A synopsis of research needs identified at the Interagency, International Symposium on Cyanobacterial Harmful Algal Blooms (ISOC-HAB).
Evidence indicates that the incidence of cyanobacterial harmful algal blooms (CHABs) is increasing in spatial extent and temporal frequency worldwide. Cyanobacterial blooms produce highly potent toxins and huge, noxious biomasses in surface Waters used for recreation, commerce, and as drinking water sources. The Interagency, International Symposium on Cyanobacterial Harmful Algal Blooms (ISOC-HAB) characterized the state of the science and identified research needed to address the risks posed by CHABs to human health and ecosystem sustainability. This chapter provides a synopsis of CHAB research needs that were identified by workgroups that addressed charges in major topic areas. The research and infrastructure needed are listed under nine categories: 1) Analytical Methods; 2) CHAB Occurrence; 3) CHAB Causes; 4) Human Health; 5) Ecosystem Sustainability; 6) CHAB Prevention; 7) CHAB Control and Mitigation; 8) Risk Assessment and; 9) Infrastructure. A number of important issues must be addressed to successfully confront the health, ecologic, and economic challenges presented by CHABs. Near-term research goals include the development of field-ready tests to identify and quantify cells and toxins, the production of certified reference standards and bulk toxins, formal assessments of CHAB incidence, improved understanding of toxin effects, therapeutic interventions, ecologically benign means to prevent and control CHABs, supplemental drinking water treatment techniques, and the development of risk assessment and management strategies. Long-term goals include the assimilation of CHAB databases into emerging U.S. and international observing systems, the development of quantitative models to predict CHAB occurrence, effects, and management outcomes, and economic analyses of CAHB costs and management benefits. Accomplishing further infrastructure development and freshwater HAB research is discussed in relationship to the Harmful Algal Blooms and Hypoxia Research and Control Act and existing HAB research programs. A sound scientific basis, the integration of CHAB infrastructure with that of the marine HAB community, and a systems approach to risk assessment and management will minimize the impact of this growing challenge to society.


Paediatric middle aortic syndrome with endovascular treatment in East Malaysia.
Middle-aortic syndrome is a surgically curable cause of childhood hypertension. Open surgery is traditionally offered but with the advance of medical technology, endovascular approached is available in many country. Failure to control BP in open surgery is as low as 4.1% compares to 13% in endovascular approaches. However, mortality is 4% in open surgery almost 2 times higher than 2.3% in endovascular approach. This article presents a case of 10 years old child treated successfully without complication with endovascular balloon dilatation, as a first case of such disease in East Malaysia.


Main partner factors associated with worse adherence to HAART among women in Baltimore, Maryland: a preliminary study.
Compared to US men, US women have worse HAART and HIV health outcomes. The study examined main partner factors associated with women's HAART adherence. The community sample comprised 85% African-Americans; 63% had a main partner and 32% relied on their partner for emotional support. Adherence was highest (92%) among those without a main partner and lowest (57%) among those with an HIV seropositive main partner. In adjusted analysis, adherence was 75% less likely among women with an HIV seropositive main partner and 78% less likely among those relying on their partner for emotional support. Furthermore, HIV seropositive versus other serostatus main partners were most likely to provide medication taking assistance and to be preferred in helping participants deal with HIV, yet were no more likely to be nominated as the most helpful to them. Findings reveal women's perceived unmet support needs from HIV seropositive main partners in this population and the need for interventions to promote their HAART adherence. Seroconcordant couples-focused intervention that enhances mutual support of HAART adherence may be an effective approach to improving women's HAART adherence and reducing US gender disparities in HIV health outcomes.


Complications of portal hypertension in adults: a French consensus.
Portal hypertension is responsible for different severe complications such as variceal bleeding, ascites and pulmonary disorders. Different pharmacological and endoscopic treatments have been proposed but some recommendations may differ. The conclusions of a French consensus conference on the prevention and treatments of the main complications of portal hypertension in adults are reported.


Demonstration of a functional variant of chloramphenicol acetyltransferase in Haemophilus influenzae.
Seven clinical isolates of chloramphenicol-resistant Haemophilus influenzae were studied. The products of chloramphenicol inactivation by chloramphenicol acetyltransferase (CAT) were identified by high performance liquid chromatography. The sole product in H. influenzae is a single monoacetyl compound, whereas variants of CAT isolated from other chloramphenicol-resistant bacteria usually produce both monoacetyl and diacetyl chloramphenicol metabolites. The chloramphenicol resistance gene was found to reside on a 65-kb plasmid which, in five of the six cases studied, appeared to be integrated into the host cell chromosome.


Rheology of polyaniline-dinonylnaphthalene disulfonic acid (DNNDSA) montmorillonite clay nanocomposites in the sol state: shear thinning versus pseudo-solid behavior.
The melt rheology of polyaniline (PANI)-dinonylnaphthalenedisulfonic acid (DNNDSA) gel nanocomposites (GNCs) with organically modified (modified with cetyl trimethylammonium bromide)-montmorillonite (om-MMT) clay has been studied for three different clay concentrations at the temperature range 120-160 degrees C. Field emission scanning electron microscopy (FE-SEM), wide angle X-ray scattering (WAXS), differential scanning calorimetry (DSC) and dc-conductivity data (approximately 10(-3) S/cm) indicate that the PANI-DNNDSA melt is in sol state and it is not de-doped at that condition. The WAXS data indicate that in GNC-1 sol clay tactoids are in exfoliated state but in the other sols they are in intercalated state. The zero shear viscosity (eta0), storage modulus (G') and loss modulus (G") increase than that of pure gel in the GNCs. The pure sol and the sols of gel nanocomposites (GNCs) exhibit Newtonian behavior for low shear rate (< 6 x 10(-3) s(-1)) and power law variation for the higher shear rate region. The characteristic time (A) increase with increasing clay concentration and the power law index (n) decreases with increase in clay concentration in the GNCs indicating increased shear thinning for the clay addition. Thus the sols of om-clay nanocomposites of PANI-DNNDSA system are easily processible. The storage modulus (G') of GNC sols are higher than that of pure PANI-DNNDSA sol, GNC1 sol shows a maximum of 733% increase in storage modulus and the percent increase decreases with increase in temperature. Exfoliated nature of clay tactoids has been attributed for the above dramatic increase of G'. The PANI-DNNDSA sol nanocomposites behave as a pseudo-solid at higher frequency where G' and loss modulus (G") show a crossover point in the frequency sweep experiment at a fixed temperature. The crossover frequency decreases with increase in clay concentration and it increases with increase in temperature for GNC sols. The pseudo-solid behavior has been explained from jamming or network formation of clay tactoids under shear. A probable explanation of the two apparently contradictory phenomena of shear thinning versus pseudo-solid behavior of the nanocomposite sols is discussed.


[Soluble Fas in acute rejection in patients with liver transplantation. Response to treatment].
It has been suggested that in the cellular rejection of hepatic graft, the lesion provoked by cytotoxic T-lymphocytes might be mediated by the Fas antigen/Fas ligand system, producing cell death by apoptosis. To determine whether soluble Fas (sFas) is increased during treatment and to evaluate response to treatment. Fourteen patients with orthotopic liver transplantation who presented an episode of acute cellular rejection were studied. Serum levels of sFas were detected by enzyme-immunoanalysis at diagnosis and again 5 days after treatment was completed. As control groups, sFas was analyzed in 12 patients with liver transplantation without rejection and in 10 healthy subjects. sFas levels were found to be significantly higher in patients with rejection than in those without rejection and in healthy subjects (24.2 +/- 39.1 vs. 2.8 +/- 4.0 vs. 0.6 +/- 1.5 UI/ml; p = 0.03). In patients with acute cellular rejection, immunosuppressive treatment significantly decreased sFas levels compared with basal values (24.2 +/- 39.1 vs. 9.9 +/- 30.2 UI/ml; p = 0.005). A clear correlation between the serum levels of sFas, glutamate oxaloacetate transaminase (GOT), glutamate-pyruvate transaminase/glutamic-pyruvic transaminase (GPT) and gamma-glutamyl transferase (GGT). a) The increase of sFas during rejection and the decrease in patients with a good evolution suggests that the Fas system may play an important role in the hepatocyte lesion produced by an apoptosis mechanism in these patients. b) Monitoring sFas could be useful in diagnosing rejection and in evaluating response to treatment.


Differential Effects of Unihemispheric Concurrent Dual-Site and Conventional tDCS on Motor Learning: A Randomized, Sham-Controlled Study.
Based on the literature, unihemispheric concurrent dual-site anodal transcranial Direct Current Stimulation (a-tDCSUHCDS) of primary Motor cortex (M1) and Dorsolateral Prefrontal Cortex (DLPFC) would be more efficient than conventional a-tDCS of M1 to induce larger and longer-lasting M1 corticospinal excitability. The main objective of the present study was to compare the effects of a-tDCSUHCDS and conventional M1 a-tDCS on the extent and durability of the motor sequence acquisition in healthy individuals. In this randomized sham-controlled study, healthy volunteers were randomly divided into three groups: experimental (a-tDCSUHCDS), control (M1 a-tDCS), and sham stimulation groups. The participants practiced serial response time task over three consecutive days when they simultaneously received a-tDCS. Using the skill measure, we assessed motor learning up to 4 weeks after the completion of experimental conditions. Data analysis revealed that all groups exhibited the improved trend over the training course (P<0.001). There were no significant differences in skill acquisition among groups at post-intervention (P>0.05), while a significant improvement was observed between experimental and sham group at the retention time (P<0.05). Moreover, there were no significant differences between the control and two other groups with regard to the retention time (P>0.05). These results revealed a significant increase in the skill acquisition by a-tDCSUHCDS technique with regard to retention issue, which could be a valuable finding in neuro-rehabilitation field.


Small molecules that regulate lifespan: evidence for xenohormesis.
Barring genetic manipulation, the diet known as calorie restriction (CR) is currently the only way to slow down ageing in mammals. The fact that CR works on most species, even microorganisms, implies a conserved underlying mechanism. Recent findings in the yeast Saccharomyces cerevisiae indicate that CR extends lifespan because it is a mild biological stressor that activates Sir2, a key component of yeast longevity and the founding member of the sirtuin family of deacetylases. The sirtuin family appears to have first arisen in primordial eukaryotes, possibly to help them cope with adverse conditions. Today they are found in plants, yeast, and animals and may underlie the remarkable health benefits of CR. Interestingly, a class of polyphenolic molecules produced by plants in response to stress can activate the sirtuins from yeast and metazoans. At least in the case of yeast, these molecules greatly extend lifespan by mimicking CR. One explanation for this surprising observation is the 'xenohormesis hypothesis', the idea that organisms have evolved to respond to stress signalling molecules produced by other species in their environment. In this way, organisms can prepare in advance for a deteriorating environment and/or loss of food supply.


Optimized synthesis, structural investigations, ligand tuning and synthetic evaluation of silyloxy-based alkyne metathesis catalysts.
Nitride- and alkylidyne complexes of molybdenum endowed with triarylsilanolate ligands are excellent (pre)catalysts for alkyne-metathesis reactions of all sorts, since they combine high activity with an outstanding tolerance toward polar and/or sensitive functional groups. Structural and reactivity data suggest that this promising application profile results from a favorable match between the characteristics of the high-valent molybdenum center and the electronic and steric features of the chosen Ar(3)SiO groups. This interplay ensures a well-balanced level of Lewis acidity at the central atom, which is critical for high activity. Moreover, the bulky silanolates, while disfavoring bimolecular decomposition of the operative alkylidyne unit, do not obstruct substrate binding. In addition, Ar(3)SiO groups have the advantage that they are more stable within the coordination sphere of a high-valent molybdenum center than tert-alkoxides, which commonly served as ancillary ligands in previous generations of alkyne metathesis catalysts. From a practical point of view it is important to note that complexes of the general type [(Ar(3)SiO)(3)Mo≡X] (X = N, CR; R = aryl, alkyl, Ar = aryl) can be rendered air-stable with the aid of 1,10-phenanthroline, 2,2'-bipyridine or derivatives thereof. Although the resulting adducts are themselves catalytically inert, treatment with Lewis acidic additives such as ZnCl(2) or MnCl(2) removes the stabilizing N-donor ligand and gently releases the catalytically active template into the solution. This procedure gives excellent results in alkyne metathesis starting from air-stable and hence user-friendly precursor complexes. The thermal and hydrolytic stability of representative molybdenum alkylidyne and -nitride complexes of this series was investigated and the structure of several decomposition products elucidated.


Fluid dynamics of gingival tissues in transition from physiological condition to inflammation.
An increase in gingival sulcular fluid filtration is a common clinical sign of early gingivitis. The aim of this study was to describe the fluid dynamics of the gingival interstitial tissues at the level of the sulcus in the transition towards inflammation. In 13 anesthetized rabbits, a silk ligature was placed around incisors close to the gingival margin, in order to prevent mechanical cleaning of plaque deposition. After 2 to 7 days, animals were anesthetized and interstitial fluid pressure measured using glass micropipettes connected to a servonull pressure system at the level of the free and attached gingiva. Interstitial pressure was 3.8 +/- 2.9 cmH2O, significantly higher than the normal physiological value (about -1 cmH2O). Colloid osmotic pressure of interstitial fluid samples collected using the wick technique was measured using an osmometer whose membrane had a molecular cut-off of 30 kD and averaged 12.8 +/- 2.8 cmH2O (unchanged relative to control). Mean gingival sulcular fluid flow, measured by placing a PE tube (0.5 mm OD, 0.28 mm ID) in the sulcus, was 0.16 +/- 0.12 microl/h; the mean colloid osmotic pressure was 13.6 +/- 6.6 cmH2O, corresponding to a protein concentration of approximately 2.8 g/dl. Proteins of gingival fluid may leak from inflamed gingival interstitium or derive from bacteria of dental plaque. Histological analysis of gingival biopsies showed neutrophilic polymorphonuclear leukocyte infiltrates in both the dermis and epidermis layer. Based on hydraulic and colloid osmotic data, the Starling pressure gradient favored filtration from gingival interstitium to the sulcular space, a condition opposite to that observed in healthy gingiva where fluid filtration is absent.


Associations of autoantibodies, autoimmune risk alleles, and clinical diagnoses from the electronic medical records in rheumatoid arthritis cases and non-rheumatoid arthritis controls.
The significance of non-rheumatoid arthritis (RA) autoantibodies in patients with RA is unclear. The aim of this study was to assess associations of autoantibodies with autoimmune risk alleles and with clinical diagnoses from the electronic medical records (EMRs) among RA cases and non-RA controls. Data on 1,290 RA cases and 1,236 non-RA controls of European genetic ancestry were obtained from the EMRs of 2 large academic centers. The levels of anti-citrullinated protein antibodies (ACPAs), antinuclear antibodies (ANAs), anti-tissue transglutaminase antibodies (AGTAs), and anti-thyroid peroxidase (anti-TPO) antibodies were measured. All subjects were genotyped for autoimmune risk alleles, and the association between number of autoimmune risk alleles present and number of types of autoantibodies present was studied. A phenome-wide association study (PheWAS) was conducted to study potential associations between autoantibodies and clinical diagnoses among RA cases and non-RA controls. The mean ages were 60.7 years in RA cases and 64.6 years in non-RA controls. The proportion of female subjects was 79% in each group. The prevalence of ACPAs and ANAs was higher in RA cases compared to controls (each P < 0.0001); there were no differences in the prevalence of anti-TPO antibodies and AGTAs. Carriage of higher numbers of autoimmune risk alleles was associated with increasing numbers of autoantibody types in RA cases (P = 2.1 × 10(-5)) and non-RA controls (P = 5.0 × 10(-3)). From the PheWAS, the presence of ANAs was significantly associated with a diagnosis of Sjögren's/sicca syndrome in RA cases. The increased frequency of autoantibodies in RA cases and non-RA controls was associated with the number of autoimmune risk alleles carried by an individual. PheWAS of EMR data, with linkage to laboratory data obtained from blood samples, provide a novel method to test for the clinical significance of biomarkers in disease.


The Cys-N-degron pathway modulates pexophagy through the N-terminal oxidation and arginylation of ACAD10.
In the N-degron pathway, N-recognins recognize cognate substrates for degradation via the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome system (hereafter autophagy). We have recently shown that the autophagy receptor SQSTM1/p62 (sequestosome 1) is an N-recognin that binds the N-terminal arginine (Nt-Arg) as an N-degron to modulate autophagic proteolysis. Here, we show that the N-degron pathway mediates pexophagy, in which damaged peroxisomal fragments are degraded by autophagy under normal and oxidative stress conditions. This degradative process initiates when the Nt-Cys of ACAD10 (acyl-CoA dehydrogenase family, member 10), a receptor in pexophagy, is oxidized into Cys sulfinic (CysO2) or sulfonic acid (CysO3) by ADO (2-aminoethanethiol (cysteamine) dioxygenase). Under oxidative stress, the Nt-Cys of ACAD10 is chemically oxidized by reactive oxygen species (ROS). The oxidized Nt-Cys2 is arginylated by ATE1-encoded R-transferases, generating the RCOX N-degron. RCOX-ACAD10 marks the site of pexophagy via the interaction with PEX5 and binds the ZZ domain of SQSTM1/p62, recruiting LC3+-autophagic membranes. In mice, knockout of either Ate1 responsible for Nt-arginylation or Sqstm1/p62 leads to increased levels of peroxisomes. In the cells from patients with peroxisome biogenesis disorders (PBDs), characterized by peroxisomal loss due to uncontrolled pexophagy, inhibition of either ATE1 or SQSTM1/p62 was sufficient to recover the level of peroxisomes. Our results demonstrate that the Cys-N-degron pathway generates an N-degron that regulates the removal of damaged peroxisomal membranes along with their contents. We suggest that tannic acid, a commercially available drug on the market, has a potential to treat PBDs through its activity to inhibit ATE1 R-transferases.Abbreviations: ACAA1, acetyl-Coenzyme A acyltransferase 1; ACAD, acyl-Coenzyme A dehydrogenase; ADO, 2-aminoethanethiol (cysteamine) dioxygenase; ATE1, arginyltransferase 1; CDO1, cysteine dioxygenase type 1; ER, endoplasmic reticulum; LIR, LC3-interacting region; MOXD1, monooxygenase, DBH-like 1; NAC, N-acetyl-cysteine; Nt-Arg, N-terminal arginine; Nt-Cys, N-terminal cysteine; PB1, Phox and Bem1p; PBD, peroxisome biogenesis disorder; PCO, plant cysteine oxidase; PDI, protein disulfide isomerase; PTS, peroxisomal targeting signal; R-COX, Nt-Arg-CysOX; RNS, reactive nitrogen species; ROS, reactive oxygen species; SNP, sodium nitroprusside; UBA, ubiquitin-associated; UPS, ubiquitinproteasome system.


Design and implementation of the European-Mediterranean Postgraduate Programme on Organ Donation and Transplantation (EMPODaT) for Middle East/North Africa countries.
This prospective study reports the design and results obtained after the EMPODaT project implementation. This project was funded by the Tempus programme of the European Commission with the objective to implement a common postgraduate programme on organ donation and transplantation (ODT) in six selected universities from Middle East/North Africa (MENA) countries (Egypt, Lebanon and Morocco). The consortium, coordinated by the University of Barcelona, included universities from Spain, Germany, Sweden and France. The first phase of the project was to perform an analysis of the current situation in the beneficiary countries, including existing training programmes on ODT, Internet connection, digital facilities and competences, training needs, and ODT activity and accreditation requirements. A total of 90 healthcare postgraduate students participated in the 1-year training programme (30 ECTS academic credits). The methodology was based on e-learning modules and face-to-face courses in English and French. Training activities were evaluated through pre- and post-tests, self-assessment activities and evaluation charts. Quality was assessed through questionnaires and semi-structured interviews. The project results on a reproducible and innovative international postgraduate programme, improvement of knowledge, satisfaction of the participants and confirms the need on professionalizing the activity as the cornerstone to ensure organ transplantation self-sufficiency in MENA countries.


Was facial width-to-height ratio subject to sexual selection pressures? A life course approach.
Sexual selection researchers have traditionally focused on adult sex differences; however, the schedule and pattern of sex-specific ontogeny can provide insights unobtainable from an exclusive focus on adults. Recently, it has been debated whether facial width-to-height ratio (fWHR; bi-zygomatic breadth divided by midface height) is a human secondary sexual characteristic (SSC). Here, we review current evidence, then address this debate using ontogenetic evidence, which has been under-explored in fWHR research. Facial measurements were collected from 3D surface images of males and females aged 3 to 40 (Study 1; US European-descent, n = 2449), and from 2D photographs of males and females aged 7 to 21 (Study 2; Bolivian Tsimane, n = 179), which were used to calculate three fWHR variants (which we call fWHRnasion, fWHRstomion, and fWHRbrow) and two other common facial masculinity ratios (facial width-to-lower-face-height ratio, fWHRlower, and cheekbone prominence). We test whether the observed pattern of facial development exhibits patterns indicative of SSCs, i.e., differential adolescent growth in either male or female facial morphology leading to an adult sex difference. Results showed that only fWHRlower exhibited both adult sex differences as well as the classic pattern of ontogeny for SSCs-greater lower-face growth in male adolescents relative to females. fWHRbrow was significantly wider among both pre- and post-pubertal males in the Bolivian Tsimane sample; post-hoc analyses revealed that the effect was driven by large sex differences in brow height, with females having higher placed brows than males across ages. In both samples, all fWHR measures were inversely associated with age; that is, human facial growth is characterized by greater relative elongation in the mid-face and lower face relative to facial width. This trend continues even into middle adulthood. BMI was also a positive predictor of most of the ratios across ages, with greater BMI associated with wider faces. Researchers collecting data on fWHR should target fWHRlower and fWHRbrow and should control for both age and BMI. Researchers should also compare ratio approaches with multivariate techniques, such as geometric morphometrics, to examine whether the latter have greater utility for understanding the evolution of facial sexual dimorphism.


Health care reform and the hospital supply chain.
With health care reform, hospitals will be differentiated in the marketplace by how well they manage the costs of services. Because products will be market priced, hospital materiel managers will have to minimize all other related acquisition costs. The key opportunities will be in changing processes to eliminate non-value added administrative, supply chain, and process activities and their attendant costs.


Validation of New Symptom-Based Fibromyalgia Criteria for Irritable Bowel Syndrome Co-morbidity Studies.
There is significant co-morbidity between irritable bowel syndrome (IBS) and fibromyalgia syndrome (FMS). However, FMS is diagnosed by physical examination, which limits the conduct of co-morbidity studies in a large population-based study. The purpose of this study was to determine the diagnostic validity of a new symptom-based criteria in patients with FMS and/or IBS using the American College of Rheumatology (ACR) criteria as a gold standard. The study participants consisted of women with FMS (n = 30), IBS (n = 27) and controls (n = 28). A new symptom-based diagnostic criteria for FMS comprised a regional pain scale and a visual analogue scale for fatigue. All subjects underwent a physical examination for FMS (ACR criteria) and structured questionnaires of regional pain scale and visual analogue scale for fatigue. A fibromyalgia intensity score was calculated and thresholds of tenderness were determined by a dolorimeter. The number of participants diagnosed with FMS in the entire study population (n = 85) was 31 by the new criteria. Compared to the ACR, the sensitivity of the new criteria was 82.9%, specificity 96.0%, positive predictive value 93.5% and negative predictive value 88.9%. In addition, new criteria were useful for the diagnosis of FMS among the subjects with IBS. A fibromyalgia intensity score was significantly correlated with the threshold of tenderness (r = -0.62, P < 0.001). The new symptom-based diagnostic criteria for the diagnosis of FMS can be used in large-scale clinical and epidemiological co-morbidity studies, in which physical examination is unfeasible. Gastroenterologists investigating the effects of co-morbid FMS in IBS patients can use these new ciriteria with confidence.


AIDS stigma as an obstacle to uptake of HIV testing: evidence from a Zimbabwean national population-based survey.
Using the 2005-2006 Zimbabwe Demographic and Health Survey, we investigated the prevalence of HIV testing uptake within a sample of women (6839) and men (5315), and identified the independent effects of AIDS stigma on testing uptake, with particular emphasis on three pathways to testing: voluntary testing, testing when offered, and testing when required. The prevalence of self-reported HIV testing was higher among women (31%) than men (22%). For women, the main pathway to testing uptake was to accept testing when it is offered (46%), whereas for men it was voluntary testing (53%). In the logistic regression models, we found that social rejection stigma was inversely associated with uptake across all pathways of testing for women, but not men. As regards observed enacted stigma, respondents who both knew someone with HIV and had observed discrimination against someone with HIV were more likely to test for HIV through all pathways, while those who knew someone with HIV but had not observed stigma were more likely to test voluntarily. Individual characteristics important to the adoption of testing included high educational attainment, religion, exposure to mass media, and ever use of condoms; while being never married and self-perceived risk were barriers to testing. Programmatic strategies aimed at increasing HIV testing uptake should consider reducing stigma toward people living with HIV/AIDS and also addressing the role of agency and structure in individual's decision to be tested for HIV.


Behaviour does not fully explain the high risk of chronic liver disease in less educated men in Hungary.
Hungary has among the highest mortality rates from chronic liver disease (CLD) and cirrhosis in Europe. Usually, conventional behavioural factors are hypothesized as the cause of the high risk of CLD. A case-control study was performed with 287 cases and 892 controls to study the relationship between socio-economic and behavioural factors and the risk of CLD. Liver disease was verified by physical examination and blood tests. Blood samples were collected for detecting hepatitis B, C and E virus infection. Information on exposure factors was recorded by the participating physicians and by self-administered questionnaire. Simple regression analysis was used to study the relationship between CLD/cirrhosis and potential risk factors as alcohol intake (amount and source), problem drinking, cigarette smoking, physical activity, viral hepatitis infections, socio-economic factors (education, financial and marital status). Multiple regression analysis was used to identify whether the effect of socio-economic factors is fully mediated by health behaviour (smoking, alcohol consumption, physical activity). The univariate analysis showed that heavy alcohol consumption, problem drinking, former and heavy cigarette smoking, single, separated or divorced marital status, bad or very bad perceived financial status and lower education significantly increased the risk of CLD/cirrhosis. The effect of marital status and of education did not change after adjustment for behavioural factors, but the effect of perceived financial status disappeared. The effect of low socio-economic status on the risk of CLD/cirrhosis is only partially explained by conventional behavioural risk factors in Hungary.


Role of intraoperative angiography in the surgical treatment of cerebral aneurysms.
The benefit of using intraoperative angiography (IA) during aneurysm surgery is still uncertain. In this prospective study, the authors evaluate the radiographically demonstrated success of surgical treatment in 151 consecutive patients harboring 173 aneurysms who selectively underwent IA examination. The authors also assess the frequency with which IA led to repositioning of the aneurysm clip. Intraoperative angiography was used selectively in this series, based on the surgeon's concern about the potential for residual aneurysm, distal branch occlusion, or parent vessel stenosis. Specific variables were analyzed to determine their impact on the incidence of clip repositioning and the accuracy of IA was evaluated by direct comparison with postoperative angiography (PA) in 90% of the cases in which IA was used. The selective use of IA led to successful treatment as shown by PA, with a low incidence of unexpected residual aneurysm (3.2%), distal branch occlusion (1.9%), and parent vessel stenosis (0%). Intraoperative angiography led to immediate repositioning of the aneurysm clip in 27% of the cases. Anterior cerebral artery aneurysms required clip repositioning less often and superior hypophyseal artery aneurysms required repositioning more often than aneurysms in other locations. Large and giant aneurysms required clip repositioning more often than small aneurysms; however, they were also more likely to display false success on IA as determined by PA. Aneurysms arising along the internal carotid artery were more likely to display successful clipping on IA, as determined by PA, than were aneurysms in other locations. The results of this series support the selective use of IA in the treatment of complex aneurysms, particularly large and giant aneurysms as well as superior hypophyseal artery aneurysms. As measured by PA, IA will improve the outcome of these patients.


Structural estimates of treatment effects on outcomes using retrospective data: an application to ductal carcinoma in situ.
Analysis of observational cohort data is subject to bias from unobservable risk selection. The authors compared econometric models and treatment effectiveness estimates using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare claims data for women diagnosed with ductal carcinoma in situ. Treatment effectiveness estimates for mastectomy and breast-conserving surgery (BCS) with or without radiotherapy were compared using three different models: simultaneous-equations model, discrete-time survival model with unobserved heterogeneity (frailty), and proportional hazards model. Overall trends in disease-free survival (DFS), or time to first subsequent breast event, by treatment are similar regardless of the model, with mastectomy yielding the highest DFS over 8 years of follow-up, followed by BCS with radiotherapy, and then BCS alone. Absolute rates and direction of bias varied substantially by treatment strategy. DFS was underestimated by single-equation and frailty models compared with the simultaneous-equations model and randomized controlled trial results for BCS with radiotherapy and overestimated for BCS alone.


Intravitreal pegaptanib for the treatment of ischemic diabetic macular edema.
Pegaptanib has been shown to be effective in treating diabetic macular edema (DME). In the original Phase II/III trial, however, patients with macular ischemia were excluded. In this study, we treated patients with ischemic DME. Macular ischemia was defined as a 30% increase in the area of the foveal avascular zone (FAZ) at 45 seconds on fundus fluorescein angiography. In addition, the participants had diffuse foveal-involving DME with a central subfield thickness (CST) of >300 μm on spectral-domain optical coherence tomography. Five intravitreal pegaptanib injections were given 6 weeks apart. The final study visit was 6 weeks after the fifth injection. The primary outcome was change in the size of FAZ. Secondary outcomes were change in best-corrected visual acuity (BCVA) and the change in CST. Thirty participants were enrolled. Three were unable to complete the full course of treatment. Their outcomes were carried forward for the first part of this analysis. There was no statistically significant change in the mean size of the FAZ from baseline to the final visit. Subclassifying participants as those with minimal/moderate ischemia (16 participants, FAZ area <1,000 pixels) and those with more severe ischemia (14 participants, FAZ area >1,000 pixels) also showed no statistically significant change in the mean area of the FAZ. On average, BCVA increased and CST decreased from baseline to the final visit, but these changes were not statistically significant. Using per protocol analysis on those participants who completed the full course of treatment, the mean BCVA increased from 49.2 to 53.9 letters (P=0.046). In this study, intravitreal injection of pegaptanib did not significantly alter the size of the FAZ in participants with varying degrees of ischemic DME. There was, however, a significant improvement in mean BCVA in those who completed the treatment course.


[Diagnosis of ischemic cardiopathy in ambulatory care patients. Multivariate analysis of clinical and electrocardiographic data].
This study was done on 113 subjects, 93 men and 20 women, whose ages ranged between 32 and 70 years (average 52.9 years). Males varied between 35 and 70 years (average 53.7) and females between 32 and 67 years (average 49.5). Our objective is: to give an account of the different discriminatory methods with mixed data usually used in medical applications, to apply these methods to all the subjects studied with the purpose of comparing their performance and, to develop a protocol for diagnosing coronary artery disease by noninvasive tests. All the subjects were referred for evaluation of chest pain, and were submitted to an exercise test on an ergometric bicycle, selective coronary angiography and left ventriculography. Patients with prior myocardial infarction, cardiomyopathy, valvular or congenital disease, mitral valve prolapse or intraventricular conduction defect were excluded. Subjects were classified as having coronary artery disease and not having coronary artery disease according to the coronarographic results. We used four clinical variables (age, sex, risk factor and chest pain) and five variables obtained from the stress test (ST depression, appearance of chest pain, appearance of arrhythmias, variations in blood pressure and R wave changes). For the analysis of this set of data we use well known univariate statistical methods, such as chi-squared test, F-test and t-test, and the following multivariate statistical methods: Fisher, Quadratic and Logistic, discriminant methods. To study the relative importance of the different variables in the discrimination of the individuals, we performed a stepwise linear discriminant analysis over the 113 subjects. Of the 9 variables tested R-wave was of little value and excluded.(ABSTRACT TRUNCATED AT 250 WORDS)


Is there any difference in organizational commitment between general hospitals and specialized hospitals? Empirical evidence from public hospitals in Beijing, China.
The purpose of the study on the one hand is to see different hospital organization commitment have difference, including the overall score and various dimensions, on the other hand, due to the different hospital type, its function orientation is different, the factors of the doctor organization commitment may also exist differences, so the study of another purpose is to determine for different types of hospital doctor organization commitment the focus and key groups, provide reference for the doctor incentive strategy. A total of 292 doctors in four large public hospitals in Beijing were investigated. Physicians' perceived organizational commitment was investigated using self-made electronic questionnaires. Data were analyzed by factor analysis, descriptive statistics, t-test, ANOVA, and multiple linear regression. In the large public hospital doctor perception of the hospital commitment status, Specialized hospitals had higher overall commitment behavior scores, it is 3.47 ± 0.86; General hospital commitment behavior scored low at 3.39 ± 0.91. In the regression results, department category, working years, administrative position, and entry mode are the influencing factors of the organizational commitment of doctors in general hospitals, while in specialized hospitals, in addition to whether to hold an administrative position, entry mode, and working hours, the influencing factors also include gender, professional title and overseas learning background. There are differences in the perceived organizational commitment by doctors in different types of public hospitals, and different factors influencing their organizational commitment.Hospital type directly influences physicians' organizational commitment and plays a moderating role in influencing other factors. A possible solution is general hospital specialization, encouraging general hospitals to develop the dominant discipline. These findings can help healthcare service hospital executives or government policymakers understand the impact of hospital specialization strategies and develop more efficient medical staff incentive systems.


The Role of Serine Proteases and Antiproteases in the Cystic Fibrosis Lung.
Cystic fibrosis (CF) lung disease is an inherited condition with an incidence rate of approximately 1 in 2500 new born babies. CF is characterized as chronic infection of the lung which leads to inflammation of the airway. Sputum from CF patients contains elevated levels of neutrophils and subsequently elevated levels of neutrophil serine proteases. In a healthy individual these proteases aid in the phagocytic process by degrading microbial peptides and are kept in homeostatic balance by cognate antiproteases. Due to the heavy neutrophil burden associated with CF the high concentration of neutrophil derived proteases overwhelms cognate antiproteases. The general effects of this protease/antiprotease imbalance are impaired mucus clearance, increased and self-perpetuating inflammation, and impaired immune responses and tissue. To restore this balance antiproteases have been suggested as potential therapeutics or therapeutic targets. As such a number of both endogenous and synthetic antiproteases have been trialed with mixed success as therapeutics for CF lung disease.


Synchronization-induced persistence versus selection for habitats in spatially coupled ecosystems.
Critical population phase transitions, in which a persistent population becomes extinction-prone owing to environmental changes, are fundamentally important in ecology, and their determination is a key factor in successful ecosystem management. To persist, a species requires a suitable environment in a sufficiently large spatial region. However, even if this condition is met, the species does not necessarily persist, owing to stochastic fluctuations. Here, we develop a model that allows simultaneous investigation of extinction due to either stochastic or deterministic reasons. We find that even classic birth-death processes in spatially extended ecosystems exhibit phase transitions between extinction-prone and persistent populations. Sometimes these are first-order transitions, which means that environmental changes may result in irreversible population collapse. Moreover, we find that higher migration rates not only lead to higher robustness to stochastic fluctuations, but also result in lower sustainability in heterogeneous environments by preventing efficient selection for suitable habitats. This demonstrates that intermediate migration rates are optimal for survival. At low migration rates, the dynamics are reduced to metapopulation dynamics, whereas at high migration rates, the dynamics are reduced to a multi-type branching process. We focus on species persistence, but our results suggest a unique method for finding phase transitions in spatially extended stochastic systems in general.


Is the action of inhibin mediated via a unique receptor?
The receptor system and the molecular mechanisms by which inhibin acts on its target cells are poorly understood, in contrast to the situation for the structurally related molecule, activin. On the basis of evidence that the biological action of inhibin in a number of systems resembles that of an activin antagonist, it has been contended that inhibin operates by competition for the activin receptor rather than through a specific inhibin receptor. However, mounting evidence indicates that inhibin also interacts with high affinity and specificity with membrane-binding proteins that are likely to be the putative inhibin receptor.


The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells.
Bispecific antibodies (bsAb) are considered as promising tools for the elimination of disseminated tumour cells in a minimal residual disease situation. The bsAb-mediated recruitment of an immune effector cell in close vicinity of a tumour cell is thought to induce an antitumoural immune response. However, classical bispecific molecules activate only a single class of immune effector cell that may not yield optimal immune responses. We therefore constructed an intact bispecific antibody, BiUII (anti-CD3 x anti-EpCAM), that not only recognizes tumour cells and T lymphocytes with its two binding arms, but also binds and activates Fcgamma-receptor positive accessory cells through its Fc-region. We have demonstrated recently that activated accessory cells contribute to the bsAb-induced antitumoural activity. We now analyse this stimulation in more detail and demonstrate here the BiUII-induced upregulation of activation markers like CD83 and CD95 on accessory cells and the induction of neopterin and biopterin synthesis. Experiments with pure cell subpopulations revealed binding of BiUII to CD64+ accessory cells and CD16+ NK cells, but not to CD32+ B lymphocytes. We provide further evidence for the importance of the Fc-region in that this bispecific molecule stimulates Fcgamma-R-positive accessory cells to eliminate tumour cells in vitro by direct phagocytosis.


Gemcitabine/nab-paclitaxel with pamrevlumab: a novel drug combination and trial design for the treatment of locally advanced pancreatic cancer.
Pancreatic ductal adenocarcinomas exhibit a high degree of desmoplasia due to extensive extracellular matrix deposition. Encasement of mesenteric vessels by stroma in locally advanced pancreatic cancer (LAPC) prevents surgical resection. This study sought to determine if the addition of a monoclonal antibody to connective tissue growth factor, pamrevlumab, to neoadjuvant chemotherapy would be safe and lead to improved resectability in this surgically adverse patient population. In this phase I/II trial, 37 patients with LAPC were randomised 2:1 to gemcitabine/nab-paclitaxel plus (Arm A, n=24) or minus (Arm B, n=13) pamrevlumab. Those who completed six cycles of treatment were assessed for surgical eligibility by protocol-defined criteria. Resection rates, progression-free and overall survival were evaluated. Eighteen (75%) patients in Arm A and seven (54%) in Arm B completed six cycles of therapy with similar toxicity patterns. In Arms A and B, carbohydrate antigen 19-9 response, as defined by ≥50% decline from baseline, occurred in 13 (65%) and 5 (42%), respectively. Sixteen (16%) per cent of patients were radiographically downstaged by National Comprehensive Cancer Network criteria (5 in Arm A (21%) and 1 (8%) in Arm B). Positron emission tomography normalised in 9 (38%) vs 3 (23%) of patients in Arm A vs Arm B, respectively, and correlated with surgical exploration. Eligibility for surgical exploration was 17 (71%) vs 2 (15%) (p=0.0019) and resection was achieved in 8 (33%) vs 1 (8%) of patients in Arm A vs Arm B (p=0.1193), respectively. Postoperative complication rates were not different between arms. Neoadjuvant chemotherapy with pamrevlumab holds promise for enhancing resection rates in patients with LAPC without added toxicity. This combination merits evaluation in a larger patient cohort.


Domestic dog ownership: a risk factor for human infection with Leishmania (Viannia) species.
An epidemiological study has shown that cumulative, village prevalence of Leishmania (Viannia) infection in dogs ranges from 8% to 45% in Huánuco, Peru. Using data from a prospective survey of human American cutaneous leishmaniasis (ACL) collected during 1994-98, it was shown that the village-level risk of human ACL did not significantly increase with dog abundance, neither in absolute terms (P = 0.659) nor in relation to dog:human ratios (P = 0.213). A significant positive association was observed between risk of human ACL and village dog ACL prevalence (P = 0.022). When controlled for village dog ACL prevalence, there also was an association between the average number of dogs per household and risk of human ACL (P = 0.033). The results suggest that dogs play a role in the (peri)domestic transmission of Le. (Viannia) to humans in Huánuco and indicate that a control intervention targeting dogs to control human ACL is warranted.


Perceived horizontal body position in healthy and paraplegic subjects: effect of centrifugation.
The perception of body position is mainly mediated by otolith information and visual cues. It has been shown, however, that proprioceptive sources are also involved. To distinguish between the contributions of the vestibular and nonvisual extra-vestibular information to graviception, we tested the effects of a stimulus that leaves the vestibular input unchanged but modifies the information from sense organs located more caudal along the trunk. This was achieved by bringing subjects into a horizontal ear-down position and rotating them around an earth-vertical axis that coincided with the interaural axis. In this paradigm, through centrifugal force, the stimulation of the vestibular and the putative extravestibular graviceptive organs in the body becomes dissociated. Healthy subjects (n = 14) and paraplegic patients with lesions between T4 and T8 (n = 7) adjusted themselves to the perceived horizontal right-ear down body position under two conditions: one with constant velocity rotation (ROT, velocity =120 degrees /s) around the earth-vertical axis of the turntable, and one without rotation (BASE). Among healthy subjects, the individual differences between BASE and ROT varied widely in both the feet-up or feet-down direction. In contrast, adjustments in paraplegic patients during ROT were always in the feet-down direction compared with BASE. A model with two extravestibular graviceptive sensors could explain our results: one sensor is located rostral to T4, and the other is caudal to T8. A load on the rostral graviceptor is interpreted as a tilt of the body in the feet-up direction and shifts the adjustments of perceived body position feet-down; a load on the caudal receptor is interpreted as a tilt in the feet-down direction and shifts the perceived body position feet-up. During ROT, healthy subjects solve the discrepant inputs of both extravestibular graviceptors in a highly variable manner, while paraplegic subjects show less variability because they are restricted to only the rostral graviceptor.


Interference of immunoglobulins in the radioimmunoassay of human beta-endorphin.
The interference of immunoglobulins in the radioimmunoassay (RIA) of human beta-endorphin was investigated. Human IgM showed no cross-reactivity. Human IgA showed a weak cross-reaction, but the dilution curve of IgA did not show parallelism with the standard curve of beta-endorphin, thus indicating its antigenic difference. The dilution curves of human IgG showed 0.18% displacement with respect to the human beta-endorphin standard curve, with good parallelism. Moreover, five patients with multiple myeloma of the IgG type showed falsely elevated beta-endorphin levels. We investigated the possibility that certain IgGs may be responsible for the displacement of [125I]beta-endorphin in the beta-endorphin kit. The apparent beta-endorphin level of plasma from multiple myeloma patients was markedly decreased after affinity chromatography of the serum on protein A-Sepharose. In another 3 patients with multiple myeloma, we examined IgG interference by measuring the beta-endorphin levels in their lyophilized IgG diluted with saline. The results demonstrated high values of 20.2, 25.5 and 21.2 pmol/l respectively, also showing good parallelism. These immunological parallels to human beta-endorphin verify that a part of the amino acid sequence of human IgG is similar to that of human beta-endorphin. Consequently, in the measurement of beta-endorphin with polyclonal antibody, the results may sometimes be spuriously high due to cross-reaction with IgG, e.g., in patients with IgG myeloma. To avoid IgG interference, a specific monoclonal antibody to synthetic beta-endorphin should be used rather than polyclonal antibodies.


Appendectomy increased the risk of ischemic heart disease.
Although the appendix may not be considered vital, recent studies have noted adverse health consequences after appendectomy. This study aimed to use a population-based data set to explore whether appendectomy increases the risk for subsequent ischemic heart disease (IHD) in a 3-y follow-up period. This study used data from the Longitudinal Health Insurance Database 2000 in Taiwan. The study cohort included 5413 patients who underwent appendectomies. The comparison cohort was selected by randomly recruiting 16,239 enrollees matched with the study group in terms of sex, age, hypertension, hyperlipidemia, and diabetes. Each individual was tracked for 3 y to identify whether he and/or she developed IHD during the follow-up period. Cox proportional hazard regressions were performed for analysis. During a 3-y follow-up, 196 (3.62%) and 375 (2.31%) IHD incidents developed in the study and the comparison cohorts, respectively. For adults aged ≥18 y, experiencing an appendectomy was independently associated with a 1.54-fold increased risk of IHD during the 3 y of follow-up (95% CI = 1.29-1.84). The association persisted in further analyses stratified by age. There is an increased risk of subsequent IHD within 3 y after appendectomy, and this underscores the need for more serious clinical decision-making in removing the appendix. Regular monitoring for IHDs is also recommended for patients who have undergone an appendectomy.


Variations in the profile and content of anthocyanins in wines made from cabernet sauvignon and hybrid grapes.
To detect adulteration of wine, it has been proposed that the ratio of acetylated to p-coumaroylated conjugates of nine characteristic anthocyanins can be used to determine whether a wine is derived from Cabernet Sauvignon or hybrid grapes. If the ratio is >3, then a wine is classified as being derived from Cabernet Sauvignon grapes. This test has significant commercial implications as it is being used to decide whether Cabernet Sauvignon-labeled wines are genuine and can be imported into Germany. To assess whether this is a valid approach, 24 wines were analyzed, 4 of which were made from hybrids and 20 from Cabernet Sauvignon, with vintages ranging from 1993 to 2000. Only 13 of the Cabernet Sauvignon wines contained all nine of the "characteristic" anthocyanins, and the ratio of acetylated to p-coumaroylated derivatives varied from 1.2 to 6.5. It is evident that the use of the anthocyanin ratio method is flawed and that examination of the whole anthocyanin profile and/or investigation of the proportion of monoglucoside and acetylated anthocyanins is a better approach to distinguish between hybrid and Cabernet Sauvignon wines.


Imaging neuroblastoma: what the radiologist needs to know.
Neuroblastoma is the most common extracranial solid malignancy in children. The tumor has variable biological behavior that can be predicted by patient age, genetic features, tumor biology and extent of disease at diagnosis. Factors chosen by various cooperative groups to define risk of treatment failure have been non-uniform. Therefore, historically, it has been difficult to compare outcomes across clinical trials performed around the world. This has hindered the advancement of treatment strategies to improve survival of these patients. The International Neuroblastoma Risk Group (INRG) was established in 2004 to develop a consensus approach to pretreatment risk stratification. The result was the development of the INRG Staging System (INRGSS) which relies on imaging-defined risk factors (IDRFs) that are determined before surgery or other therapy. With the application of the INRGSS the radiologist's role in staging children with neuroblastoma is increased. This review provides an overview of the INRGSS and the IDRFs.


Institutional trust is a distinct construct related to vaccine hesitancy and refusal.
Vaccine hesitancy is driven by a heterogeneous and changing set of psychological, social and historical phenomena, requiring multidisciplinary approaches to its study and intervention. Past research has brought to light instances of both interpersonal and institutional trust playing an important role in vaccine uptake. However, no comprehensive study to date has specifically assessed the relative importance of these two categories of trust as they relate to vaccine behaviors and attitudes. In this paper, we examine the relationship between interpersonal and institutional trust and four measures related to COVID-19 vaccine hesitancy and one measure related to general vaccine hesitancy. We hypothesize that, across measures, individuals with vaccine hesitant attitudes and behaviors have lower trust-especially in institutions-than those who are not hesitant. We test this hypothesis in a sample of 1541 Canadians. A deficit in both interpersonal and institutional trust was associated with higher levels of vaccine hesitant attitudes and behaviors. However, institutional trust was significantly lower than interpersonal trust in those with high hesitancy scores, suggesting that the two types of trust can be thought of as distinct constructs in the context of vaccine hesitancy. Based on our findings, we suggest that diminished institutional trust plays a crucial role in vaccine hesitancy. We propose that this may contribute to a tendency to instead place trust in interpersonally propagated belief systems, which may be more strongly misaligned with mainstream evidence and thus support vaccine hesitancy attitudes. We offer strategies rooted in these observations for creating public health messages designed to enhance vaccine uptake.


Next-day memory impairment with triazolam use.
The prevalence, rate, and degree of memory impairment for next-day activities during a short, intermittent course of bedtime doses of triazolam, temazepam, and placebo were assessed in a double-blind parallel-group study. 5 of the 6 subjects in the triazolam group reported at least one episode of next-day memory impairment/amnesia, with a total of 12 episodes being reported for the 30 subject-drug nights (a rate of 40%). In the temazepam group there were no such episodes of memory impairment. Immediate and delayed recall were also tested and related to whether active drug or placebo had been taken the night before. Impairment of delayed recall was significantly and several times greater than that in the temazepam or placebo groups. Next-day memory impairment/amnesia after a bedtime dose of triazolam tended to increase with continued or intermittent drug use. Cognitive impairments associated with triazolam probably represent a spectrum of organic brain dysfunction, with memory impairment/amnesia and confusion being the commonest, and milder manifestations and hallucinations and delusions the more severe and less common, features.


The specialized centers of research in rheumatoid arthritis. Recent progress and prospects for future advances.
Specialized Centers of Research (SCOR) in arthritis are interdisciplinary research programs to investigate disease pathogenesis as well as advance diagnosis and treatment. A recent meeting of investigators from the three SCOR programs in rheumatoid arthritis demonstrated progress in several important research areas. Because of the multiplier effects of SCOR programs, new investigators have been enlisted into arthritis research as issues related to this disease become a focus of investigation throughout universities and medical centers. Continued progress by the SCOR programs should provide new targets for therapeutic intervention as well as strategies for monitoring disease activity.


Biologic and phenotypic analysis of early hematopoietic progenitor cells in umbilical cord blood.
Umbilical cord blood (UCB) is an attractive potential alternative to bone marrow (BM) as a source of hematopoietic progenitor cells since the number of progenitors in UCB is similar or even greater than that in normal BM. It was the aim of the present study to analyze the degree of immaturity of UCB progenitor cells. UCB mononuclear (MNC) and/or CD34+ cells were tested for surface antigen phenotype, expression of cytokines receptor, effect of stem cell factor (SCF) on colony growth, resistance to mafosfamide and replating potential. We have found that 34.9 +/- 3.4% and 77.9 +/- 2.6% of UCB CD34+ cells did not express CD38 and CD45RA antigens, respectively, suggesting that UCB contains a high proportion of immature progenitor cells. By means of three-color analysis, the receptor for SCF was detected on the majority of the CD34+ HLA-DR+ subpopulation; in fact, 81.8% +/- 4.3% of CD34+ HLA-DR+ cells were defined as SCF(low) and 8.1 +/- 1.5% as SCF(high). Colony growth of MNC and CD34+ cells was enhanced by the addition of SCF to methylcellulose mixture, resulting in a statistically significant increase in CFU-GM and CFU-GEMM but not in BFU-E numbers. UCB progenitor cells showed a higher resistance to mafosfamide treatment, in comparison to BM; the addition of SCF to the culture medium resulted in a statistically significant increase in mafosfamide concentration required to inhibit 95% of colony growth (P < or = 0.05). Moreover, as shown by single colony transfer assays, the presence of SCF in primary cultures promoted a significantly higher replating potential for both untreated (42 +/- 3.3% vs 21 +/- 4.6%, P < or = 0.018) and mafosfamide-treated samples (62 +/- 5.6% vs 44 +/- 6.1%, P < or = 0.018). In conclusion, UCB is a source of progenitor cells with immature characteristics in terms of surface antigen expression, distribution of SCF receptor, resistance to mafosfamide and replating potential. Therefore, UCB progenitor cells represent an ideal candidate population for experimental programs involving gene transfer and ex vivo stem cell expansion.


Proteomic analysis of menstrual blood.
Menstruation is the expulsion of the endometrial lining of the uterus following a nearly month long preparation for embryo implantation and pregnancy. Increasingly, the health of the endometrium is being recognized as a critical factor in female fertility, and proteomes and transcriptomes from endometrial biopsies at different stages of the menstrual cycle have been studied for both diagnostic and therapeutic purposes (1 Kao, L. C., et al. 2003 Endocrinology 144, 2870-2881; Strowitzki, Tet al. 2006 Hum. Reprod. Update 12, 617-630; DeSouza, L., et al. 2005 Proteomics 5, 270-281). Disorders of the uterus ranging from benign to malignant tumors, as well as endometriosis, can cause abnormal menstrual bleeding and are frequently diagnosed through endometrial biopsy (Strowitzki, Tet al. 2006 Hum. Reprod. Update 12, 617-630; Ferenczy, A. 2003 Maturitas 45, 1-14). Yet the proteome of menstrual blood, an easily available noninvasive source of endometrial tissue, has yet to be examined for possible causes or diagnoses of infertility or endometrial pathology. This study employed five different methods to define the menstrual blood proteome. A total of 1061 proteins were identified, 361 were found by at least two methods and 678 were identified by at least two peptides. When the menstrual blood proteome was compared with those of circulating blood (1774 proteins) and vaginal fluid (823 proteins), 385 proteins were found unique to menstrual blood. Gene ontology analysis and evaluation of these specific menstrual blood proteins identified pathways consistent with the processes of the normal endometrial cycle. Several of the proteins unique to menstrual blood suggest that extramedullary uterine hematopoiesis or parenchymal hemoglobin synthesis may be occurring in late endometrial tissue. The establishment of a normal menstrual blood proteome is necessary for the evaluation of its usefulness as a diagnostic tool for infertility and uterine pathologies. Identification of unique menstrual blood proteins should aid the forensic community in distinguishing menstrual blood from circulating blood.


The Power of LC-MS Based Multiomics: Exploring Adipogenic Differentiation of Human Mesenchymal Stem/Stromal Cells.
The molecular study of fat cell development in the human body is essential for our understanding of obesity and related diseases. Mesenchymal stem/stromal cells (MSC) are the ideal source to study fat formation as they are the progenitors of adipocytes. In this work, we used human MSCs, received from surgery waste, and differentiated them into fat adipocytes. The combination of several layers of information coming from lipidomics, metabolomics and proteomics enabled network analysis of the biochemical pathways in adipogenesis. Simultaneous analysis of metabolites, lipids, and proteins in cell culture is challenging due to the compound's chemical difference, so most studies involve separate analysis with unimolecular strategies. In this study, we employed a multimolecular approach using a two-phase extraction to monitor the crosstalk between lipid metabolism and protein-based signaling in a single sample (~105 cells). We developed an innovative analytical workflow including standardization with in-house produced 13C isotopically labeled compounds, hyphenated high-end mass spectrometry (high-resolution Orbitrap MS), and chromatography (HILIC, RP) for simultaneous untargeted screening and targeted quantification. Metabolite and lipid concentrations ranged over three to four orders of magnitude and were detected down to the low fmol (absolute on column) level. Biological validation and data interpretation of the multiomics workflow was performed based on proteomics network reconstruction, metabolic modelling (MetaboAnalyst 4.0), and pathway analysis (OmicsNet). Comparing MSCs and adipocytes, we observed significant regulation of different metabolites and lipids such as triglycerides, gangliosides, and carnitine with 113 fully reprogrammed pathways. The observed changes are in accordance with literature findings dealing with adipogenic differentiation of MSC. These results are a proof of principle for the power of multimolecular extraction combined with orthogonal LC-MS assays and network construction. Considering the analytical and biological validation performed in this study, we conclude that the proposed multiomics workflow is ideally suited for comprehensive follow-up studies on adipogenesis and is fit for purpose for different applications with a high potential to understand the complex pathophysiology of diseases.


Development by design of experiment and validation of a HPLC-UV method for simultaneous quantification of 1-nitro-2-phenylethane and methyleugenol: Application to nail permeation/retention studies.
Aniba canelilla (Kunth) Mez is an aromatic tree from Amazon region whose essential oil presents 1-nitro-2-phenylethane (NP) and methyleugenol (ME) as major compounds. Several properties are attributed to Aniba canelilla essential oil (ACEO), such as antifungal. Onychomycoses are fungal nail infections that require novel therapeutic alternatives, especially topical ones. However, to ensure the success of topical therapy, the active compound should be able to penetrate/permeate the nail plate, which is challenging due to the highly keratinized composition of this structure. Thus, the aims of this article were to develop, validate and apply a high-performance liquid chromatography method (HPLC-UV) to quantify NP and ME in porcine hoof extract (PHE) and receptor fluid (RF) during in vitro permeation/retention studies in nail model, for which porcine hoof membranes were used. For method development, two Designs of Experiment (DoE) were adopted: 23 Full Factorial and Box-Behnken. Retention times of 5.65 and 7.49 min were achieved for NP and ME, respectively. The method was full validated for NP and ME quantification in receptor fluid, in accordance with the recommended parameters by ICH Q2(R1) Guideline. In addition, the method was full validated for NP and ME quantification in porcine hoof extract, considering the parameters and criteria of ICH M10 Guideline. In vitro permeation/retention studies were carried out in nail model, and promising results were obtained. NP reached the receptor fluid in the order of 441.1 ± 92.1 µg/cm2 at 72 h. The amount of NP and ME retained into porcine hoof membrane was 1272.6 ± 225.7 µg/cm2 and 84.7 ± 20.4 µg/cm2, respectively, at 72 h. Our findings open perspective to develop topical formulations containing ACEO as active compound aiming the management of onychomycosis.


Impact of cigarette smoking in high-risk patients participating in a clinical trial. A substudy from the Heart Outcomes Prevention Evaluation (HOPE) trial.
In recent large cardiovascular trials done in stable patients, 14-31% of the participants were smokers; the consequences of smoking in these trials using medications known to reduce cardiovascular events, have not been assessed. We evaluated the cardiovascular outcomes according to smoking status of men and women participating in the Heart Outcomes Prevention Evaluation trial. The occurrence of cardiovascular events was documented among participants who did not change their smoking status during the trial. There were 2728 'never smokers', 5241 'former smokers' and 936 'current smokers', and all had stable cardiovascular disease or diabetes with at least one other risk factor. None had previous congestive heart failure or known left ventricular ejection fraction < 0.40. During the 4.5-year follow-up, there were 641 cardiovascular deaths, 978 myocardial infarctions, 358 strokes and 1021 deaths. In comparison to 'never smokers', smokers had relative risks adjusted for confounding variables including medications known to reduce cardiovascular mortality and morbidity, for cardiovascular death of 1.65 [95% confidence interval (CI), 1.28-2.14], for myocardial infarction of 1.26 (95% CI, 1.01-1.58), for stroke of 1.42 (95% CI, 1.00-2.04), and for total mortality of 1.99 (95% CI, 1.63-2.44). The rates of these events among 'former smokers' were not different from those of 'never smokers'. Smoking increased the risk of mortality and morbidity among high-risk patients despite the use of medications known to reduce cardiovascular events. Smoking cessation programs should be reinforced even for patients participating in clinical trials.


Elevated serum tobramycin concentrations after treatment with tobramycin inhalation in a preterm infant.
High-dose inhaled tobramycin has been increasingly used for treatment and suppression of Pseudomonas aeruginosa pulmonary infections, especially in patients with cystic fibrosis. The advantage of inhalation over other routes of administration is minimal systemic absorption, which reduces the potential for adverse effects. However, cases of adults who had elevated serum concentrations and experienced systemic adverse effects due to excessive systemic absorption after inhaled tobramycin have been reported. We describe a prematurely born infant with numerous congenital and acquired disorders who required assisted mechanical ventilation and a 60-day stay in the neonatal intensive care unit (NICU). Tracheostomy and mechanical ventilatory support were required throughout the infant's hospital stay. The patient developed several pulmonary infections caused by various bacteria. He was treated with multiple antibiotics, including two different dose preparations of inhaled tobramycin 80 mg and 300 mg, administered through the tracheostomy and the ventilator. The infant was given a total of five preparations of tobramycin 80 mg/dose and three of 300 mg/dose, for a total cumulative dose of 1,300 mg over a 6-day period. His tobramycin concentrations increased, prompting discontinuation of the inhaled tobramycin. The infant died on day 60. To our knowledge, this is the first report of elevated tobramycin concentrations after inhalation in an infant. Although studies have found that tobramycin is safe and effective, certain patient populations are more at risk for toxicity. Tobramycin concentrations should be closely monitored in patients with significant underlying renal disorders, especially those in age-group extremes.


[Multiple antibiotic resistance of associative microflora during urogenital pathology].
Susceptibility of associative microflora isolated from patients with inflammatory diseases of urogenital tract was investigated. Etiologic structure of the diseases and cross-resistance to antibiotics of Escherichia coli, Staphylococcusaureus, and Klebsiella pneumoniae strains isolated from women with endocervicitis and men with urethritiswas assessed. Ciprofloxacin and gentamycin had the highest activity, whereas beta-lactam antibiotics were mildly active. Isolated strainswere resistant to macrolides, penicillines and imipenem. Main types of multidrug resistance to antibiotics were presented in strains circulated in Dagestan.


Tunable, Liquid Resistant Tip Enhanced Raman Spectroscopy Probes: Toward Label-Free Nano-Resolved Imaging of Biological Systems.
Tip enhanced Raman spectroscopy (TERS) has been established as a powerful, noninvasive technique for chemical identification at the nanoscale. However, difficulties, including the degradation of probes, limit its use in liquid systems. Here TERS probes for studies in aqueous environments have been demonstrated using titanium nitride coatings with an alumina protective layer. The probes show enhancement in signal intensity as high as 380% in liquid measurements, and the probe resonance can be tuned by varying deposition conditions to optimize performance for different laser sources and types of samples. This development of inexpensively produced probes suited for studies in aqueous environments enables its wider use for fields such as biology and biomedicine in which aqueous environments are the norm.


Ultrasound-guided percutaneous microwave ablation assisted by three-dimensional visualization operative treatment planning system and percutaneous transhepatic cholangial drainage with intraductal chilled saline perfusion for larger hepatic hilum hepatocellular (D ≥ 3 cm): preliminary results.
To assess the clinical efficiency of ultrasound-guided percutaneous microwave ablation (US-PMWA) assisted by three-dimensional (3D) visualization operative treatment planning system and percutaneous transhepatic cholangial drainage with intraductal chilled saline perfusion (PTCD-ICSP) for larger hepatic hilum hepatocellular carcinoma (HH-HCC) (D ≥ 3 cm). The combination therapy was performed in 14 patients from Sep 2011 to May 2017. The major outcomes for assessment were biliary duct complications, local tumor recurrence, distant recurrence and overall survival rates. Median follow-up period was 26 months. The series of 3D visualization operative treatment planning, PTCD-ICSP and US-PMWA were successfully performed and complete ablation was achieved in all cases. The mean session for one tumor was 1.0 ± 0.4. The mean ablation time for per tumor was 1805 ± 567s. The saline volume used for the PTCD-ICSP was 250-450 ml per session. The 1-, 2-, and 3-year local tumor recurrence rates were 7.1%, 14.3%, and 35.7%, the 1-, 2-, and 3-year distant recurrence rates were 0%, 14.3%, and 28.6%, and 1-, 2-, and 3-year overall survival rates were 100%, 92.9%, and 71.4%, respectively. No severe complications related to ablation occurred. US-PMWA assisted by 3D visualization operative treatment planning system and PTCD-ICSP appears to be a safe, effective and innovative technique for management for larger HH-HCCs, which improved the prognosis.


99mTc-MIBI scintigraphy as a functional method for the evaluation of multidrug resistance in breast cancer patients.
To evaluate the clinical application of (99m) Tc-methoxyisobutylisonitrile (MIBI) scintigraphy as a functional method for assessment of multidrug resistance (MDR) in breast cancer patients and the correlation of these results with P-glycoprotein (P-gp) overexpression and objective response to chemotherapy. 22 women, 35-68 years old with breast cancer, suitable for neoadjuvant chemotherapy were included onto this study. Two or three cycles of neoadjuvant chemotherapy were administered (FEC in 15 and CMF in 7 patients). Planar and SPECT (99m) Tc-MIBI scintigraphy was carried out before and after neoadjuvant chemotherapy. Focal (99m) Tc-MIBI uptake in breast cancer lesions was used as a scintigraphic criterion of abnormality. Tumor/background uptake (T/B Index) was calculated. Immunohistochemistry was carried out after surgery for P-gp detection in all cases. The degree of expression was evaluated according to semiquantitative score analysis from 0 to 4. Planar imaging was true positive in 20 patients, false positive in 1 (with breast cancer and mastopathy), and false negative in 1 (with wide tumor necrosis and deep location in the breast). SPECT imaging was true positive in 21 patients and false positive in 1. In 3 patients with multifocal disease additional tumour masses were visualized using SPECT. Sensitivity was 95% (21/22) and 100% (22/22), respectively, for planar and SPECT detection of breast cancer. P-gp expression was positive in 40.8% of the patients and negative in 59.2%. Intense (99m) Tc-MIBI uptake was shown on the planar images in 21 patients independently of the P-gp expression. There was no significant relationship between T/B Index and P-gp detection. Objective response included 2 clinical complete remissions, partial response in 1 patient, minimal response in 12, and no change in 7. Some clinical results corresponded to (99m) Tc-MIBI scintigraphic data: after neoadjuvant chemotherapy T/B Index was reduced > or = 20% in 9 patients with objective response. SPECT is an important diagnostic approach for identification of breast cancer with deep location and satellite tumour spots in multifocal disease. T/B Index did not correlate with P-gp overexpression on baseline (99m) Tc-MIBI scan. Objective clinical results after neoadjuvant chemotherapy corresponded to scintigraphic results in 75% of the patients with minimal response.


Accelerated recovery from acute hypoxia in obese mice is due to obesity-associated up-regulation of interleukin-1 receptor antagonist.
The proinflammatory consequences of obesity are thought to be due, in part, to macrophage infiltration into adipose tissue. There are, however, potential antiinflammatory consequences of obesity that include obesity-associated up-regulation of IL-1 receptor antagonist (IL-1RA). Here we show that obesity-associated up-regulation of IL-1RA speeds recovery from hypoxia. We found that high-fat diet-fed (HFD) mice recovered from acute hypoxia 5 times faster than normal-diet-fed (ND) mice. HFD mice had a 10-fold increase in serum IL-1RA when compared with ND mice. White adipose tissue (WAT) was a significant source of IL-RA, generating 330 +/- 77 pg/mg protein in HFD mice as compared with 15 +/- 5 pg/mg protein in ND mice. Peritoneal macrophages isolated from HFD mice showed little difference in IL-1RA production when compared with ND mice, but WAT macrophages from HFD mice generated 11-fold more IL-1RA than those from ND mice. When ND mice were given an ip transfer of the stromal vascular fraction portion of WAT from HFD mice, serum IL-1RA increased 836% and recovery from acute hypoxia was faster than in mice that did not receive a stromal vascular fraction transfer. To determine whether IL-1RA was important to this accelerated recovery, ND mice were administered exogenous IL-1RA prior to hypoxia, and their recovery matched that of HFD mice. Inversely, when IL-1RA was immunoabsorbed in HFD mice with IL-1RA antiserum, recovery from acute hypoxia was attenuated. Taken together these data demonstrate that HFD-induced obesity speeds recovery from hypoxia due to obesity-associated up-regulation of IL-1RA.


The Relationship Between Efavirenz as Initial Antiretroviral Therapy and Suicidal Thoughts Among HIV-Infected Adults in Routine Care.
Evidence about the effect of initiating efavirenz-containing combination antiretroviral therapy (ART) as the first-line therapy on suicidal thoughts remains conflicting. Using data from a cohort of HIV-infected adults enrolled in routine care across 5 sites in the United States, we included participants with a baseline patient-reported outcome measure and detectable viral load who initiated ART between 2011 and 2014. Participants were followed until the earliest of the following: first suicidal thoughts, discontinuation of initial ART regimen, death, loss to care (>12 months with no HIV appointments), or administrative censoring (2014-2015). Suicidal thoughts were measured using a Patient Health Questionnaire-9 item. We used weighted marginal structural Cox models to estimate the effect of initiating efavirenz-containing ART, versus efavirenz-free ART, on the hazard of active or passive suicidal thoughts after ART initiation, accounting for confounding by channeling bias. Overall, 597 participants were followed for a median of 19 months (13,132 total person-months); 147 (25%) initiated efavirenz-containing ART. At ART initiation, 38% of participants reported suicidal thoughts or depressive symptoms. Initiating efavirenz-based ART was associated with a hazard ratio (HR) for suicidal thoughts below the null in the crude analysis [HR, 0.88; 95% confidence interval (CI): 0.53 to 1.45] and above the null in the weighted analysis (HR, 1.21; 95% CI: 0.66 to 2.28). Among those with a prior mental health issue, the weighted HR was 1.76 (95% CI: 0.45 to 6.86). After accounting for measured channeling bias, we observed no strong evidence that initiating efavirenz-containing ART increased the hazard of suicidal thoughts.


[Light chain deposition disease. Experience in our environment].
The Light chain deposition disease (LCDD) is a strange entity characterised by the deposition of only one type of light chain in the renal tubular basement membranes. It can be associated to a plasma cell dyscrasia, however, it can occur in the absence of any detectable hematological disorder and it is called idiopathic LCDD. The clinical manifestation is renal insufficiency and nephrotic proteinuria, it does not have a clearly fixed treatment and has a severe prognosis. The aim of this work is to analyse the characteristics of the LCDD cases diagnosed within our environment. Six cases were identified, all of them between 1999 and 2005, from a total amount of 640 renal biopsies performed during this period, 4 women and 2 men, average age of 57. Multiple myeloma in 3 patients were detected (50%). The acute renal failure or rapidly progressive renal insufficiency was the most frequent clinical presentation (66%) together with nephrotic proteinuria (66%). All the biopsies showed tubular basement membranes thickening and kappa chains with a linear distribution within the same. The most frequent glomerular pathological finding was the nodular sclerosing glomerulopathy (83%). In one of the cases the affectation was exclusively tubular interstitial with tubular casts. 3 patients were treated, 2 with multiple myeloma. 5 patients needed dialysis: 3 with idiopathic LCDD within an average time of 7 days from the diagnosis to its reception and 2 with myeloma, who started needing dialysis in an average of 46 days. 4 patients died, 2 of them with myeloma. The monitoring time until the death was 13 weeks for the patients with myeloma and 110 weeks for the rest. The LCDD seems to be more frequent than what has been published and it is associated to the myeloma in half of the cases. It appears together with severe renal insufficiency and the patient's and renal prognosis is poor.


Fixed points for planar maps with multiple twists, with application to nonlinear equations with indefinite weight.
In this paper, we investigate the dynamical properties associated with planar maps which can be represented as a composition of twist maps together with expansive-contractive homeomorphisms. The class of maps we consider present some common features both with those arising in the context of the Poincaré-Birkhoff theorem and those studied in the theory of topological horseshoes. In our main theorems, we show that the multiplicity results of fixed points and periodic points typical of the Poincaré-Birkhoff theorem can be recovered and improved in our setting. In particular, we can avoid assuming area-preserving conditions and we also obtain higher multiplicity results in the case of multiple twists. Applications are given to periodic solutions for planar systems of non-autonomous ODEs with sign-indefinite weights, including the non-Hamiltonian case. The presence of complex dynamics is also discussed. This article is part of the theme issue 'Topological degree and fixed point theories in differential and difference equations'.


[Suspected syphilis during pregnancy due to cross reactions in Borrelia infection].
A weakly positive titre (1:20) in the Treponema pallidum haemagglutination test and a highly positive titre (1:1280) in the fluorescence Treponema antibody absorption test, but negative result for IgM antibodies, were found in the serum of a 23-year-old pregnant woman. The cardiolipin microflocculation test was at first borderline positive, but negative on repeat. In the absence of a history of syphilis tests for Borrelia antibodies were performed. Those for antibodies against B. burgdorferi were highly positive in the ELISA test (550 units), in the indirect Borrelia immunofluorescence test 1:1280 for IgG antibodies and 1:160 for IgM antibodies. In the Borrelia-specific indirect haemagglutination test, which measures both IgG and IgM antibodies, the titres were 1:640 to 1:1280. These results confirmed the presence of an infection with B. burgdorferi and not with Treponema pallidum.


SAFER Care: Improving Caregiver Comprehension of Discharge Instructions.
One in five pediatric patients suffers from adverse events related to hospital discharge. Current literature lacks evidence on effective interventions to improve caregiver comprehension (CC) of discharge instructions. We examined if a standardized framework for written and verbal discharge counseling was associated with increased CC of key discharge instructions after discharge from a general pediatric inpatient unit. An interprofessional team created the SAFER Care framework to encourage standard, comprehensive discharge counseling. Plan-do-study-act cycles included electronic health record smartphrases, educational initiatives, data feedback, visual aids, and family outreach. Caregivers were surveyed by phone within 4 days of discharge. Our primary outcome was the proportion of caregivers correctly responding to all questions related to discharge care, comparing pre- and postintervention periods. Data were plotted on a statistical process control chart to assess the effectiveness of interventions. A total of 171 surveys were analyzed in the preintervention period, and 262 surveys were analyzed in the postintervention period. A total of 37% of caregivers correctly responded to all questions in the preintervention period, compared with 62% of caregivers in the postintervention period, meeting rules for special cause variation. Development of the SAFER Care framework and its use in written and verbal discharge counseling was associated with significantly improved CC of discharge instructions in a general pediatric inpatient unit. Further studies should be focused on expanding this to other populations, particularly limited-English-proficiency families.


Knockdown of cytosolic glutaredoxin 1 leads to loss of mitochondrial membrane potential: implication in neurodegenerative diseases.
Mitochondrial dysfunction including that caused by oxidative stress has been implicated in the pathogenesis of neurodegenerative diseases. Glutaredoxin 1 (Grx1), a cytosolic thiol disulfide oxido-reductase, reduces glutathionylated proteins to protein thiols and helps maintain redox status of proteins during oxidative stress. Grx1 downregulation aggravates mitochondrial dysfunction in animal models of neurodegenerative diseases, such as Parkinson's and motor neuron disease. We examined the mechanism underlying the regulation of mitochondrial function by Grx1. Downregulation of Grx1 by shRNA results in loss of mitochondrial membrane potential (MMP), which is prevented by the thiol antioxidant, alpha-lipoic acid, or by cyclosporine A, an inhibitor of mitochondrial permeability transition. The thiol groups of voltage dependent anion channel (VDAC), an outer membrane protein in mitochondria but not adenosine nucleotide translocase (ANT), an inner membrane protein, are oxidized when Grx1 is downregulated. We then examined the effect of beta-N-oxalyl amino-L-alanine (L-BOAA), an excitatory amino acid implicated in neurolathyrism (a type of motor neuron disease), that causes mitochondrial dysfunction. Exposure of cells to L-BOAA resulted in loss of MMP, which was prevented by overexpression of Grx1. Grx1 expression is regulated by estrogen in the CNS and treatment of SH-SY5Y cells with estrogen upregulated Grx1 and protected from L-BOAA mediated MMP loss. Our studies demonstrate that Grx1, a cytosolic oxido-reductase, helps maintain mitochondrial integrity and prevents MMP loss caused by oxidative insult. Further, downregulation of Grx1 leads to mitochondrial dysfunction through oxidative modification of the outer membrane protein, VDAC, providing support for the critical role of Grx1 in maintenance of MMP.


Left ventricular hypertrophy induced by aortic banding impairs relaxation of isolated coronary arteries.
LVH (left ventricular hypertrophy) is associated with impaired coronary vascular reserve. In the present study, we examined the effect of pressure-overload hypertrophy on vasorelaxant responses of guinea-pig isolated coronary small arteries and compared them with mesenteric small arteries. Pressure-overload was induced by banding the ascending aorta of guinea-pigs. Haemodynamics, and ventricular, atrial and lung weights were measured 168 days after banding. Isolated coronary and mesenteric small arteries were contracted with a thromboxane mimetic (U46619) and relaxation to ACH (acetylcholine), ISO (isoprenaline), FSK (forskolin) and SNP (sodium nitroprusside) was examined. Arterial wall morphology was examined by light microscopy. Aortic banding reduced cardiac output and increased systemic vascular resistance; atrial, ventricular and lung weights were increased. Coronary artery adventitial and medial thickness were increased, but mesenteric arterial wall morphology was unaffected. Coronary artery relaxation to ACH, ISO, FSK and SNP were reduced in banded animals. In contrast, relaxation of mesenteric arteries to ACH, FSK and SNP were unaffected by banding, although ISO-induced relaxation was reduced. A COX (cyclo-oxygenase) inhibitor, indomethacin, had no effect on coronary artery responses to ACH in banded or sham animals, but the differences in relaxation of coronary arteries between banded and sham animals were no longer significant following pre-incubation with the NO inhibitors L-NMMA (N(G)-monomethyl-L-arginine) and oxyhaemoglobin. In conclusion, pressure-overload-induced LVH causes impaired relaxation of small coronary arteries to endothelium-dependent and -independent relaxants. These findings are indicative of alterations in vascular smooth muscle responsiveness to vasodilators. Impairment of coronary arterial vasodilation may contribute to the reduced coronary vascular reserve seen in LVH.


Coarse-grained modeling of DNA oligomer hybridization: length, sequence, and salt effects.
A recently published coarse-grained DNA model [D. M. Hinckley, G. S. Freeman, J. K. Whitmer, and J. J. de Pablo, J. Chem. Phys. 139, 144903 (2013)] is used to study the hybridization mechanism of DNA oligomers. Forward flux sampling is used to construct ensembles of reactive trajectories from which the effects of sequence, length, and ionic strength are revealed. Heterogeneous sequences are observed to hybridize via the canonical zippering mechanism. In contrast, homogeneous sequences hybridize through a slithering mechanism, while more complex base pair displacement processes are observed for repetitive sequences. In all cases, the formation of non-native base pairs leads to an increase in the observed hybridization rate constants beyond those observed in sequences where only native base pairs are permitted. The scaling of rate constants with length is captured by extending existing hybridization theories to account for the formation of non-native base pairs. Furthermore, that scaling is found to be similar for oligomeric and polymeric systems, suggesting that similar physics is involved.


Computed tomography-guided percutaneous trigeminal tractotomy-nucleotomy.
The destruction of the descending trigeminal tractus in the medulla is known as trigeminal tractotomy (TR), whereas the lesioning of the nucleus caudalis is known as trigeminal nucleotomy (NC). Trigeminal TR and/or NC procedures can be used in a large group of pain syndromes, such as glossopharyngeal, vagal, and geniculate neuralgias, atypical facial pain, craniofacial cancer pain, postherpetic neuralgias, and atypical forms of trigeminal neuralgia. In this study, anatomic and technical details of the procedure and the experience gained from 65 patients over the course of 20 years are discussed. Patients' pain scores and Karnofsky Performance Scale scores were evaluated pre- and postoperatively (postoperative Day 1). The best results were obtained in the second-largest group (vagoglossopharyngeal neuralgia, n = 17) and in geniculate neuralgia (n = 4). Patients with atypical facial pain (n = 21; 13 women, eight men) accounted for the largest group to undergo computed tomography-guided TR-NC surgery; pain relief was achieved in 19 of these patients. In the third-largest group (craniofacial and oral cancer pain, n = 13), 11 of 13 patients were successfully treated with TR-NC. Four of five patients with failed trigeminal neuralgia were also effectively treated with TR-NC. We propose that computed tomography-guided TR-NC provides direct visualization of the target-electrode relation and can be considered a first-step procedure in patient management. In view of its high efficacy, low complication rate, and minimal invasiveness, computed tomography-guided trigeminal TR-NC is a safe and effective procedure in the treatment of intractable facial pain syndromes.


Prospects for Radiopharmaceuticals as Effective and Safe Therapeutics in Oncology and Challenges of Tumor Resistance to Radiotherapy.
The rapid advances in nuclear medicine have resulted in significant advantages for the field of oncology. The focus is on the application of radiopharmaceuticals as therapeuticals. In addition, the latest developments in cell biology (the understanding of the cell structure, function, metabolism, genetics, signaling, transformation) have given a strong scientific boost to radiation oncology. In this regard, the article discusses what is soon going to be a new jump in radiation oncology based on the already accumulated considerable knowledge at the cellular level about the mechanisms of cell transformation and tumor progression, cell response to radiation, cell resistance to apoptosis and radiation and cell radio-sensitivity. The mechanisms of resistance of tumor cells to radiation and the genetically determined individual sensitivity to radiation in patients (which creates the risk of radiation-induced acute and late side effects) are the 2 major challenges to overcome in modern nuclear medicine. The paper focuses on these problems and makes a detailed summary of the significance of the differences in the ionizing properties of radiopharmaceuticals and the principle of their application in radiation oncology that will shed additional light on how to make the anti-cancer radiotherapies more efficient and safe, giving some ideas for optimizations.


Should we care about Plasmodium vivax and HIV co-infection? A systematic review and a cases series from the Brazilian Amazon.
Malaria and HIV are two important public health issues. However, evidence on HIV-Plasmodium vivax co-infection (HIV/PvCo) is scarce, with most of the available information related to Plasmodium falciparum on the African continent. It is unclear whether HIV can change the clinical course of vivax malaria and increase the risk of complications. In this study, a systematic review of HIV/PvCo studies was performed, and recent cases from the Brazilian Amazon were included. Medical records from a tertiary care centre in the Western Brazilian Amazon (2009-2018) were reviewed to identify HIV/PvCo hospitalized patients. Demographic, clinical and laboratory characteristics and outcomes are reported. Also, a systematic review of published studies on HIV/PvCo was conducted. Metadata, number of HIV/PvCo cases, demographic, clinical, and outcome data were extracted. A total of 1,048 vivax malaria patients were hospitalized in the 10-year period; 21 (2.0%) were HIV/PvCo cases, of which 9 (42.9%) had AIDS-defining illnesses. This was the first malaria episode in 11 (52.4%) patients. Seven (33.3%) patients were unaware of their HIV status and were diagnosed on hospitalization. Severe malaria was diagnosed in 5 (23.8%) patients. One patient died. The systematic review search provided 17 articles (12 cross-sectional or longitudinal studies and 5 case report studies). A higher prevalence of studies involved cases in African and Asian countries (35.3 and 29.4%, respectively), and the prevalence of reported co-infections ranged from 0.1 to 60%. Reports of HIV/PvCo are scarce in the literature, with only a few studies describing clinical and laboratory outcomes. Systematic screening for both co-infections is not routinely performed, and therefore the real prevalence of HIV/PvCo is unknown. This study showed a low prevalence of HIV/PvCo despite the high prevalence of malaria and HIV locally. Even though relatively small, this is the largest case series to describe HIV/PvCo.