A man with abdominal pain and eosinophilia : tissue is the issue.

A 24-year-old male presented with abdominal pain, postprandial vomiting and weight loss. Lab results showed an elevated serum eosinophil count and CT-scan demonstrated a thickened antral, duodenal and jejunal wall. Repetitive endoscopic mucosal biopsies were normal. Work-up of eosinophilia-associated gastro-intestinal disorders excluded secondary causes. Bone marrow showed an elevated eosinophil count without arguments for a primary hypereosinophilic syndrome. Endoscopic ultrasound-guided fine needle biopsy detected a strongly elevated number of eosinophils in the muscularis layer of the duodenum. The diagnosis of muscularispredominant eosinophilic gastroenteritis together with a secondary hypereosinophilic syndrome was made. The patient was started on steroids and all symptoms vanished within a few days.

Adult intussusception: 10-year experience in two Belgian centres.

BACKGROUND: adult intussusception is a rare entity with a different clinical presentation and aetiology than in children. Objective: To provide a comprehensive overview of the clinical presentation, aetiology, diagnosis and management of adult intussusception. METHODS: We review 43 cases with a preoperative diagnosis of symptomatic gastrointestinal adult intussusception. RESULTS: In 67% of the cases an underlying lead point was discovered. Most intussusceptions were of the enteric type (65%) with a predominant benign or idiopathic origin. Malignancy was present in half of the cases with a colonic lead point. CT was the preferred imaging technique (81%) with a sensitivity of 94%. Colonoscopy provided the correct diagnosis in 89% of the cases involving a colonic lead point. Surgical intervention occurred in 72% of the cases. CONCLUSIONS: The combination of low incidence and non-specific symptoms makes intussusception in the adult difficult to diagnose. Modern imaging techniques often provide the correct preoperative diagnosis. A culprit lesion is usually identified after a careful search. Suspicion for a malignant lead point should be high in case of colonic involvement and colonoscopy can be of added value in these cases. The therapeutic strategy depends on several variables and requires for a patient-tailored approach mostly involving surgery. (Acta gastro-enterol. belg., 2016, 79, 301-308).

Prolonged course of hepatic granulomatous disease due to Bartonella henselae infection.

Cat-scratch disease (CSD) is an emerging zoonosis caused by Bartonella henselae. The disease is usually self-limiting and typically presents in about 90% of all cases as a subacute regional lymphadenopathy. We present a case report of an unusual CSD presentation, persistent hepatic granulomatous disease due to Bartonella henselae infection despite combination therapy with doxycycline and rifampicin. Furthermore, a review of literature was conducted. (Acta gastroenterol. belg., 2016, 79, 497-499).

A suspicious pancreatic mass in chronic pancreatitis: pancreatic actinomycosis.

Introduction. Pancreatic actinomycosis is a chronic infection of the pancreas caused by the suppurative Gram-positive bacterium Actinomyces. It has mostly been described in patients following repeated main pancreatic duct stenting in the context of chronic pancreatitis or following pancreatic surgery. This type of pancreatitis is often erroneously interpreted as pancreatic malignancy due to the specific invasive characteristics of Actinomyces. Case. A 64-year-old male with a history of chronic pancreatitis and repeated main pancreatic duct stenting presented with weight loss, fever, night sweats, and abdominal pain. CT imaging revealed a mass in the pancreatic tail, invading the surrounding tissue and resulting in splenic vein thrombosis. Resectable pancreatic cancer was suspected, and pancreatic tail resection was performed. Postoperative findings revealed pancreatic actinomycosis instead of neoplasia. Conclusion. Pancreatic actinomycosis is a rare type of infectious pancreatitis that should be included in the differential diagnosis when a pancreatic mass is discovered in a patient with chronic pancreatitis and prior main pancreatic duct stenting. Our case emphasizes the importance of pursuing a histomorphological confirmation.

Intermittent adult ileocecal intussusception: a case report and review of literature.

We report the case of a 56-year-old male patient who was admitted to the emergency department with crescendo abdominal pain since 2 weeks. In the past 2 years, similar but less pronounced episodes were present, each time resolving spontaneously after spasmolytic drugs. Abdominal ultrasound revealed an ileocecal intussusception. An attempt for preoperative reduction was partially successful. A colonoscopy was performed and showed a tubulovillous adenomatous polyp with high-grade dysplasia, but subsequent right hemicolectomy revealed an underlying cecal adenocarcinoma. The combination of the low incidence and the non-specific symptoms of ileocecal intussusception in the adult makes this entity difficult to diagnose. In most cases, modern imaging techniques such as CT scan, ultrasound, or MRI make the correct preoperative diagnosis. Especially when colonic involvement is present, suspicion of a malignant lead point (i.e. culprit lesion) is primordial. The therapeutic strategy depends on several variables and asks for a patient-tailored, selective approach mostly involving surgery. Based on this case and a short review of literature, we discuss the clinical presentation, diagnostic tools, treatment, and challenges of adult ileocecal intussusception.

QT and JT dispersion in the drug-induced long QT syndrome in anaesthetized rabbits is accurately detected by a three-lead surface ECG measurement.

INTRODUCTION: QT dispersion (QTd) can be measured from three leads of the ECG in patients with myocardial ischemia. However, whether QT and JT dispersion (QTd, JTd) can be calculated from a three-lead of the ECG in drug-induced long QT syndrome (LQTS) in animals remains elusive. Therefore, we determined to what extent a three-lead measurement of the surface ECG accurately detects dispersion of QT and JT in comparison with multi-lead assessments in anaesthetized rabbits, challenged with methoxamine and additionally infused intravenously with solvent or dofetilide. METHODS: Using several ECG leads in anaesthetized rabbits challenged intravenously with an alpha(1)-adrenoceptor agonist methoxamine, we assessed the QT and JT interval, as well as QT and JT dispersion, at baseline and in response to solvent or dofetilide (0.02 or 0.04 mg/kg/min iv for 60 min), an I(Kr) blocker. For that purpose, we recorded and analyzed the surface ECG and assessed QT and JT dispersion by four methods: (1) 12-lead ECG; (2) six precordial leads (V1-V6); (3) three leads most likely to contribute to the dispersion (aVF, V1, and V4); (4) three quasi-orthogonal leads (aVF, I, and V2). QT and JT dispersion were significantly lower in 6- and 3-lead measurements than in 12-lead measurement, both at baseline and during infusion of solvent or dofetilide. At 5 and 10 min of infusion, dofetilide at 0.02 or 0.04 mg/kg/min iv markedly increased QT and JT dispersion by 100% to 500% in all four ECG lead combinations. This dose regimen of dofetilide markedly prolonged QT and JT intervals in lead II, and was associated with high incidences of polymorphous ventricular tachycardia (PVT: 30% at 0.02 mg/kg/min; 100% at 0.04 mg/kg/min) and of ventricular fibrillation (VF: 17% with 0.02 mg/kg/min; 58% with 0.04 mg/kg/min). CONCLUSIONS: Our present study shows that the measurement of QT and JT dispersion in three surface ECG leads only (aVF, I, V2 or aVF, V1 V4), instead of 12 ECG leads, is an appropriate approach to assess drug-induced heterogeneity or dispersion of ventricular repolarization in anaesthetized rabbits, both at baseline and during arrhythmogenic sensitization with methoxamine and challenged with dofetilide.

Modulation of airway hyperresponsiveness by thiols in a murine in vivo model of allergic asthma.

OBJECTIVE AND DESIGN: Since oxidative stress contributes to the pathogenesis of asthma, this study addressed the question whether supplementing the endogenous antioxidant, glutathione (GSH), would alleviate features of allergic asthma in the mouse. MATERIAL AND METHODS: Ovalbumin-sensitized mice received aerosols of the GSH-donors, glutathione-ethyl ester (GSEt) or N-acetylcysteine, before or during respiratory allergen challenges, or during methacholine challenges given one day after the last allergen challenge. Lung GSH levels were measured shortly after allergen or methacholine challenge. In addition, the effect of GSH supplements on airway hyperresponsiveness and inflammatory cell numbers in the airway lumen was assessed. RESULTS: GSEt decreased allergen-induced airway hyperresponsiveness when given in combination with methacholine. However, when given before or during allergen challenge, both GSH-donors failed to decrease the methacholine-induced airway contractility, change cell numbers in the airway lumen, or increase lung GSH levels. In addition, allergen challenges of sensitized mice did not decrease lung GSH levels. CONCLUSION: In contrast to guinea pigs and humans, allergen challenges in mice does not lead to acute oxidative stress.

Female gender is a risk factor for drug-induced long QT and cardiac arrhythmias in an in vivo rabbit model.

INTRODUCTION: Clinical observations and in vitro experimental data indicate that females have a longer QT interval than males, which is associated with a higher risk of drug-induced cardiac arrhythmias. Little is known about this gender difference in anesthetized animals, which may affect the outcome of in vivo drug tests. METHODS AND RESULTS: We evaluated potential gender differences in ventricular repolarization (QT, QTc, JT, and JTc interval) and its dispersion, as well as in its response to dofetilide, an IKr blocker, in anesthetized rabbits challenged with the alpha1-adrenoceptor agonist methoxamine. A 12-lead ECG was recorded during the experiments. At baseline, there were no significant gender differences in ventricular repolarization values in male and female rabbits under anesthesia. Dofetilide (0.04 mg/kg/min IV for 60 min; n = 10 per gender) produced marked prolongation of the ventricular repolarization time and its dispersion, associated with a high incidence of polymorphic ventricular tachycardia (PVT; 100% in females vs 80% in males) and ventricular fibrillation (VF; 80% in females vs 50% in males; P > 0.05). QT and JT interval at 2 minutes as well as QT and JT dispersion at 10 and 30 minutes during dofetilide infusion were significantly higher in female than in male rabbits. After 30 minutes of dofetilide infusion, 10 of 10 female rabbits had severe cardiac arrhythmias (complete AV block, PVT, or VF), so ECG parameters were impossible to assess (vs 3/10 males with severe cardiac arrhythmias; P < 0.05). During dofetilide infusion, female rabbits developed complete AV block, PVT, or VF at doses about 50% lower than those given to males. CONCLUSION: The present study indicates that female rabbits are more susceptible to drug-induced long QT and cardiac arrhythmias than are male rabbits; therefore, female rabbits are more appropriate for testing drug-induced cardiac arrhythmias.

Phase 2 prolongation, in the absence of instability and triangulation, antagonizes class III proarrhythmia.

OBJECTIVE: To evaluate whether prolongation of the plateau of the action potential duration, in the absence of instability and triangulation, can reverse the proarrhythmia elicited by a class III antiarrhythmic agent. METHODS: The effects of almokalant, erythromycin and their combination, on cardiac electrophysiological parameters (action potential duration (APD), instability, triangulation and ectopics) were evaluated in isolated hearts from female albino rabbits. In this study, proarrhythmia was estimated quantitatively by number of ectopic beats. RESULTS: Erythromycin lengthened the APD primarily by a prolongation of the plateau, while having only minor effects upon phase 3 repolarization. The prolongation did not induce much instability, triangulation or reverse use dependence and, as expected, erythromycin did not induce significant proarrhythmia. Almokalant also lengthened APD, but it did not lengthen the plateau; instead, it prolonged phase 3 repolarization. The prolongation markedly triangulated the action potential, elicited much instability and marked reverse use dependence. This combination of effects induced very marked proarrhythmia. When almokalant and erythromycin were combined, their effects upon APD appeared additive: both the plateau and the repolarization phase were prolonged. However, the larger prolongation of APD did not lead to more proarrhythmia; this suggests that a prolongation of APD is not proarrhythmic per se. On the contrary, proarrhythmia as a function of APD prolongation was reduced in the presence of erythromycin (P<0.05). CONCLUSION: Instability plus triangulation consistently lead to serious proarrhythmia especially when combined with reverse use dependence, but prolongation of APD in itself is not necessarily proarrhythmic. In fact, APD prolongation in the absence of instability and triangulation can be antiarrhythmic.

Species plays an important role in drug-induced prolongation of action potential duration and early afterdepolarizations in isolated Purkinje fibers.

INTRODUCTION: Although isolated Purkinje fibers (PFs) often are used to evaluate the electrophysiologic effects of new drugs in terms of prolongation of action potential duration (APD) and induction of early afterdepolarizations (EADs), species differences in this respect remain elusive. We evaluated potential species-specific differences in drug-induced prolongation of APD and EADs in isolated PF from various species. METHODS AND RESULTS: Using a microelectrode technique, PFs (n = 7 to 11 per species) were isolated from hearts of rabbits, guinea pigs, dogs, swine, goats, or sheep, superperfused in Tyrode's solution with dofetilide (1 x 10(-8) M) or quinidine (1 x 10(-5) M) for 25 minutes, and stimulated at 1 Hz for 20 minutes and at 0.2 Hz for another 5 minutes. Dofetilide increased APD at 90% repolarization (APD90) at 1 Hz by 83% (rabbit), 24% (guinea pig), 65% (dogs), 18% (swine), 61% (goat), and 30% (sheep), and prolonged APD90 at 0.2 Hz by 187% (rabbit), 31% (guinea pig), 154% (dog), 17% (swine), 61% (goat), and 8% (sheep). Similarly, quinidine changed APD90 by 93% (rabbit), 0% (guinea pig), 16% (dog), -3% (swine), 0% (goat), and -24% (sheep) at 1 Hz, and by 124% (rabbit), 15% (guinea pig), 53% (dog), 17% (swine), 11% (goat), and -39% (sheep) at 0.2 Hz in PF. During superfusion of dofetilide or quinidine, EADs occurred in most preparations in rabbit PFs at 0.2 Hz, but not in any of the PFs from other species at 0.2 Hz. CONCLUSION: Our study demonstrates that species plays an important role in the response of PF to drug-induced prolongation of APD and EADs. Rabbit PFs constitute the most sensitive model for detecting drug-induced, potential long APD and proarrhythmogenic effects in vitro.

Nonselective I(Kr)-blockers do not induce torsades de pointes in the anesthetized rabbit during alpha1-adrenoceptor stimulation.

Selective I(Kr)- (the rapid component of the delayed rectifier potassium current) blockers are known to induce torsades de pointes (TdPs) in anesthetized rabbits during alpha1-adrenoreceptor stimulation. However, effects of nonselective I(Kr)-blockers, which produce TdPs in other animal models and in humans, are not known in this model. We examined two nonselective I(Kr)-blockers (quinidine, 1.25 mg/kg/min i.v [n = 7]; and terfenadine, 0.31 mg/kg/min i.v. [n = 7]) for their effects on electrocardiographic parameters and on incidence of cardiac arrhythmias in anesthetized rabbits during alpha1-adrenoceptor stimulation with methoxamine. We compared the drugs with two highly selective I(Kr)-blockers (dofetilide, 0.04 mg/kg/min i.v. [n = 7]; and clofilium, 0.08 mg/kg/min i.v. [n = 6]). Polymorphic ventricular tachycardia or TdPs were induced by dofetilide and clofilium at mean doses > or =0.33 mg/kg and 0.4 mg/kg i.v., in all animals tested (vs. none in solvent; p < 0.05). TdPs usually developed into ventricular fibrillation and developed after prolongation of QT/JT interval and of QT dispersion. Terfenadine and quinidine significantly increased PQ, QT, and QTc interval and largely increased QRS duration and QT dispersion. These compounds elicited intraventricular conduction defects and cardiac arrest, due to asystole, in all animals tested (vs. 0% in solvent; p < 0.05). Interestingly, these two nonselective I(Kr)-blockers did not produce TdPs or ventricular fibrillation in any animals tested. Our results thus indicate that selective I(Kr)-blockers elicit TdPs, whereas nonselective I(Kr)-blockers do not induce this type of arrhythmia in this rabbit model. Consequently, it should be noted that this rabbit model is not always useful to evaluate nonselective I(Kr)-blocker-induced TdPs and QT interval and QT dispersion, rather than TdPs, are also important indicators for drug-induced cardiac arrhythmias.

Are there sex-specific differences in ventricular repolarization or in drug-induced early afterdepolarizations in isolated rabbit purkinje fibers?

Women are known to have a longer QT interval than men and a greater propensity toward drug-induced "torsades de pointes" (TdPs). However, little is known about these sex differences in isolated cardiac tissues. We evaluated potential sex differences in repolarization in isolated rabbit Purkinje fibers using a microelectrode technique. Isolated male or female Purkinje fibers were perfused in a Tyrode's solution with solvent, dofetilide (1 x 10(-8) M) or quinidine (1 x 10(-5) M), and stimulated at 1 or 0.2 Hz. Female Purkinje fibers with solvent (n = 11) tended to have a longer duration of the action potential at 90% repolarization (APD90) than male fibers with solvent (n = 10): 331 (median) vs. 272 ms at 1 Hz (p > 0.05); 473 vs. 367 ms at 0.2 Hz (p < 0.05). Dofetilide (1 x 10(-8) M) significantly increased APD90 more in female Purkinje fibers (n = 11) than in male fibers (n = 10): 670 vs. 385 ms at 1 Hz, at 20 min after the infusion (p < 0.05), and 1,000 vs. 937 ms at 0.2 Hz at the end of the 25-min infusion (p < 0.05), respectively. Quinidine (1 x 10(-5) M) tended to increase APD90 more in female Purkinje fibers (n = 11) than in male fibers (n = 10): 705 vs. 500 ms at 1 Hz, at 20 min after the infusion (p > 0.05). Furthermore, dofetilide (1 x 10(-8) M) and quinidine (1 x 10(-5) M) elicited a higher incidence of early afterdepolarizations in female Purkinje fibers than in male fibers at 0.2 Hz (100 vs. 60%, p < 0.05; and 91 vs. 50%, p > 0.05). Our data indicate that female Purkinje fibers tend to have longer ventricular repolarization and are at higher risk of drug-induced early afterdepolarizations at a slow stimulation rate than male fibers. This may contribute to a sex difference in QT interval and to a greater tendency on the part of women to the development of drug-induced TdPs.

Reduction in QT dispersion and ventricular arrhythmias by ischaemic preconditioning in anaesthetized, normotensive and spontaneously hypertensive rats.

QT dispersion is a marker for dispersion of ventricular repolarization and electrical instability of the heart. However, QT dispersion remains undocumented in both normotensive rats (NTRs) and spontaneously hypertensive rats (SHRs), in particular in conditions of myocardial ischaemia/reperfusion (isch./rep.) and ischaemic preconditioning (IP). Therefore, we assessed the effects of IP on the dynamic change of QT and QTc dispersion during isch./rep., and on isch.- and rep.-induced ventricular arrhythmias in both NTRs and SHRs. Isch. and rep. were produced by occlusion and release of a snare around the left coronary artery in all rats. The effect of IP (three cycles of 3 min coronary artery occlusion and 5 min rep.) on myocardial repolarization and on development of isch.- and rep.-induced ventricular arrhythmias was studied in 12 NTRs and 12 SHRs. Another 12 NTRs or 12 SHRs were subjected to 10 min of isch. followed by 10 min rep. without IP. SHRs have significantly longer QT- and QTc-intervals as well as QT and QTc dispersion before isch. compared to NTRs. Myocardial isch. and early rep. largely increased QT and QTc dispersion in both NTRs and SHRs and resulted in a high incidence of isch.- and rep.-induced ventricular tachycardia (VT) and fibrillation (VF). IP significantly reduced QT and QTc dispersion in SHRs before isch., and remarkably reduced the elevation of QT and QTc dispersion during a prolonged period of isch. and rep. in all rats. This protective effect on electrophysiology of IP was associated with an antiarrhythmic effect against both isch.- and rep.-induced ventricular arrhythmias in NTRs and SHRs. Our data indicate that: 1) SHRs have a significantly higher baseline dispersion of ventricular repolarization than NTRs; 2) IP provides protection against ventricular arrhythmias in SHRs; 3) the increasing QT dispersion provoked by myocardial isch. and rep. is associated with a high incidence of isch.- and rep.-induced ventricular arrhythmias and; 4) the reduction of QT dispersion by IP may be involved in its protective effect against isch.- and rep.-induced arrhythmias in both NTRs and SHRs.

Betamethasone prevents virus-induced airway inflammation but not airway hyperresponsiveness in guinea pigs.

In this study the effect of betamethasone was investigated in guinea pigs that demonstrate airway inflammation and airway hyperresponsiveness after a viral respiratory tract infection with parainfluenza-3 (PI3) virus. Guinea pigs were pretreated with saline or betamethasone 8 mg/kg intraperitoneally twice a day for five consecutive days, starting on day 0 and ending on day 4. On day 1, the guinea pigs were inoculated with either control solution (medium) or PI3 virus. On day 5, airway responsiveness was measured. Furthermore, a blood sample was taken, lungs were lavaged, blood leucocytes were counted, and bronchoalveolar lavage (BAL) cells were counted and differentiated. Accordingly, the activity of the bronchoalveolar cells was measured by lucigenin-amplified chemiluminescence. In virus-infected guinea pigs the total bronchoalveolar cell number was increased by 44% compared with medium-treated guinea pigs. This was mainly due to the increase in macrophages (70%, P < 0.05) and eosinophils (344%, P < 0.001). The increase in both total and differential (macrophages and eosinophils) cell numbers in virus-infected guinea pigs was completely abolished in animals treated with betamethasone. Moreover, betamethasone prevented the decrease in number of blood leucocytes in virus-infected guinea pigs. In contrast, betamethasone did not prevent the increase in airway responsiveness to both histamine (>200%) and methacholine (>100%) after the virus infection. In conclusion, betamethasone treatment prevents virus-induced airway inflammation but not airway hyperresponsiveness in guinea pigs.

Maternal food restriction in the second half of pregnancy affects vascular function but not blood pressure of rat female offspring.

Food restriction during pregnancy in rats induces intrauterine growth retardation with consequences persisting into adulthood. In the present study we have investigated the hypothesis that malnutrition in pregnant rats may lead to altered cardiovascular function in adult female offspring. Perinatal growth retardation was induced by a 50% reduction of normal dietary intake in rats during the second half of pregnancy. Systolic and diastolic blood pressure values and heart rate were recorded in conscious female offspring (100 d old) using a femoral artery probe. No significant differences in heart rate, or in systolic and diastolic blood pressures were recorded between control offspring and offspring of nutritionally deprived rats. In order to ascertain whether cardiovascular variables in the offspring were influenced by lactation, subgroups of offspring from food-restricted dams were fostered with lactating dams fed on a normal diet. Blood pressure and heart rate were also found to be normal in these offspring. The rise in blood pressure associated with NO inhibition was similar in all groups. Isolated resistance artery function was assessed in vitro in offspring (100-120 d old) of a second group of semi-starved dams. Small mesenteric arteries from these animals showed reduced endothelium-dependent relaxation (to acetylcholine and bradykinin), but enhanced sensitivity to exogenous NO (sodium nitroprusside). We conclude that food restriction during the second half of pregnancy and/or lactation does not induce hypertension in adult offspring, but may effect subtle changes in vascular function.

Ischemia/reperfusion-induced arrhythmias in anaesthetized rats: a role of Na+ and Ca2+ influx.

We hypothesized that by limiting the Na+ and Ca2+ loading by a blocker/inhibitor of the Na+ channel (lidocaine), Na+ overload (R56865: N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]-N-methyl-2-benzothiazo lamine), Ca2+ channel (verapamil), Na+ -H+ exchange (ethylisobutyl amiloride) or of Na+ -Ca2+ exchange (No. 7943: 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate), it should be possible to reduce ischemia/reperfusion-induced arrhythmias. To test this hypothesis, we used anaesthetized rats subjected to 5 min of coronary artery occlusion followed by 10 min of reperfusion to study antiarrhythmic effects of above compounds on reperfusion-induced ventricular premature beats, ventricular tachycardia, and reversible and irreversible ventricular fibrillation. Compound or saline was administered as an intravenous bolus injection at 5 min before ischemia. Pretreatment with lidocaine (5 mg/kg), verapamil (0.63 mg/kg), R56865 (0.63 mg/kg) or ethylisobutyl amiloride (1.25 mg/kg) significantly reduced or abolished all types of ventricular arrhythmias. However, pretreatment with verapamil was associated with second or third degree heart block in 3 out of 12 animals. Pretreatment with No. 7943 did not significantly influence the ischemia/reperfusion-induced ventricular arrhythmias. The present results suggest that both intracellular Na+ -and Ca2+ -loading play important roles in reperfusion-induced ventricular arrhythmias and the inhibition of Na+ -Ca2+ exchange to limit Ca2+ loading probably does not play any important role in ischemia/reperfusion-induced arrhythmias in anaesthetized rats.

Streptozotocin diabetes in the pregnant rat induces cardiovascular dysfunction in adult offspring.

Severe diabetes in pregnant rats produces persistent metabolic consequences in adult offspring. This study investigated whether diabetes in pregnant rats could also lead to cardiovascular abnormalities in the adult offspring. Blood pressure, heart rate and in vitro vascular reactivity of small arteries were evaluated in female adult offspring of control rats and of rats rendered diabetic with streptozotocin. Rise in blood pressures were similar in both groups of offspring but heart rate was lower in the diabetic offspring (p < 0.05). The rise in blood pressure associated with infusion of a nitric oxide synthase inhibitor was similar in both groups, but the associated decrease in heart rate was more pronounced in diabetic offspring (p < 0.01). Small mesenteric arteries from this group showed enhanced sensitivity to noradrenaline (p < 0.05) and abnormal endothelium-dependent relaxation to acetylcholine (p < 0.01) and bradykinin (p < 0.05). Reduction in acetylcholine induced relaxation, reflected reduced synthesis of nitric oxide or a cyclooxygenase product and was not attributable to an endothelium-derived hyperpolarizing factor. Sensitivity to exogenous nitric oxide was normal. A subgroup of pups born to diabetic dams were suckled by control maternal dams and a subgroup of those born to controls by diabetic dams. Suckling was an important determinant of impaired growth; offspring of diabetic rats suckled by their own mother and those of control rats by diabetic dams showed impaired growth rates whereas growth of offspring of diabetic rats suckled by control dams paralleled those of control rats suckled by their own mother.

Synthetic inhibitors of human tissue kallikrein.

We have developed a series of novel, potent low molecular weight (4-600 Da) inhibitors of TK which were stable to cleavage by the enzyme and showed a high degree of selectivity for TK over several other serine proteases. Compound 7 (CH-2856) was found to reduce eosinophilia in a model of allergic inflammation. The effects observed in vivo provide further evidence for the involvement of TK and kinins in the pathophysiology of allergic diseases such as asthma.