The quorum-sensing molecule 2-phenylethanol impaired conidial germination, hyphal membrane integrity and growth of Penicillium expansum and Penicillium nordicum.

AIMS: The aim of the study was to investigate the antifungal effects of a quorum sensing-molecule, 2-phenylethanol, against the food spoilage moulds Penicillium expansum and Penicillium nordicum. METHODS AND RESULTS: Conidial germination of the tested Penicillium spp. (three strains in total) were inhibited by treatments with 2-phenylethanol in a concentration-dependent manner. Germinated conidia was significantly reduced from 4·4-16·7% at 7·5 mmol l-1 and completely inhibited at 15 mmol l-1 2-phenylethanol. Integrity of conidial cell membranes was unaffected by 2-phenylethanol resulting in reversible inhibition pattern of germination. In contrast, membrane permeability of actively growing hyphae was severely compromised, showing 63·5 - 75·7% membrane damage upon treatment with 15 mmol l-1 2-phenylethanol. The overall inhibitory effect of 2-phenylethanol on colony development and growth of P. expansum and P. nordicum was additionally confirmed. CONCLUSIONS: 2-phenylethanol inhibits conidial germination and growth of P. expansum and P. nordicum in a nonlethal, reversible and concentration-dependent manner. SIGNIFICANCE AND IMPACT OF THE STUDY: The study indicates that 2-phenylethanol can find potential application as an antifungal agent for biological control of moulds in the food industry.

Trends in social inequality in loneliness among adolescents 1991-2014.

BACKGROUND: Loneliness and social inequality in health are important public health concerns. We examined (i) trends in loneliness among adolescents from 1991 to 2014 in Denmark and (ii) trends in social inequality in loneliness. METHODS: Study population: 11-15-year olds in random samples of schools in 1991, 1994, 1998, 2006 and 2014, n = 19 096. Loneliness was measured by a single item and social background by parents' occupational social class (OSC). We calculated absolute (%) differences in loneliness between high and low OSC and relative differences by odds ratio for loneliness. RESULTS: Across all surveys, 6.3% reported feeling lonely. The prevalence increased from 4.4% in 1991 to 7.2% in 2014. The prevalence of loneliness in high, middle and low OSC was 5.8, 5.9 and 8.0%. The increase in loneliness was more pronounced in higher than lower OSC, resulting in a decreasing absolute social inequality in loneliness. The statistical interaction between OSC and survey year was significant, P = 0.0176, i.e. the relative social inequality in loneliness also decreased from 1991 to 2014. CONCLUSION: The prevalence of loneliness increased from 1991 to 2014. The social inequality in loneliness decreased in both absolute and relative terms because of a rising prevalence of loneliness among children from high OSC.

Transcriptional responses in Lactococcus lactis subsp. cremoris to the changes in oxygen and redox potential during milk acidification.

UNLABELLED: Milk acidification and metabolic activity of the starter cultures are affected by oxygen; however, molecular factors related to the redox changes are poorly defined. The objective of the study was to investigate transcriptional responses in Lactococcus lactis subsp. cremoris CHCCO2 grown in milk to the shifts of oxygen and redox potential (Eh7 ). Transcriptomic studies were performed with the use of Illumina HiSeq 2000 mRNA sequencing and validated by the real-time quantitative PCR. In total 105 differentially expressed genes were assigned functional gene names. Most of the differentially expressed genes were detected during aerobic reduction phase. Upregulated genes were implicated in lactose utilization, glycogen biosynthesis, amino sugar metabolism, oxidation-reduction, pyrimidine biosynthesis and DNA integration processes. Genes of purine nucleotide biosynthesis and genes encoding amino acid, multidrug resistance and ion ABC transporters were mostly downregulated, while oligopeptide transporter genes were reduced during oxygen depletion and induced at minimum Eh7 . SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding of gene responses in starter cultures to the changes of oxidation-reduction state is important for the better control and reproducibility of dairy fermentations. We applied mRNA sequencing by Illumina HiSeq 2000 to investigate gene expression profile in a dairy strain of Lactococcus lactis subsp. cremoris during milk acidification. Novelty of this study lies in linking transcriptional responses to oxygen depletion and the changes of redox potential with the fermentation kinetics and clarification of molecular factors specifically expressed in milk which might be essential for bacterial performance and the final quality of cheeses.

Non-Saccharomyces yeasts protect against epithelial cell barrier disruption induced by Salmonella enterica subsp. enterica serovar Typhimurium.

UNLABELLED: The human gastrointestinal epithelium makes up the largest barrier separating the body from the external environment. Whereas invasive pathogens cause epithelial barrier disruption, probiotic micro-organisms modulate tight junction regulation and improve epithelial barrier function. In addition, probiotic strains may be able to reduce epithelial barrier disruption caused by pathogenic species. The aim of this study was to explore non-Saccharomyces yeast modulation of epithelial cell barrier function in vitro. Benchmarking against established probiotic strains, we evaluated the ability of four nonpathogenic yeast species to modulate transepithelial electrical resistance (TER) across a monolayer of differentiated human colonocytes (Caco-2 cells). Further, we assessed yeast modulation of a Salmonella Typhimurium-induced epithelial cell barrier function insult. Our findings demonstrate distinct patterns of non-Saccharomyces yeast modulation of epithelial cell barrier function. While the established probiotic yeast Saccharomyces boulardii increased TER across a Caco-2 monolayer by 30%, Kluyveromyces marxianus exhibited significantly stronger properties of TER enhancement (50% TER increase). In addition, our data demonstrate significant yeast-mediated modulation of Salmonella-induced epithelial cell barrier disruption and identify K. marxianus and Metschnikowia gruessii as two non-Saccharomyces yeasts capable of protecting human epithelial cells from pathogen invasion. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates distinct patterns of non-Saccharomyces yeast modulation of epithelial cell barrier function in vitro. Further, our data demonstrate significant yeast-mediated modulation of Salmonella Typhimurium-induced epithelial cell barrier disruption and identify Kluyveromyces marxianus and Metschnikowia gruessii as two non-Saccharomyces yeasts capable of protecting human epithelial cells from pathogen invasion. This study is the first to demonstrate significant non-Saccharomyces yeast-mediated epithelial cell barrier protection from Salmonella invasion, thus encouraging future efforts aimed at confirming the observed effects in vivo and driving further strain development towards novel yeast probiotics.

Advanced paternal age and mortality of offspring under 5 years of age: a register-based cohort study.

STUDY QUESTION: Do children born to fathers of advanced age have an increased risk of dying before the age of 5 years? SUMMARY ANSWER: Children born to fathers aged 40 years or more have an increased risk of dying in early childhood due to an excess risk of fatal congenital anomalies, malignancies and external causes. WHAT IS KNOWN ALREADY: Advanced paternal age has previously been associated with adverse reproductive outcomes and some long-term health problems in the offspring. This is possibly due to specific point mutations, a condition known to increase in the sperm with increasing paternal age. STUDY DESIGN, SIZE, DURATION: A Danish population-based register study, designed as a prospective cohort study, of 1 575 521 live born children born from 1978 to 2004. The age of the child (in days) was used as the underlying time and the children entered the cohort the day they were born and were followed until 31 December 2009. The children were censored on date of turning 5 years, date of death or date of emigration, whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from population-covering registers from Statistics Denmark including the Integrated Database for Labour Market Research, the Medical Birth Registry and the Registry of Causes of Death was linked using the unique civil registry number. Hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the risk of under-five mortality. The effect of paternal age was examined using restricted cubic splines and paternal age groups. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with children born to fathers aged 30-34 years, a statistically significant excess risk was found for children born to fathers aged 40-44 years [HR: 1.10 (95% CI: 1.00-1.21)] and children born to fathers aged 45+ years [HR: 1.16 (95% CI: 1.02-1.32)]. When only looking at 1-5 year olds, the relative risk (HR) among children born to fathers aged 40-44 years increased to 1.24 (95% CI: 1.00-1.53) and the risk in the oldest paternal age group (45+ years) rose to 1.65 (95% CI: 1.24-2.18). The results suggest that the elevated risk for children of fathers aged 40 years or more was primarily attributed to an elevated risk of dying from congenital malformations, malignancies and external causes. LIMITATIONS, REASONS FOR CAUTION: Specific causes of death might be misclassified; however, this is not likely to be dependent on paternal age. In some cases, the biological father may differ from the father registered. This misclassification is most likely non-differential. WIDER IMPLICATIONS OF THE FINDINGS: The excess risk of mortality among children born to older fathers is in accordance with the literature. The association needs further attention as it can provide valuable knowledge of the etiology of genetic diseases. Also, the association could become of greater importance in the future if the proportion of fathers aged 40+ years keeps growing. STUDY FUNDING/COMPETING INTEREST (S): None.

Phytase-active yeasts from grain-based food and beer.

AIMS: To screen yeast strains isolated from grain-based food and beer for phytase activity to identify high phytase-active strains. METHODS AND RESULTS: The screening of phytase-positive strains was carried out at conditions optimal for leavening of bread dough (pH 5·5 and 30°C), in order to identify strains that could be used for the baking industry. Two growth-based tests were used for the initial testing of phytase-active strains. Tested strains belonged to six species: Saccharomyces cerevisiae, Saccharomyces pastorianus, Saccharomyces bayanus, Kazachstania exigua (former name Saccharomyces exiguus), Candida krusei (teleomorph Issachenkia orientalis) and Arxula adeninivorans. On the basis of initial testing results, 14 strains were selected for the further determination of extracellular and intracellular (cytoplasmic and/or cell-wall bound) phytase activities. The most prominent strains for extracellular phytase production were found to be S. pastorianus KVL008 (a lager beer strain), followed by S. cerevisiae KVL015 (an ale beer strain) and C. krusei P2 (isolated from sorghum beer). Intracellular phytase activities were relatively low in all tested strains. CONCLUSIONS: Herein, for the first time, beer-related strains of S. pastorianus and S. cerevisiae are reported as phytase-positive strains. SIGNIFICANCE AND IMPACT OF THE STUDY: The high level of extracellular phytase activity by the strains mentioned previously suggests them to be strains for the production of wholemeal bread with high content of bioavailable minerals.

Ammonia production and its possible role as a mediator of communication for Debaryomyces hansenii and other cheese-relevant yeast species.

Ammonia production by yeasts may contribute to an increase in pH during the ripening of surface-ripened cheeses. The increase in pH has a stimulatory effect on the growth of secondary bacterial flora. Ammonia production of single colonies of Debaryomyces hansenii, Saccharomyces cerevisiae, Yarrowia lipolytica, and Geotrichum candidum was determined on glycerol medium (GM) agar and cheese agar. The ammonia production was found to vary, especially among yeast species, but also within strains of D. hansenii. In addition, variations in ammonia production were found between GM agar and cheese agar. Ammonia production was positively correlated to pH measured around colonies, which suggests ammonia production as an additional technological parameter for selection of secondary starter cultures for cheese ripening. Furthermore, ammonia appeared to act as a signaling molecule in D. hansenii as reported for other yeasts. On GM agar and cheese agar, D. hansenii showed ammonia production oriented toward neighboring colonies when colonies were grown close to other colonies of the same species; however, the time to oriented ammonia production differed among strains and media. In addition, an increase of ammonia production was determined for double colonies compared with single colonies of D. hansenii on GM agar. In general, similar levels of ammonia production were determined for both single and double colonies of D. hansenii on cheese agar.

Enhancement of hammerhead ribozyme catalysis by glyceraldehyde-3-phosphate dehydrogenase.

A specific tumour necrosis factor alpha ribozyme (TNF-alpha-Rz) binding activity has been purified and identified by N-terminal microsequencing as the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The purified protein as well as commercial GAPDH binds tightly to TNF-alpha ribozyme compared to a variety of other ribozymes and RNAs. Binding of GAPDH to the TNF-alpha-Rz and its derivatives was inhibited by NAD+ and ATP, suggesting that the GAPDH Rossmann fold structure is a part of the ribozyme binding site. Interestingly, GAPDH increased the in vitro cleavage rates of hammerhead ribozymes by up to 25-fold, while no significant stimulation was observed with the lactate dehydrogenase (LDH). This effect was found to be due to the unfolding activity of GAPDH. In fact, pulse-chase experiments demonstrate directly that GAPDH has the capacity to accelerate the ribozyme/substrate association, especially of ribozymes and/or substrates whose predicted secondary structure might interfere with the association step. Under our conditions, the presumed unfolding activity of GAPDH also enhances the turnover of ribozymes by increasing the rate of product dissociation, although only for short cleavage products. Longer duplexes required more incubation time to dissociate. In vitro non-specific interaction of the GAPDH with hammerhead ribozymes and RNA substrates was found to be adequate for the cleavage enhancement effect to occur. However, an analysis of the ability of various prototypical ribozymes to inhibit the expression of interleukin-2 suggests that the addition of a sequence having a high affinity for GAPDH improves the efficacy of ribozymes in the cells. Thus the characterization of cellular proteins with unfolding activity, which specifically bind to hammerhead ribozyme, should facilitate the design of a more effective ribozyme in vivo.

Cardiac mass and peripheral vascular structure in hydralazine-treated spontaneously hypertensive rats.

We have examined the effect of antihypertensive treatment on heart weight and on structural and functional characteristics of isolated mesenteric resistance vessels (internal diameter 170-220 micron) in spontaneously hypertensive rats (SHR) and in Wistar-Kyoto rats (WKY). The SHR and WKY were treated with hydralazine from the age of 4 weeks and were examined at ages 12 to 14 weeks and 23 to 27 weeks. Treated SHR had a mean blood pressure as much as 29% below that of control WKY, which in turn was 25 to 40% less than that of control SHR. In 12- to 14-week-old rats the heart to body weight ratio (which in control SHR was 13% greater than of WKY) was unaffected by treatment. Thereafter, the heart to body weight ratio of treated SHR did not increase as much as usual. At both ages, the media thickness and contractile response of the resistance vessels of the SHR (which were, respectively, 37% and 30% greater than those of vessels of WKY) were unaffected by treatment. However, because treatment caused a small (8%) increase in the lumen diameter of the vessels of the SHR, treatment did cause small, but possibly physiologically important, decreases both in the media to lumen ratio (11%) and in the pressure against which these vessels would have been able to contract (10%). Treatment had little effect on the pharmacological characteristics of vessels of either SHR or WKY. The results suggest that the increased heart weight, media thickness, and contractile response in mesenteric resistance vessels of SHR up to ages 23 to 27 weeks are due primarily to factors other than increased pressure.

Repetitive natriuresis and blood pressure. Long-term calcium entry blockade with isradipine.

The long-term effects (3.5 months) of a new calcium entry blocker of the 1-4-dihydropyridine class, isradipine (PN 200-110), on renal hemodynamics and excretional parameters were investigated in 10 essential hypertensive subjects (World Health Organization Classes I and II). Blood pressure and renal vascular resistance fell significantly (p less than 0.001), and a slight increase in glomerular filtration rate and renal plasma flow was seen (p less than 0.05). Output of fluid from the proximal tubules, measured as clearance of lithium and uric acid, increased significantly (p less than 0.01 and p less than 0.05, respectively), and a compensatory increase in absolute reabsorption of sodium beyond the proximal tubular level accompanied by an increase in clearance of potassium was noted. A 40% increase in the resultant clearance of sodium (p less than 0.01) and an increase in diuresis (p less than 0.05) followed the morning dose of isradipine after 3.5 months of treatment. Changes in blood pressure were significantly correlated with changes in absolute proximal reabsorption of sodium (r = 0.81), excretion of sodium (r = -0.64), and diuresis (r = -0.80). Thus, the natriuretic properties of calcium entry blockers may be more important for the long-term antihypertensive effect than the vasodilator effect per se. A model for renal sodium handling following treatment with calcium entry blockers was proposed. Although a causal relationship is not implied, isradipine induced a sustained, repetitive postdose effect on proximal fluid output, net natriuresis, and diuresis, that was intimately related to the long-term blood pressure-regulating response.

Differential effects of isradipine and atenolol on peripheral hemodynamics and arterial compliance.

In a double-blind parallel-group randomized study, 28 patients with essential hypertension (World Health Organization class I/II) were allocated in equal numbers to one of two groups for treatment with either isradipine 5 to 20 mg twice daily or atenolol 50 to 100 mg once daily. At the end of the study, 12 patients were evaluable in the isradipine group and nine in the atenolol group. Assessments at baseline and after 20 weeks of treatment included arterial and venous compliance, mean peripheral perfusion pressure, heart rate, and digital vascular resistance using photoplethysmography. Isradipine had a direct relaxing effect on the arterioles, revealed by a significant increase in arterial compliance and a concomitant normalization of the digital vascular resistance. Atenolol had no significant effect on these parameters but, as expected, it lowered the heart rate, which was not affected by isradipine in the long term. The venous compliance remained low in both groups and, since isradipine--unlike atenolol--is known to have venodilating properties in vitro, its lack of effect in vivo is most likely due to reflex activation of sympathetically mediated venous tone. Because of the preference of isradipine for the arterial side of the peripheral vascular tree, the mean peripheral perfusion pressure remained higher in this group than in the atenolol group, although central systemic blood pressure was lowered equally and satisfactorily in both groups.

Long-term effects of isradipine on blood pressure and renal function.

The hemodynamic and renal effects of isradipine were investigated in 10 hypertensive patients treated for 3.5 months and in a further nine patients treated for two years. Both groups achieved significant and sustained reductions in systolic blood pressure/diastolic blood pressure (-15 percent/-12 percent and -15 percent/-20 percent, respectively; p less than 0.001). Renal parameters were investigated two to three hours after the morning dose of isradipine, using a water-loading procedure. After 3.5 months of treatment, the glomerular filtration rate and renal plasma flow showed small increases (+6 percent and +9 percent, respectively, p less than 0.05), whereas, after two years, these changes were no longer present (+4 percent and 0 percent). Clearance of sodium and uric acid was increased by 40 percent (p less than 0.01) and 21 percent (p less than 0.01), respectively, after 3.5 months, and by 45 percent (p less than 0.05) and 23 percent (p less than 0.01), respectively, after two years. Lithium clearance studies revealed the natriuretic effect to be located in the proximal tubule. After 3.5 months, a significant relationship was found between the blood pressure response and the change in sodium excretion, but this relationship also was no longer present after two years. In conclusion, because of a maintained blood pressure-lowering effect while preserving renal function, and sustained natriuretic and uricosuric actions, isradipine can be considered a promising agent in the long-term treatment of arterial hypertension.

Antitrophic properties of antihypertensive drugs may depend solely on their blood pressure-lowering capability. A comparative study of isradipine, hydralazine, and metoprolol.

The objective of this study was to examine the effect of antihypertensive treatment on the structure of intramyocardial resistance vessels in spontaneously hypertensive rats. The rats were divided into four groups: one was used as control and the other three were treated from the age of four to 24 weeks with isradipine, hydralazine, and metoprolol, respectively. Half of the animals in each group were examined at the end of active treatment and the rest were examined three weeks later. The rats were anesthetized and killed during constant flow perfusion with 1 percent glutaraldehyde. The media index was determined by point counting. The media indices of rats treated with isradipine and hydralazine were significantly smaller than those of age-matched spontaneously hypertensive rat controls, whereas the media indices of rats in the metoprolol group did not differ significantly. Three weeks after treatment withdrawal, the media index tended to increase in all three groups, but the values for the isradipine and hydralazine groups were still significantly reduced. Non-invasive blood pressure measurements taken at the same time demonstrated a significant blood pressure reduction in all groups, although differences within each treatment group were evident. All pressures had stabilized on the level of spontaneously hypertensive rats three weeks after withdrawal. Thus, it is evident that both isradipine and hydralazine were able to prevent hypertrophy of intramyocardial vascular structure and continue to do so even after treatment withdrawal. This finding is consistent with previous findings, suggesting a close relationship between the extent of blood pressure reduction and the degree of prevention of vascular hypertrophy.

Can mean arterial pressure be estimated from measurements of systolic and diastolic blood pressure, and vice versa?

We investigated the reliability of calculating the mean blood pressure (MBP) in spontaneously hypertensive rats (SHR) from the systolic and diastolic blood pressures (SBP; DBP), using a form factor, calculated as: (MBP - DBP)/(SBP - DBP). The mean values of this form factor, as determined by blood pressure curve integration, were 0.459 and 0.450 in awake and anaesthetized SHR, respectively. There was no change in the form factor with pulse frequency. When direct femoral artery MBP measurements (x) were compared with MBP values (y) calculated from tail-cuff measurements of SBP and DBP using the form factor, the linear relationship between the two parameters was: y = 0.91x + 1.5 mmHg (r = 0.98). Actually, direct measurements confirmed that the tail artery MBP was 6-7% lower than the femoral artery MBP. In awake Wistar-Kyoto (WKY) rats, the form factor was 0.468. We therefore concluded that an approximate form factor value of 0.46 could be used in rats to estimate the MBP from known values of SBP and DBP. We further suggest that, because pulse pressure in any given rat remains relatively constant with time, SBP and DBP can be estimated in experiments by initially measuring the pulse pressure; thus, only the MBP need be recorded thereafter.

Development of blood pressure in spontaneously hypertensive rats after withdrawal of long-term treatment related to vascular structure.

We have studied the effects of long-term treatment with different antihypertensive drugs on blood pressure and mesenteric resistance vessel structure of spontaneously hypertensive rats (SHR), both during treatment and after withdrawal of treatment. Young SHR were treated from 4 to 24 weeks with five different drugs: perindopril (1.5 mg/kg per day), captopril (60 mg/kg per day), hydralazine (25 mg/kg per day), isradipine (42 mg/kg per day) and metoprolol (130 mg/kg per day). At 24 weeks, 24-h mean blood pressures (MBP), measured invasively, were 121 mmHg (perindopril), 137 mmHg (captopril), 140 mmHg (hydralazine), 149 mmHg (isradipine) and 146 mmHg (metoprolol), compared to control values of 177 mmHg (SHR) and 132 mmHg (Wistar-Kyoto rats, WKY). Mesenteric resistance vessel structure, measured as media:lumen ratio (m:l), was also reduced to different extents: to WKY-level by perindopril (m:l = 4.4%), to midway between SHR- and WKY-levels by captopril, hydralazine and isradipine (m:l = 5.9%), and not at all by metoprolol (m:l = 6.8%). When treatment was discontinued, low MBP (ca 151 mmHg) persisted for 12 weeks in rats treated with the angiotensin converting enzyme inhibitors (perindopril and captopril), but rose rapidly in rats which had received the other treatments. At 3-12 weeks after withdrawal of treatment vascular structure was closely correlated with the blood pressure expected from the SHR- and WKY-control values, as were the left ventricle: body weight ratios. The results suggest that the ability of a drug to control vascular structure during treatment is not in itself a predictor of a persistent effect on blood pressure after withdrawal of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

A novel principle for detection of systolic and diastolic blood pressure tested in man and rat with special reference to its applicability in rat studies.

A non-invasive procedure for the application of a photodetector method in rat studies to obtain both systolic and diastolic blood pressure measurements is described. The method has been tested against well-established procedures in rats and in human beings and has proved sufficiently fast and reliable for use in long-term studies. Regression analysis of simultaneously obtained invasive versus non-invasive measurements yielded correlation coefficients of 0.99 and 0.98 respectively. Comparison with the Korotkoff principle in human beings yielded correlation coefficients of 0.96 and 0.78 respectively.

Aggressive long-term antihypertensive therapy with pinacidil does not cause regression of cardiovascular hypertrophy in the spontaneously hypertensive rat.

After dosage titration from the age of 1 month to the age of 3 months, spontaneously hypertensive rats (SHR) were treated with pinacidil 10 mg/kg daily until the age of 6 or 12 months. Morphometric data were obtained from the treated SHR as well as from untreated age-matched SHR and normotensive Wistar-Kyoto rats (WKY) at these two developmental stages. Heart:body weight ratios and media:lumen ratios for resistance vessels were determined. Vessels obtained from the mesenteric region were investigated on a myograph. Vessels from heart, kidney and lung were investigated by morphometric analysis of histological sections, only specimens from 12-month-old rats were used. In SHR no effects of either ageing or treatment were detectable, although their blood pressure had been effectively held at normotensive levels throughout the life of the treated animals from the age of 3 months. With the exception of the media index of the pulmonary vessels, which was not statistically different from treated or control SHR, the WKY morphological parameters were significantly lower. In conclusion, pinacidil normalized blood pressure without complications, but this did not affect SHR cardiovascular structure. It is suggested that development of this strain-specific enlargement can only be modified if blood pressure is kept at hypotensive levels, or if the effect of a hitherto unidentified causative factor is antagonized by more-specific pharmacological treatment.

Effect of endogenous vasoconstrictors on maternal intramyometrial and fetal stem villous arteries in pre-eclampsia.

The contractile responses to various endogenous vasoactive agents were investigated in isolated human uteroplacental arteries from normotensive (NT) patients and patients with pre-eclampsia (PE) undergoing caesarian section. Tissue samples were obtained from the uterine incision and from macroscopically normal cotyledons. Vascular ring preparations of intramyometrial and stem villous arteries (length 1.0-1.3 mm, outer diameter 400-600 microns) were dissected and mounted in organ baths and isometric tension was recorded. Concentration-response relationships for vasopressin (VP), oxytocin (OX), angiotensin II (Ang II), noradrenaline (NA), 5-hydroxytryptamine (5-HT), prostaglandin F2 alpha (PGF2 alpha) and prostaglandin E2 (PGE2) were assessed. For each compound, the mean maximum contractile effect (Emax) and the drug concentration producing half-maximal response (EC50) were determined. In intramyometrial arteries from NT and PE patients, VP, Ang II, NA, 5-HT and PGF2 alpha induced contraction while OX and PGE2 produced weak or no responses. Preparations from PE patients showed higher Emax values, while no differences in EC50 were found between the two groups. In fetal stem villous arteries, Ang II, 5-HT, PGF2 alpha and PGE2 induced contractions, while VP, NA and OX produced weak responses. No differences in Emax or EC50 values were found between the fetal vessels of PE and NT patients. No qualitative differences were demonstrated in response to the agents tested between the vessels (fetal and maternal) from NT women at term and PE patients. However, the results may reflect quantitative differences, suggesting increased contractility of maternal uteroplacental arteries from women with PE.

Nicotine patches for pregnant smokers: a randomized controlled study.

OBJECTIVE: To assess the effect of nicotine patches on continine-validated smoking cessation in pregnant women and the effect of nicotine on birth weight and preterm delivery. METHODS: Pregnant women who smoked ten or more cigarettes after the first trimester (N = 250) were randomly assigned to receive nicotine patches (n = 124) or placebo patches (n = 126). Women randomized to nicotine were treated with 15-mg patches (16 hours/day) for 8 weeks, and 10-mg patches (16 hours/day) for 3 weeks. RESULTS: Overall, 26% stopped smoking and 14% were nonsmokers 1 year after delivery. There was no difference between nicotine and placebo groups. At the end of the intervention, the mean value of cotinine in saliva in women assigned to nicotine was 120 ng/mL and placebo 153 ng/mL (mean difference -33; 95% CI -72, 6 ng/mL). Mean birth weight difference was 186 g (95% CI 35, 336 g) higher in the nicotine than placebo group, and there was an insignificantly lower rate of low birth weight (under 2500 g) in the former group. There was no difference in the rate of preterm delivery between the two groups. CONCLUSION: Nicotine patches had no influence on smoking cessation during pregnancy, although they might increase birth weight in comparison with placebo.

Combined actions of isradipine and captopril on renal function in hypertension.

The object of this study was to test the hypothesis that the natriuretic and uricosuric effect of calcium-entry blockers could be mediated through antagonism of angiotensin II dependent intrarenal mechanisms. The antihypertensive efficacy, haemodynamic and excretional effects of superimposed calcium blockade with isradipine were investigated in seven hypertensives with unsatisfactorally controlled blood pressure with captopril 50 mg twice daily. Glomerular filtration rate (GFR) and renal plasma flow (RPF), clearances (C) of sodium (Na), potassium (K), uric acid (UA) and lithium (Li), were measured before and after a low-dose bolus of isradipine, i.v. Subsequently, measurements were repeated during constant i.v. infusion of a higher dose with definite systemic haemodynamic effects. After 4 months of combined treatment with isradipine and captopril renal investigations were carried out again. The low isradipine dose induced a slight but statistically significant increment in CNa (22% +/- 28) and heart rate (4% +/- 4), whereas no other variables changed significantly. Infusion of the high isradipine dose caused a pronounced fall in renal vascular resistance (27% +/- 14), systolic (8% +/- 2) and diastolic blood pressure (17% +/- 5). RPF increased significantly (15% +/- 18) whereas no changes were noted in GFR, filtration fraction and urinary albumin excretion rate. In spite of the pronounced fall in BP during the high dose infusion, significant increments in natriuresis (91% +/- 63) and diuresis (41% +/- 27) were induced. The natriuresis was caused by a proximal tubular action as indicated by increased CLi and CLi/GFR.(ABSTRACT TRUNCATED AT 250 WORDS)