Mortality trends in type 1 diabetes: a multicountry analysis of six population-based cohorts.

AIMS/HYPOTHESIS: Mortality has declined in people with type 1 diabetes in recent decades. We examined how the pattern of decline differs by country, age and sex, and how mortality trends in type 1 diabetes relate to trends in general population mortality. METHODS: We assembled aggregate data on all-cause mortality during the period 2000-2016 in people with type 1 diabetes aged 0-79 years from Australia, Denmark, Latvia, Scotland, Spain (Catalonia) and the USA (Kaiser Permanente Northwest). Data were obtained from administrative sources, health insurance records and registries. All-cause mortality rates in people with type 1 diabetes, and standardised mortality ratios (SMRs) comparing type 1 diabetes with the non-diabetic population, were modelled using Poisson regression, with age and calendar time as quantitative variables, describing the effects using restricted cubic splines with six knots for age and calendar time. Mortality rates were standardised to the age distribution of the aggregate population with type 1 diabetes. RESULTS: All six data sources showed a decline in age- and sex-standardised all-cause mortality rates in people with type 1 diabetes from 2000 to 2016 (or a subset thereof), with annual changes in mortality rates ranging from -2.1% (95% CI -2.8%, -1.3%) to -5.8% (95% CI -6.5%, -5.1%). All-cause mortality was higher for male individuals and for older individuals, but the rate of decline in mortality was generally unaffected by sex or age. SMR was higher in female individuals than male individuals, and appeared to peak at ages 40-70 years. SMR declined over time in Denmark, Scotland and Spain, while remaining stable in the other three data sources. CONCLUSIONS/INTERPRETATION: All-cause mortality in people with type 1 diabetes has declined in recent years in most included populations, but improvements in mortality relative to the non-diabetic population are less consistent.

Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure: A Phase 1/2 Randomized Controlled Trial (RIMECARD Trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy]).

RATIONALE: Umbilical cord-derived mesenchymal stem cells (UC-MSC) are easily accessible and expanded in vitro, possess distinct properties, and improve myocardial remodeling and function in experimental models of cardiovascular disease. Although bone marrow-derived mesenchymal stem cells have been previously assessed for their therapeutic potential in individuals with heart failure and reduced ejection fraction, no clinical trial has evaluated intravenous infusion of UC-MSCs in these patients. OBJECTIVE: Evaluate the safety and efficacy of the intravenous infusion of UC-MSC in patients with chronic stable heart failure and reduced ejection fraction. METHODS AND RESULTS: Patients with heart failure and reduced ejection fraction under optimal medical treatment were randomized to intravenous infusion of allogenic UC-MSCs (Cellistem, Cells for Cells S.A., Santiago, Chile; 1×106 cells/kg) or placebo (n=15 per group). UC-MSCs in vitro, compared with bone marrow-derived mesenchymal stem cells, displayed a 55-fold increase in the expression of hepatocyte growth factor, known to be involved in myogenesis, cell migration, and immunoregulation. UC-MSC-treated patients presented no adverse events related to the cell infusion, and none of the patients tested at 0, 15, and 90 days presented alloantibodies to the UC-MSCs (n=7). Only the UC-MSC-treated group exhibited significant improvements in left ventricular ejection fraction at 3, 6, and 12 months of follow-up assessed both through transthoracic echocardiography (P=0.0167 versus baseline) and cardiac MRI (P=0.025 versus baseline). Echocardiographic left ventricular ejection fraction change from baseline to month 12 differed significantly between groups (+7.07±6.22% versus +1.85±5.60%; P=0.028). In addition, at all follow-up time points, UC-MSC-treated patients displayed improvements of New York Heart Association functional class (P=0.0167 versus baseline) and Minnesota Living with Heart Failure Questionnaire (P<0.05 versus baseline). At study completion, groups did not differ in mortality, heart failure admissions, arrhythmias, or incident malignancy. CONCLUSIONS: Intravenous infusion of UC-MSC was safe in this group of patients with stable heart failure and reduced ejection fraction under optimal medical treatment. Improvements in left ventricular function, functional status, and quality of life were observed in patients treated with UC-MSCs. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/ct2/show/NCT01739777. Unique identifier: NCT01739777.

Decreasing incidence of pharmacologically and non-pharmacologically treated type 2 diabetes in Norway: a nationwide study.

AIMS/HYPOTHESIS: This study aimed to examine recent time trends in the incidence and prevalence of type 2 diabetes in Norway. METHODS: In this Norwegian nationwide cohort study, we linked data from national registries with prospectively collected data on diabetes medication and diabetes diagnoses for all residents in Norway aged 30 to 89 years (>3.2 million people). We analysed trends in incidence and prevalence of type 2 diabetes from 2009 to 2014 by type of treatment, sex, age, education level and place of birth. RESULTS: During 15,463,691 person-years of follow-up from 2009 to 2014, we identified 75,496 individuals with new-onset type 2 diabetes. Of these, 36,334 (48%) were treated with blood-glucose-lowering drugs within 6 months of diagnosis. A low education level and being born in Asia, Africa or South America were significant risk factors for incident type 2 diabetes. While the prevalence of type 2 diabetes increased from 4.9% to 6.1% during the study period, the incidence decreased significantly from 609 cases per 100,000 person-years in 2009 to 398 cases per 100,000 in 2014, an annual reduction of 10.1% (95% CI -10.5, -9.6). A declining incidence was seen for both pharmacologically and non-pharmacologically treated type 2 diabetes, and in all subgroups defined by sex, age group, education level and place of birth. CONCLUSIONS/INTERPRETATIONS: This nationwide study shows that, despite a decreasing incidence of type 2 diabetes in Norway, the prevalence continues to rise, probably due to diagnosis at a younger age and increased longevity.

Pandemic influenza and subsequent risk of type 1 diabetes: a nationwide cohort study.

AIMS/HYPOTHESIS: Case reports have linked influenza infections to the development of type 1 diabetes. We investigated whether pandemic and seasonal influenza infections were associated with subsequent increased risk of type 1 diabetes. METHODS: In this population-based registry study, we linked individual-level data from national health registries for the entire Norwegian population under the age of 30 years for the years 2006-2014 (2.5 million individuals). Data were obtained from the National Registry (population data), the Norwegian Patient Registry (data on inpatient and outpatient specialist care), the Primary Care Database, the Norwegian Prescription Database and the Norwegian Surveillance System for Communicable Diseases. Pandemic influenza was defined as either a clinical influenza diagnosis during the main pandemic period or a laboratory-confirmed test. Seasonal influenza was defined by a clinical diagnosis of influenza between 2006 and 2014. We used Cox regression to estimate HRs for new-onset type 1 diabetes after an influenza infection, adjusted for year of birth, sex, place of birth and education. RESULTS: The adjusted HR for type 1 diabetes after pandemic influenza infection was 1.19 (95% CI 0.97, 1.46). In the subgroup with laboratory-confirmed influenza A (H1N1), influenza was associated with a twofold higher risk of subsequent type 1 diabetes before age 30 years (adjusted HR: 2.26, 95% CI 1.51, 3.38). CONCLUSIONS/INTERPRETATION: Overall, we could not demonstrate a clear association between clinically reported pandemic influenza infection and incident type 1 diabetes. However, we found a twofold excess of incident diabetes in the subgroup with laboratory-confirmed pandemic influenza A (H1N1).

Apical negative pressure irrigation versus syringe irrigation: a systematic review of cleaning and disinfection of the root canal system.

The aim of this study was to systematically review and critically analyse the published data on the treatment outcome (primary outcome) and on the cleaning and disinfection of root canals (secondary outcomes) achieved by negative pressure irrigation as compared to syringe irrigation. An electronic search was conducted in EMBASE, LILACS, PubMed, SciELO, Scopus and Web of Knowledge using both free-text keywords and controlled vocabulary. Additional studies were sought through hand searching of endodontic journals and of the relevant chapters of endodontic textbooks. No language restriction was imposed. The retrieved studies were screened by two reviewers according to predefined criteria. Included studies were critically appraised and the extracted data were arranged in tables. The electronic search and hand search retrieved 489 titles. One clinical study and 14 in vitro studies were finally included in the review; none of these studies assessed treatment outcome, four studies assessed the antimicrobial effect, seven studies evaluated the removal of pulp tissue remnants, and four studies investigated the removal of hard tissue debris or both hard tissue debris and pulp tissue remnants. Poor standardization and description of the protocols was evident. Inconclusive results were reported about the cleaning and disinfection accomplished by the two irrigation methods. Negative pressure irrigation was more effective under certain conditions when compared to suboptimal syringe irrigation; however, the variability of the protocols hindered quantitative synthesis. There is insufficient evidence to claim general superiority of any one of these methods. The level of the available evidence is low, and the conclusions should be interpreted with caution.

Modeling Meropenem Treatment, Alone and in Combination with Daptomycin, for KPC-Producing Klebsiella pneumoniae Strains with Unusually Low Carbapenem MICs.

Klebsiella pneumoniae strains producing K. pneumoniae carbapenemase (KPC) cause serious infections in debilitated and immunocompromised patients and are associated with prolonged hospital stays and increased mortality rates. Daptomycin is a lipopeptide used against Staphylococcus aureus infection and considered inactive against Gram-negative bacteria. We investigated the effectiveness of a daptomycin-meropenem combination by synergy kill curve and a pharmacokinetic/pharmacodynamic model. The combination may represent a novel therapeutic strategy against infections caused by KPC-producing K. pneumoniae strains.

Removal of Giardia spp. and Cryptosporidium spp. from water supply with high turbidity: analytical challenges and perspectives.

Giardia and Cryptosporidium species are a serious problem if present in water supplies. The removal of these protozoans and the adaptation of existing protocols are essential for supplying drinking water to developing countries. Considering this, the aim of this study is to evaluate, on a bench level, the removal of Giardia spp. cysts and of Cryptosporidium spp. oocysts from water with high turbidity, using polyaluminium chloride as a coagulant. Filtration using mixed cellulose ester membranes, followed, or not, by purification through immunomagnetic separation (IMS) was used for detecting protozoans. By evaluating the adopted protocol, without using IMS, retrievals of 80% of cysts and 5% of oocysts were obtained, whereas by using IMS, recoveries of 31.5% of cysts and 5.75% of oocysts were reached. When analyzing the coagulant performance, a dosage of 65 mg L(-1) showed contamination from protozoans in all the samples of filtered water. A dosage of 25 mg L(-1) presented protozoans in 50% of the filtered water samples. The results showed an improved performance for the 25 mg L(-1) dosage; therefore, the control of coagulation and adaptation of detection protocols must be evaluated according to the features of raw water and availability of local resources.

The Spanish Psoriasis Patients' Association According to Its Members: Cross-Sectional Descriptive Study of Members' Opinions of the Association's Functions. / Función y respaldo a la asociación de pacientes con psoriasis en España según sus miembros: estudio descriptivo transversal.

INTRODUCTION: Patient associations form part of health care systems, but little is known about how their members' view the functionality of these associations and whether they endorse their goals and activities. OBJECTIVE: To study how the members of the leading Spanish association of patients with psoriasis and their relatives view the group's functioning. MATERIAL AND METHODS: Survey study using a self-administered questionnaire answered by members of the association (total membership, 26 349 persons). The credibility of the association and respondents' confidence in and satisfaction with it were studied and compared with their attitudes toward other agents in the health care system. A Rasch model was used to analyze respondents' ranking of functions. Analysis of variance was used to study between-group differences. RESULTS: A total of 746 members participated (response rate 2.83%). The association's credibility was rated in second place, after that of specialists who treat psoriasis. Support for the association functions was good (7.53 on a scale of 0 to 10). The function the members rated highest was the raising of societal awareness of psoriasis and its problems. Rated lowest were functions related to personal services for members. Educational level was the only participant factor associated with significant differences in evaluations (P<.05). CONCLUSIONS: The psoriasis association contributes by disseminating information about the disease and patient care, and it serves to represent patients. Health professionals and institutions should take the association into account in their efforts to deal with the disease and in designing effective policies.

Strains of Enterococcus faecalis differ in their ability to coexist in biofilms with other root canal bacteria.

AIM: To investigate the relationship between protease production and the ability of Enterococcus faecalis strains to coexist in biofilms with other bacteria commonly recovered from infected root canals. METHODOLOGY: Biofilms with bacteria in mono-, dual- and four-species communities were developed in flow chambers. The organisms used were Lactobacillus salivarius, Streptococcus gordonii and Actinomyces naeslundii and E. faecalis strains, GUL1 and OG1RF. Biovolume and species distribution were examined using 16S rRNA fluorescence in situ hybridization in combination with confocal microscopy and image analysis. The full proteome of the E. faecalis strains was studied using two-dimensional gel electrophoresis. Spots of interest were identified using tandem mass spectroscopy and quantified using Delta 2D software. RESULTS: All bacteria formed biofilms and an anova analysis revealed that the biofilm biomass increased significantly (P ≤ 0.01) between 6 and 24 h. L. salivarius, S. gordonii and A. naeslundii formed mutualistic biofilm communities, and this pattern was unchanged when E. faecalis GUL1 was included in the consortium. However, with OG1RF, L. salivarius and S. gordonii were outcompeted in a 24-h biofilm. Proteomic analysis revealed that OG1RF secreted higher levels of proteases, GelE (P = 0.02) and SprE (P = 0.002) and a previously unidentified serine protease (P = 0.05), than GUL1. CONCLUSIONS: Different strains of E. faecalis can interact synergistically or antagonistically with a consortium of root canal bacteria. A possible mechanism underlying this, as well as potential differences in virulence, is production of different levels of proteases, which can cause detachment of neighbouring bacteria and tissue damage.

[Maintenance of chest compressions skill in cardiopulmonary resuscitation in primary health care professionals: Quasi-experimental study]. / Mantenimiento de la habilidad de las compresiones torácicas en reanimación cardiopulmonar en profesionales de la atención primaria de salud: estudio cuasiexperimental.

OBJECTIVE: To validate the efficacy of brief CPR training with dual feedback to maintain the ability to perform quality chest compressions. MATERIALS AND METHODS: Quasi-experimental study with two groups to evaluate a brief theoretical training followed by a practice with manikin with feedback; Participants: 155 health and non-health professionals from 5 primary care health centers of urban area (43 losses); Main measurements: Characteristics of compressions that were measured before and after the brief training and their maintenance at 3 and 6 months according to the study group. The effect of training and maintenance of skills were analyzed using multiple linear regression models. RESULTS: 155 participants were included, mean age 39.7 years (SD=12.0) with 82.7% female. The training effect had an improvement in mean compression depth (pre-post difference: 3.5, P<.001), total compressions with adequate depth (pre-post difference: 0.2, P<.001) and Total Compressions with Adequate Rhythm (pre-post difference: 0.4, P<.001). The second phase was completed by 112 participants (72.2%). Compression skills declined at 3 months and were lower at 6 months, although the loss of skills was not statistically significant between the two groups. CONCLUSIONS: An individualized, brief training action with feedback immediately improves the quality of compressions. The progressive loss of skills from 3 to 6 months is not relevant.

Daylight exposure and mood in real life: Direct association and mediating role of sleep and routine regularity.

The light/dark cycle is the main external cue to synchronize the human biological clock. Modern lifestyles typically lead to less daylight exposure and blunted 24 h-amplitude. We evaluated the association of outdoor daylight exposure (frequency, duration, regularity and shift) with chronotype estimated by sleep phase, regularity of routines, sleep, well-being (WHO-5), and depressive symptoms (PHQ-9), in a sample of 1,095 participants (81.8% female; 87.9% aged 18-49) surveyed online between July and November 2020. We analyzed direct and indirect associations in daylight-mood relationship with chronotype-estimate, routine regularity, and sleep as mediators. Outdoor daylight exposure was associated with WHO-5/PHQ-9 scores in mediation models, with higher total effects when the exposure was every day (ß = 4.13 ± 0.53/ ß = -3.81 ± 0.67), for more than 4 hours (ß = 3.77 ± 0.91/ ß = -3.83 ± 1.31) and during the morning (ß = 3.41 ± 0.53/ ß = -3.74 ± 0.70) in reference to lack of exposure. Chronotype-estimate, routine regularity score, and sleep problems acted as mediators, while social jetlag and sleep duration did not play an important role in this association. This study advanced the understanding of the complex interplay between light exposure, mental health, and individual characteristics of sleep and other routine regularities, and showed the benefits of optimizing daylight exposure to improve mental health.

Greater within- and between-day instability is associated with worse anxiety and depression symptoms.

BACKGROUND: Depression and anxiety affect hundreds of millions of people worldwide, and their prevalence increased during the COVID-19 pandemic as social schedules were disrupted. This study explores the associations between anxiety and depression and within- and between-day instability of affective, somatic, and cognitive symptoms during the early pandemic stages. METHODS: Participants (n = 153, ages 18-77, 72 % female) reported daily levels of affective (anxiety/sadness), somatic (appetite/sleepiness), and cognitive (concentration/energy) symptoms for 14-44 days at five timepoints: 0, 3, 6, 9, and 12 h after awakening. At the end of the study, participants completed validated scales for anxiety (GAD-7) and depression (PHQ-9). Symptom instability was assessed using the Absolute Real Variability (ARV) index. Regression models examined within-day instability (WD-I) and between-day instability (BD-I) with GAD-7 and PHQ-9 scores as outcomes. RESULTS: Greater instability (both WD-I and BD-I) of affective symptoms correlated with elevated GAD-7 and PHQ-9 scores. For somatic and cognitive symptoms, greater BD-I was associated with higher scores. LIMITATIONS: The study used retrospective daily data, which could benefit from real-time assessments for improved accuracy. CONCLUSIONS: This study provides empirical evidence of a connection between greater anxiety and depression severity and increased instability in daily mood and physiological symptoms. The findings underscore the importance of consistent symptom monitoring to understand overall mental health trajectories. Additionally, it highlights the role of daily routines in stabilizing the circadian system, potentially regulating physiological and psychological processes and reducing symptom instability.

A hyperpolarization-activated ion current of amphibian oocytes.

A comparative analysis of a hyperpolarization-activated ion current present in amphibian oocytes was performed using the two-electrode voltage-clamp technique in Xenopus laevis, Xenopus tropicalis, and Ambystoma mexicanum. This current appears to be driven mainly by Cl(-) ions, is independent of Ca(2+), and is made evident by applying extremely negative voltage pulses; it shows a slow activating phase and little or no desensitization. The pharmacological profile of the current is complex. The different channel blocker used for Cl(-), K(+), Na(+) and Ca(2+) conductances, exhibited various degrees of inhibition depending of the species. The profiles illustrate the intricacy of the components that give rise to this current. During X. laevis oogenesis, the hyperpolarization-activated current is present at all stages of oocytes tested (II-VI), and the amplitude of the current increases from about 50 nA in stage I to more than 1 µA in stage VI; nevertheless, there was no apparent modification of the kinetics. Our results suggest that the hyperpolarization-activated current is present both in order Anura and Urodela oocytes. However, the electrophysiological and pharmacological characteristics are quite perplexing and seem to suggest a mixture of ionic conductances that includes the activation of both anionic and cationic channels, most probably transiently opened due to the extreme hyperpolarizion of the plasma membrane. As a possible mechanism for the generation of the current, a kinetic model which fits the data suggests the opening of pores in the plasma membrane whose ion selectivity is dependent on the extracellular Cl(-) concentration. The extreme voltage conditions could induce the opening of otherwise latent pores in plasma membrane proteins (i.e., carriers), resembling the ´slippage´ events already described for some carriers. These observations should be valuable for other groups trying to express cloned, voltage-dependent ion channels in oocytes of amphibian in which hyperpolarizing voltage pulses are applied to activate the channels.

The concept of the immune-pineal axis tested in patients undergoing an abdominal hysterectomy.

OBJECTIVE: Activation of the immune-pineal axis induces a transient reduction in nocturnal melatonin in the plasma during the proinflammatory phase of an innate immune response to allow the proper migration of leukocytes to the lesion site. This transient reduction should be regulated by inflammatory mediators, which are responsible for the fine-tuning of the process. In the present study, we measured the pre- and postoperative serum concentrations of melatonin, tumor necrosis factor (TNF) and cortisol in women who underwent an elective hysterectomy and correlated the variation in melatonin with postoperative pain. METHODS: We evaluated 12 women who had an abdominal hysterectomy. Blood was collected at 10.00 and 22.00 h 1 week and 1 day before the surgery, on the 1st and 2nd days after the surgery and at 22.00 h on the day of the surgery. RESULTS: On the night after the surgery, there was no melatonin detected at 22.00 h. High TNF levels were accompanied by a lower nocturnal melatonin output, higher postoperative pain according to a visual analog scale and the request of higher doses of analgesics. In addition, low cortisol levels were accompanied by a lower nocturnal melatonin output. CONCLUSION: Our results confirm that the same antagonistic pattern between TNF and glucocorticoids observed in cultured pineal glands also occurs in humans. This integrative pattern suggests that the cross talk between the immune and endocrine system orchestrates longitudinal changes in pineal activity, reinforcing the hypothesis of an immune-pineal axis.

A device to record ultra-rapid cooling profiles.

This work deals with the construction and performance of a measuring system capable of estimating temperature at sufficiently high speed (up to 1000 samples per sec). Due to its simple design and the utilization of standard materials, it could serve to recording the cooling profile of ultra-rapid procedures. An immersion device was also developed with the purpose of normalize the penetration speed of the sample in the LN2. The device allows also the comparative analysis of different cooling profiles. The system consists of an immersion device of the sample in the cooling agent, a temperature measurement system developed by Kleihans F and a laptop computer. To test the system, we recorded the cooling profiles of 10 uL of distilled water and 6 M glycerol solution, obtaining a cooling rate of 8732 C/min and 4441 C/min respectively. Also we determine a cooling rate of 204.012 C/min during the immersion of the thermocouple assembly in LN2. Although, the same device, with small technical modifications related to the handling of the sample, could be used to evaluate the recovery from LN2 temperature to room temperature (re-warming).

Factors associated with the time taken for diagnosis of amyotrophic lateral sclerosis (ALS) in Brazil. An online population-based inquiry. / Factores asociados al tiempo necesario para el diagnóstico de esclerosis lateral amiotrófica (ELA) en Brasil. Una encuesta poblacional en línea.

OBJECTIVE: This study evaluated factors associated with the time, in months, between the onset of symptoms and the diagnosis (time taken for diagnosis) of ALS for patients in Brazil, in the year 2014. PATIENTS AND METHODS: An electronic questionnaire composed of 38 questions was developed and applied through internet-based social networks of patients. From the 210 replies, 194 were considered (86 from women, 108 from men). Most respondents were 51 to 60 years old. The Mann-Whitney test was used to compare the time taken for diagnosis between the strata of the sample. RESULTS: The mean time taken for diagnosis was 14.21 (±16.87) months. There was a statistically significant difference only for higher education conditions (p = 0.009) and low education status (p = 0.042). There was no statistically significant difference between sexes, bulbar onset, age groups, and the presence of spouse, or 'partnership with ALS patients associations or exchange of experiences'. CONCLUSION: These data suggest that the time taken for diagnosis of ALS is influenced by socioeconomic conditions that promote access to information and/or health services.

TITLE: Factores asociados al tiempo necesario para el diagnóstico de esclerosis lateral amiotrófica (ELA) en Brasil. Una encuesta poblacional en línea.Objetivo. Este estudio evaluó los factores asociados con el tiempo, en meses, entre el inicio de los síntomas y el diagnóstico (tiempo necesario para el diagnóstico) de esclerosis lateral amiotrófica (ELA) de los pacientes en Brasil en 2014. Pacientes y métodos. Se elaboró un cuestionario electrónico compuesto por 38 preguntas y se aplicó a través de redes sociales de pacientes basadas en Internet. De las 210 respuestas, se consideraron 194 (86 de mujeres y 108 de hombres). La mayoría de los encuestados tenía entre 51 y 60 años. Se utilizó la prueba de Mann-Whitney para comparar el tiempo transcurrido hasta el diagnóstico entre los estratos de la muestra. Resultados. El tiempo medio transcurrido hasta el diagnóstico fue de 14,21 (±16,87) meses. Hubo una diferencia estadísticamente significativa sólo para las condiciones de educación superior (p = 0,009) y bajo nivel educativo (p = 0,042). No hubo diferencias estadísticamente significativas entre sexos, inicio bulbar, grupos de edad y presencia de cónyuge, o colaboración con asociaciones de pacientes con ELA o intercambio de experiencias. Conclusión. Estos datos sugieren que el tiempo que se tarda en diagnosticar la ELA está influido por las condiciones socioeconómicas que favorecen el acceso a la información y/o a los servicios sanitarios.

Regulation of bacteriocin production and cell death by the VicRK signaling system in Streptococcus mutans.

The VicRK two-component signaling system modulates biofilm formation, genetic competence, and stress tolerance in Streptococcus mutans. We show here that the VicRK modulates bacteriocin production and cell viability, in part by direct modulation of competence-stimulating peptide (CSP) production in S. mutans. Global transcriptome and real-time transcriptional analysis of the VicK-deficient mutant (SmuvicK) revealed significant modulation of several bacteriocin-related loci, including nlmAB, nlmC, and nlmD (P < 0.001), suggesting a role for the VicRK in producing mutacins IV, V, and VI. Bacteriocin overlay assays revealed an altered ability of the vic mutants to kill related species. Since a well-conserved VicR binding site (TGTWAH-N(5)-TGTWAH) was identified within the comC coding region, we confirmed VicR binding to this sequence using DNA footprinting. Overexpression of the vic operon caused growth-phase-dependent repression of comC, comDE, and comX. In the vic mutants, transcription of nlmC/cipB encoding mutacin V, previously linked to CSP-dependent cell lysis, as well as expression of its putative immunity factor encoded by immB, were significantly affected relative to the wild type (P < 0.05). In contrast to previous reports that proposed a hyper-resistant phenotype for the VicK mutant in cell viability, the release of extracellular genomic DNA was significantly enhanced in SmuvicK (P < 0.05), likely as a result of increased autolysis compared with the parent. The drastic influence of VicRK on cell viability was also demonstrated using vic mutant biofilms. Taken together, we have identified a novel regulatory link between the VicRK and ComDE systems to modulate bacteriocin production and cell viability of S. mutans.

Integrins are required for cardioblast polarisation in Drosophila.

BACKGROUND: The formation of a tubular organ, such as the heart, requires the communication of positional and polarity signals between migratory cells. Key to this process is the establishment of a new luminal domain on the cell surface, generally from the apical domain of a migratory cell. This domain will also acquire basal properties, as it will produce a luminal extracellular matrix. Integrin receptors are the primary means of cell adhesion and adhesion signaling with the extracellular matrix. Here we characterise the requirement of Integrins in a genetic model of vasculogenesis, the formation of the heart in Drosophila. RESULTS: As with vertebrates, the Drosophila heart arises from lateral mesoderm that migrates medially to meet their contralateral partners, to then assemble a midline vessel. During migration, Integrins are among the first proteins restricted to the presumptive luminal domain of cardioblasts. Integrins are required for normal levels of leading edge membrane motility. Apical accumulation of Integrins is enhanced by Robo, and reciprocally, apicalisation of luminal factors like Slit and Robo requires Integrin function. Integrins may provide a template for the formation of a lumen by stabilising lumen factors like Robo. Subsequent to migration, Integrin is required for normal cardioblast alignment and lumen formation. This phenotype is most readily modified by other mutations that affect adhesion, such as Talin and extracellular matrix ligands. CONCLUSION: Our findings reveal an instructive role for Integrins in communicating polarising information to cells during migration, and during transition to an epithelial tube structure.

Breast MR imaging changes after neoadjuvant chemotherapy: correlation with molecular subtypes.

OBJECTIVE: MRI is the imaging technique that is best suited to evaluating the response to neoadjuvant chemotherapy for locally advanced breast cancer. We aimed to a) quantify the response in the molecular subtypes, b) describe the morphological and dynamic variation, and c) determine whether the molecular phenotype changes after chemotherapy. MATERIAL AND METHODS: This is a retrospective study of 75 carcinomas in 69 patients who underwent MRI both before and after neoadjuvant chemotherapy. The response to treatment was classified as a) complete response, b) major partial response, c) minor partial response, or d) no response. We quantified the response in each molecular subtype (Luminal A, Luminal B, Her2+, and triple negative). The morphological changes were classified as a) concentric reduction, b) fragmentation, c) ductal enhancement, or d) necrosis. The dynamic changes affected the maximum intensity peak and the post-initial enhancement. RESULTS: In the 4 molecular subtypes, the 4 types of response were seen. The response was good in 84.6% of the triple negative subtype, in 76.9% of the Luminal B subtype, in 75.6% of the Luminal A subtype, and in 69.2% of the Her2+ subtype. The predominant morphological change was concentric reduction (75%). The predominant dynamic change was a decrease in the maximum intensity peak (<100% in 64.2%), and type I or II curves were seen in 85.7%. CONCLUSIONS: The triple negative subtype responded best to neoadjuvant chemotherapy. The most common changes were concentric reduction and a decrease in the maximum intensity peak, with fewer washout curves. We observed a change in the molecular phenotype between the specimen at diagnosis and the final study in 12.2% of cases.