Taurine: a potential marker of apoptosis in gliomas

New cancer therapies are being developed that trigger tumour apoptosis and an in vivo method of apoptotic detection and early treatment response would be of great value. Magnetic resonance spectroscopy (MRS) can determine the tumour biochemical profile in vivo, and we have investigated whether a specific spectroscopic signature exists for apoptosis in human astrocytomas. High-resolution magic angle spinning (HRMAS) 1H MRS provided detailed 1H spectra of brain tumour biopsies for direct correlation with histopathology. Metabolites, mobile lipids and macromolecules were quantified from presaturation HRMAS 1H spectra acquired from 41 biopsies of grades II (n=8), III (n=3) and IV (n=30) astrocytomas. Subsequently, TUNEL and H&E staining provided quantification of apoptosis, cell density and necrosis. Taurine was found to significantly correlate with apoptotic cell density (TUNEL) in both non-necrotic (R=0.727, P=0.003) and necrotic (R=0.626, P=0.0005) biopsies. However, the ca 2.8 p.p.m. polyunsaturated fatty acid peak, observed in other studies as a marker of apoptosis, correlated only in non-necrotic biopsies (R=0.705, P<0.005). We suggest that the taurine 1H MRS signal in astrocytomas may be a robust apoptotic biomarker that is independent of tumour necrotic status

Association between different measurements of blood pressure variability by ABP monitoring and ankle-brachial index

<p>Abstract</p> <p>Background</p> <p>Blood pressure (BP) variability has been associated with cardiovascular outcomes, but there is no consensus about the more effective method to measure it by ambulatory blood pressure monitoring (ABPM). We evaluated the association between three different methods to estimate BP variability by ABPM and the ankle brachial index (ABI).</p> <p>Methods and Results</p> <p>In a cross-sectional study of patients with hypertension, BP variability was estimated by the time rate index (the first derivative of SBP over time), standard deviation (SD) of 24-hour SBP; and coefficient of variability of 24-hour SBP. ABI was measured with a doppler probe. The sample included 425 patients with a mean age of 57 ± 12 years, being 69.2% women, 26.1% current smokers and 22.1% diabetics. Abnormal ABI (≤ 0.90 or ≥ 1.40) was present in 58 patients. The time rate index was 0.516 ± 0.146 mmHg/min in patients with abnormal ABI versus 0.476 ± 0.124 mmHg/min in patients with normal ABI (P = 0.007). In a logistic regression model the time rate index was associated with ABI, regardless of age (OR = 6.9, 95% CI = 1.1- 42.1; P = 0.04). In a multiple linear regression model, adjusting for age, SBP and diabetes, the time rate index was strongly associated with ABI (P < 0.01). None of the other indexes of BP variability were associated with ABI in univariate and multivariate analyses.</p> <p>Conclusion</p> <p>Time rate index is a sensible method to measure BP variability by ABPM. Its performance for risk stratification of patients with hypertension should be explored in longitudinal studies.</p

Preferential Fas-mediated apoptotic execution at G1 phase: the resistance of mitotic cells to the cell death

Apoptosis is induced by various stresses generated from the extracellular and intracellular environments. The fidelity of the cell cycle is monitored by surveillance mechanisms that arrest its further progression if any crucial process has not been completed or damages are sustained, and then the cells with problems undergo apoptosis. Although the molecular mechanisms involved in the regulation of the cell cycle and that of apoptosis have been elucidated, the links between them are not clear, especially that between cell cycle and death receptor-mediated apoptosis. By using the HeLa.S-Fucci (fluorescent ubiquitination-based cell cycle indicator) cells, we investigated the relationship between the cell cycle progression and apoptotic execution. To monitor apoptotic execution during cell cycle progression, we observed the cells after induction of apoptosis with time-lapse fluorescent microscopy. About 70% of Fas-mediated apoptotic cells were present at G1 phase and about 20% of cells died immediately after cytokinesis, whereas more than 60% of etoposide-induced apoptotic cells were at S/G2 phases in random culture of the cells. These results were confirmed by using synchronized culture of the cells. Furthermore, mitotic cells showed the resistance to Fas-mediated apoptosis. In conclusion, these findings suggest that apoptotic execution is dependent on cell cycle phase and Fas-mediated apoptosis preferentially occurs at G1 phase

State of emergency medicine in Spain

Spain has universal public health care coverage. Emergency care provisions are offered to patients in different modalities and levels according to the characteristics of the medical complaint: at primary care centers (PCC), in an extrahospital setting by emergency medical services (EMS) and at hospital emergency departments (ED). We have more than 3,000 PCCs, which are run by family doctors (general practitioners) and pediatricians. On average, there is 1 PCC for every 15,000 to 20,000 inhabitants, and every family doctor is in charge of 1,500 to 2,000 citizens, although less populated zones tend to have lower ratios. Doctors spend part of their duty time in providing emergency care to their own patients. While not fully devoted to emergency medicine (EM) practice, they do manage minor emergencies. However, Spanish EMSs contribute hugely to guarantee population coverage in all situations. These EMS are run by EM technicians (EMT), nurses and doctors, who usually work exclusively in the emergency arena. EDs dealt with more than 25 million consultations in 2008, which implies, on average, that one out of two Spaniards visited an ED during this time. They are usually equipped with a wide range of diagnostic tools, most including ultrasonography and computerized tomography scans. The academic and training background of doctors working in the ED varies: nearly half lack any structured specialty residence training, but many have done specific master or postgraduate studies within the EM field. The demand for emergency care has grown at an annual rate of over 4% during the last decade. This percentage, which was greater than the 2% population increase during the same period, has outpaced the growth in ED capacity. Therefore, Spanish EDs become overcrowded when the system exerts minimal stress. Despite the high EM caseload and the potential severity of the conditions, training in EM is still unregulated in Spain. However, in April 2009 the Spanish Minister of Health announced the imminent approval of an EM specialty, allowing the first EM resident to officially start in 2011. Spanish emergency physicians look forward to the final approval, which will complete the modernization of emergency health care provision in Spain

Blood pressure variability and leukoaraiosis in acute ischemic stroke

Higher blood pressure, blood pressure variability, and leukoaraiosis are risk factors for early adverse events and poor functional outcome after ischemic stroke, but prior studies differed on whether leukoaraiosis was associated with blood pressure variability, including in ischemic stroke. In the Third International Stroke Trial, blood pressure was measured in the acute phase of ischemic stroke immediately prior to randomization, and at 0.5, 1, and 24 h after randomization. Masked neuroradiologists rated index infarct, leukoaraiosis, and atrophy on CT using validated methods. We characterized blood pressure variation by coefficient of variance and three other standard methods. We measured associations between blood pressure, blood pressure variability, and leukoaraiosis using generalized estimating equations, adjusting for age, and a number of covariates related to treatment and stroke type/severity. Among 3017 patients, mean (±SD) systolic and diastolic blood pressure decreased from 155(±24)/82(±15) mmHg pre-randomization to 146(±23)/78(±14) mmHg 24 h later ( P &lt; 0.005). Mean within-subject coefficient of variance was 0.09 ± 0.05 for systolic and 0.11 ± 0.06 for diastolic blood pressure. Patients with most leukoaraiosis were older and had higher blood pressure than those with least ( P &lt; 0.0001). Although statistically significant in simple pairwise comparisons, no measures of blood pressure variability were associated with leukoaraiosis when adjusting for confounding variables ( P &gt; 0.05), e.g. age. Our results suggest that blood pressure variability is not a potential mechanism to explain the association between leukoaraiosis and poor outcome after acute stroke

Sistemas de transporte de nuc1eósidos en células parenquimales hepáticas. Patrón de expresión de isoformas durante la diferenciación del hepatocito

Nucleoside uptake into rat hepatocytes is mediated by, at least, three independent transport systems, a Na+-dependent purine-preferring system (NI-like), a Na+-dependent pyrimidine-preferring transport system (N2-like) and, finally, a Na+-independent agency which is NBTI-insensitive. The concentrative component oftransport is highly regulated, since it is induced in liver hypertrophia and hyperplasia and up-regulated by pancreatic hormones. Two different cDNAs, SPNT and cNTl , apparently related to NI and N2 transport activities respectively, have been characterized so far in liver. The SPNT mRNA is more abundant than the cNTI mRNA, but the biological activities associated with NI and N2 transport systems are rather equivalent. Transformed liver parenchymal cells (hepatoma cell lines) and fetal hepatocytes show a different pattem of nucleoside transport systems. These highly proliferative cells show high nucleoside transport activity although this is mediated mostly by a Na+-independent transport component which is mostly sensitive to NBTI inhibition. This equilibrative NBTI-sensitive transport system is not detected in adult hepatocytes. We conclude that the translocation of nucleosides across the plasma membrane of the hepatocyte involves a complex combination of carrier proteins which may differ depending on the differentiated state of the cell rather than by their proliferative status.La captación de nucleósidos por el hepatocito está mediada por un mínimo de tres sistemas de transporte, dos dependientes de sodio con especificidades para purinas y pirimidinas (NI y N2 respectivamente) y un tercer sistema independiente de sodio e insensible a NBTI. La componente de transporte concentrativa está fuertemente regulada, ya que se induce en la hipertrofia e hiperplasia hepática y es estimulada por hormonas pancreáticas. Hasta la fecha se han caracterizado únicamente dos ADNc susceptibles de codificar proteínas transportadoras de nucleósidos de tipo N I y N2 (SPNT y cNTl respectivamente). La cantidad de ARNm para SPNT es más elevada que la de cNTl , si bien la actividad biológica de ambos sistemas es similar. Tanto las líneas celulares derivadas de hepatomas como los hepatocitos fetales presentan un patrón de expresión de transportadores de nucleósidos marcadamente distinta a la de un he pato cito adulto. Su elevada tasa de proliferación se acompaña de una elevada capacidad de transporte de nucleósidos, pero ésta se debe, en gran medida o casi exclusivamente, a una componente equilibrativa, independiente de sodio y sensible a NBTI. Esta componente de transporte no se detecta en el hepatocito diferenciado. Concluimos que la translocación de nucleósidos a través de membrana plasmática del hepatocito esta mediada por varias proteínas de membrana, cuyos niveles de expresión dependen más del estado de diferenciación de la célula que de su estado proliferativo

Prevalence of clozapine-induced sialorrhea and its effect on quality of life

Rationale: Clozapine has proven to be superior to other antipsychotic drugs in the treatment of schizophrenia but is under-prescribed due to its potentially severe side effects. Clozapine-induced sialorrhea (CIS) is a frequent and extremely uncomfortable side effect, which remains understudied. Objectives: To examine the prevalence of diurnal and nocturnal CIS in a sample of patients treated with clozapine, and to evaluate its impact on quality of life. Methods: We conducted a cross-sectional, observational study of 130 patients with schizophrenia spectrum disorders treated with clozapine. The prevalence of CIS was evaluated via specific sialorrhea scales. None of the patients included in the study was receiving a specific treatment for hypersalivation during the study period. Possible associations between sialorrhea and clinical and quality of life variables were analyzed. Results: Of 130 subjects, 120 (92.3%) suffered from CIS. Eighty-one (62.31%) suffered from diurnal CIS, 115 (88.56%) from nocturnal CIS, and 85 (65.38%) suffered from both. Significant positive associations between quality of life and diurnal CIS (B = 0.417; p = 2.1e - 6, R2 = 0.156) and nocturnal CIS (B = 0.411; p = 7.7e - 6, R2 = 0.139) were detected. Thirty per cent of the subjects reported a moderate to severe negative impact of sialorrhea on their quality of life. Conclusions: The present study suggests that CIS is highly prevalent in patients with schizophrenia and has an important impact on quality of life in one-third of our sample. Therefore, the inclusion of a systematic evaluation and treatment of CIS in standard clinical practice is highly recommended. Trial registration: Clinical Trials ( https://clinicaltrials.gov ) under reference NCT04197037