Coiled-coil irregularities of the M1 protein structure promote M1–fibrinogen interaction and influence group A Streptococcus host cell interactions and virulence

Group A Streptococcus (GAS) is a human pathogen causing a wide range of mild to severe and life-threatening diseases. The GAS M1 protein is a major virulence factor promoting GAS invasiveness and resistance to host innate immune clearance. M1 displays an irregular coiled-coil structure, including the B-repeats that bind fibrinogen. Previously, we found that B-repeat stabilisation generates an idealised version of M1 (M1*) characterised by decreased fibrinogen binding in vitro. To extend these findings based on a soluble truncated version of M1, we now studied the importance of the B-repeat coiled-coil irregularities in full length M1 and M1* expressed in live GAS and tested whether the modulation of M1–fibrinogen interactions would open up novel therapeutic approaches. We found that altering either the M1 structure on the GAS cell surface or removing its target host protein fibrinogen blunted GAS virulence. GAS expressing M1* showed an impaired ability to adhere to and to invade human endothelial cells, was more readily killed by whole blood or neutrophils and most importantly was less virulent in a murine necrotising fasciitis model. M1-mediated virulence of wild-type GAS was strictly dependent on the presence and concentration of fibrinogen complementing our finding that M1–fibrinogen interactions are crucial for GAS virulence. Consistently blocking M1–fibrinogen interactions by fragment D reduced GAS virulence in vitro and in vivo. This supports our conclusion that M1–fibrinogen interactions are crucial for GAS virulence and that interference may open up novel complementary treatment options for GAS infections caused by the leading invasive GAS strain M1.     

Acceptability and Feasibility of Examining Physical Activity in Young Children with Type 1 Diabetes

Physical activity is important but may be difficult to evaluate in young children (YC) with Type 1 diabetes (T1D) because of parents' fears of hypoglycemia, difficulties engaging YC in physical activity, and use of assessment devices. This study aimed to explore the acceptability and feasibility of an in-lab exercise session for YC with T1D. Ten YC ages 3 through7 years with T1D participated in a 20-minute exercise session while wearing blinded continuous glucose monitors and accelerometers. High acceptability was found for participation in the exercise session; high feasibility and acceptability were reported for the assessments. Although most children completed the session, it did not produce moderate to vigorous physical activity. YC were found to spend most of their day sedentary, and they had frequent blood glucose excursions. Findings support the feasibility of conducting a more extensive examination of the relationship among blood glucose levels and physical activity in YC with T1D.     

Temporal Effects on Monaural Amplitude-Modulation Sensitivity in Ipsilateral,Contralateral and Bilateral Noise

The amplitude modulations (AMs) in speech signals are useful cues for speech recognition. Several adaptation mechanisms may make the detection of AM in noisy backgrounds easier when the AM carrier is presented later rather than earlier in the noise. The aim of the present study was to characterize temporal adaptation to noise in AM detection. AM detection thresholds were measured for monaural (50 ms, 1.5 kHz) pure-tone carriers presented at the onset (‘early’ condition) and 300 ms after the onset (‘late’ condition) of ipsilateral, contralateral, and bilateral (diotic) broadband noise, as well as in quiet. Thresholds were 2–4 dB better in the late than in the early condition for the three noise lateralities. The temporal effect held for carriers at equal sensation levels, confirming that it was not due to overshoot on carrier audibility. The temporal effect was larger for broadband than for low-band contralateral noises. Many aspects in the results were consistent with the noise activating the medial olivocochlear reflex (MOCR) and enhancing AM depth in the peripheral auditory response. Other aspects, however, indicate that central masking and adaptation unrelated to the MOCR also affect both carrier-tone and AM detection and are involved in the temporal effects.     

Characteristics and Outcome of Minority Group Patients in Methadone Maintenance Treatment

Minority status is associated with mental and physical morbidity, substance dependence, and poor outcomes. To compare characteristics and treatment outcomes between patients from two minority groups in Israel (Christians and Muslims) and patients from the majority population (Jews) in methadone maintenance treatment (MMT), we prospectively studied all patients admitted to our clinic between 1993 and 2012 and followed up until 2013; 655 Jews, 67 Christians, and 37 Muslims. Christian patients differed from Jews and Muslims by younger age at admission to MMT, greater prevalence of drug injectors, and a higher proportion of Hepatitis-C and HIV sera positive. Muslims had comparatively less education and a lower proportion of females. The three groups had similar rates of one-year retention (75.9%) and opiate abstinence (68.1%). They also did not differ in long-term retention (up to 20 years): Muslims 5.5 years (95%CI 3.6-7.4), Christians 7.5 years (95%CI 6-9.1), and Jews 7.6 years (95%CI 7-8.2, p = .3). The Hepatitis-C incidence, however, was higher among the 21 admitted Hepatitis-C seronegative minorities (5.0/100 person years) than the 207 Hepatitis-C seronegative non-minority patients (1.7/100 person years, p=0.03). All groups had good treatment outcomes, except for Hepatitis-C seroconversion, which necessitates a specific preventive intervention among the minority groups.     

Cyclin Kinase Inhibitors in Breast Cancer: From Bench to Bedside

A precise knowledge of cell-cycle machinery and its effect on tumorigenesis has led to the development of a large number of anticancer drugs targeting this pathway. In breast cancer research, the promising results of recent clinical trials of novel selective CDK-inhibitors, for example palbociclib, have generated high expectations for this field. This review gathers the results of the most recent clinical trials of CDK inhibitors for breast cancer, and outlines their potential as anticancer therapy.     

Vivencias y percepción de los profesionales sanitarios de las urgencias extrahospitalarias ante las agresiones

ObjetivoConocer las opiniones de los profesionales sanitarios que trabajan en el Punto de Atención Continuada de Ourense (PAC) con relación a las agresiones laborales.DiseñoEstudio cualitativo con enfoque fenomenológico realizado entre enero y mayo del 2019.EmplazamientoPAC.ParticipantesVeinte profesionales de distintas categorías.MédodoMuestreo estructural. Se emplearon entrevistas abiertas grabadas en audio, previo consentimiento de los participantes.ResultadosLos profesionales entrevistados manifiestas haber sido víctimas de agresiones, sobre todo verbales. Estas agresiones según los participantes son tan habituales que las han normalizado dentro de su jornada laboral. Ninguno ha denunciado nunca este tipo de conductas, en gran medida porque consideran que la burocracia y los trámites administrativos son tediosos, y otros por desconocimiento del procedimiento. Este tipo de situaciones, a nivel laboral, les causa sentimientos de tristeza, rabia e impotencia y son la causa, según ellos, del aumento de la medicina defensiva. Los profesionales consideran que la causa del aumento de las agresiones entre el colectivo es la mala educación y la gestión inadecuada del empoderamiento del paciente.ConclusionesLos profesionales sanitarios sufren continuamente agresiones, sobre todo de tipo verbal, siendo algo habitual en su día a día. Estas agresiones no son denunciadas, pero les causan múltiples sentimientos negativos y disruptivos, llegando a modificar su manera de trabajar.Palabras clave: Violencia laboral, Personal de salud, Agresión, Violencia