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At least 145 records · Page 8Linked to original sources
PubMed2000

Late post-myocardial infarction induces a tetrodotoxin-resistant Na(+)Current in rat cardiomyocytes.

Left ventricular remodeling after myocardial infarction is accompanied by electrical abnormalities that might predispose to rhythm disturbances. To get insight into the ionic mechanisms involved, we studied myocytes isolated from four different regions of the rat ventricles, 4-6 months after ligation of the left coronary artery. Using the whole-cell patch-clamp technique, we never observed T-type Ca(2+)current in both diseased and control hearts. In contrast, in 41 out of 78 cells isolated from 16 post-myocardial infarcted rats, analysed in the presence of 30 m m Na(+)ions, we found a tetrodotoxin (TTX)-resistant Na(+)current with quite variable amplitude in every investigated region. Albeit being resistant to 100 microM TTX, this Na(+)-dependent current was highly sensitive to lidocaine since 3 microM lidocaine induced about 65% tonic block. It was also inhibited by 5 microM nifedipine and 2 m m Co(2+), but was insensitive to 100 microM Ni(2+). The TTX-resistant Na(+)channel availability was shifted rightward by 25-30 mV with respect to TTX-sensitive Na(+)current; therefore, a large "window current" might flow in the voltage range from -70 to -20 mV. In conclusion, in late post-myocardial infarction, a Na(+)current with specific kinetics and pharmacology may provide inward charges in a critical range of membrane voltages that are able to alter action potential time course and trigger ventricular arrhythmia. These apparent new characteristics of the Na(+)channel might result in part from environmental changes during heart remodeling.

Animals↗
PubMed1998

Influence of baseline values on lipids and lipoprotein changes during amlodipine treatment of hypertension.

Twenty adult hypertensive patients classified as having 'low', 'medium' and 'high' baseline values, underwent plasma lipids and lipoproteins assessment after 12 weeks treatment with amlodipine. For the patients with low baseline values, the mean triglycerides and very low density lipoprotein-cholesterol levels increased after amlodipine therapy. No significant variation was observed in the mean values of the lipids and lipoproteins before and after amlodipine therapy for the patients with 'medium baseline values', while in patients with 'high baseline values', mean low density lipoprotein-cholesterol decreased after amlodipine therapy. These findings therefore suggest that the levels of the baseline lipid and lipoprotein profiles may have a significant influence on the lipid altering actions of amlodipine pharmacotherapy.

Adult↗
PubMed1982

The use of matrices in analyzing the three-dimensional behavior of the vestibulo-ocular reflex.

The vestibulo-ocular reflex rotates the eye about the axis of a head rotation at the same speed but in the opposite direction to make the visual axes in space independent of head motion. This reflex works in all three degrees of freedom: roll, pitch, and yaw. The rotations may be described by vectors and the reflex by a transformation in the form of a matrix. The reflex consists of three parts: sensory, central, and motor. The transduction of head rotation into three neural signals, which may also be described by a vector, is described by a canal matrix. The neural, motor-command vector is transformed to an eye rotation by a muscle matrix. Since these two matrices are known, one can solve for the central matrix which gives the strength of the connections between all the vestibular neurons and all the eye-muscle motoneurons. The role of the metric tensor in these transformations is described. This method of analysis is used in three applications. A lesion may be simulated by altering the elements in any or all of the three component matrices. By matrix multiplication, the resulting abnormal behavior of the reflex can be described quantitatively in all degrees of freedom. The method is also used to directly compare the differences in brain-stem connections between humans and rabbits that accommodate the altered actions of the muscles of the two species. Finally the method allows a quantitative assessment of the changes that take place in the brain-stem connections when plastic changes are induced by artificially dissociating head movements from apparent motion of the visual environment.

Animals↗
PubMed1998

Molecular aspects of adrenergic signal transduction in cardiac failure.

Abnormal beta-adrenergic signal transduction and intracellular Ca2+ handling appear to be a major cause of systolic and diastolic dysfunction in humans with heart failure. The precise mechanisms which cause an alteration in Ca2+ handling have been a subject of investigation in recent years. Several lines of evidence suggest that activation of neurohormonal systems plays a central role. Altered Ca2+-handling (increased diastolic concentrations, reduced systolic Ca2+ release) have a strong impact on diastolic and systolic performance of failing hearts. Sarcoplasmic reticulum Ca2+ ATPase is reduced in activity and in steady-state mRNA concentration. The Na+-Ca2+ exchanger is upregulated at the mRNA and protein levels. Phospholamban depends strongly on cAMP-dependent phosphorylation. A strong sympathetic activation has been shown to desensitize the cAMP system. At the receptor level, there is downregulation of beta1-adrenergic receptors. An uncoupling of beta2-adrenoceptors has been attributed to an increased activity and gene expression of beta-adrenergic receptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. Finally, recent evidence suggests that cAMP-dependent transcription mechanisms may play a role during beta-adrenergic stimulation and cardiomyopathy with heart failure - by means of altered actions of cAMP response element binding protein, the cAMP response element modulator, or the activating transcription factor 1. The exact characterization of signal transduction defects could offer novel approaches to the pharmacological treatment of heart failure.

Animals↗
PubMed2026

Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC): An Aggressive Disease Course and Limitations for Personalized Oncology.

Neuroendocrine carcinoma (NEC) is a rare, aggressive malignancy with limited treatment options and poor prognosis. We report a male patient diagnosed with a gastroenteropancreatic (GEP)-NEC with synchronous liver metastasis at the time of surgery who underwent a radical resection attempt. Despite radical-intent surgery followed by adjuvant carboplatin/etoposide, early recurrence developed with progression through multiple subsequent chemotherapy lines. During the treatment process, genetic profiling was performed twice to identify actionable genomic targets, with inclusion in the national IMPRESS study as a last resort. Comprehensive genomic profiling revealed TP53 mutation and RB1 loss but no actionable alterations. A patient-derived organoid (PDO) was successfully established from resected tumor tissue and retained key neuroendocrine and proliferative features, with partial genomic concordance to the primary tumor. Differences between the primary and subsequent PDO in variant allele frequencies suggest clonal selection during culture. Exploratory metabolomic profiling of tryptophan pathway metabolites in patient serum and PDO-culture media indicated tumor-associated metabolic alterations. We present clinical and translational efforts in difficult-to-treat NEC, illustrating both the translational challenges and the potential role of PDOs in advancing personalized treatment strategies for a cancer with very limited treatment options.

Gastroenteropancreatic neuroendocrine carcinoma↗
PubMed1984

Hepatic microsomal enzymes in Schistosoma mansoni-infected mice: I. Effect of duration of infection and lindane administration on dimethylnitrosamine demethylases.

The prevalence of schistosomiasis in Egypt, its suspected relationship to carcinoma of the bladder, and the inevitable exposure of schistosomal patients to insecticides prompted the undertaking of this study. Dimethylnitrosamine (DMN) demethylases, responsible for the activation of DMN, were assessed in the hepatic microsomes from albino mice under the influence of Schistosoma mansoni infection and/or lindane administration. DMN-demethylase I responded to infection by an early increase in activity, reaching a peak 30 days after disease induction and declining sharply afterwards. DMN-demethylase II followed the same general pattern, but it reached its peak 20 days after infection and declined at a slower rate than DMN-demethylase I. The effects of lindane, an organochlorine insecticide, were also studied on these two enzymes in uninfected mice and in S. mansoni-infected animals after different durations of disease induction. Given orally, in a dose of 40 mg/kg/day for 3 consecutive days, lindane increased the activity of both enzymes. Since DMN requires metabolic activation for its hepatotoxic and carcinogenic actions, alterations in its activating enzymes, as a consequence to schistosomiasis and/or exposure to lindane, may change susceptibility to its toxic and carcinogenic potentials.

Animals↗
PubMed1994

Effects of chronic receptor blockade on excitation-contraction coupling in rat aortic rings.

The effects of an intracellular Ca2+ depletor (ryanodine), a Ca2+ channel antagonist (felodipine), a protein kinase C inhibitor (staurosporine) as well as caffeine, cholera and pertussis toxin have been examined on noradrenaline-induced contractions in aortic rings from rats pretreated i.v. with either saline or phenoxybenzamine for 7 days. Ryanodine (3 and 10 microM) was able to both potentiate and inhibit noradrenaline-evoked contractions in aortic rings from phenoxybenzamine-treated rats. However, ryanodine did not affect the concentration-response curves to noradrenaline in tissues from saline-treated rats. Further, felodipine (1 and 10 nM) and staurosporine (10 nM) inhibited noradrenaline-induced contractions in aortic rings from phenoxybenzamine- but not saline-treated rats. Pertussis toxin (100 ng/ml) also inhibited contractions produced by noradrenaline in rings from phenoxybenzamine- but not saline-treated rats. In contrast to these observations, both caffeine (1 mM) and cholera toxin (3 micrograms/ml) inhibited noradrenaline-evoked contractions in aortic rings from phenoxybenzamine- and saline-treated rats. The results suggest that chronic receptor blockade by phenoxybenzamine leads to alteration in alpha-adrenoceptor-mediated signal transduction in the aorta. The changes include alteration in Ca2+ handling at the plasmalemmal and intracellular levels, as well as an altered action of pertussis toxin-sensitive G-protein, but not of cholera toxin-sensitive G-protein.

Alkaloids↗
PubMed1986

Decreased effectiveness of GABA-mediated inhibition in the inferior colliculus of the genetically epilepsy-prone rat.

The inferior colliculus (IC) is a critical site for induction of audiogenic seizures in the genetically epilepsy-prone rat (GEPR). Abnormal response properties observed in inferior colliculus neurons of that strain include a high incidence of onset-offset responses which may be a form of afterdischarge. These response abnormalities may involve altered actions of neurotransmitters in that region of the brain. GABA is implicated as a transmitter in endogenous sound-induced inhibition in the inferior colliculus. Endogenous inhibition and the actions of agents that affect GABA receptors were examined in inferior colliculus neurons in epileptic and normal rats. The iontophoretic dose (current) of GABA required to suppress neuronal firing in the epilepsy-prone rat was significantly greater than that required in neurons of the normal rat. A form of endogenous (binaural) inhibition in inferior colliculus neurons, which is proposed to be GABA-mediated, was also significantly reduced in the epilepsy-prone rat as compared with the normal rat. A benzodiazepine (flurazepam) which enhances the action of GABA in many brain sites including the inferior colliculus was significantly less effective than normal when applied iontophoretically onto the same neurons of the epilepsy-prone rat. The GABAA antagonist, bicuculline, which blocks the effect of GABA on inferior colliculus neurons, frequently induced the onset-offset response in neurons not previously exhibiting this pattern. These findings suggest that the reduction of GABA-mediated inhibition in the genetically epilepsy-prone rat may result in the increased incidence of afterdischarges in neurons of the inferior colliculus and may serve as an important mechanism of epileptogenesis in audiogenic seizures in this genetic form of epilepsy.

Animals↗
PubMed1982

Retinal sensitivity measured by the pupillary light reflex in RCS and albino rats.

The effects of retinal degeneration on the sensitivity of the retina were studied in the Royal College of Surgeons (RCS) rat by measuring the light reflex of the pupil in response to ganzfeld (full field) flashes. Light reflex thresholds were measured for animals from 32 to 683 days of age, and an age-related decrease in sensitivity of 5.2 log units (maximum) was measured. In contrast, thresholds for non-dystrophic albino controls increased only slightly during a comparable period. RCS rat thresholds increased more for short wavelength light than for long wavelength light. The end result was an altered action spectrum of the light reflex which largely, but not exclusively, reflected cone function. Even in cases of advanced degeneration the light reflex thresholds we measured showed significant input from rods. Pupiliary dark adaptation measured following ganzfeld bleaches (10%) with test stimuli of two different wavelengths revealed two mechanisms; a photopic mechanism (gamma max = 520) determined thresholds early in dark adaptation, but later a scotopic mechanism (gamma max = 500) participated in the light reflex.

Aging↗
PubMed2026

Genomic profiling by circulating tumor DNA in patients with hormone receptor-positive/HER2-negative advanced breast cancer: Prevalence of actionable mutations across treatment lines.

INTRODUCTION: Plasma next-generation sequencing (NGS) is endorsed by ESMO as an alternative to tissue testing in advanced hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC), particularly after progression on endocrine therapy plus CDK4/6 inhibitors. However, prospective real-world data across distinct therapeutic contexts remain limited. PATIENTS AND METHODS: In this prospective observational study conducted within a nationwide cancer network in Brazil, centralized plasma NGS, and tissue NGS when available, was performed in two independent cohorts: prior to initiation of first-line endocrine therapy in the metastatic setting (Cohort 1) and at progression on endocrine therapy plus a CDK4/6 inhibitor (Cohort 2). The primary objective was to evaluate plasma-detected ESR1 mutation prevalence across these therapeutic contexts, and secondarily to assess other actionable drivers detected by plasma or tissue NGS. RESULTS: Among 86 collected plasma samples, 72 (84%) had evaluable NGS results (Cohort 1, n = 37; Cohort 2, n = 35). ESR1 mutations were identified in 18.9% of patients in Cohort 1 and 40.0% in Cohort 2, mostly at low variant allele fractions (<0.5%), corresponding to an absolute prevalence difference of 21.1 percentage points (95% CI, -0.2 to 40.3; P value=0.07). When considering any actionable alteration detected by plasma, including ESR1, PIK3CA, AKT1, PTEN, BRCA1, BRCA2, and ERBB2, prevalences were 43.2% and 68.6%, respectively (P value=0.04). Only four patients had ESR1 mutations identified in tissue, three in metastatic samples. Plasma-tissue concordance was higher for PIK3CA mutations (85.1%). CONCLUSION: Plasma NGS identified clinically meaningful ESR1 mutation rates across both contexts, supporting guideline-endorsed plasma-based genomic profiling in HR+/HER2- mBC.

CDK4/6 inhibitors↗
PubMed2005

Accuracy and utility of a 10-test disk blood glucose meter.

We evaluated the clinical accuracy, precision, and ease-of-use of a whole blood referenced glucose meter system that uses a 10-test disk (Ascensia Confirm Blood Glucose Monitoring System, Bayer Healthcare LLC). The meter system was tested by 100 subjects and eight health care professionals at two separate diabetes centers. Meter blood glucose test results, obtained by the subjects and health care professionals, were accurate and correlated well when compared with laboratory results. The means of the subject and healthcare professional blood glucose results were within 4.8% of the laboratory mean glucose result. When compared with laboratory results, the correlation coefficient was 0.96 for subject meter results and 0.97 for health care professional meter results. Error grid analyses demonstrated that all subject and health care professional blood glucose measurements fell within zones A and B ('no effect on clinical action' and 'altered clinical action with little or no effect on clinical outcome,' respectively). Ninety-three percent (93%) of subjects rated the meter system favorably on an 'ease-of-use' questionnaire. A majority of subjects correctly performed blood glucose self-monitoring tasks simply by reviewing the user guide. In summary, this unique meter that uses a 10-test disk was shown to be both accurate and precise, and subjects with diabetes were able to use the system properly with minimal instructions.

Blood Glucose↗
PubMed2026

Multiregion profiling of genomic and transcriptional heterogeneity in head and neck squamous-cell carcinoma.

BACKGROUND: Intratumoral heterogeneity (ITH) is thought to contribute to tumour evolution and treatment resistance but its biological and clinical significance in localised head and neck squamous-cell carcinoma (HNSCC) remains incompletely understood. PATIENTS AND METHODS: In the prospective SCANDARE study, we analysed 87 patients with resectable HNSCC treated with upfront surgery. Two to five spatially distinct tumour regions per patient underwent pathological evaluation, targeted DNA sequencing, and bulk RNA sequencing. Genomic ITH (gITH) was quantified using clonal deconvolution and Shannon diversity indices, whereas transcriptional heterogeneity (tITH) was assessed using the intratumour expression distance metric. Associations between ITH, molecular features, tumour microenvironment composition, and clinical outcomes were explored using multivariable statistical models. RESULTS: Pathology-based spatial heterogeneity showed limited prognostic value. gITH was common, with 37% of tumours displaying regionally heterogeneous pathogenic variants, including spatially actionable alterations in 10% of patients. In an initial multivariable Cox model, higher gITH was associated with shorter disease-free survival. However, after Ridge-penalised modelling and bootstrap internal validation, the effect size was attenuated [corrected hazard ratio 1.42, 95% confidence interval (CI) 0.91-2.75]. The overall model retained moderate discriminative performance (optimism-corrected C-index 0.69, 95% CI 0.59-0.79). gITH was associated with tumour cellularity, reduced estimated endothelial cell infiltration, and alterations in KMT2C and PIK3CA. tITH differed according to human papillomavirus (HPV) status, with lower tITH in HPV-positive tumours, and was associated with distinct biological pathways and genomic alterations. Genomic and tITH were not correlated. CONCLUSIONS: This prospective multiregion study provides a comprehensive characterisation of genomic and tITH in localised HNSCC. Our findings highlight substantial spatial molecular diversity within primary tumours and suggest potential associations between heterogeneity, tumour biology, and clinical outcome that warrant validation in independent cohorts.

head and neck squamous-cell carcinoma (HNSCC)↗
PubMed2005

Effects of human atrial natriuretic peptide on cardiac function and hemodynamics in patients with high plasma BNP levels.

Both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) bind preferentially to the natriuretic peptide A receptor. Therefore, we hypothesized that the positive inotropic and lusitropic effects of ANP might be blunted in patients with moderate congestive heart failure and high BNP levels. Micromanometers and conductance catheters were used to obtain relatively load-insensitive left ventricular pressure-volume analysis in order to compare the myocardial and load-altering actions of ANP in 20 patients with low and high plasma BNP levels. In the low-BNP group (plasma BNP levels <230 pg/ml), ANP infusion significantly decreased end-systolic pressure and end-diastolic pressure and volume, increased end-systolic elastance, and shortened left ventricular relaxation. By contrast, in the high-BNP group (plasma BNP levels >230 pg/ml), the effect of ANP infusion on LV contractility was blunted but its beneficial effects on LV diastolic function and LV-arterial coupling remained. Thus, ANP infusion may improve LV diastolic function even in patients with moderate heart failure and high plasma BNP levels.

Aged↗
PubMed2026

The future of blood-based biomarkers in liver cancer.

Liquid biomarkers hold substantial promise in liver cancer, with potential applications in risk stratification, surveillance and early detection, therapeutic decision-making, and treatment-response monitoring. In parallel with oncologic advances, liquid biopsy has gained increasing attention. However, despite expanded research efforts, prospective clinical validation remains limited. While cell-free DNA-based detection of actionable alterations has entered clinical practice in select contexts, most candidate liquid biomarkers still require rigorous evaluation through translational research embedded in clinical trials and prospective cohort studies. In this review, we summarise the current landscape of blood-based biomarkers across the cancer care continuum for individuals at risk, or diagnosed with hepatocellular carcinoma and biliary tract cancers, and discuss the key challenges and opportunities that lie ahead.

Humans↗
PubMed2026

Detection of a Rare Intra-ALK Inversion and ALK Rearrangement in a Lung Adenocarcinoma Patient by FoundationOne Liquid CDx and Successful Treatment with Alectinib: Case Report.

A 50-year-old woman with stage IVB lung adenocarcinoma tested negative for driver mutations using the Oncomine Dx Target Test Multi-CDx system (Thermo Fisher Scientific, Waltham, MA). After undergoing chemotherapy and immunotherapy, FoundationOne Liquid CDx (Foundation Medicine, Inc., Cambridge, MA) identified a rare EML4-ALK gene rearrangement. Treatment with alectinib led to rapid clinical improvement and sustained disease control for more than 7 months. This case highlights the value of next-generation sequencing-based profiling in detecting rare actionable alterations missed by standard tests. We also include a discussion on why the EML4-AKL fusion was not detected in the usual test.

ALK-EML4 rearrangement↗
PubMed2006

Pravastatin reverses the down-regulating effect of inflammation on beta-adrenergic receptors: a disease-drug interaction between inflammation, pravastatin, and propranolol.

Inflammatory conditions reduce the potency to prolong the PR interval of certain cardiovascular drugs including propranolol, sotalol, and verapamil in rats and humans despite elevated plasma drug concentrations. We tested whether pravastatin restores altered action and disposition of propranolol as well as inflammatory mediators concentrations in the Pre-Adjuvant Arthritis (Pre-AA) Sprague-Dawley rat model. Rats [Healthy/Placebo, Arthritis/Placebo, Healthy/Statin, and Arthritis/Statin groups (n=14-16/group)] received Mycobacterium butyricum on day 0 followed by 6 mg/kg pravastatin or placebo twice daily during days 4-8. PR-interval response to 25 mg/kg oral propranolol was measured on days 0, 4 and 8. On day 8, blood samples were collected for interferon-gamma, interleukin-10, C-reactive protein, and nitrite measurements. Propranolol enantiomer pharmacokinetics were delineated using another 4 groups (healthy n=5, Pre-AA n=9) on day 8. Pre-AA significantly reduced propranolol response despite a 10-fold increase in concentrations. Pravastatin restored the response but not the drug concentrations. Area under the % effect-time curve (% min) was 714+/-214 in Healthy/Placebo, 256+/-249 in Arthritis/Placebo, 1534+/-367 in Healthy/Statin, and 1713+/-393 in Arthritis/Statin. While pravastatin reduced elevated serum interferon-gamma concentration in the Pre-AA model, it did not influence other biomarkers. Pravastatin restores response to propranolol in inflamed rat but has no effect on the elevated propranolol concentrations. This was associated with lower serum interferon-gamma concentrations.

Adrenergic beta-Antagonists↗
PubMed2003

5-HT2 and 3 receptor antagonists suppress the response of rat type I slowly adapting mechanoreceptor: an in vitro study.

Previous experiments have shown an increase in rat type I mechanoreceptor responsiveness during arterial serotonin (5-hydroxytryptamine) infusion and the presence of serotonin immunostaining in Merkel cells. The current findings demonstrate that the 5-HT(2) antagonists ritanserin and ketanserin, as well as the 5-HT(3) antagonist MDL 72222, reduce type I response to a standardized mechanical stimulus in an in vitro skin preparation. In addition, ritanserin blocked the enhancement of type I response produced by 5-HT. These experiments suggest that serotonin is released during mechanical distortion of the Merkel cell membrane and alters action potential generation by the type I ending. In addition, it is possible that serotonin, released from outside the type I complex, influences mechanoreceptor responsiveness. For example, serotonin generated during inflammatory events could enhance type I response to mechanical stimulation and thereby increase symptoms of mechanical allodynia.

Action Potentials↗
PubMed1999

Ca channels in cardiac myocytes: structure and function in Ca influx and intracellular Ca release.

There are Ca channels in the plasma membrane and also the sarcoplasmic reticulum (SR) membrane in cardiac myocytes. The relationship between channel structure, associated proteins and function of these Ca channels is discussed. The sarcolemmal Ca channels are crucial both to the basic cellular electrophysiological properties and control of cardiac contractility (via excitation-contraction coupling). The intracellular Ca release channels (or ryanodine receptors) respond to triggering events mediated by sarcolemmal ion currents and are largely responsible for releasing Ca which activates the myofilaments to produce contraction. Several possible mechanisms of excitation-contraction coupling are discussed. The Ca released from the SR can also feedback on several sarcolemmal ion currents and alter action potential configuration as well as contribute to arrhythmogenesis.

Action Potentials↗