Carotid Pulse Wave Analysis: Future Direction of Hemodynamic and Cardiovascular Risk Assessment.

Evaluation of the hemodynamic function of the cardiovascular system via measurement of the mechanical properties of the large arteries may provide a substantial improvement over present techniques. Practitioners are familiar with the problem of low reproducibility of conventional sphygmomanometry, which exhibits reasonable accuracy but low precision owing to its marked variability over time and in different circumstances (e.g., the white coat effect). Arterial wall stiffness is a consequence of atherosclerosis developing over time; thus, it has little short-term variability and is thus preferable to be used as a prognostic marker. In particular, arterial stiffness can be evaluated at the carotid artery using noninvasive approaches based on wearable sensor technologies for pulse wave analysis. These enable the assessment of central pressures and pulse waveform parameters that are expected to replace peripheral blood pressure measurement using the inflatable cuff. In this study, we discuss this simple and inexpensive technique, which has been shown to be reliable with the clinical and epidemiological evidence for its use as a biomarker of cardiovascular risk.

A look beyond the priority: A systematic review of the genotoxic, mutagenic, and carcinogenic endpoints of non-priority PAHs.

Knowledge of the toxic potential of polycyclic aromatic hydrocarbons (PAHs) has increased over time. Much of this knowledge is about the 16 United States - Environmental Protection Agency (US - EPA) priority PAHs; however, there are other US - EPA non-priority PAHs in the environment, whose toxic potential is underestimated. We conducted a systematic review of in vitro, in vivo, and in silico studies to assess the genotoxicity, mutagenicity, and carcinogenicity of 13 US - EPA non-priority parental PAHs present in the environment. Electronic databases, such as Science Direct, PubMed, Scopus, Google Scholar, and Web of Science, were used to search for research with selected terms without time restrictions. After analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol, 249 articles, published between 1946 and 2020, were selected and the quality assessment of these studies was performed. The results showed that 5-methylchrysene (5-MC), 7,12-dimethylbenz[a]anthracene (7,12-DMBA), cyclopenta[cd]pyrene (CPP), and dibenzo[al]pyrene (Db[al]P) were the most studied PAHs. Moreover, 5-MC, 7,12-DMBA, benz[j]aceanthrylene (B[j]A), CPP, anthanthrene (ANT), dibenzo[ae]pyrene (Db[ae]P), and Db[al]P have been reported to cause mutagenic effects and have been being associated with a risk of carcinogenicity. Retene (RET) and benzo[c]fluorene (B[c]F), the least studied compounds, showed evidence of a strong influence on the mutagenicity and carcinogenicity endpoints. Overall, this systematic review provided evidence of the genotoxic, mutagenic, and carcinogenic endpoints of US - EPA non-priority PAHs. However, further studies are needed to improve the future protocols of environmental analysis and risk assessment in severely exposed populations.

Motor function measure: validation of a short form for young children with neuromuscular diseases.

OBJECTIVE: To validate a useful version of the Motor Function Measure (MFM) in children with neuromuscular diseases aged <7 years old. DESIGN: Two prospective cohort studies that documented the MFM completion of children aged between 2 and 7 years old. SETTING: French-speaking rehabilitation departments from France, Belgium, and Switzerland. PARTICIPANTS: Healthy children (n=194) and children with a neuromuscular disease (n=88). INTERVENTIONS: Patients were rated by the MFM either once or twice by trained medical professionals, with a delay between the 2 MFMs ranging between 8 and 30 days. MAIN OUTCOME MEASURE: Intra- and interrater reliability of the MFM. RESULTS: The subtests making up the MFM-32, a scale monitoring severity and progression of motor function in patients with a neuromuscular disease in 3 functional domains, were carried out in healthy children aged 2 to 7 years. Twenty items of the MFM-32 were successfully completed by these children and were used to constitute the MFM-20. Principal component analysis of the MFM-20 confirmed the 3 functional domains. Inter- and intrarater reliability of the 3 subscores and total score were high (intraclass correlation coefficient >.90), and discriminant validity was good. CONCLUSIONS: The MFM-20 can be used as an outcome measure for assessment of motor function in young children with neuromuscular disease.

Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines.

BACKGROUND: Colorectal cancer (CRC) is a heterogeneous and biologically poorly understood disease. To tailor CRC treatment, it is essential to first model this heterogeneity by defining subtypes of patients with homogeneous biological and clinical characteristics and second match these subtypes to cell lines for which extensive pharmacological data is available, thus linking targeted therapies to patients most likely to respond to treatment. METHODS: We applied a new unsupervised, iterative approach to stratify CRC tumor samples into subtypes based on genome-wide mRNA expression data. By applying this stratification to several CRC cell line panels and integrating pharmacological response data, we generated hypotheses regarding the targeted treatment of different subtypes. RESULTS: In agreement with earlier studies, the two dominant CRC subtypes are highly correlated with a gene expression signature of epithelial-mesenchymal-transition (EMT). Notably, further dividing these two subtypes using iNMF (iterative Non-negative Matrix Factorization) revealed five subtypes that exhibit activation of specific signaling pathways, and show significant differences in clinical and molecular characteristics. Importantly, we were able to validate the stratification on independent, published datasets comprising over 1600 samples. Application of this stratification to four CRC cell line panels comprising 74 different cell lines, showed that the tumor subtypes are well represented in available CRC cell line panels. Pharmacological response data for targeted inhibitors of SRC, WNT, GSK3b, aurora kinase, PI3 kinase, and mTOR, showed significant differences in sensitivity across cell lines assigned to different subtypes. Importantly, some of these differences in sensitivity were in concordance with high expression of the targets or activation of the corresponding pathways in primary tumor samples of the same subtype. CONCLUSIONS: The stratification presented here is robust, captures important features of CRC, and offers valuable insight into functional differences between CRC subtypes. By matching the identified subtypes to cell line panels that have been pharmacologically characterized, it opens up new possibilities for the development and application of targeted therapies for defined CRC patient sub-populations.

Chemoprevention of precancerous gastric lesions with antioxidant vitamin supplementation: a randomized trial in a high-risk population.

BACKGROUND: Gastric cancer is one of the most common malignancies worldwide. Histopathologic studies have identified a sequence of changes in the gastric mucosa that mark the slow progression from normal tissue to carcinoma. Epidemiologic evidence suggests that a diet rich in fresh fruit and vegetables could be a protective factor against this disease. This effect may be mediated through antioxidant vitamins. METHODS: A randomized, double-blind chemoprevention trial was conducted among 1980 subjects in Tachira State, Venezuela (whose population is at high risk for gastric cancer), to determine the effect of dietary supplementation with vitamin C, vitamin E, and beta-carotene on the progression and regression of precancerous gastric lesions. Subjects were randomly assigned to receive either a combination of vitamin C (750 mg/day), vitamin E (600 mg/day), and beta-carotene (18 mg/day) or placebo for 3 years. Changes in the gastric mucosa were determined by histologic diagnosis based on five biopsies taken from prespecified areas of the stomach at baseline and annually for 3 years. All biopsies were reviewed by a single expert pathologist. Progression rates (and regression rates) were calculated by comparing the first and last available gastroscopies for each subject and dividing the number of subjects whose diagnoses increased (decreased) in severity by the total follow-up time. Overall rate ratios were calculated by Poisson regression, controlling for baseline diagnosis. All statistical tests were two-sided. RESULTS: Median plasma vitamin levels were increased in the treatment group between baseline and 1 year after randomization from 0.43 micromol/L (interquartile range [IQR] = 0.26-0.69) to 2.89 micromol/L (IQR = 1.76-4.22) for beta-carotene, from 26.7 micromol/L (IQR = 23.1-31.2) to 54.9 micromol/L (IQR = 42.8-67.6) for alpha-tocopherol, and from 47.70 micromol/L (IQR = 36.9-58.5) to 61.9 micromol/L (IQR = 52.2-72.7) for vitamin C. Overall progression rates per 100 person-years were 74.3 in the placebo group and 67.8 in the group randomly assigned to vitamins. Overall regression rates were 109.4 in the placebo group and 116.5 in the group randomly assigned to vitamins. There was no statistically significant difference in progression rate (rate ratio = 0.92, 95% confidence interval [CI] = 0.74 to 1.15) or regression rate (rate ratio = 1.09, 95% CI = 0.90 to 1.33) between vitamin and placebo groups. CONCLUSION: Supplementation with antioxidant micronutrients is not an effective tool for gastric cancer control in this high-risk population. The results of this trial are consistent with previous findings on the lack of effect of nutritional supplementation on precancerous gastric lesions.

Acute effects of 6-hydroxydopamine on dopaminergic neurons of the rat substantia nigra pars compacta in vitro.

6-Hydroxydopamine (6-OHDA) is a neurotoxin which has been implicated in the degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNc) in Parkinson's disease (PD), and is frequently used to produce animal models of the disease. The aim of our study, conducted on midbrain slices obtained from young Wistar rats, was to determine the little known acute effects of this toxin (0.2-2.0 mM; 10-20 min exposure; 34 degrees C) on electrophysiological properties, intracellular Ca2+ levels and dendritic morphology of SNc neurons. Four experimental approaches were used: extracellular recording of firing frequency, whole-cell patch-clamping, ratiometric fura-2 imaging, and cell labeling with lucifer yellow (LY) or dextran-rhodamine. Extracellular recording revealed a concentration-dependent decrease in the tonic, pacemaker-like firing. In whole-cell recordings in voltage-clamp (V(hold) -60 mV), smaller doses (0.2-0.5 mM) induced an outward current (or cell membrane hyperpolarization in current-clamp), which could in some cells be reversed with tolbutamide (blocker of ATP-dependent K+ channels). A higher dose (1.0-2.0 mM) caused rapid reductions of cell membrane capacitance and membrane resistance. Toxin exposure gradually increased the intracellular Ca2+ level, which did not subsequently return to control. The increase in Ca2+ signal was not prevented by depletion of intracellular Ca2+ stores with thapsigargin (10 microM) or cyclopiazonic acid (30 microM), nor by removing extracellular Ca2+. Cell membrane current and Ca2+ responses were not prevented by blocking dopamine transporter (DAT). Cells loaded with LY or dextran-rhodamine showed signs of damage (cell membrane blebbing) in dendrites following toxin exposure (1 mM; 10-20 min). These results demonstrate that the oxidative and metabolic stress induced in SNc neurons by 6-OHDA results in rapid dose-dependent changes of cell membrane properties with morphological evidence of dendritic damage, as well as in disturbance of intracellular Ca2+ homeostasis.

Effects of muscarinic acetylcholine receptor activation on membrane currents and intracellular messengers in medium spiny neurones of the rat striatum.

Acetylcholine, acting through muscarinic receptors, modulates the excitability of striatal medium spiny neurones. However, the underlying membrane conductances and intracellular signalling pathways have not been fully determined. Our aim was to characterize excitatory effects mediated by M1 muscarinic acetylcholine receptors in these neurones using whole-cell patch-clamp recordings in brain slices of postnatal rats. Under voltage-clamp, muscarine evoked an inward current associated with an increase in cell membrane resistance. The current, which reversed at -85 mV, was sensitive to the M1 receptor antagonist pirenzepine. Blocking the potassium conductance attenuated the response and the residual current was further reduced by ruthenium red (50 microm) and reversed at +15 mV. Simultaneous recordings from cholinergic interneurones and medium spiny neurones in conjunction with spike-triggered averaging revealed small unitary excitatory postsynaptic currents in four of 39 cell pairs tested. The muscarine-induced inward current was attenuated by a phospholipase C (PLC) inhibitor, U73122, but not by a protein kinase C inhibitor, chelerythrine, or by the intracellular calcium chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid, suggesting that the current was associated with PLC in a protein kinase C- and Ca2+ -independent manner. The phosphatidylinositol 4-kinase inhibitor wortmannin (10 microm) reduced the recovery of the inward current, indicating that the recovery process was dependent on the removal of diacylglycerol and/or inositol 1,4,5 triphosphate or resynthesis of phospholipid phosphatidylinositol 4,5-bisphophate. Ratiometric measurement of intracellular calcium after cell loading with fura-2 demonstrated a muscarine-induced increase in calcium signal that originated mainly from intracellular stores. Thus, the cholinergic excitatory effect in striatal medium spiny neurones, which is important in motor disorders associated with altered cholinergic transmission in the striatum such as Parkinson's disease, is mediated through M1 receptors and the PLC-dependent pathway.

Strongyloides stercoralis en pacientes alcohólicos / Strongyloides stercoralis infection in alcoholic patients

Se evaluó la infección con strongyloides stercoralis en 106 pacientes alcohólicos crónicos, usando el método de Baermann, el cultivo en plato de agar (CPA) y la observación microscópica de frotis de heces. El parásito fue observado en 6 (5,7 por ciento) casos. Todos diagnosticados por Baermann, 5 por CPA (sensibilidad = 83,3 por ciento), y solo 2 por el frotis directo (sensibilidad = 33,3 por ciento). Otros parásitos intestinales diagnosticados fueron endolimax nana (16 por ciento), giardia lamblia (7,3 por ciento), entamoeba coli (6,6 por ciento), entamoeba histolytica (4,7 por ciento), uncinarias (0,9 por ciento), hymenolepis nana (0,9 por ciento) y entamoeba hartmanni (0,9 por ciento). La prevalencia global de parásitos intestinales en los pacientes estudiados fue del 30 por ciento, un valor relativamente bajo; pero en concordancia con la prevalencia a nivelnacional que fue 21 por ciento o menor al 5 por ciento si sólo se consideran los helmintos intestinales. Además, es importante la comparación de las infecciones por uncinarias y S. stercoralis en pacientes alcohólicos, porque ambos parásitos tienen mecanismos de infección similares; pero nuestros datos muestran una mayor prevalencia para el último, lo que denota un posible incremento en el riesgo para esta infección en pacientes alcohólicos