Apoptotic gene expression in neuropathic pain

Pain initiated or caused by a primary lesion or dysfunction in the nervous system is defined as neuropathic pain. It results from direct injury to nerves in the peripheral or central nervous system and is associated with several clinical symptoms. Neuropathic pain treatment is extremely difficult, as it is a very complex disease, involving several molecular pathways. Excitatory or inhibitory pathways controlling neuropathic pain development show altered gene expression, caused by peripheral nerve injury.
This study used several experimental pain models to demonstrate the occurrence of programmed cell death in the centers controlling pain induction and maintenance, such as spinal cord and pre-frontal cortex. We combined behavioural, molecular and morphological approaches to assess the involvement of bcl-2 gene family and caspases in neuropathic pain. Chronic constriction injury (CCI) and spared nerve injury (SNI) of rodent sciatic nerve induced the appearance of pain-like behaviours, such as hyperalgesia and allodynia. An early (2-3 days post-CCI) apoptosis appeared in the spinal cord neurons as the pro-apoptotic bax gene increased (320±19%). The incidence of apoptosis appeared to be limited to the first few days following nerve injury. Subsequently, increased expression of anti-apoptotic bcl-2 family genes may inhibit further neuron loss. SNI triggered apoptotic pathway and caspases activation in pre-frontal cortex 7, 14, and 21 days post-injury. Among the time-points analyzed, RT-PCR analysis showed increased expression of the bax/bcl-2 ratio (40±2%), bid (16±2%), caspase-1 (84±3%), caspase-8 (53±6%), caspase-9 (25±6%), caspase-12 (58±2%), TNF (32±2%) genes in the cortex by 7 days post-injury. Western blot analysis showed increased active Caspase-3 protein levels in the cortex at 3, 7, 14, and 21 post-surgery. This study shows that apoptotic genes could be an useful pharmacological target in neuropathic pain controlling.
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A step test to assess exercise-related oxygen desaturation in interstitial lung disease

A 6-min step test (6MST) may constitute a practical method for routinely assessing effort tolerance and exercise-related oxyhaemoglobin desaturation (ERD) in the primary care of patients with interstitial lung disease.In total, 31 patients (19 males) with idiopathic pulmonary fibrosis I and chronic hypersensitivity pneumonia were submitted, on different days, to two 6MSTs. Physiological responses were compared with those found on maximal and submaximal cycle ergometer tests at the same oxygen uptake I Chronic breathlessness was also determined, as measured by the baseline dyspnoea index (BDI).Responses to 6MST were highly reproducible: 1.3 +/- 2.0 steps(.)min(-1), +/- 5 beats(.)min(-1) (cardiac frequency), +/- 50 mL(.)min(-1) (V'O-2), +/- 7 L(.)min(-1) (minute ventilation) and +/- 2% (arterial oxygen saturation measured by pulse oximetry (Sp,O-2)). the number of steps climbed in 6 min was correlated to peak V'O-2 and the BDI. There were significant associations among the tests in relation to presence (change in Sp,O-2 between rest and exercise >= 4%) and severity (Sp,O-2 < 88%) of ERD. Four patients, however, presented ERD only in response to 6MST. Resting diffusing capacity of the lung for carbon monoxide and alveolar-arterial oxygen tension difference were the independent predictors of the number of steps climbed.A single-stage, self-paced 6-min step test provided reliable and reproducible estimates of exercise capacity and exercise-related oxyhaemoglobin desaturation in interstitial lung disease patients.UNIFESP, EPM, Dept Med,SEFICE, Div Resp,Pulm Funct & Clin Exercise Physiol Unit, BR-04020050 São Paulo, BrazilUNIFESP, EPM, Dept Med,SEFICE, Div Resp,Pulm Funct & Clin Exercise Physiol Unit, BR-04020050 São Paulo, BrazilWeb of Scienc

The pattern and timing of breathing during incremental exercise: a normative study

Clinical evaluation of the pattern and timing of breathing during submaximal exercise can be valuable for the identification of the mechanical ventilatory consequences of different disease processes and for assessing the efficacy of certain interventions.Sedentary individuals (60 male/60 female, aged 20-80 yrs) were randomly selected from >8,000 subjects and submitted to ramp incremental cycle ergometry. Tidal volume (V-T)/ resting inspiratory capacity, respiratory frequency, total respiratory time (Trot), inspiratory time (T-I), expiratory time (T-E), duty cycle (TI/Ttot) and mean inspiratory flow (V-T/T-I) were analysed at selected submaximal ventilatory intensities.Senescence and female sex were associated with a more tachypnoeic breathing pattern during isoventilation. the decline in T-tot was proportional to the TI and TE P reductions, i.e. T-I/T-tot was remarkably constant across age strata, independent of sex. the pattern, but not timing, of breathing was also influenced by weight and height; a set of demographically and anthropometrically based prediction equations are therefore presented.These data provide a frame of reference for assessing the normality of some clinically useful indices of the pattern and timing of breathing during incremental cycle ergometry in sedentary males and females aged 20-80 yrs.Universidade Federal de São Paulo, Pulmonary Funct & Clin Exercise Physiol Unit, Div Resp, Dept Med,Paulista Sch Med, BR-04020050 São Paulo, BrazilUniv Glasgow, Ctr Exercise Sci & Med, Inst Biol & Life Sci, Glasgow, Lanark, ScotlandUniversidade Federal de São Paulo, Pulmonary Funct & Clin Exercise Physiol Unit, Div Resp, Dept Med,Paulista Sch Med, BR-04020050 São Paulo, BrazilWeb of Scienc

A step test to assess exercise-related oxygen desaturation in interstitial lung disease

A 6-min step test (6MST) may constitute a practical method for routinely assessing effort tolerance and exercise-related oxyhaemoglobin desaturation (ERD) in the primary care of patients with interstitial lung disease.In total, 31 patients (19 males) with idiopathic pulmonary fibrosis I and chronic hypersensitivity pneumonia were submitted, on different days, to two 6MSTs. Physiological responses were compared with those found on maximal and submaximal cycle ergometer tests at the same oxygen uptake I Chronic breathlessness was also determined, as measured by the baseline dyspnoea index (BDI).Responses to 6MST were highly reproducible: 1.3 +/- 2.0 steps(.)min(-1), +/- 5 beats(.)min(-1) (cardiac frequency), +/- 50 mL(.)min(-1) (V'O-2), +/- 7 L(.)min(-1) (minute ventilation) and +/- 2% (arterial oxygen saturation measured by pulse oximetry (Sp,O-2)). the number of steps climbed in 6 min was correlated to peak V'O-2 and the BDI. There were significant associations among the tests in relation to presence (change in Sp,O-2 between rest and exercise >= 4%) and severity (Sp,O-2 < 88%) of ERD. Four patients, however, presented ERD only in response to 6MST. Resting diffusing capacity of the lung for carbon monoxide and alveolar-arterial oxygen tension difference were the independent predictors of the number of steps climbed.A single-stage, self-paced 6-min step test provided reliable and reproducible estimates of exercise capacity and exercise-related oxyhaemoglobin desaturation in interstitial lung disease patients.UNIFESP, EPM, Dept Med,SEFICE, Div Resp,Pulm Funct & Clin Exercise Physiol Unit, BR-04020050 São Paulo, BrazilUNIFESP, EPM, Dept Med,SEFICE, Div Resp,Pulm Funct & Clin Exercise Physiol Unit, BR-04020050 São Paulo, BrazilWeb of Scienc

Incorporating multiparametric MRI staging and the new histological Grade Group system improves risk-stratified detection of bone metastasis in prostate cancer

$\textbf{BACKGROUND}$: There remains uncertainty on the need for bone staging in men with intermediate-risk prostate cancer. Current guidelines do not use mpMRI-staging information and rely on historic pathology grading. $\textbf{METHODS}$: We investigated the ability of mpMRI and the new Grade Group system to better predict bone metastasis status in a retrospective cohort study of 438 men with prostate cancer undergoing baseline mpMRI and isotope bone scintigraphy (BS). $\textbf{RESULTS}$: Including mpMRI-staging information significantly increased the specificity of bone metastasis detection from 3.0% to 24.2% (P<0.01) and sensitivity from 89.2% to 97.3%. The new Grade Group score demonstrated progressive increase in bone metastasis rates (P<0.001). A novel risk-stratification model combining Grade Groups, PSA and mpMRI staging shows promise in predicting bone metastasis and could potentially reduce BS usage by 22.4%-34.7%. $\textbf{CONCLUSIONS}$: Incorporating the new Grade Group system and mpMRI staging more accurately identified bone metastatic risk and suggests men with Grade Group ⩽2 and/or without radiological T3 disease could safely avoid routine bone staging.We thank research support from the National Institute of Health Research, Cambridge Biomedical Research Centre, Cancer Research UK, Cancer Research UK and the Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester and the Cambridge Experimental Cancer Medicine Centre

Opium: An emerging risk factor for gastric adenocarcinoma

Opium use has been associated with higher risk of cancers of the esophagus, bladder, larynx, and lung; however, no previous study has examined its association with gastric cancer. There is also little information on the associations between hookah (water pipe) smoking or the chewing of tobacco products and the risk of gastric cancer. In a case-control study in Golestan Province of Iran, we enrolled 309 cases of gastric adenocarcinoma (118 noncardia, 161 cardia and 30 mixed-location adenocarcinomas) and 613 matched controls. Detailed information on long-term use of opium, tobacco products and other covariates were collected using structured and validated lifestyle and food frequency questionnaires. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were obtained using conditional logistic regression models. Opium use was associated with an increased risk of gastric adenocarcinoma, with an adjusted OR (95% CI) of 3.1 (1.9-5.1), and this increased risk was apparent for both anatomic subsites (cardia and noncardia). There was a dose-response effect, and individuals with the highest cumulative opium use had the strongest association (OR: 4.5; 95% CI: 2.3-8.5). We did not find a statistically significant association between the use of any of the tobacco products and risk of gastric adenocarcinoma, overall or by anatomic subsite. We showed, for the first time, an association between opium use and gastric adenocarcinoma. Given that opium use is a traditional practice in many parts of the world, these results are of public health significance. Copyright © 2013 UICC

STOP: A gamified approach to support obese patients in changing their health habits

Obesity is a challenge for the whole world and it is necessary to find new ways to reduce it and to help people in this situation by facilitating the acquisition of healthy habits to replace unhealthy ones. STOP is a project aimed at facing the challenge of obesity through a digital methodology and through a synergy between experts from the industry and academia. By tracing patients' habits, integrating these data with other data already present in databases and providing personalized paths and feedback the «STop Obesity Platform» can be a valuable help for both patients and Healthcare Professionals. All this is inserted in a gamification frame by the creation of an app that establishes an analogy to the wellknown Dorian Gray mirror with the aim of encouraging the performance of the user or the acquisition of healthy behavior through a stimulating and engaging experience. This paper shows the main objectives of the project, defines the general structure of the app and provides some examples of prototype application

Regulation of HuR structure and function by dihydrotanshinone-I

The Human antigen R protein (HuR) is an RNA-binding protein that recognizes U/AU-rich elements in diverse RNAs through two RNA-recognition motifs, RRM1 and RRM2, and post-transcriptionally regulates the fate of target RNAs. The natural product dihydrotanshinone-I (DHTS) prevents the association of HuR and target RNAs in vitro and in cultured cells by interfering with the binding of HuR to RNA. Here, we report the structural determinants of the interaction between DHTS and HuR and the impact of DHTS on HuR binding to target mRNAs transcriptome-wide. NMR titration and Molecular Dynamics simulation identified the residues within RRM1 and RRM2 responsible for the interaction between DHTS and HuR. RNA Electromobility Shifts and Alpha Screen Assays showed that DHTS interacts with HuR through the same binding regions as target RNAs, stabilizing HuR in a locked conformation that hampers RNA binding competitively. HuR ribonucleoprotein immunoprecipitation followed by microarray (RIP-chip) analysis showed that DHTS treatment of HeLa cells paradoxically enriched HuR binding to mRNAs with longer 3'UTR and with higher density of U/AU-rich elements, suggesting that DHTS inhibits the association of HuR to weaker target mRNAs. In vivo, DHTS potently inhibited xenograft tumor growth in a HuR-dependent model without systemic toxicity