Tumour microvessel density as predictor of chemotherapy response in breast cancer patients

The aim of this study was to evaluate the predictive value of intratumoural microvessel density in breast cancer. We studied immunohistochemically primary tumours of 104 patients with metastasised breast cancer who took part in a randomised multicentre trial comparing docetaxel to sequential methotrexate and 5-fluorouracil. Vessels were highlighted with factor VIII staining and counted microscopically. Microvessel density was compared with clinical response to chemotherapy and patient survival. The microvessel density of the primary tumour was not significantly associated with patient's response to chemotherapy, time to progression or overall survival in the whole patient population or in the docetaxel or methotrexate and 5-fluorouracil groups. However, disease-free survival was longer in patients with low microvessel density (P=0.01). These findings suggest that microvessel density of the primary tumour cannot be used as a predictive marker for chemotherapy response in advanced breast cancer

Association between muscular strength and mortality in men: prospective cohort study

Objective: To examine prospectively the association between muscular strength and mortality from all causes, cardiovascular disease, and cancer in men. Design: Prospective cohort study. Setting: Aerobics center longitudinal study. Participants: 8762 men aged 20-80. Main outcome measures: All cause mortality up to 31 December 2003; muscular strength, quantified by combining one repetition maximal measures for leg and bench presses and further categorised as age specific thirds of the combined strength variable; and cardiorespiratory fitness assessed by a maximal exercise test on a treadmill. Results: During an average follow-up of 18.9 years, 503 deaths occurred (145 cardiovascular disease, 199 cancer). Age adjusted death rates per 10,000 person years across incremental thirds of muscular strength were 38.9, 25.9, and 26.6 for all causes; 12.1, 7.6, and 6.6 for cardiovascular disease; and 6.1, 4.9, and 4.2 for cancer (all P Conclusion: Muscular strength is inversely and independently associated with death from all causes and cancer in men, even after adjusting for cardiorespiratory fitness and other potential confounders

Efectos de un programa escolar orientado a la mejora de la condición física sobre el perfil lipídico de adolescentes: estudio EDUFIT

Observational studies have reported an association among physical activity, fitness and lipid profile in youth. The purpose of this study was to analyse the effect of a school-based intervention focused on increasing the number and intensity of Physical Education (PE) sessions a week, on adolescents' lipid profile. METHODS: A 4-month group-randomized controlled trial was conducted in 67 adolescents (12-14 years-old) from South-East Spain, 2007. Three school classes were randomly allocated into control group (CG), experimental group-1 (EG1) and experimental group-2 (EG2). The CG received the usual PE in Spain (2 sessions/week), the EG1 received 4 PE sessions/week, and the EG2 received 4 PE sessions/week of high intensity. The main study outcomes were fasting levels of total cholesterol, high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc) and triglycerides. All the analyses were adjusted for sex, sexual maturation, attendance and baseline value of the outcome studied. RESULTS: The intervention did not positively affect cardio-metabolic parameters except for LDLc, that was marginally yet significantly reduced in EG2 (-10.4 mg/dl), compared with the CG (+4.1 mg/dl) (p = 0.04); no differences were observed however for the LDLc/HDLc ratio. No significant effects were observed in EG1. DISCUSSION: Overall, a 4-month school-based physical activity intervention did not substantially influence lipid profile in adolescents. However, the results suggest that increasing both frequency and intensity of PE sessions had a modest effect on LDLc in youth. Future studies involving larger sample sizes and longer interventions should focus on the separate effects of volume and intensity of PE.Objetivos: Los estudios observacionales han notificado una asociación entre la actividad física, la forma física y el perfil lipídico en la juventud. El propósito de este estudio fue analizar el efecto de una intervención basada en la escuela centrada en aumentar el número y la intensidad de las sesiones de educación física (EF) a lo largo de la semana, en el perfil lipídico de los adolescentes. Métodos: Se realizó un estudio controlado de distribución aleatoria en 67 adolescentes (12-14 2013s) del sudeste de España, en 2007. Tres clases fueron distribuidas al azar a un grupo control (GC), un grupo experimental-1 (GE1) y un grupo experimental-2 (GE2). El GC recibió las sesiones habituales de EF en España (2 sesiones semanales), el GE1 recibió 4 sesiones de EF /semana y el GE2 recibió 4 sesiones de EF /semana de alta intensidad. Los criterios de valoración principales del estudio fueron las concentraciones en ayunas de colesterol toral, lipoproteínas de densidad elevada-colesterol (HDLc), lipoproteínas de densidad baja-colesterol (LDLc) y de triglicéridos. Se ajustaron todos los análisis para el sexo, maduración sexual, asistencia y valor basal de la variable estudiada. Resultados: La intervención no afectó de forma positiva a los parámetros cardiovasculares a excepción de las LDLc que disminuyeron marginal aunque significativamente en el GE2 (-10,4 mg/dl), en comparación del GC (+4,1 mg/dl) (p = 0,04); sin embargo, no se observaron diferencias para el cociente LDLc/HDLc ratio. No se observaron efectos significativos en el GE1. Discusión: De forma global, una intervención de actividad física basada en la escuela durante 4 meses no influyó de forma sustancial en el perfil lipídico de los adolescentes. Sin embargo, los resultados sugieren que el aumentar tanto la frecuencia como la intensidad de las sesiones de EF tiene un efecto modesto sobre las LDLc en los jóvenes. Los estudios futuros que impliquen una muestra mayor e intervenciones más duraderas deberían centrarse en los efectos separados del volumen e intensidad de la EF

Zastosowanie leku XENical w zapobieganiu cukrzycy u osób z otyłością — badanie XENDOS. Badanie randomizowane z zastosowaniem orlistatu jako dodatkowego, oprócz zmian stylu życia, czynnika zapobiegania cukrzycy typu 2 u pacjentów z otyłością

INTRODUCTION. It is well established that the risk of developing type 2 diabetes is closely linked to the presence and duration of overweight and obesity. A reduction in the incidence of type 2 diabetes with lifestyle changes has previously been demonstrated. We hypothesized that adding a weight-reducing agent to lifestyle changes may lead to an even greater decrease in body weight, and thus the incidence of type 2 diabetes, in obese patients. MATERIAL AND METHODS. In a 4-year, double-blind, prospective study, we randomized 3,305 patients to lifestyle changes plus either orlistat 120 mg or placebo, three times daily. Participants had a BMI &#8805; 30 kg/m2 and normal (79%) or impaired (21%) glucose tolerance (IGT). Primary endpoints were time to onset of type 2 diabetes and change in body weight. Analyses were by intention to treat. RESULTS. Of orlistat-treated patients, 52% completed treatment compared with 34% of placebo recipients (P < 0.0001). After 4 years&#8217; treatment, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P = 0.0032). Exploratory analyses indicated that the preventive effect was explained by the difference in subjects with IGT. Mean weight loss after 4 years was significantly greater with orlistat (5.8 vs. 3.0 kg with placebo; P < 0.001) and similar between orlistat recipients with impaired (5.7 kg) or normal glucose tolerance (NGT) (5.8 kg) at baseline. A second analysis in which the baseline weights of subjects who dropped out of the study was carried forward also demonstrated greater weight loss in the orlistat group (3.6 vs. 1.4 kg; P < 0.001). CONCLUSIONS. Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced greater weight loss in a clinically representative obese population. Difference in diabetes incidence was detectable only in the IGT subgroup; weight loss was similar in subjects with IGT and or NGT.WSTĘP. Ryzyko rozwoju cukrzycy typu 2 wiąże się ściśle z obecnością i czasem trwania nadwagi oraz otyłości. Wpływ wprowadzenia zmian stylu życia na zmniejszenie częstości cukrzycy typu 2 potwierdzono we wcześniejszych badaniach. Wysunięto hipotezę, według której zastosowanie dodatkowego czynnika powodującego zmniejszenie masy ciała u chorych, którym udało się ten cel częściowo osiągnąć pod wpływem zmiany stylu życia, pozwala uzyskać jeszcze lepsze efekty, a w konsekwencji prowadzi do dalszej redukcji częstości cukrzycy typu 2 u pacjentów z otyłością. MATERIAŁ I METODY. Do trwającego 4 lata, prospektywnego, randomizowanego badania, przeprowadzonego metodą podwójnie ślepej próby zakwalifikowano 3305 pacjentów, których losowo podzielono na dwie grupy. W pierwszej grupie, obok wprowadzenia zmian stylu życia, pacjentom podawano 3 razy na dobę orlistat w dawce 120 mg, a w drugiej &#8212; placebo. Wskaźnik masy ciała (BMI, body mass index) uczestników badania był większy lub równy 30 kg/m2, stężenie glukozy było prawidłowe (79%) lub rozpoznawano upośledzoną tolerancję glukozy (IGT, impaired glucose tolerance) (21%). Jako główne kryterium oceny badania przyjęto czas do wystąpienia cukrzycy typu 2 oraz zmianę masy ciała. Przeprowadzono analizę według pierwotnej intencji leczenia (intention to treat). WYNIKI. Leczenie ukończyło 52% badanych otrzymujących orlistat i 34% przyjmujących placebo (p < 0,0001). Po 4 latach terapii skumulowane ryzyko wystąpienia cukrzycy w grupie otrzymującej placebo wyniosło 9%, natomiast w grupie przyjmującej orlistat &#8212; 6,2%, co oznacza redukcję ryzyka o 37,3% (p = 0,0032). Na podstawie analizy uzyskanych danych stwierdzono, że efekt prewencyjny wynikał z różnic wśród pacjentów z upośledzoną tolerancją glukozy. Średnia redukcja masy ciała po 4 latach obserwacji była znacząco wyższa w grupie leczonej orlistatem (5,8 vs. 3,0 kg w grupie otrzymującej placebo; p < 0,001) oraz podobna u pacjentów otrzymujących orlistat z wyjściową upośledzoną (5,7 kg) lub prawidłową tolerancją glukozy (NGT, normal glucose tolerance) (5,8 kg). W drugiej analizie, w której uwzględniono zmiany masy ciała u osób wyłączonych z badania, również wykazano większą redukcję masy ciała w grupie leczonej orlistatem (3,6 vs. 1,4 kg; p < 0,001). WNIOSKI. W badaniu przeprowadzonym w reprezentatywnej populacji osób z otyłością wykazano, że w porównaniu z postępowaniem opartym wyłącznie na zmianie stylu życia, dodanie orlistatu spowodowało większy spadek częstości cukrzycy typu 2 oraz większą redukcję masy ciała w okresie 4 lat. Różnica w częstości cukrzycy była widoczna tylko w podgrupie z IGT, zmniejszenie masy ciała było podobne zarówno w podgrupie z IGT, jak i z NGT

Analysis of the intraspinal calcium dynamics and its implications on the plasticity of spiking neurons

The influx of calcium ions into the dendritic spines through the N-metyl-D-aspartate (NMDA) channels is believed to be the primary trigger for various forms of synaptic plasticity. In this paper, the authors calculate analytically the mean values of the calcium transients elicited by a spiking neuron undergoing a simple model of ionic currents and back-propagating action potentials. The relative variability of these transients, due to the stochastic nature of synaptic transmission, is further considered using a simple Markov model of NMDA receptos. One finds that both the mean value and the variability depend on the timing between pre- and postsynaptic action-potentials. These results could have implications on the expected form of synaptic-plasticity curve and can form a basis for a unified theory of spike time-dependent, and rate based plasticity.Comment: 14 pages, 10 figures. A few changes in section IV and addition of a new figur

Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial

BACKGROUND: Reductions in albuminuria are associated with a subsequent lower risk of kidney failure in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney function. Whether this effect persists in patients with chronic kidney disease with and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on albuminuria in patients with chronic kidney disease with and without type 2 diabetes in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial. METHODS: DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) between 25 mL/min per 1·73 m2 and 75 mL/min per 1·73 m2 and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6 to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca; Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered, fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio. Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from less than 3000 mg/g to 3000 mg/g or greater, were additional discrete endpoints. The trial is registered with ClinicalTrials.gov, NCT03036150. FINDINGS: Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949 mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric mean UACR by 29·3% (95% CI -33·1 to -25·2; p<0·0001); relative to placebo, treatment with dapagliflozin resulted in a geometric mean percentage change of -35·1% (95% CI -39·4 to -30·6; p<0·0001) in patients with type 2 diabetes and -14·8% (-22·9 to -5·9; p=0·0016) in patients without type 2 diabetes over the follow-up visits (pinteraction<0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60 to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions in UACR at day 14 during dapagliflozin treatment were significantly associated with attenuated eGFR decline during subsequent follow-up (β per log unit UACR change -3·06, 95% CI -5·20 to -0·90; p=0·0056). INTERPRETATION: In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR, suggest that part of the protective effect of dapagliflozin in patients with chronic kidney disease might be mediated through pathways unrelated to reduction in albuminuria. FUNDING: AstraZeneca

Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial

BACKGROUND: Dapagliflozin reduced the risk of kidney failure in patients with chronic kidney disease with and without type 2 diabetes in the DAPA-CKD trial. In this pre-specified analysis, we assessed the effect of dapagliflozin on the rate of change in estimated glomerular filtration rate (eGFR)-ie, the eGFR slope. METHODS: DAPA-CKD was a randomised controlled trial that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio (UACR) of 200-5000 mg/g, and an eGFR of 25-75 mL/min per 1·73m2. Participants were randomly assigned (1:1) to oral dapagliflozin 10 mg once daily or placebo, added to standard care. In this pre-specified analysis, we analysed eGFR slope using mixed-effect models with different slopes from baseline to week 2 (acute eGFR decline), week 2 to end of treatment (chronic eGFR slope), and baseline to end of treatment (total eGFR slope). DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150, and is now complete. FINDINGS: Between Feb 2, 2017, and April 3, 2020, 4304 participants were recruited, of whom 2152 (50%) were assigned to dapagliflozin and 2152 (50%) were assigned to placebo. At baseline, the mean age was 62 years (SD 12), 1425 (33·1%) participants were women, 2906 (67·5%) participants had type 2 diabetes. The median on-treatment follow-up was 2·3 years (IQR 1·8-2·6). From baseline to the end of treatment, dapagliflozin compared with placebo slowed eGFR decline by 0·95 mL/min per 1·73 m2 per year (95% CI 0·63 to 1·27) in the overall cohort. Between baseline and week 2, dapagliflozin compared with placebo resulted in an acute eGFR decline of 2·61 mL/min per 1·73 m2 (2·16 to 3·06) in patients with type 2 diabetes and 2·01 mL/min per 1·73 m2 (1·36 to 2·66) in those without type 2 diabetes. Between week 2 and end of treatment, dapagliflozin compared with placebo reduced the mean rate of eGFR decline by a greater amount in patients with type 2 diabetes (mean difference in chronic eGFR slope 2·26 mL/min per 1·73 m2 per year [1·88 to 2·64]) than in those without type 2 diabetes (1·29 mL/min per 1·73 m2 per year [0·73 to 1·85]; pinteraction=0·0049). Between baseline and end of treatment, the effect of dapagliflozin compared with placebo on the decline of total eGFR slope in patients with type 2 diabetes was 1·18 mL/min per 1·73 m2 per year (0·79 to 1·56) and without type 2 diabetes was 0·46 mL/min per 1·73 m2 per year (-0·10 to 1·03; pinteraction=0·040). The total eGFR slope was steeper in patients with higher baseline HbA1c and UACR; the effect of dapagliflozin on eGFR slope was also more pronounced in patients with higher baseline HbA1c and UACR. INTERPRETATION: Dapagliflozin significantly slowed long-term eGFR decline in patients with chronic kidney disease compared with placebo. The mean difference in eGFR slope between patients treated with dapagliflozin versus placebo was greater in patients with type 2 diabetes, higher HbA1c, and higher UACR. FUNDING: AstraZeneca

Does physical activity counselling enhance the effects of a pedometer-based intervention over the long-term : 12-month findings from the Walking for Wellbeing in the West study

Peer reviewedPublisher PD

Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial

AIMS : Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death. METHODS AND RESULTS : DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo. CONCLUSION : In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death

A Comprehensive Workflow for General-Purpose Neural Modeling with Highly Configurable Neuromorphic Hardware Systems

In this paper we present a methodological framework that meets novel requirements emerging from upcoming types of accelerated and highly configurable neuromorphic hardware systems. We describe in detail a device with 45 million programmable and dynamic synapses that is currently under development, and we sketch the conceptual challenges that arise from taking this platform into operation. More specifically, we aim at the establishment of this neuromorphic system as a flexible and neuroscientifically valuable modeling tool that can be used by non-hardware-experts. We consider various functional aspects to be crucial for this purpose, and we introduce a consistent workflow with detailed descriptions of all involved modules that implement the suggested steps: The integration of the hardware interface into the simulator-independent model description language PyNN; a fully automated translation between the PyNN domain and appropriate hardware configurations; an executable specification of the future neuromorphic system that can be seamlessly integrated into this biology-to-hardware mapping process as a test bench for all software layers and possible hardware design modifications; an evaluation scheme that deploys models from a dedicated benchmark library, compares the results generated by virtual or prototype hardware devices with reference software simulations and analyzes the differences. The integration of these components into one hardware-software workflow provides an ecosystem for ongoing preparative studies that support the hardware design process and represents the basis for the maturity of the model-to-hardware mapping software. The functionality and flexibility of the latter is proven with a variety of experimental results