The corticotrophin-releasing hormone test is the most reliable noninvasive method to differentiate pituitary from ectopic ACTH secretion in Cushing's syndrome

OBJECTIVE: It has been reported previously that the paired interpretation of the corticotrophin-releasing hormone (CRH) test and the 8-mg dexamethasone suppression test (HDDST) could have higher diagnostic power than any single test in the differential diagnosis of ACTH-dependent Cushing's syndrome. This finding has not been confirmed thereafter in large series. The aim of the present study has been to assess the operating characteristics of either the CRH test or the overnight HDDST and also to evaluate the potential utility of combining the interpretation of both tests in the differential diagnosis of ACTH-dependent Cushing's syndrome. DESIGN AND PATIENTS: We have reviewed the medical records of 59 consecutive cases with ACTH-dependent Cushing's syndrome: 49 patients with proven Cushing's disease (CD) and 10 patients with proven ectopic ACTH syndrome (EAS). Univariate curves of the receiver operating characteristics (ROC) have been performed to define the best cut-off values, the sensitivity and the specificity for CRH and overnight HDDST. A comparison between the areas under the ROC curves has also been performed. RESULTS: For the CRH test, the point on the ROC curve closest to 1 corresponded to a value of ACTH percentage increment of 50%[sensitivity 86% (72.6-94.8) and specificity 90% (55.5-98.3)]. The best threshold for cortisol percentage (30%) increment gave inferior results [sensitivity 61% (45.5-75.6) and specificity 70% (34.8-93.0)]. For the HDDST, the point on the ROC curve closest to 1 corresponded to a value of cortisol decrease from the baseline of 50%[sensitivity 77% (62.7-88.5), specificity 60% (26.4-87.6)]. The area under the ROC curve of the ACTH percentage increment after CRH was significantly greater than the area under the diagonal [0.9 (0.7-1.0), P= 0.0001]. Conversely, the area under the cortisol percentage decrement after dexamethasone was not different from that obtained by chance [0.7 (0.5-0.9), P= ns]. The area under the ROC curve of CRH is significantly greater than that of overnight HDDST (P = 0.03). A correct diagnosis has been achieved by the CRH test in 86.5% of cases and by the HDDST in 73% (P = 0.06). The combination of both tests has given a correct diagnosis in a significantly lower percentage of cases than the CRH test alone (69%, P= 0.04). The bilateral inferior petrosal sinus sampling (BIPSS) has been performed in 29 patients (24 CD, five EAS) who had negative imaging and/or discordant results of the noninvasive tests. Considering the criterion of a central to peripheral ACTH ratio > 3 after CRH stimulation, a correct diagnosis was achieved in all cases. CONCLUSIONS: The present data suggest that the CRH is likely to be the most reliable noninvasive diagnostic procedure for the differential diagnosis of the ACTH-dependent Cushing's syndrome. The criterion for a diagnosis of EAS is an ACTH percentage increment lower than 50%. The use of a combination of tests is not recommended because it does not add valuable information and may even impair the outcome of the CRH test. Cases with discordant results in pituitary imaging and CRH test should undergo BIPSS. The validity of this approach, which is straightforward and easily applicable in clinical practice, should be verified in larger series.     

Pan-enteric dysmotility, impaired quality of life and alexithymia in a large group of patients meeting ROME Ⅱ criteria for irritable bowel syndrome

AIM: Psychological factors, altered motility and sensationd isorders of the intestine can be variably associated with irritable bowel syndrome (IBS). Such aspects have not been investigated simultaneously. The aim of this paper was to evaluate gastrointestinal motility and symptoms, psychological spectrum and quality of life in a large group of IBS patients in southern Italy. METHODS: One hundred IBS patients (F:M=73:27, age48±2 years, mean±SE) fulfilling ROME Ⅱ criteria matched with 100 healthy subjects (F:M=70:30, 45±2 years). Dyspepsia,bowel habit, alexithymia, psycho-affective profile and quality of life were assessed using specific questionnaires. Basally and postprandially, changes in gallbladder volumes and antral areas after liquid meal and orocaecal transit time (OCTT) were measured respectively by ultrasonography and H2-breath test. Appetite, satiety, fullness, nausea, and epigastric pain/discomfort were monitored using visual-analogue scales. RESULTS: Compared with controls, IBS patients had increased dyspepsia (score 12.6±0.7 vs 5.1±0.2, P<0.0001),weekly bowel movements (12.3±0.4 vs 5.5±0.2, P<0.00001, comparable stool shape), alexithymia (score 59.1±1.1 vs40.5±1.0, P=0.001), poor quality of life and psychoaffective profile. IBS patients had normal gallbladder emptying, but delayed gastric emptying (T50:35.5±1.0 vs 26.1±0.6 min, P=0.00001) and OCTT (163.0±5.4 vs 96.6±1.8min, P=0.00001). Fullness, nausea, and epigastric pain/discomfort were greater in IBS than in controls. CONCLUSION: ROME Ⅱ IBS patients have a pan-enteric dysmotility with frequent dyspepsia, associated with psychological morbidity and greatly impaired quality of life. The presence of alexithymia, a stable trait, is a novel finding of potential interest to detect subgroups of IBS patients with different patterns recoveed after therapy.     

Drug resistant falciparum malaria and the use of artesunate-based combinations: focus on clinical trials sponsored by TDR

Antimalarial drug resistance has now become a serious global challenge and is the principal reason for the decline in antimalarial drug efficacy. Malaria endemic countries need inexpensive and efficacious drugs. Preserving the life spans of antimalarial drugs is a key part of the strategy for rolling back malaria. Artemisinin-based combinations offer a new and potentially highly effective way to counter drug resistance. Clinical trials conducted in African children have attested to the good tolerability of oral artesunate when combined with standard antimalarial drugs. The cure rates of the different combinations were generally dependent on the degree of resistance to the companion drug. They were high for amodiaquine-artesunate, variable for sulfadoxine/pyrimethamine-artesunate, and poor for chloroquine-artesunate.     

Hydrophilic but not hydrophobic bile acids prevent gallbladder muscle dysfunction in acute cholecystitis

The pathogenesis of acute cholecystitis (AC) is controversial. Bile acids may be involved in the pathogenesis of AC because the hydrophobic chenodeoxycholic acid (CDCA) reproduced in vitro the muscle dysfunction observed in AC and was prevented by the hydrophilic ursodeoxycholic acid (UDCA). The present study examined the in vivo effects of UDCA or CDCA on gallbladder muscle dysfunction caused by AC. Guinea pigs were treated with placebo, UDCA, or CDCA for 2 weeks before sham operation or induction of AC by bile duct ligation (BDL) for 3 days. Pretreatment with oral UDCA prevented the defective contraction in response to agonists (acetylcholine [ACh], cholecystokinin 8 [CCK-8], and KCl) that occurs after BDL. Prostaglandin (PG) E(2)-induced contraction remained normal in the placebo and UDCA-treated groups but was impaired in the CDCA-treated group. Treatment with UDCA also prevented the expected increase in the levels of H(2)O(2), lipid peroxidation, and PGE(2) content in the placebo-treated AC group, whereas CDCA caused further increases in these oxidative stress markers. The binding capacity of PGE(2) to its receptors and the activity of catalase were reduced after treatment with CDCA. Treatment with UDCA enriched gallbladder bile acids with its conjugates and reduced the percentage of CDCA conjugates. In contrast, treatment with CDCA significantly decreased the percentage of UDCA in bile. In conclusion, oral treatment with UDCA prevents gallbladder muscle damage caused by BDL, whereas oral treatment with CDCA worsens the defective muscle contractility and the oxidative stress.     

Spiral computed tomography angiography (SCTA) and color coded duplex ultrasound (CCDUS): two complementary diagnostic techniques for assessment of extracranial cerebral artery stenosis

Atherosclerotic lesions of the extracranial cerebral arteries account for ischemic stroke in over half of all cases. The risk of stroke associated with symptomatic carotid artery disease is related to the severity of the stenosis. Results of the two major clinical trials, North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST), showed that patients with symptomatic carotid artery disease may benefit from carotid endarterectomy. Therefore, detection and quantification of stenosis are essential. Discrepancies in the angiographic criteria used in both NASCET and ECST trials resulted in continued controversy about the most accurate method of measuring carotid artery stenosis. Moreover, to avoid complications related to the angiography procedure, a good evaluation of vessel wall and plaque composition need to be considered. Both SCTA and CCDUS are non invasive techniques that could overcome angiographic complications and give detailed information on stenosis grading and plaque characteristics. They have been used to evaluate carotid stenosis as a single or combined methods.     

Effect of Blood Ammonia Elevation Following Oral Glutamine Load on the Psychometric Performance of Cirrhotic Patients

Oral glutamine challenge is a method to increase blood ammonia and may be used to study the ammonia lowering effect of drugs potentially useful in hepatic encephalopathy (HE). We tested its influence on the psychometric performance of 18 cirrhotic patients without HE. Twelve nonencephalopatic cirrhotic patients were studied before and after glutamine load (20 g in 100 mL tap water) and six patients before and after placebo (100 mL tap water) by using the Number Connection Test (NCT), the Covert Visual Attention Orienting Test (CVAOT), and the Scan Test (SCT). Blood ammonia increased significantly after glutamine (from 79 ± 34 to 211 ± 66 g/dL) but not after placebo (from 94 ± 41 to 88 ± 26). No difference in the NCT was found before and after glutamine load or placebo. The CVAOT was similar after glutamine challenge and placebo, nor any interaction between Loads (glutamine or placebo) × Cue position was found, suggesting that glutamine load did not influence attention-orienting. SCT results were also similar after glutamine and placebo, suggesting a lack of influence on the working memory. Glutamine challenge is a safe method to induce hyperammonemia in nonencephalopatic cirrhotic patients and, therefore, to study the efficacy of ammonia lowering treatments.     

Co-administration of nitric oxide-aspirin (NCX-4016) and aspirin prevents platelet and monocyte activation and protects against gastric damage induced by aspirin in humans

OBJECTIVES: The goal of this study was to test the hypothesis that NCX-4016 may have broader anti-inflammatory and antithrombotic effects as well as better gastric tolerability than aspirin in humans. BACKGROUND: NCX-4016 is an aspirin derivative containing a nitric oxide-releasing moiety that prevents platelet activation and modulates tissue factor (TF) expression and cytokine release from lipopolysaccharide (LPS)-stimulated monocytes. METHODS: This was a blind-observer, placebo-controlled, parallel-group study in which 48 healthy subjects were randomized to receive NCX-4016 800 mg twice a day, NCX-4016 800 mg twice a day plus aspirin 325 mg, aspirin 325 mg, or placebo for 21 days. RESULTS: Similar to aspirin alone, NCX-4016 effectively inhibited platelet aggregation induced by 0.6 mmol/ arachidonic acid, clot-stimulated thromboxane (TX) B2 generation in whole blood, and urinary excretion of 11-dehydro-TXB2. Unlike aspirin alone, the administration of NCX-4016 significantly inhibited TF expression in monocytes stimulated ex vivo with 10 micromol/l LPS (determined by flow-cytometry analysis of TF on CD14 positive cells). NCX-4016 also inhibited the rapid TF expression induced in monocytes by a proteinase activated receptor agonist (thrombin receptor activator protein, 2 micromol/l) as well as LPS-induced expression of CD11b . Ex vivo, release of MCP-1 and interleukin-6 were significantly inhibited by NCX-4016, but not by aspirin. NCX-4016 was not associated with gastric damage, and significantly reduced gastric injury when co-administered with aspirin, although both drugs reduced gastric PGE2 production to the same extent. CONCLUSIONS: NCX-4016 is equally effective as aspirin in inhibiting cyclooxygenase activity. However, NCX-4016 causes less gastric damage and prevents monocyte activation. Larger multicenter trials are warranted to establish clinical efficacy and safety of NCX-4016.