Changes in social status were essential for QL in RA patients. QL is an integral indicator of health status in RA patients. It can be estimated basing on only one questionnaire--AIMS as it includes all the necessary components.


Immunoglobulin A autoantibodies against transglutaminase 2 in the small intestinal mucosa predict forthcoming coeliac disease.
Reliable markers of early developing coeliac diseases are needed. Coeliac autoantibodies in the serum or Marsh I inflammation may be indicators of subsequent coeliac disease. To investigate whether determination of intestinal transglutaminase 2-targeted autoantibody deposits would detect early developing coeliac disease better than previous methods. The study investigated patients previously excluded for coeliac disease: 25 had positive serum coeliac autoantibodies (endomysial), 25 antibody-negative had Marsh I, and 25 antibody-negative had Marsh 0 finding. Seven (median) years after baseline investigation, new coeliac cases were recorded, and small bowel biopsy was offered to the rest of the patients. Serum and intestinal coeliac autoantibodies and intraepithelial lymphocytes were assessed as indicators of developing coeliac disease. Seventeen patients had developed coeliac disease: 13 in the autoantibody-positive group, three in the Marsh I group and one in the Marsh 0 group. At baseline, intestinal coeliac autoantibody deposits had a sensitivity and specificity of 93% and 93% in detecting subsequent coeliac disease, CD3+ 59% and 57%, gammadelta+ 76% and 60%, and villous tip intraepithelial lymphocytes 88% and 71%, respectively. Endomysial antibodies with normal histology indicates early developing coeliac disease. Transglutaminase 2-targeted intestinal autoantibody deposits proved the best predictor of subsequent coeliac disease.


Cloning of mouse islet amyloid polypeptide gene and characterization of its promoter.
Islet amyloid polypeptide (IAPP) was isolated from islet amyloid deposits in patients with insulinoma and pancreatic islets of non-insulin-dependent diabetes mellitus (NIDDM) and several reports suggested that it may contribute to the development of NIDDM. IAPP is mainly expressed and synthesized in pancreatic B cells and cosecreted with insulin, so analysis of the transcriptional regulation of the IAPP gene would be helpful for the elucidation of pancreatic B cell specific gene expression. The mouse IAPP gene spans about 5.8 kb and, like the human and rat genes, it consists of three exons, and analysis of the promoter/enhancer activity of mouse IAPP gene reveals the region from -171 to -87 bp to be essential. Within this region, an E-box like sequence, CACCTG (-122 to -117 bp), and a TAAT-box like sequence, TTAATG (-139 to -134 bp), are thought to be important. The disruption of each sequence resulted in a severe decrease in promoter activity, although the decrease was less in the disruption of the E-box than that of TAAT-box like sequence, suggesting the latter is more important for IAPP gene transcription. Like the rat IAPP gene, the CCAAT-box, which does not exist in the human gene, was identified in the mouse gene, indicating the possibility of species difference in the IAPP gene transcriptional mechanism. An enhancer-like activity was also identified within intron 1, although further elucidation is necessary.


Adiponectin effects on human breast cancer cells are dependent on 17-beta estradiol.
Adiponectin, an adipocyte-derived serum protein, is known to positively affect the glucose and lipid metabolism and these effects are mediated by its receptors, AdipoR1 and R2. Serum adiponectin levels are inversely associated with breast cancer risk, but the molecular mechanisms underlying this association are not fully elucidated. Thus, the purpose of this study was to investigate the influence of adiponectin on breast cancer cells in vitro. We were able to demonstrate the expression of AdipoR1 and R2 in MCF-7, MDA-MB-231 and SK-BR-3 breast cancer cells on the mRNA level. Furthermore, the AdipoR1 protein could be detected by immunoblot analysis. In MCF-7 breast cancer cells, the expression of AdipoR1 significantly declined after stimulation with 17-beta estradiol, whereas the cyclin A2 expression significantly increased. Both effects were inhibited by the addition of adiponectin. Treatment with different concentrations of adiponectin in steroid-hormone-free medium did not affect cell proliferation or apoptosis. In contrast, after the addition of 17-beta estradiol, adiponectin slightly decreased the growth of the MDA-MB-231 and SK-BR3 cells but increased proliferation of the hormone-dependent MCF-7 breast cancer cells. Adiponectin also triggered cellular apoptosis in MDA-MB-231 breast cancer cells in the presence of 17-beta estradiol. These findings suggest that a cross-talk between adiponectin and estrogen receptor signaling exists in breast cancer cells and that adiponectin effects on the growth and apoptosis of breast cancer cells in vitro are dependent on the presence of 17-beta estradiol.