Cigarette smoking and hypertension Virdis, A; Giannarelli, C; Neves, M Fritsch ...
Current pharmaceutical design,
08/2010, Volume:
16, Issue:
23
Journal Article
Peer reviewed
Cigarette smoking is a powerful cardiovascular risk factor and smoking cessation is the single most effective lifestyle measure for the prevention of a large number of cardiovascular diseases. ...Impairment of endothelial function, arterial stiffness, inflammation, lipid modification as well as an alteration of antithrombotic and prothrombotic factors are smoking-related major determinants of initiation, and acceleration of the atherothrombotic process, leading to cardiovascular events. Cigarette smoking acutely exerts an hypertensive effect, mainly through the stimulation of the sympathetic nervous system. As concern the impact of chronic smoking on blood pressure, available data do not put clearly in evidence a direct causal relationship between these two cardiovascular risk factors, a concept supported by the evidence that no lower blood pressure values have been observed after chronic smoking cessation. Nevertheless, smoking, affecting arterial stiffness and wave reflection might have greater detrimental effect on central blood pressure, which is more closely related to target organ damage than brachial blood pressure. Hypertensive smokers are more likely to develop severe forms of hypertension, including malignant and renovascular hypertension, an effect likely due to an accelerated atherosclerosis.
Aims
Improving glycaemic control in people with Type 1 diabetes is known to reduce complications. Our aim was to compare glycaemic control among people with Type 1 diabetes using data gathered in ...regional or national registries.
Methods
Data were obtained for children and/or adults with Type 1 diabetes from the following countries (or regions): Western Australia, Austria, Denmark, England, Champagne‐Ardenne (France), Germany, Epirus, Thessaly and Thessaloniki (Greece), Galway (Ireland), several Italian regions, Latvia, Rotterdam (The Netherlands), Otago (New Zealand), Norway, Northern Ireland, Scotland, Sweden, Volyn (Ukraine), USA and Wales) from population or clinic‐based registries. The sample size with available data varied from 355 to 173 880. Proportions with HbA1c < 58 mmol/mol (< 7.5%) and ≥ 75 mmol/mol (≥ 9.0%) were compared by age and sex.
Results
Data were available for 324 501 people. The proportions with HbA1c 58 mmol/mol (< 7.5%) varied from 15.7% to 46.4% among 44 058 people aged < 15 years, from 8.9% to 49.5% among 50 766 people aged 15–24 years and from 20.5% to 53.6% among 229 677 people aged ≥ 25 years. Sex differences in glycaemic control were small. Proportions of people using insulin pumps varied between the 12 sources with data available.
Conclusion
These results suggest that there are substantial variations in glycaemic control among people with Type 1 diabetes between the data sources and that there is room for improvement in all populations, especially in young adults.
What's new?
We present HbA1c data from registries in 19 different countries describing control in 324 501 people with Type 1 diabetes, across all age groups.
These data are the best representation of diabetes care available and therefore describe the ‘state of the art’.
We show clearly that Type 1 diabetes control is not as good as suggested in guidelines, but that some healthcare systems appear to result in better control than others.
These data present a challenge to diabetes services. Leaders in diabetes units/service can compare their local data to our data and encourage improvement.
The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) ...thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.
Aims
To characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon‐like peptide‐1 (GLP‐1) and glucagon receptors.
Materials and methods
MEDI0382 was evaluated in vitro for its ...ability to stimulate cAMP accumulation in cell lines expressing transfected recombinant or endogenous GLP‐1 or glucagon receptors, to potentiate glucose‐stimulated insulin secretion (GSIS) in pancreatic β‐cell lines and stimulate hepatic glucose output (HGO) by primary hepatocytes. The ability of MEDI0382 to reduce body weight and improve energy balance (i.e. food intake and energy expenditure), as well as control blood glucose, was evaluated in mouse models of obesity and healthy cynomolgus monkeys following single and repeated daily subcutaneous administration for up to 2 months.
Results
MEDI0382 potently activated rodent, cynomolgus and human GLP‐1 and glucagon receptors and exhibited a fivefold bias for activation of GLP‐1 receptor versus the glucagon receptor. MEDI0382 produced superior weight loss and comparable glucose lowering to the GLP‐1 peptide analogue liraglutide when administered daily at comparable doses in DIO mice. The additional fat mass reduction elicited by MEDI0382 probably results from a glucagon receptor‐mediated increase in energy expenditure, whereas food intake suppression results from activation of the GLP‐1 receptor. Notably, the significant weight loss elicited by MEDI0382 in DIO mice was recapitulated in cynomolgus monkeys.
Conclusions
Repeated administration of MEDI0382 elicits profound weight loss in DIO mice and non‐human primates, produces robust glucose control and reduces hepatic fat content and fasting insulin and glucose levels. The balance of activities at the GLP‐1 and glucagon receptors is considered to be optimal for achieving weight and glucose control in overweight or obese Type 2 diabetic patients.
Abstract X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in ...SH2D1A . In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n = 6), severe infectious mononucleosis (n = 4), isolated splenomegaly (n = 3), uveitis (n = 1), periodic fever (n = 1), fistulating skin abscesses (n = 1) and severe Giardia enteritis (n = 1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.
Meiosis in pollen mother cells (PMCs) was studied of 23 Iranian Allium species (33 accessions, 105 individuals) that belong to two subgenera and six sections. Materials of 13 species were sampled ...from (near) type locations. Gametic chromosome numbers, chromosome configurations at metaphase I, chiasma frequency, as well as type and percentages of abnormalities were recognized. The basic chromosome number for all taxa investigated was x = 8. Most taxa were diploid and showed eight bivalents or in rare cases two or four pairs of univalents, but in A. subakaka, A. ubipetrense and A. zagricum tetravalents also occurred. Meiosis in less than 10% of PMCs of diploid accessions was disturbed displaying lagging chromosomes, chromatid bridges, micronuclei, or unbalanced chromosome segregations, but very rarely more than one kind of irregularities were found within one dividing cell. One to three B chromosomes were found in 11 accessions, and were recognized for the first time in A. alamutense, A. elburzense and A. iranshahrii. Our data showed no correlation between the occurrence of B chromosomes and the chiasma frequency, and also no noticeable effect of habitat factors on meiotic chromosome behavior. The studied accessions of A. atroviolaceum and A. sabalense were tetraploid (n = 16) showing irregular meiosis in 20-69% of the PMCs which is regarded as sign of autopolyploidy. Since only two out of 31 investigated accessions belonging to subg. Melanocrommyum were tetraploid, we may suggest a trivial role of polyploidy in the evolution of this subgenus.
Detection and quantification of tumor-derived KRAS and NRAS mutations in plasma cell-free DNA (cfDNA) holds great potential for cancer diagnostics and treatment response monitoring. Because of high ...sensitivity, specificity, robustness, and affordability, digital droplet PCR (ddPCR) is ideally suited for this application but requires discriminatory multiplexing when used as screening assay. We therefore designed, optimized, and clinically validated mutation-specific locked nucleic acid–based ddPCR assays for 14 commonly occurring KRAS and NRAS mutations and assembled these assays into seven discriminatory multitarget screening assays covering two to six single-nucleotide variants each. Limit of detection, limit of blank, and interassay accuracy were determined. Assay performance and suitability for screening in cfDNA were validated with plasma samples from a clinically fully characterized cohort of pancreatic cancer patients and healthy controls. Limits of detection for single-target assays were between 0.0015% and 0.069% variant allele fraction, and between 0.022% and 0.16% for multitarget assays. Dilution linearity and interassay accuracy were excellent throughout (r2 > 0.99). Multitarget assay screening of cfDNA extracted from pancreatic cancer patients with unknown KRAS mutational status correctly identified single-nucleotide variants in 45 of 45 (100%) of tumor-derived cell-free DNA–positive samples. In summary, we herein present and clinically validate generic single-target and discriminatory multitarget ddPCR assays for KRAS and NRAS hot spot mutations with broad applicability for clinical and translational research.
A new species,
, is described from northern Balochistan and southern Khyber Pakhtunkhwa in Pakistan based on morphological, molecular, and cytological studies. The new species is characterised by ...long runner-like cylindrical rhizomes of adult plants, cylindrical bulbs, linear leaves with minute soft hairs along veins, campanulate perigonium, and white to creamy white, ovate to elliptical, 4.5-5-mm-long acute tepals, with brownish to purplish nerves, stamens as long as to slightly longer than tepals, yellow to brick red anthers, hexagonal ovary, and white and papillate/warty along angles. The presence of long herbaceous rhizomes indicated serious isolation of the new species; hence, a new section
is proposed to accommodate the new species. The new species is diploid with a chromosome number of 2n = 16. Detailed morphological description, illustrations, phylogenetic analyses based on sequences of plastid spacers (
32-
L (UAG) and
Q-
16) and nuclear ITS, karyotype features, and a distribution map of the new species are provided.
Novel biomarkers and molecular monitoring tools hold potential to improve outcome for patients following resection of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that the combined ...longitudinal analysis of mutated cell-free plasma KRAS (cfKRAS
) and CA 19-9 during adjuvant treatment and follow-up might more accurately predict disease course than hitherto available parameters.
Between 07/2015 and 10/2018, we collected 134 plasma samples from 25 patients after R0/R1-resection of PDAC during adjuvant chemotherapy and post-treatment surveillance at our institution. Highly sensitive discriminatory multi-target ddPCR assays were employed to screen plasma samples for cfKRAS
. cfKRAS
and CA 19-9 dynamics were correlated with recurrence-free survival (RFS) and overall survival (OS). Patients were followed-up until 01/2020.
Out of 25 enrolled patients, 76% had undergone R0 resection and 48% of resected PDACs were pN0. 17/25 (68%) of patients underwent adjuvant chemotherapy. Median follow-up was 22.0 months, with 19 out of 25 (76%) patients relapsing during study period. Median RFS was 10.0 months, median OS was 22.0 months. Out of clinicopathologic variables, only postoperative CA 19-9 levels and administration of adjuvant chemotherapy correlated with survival endpoints. cfKRAS
was detected in 12/25 (48%) of patients, and detection of high levels inversely correlated with survival endpoint. Integration of cfKRAS
and CA 19-9 levels outperformed either individual marker. cfKRAS
outperformed CA 19-9 as dynamic marker since increase during adjuvant chemotherapy and follow-up was highly predictive of early relapse and poor OS.
Integrated analysis of cfKRAS
and CA 19-9 levels is a promising approach for molecular monitoring of patients following resection of PDAC. Larger prospective studies are needed to further develop this approach and dissect each marker's specific potential.
The presence or degree of haemodynamic impairment due to occlusive cerebrovascular disease is often inferred from measurements of cerebral blood flow (CBF), cerebral blood volume (CBV), oxygen ...extraction fraction (OEF) and the cerebral rate for oxygen metabolism (CMRO2). However, the relationship of these variables, in particular CBV, to regional cerebral haemodynamics is not clearly established in humans with subacute or chronic disease. In the present study, we investigated the relationship of CBV to OEF, CBF and CMRO2, and to subsequent stroke risk in patients with unilateral carotid artery occlusion, in order to define better the associated haemodynamic and metabolic changes. We reviewed data from 81 patients with symptomatic carotid occlusion enrolled in a prospective study of haemodynamic factors and stroke risk. Measurements of CBV, CBF, OEF and CMRO2 were made on entry using PET. Patients were divided into groups by hemispheric ratios and absolute ipsilateral values of OEF and CBV, based on comparison with normal controls. Haemodynamic and metabolic values, risk factors and stroke risk were compared between groups. Based on hemispheric ratios, 45 patients had increased ipsilateral OEF; CBV was increased in 19 of these 45 patients. No differences in CBF, CMRO2 or clinical risk factors were found between these 19 patients and the remaining 26 patients with increased OEF and normal or reduced CBV. Thirteen ipsilateral strokes occurred during follow-up, and 10 of the 13 occurred in the 19 patients with increased OEF and CBV (log rank P < 0.0001). Thirty-two of the 68 patients with complete quantitative PET data had increased OEF by absolute ipsilateral values. CBV was increased in 20 of the 32 patients. No differences in CBF, CMRO2 or clinical risk factors were found between these 20 patients and the remaining 12 patients with increased OEF and normal CBV. Seven of the nine ipsilateral strokes that occurred in the 68 patients occurred in those 20 patients with increased OEF and increased CBV (log rank P = 0.003). The higher risk of ischaemic stroke in patients with increased OEF and CBV suggests that their degree of haemodynamic compromise is more severe than those with increased OEF and normal CBV. In patients with chronic carotid occlusion and increased OEF, increased CBV may indicate pronounced vasodilation due to exhausted autoregulatory vasodilation. The physiological explanation for the measurement of normal CBV in patients with increased OEF is less certain and may reflect preserved autoregulatory capacity.
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