Endothelium-dependent vasodilation in normotensive subjects with a familial history of essential hypertension and in young subjects with borderline hypertension

OBJECTIVE: To investigate if young normotensive subjects with a familial history of essential hypertension (FHH) or young borderline-hypertensive (BHT) subjects have a defect endothelial function. METHODS: Fifteen young (26 +/- 4 years) healthy normotensive (115 +/- 8/71 +/- 6 mmHg) subjects with a FHH, 31 matched healthy normotensive subjects without FHH and seven BHT (143 +/- 12/92 +/- 2 mmHg), otherwise healthy, young males underwent evaluation of endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIDV), by means of local intra-arterial infusions of methacholine (MCh, evaluating EDV) and sodium nitroprusside (SNP, evaluating EIDV) in the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. RESULTS: Although there was no significant difference between normotensive subjects with and without a FHH regarding FBF during vasodilation induced by MCh or SNP, the subjects with a FHH presented a significantly suppressed endothelial function index, calculated as the ratio between EDV and EIDV, when compared to subjects without FHH (1.04 +/- 0.15 vs. 1.24 +/- 0.23, p < 0.01). Also in the group of BHT subjects, the endothelial function index was suppressed (1.01 +/- 0.18, p < 0.01), in this case due to a significantly attenuated EDV (p < 0.05), when compared to male subjects without a FHH. CONCLUSION: The present findings suggest an early occurrence of endothelial dysfunction in the development of essential hypertension.     

Smoking Is a Risk Factor for Recurrence of Groin Hernia

Studies of connective tissue from patients with inguinal hernia have shown that smoking may be associated with hernia formation due to a defective connective tissue metabolism. Whether smoking is a risk factor for recurrence, too, was examined in this study. From December 1990 through December 1995, 649 patients underwent hernia repair as open sutured repair (Cooper ligament or abdominal ring repair) or as open mesh repair. Five hundred forty-four eligible patients were evaluated for recurrence 2 years postoperatively. Association between recurrence and 17 patient-, disease-, and intraoperative variables were analyzed by multiple logistic regression. The results showed that smoking was significantly and independently associated with recurrence compared to nonsmoking [odds ratio (OR = 2.22; 95% confidence interval (95% CI) = 1.19–4.15)]. Open sutured repair compared to open mesh repair was the most significant predictor for recurrence (OR = 7.23; 95% CI = 3.01–17.37). Surprisingly, local anesthesia was associated with a higher risk of recurrence compared to general anesthesia (OR = 2.44; 95% CI = 1.19–5.09). Potential confounders and other risk factors for hernia recurrence such as age, alcohol consumption, previous surgery, and anatomical characteristics of the hernia were adjusted for in the analysis. In conclusion, smoking is an important risk factor for recurrence of groin hernia, presumably due to an abnormal connective tissue metabolism in smokers.     

Neurological signs are common in patients with urodynamically verified "idiopathic" bladder overactivity

Overactive bladder dysfunction is an expression of defective neuromuscular control of the lower urinary tract. The causes and the way to classify this problem are currently under debate. In some patients the overactive bladder is one sign of a neurological disorder, in so called "idiopathic detrusor instability" the cause is less obvious. That an overactive bladder has a neurogenic cause is a reasonable hypothesis. We made a detailed neurological investigation in 45 patients with idiopathic overactive bladder. Cerebrospinal fluid (CSF) was examined and blood tests for vitamin B(12)and folic acid deficiency were checked, too. In 37 of the 45 patients (82%) pathological signs were observed in the neurological tests. The most common finding was central or peripheral paresis of the legs appearing in 24 patients (53%). Of the 45 patients, eight received a neurological diagnosis, definite or possible MS or dorsal column sensation neuropathy. The results of this study give an indication of the importance of the neurological examination and suggest that neuropathy might not be uncommon in patients with so-called idiopathic detrusor instability. This also invites to reconsideration of the current classification. It is possible that a new classification based on a functional view could provide a better fundament in the search of etiologic and pathogenetic factors and also guide in the selection of the treatment most optimal for the individual patient.     

The risk of lower urinary tract symptoms five years after the first delivery

AIM of the STUDY: To estimate the prevalence and 5-year incidence of lower urinary tract symptoms (LUTS) after the first delivery and to evaluate the impact of pregnancy per se and delivery per se on long-lasting symptoms. MATERIALS and METHODS: A longitudinal cohort study of 305 primiparae questioned a few days, 3 months, and 5 years after their delivery. The questionnaire used was tested and validated, and the questions were formulated according to the definitions of the International Continence Society (ICS). Maternal, obstetric, and neonatal data concerning every delivery and objective data concerning surgeries during the observation period were obtained from the records. From the sample of 278 women (91%) who responded 5 years after their first delivery, three subpopulations were defined: 1) women without initial LUTS before or during the first pregnancy or during the puerperal period, 2) women with onset of LUTS during the first pregnancy, and 3) women with onset of LUTS during the first puerperium. The risk of LUTS 5 years after the first delivery was examined using bivariate analyses. The obstetric variables in the bivariate tests with a significant association with long-lasting urinary incontinence were entered into a multivariate logistic regression. RESULTS: The prevalence of stress and urge incontinence 5 years after first delivery was 30% and 15%, respectively, whereas the 5-year incidence was 19% and 11%, respectively. The prevalence of urgency, diurnal frequency, and nocturia 5 years after the first delivery was 18%, 24%, and 2%, respectively, whereas the 5-year incidence was 15%, 20%, and 0.5%, respectively. The prevalence of all LUTS except nocturia increased significantly during the 5 years of observation. The risk of long-lasting stress and urge incontinence was related to the onset and duration of the symptom after the first pregnancy and delivery in a dose-response-like manner. Vacuum extraction at the first delivery was used significantly more often in the group of women with onset of stress incontinence during the first puerperium, whereas an episiotomy at the first delivery was performed significantly more often in the group of women with onset of stress incontinence in the 5 years of observation. The prevalence of urgency and diurnal frequency 5 years after the first delivery was not increased in women with symptom onset during the first pregnancy or puerperium compared with those without such symptoms. The frequency of nocturia 5 years after the first delivery was too low for statistical analysis. CONCLUSION: The first pregnancy and delivery may result in stress and urge incontinence 5 years later. Women with stress and urge incontinence 3 months after the first delivery have a very high risk of long-lasting symptoms. An episiotomy or a vacuum extraction at the first delivery seems to increase the risk. Subsequent childbearing or surgery seems without significant contribution. Long-lasting urgency, diurnal frequency, or nocturia cannot be predicted from onset during the first pregnancy or puerperium.     

Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy

OBJECTIVE: UDP-glucuronosyltransferase (UGT) 2B7 is the major UGT isoform responsible for the 3- and 6-glucuronidation of morphine in humans. Studies in rats have indicated that UGT1A1 may also contribute to the formation of morphine 3-glucuronide (M3G). Our objective was to investigate whether the UGT2B7 H268Y and UGT1A1*28 polymorphisms contribute to the variability in morphine glucuronide-to-morphine plasma ratios among cancer patients undergoing analgesic therapy with morphine. METHODS: Seventy patients with normal hepatic and renal function using slow-release morphine to relieve cancer pain were included. UGT2B7 genotyping was performed using restriction enzyme analysis of polymerase chain reaction (PCR)-amplified DNA fragments. Wild-type and variant alleles of the UGT1A1 gene were identified using sizing of PCR-amplified fragments. Morphine 6-glucuronide (M6G)/morphine, M3G/morphine, and M3G/M6G plasma ratios were compared between genotypes. RESULTS: The M3G/morphine, M6G/morphine, and M3G/M6G plasma ratios varied 16-, 42-, and sevenfold, respectively, among individuals. No statistically significant differences in plasma ratios were found between individuals possessing UGT2B7 H/H ( n=20), H/Y ( n=30), or Y/Y ( n=20) genotypes. Five patients were homozygous for the UGT1A1 TA(7) allele, which is associated with reduced UGT1A1 gene expression. However, the mean M3G/M6G and M3G/morphine plasma ratios in TA(7) homozygous subjects did not differ significantly from those of heterozygous or homozygous wild-type (TA(6)) individuals. CONCLUSION: The UGT2B7 H268Y polymorphism cannot account for the considerable variation in glucuronide-to-morphine ratios in cancer patients. Moreover, the contribution of UGT1A1 to the formation of M3G appears to be of minor biological significance, at least in a UGT2B7 background.     

Time-dependent cardioprotection with calcium antagonism and experimental studies with clevidipine in ischemic-reperfused pig hearts: part II

The intracellular calcium level is increased during ischemia and early reperfusion. The aim of this study was to study the role of the calcium influx in the development of myocardial ischemic and reperfusion injury during the early and late phases of ischemia and during early reperfusion. An ultrashort-acting calcium antagonist, clevidipine, was used as a tool for this investigation. Pentobarbital-anesthetized pigs were subjected to 45 minutes of LAD occlusion followed by 240 minutes of reperfusion. In the first set of experiments, clevidipine (0.3 nmol/kg per minute) was infused over 5 minutes into the ischemic myocardium via a catheter in the LAD, starting at 5, 35, or 44 minutes following the onset of ischemia (n = 6 in each group). The area at risk and the infarct size were determined after 240 minutes of reperfusion by staining with Evans blue dye and triphenyl tetrazolium chloride (TTC), respectively. In a second set of experiments, two groups of animals (n = 6 in each) were subjected to the same periods of ischemia and reperfusion; one group received no infusion during ischemia, whereas the other group received vehicle infusion during a 5-minute period between 5 and 10 minutes of ischemia. In the first set of experiments, there were no significant differences between the groups with regard to hemodynamic variables. The area at risk expressed as a percentage of the left ventricle was of similar magnitude in all three clevidipine-treated groups (about 18%). The infarct size, expressed as a percentage of the area at risk, was significantly smaller in pigs given clevidipine after 5 minutes (58 +/- 17%; p < 0.01) and after 44 minutes (42 +/- 6%; p < 0.01) of ischemia than in pigs receiving clevidipine after 35 minutes of ischemia (85 +/- 4%). The difference in infarct size between pigs given clevidipine after 5 or 44 minutes of ischemia was not significant. In the second set of experiments, there was a similar area at risk and no significant difference in infarct size between the noninfusion group and the 5-minute vehicle infusion group, indicating that the LAD infusion per se did not affect infarct size. The present results demonstrate that blockade of calcium influx by the short-acting dihydropyridine calcium antagonist clevidipine during the early phase of ischemia and at the time of reperfusion, but not during a late phase of ischemia, limits infarct size induced by ischemia and reperfusion. This indicates that the pathophysiological importance of calcium influx varies according to the different phases of myocardial ischemia and reperfusion.     

Functional versus chemical diversity: is biodiversity important for drug discovery?

Prospecting the full biodiversity of nature to find leads for new drugs is not necessary. Because finding leads is aimed at identifying biological activity, structure is of secondary importance. Furthermore, although natural chemical diversity might be unrivalled, functional diversity is bound to be considerably less. It is likely that many millions of chemically distinct molecules exist in nature but it is inconceivable that the number of different biological functions is near this number. This is corroborated by knowledge obtained from the genome sequences of an increasing number of species. It is unlikely that ligands for specific molecular targets are restricted to one species and even individual compounds are often found in more than one species. Important molecular mechanisms are likely to be ubiquitous and there are no a priori reasons to assume that some are restricted to, for example, tropical rainforests. Thus, there are no obvious advantages of "biodiversity prospecting", which will, possibly, endanger fragile ecosystems in the search for rare species.     

A novel high-through-put assay for screening of pro-apoptotic drugs

Screening for anti-cancer substances iscommonly conducted using viability assays.An inherent problem with this approach isthat all compounds that are toxic andgrowth inhibitory, irrespective ofmechanism of action, will score positive.It would be beneficial to be able to screenfor compounds that specifically induceapoptosis. We here describe an ELISA-assaybased on a monoclonal antibody (M30) whichrecognizes a neo-epitope on cytokeratin 18exposed after cleavage by caspases duringapoptosis. We show that this assay detectsapoptosis in epithelial cells and that thesensitivity is sufficient for screening inthe 96-well format. We used the M30-ELISAassay to screen 500 low molecular weightcompounds from a chemical library from theNational Cancer Institute and identified 16drugs with strong pro-apoptotic activity,suggesting that the assay is a useful toolfor discovery of pro-apoptotic drugs.     

An observational study of slimming behavior in Denmark in 1992 and 1998

OBJECTIVE: To elucidate how frequent weight-loss attempts are made, the methods used to achieve weight loss, and the extent to which the outcome is positive. RESEARCH METHODS AND PROCEDURES: Two independent interviews were conducted in 1992 and in 1998, each with 1200 randomly selected adult subjects. Each survey was designed to ensure an equal distribution of age, gender, and geographical regions in Denmark. RESULTS: The proportion of subjects having attempted weight loss did not change from 1992 to 1998, although the prevalence of overweight and obesity increased from 1992 (overweight, 30%; obesity, 6%) to 1998 (overweight, 35%; obesity, 8%). Almost twice as many women (61%) than men (32%) had attempted weight loss (p < 0.0001). Slimming occurred more often in subjects <50 years (51%) than >50 years (39%) (p < 0.0001), although overweight and obesity were more frequent in the elderly. Over-the-counter diet pills or meal replacements were associated with a negative outcome of slimming treatment (p < 0.0001). DISCUSSION: Approximately half of all adult Danes have attempted weight loss, particularly women and individuals <50 years. This finding is inconsistent with the fact that overweight and obesity are more prevalent in men and in individuals >50 years. Changes in habitual diet and increased physical activity are the most prevalent modes of slimming, whereas the use of over-the-counter diet pills or meal replacements has decreased from 1992 to 1998. This development may have a positive impact on future body- weight-management strategies.