Studies on the mode of action of somatostatin on insulin secretion.

The effect of somatostatin on insulin release by incubated slices of rat pancreas was studied. Somatostatin inhibited insulin release induced by arginine/glucose (A/G), glucagon, glibenclamide, pentoxifyllin, 3',5'-adenosine monophosphate (cAMP), phentolamine, and KCl. When A/G was used as a stimulus, the quantial inhibitory effect of somatostatin was not neutralized by progressively increasing glucose concentrations. The alpha adrenergic blocking agent phentolamine, the phosphodiesterase inhibitors theophylline (10 mM) or pentoxifyllin (10 mM), and KCl partially reversed the inhibitory effect of somatostatin on A/G stimulation. The maximal reversal of somatostatin inhibition was obtained when the slices of pancreas were stimulated with A/G in the presence of the calcium ioniphore A23187 plus ATP. These results suggest that the inhibitory effect of somatostatin on insulin secretion could result from calcium translocation in pancreatic beta cells.     

Effects of Alprazolam,a Benzodiazepine,on the ACTH-, GH- and PRL-Releasing Activity of Hexarelin,a Synthetic Peptidyl GH Secretagogue (GHS), in Patients with Simple Obesity and in Patients with Cushing's Disease

GH secretagogues (GHS) possess potent GH-releasing activity but also stimulate PRL, ACTH and cortisol (F) secretion. To further clarify the endocrine activities of GHS, in 9 obese patients, 9 patients with Cushing's Disease and 14 controls we studied the ACTH, F, GH and PRL responses to hexarelin (HEX, 2.0 µg/kg i.v.), a peptidyl GHS, alone and preceeded by alprazolam (ALP, 0.02 mg/kg p.o.), a benzodiazepine. The HEX-induced ACTH response in controls was similar to that in obese patients (peak: 9.9 ± 1.9 and 24.7 ± 7.6 ng/L, respectively) and both were lower (p < 0.002) than that in Cushing's patients (peak: 210.7 ± 58.4 ng/L). The GH response to HEX in controls (peak: 58.1 ± 10.3 g/L) was higher (p < 0.001) than those in obese and Cushing's patients (18.2 ± 3.8 and 12.6 ± 5.4 /L, respectively) which, in turn, were similar. The PRL responses to HEX in controls, obese and Cushing's patients (peak: 11.9 ± 1.6, 18.0 ± 4.5 and 12.4 ± 1.4 /L, respectively) were similar. In controls the HEX-induced ACTH response was abolished by ALP (peak: 8.6 ± 2.4 vs 28.0 ± 6.7 ng/L, p < 0.03) which, on the other hand, only blunted that in obese (peak: 12.7 ± 2.1 vs 42.4 ± 8.4 ng/L, p < 0.02) and did not modify that in Cushing's patients (205.6 ± 55.4 vs 175.9 ± 47.6 ng/L). ALP blunted the GH response to HEX in controls (peak: 31.0 ± 7.1 /L, p < 0.03) while did not modify those in obese and in Cushing's patients (14.5 ± 5.3 and 13.3 ± 11.1 /L, respectively). ALP did not modify the HEX-induced PRL response in controls, obese and Cushing's patients (peak: 13.8 ± 0.9, 16.3 ± 2.4 and 19.2 ± 1.1 /L, respectively). In conclusion, alprazolam inhibits the ACTH response to hexarelin in normal and obese subjects while fails to modify the exaggerated ACTH response in Cushing's Disease suggesting that GHS activate the HPA axis via the hypothalamus in normal and obese subjects but not in patients with Cushing's disease. Alprazolam is also able to blunt the GH-releasing activity of hexarelin in normal subjects but not the low GH response to the hexapeptide in obese and Cushing's patients. The PRL-releasing activity of hexarelin in controls, obese and hypercortisolemic patients is similar and is not modified by alprazolam pretreatment.     

Protracted, but not acute, hepatitis A virus infection is strongly associated with HLA-DRB*1301, a marker for pediatric autoimmune hepatitis

HLA alleles are known to be associated with susceptibility to develop autoimmune hepatitis (AH), and hepatitis A virus (HAV) infection is postulated as a putative trigger for AH. We investigated whether HLA may influence the outcome of the HAV infection by studying 67 children with self-limited and 39 children with protracted forms of this infection. HLA typing of the uncomplicated forms showed no significant increase of any HLA class I or II alleles. In contrast, DRB1*1301 was present in 46.1% of the children with protracted forms (vs. 9.8% in healthy controls; relative risk [RR]: 7.6; chi(2) = 33.3; P = 2 x 10(-9)). In uncomplicated hepatitis, 45% developed anti-smooth muscle antibody (SMA)/actin antibodies, but only 1 child had detectable antibodies after 3 months of infection onset. In contrast, after 1 year, 69% of the patients suffering protracted forms had titers of anti-SMA/actin antibodies that ranged between 1:40 and 1:160. Within their follow-up, 2 patients developed a Hashimoto's thyroiditis, but the remaining patients showed no signs of developing autoimmune hepatitis. We conclude that the DRB1*1301 haplotype is strongly associated with the protracted forms of HAV infection and suggest that the infection allows a sustained release of liver self-antigens. However, other still-unknown susceptibility genes are required for the full development of pediatric AH.     

Hormonal profile and participation of nitric oxide in salt-sensitive and salt-resistant essential arterial hypertension

Recent studies have shown that cardiovascular events and end-organ damage occur more frequently in patients with salt-sensitive essential hypertension (SH) than in salt-resistant essential hypertension (RH). Nitric oxide (NO) plays an important role in regulating the pressure-natriuresis relationship. Therefore impaired NO synthesis may produce or aggravate salt-sensitive hypertension. This study was conducted to determine the hormonal levels and nitric oxide metabolites in hypertensive patients. 25 patients underwent salt sensitivity testing. 24 h ambulatory blood pressure was recorded after a 5-day period on low salt diet (20 mEq/d) and after a 5-day period on a high salt diet (200 mEq/d). Subjects showing > or = 10 mmHg increase in mean BP when changing from low to high dietary salt intake were classified as salt sensitive and as salt resistant when the BP changes were < 10 mmHg. Based on BP recordings 13 patients were characterised as white coat hypertension (WC), 13 patients as salt resistant (SR) and 12 as salt sensitive (SS). A significative relationship was seen between plasma glucose-insulin concentration and body mass index. The ventricular mass index was similar in SS and SR patients. The plasma uric acid, triglicerides and PAI-I were elevated in SS compared with SR, and control group (C). During low sodium intake, plasma renin and aldosterone were decreased in SS compared with SR, and C. No differences in plasma catecholamines or their changes with intake sodium modifications were seen among the patients. During high sodium intake urinary NO excretion increased in SR (38 +/- 9 vs 18 +/- 2 mg/g creat), and C (24 +/- 2 vs 16 +/- 3 mg/g creat) (p < 0.01) but not in SS patients (21 +/- 3 vs 26 +/- 4 mg/g creat). The NO excretion changes showed negative correlation with BP changes (r = 0.49, p < 0.01). During low sodium intake, SR and SS patients showed a normal nocturnal decrease of BP (dippers). During high sodium intake SS patients became non-dippers. Our results showed that patients with salt sensitive hypertension displayed a suppressed renin-aldosterone system, an attenuated nocturnal decline in blood pressure on high-salt diet and an impairment of endothelial function. The relationship between urinary nitrate excretion and arterial pressure suggest that the salt sensitivity of arterial pressure may be related bo blunted generation of endogenous nitric oxide.     

Omeprazole and Ranitidine in Long-Term Treatment of Duodenal Ulcer A Double-Blind Comparison of Length of Time in Remission

In most patients duodenal ulcer is a chronicrelapsing disease. If no active maintenance treatment oreradication therapy is given after healing, around70-100% of patients have a relapse during the first year. We conducted a double-blind multicenterstudy in 472 patients with duodenal ulcer. They weretreated with omeprazole 20 mg every morning for four oreight weeks and when healed were randomly allocated to maintenance treatment with either omeprazole20 mg every morning or ranitidine 150 mg at bedtime forup to six months. The patients were assessed byendoscopy at monthly intervals until healing occurred. Thereafter scheduled endoscopy was carried outafter 1, 3, and 6 months of maintenance treatment orimmediately in the event of a suspected relapse. Healingstatus (intention to treat approach) was 87% at four weeks and 93% at eight weeks. At sixmonths the estimated remission rate was 90% foromeprazole and 82% for ranitidine (P = 0.03, 95% CI1-15%). The incidence of adverse events was similarduring the two maintenance treatments. Treatment withomeprazole 20 mg every morning maintained significantlymore patients in remission than treatment withranitidine 150 mg at bedtime.     

The changing pattern of tuberculosis and HIV co-infection in immigrants and Spaniards in the last 20 years

OBJECTIVES: To evaluate the impact of immigration on tuberculosis (TB)-HIV co-infection in Spain in a prospective cohort of HIV patients. METHODS: Among 7761 HIV patients, we evaluated 1284 with at least one episode of TB between 1987 and 2006. Variables were compared between immigrants and Spaniards. RESULTS: Incidence of TB decreased from 20 to five cases per 100 patient-years in 2006 (P<0.01) and was always higher in immigrants than in Spaniards. The proportion of immigrants increased, reaching almost 50% of both new cases of HIV and TB-HIV co-infection in 2006. In 34.4% of patients, TB and HIV infection were diagnosed within the same year; simultaneous diagnosis was more frequent in immigrants (83.3%vs. 16.7%, P<0.001). Mortality was associated independently with age [hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.01-1.05], TB diagnosis before 1996 (HR 2.6, 95% CI 1.8-3.6), use of highly active antiretroviral treatment (HR 0.494, 95% CI 0.37-0.66) and CD4 cell count at TB diagnosis (HR 0.996, 95% CI 0.995-0.997). CONCLUSIONS: Immigrants have a major impact on the incidence of TB in HIV patients, slowing down the decreasing trend in Spain. Simultaneous diagnosis of the co-infection in immigrants reveals a need to intensify HIV case finding in immigrants in Spain.     

Bone loss in diabetic patients with chronic kidney disease.

OBJECTIVE: We investigated whether loss of bone is detectable during follow-up of diabetic patients with chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: In 40 initially non-dialysed diabetic patients with CKD (isotopic glomerular filtration rate < 60 ml/min/1.73 m(2) or albumin excretion rate > 30 mg/24 h), body composition (DEXA scan) and glomerular filtration rate (GFR determined from (51)Cr-EDTA clearance) were measured at a 2-year interval, and compared by paired t-tests. RESULTS: The 40 patients, mainly with Type 2 diabetes (n = 28), were men (n = 28), aged 65 +/- 11 years, with diabetes duration 18 +/- 11 years. GFR was initially 38.0 (range 8-89) ml/min/1.73 m(2). CKD progressed during follow-up: eight started haemodialysis and GFR declined in the 32 others (P < 0.05 vs. initial). T-scores for total body (initial -0.61 +/- 1.11, final -1.11 +/- 1.40; P < 0.001) and femoral neck (initial -1.88 +/- 0.15, final -2.07 +/- 0.15; P < 0.05) declined. Ten patients were osteopaenic at baseline (no osteoporosis), whereas most were osteopaenic (n = 21, P < 0.05) and five were osteoporotic at final assessment. The 16 patients who became osteopaenic or osteoporotic during follow-up did not differ from the others for the type of diabetes, age, GFR, albumin excretion rate, HbA(1c), GFR reduction and the requirement for dialysis during follow-up. They were all men (P < 0.01 by chi-squared test), with reduced initial total body T-score (-1.20 +/- 0.82, others -0.32 +/- 1.13; P < 0.05) and a lower body mass index (24.6 +/- 4.3; others 27.7 +/- 4.3; P < 0.05). CONCLUSION: Bone loss, especially in the femoral neck, is progressive in diabetic patients with CKD.     

New model of ventricular fibrillation

The purpose of this study was to develop a more efficient and stable model of ventricular fibrillation (VF) in the isolated rabbit heart, because there is not a satisfactory model with this animal. We also observed the effects of increasing extracellular calcium in the stability and reversibility of the arrhythmia. After suspending the hearts in a classical Langendorff preparation, VF was induced by burst stimulation (current = 2.0 mA, pulse duration = 3 milliseconds, frequency = 50 Hz, voltage = 10 V, duration of stimulation = 5 minutes). The hearts were then divided into 2 groups, A and B. The hearts in group B were perfused with a modified Krebs-Henseleit solution, which contained twice as much calcium as the solution used in the other group. The rate of success with this model was 100% for both groups. The hearts fibrillated up to 30 minutes in group A and more than 40 minutes in group B, longer then all studies ever published in rabbit hearts. Ventricular fibrillation reverted to sinus rhythm in 100% of the hearts of group A when treated with an antifibrillatory drug, whereas no reversion at all was observed in the hearts of group B. We conclude that high extracellular calcium makes the reversion to sinus rhythm more difficult in this model. Our high rate of success and the exceptionally stable and long-lasting VF turn our model very effective for the study of antiarrhythmic interventions in the isolated rabbit heart.     

Antimicrobial Agents Used in the Treatment of Peri‐Implantitis Alter the Physicochemistry and Cytocompatibility of Titanium Surfaces

Background: Chemotherapeutic agents (ChAs) are considered an integral part of current treatment protocols for the decontamination of titanium implants with peri‐implantitis, based on their antimicrobial effect. Despite the proven antimicrobial effect of ChAs on titanium‐bound biofilms, previous studies have elucidated an unexpected disassociation between bacterial reduction and biologically acceptable treatment outcomes. In this study, the authors hypothesize that ChAs residues alter titanium physicochemistry and thus compromise cellular response to decontaminated surfaces. Methods: Grit‐blasted acid‐etched titanium disks were contaminated with multispecies microcosm biofilms grown from in vivo peri‐implant plaque samples. To simulate implant decontamination, the contaminated disks were burnished with 0.12% chlorhexidine, 20% citric acid, 24% EDTA/1.5% NaOCl, or sterile saline and assessed surface physicochemical properties. Sterile untreated surfaces were the controls. The biologic effects of decontamination were assessed via cell proliferation and differentiation assays. Results: Bacterial counts after decontamination confirmed that the ChAs were antimicrobial. X‐ray photoelectron spectroscopy invariably detected elemental contaminants associated with each ChA molecule or salt that significantly altered wettability compared with controls. Notably, all surfaces with ChA residues showed some cytotoxic effect compared with controls (P <0.05). Increased cell counts were consistently found in the saline‐treated group compared with chlorhexidine (P = 0.03). Interestingly, no association was found between antimicrobial effect and cell counts (P >0.05). Conclusions: ChA‐specific residues left on the titanium surfaces altered titanium physical properties and adversely affected the osteoblastic response irrespective of their observed antimicrobial effect. Chlorhexidine may compromise the biocompatibility of titanium surfaces, and its use is not recommended to detoxify implants. Sterile saline, citric acid, and NaOCl‐EDTA may be proposed for use in the treatment of peri‐implantitis. Contrary to previous studies that recommended the selection of ChAs for the decontamination of titanium implants according to their antimicrobial effects, the present study demonstrated that the restoration of the biocompatibility of contaminated titanium surfaces is also contingent on the preservation of titanium material properties.     

Diagnostic accuracy of ultrasound in acute cholecystitis

This work attempts to assess the diagnostic accuracy of ultrasound for acute cholecystitis in 98 clinically suspected patients from the emergency unit in whom at least 3 of 6 relevant criteria are present. Gallbladder distention to 5 cm or more transversely or in the anterior-posterior axis (criterion 1) was present in 64 patients; thickening of the gallbladder wall of at least 5 mm (criterion 2) in 95; cholelithiasis (criterion 3) in 86; sonolucent halo in the gallbladder wall (criterion 4) in 40; sonolucent fluid band surrounding the gallbladder (criterion 5) in 27; and intraluminal echogenic mass with no posterior acoustic shadow (criterion 6) in 35. A diagnostic accuracy index, corrected for chance, was statistically and clinically more relevant with 3 as the minimum number of criteria for the ultrasonic diagnosis of acute cholecystitis.