Acute gastrointestinal illness in adults in Germany: a population-based telephone survey.

Population-based estimates of incidence and risk factors for acute gastrointestinal illness (AGI) are important for infectious disease surveillance and healthcare planning. We conducted a nationwide representative cross-sectional telephone survey of 21,262 adults over a 12-month period during 2008-2009 in Germany. Participants were asked if they had either AGI-related diarrhoea or vomiting in a 4-week recall period. We estimated 0·95 episodes/person per year (95% confidence interval 0·90-0·99), corresponding to 64·9 million episodes of AGI annually in adults, which results in 24·5 million outpatient visits, 19·9 million hospital days and 63·2 million days of work lost. We observed an overall declining trend of AGI with increasing age. Diarrhoea was more often reported than vomiting. The mean duration of illness was 3·8 days and did not differ between age groups. Social factors seemed to be weak predictors compared to state of health and health behaviour characteristics. This study allows international comparisons and contributes to the estimation of the global burden of AGI.

Community incidence of pathogen-specific gastroenteritis: reconstructing the surveillance pyramid for seven pathogens in seven European Union member states.

By building reconstruction models for a case of gastroenteritis in the general population moving through different steps of the surveillance pyramid we estimated that millions of illnesses occur annually in the European population, leading to thousands of hospitalizations. We used data on the healthcare system in seven European Union member states in relation to pathogen characteristics that influence healthcare seeking. Data on healthcare usage were obtained by harmonized cross-sectional surveys. The degree of under-diagnosis and underreporting varied by pathogen and country. Overall, underreporting and under-diagnosis were estimated to be lowest for Germany and Sweden, followed by Denmark, The Netherlands, UK, Italy and Poland. Across all countries, the incidence rate was highest for Campylobacter spp. and Salmonella spp. Incidence estimates resulting from the pyramid reconstruction approach are adjusted for biases due to different surveillance systems and are therefore a better basis for international comparisons than reported data.

C-FOS expression in the rat brain in response to substance P and neurokinin B.

Substance P, the principal neurokinin peptide in the mammalian brain and the natural ligand for the NK(1) tachykinin receptor, plays an integrative role in the regulation of cardiovascular, neuroendocrine and behavioural responses to stress. In rats, stimulation of periventricular NK(1) receptors in the forebrain induces a distinct pattern of cardiovascular responses which is accompanied by intense grooming behaviour. Ligands for NK(3) receptors induce a different pattern of cardiovascular and behavioural responses which comprises an increased release of vasopressin from the posterior pituitary and wet-dog shakes behaviour. To define the brain areas in the rat which respond to stimulation of forebrain NK(1) and NK(3) receptors and participate in the generation of these responses, the induction of c-Fos immunoreactivity was examined in brains following intracerebroventricular injections of substance P and neurokinin B in conscious rats. Stimulation of central NK(1) receptors by substance P (25, 100 and 500 pmol) injected into the lateral ventricle elicited grooming behaviour (face washing and hind limb grooming) and resulted in a marked c-Fos expression in the paraventricular, dorsomedial and parabrachial nuclei and in the medial thalamus. At 25 pmol, substance P did not significantly increase c-Fos expression, at 100 pmol, maximal c-Fos activation was induced in all four brain regions which responded to the peptide. Intracerebroventricular pretreatment of rats with the selective and high-affinity, non-peptide NK(1) receptor antagonist, RP 67580 (500 pmol), but not with its inactive enantiomer, RP 68651, completely abolished the behavioural response to substance P and reduced the substance P-induced c-Fos expression in all brain areas to nearly control levels. Intracerebroventricular injection of the natural ligand for NK(3) receptors, neurokinin B (500 pmol), elicited wet-dog shakes behaviour and activated c-Fos expression in localized regions of the forebrain including the organum vasculosum laminae terminalis, subfornical organ, median preoptic nucleus, paraventricular, supraoptic and anterior hypothalamic nuclei, medial thalamus and in the ventral tegmental area. These results demonstrate that the neurokinins, substance P and neurokinin B, induce specific and different patterns of c-Fos expression in distinct regions of the rat brain. Brain areas which selectively responded to substance P have been traditionally linked to the central regulation of cardiovascular and neuroendocrine reactions to stress or involved in the processing of nociceptive responses. On the other side, brain areas activated by neurokinin B are known to be involved in the central regulation of blood pressure, water and salt homeostasis or control of behaviour.

Significance of timing of angiotensin AT1 receptor blockade in rats with myocardial infarction-induced heart failure.

OBJECTIVE: Blockade of angiotensin AT(1) receptors has been shown to prevent cardiac remodeling and improve left ventricular function and survival after myocardial infarction (MI). However, the timing of initiation of treatment has not been fully elucidated. Therefore, the purpose of the present study was to compare the effects of very early (30 min after MI), early (3 and 24 h after MI) and delayed (7 days after MI) treatments with the angiotensin AT(1) receptor antagonist fonsartan (HR 720) on cardiac morphological and hemodynamic parameters in a rat model of MI-induced heart failure and to establish the therapeutic window for the start of treatment. METHODS: Male Wistar rats underwent coronary ligation and were randomized fonsartan (HR720) treatment starting 30 min, 3 h, 24 h and 7 days after MI or no treatment. Treatment was continued up to 6 weeks post MI. RESULTS: Fonsartan (HR720) treatment attenuated cardiac hypertrophy when treatment started 30 min or later after MI, limited infarct size when treatment initiated 3 and 24 h after MI, decreased left ventricular end-diastolic pressure when treatment started 3 h to 7 days after MI, and improved dP/dt(max) when treatment commenced 24 h and 7 days after MI compared to untreated infarct group. CONCLUSION: Our results show that angiotensin AT(1) receptor blockade with fonsartan (HR720) produced the best cardioprotective effects when treatment was started 3 to 24 h after MI although a start of treatment 7 days following MI still could improve functional parameters. These results suggest an optimal time window for the start of treatment with angiotensin AT(1) receptor antagonists seems to be between 3 and 24 h post MI.

Cardioprotective effects of the Na(+)/H(+)-exchange inhibitor cariporide in infarct-induced heart failure.

OBJECTIVE: We investigated the effect of chronic treatment with the new Na(+)/H(+)-exchange inhibitor, cariporide, on cardiac function and remodelling 6 weeks after myocardial infarction (MI) in rats. METHODS: Treatment with cariporide was commenced either 1 week pre or 30 min, 3 h, 24 h or 7 days after ligation of the left ventricular artery and was continued until haemodynamic parameters were obtained 6 weeks after MI in conscious rats. RESULTS: Compared to sham animals, untreated MI-controls developed pronounced heart failure after 6 weeks. Basal left ventricular end-diastolic pressure (in mmHg) was reduced in the groups in which cariporide was started 1 week pre (16.0+/-1.7) or 30 min (12.5+/-1.1), 3 h (11.8+/-1.0) and 24 h (13.0+/-2.5) after MI compared to untreated MI-controls (22. 4+/-1.5; P<0.01). Basal myocardial contractility (in 1000 mmHg/s) was only increased when treatment was initiated after 30 min (9. 0+/-0.7), 3 h (8.5+/-0.3) and 24 h (8.0+/-0.7) compared to untreated MI-controls (5.8+/-0.7; P<0.05-0.01). Infarct size (in % of left ventricular circumference) was 40.0+/-2.1 in MI-controls and was decreased when treatment was begun after 30 min (32.6+/-2.7) or 3 h (32.4+/-2.3) (P<0.05). In animals, in which cariporide was started 3 h after induction of MI, heart weight/body weight ratio was significantly decreased, indicating reduced cardiac hypertrophy. When treatment started 7 days after MI, cariporide did not exert any beneficial actions on structural and functional cardiac parameters. CONCLUSION: Our results show for the first time that chronic treatment with the Na(+)/H(+)-exchange inhibitor cariporide engendered marked cardioprotective effects when commenced before and up to 24 h after MI. The optimal time for the start of treatment was between 30 min and 3 h post MI.

Tachykinin receptor inhibition and c-Fos expression in the rat brain following formalin-induced pain.

Recent pharmacological evidence has implicated substance P and neurokinin A, natural ligands for neurokinin-1 and neurokinin-2 receptors, respectively, as neurotransmitters in brain neuronal circuits activated upon noxious stimulation. The expression of the inducible transcription factor, c-Fos, was used to identify areas in the brain activated by a noxious stimulus (the subcutaneous injection of formalin), and to investigate the effects of intracerebroventricular administration of selective, nonpeptide antagonists for neurokinin-1 and neurokinin-2 tachykinin receptors on the neural activity in these areas and on the behavioural response to formalin-induced pain. Formalin (5%, 50 microl), injected subcutaneously through a chronically implanted catheter in the region of the lower hindlimb, increased c-Fos expression in a number of brain areas related to nociceptive transmission or the integration of stress responses. Grooming behaviour, licking and biting directed to the injected site, was the most frequent behavioural response. Intracerebroventricular pretreatment of rats with either RP 67580 (500 pmol), the active enantiomer of a neurokinin-1 receptor antagonist, or with SR 48968 (500 pmol), the active enantiomer of a neurokinin-2 receptor antagonist, reduced the formalin-induced c-Fos staining in the prefrontal cortex, dorsomedial and ventromedial nuclei of the hypothalamus, the locus coeruleus and the periaqueductal gray. The neurokinin-1, but not the neurokinin-2, receptor antagonist attenuated the formalin-induced activation of c-Fos in the paraventricular nucleus of the hypothalamus. Simultaneous intracerebroventricular pretreatment with both neurokinin-1 and neurokinin-2 receptor antagonists did not produce any additional inhibitory effect on the post-formalin c-Fos expression. None of the tachykinin receptor antagonists had an effect on the formalin-induced c-Fos expression in the septohypothalamic nucleus, medial thalamus, parabrachial nucleus and central amygdaloid nucleus, indicating that neurotransmitters other than neurokinins are most probably responsible for the activation of these areas in response to noxious stimulation. While both tachykinin receptor antagonists reduced the grooming behaviour to formalin, the neurokinin-1 receptor antagonist was clearly more effective than the neurokinin-2 receptor antagonist. Intracerebroventricular pretreatment of rats with the inactive enantiomers of the tachykinin receptor antagonists, RP 68651 and SR 48965, was without effect. Our results show that (i) the modified formalin test elicited an intense grooming behaviour and expression of c-Fos in numerous forebrain and brainstem areas, (ii) both tachykinin receptor antagonists were able to attenuate the behavioural response to pain and to reduce the formalin-induced c-Fos expression in some, but not all, brain areas, and (iii) the neurokinin-1 antagonist, RP 67580, was more effective in inhibiting the behavioural response to formalin and the pain-induced activation of c-Fos than the antagonist for neurokinin-2 receptors, SR 48968, indicating that neurokinin-1 receptors are preferentially activated in neurokinin-containing pathways responding to noxious stimuli. Our results demonstrate that blockade of brain tachykinin receptors, especially of the neurokinin-1 receptor, reduces the behavioural response to pain and the pain-induced c-Fos activation in distinct brain areas which are intimately linked with nociceptive neurotransmission and the initiation and integration of central stress responses. Together with the previous findings of the inhibition of hypertensive and tachycardic responses to pain, the present data indicate that tachykinin receptor antagonists can effectively inhibit the generation of an integrated cardiovascular and behavioural response pattern to noxious stimuli.

Effects of a novel angiotensin AT(1) receptor antagonist, HR720, on rats with myocardial infarction.

Cardiac remodeling after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of the present study was to assess the effects of chronic treatment with a novel angiotensin AT(1) receptor antagonist 2-butyl-4-(methylthio-)-1-[[2'[[[(propylamino)carbonyl]amino]sulfonyl ](1,1'-biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate (HR720), on cardiac remodeling and left ventricular dysfunction in a rat model of large myocardial infarction. Rats were subjected to permanent ligation of the left coronary artery and were treated for six weeks with placebo or HR720 (3 mg/kg/day) initiated 24 h after surgery. Sham-operated rats served as normal controls. Mean arterial blood pressure, the maximum rate of rise of the left ventricular systolic pressure (dP/dt(max)), left ventricular end-diastolic pressure, left ventricular inner diameter and circumference, septal thickness, left ventricular collagen content and heart weight were measured at the end of the treatment. HR720 treatment versus placebo attenuated the cardiac hypertrophy (heart weight/body weight: 2.88+/-0.08 mg/g vs. 3.16+/-0.09 mg/g, P<0.05), reduced interstitial collagen content (3. 47+/-0.28% vs. 5.25+/-0.45%, P<0.01), limited infarct size (33.0+/-3. 0% vs. 41.5+/-2.3%, P<0.05), decreased left ventricular end-diastolic pressure (13.7+/-2.2 vs. 21.4+/-1.6 mm Hg, P<0.01) and improved dP/dt(max) (9000+/-430 vs. 6000+/-840 mm Hg/s, P<0.05). The present results demonstrate that chronic treatment with the angiotensin AT(1) receptor antagonist HR720 can limit infarct size, partially prevent cardiac hypertrophic remodeling and improve left ventricular function in rats with myocardial infarction.

Effects of the calcium channel antagonist mibefradil on haemodynamic and morphological parameters in myocardial infarction-induced cardiac failure in rats.

OBJECTIVE: Calcium channel antagonists (CCA) have been proposed for the prevention of cardiac events after myocardial infarction (MI). Mibefradil is a CCA featuring a selective blockade of T-type Ca2(+)-channels. The aim of the study was to characterize the effects of mibefradil on haemodynamic and morphological parameters in a model of postMI chronic heart failure and to establish the "therapeutic window" for the start of therapy. METHODS: MI was induced by permanent ligation of the left coronary artery in male normotensive Wistar rats. Animals were assigned to placebo- or mibefradil-treated (10 mg/kg/day p.o.) groups as follows: (1) sham operation; (2) MI placebo treatment; (3) 7 days preMI start of treatment; (4) 3 h postMI start of treatment; (5) 24 h postMI start of treatment; (6) 3 days postMI start of treatment; (7) 7 days postMI start of treatment. Treatment was continued for 6 weeks postMI. At this time point, mean arterial blood pressure (MAP), heart rate, left ventricular enddiastolic pressure (LVEDP) and contraction force (dP/dtmax) were measured in conscious rats at baseline and after methoxamine (MEX; 0.5-1.0 mg/h i.v.) stimulation to increase afterload. The hearts were subjected to histological determination of infarct size (IS), infarct length (IL), noninfarcted length (NL), left ventricular circumference (LVC), inner LV-diameter (LVD) and septal thickness (ST). RESULTS: Six weeks after MI, MAP was lowered, LVEDP increased and dP/dtmax reduced. Mibefradil treatment increased basal MAP in groups 3-5 compared to the placebo-treated MI group. Under mibefradil, LVEDP was reduced at baseline in groups 3-6 and, after MEX, in all groups. dP/dtmax was increased in groups 3-4 at baseline and after MEX. In the placebo-treated MI group, the infarcted area was 39% of the LV and heart weight, LVD and LVC were increased. Heart weights of mibefradil-treated rats (groups 3-6) did not differ from those of the placebo-treated group. Early onset of treatment with mibefradil reduced IS and IL and increased NL in groups 3-4. LVD and LVC were decreased in group 3 only. ST was increased in groups 3-5. CONCLUSION: Chronic treatment with mibefradil exerts beneficial actions on cardiac structure and performance in postMI cardiac failure in rats, especially when the onset of treatment is either prior to or within hours after the acute ischemic event.

A new formalin test allowing simultaneous evaluation of cardiovascular and nociceptive responses.

The formalin test for nociception, predominantly used with rodents, is characterized by continuous pain due to tissue injury induced by formalin. In addition to the pain generated by formalin itself, the classical formalin test for nociception comprises a number of additional strong stressful events such as restraint and injury caused by needle insertion. These events have hampered its use as a model of stress employing continuous pain as a stress stimulus. We describe here a new, simple method of a subcutaneous application of formalin in conscious rats without restraint and needle insertion. Formalin or physiological saline (controls) was injected subcutaneously through a chronically implanted catheter in the region of the lower leg. In most animals, the cardiovascular and behavioural responses to subcutaneously injected formalin were biphasic. The early phase was quantitatively characterized. Formalin (2.5%, 50 microL) induced a marked increase in mean arterial pressure and heart rate. Maximal increases occurred during the first 3 min after formalin injection and were followed by a gradual decline of both cardiovascular parameters to levels higher than the preinjection baseline. Subcutaneous saline injection did not induce any changes in mean arterial pressure and heart rate. The behavioural response to formalin featured intensive licking and biting of the injection site. The behavioural response to subcutaneous saline did not differ from the spontaneous behavioural activity recorded in noninjected rats. Subcutaneously injected formalin induced an immediate increase in plasma corticotrophin (ACTH), corticosterone, noradrenaline, and adrenaline levels, and all hormones remained increased during the whole observation period (60 min). Adrenaline and noradrenaline levels in plasma were slightly, but significantly, elevated during the initial 5 min after subcutaneous saline application but returned to basal values after 15 min. The magnitude of the hormonal responses characterizes the described formalin test as a moderate stress stimulus. The complex response pattern to formalin injected through the subcutaneous catheter is brought about exclusively by pain generated by formalin-induced tissue injury. The described technique of subcutaneous formalin injection represents a new tool to study mechanisms activating brain neuronal circuits that generate the cardiovascular, endocrine, and behavioural responses of the reaction to pain.

Substrate metabolism, hormone interaction, and angiotensin-converting enzyme inhibitors in left ventricular hypertrophy.

Left ventricular hypertrophy is considered to be an independent risk factor giving rise to ischemia, arrhythmias, and left ventricular dysfunction. Slow movement of intracellular calcium contributes to the impaired contraction and relaxation function of hypertrophied myocardium. Myofibril content may also be shifted to fetal-type isoforms with decreased contraction and relaxation properties in left ventricular hypertrophy. Myocyte hypertrophy and interstitial fibrosis are regulated independently by mechanical and neurohumoral mechanisms. In severely hypertrophied myocardium, capillary density is reduced, the diffusion distance for oxygen, nutrients, and metabolites is increased, and the ratio of energy-production sites to energy-consumption sites is decreased. The metabolic state of severely hypertrophied myocardium is anaerobic, as indicated by the shift of lactate dehydrogenase marker enzymes. Therefore, the hypertrophied myocardium is more vulnerable to ischemic events. As a compensatory response to severe cardiac hypertrophy and congestive heart failure, the ADP/ATP carrier is activated and atrial natriuretic peptide is released to increase high-energy phosphate production and reduce cardiac energy consumption by vasodilation and sodium and fluid elimination. However, in severely hypertrophied and failing myocardium, vasoconstrictor and sodium- and fluid-retaining factors, such as the renin-angiotensin system, aldosterone, and sympathetic nerve activity, play an overwhelming role. Angiotensin-converting enzyme inhibitors (ACEIs) are able to prevent cardiac hypertrophy and improve cardiac function and metabolism. Under experimental conditions, these beneficial effects can be ascribed mainly to bradykinin potentiation, although a contribution of the ACEI-induced angiotensin II reduction cannot be excluded.

Angiotensin AT1 receptor-mediated vasopressin release and drinking are potentiated by an AT2 receptor antagonist.

Stimulation of angiotensin II AT2 receptors has been shown to inhibit AT1 receptor-mediated actions in peripheral tissues. The role of AT2 receptors in the central actions of angiotensin is not well understood. In the present study, plasma vasopressin levels and water intake in response to intracerebroventricular angiotensin II (10 pmol) were determined after intracerebroventricular pretreatment with PD 123177 (1-(4-amino-3-methylphenyl)methyl-5-diphenylacetyl-4,5,6,7-tetrahy dro-1H- imidazo[4,5-c]pyridine-6-carboxylic acid-2HCl), a selective AT2 receptor antagonist (10, 100 and 1000 pmol), or with losartan (2-n-butyl-4-chloro-5-hydroxy-methyl-1-2'-(1H-tetrazole-5-yl)biphenyl-4- yl)methylimidazole, potassium salt), a specific AT1 receptor antagonist (0.2, 2 and 10 nmol). Blood samples for vasopressin determination were drawn 90 s after angiotensin II injection and the drinking response was determined in a time interval of 10 min after intracerebroventricular angiotensin II. Losartan at a dose of 2 nmol or higher completely prevented vasopressin release and drinking response to angiotensin II. The drinking response was already attenuated after pretreatment with the lowest dose of losartan. In contrast, PD 123177 potentiated the angiotensin II-induced vasopressin release (39.7 +/- 2.7 pg/ml after 1000 pmol PD 123177 vs. 21.3 +/- 2.9 pg/ml in vehicle-pretreated controls, P < 0.05). The dipsogenic response to angiotensin II was also potentiated by PD 123177 (9.5 +/- 0.7 ml after 1000 pmol PD 123177 vs. 5.1 +/- 1.3 ml in vehicle-pretreated controls, P < 0.05). Our results suggest that the angiotensin II-induced vasopressin release and drinking, mediated by central AT1 receptors, are under inhibitory control by central AT2 receptors.

Effects of the tachykinin NK1 receptor antagonist, RP 67580, on central cardiovascular and behavioural effects of substance P, neurokinin A and neurokinin B.

1. We have investigated the effects of the non-peptide NK1 tachykinin receptor antagonist, RP 67580, and its inactive enantiomer, RP 68651, on the cardiovascular and behavioural responses to substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) injected intracerebroventricularly (i.c.v.) in conscious rats. 2. The SP and NKA (25 pmol)-induced increases in blood pressure (BP) and heart rate (HR) were of the same magnitude. The cardiovascular responses to both peptides were associated with excessive grooming behaviour and wet dog shakes (WDS). Relative to SP, NKA was weaker in inducing hindquarter grooming (HG), but more effective in eliciting WDS. The cardiovascular response to NKB (50 pmol) comprised an increase in BP and HR, while the behavioural response was weak. 3. RP 67580 (100 pmol), injected 10 or 30 min prior to SP, effectively inhibited the cardiovascular and behavioural responses to the peptide whereas lower doses were ineffective. Pretreatment with 500 pmol of RP 67580, 10 or 30 min prior to SP, reduced the BP response. Of the behavioural manifestations, only face washing was attenuated when the antagonist was injected 10 min before SP. At 2500 pmol, the antagonist exaggerated the BP response to the peptide without affecting the behavioural response. RP 68651 (100 or 2500 pmol) did not modify the central responses to SP. 4. Neither RP 67580 nor RP 68651 (100 pmol), affected the cardiovascular and behavioural responses to NKA or NKB. 5. Our results indicate that RP 67580 is a selective and high affinity antagonist at central NK1 tachykinin receptors in the rat.