What doesn't kill you makes you stranger: Dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands

Dipeptidyl peptidase 4 (DPP4) is an exopeptidase found either on cell surfaces where it is highly regulated in terms of its expression and surface availability (CD26) or in a free/circulating soluble constitutively available and intrinsically active form. It is responsible for proteolytic cleavage of many peptide substrates. In this review we discuss the idea that DPP4-cleaved peptides are not necessarily inactivated, but rather can possess either a modified receptor selectivity, modified bioactivity, new antagonistic activity, or even a novel activity relative to the intact parent ligand. We examine in detail five different major DPP4 substrates: glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide tyrosine-tyrosine (PYY), and neuropeptide Y (NPY), and stromal derived factor 1 (SDF-1 aka CXCL12). We note that discussion of the cleaved forms of these five peptides are underrepresented in the research literature, and are both poorly investigated and poorly understood, representing a serious research literature gap. We believe they are understudied and misinterpreted as inactive due to several factors. This includes lack of accurate and specific quantification methods, sample collection techniques that are inherently inaccurate and inappropriate, and a general perception that DPP4 cleavage inactivates its ligand substrates. Increasing evidence points towards many DPP4-cleaved ligands having their own bioactivity. For example, GLP-1 can work through a different receptor than GLP-1R, DPP4-cleaved GIP can function as a GIP receptor antagonist at high doses, and DPP4-cleaved PYY, NPY, and CXCL12 can have different receptor selectivity, or can bind novel, previously unrecognized receptors to their intact ligands, resulting in altered signaling and functionality. We believe that more rigorous research in this area could lead to a better understanding of DPP4’s role and the biological importance of the generation of novel cryptic ligands. This will also significantly impact our understanding of the clinical effects and side effects of DPP4-inhibitors as a class of anti-diabetic drugs that potentially have an expanding clinical relevance. This will be specifically relevant in targeting DPP4 substrate ligands involved in a variety of other major clinical acute and chronic injury/disease areas including inflammation, immunology, cardiology, stroke, musculoskeletal disease and injury, as well as cancer biology and tissue maintenance in aging

Conocimientos y prácticas sobre las medidas de control de infección por tuberculosis en una institución de salud

Introduction: Some health workers have knowledge and wrong practices regarding the measurements of control of tuberculosis, which increases the probability of infection in health institutions. Objective: To describe knowledge and practices regarding the control measurements for infection with tuberculosis in workers in the health areas, before and after an educational intervention. Method: Assessment study with a pre and post model. The project lasted 12 months. We applied a previous test to the workers, then we designed an intervention based in andragogy and we applied an after-test, six months later. We used descriptive statistics and we carried out the non-parametric McNemar test for samples related or dependent. Results: 216 health workers took part. We found out a meaningful increase after the pedagogical intervention regarding the knowledge and practice of the control measurements of tuberculosis in aspects as the tuberculine test (P < 0,05), the testing of respiratory symptoms (P< 0,05), crossed natural ventilation (P < 0,05), mechanic ventilation (P< 0,05), high efficiency mask N95 (P < 0,05) and the implementation of adequate steps to use this element of personal protection. (P <0,05). Conclusion: The pedagogical intervention contributed to improve knowledge and practices of health workers regarding the control measurements for the infection with tuberculosis. Educational interventions may contribute to the control of tuberculosis in health institutions.      Introducción: Algunos trabajadores de la salud tienen conocimientos y prácticas erróneas sobre las medidas de control de tuberculosis, lo que aumenta su probabilidad de contagio en las instituciones de salud. Objetivo: Describir los conocimientos y las prácticas sobre las medidas de control de infección por tuberculosis en trabajadores de la salud antes y después de una intervención educativa. Métodos: Estudio de tipo evaluativo con modelo antes-después. El proyecto tuvo una duración de 12 meses. Se aplicó un pre-test a los trabajadores de la salud, se diseñó una intervención educativa sustentada en la andragogía y se aplicó un pos-test seis meses después. Se utilizaron estadísticos descriptivos, se realizó la prueba no paramétrica de McNemar para muestras relacionadas o dependientes. Resultados: Participaron 216 trabajadores de la salud. Se encontró un aumento significativo después de la intervención educativa sobre los conocimientos y las prácticas de las medidas de control de tuberculosis en aspectos como la prueba de tuberculina (P < 0,05), la captación de sintomáticos respiratorios (P < 0,05), ventilación natural cruzada (P < 0,05), ventilación mecánica (P < 0,05), mascarilla de alta eficiencia N95 (P < 0,05) y la implementación de los pasos adecuados para usar este elemento de protección personal (P < 0,05). Conclusión: La intervención educativa contribuyó a mejorar los conocimientos y las prácticas de los trabajadores de la salud sobre las medidas de control de la infección por tuberculosis. Las intervenciones educativas pueden contribuir al control de la tuberculosis en las instituciones de salud

Evaluation of the insertion torque, implant stability quotient and drilled hole quality for different drill design: an in vitro Investigation

This is the peer reviewed version of the following article: Gehrke SA, Guirado JLC, Bettach R, Fabbro MD, Martınez CP-A, Shibli JA. Evaluation of the insertion torque, implant stability quotient and drilled hole quality for different drill design: an in vitro Investigation. Clin. Oral Impl. Res. 00, 2016, 1–7], which has been published in final form at 10.1111/clr.12808. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Objective: The purpose of the present study was to compare the insertion torque and implant stability quotient between different drill design for implant site preparation. Materials and Methods: Synthetic blocks of bone (type I density) were used for drilling procedures. Three groups were evaluated: Group G1 - drilling with a single bur for a 4.2 mm conical implant; Group G2 and Group G3 - drilling with three consecutive burs for a 4.1 mm cylindrical implant and for a 4.3 mm conical implant respectively. For each group, 15 drilling procedures were performed without irrigation for 10-mm in-depth. The drilled hole quality (HQ) after the osteotomy for implant site preparation was measured in the five-first holes through a fully automated roundness/cylindricity instrument at three levels (top, middle, and bottom of the site). The insertion torque value (ITV) was achieved with a computed torquimeter and the implant stability quotient (ISQ) values were measured using a resonance frequency apparatus. Results: Thesingledrill(group1)achievedasignificantlyhigherITVandISQthanthemultipledrills for osteotomy (groups 2 and 3). Group 1 and 3 displayed significantly better HQ than group 2. Conclusions: Within the limitations of the study, the results suggest that the hole quality, in addition to the insertion torque, may significantly affect implant primary stability.Odontologí

Machine learning in the loop for tuberculosis diagnosis support

The use of machine learning (ML) for diagnosis support has advanced in the field of health. In the present paper, the results of studying ML techniques in a tuberculosis diagnosis loop in a scenario of limited resources are presented. Data are analyzed using a tuberculosis (TB) therapy program at a health institution in a main city of a developing country using five ML models. Logistic regression, classification trees, random forest, support vector machines, and artificial neural networks are trained under physician supervision following physicians' typical daily work. The models are trained on seven main variables collected when patients arrive at the facility. Additionally, the variables applied to train the models are analyzed, and the models' advantages and limitations are discussed in the context of the automated ML techniques. The results show that artificial neural networks obtain the best results in terms of accuracy, sensitivity, and area under the receiver operating curve. These results represent an improvement over smear microscopy, which is commonly used techniques to detect TB for special cases. Findings demonstrate that ML in the TB diagnosis loop can be reinforced with available data to serve as an alternative diagnosis tool based on data processing in places where the health infrastructure is limited

Subjective response to antipsychotic treatment and compliance in schizophrenia. A naturalistic study comparing olanzapine, risperidone and haloperidol (EFESO Study)

BACKGROUND: In order to compare the effectiveness of different antipsychotic drugs in the treatment of schizophrenia it is very important to evaluate subjective response and compliance in patient cohorts treated according to routine clinical practice. METHOD: Outpatients with schizophrenia entered this prospective, naturalistic study when they received a new prescription for an antipsychotic drug. Treatment assignment was based on purely clinical criteria, as the study did not include any experimental intervention. Patients treated with olanzapine, risperidone or haloperidol were included in the analysis. Subjective response was measured using the 10-item version of the Drug Attitude Inventory (DAI-10), and treatment compliance was measured using a physician-rated 4 point categorical scale. RESULTS: A total of 2128 patients initiated treatment (as monotherapy) with olanzapine, 417 with risperidone, and 112 with haloperidol. Olanzapine-treated patients had significantly higher DAI-10 scores and significantly better treatment compliance compared to both risperidone- and haloperidol-treated patients. Risperidone-treated patients had a significantly higher DAI-10 score compared to haloperidol-treated patients. CONCLUSION: Subjective response and compliance were superior in olanzapine-treated patients, compared to patients treated with risperidone and haloperidol, in routine clinical practice. Differences in subjective response were explained largely, but not completely, by differences in incidence of EPS

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Background: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0·771) was similar. Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status

Extrapulmonary tuberculosis A perspective from a third-level hospital

Introducción: la tuberculosis sigue siendo una enfermedad de alta prevalencia y muestra, además, un aumento considerable en los pacientes VIH/SIDA; de igual manera, las formas extrapulmonares vienen tomando cada vez mayor relevancia. Se informan aproximadamente 9 millones de casos nuevos y más de 1 millón y medio de muertes cada año por tuberculosis, así mismo toma importancia cardinal el incremento en la incidencia de casos de tuberculosis extrapulmonar. Objetivos: evaluar y presentar los datos de un hospital de tercer nivel en relación con tuberculosis extrapulmonar y ofrecer recomendaciones generales para su diagnóstico y tratamiento. Diseño, materiales y métodos: se revisaron los registros clínicos y las bases epidemiológicas del programa de tuberculosis de los últimos 12 años de un hospital de tercer nivel de Bogotá, Colombia (Hospital Santa Clara ESE) y se hizo una revisión de la literatura en lo que respecta a la tuberculosis y su presentación extrapulmonar. Resultados: en el consolidado de casos de tuberculosis extrapulmonar de la población del Hospital Santa Clara ESE de 12 años se obtuvieron 30% de casos extrapulmonares en pacientes no VIH/SIDA y 47% en pacientes con SIDA. Las formas de presentación extrapulmonar más frecuentes fueron la ganglionar, el compromiso del sistema nervioso central y la miliar. Conclusiones: se encontró una importante incidencia en los casos extrapulmonares. El reto más importante en la tuberculosis extra-pulmonar radica en la sospecha clínica y en la selección del método para la confirmación diagnóstica. Esta formas son paucibacilares y de bajo contagio, pero pueden producir alta morbi-mortalidad, la misma que puede ser mayor en los pacientes con VIH/SIDA.Artículo original16-26Introduction: the prevalence of tuberculosis (TB) continues to be high, and shows an important increase in patients with HIV/AIDS. The relevance of extrapulmonary forms of the disease has likewise become increasingly greater. Approximately 9 million new cases of tuberculosis are reported every year, with more than one and a half million deaths due to the disease during the same period of time. Objectives: to evaluate and present the data of a third-level hospital with regard to extrapulmonary tuberculosis, and to give some general recommendations for its diagnosis and treatment. Design, Materials and Methods: the clinical charts and the epidemiologic databases of the tuberculosis program carried out over the past 12 years at a third-level hospital of Bogotá, Colombia (Hospital Santa Clara E.S.E.) were evaluated, and a review of the literature concerning tuberculosis and its extrapulmonary presentation was carried out. Results: The consolidated data of cases of extrapulmonary tuberculosis among the population of the Hospital Santa Clara E.S.E. over a 12-year period: 30% of extrapulmonary cases were found in non-HIV/AIDS-infection patients and 47% in patients with AIDS. The most common forms of extrapulmonary presentation were: of the lymph nodes, of the central nervous system, and of the miliary type. Conclusions: An important incidence of extrapulmonary cases was found. The challenge with regard to extrapulmonary tuberculosis lies on clinical suspicion and on the selection of the method for diagnostic confirmation. These forms are paucibacillary and not very contagious, but can produce high morbidity and mortality rates, especially in patients with HIV/AIDS

High levels of anti-tuberculin (IgG) antibodies correlate with the blocking of T-cell proliferation in individuals with high exposure to Mycobacterium tuberculosis

SummaryObjectivesTo determine the effect of anti-tuberculin antibodies in the T-cell proliferation in response to tuberculin and Candida antigens in individuals with different levels of tuberculosis (TB) risk.MethodsSixteen high-risk TB individuals, 30 with an intermediate TB risk (group A), and 45 with a low TB risk (group B), as well as 49 control individuals, were studied. Tuberculin skin test (TST) results were analyzed and serum levels of antibodies (IgG and IgM) against purified protein derivative (PPD) were measured by ELISA. Tuberculin and Candida antigens were used to stimulate T-cell proliferation in the presence of human AB serum or autologous serum.ResultsHigh levels of anti-tuberculin IgG antibodies were found to be significantly associated with the blocking of T-cell proliferation responses in cultures stimulated with tuberculin but not with Candida antigens in the presence of autologous serum. This phenomenon was particularly frequent in high-risk individuals with high levels of anti-tuberculin IgG antibodies in the autologous serum when compared to the other risk groups, which exhibited lower levels of anti-tuberculin antibodies.ConclusionsAlthough cellular immunity plays a central role in the protection against TB, humoral immunity is critical in the control of Mycobacterium tuberculosis infection in high-risk individuals with latent TB infection

Early tumour response as a survival predictor in previously- treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer

Background: Early tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m2) and triplet hepatic artery infusion (HAI) within European trial OPTILIV. Methods: Irinotecan (180 mg/m2), 5-fluorouracil (2800 mg/m2) and oxaliplatin (85 mg/m2) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models. Results: Response was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33–76 years, with a median of 12 liver metastases (LMs) (2–50), involving five segments (1–8). Ten patients had a late response, and 31 patients had no response. Grade 3–4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation—odds ratio (OR): 6.0 (1.2–29.8; p = 0.029)—and LM diameter ≤57 mm—OR: 5.3 (1.1–25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection—OR: 11.8 (1.4–100.2; p = 0.024) and overall survival—hazard ratio: 0.39 (0.17–0.88; p = 0.023) in multivariate analyses. Conclusions: Early tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making