β1-Adrenoceptor stimulation suppresses endothelial IKCa-channel hyperpolarization and associated dilatation in resistance arteries

Background and Purpose

In small arteries, small conductance Ca²⁺-activated K⁺ channels (SK_Ca) and intermediate conductance Ca²⁺-activated K⁺ channels (IK_Ca) restricted to the vascular endothelium generate hyperpolarization that underpins the NO- and PGI₂-independent, endothelium-derived hyperpolarizing factor response that is the predominate endothelial mechanism for vasodilatation. As neuronal IK_Ca channels can be negatively regulated by PKA, we investigated whether β-adrenoceptor stimulation, which signals through cAMP/PKA, might influence endothelial cell hyperpolarization and as a result modify the associated vasodilatation.

Experimental Approach

Rat isolated small mesenteric arteries were pressurized to measure vasodilatation and endothelial cell [Ca²⁺]_i, mounted in a wire myograph to measure smooth muscle membrane potential or dispersed into endothelial cell sheets for membrane potential recording.

Key Results

Intraluminal perfusion of β-adrenoceptor agonists inhibited endothelium-dependent dilatation to ACh (1 nM–10 μM) without modifying the associated changes in endothelial cell [Ca²⁺]_i. The inhibitory effect of β-adrenoceptor agonists was mimicked by direct activation of adenylyl cyclase with forskolin, blocked by the β-adrenoceptor antagonists propranolol (non-selective), atenolol (β₁) or the PKA inhibitor KT-5720, but remained unaffected by ICI 118 551 (β₂) or glibenclamide (ATP-sensitive K⁺ channels channel blocker). Endothelium-dependent hyperpolarization to ACh was also inhibited by β-adrenoceptor stimulation in both intact arteries and in endothelial cells sheets. Blocking IK_Ca {with 1 μM 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34)}, but not SK_Ca (50 nM apamin) channels prevented β-adrenoceptor agonists from suppressing either hyperpolarization or vasodilatation to ACh.

Conclusions and Implications

In resistance arteries, endothelial cell β₁-adrenoceptors link to inhibit endothelium-dependent hyperpolarization and the resulting vasodilatation to ACh. This effect appears to reflect inhibition of endothelial IK_Ca channels and may be one consequence of raised circulating catecholamines.     

Determinants of the range of drugs prescribed in general practice: a cross-sectional analysis

Background  

Current health policies assume that prescribing is more efficient and rational when general practitioners (GPs) work with a formulary or restricted drugs lists and thus with a limited range of drugs. Therefore we studied determinants of the range of drugs prescribed by general practitioners, distinguishing general GP-characteristics, characteristics of the practice setting, characteristics of the patient population and information sources used by GPs.     

Partial characterization of two major liver I-compounds as unstable adducts which are readily hydrolyzed to unmodified guanine nucleotides

I-compounds are endogenous bulky DNA modifications which are detected by nuclease P1-enhanced 32P-post-labeling in tissue DNA of animals not knowingly exposed to carcinogens. Their profiles and levels depend inter alia on animal age, species, strain, tissue, gender, diet and exposure to chemicals such as cytochrome P450 inducers and carcinogens. Due to lack of sufficient material obtainable from in vivo sources, chemical structures of I-compounds and their parent normal bases have not yet been identified. In this report we provide 32P-post-labeling and chromatographic evidence that two prominent I-compounds, herein called C1 and C2, which occur at relatively high levels in pig liver DNA are guanine derivatives. This result was obtained by showing that both compounds, isolated from 32P-post-labeling thin-layer maps, were chemically unstable, i.e. they could be readily hydrolyzed to 32P-post- labeled deoxyguanosine 3',5'-bisphosphate by heating in water. C1 appeared particularly labile, undergoing hydrolysis during thin-layer chromatography at pH 3.3 without heating. Several other I-compounds and adducts, as well as the four normal DNA nucleotides, were, however, highly resistant to hydrolysis under the conditions used here. The possible significance of these findings will be briefly discussed.      

ECG and echocardiographic diagnosis of pulmonary thromboembolism associated with central venous lines

The aim was to establish the prevalence of pulmonary embolism in 21 children (median age 12 months; range 5-132 months) with central venous lines in situ > 3 months (median 10 months; range 3-47). Twelve-lead electrocardiograms (ECGs) and echocardiograms were analysed in a retrospective study using ECG and echocardiographic criteria for pulmonary embolism-previously established and validated in adult patients- and standard paediatric ECG values as control data. Patients were scored as having definite (n = 7), probable (n = 5), or no pulmonary embolism (n = 9). Overall 57% of ECGs showed abnormalities compatible with pulmonary embolism. In two patients, serial ECGs obtained during an acute cardiorespiratory illness showed cumulative changes diagnostic of pulmonary embolism. Eight of 12 patients with abnormal ECGs had echocardiography; in seven of these (88%) the right ventricular end diastolic diameter was > 2SD above the mean value for age. Twelve of the patients included in this study have died; two died following an acute respiratory illness. There was postmortem evidence of pulmonary thromboembolism in both of the two children for whom necropsy information was available. The data suggest that pulmonary embolism is common in children who have central venous lines in situ for > 3 months. Serial studies are of value in some patients. Pulmonary embolism may compromise the long term survival of children with small bowel failure and preclude consideration for liver and small bowel transplantation.     

Correlates of prone infant sleeping position by period of birth

Intervention to avoid the prone sleeping position during infancy has occurred in various countries after evidence that it increases the risk of sudden infant death syndrome (SIDS). This study examined cohort data to determine if correlates of the prone position differed by period of birth, before intervention (1 May 1988 to 30 April 1991) compared with after intervention (1 May 1991 to 30 April 1992). The usual prone sleeping position was more closely associated with the following factors after intervention: teenage motherhood, low maternal education, paternal unemployment, unmarried motherhood, non-specialist antenatal care, not reading books to prepare for a baby, poor smoking hygiene, and bottle feeding. For example, the association of usual prone position with being unmarried shown by the odds ratio (95% confidence interval) was 0.54 (0.47 to 0.63) in the period before intervention and 1.92 (1.18 to 3.15) in the period after intervention. The alteration in correlates of the prone position reported here provide an example to support the theoretical concept that well known 'modifiable' risk factors for disease tend to be associated with each other in both populations and individuals. This phenomenon was not evident in the population before intervention, that is, before the prone sleeping position became a well known SIDS risk factor.     

Twin and singleton growth patterns compared using US

Sonography has been used widely in the evaluation of singleton fetal growth. Twin gestations, however, have received less careful attention. In a statistical study of 103 twin pregnancies, the growth patterns of twin biparietal diameter (BPD), fetal femur length (FFL), and abdominal circumference (AC) were compared with those of singletons. The results of the study revealed a decrease in twin BPD growth after 31 to 32 weeks of gestation relative to singletons. Twin AC growth rate decreases after 32-33 weeks of gestation relative to singletons, but the twin FFL growth pattern does not deviate from that of singletons throughout gestation. Because of the significant difference in growth patterns of BPD and AC between twins and singletons in our population, new growth charts for twin BPD and AC are proposed.     

Microbial challenge of a blood cell separator outside-seal bowl system

The ability to store platelets beyond 24 hours requires a functionally closed system. This study tested the ability of a cell separator bowl seal system to resist penetration of microbial contamination under normal running conditions and under extreme environmental stress. Three test organisms, Micrococcus luteus, Serratia marcescens, and Staphylococcus epidermidis, were applied directly to the bowl at the edge of the seal or aerosolized and passed through the centrifuge chamber while the cell separator was run through a simulated platelet collection. A sterile, bacteriologic nutrient medium was perfused through the tubing set, thus simulating the flow of blood fractions. Following the procedure, the medium was examined for microbial growth. The concentration of aerosolized bacteria ranged from 5.2 x 10(1) to 3.9 x 10(3) colony-forming units (CFU) per mL, and the concentration of bacteria applied to the edge of the seal ranged from 1.9 x 10(5) to 2.8 x 10(9) CFU per mL. The positive control, direct inoculation of S. marcescens into the circulating medium (50 CFU/500 mL), resulted in recovery of the identical organism after 24 hours' incubation. No contamination of the system was detected in 40 experiments with aerosolized bacteria or in 32 experiments in which bacteria were applied directly to the seal. This study demonstrates that this sealed-bowl system resists microbial contamination.     

Predicting regional control based on pretreatment nodal size in squamous cell carcinoma of the head and neck treated with chemoradiotherapy: A clinican’s guide

The aim of this study was to determine the regional control rate with concurrent chemoradiotherapy (CRT) based on pretreatment nodal size in mucosal head and neck squamous cell carcinoma (HNSCC) in patients who achieved a complete response (CR) at the primary site by 12 weeks post‐treatment. Between December 1997 and November 2003, 117 patients with node‐positive HNSCC were treated with concurrent CRT, with 108 (92%) achieving a CR at the primary site by 12 weeks. There were 93 males (86%), median age 55 (37–79) years and the most common primary site was the oropharynx (65%). Patients were divided into three subgroups: ≤3.0 cm 70 (65%), 3.1–6.0 cm 30 (28%) and ≥6.1 cm 8 (7%). All patients received concurrent platinum‐based chemotherapy and the median radiation dose was 70 Gy (60–72 Gy). The 3‐year regional control rate based on pretreatment nodal size was ≤3.0 cm 88% (95% confidence interval (CI) 78–94%), 3.1–6.0 cm 72% (95%CI 49–86%) and ≥6.1 cm 50% (95%CI 15–77%) (P = 0.001). The 3‐year regional control rate based on pre‐treatment nodal size was ≤3.0cm 88% (95%CI 78–94%), 3.1–6.0 cm 72% (95%CI 49–86%) and ≥6.1 cm 50% (95%CI 15–77%) (P = 0.001). These results provide a quantitative guide for the clinician as to the likelihood of regional control based on pretreatment nodal size following CRT in patients who achieve a CR at the primary site by 12 weeks post‐treatment.     

来那度胺＋低剂量地塞米松治疗多发性骨髓瘤疗效佳毒性低

高剂量地塞米松为多发性骨髓瘤常用治疗方案。本研究比较了高、低剂量地塞米松分别联合来那度胺治疗多发性骨髓瘤的临床疗效及毒副作用。