Cytokine release in healthy donors and patients with chronic granulomatous disease upon stimulation with Aspergillus fumigatus

The release of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-10 upon stimulation with non-viable conidia and hyphal fragments from Aspergillus fumigatus was investigated in an ex vivo whole-blood model. In healthy volunteers, high numbers of conidia (between 10(6) and 3 x 10(8)/ml) induced a moderate release of TNF-alpha and IL-6. Hyphal fragments (2.5 x 10(5)/ml) were more potent in stimulating the release of these pro-inflammatory cytokines. Although some IL-10 release was observed upon stimulation with either conidia or hyphal fragments, it was not significantly different from that in unstimulated controls. In comparison, in whole blood obtained from 4 patients with chronic granulomatous disease (CGD), a high release of pro-inflammatory cytokines together with a significantly higher IL-10 release than in the healthy controls was seen after stimulation with A. fumigatus. In conclusion, A. fumigatus can trigger the release of pro-inflammatory cytokines in a human whole-blood system, which is likely to be central to the activation of antifungal defence mechanisms. In contrast, A. fumigatus stimulates a higher release of anti-inflammatory cytokines in CGD patients, which may suggest that a dysregulation between pro- and anti-inflammatory cytokines contributes to the increased susceptibility to invasive aspergillosis in this patient group.     

Gastrointestinal stromal tumors: insights from a new familial GIST kindred with unusual genetic and pathologic features

Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder. We report the second family to date with a germline point mutation in exon 17 of the KIT gene that leads to substitution of aspartic acid at position 820 with tyrosine (D820Y). One or more GISTs was documented in three generations of this kindred, and there was associated hyperplasia of the interstitial cells of Cajal (ICC). One affected family member complained of dysphagia and another suffered small intestinal diverticulosis with perforation, which may represent additional consequences of ICC hyperplasia. Diffuse and nodular ICC hyperplasia associated with the latter family member's small intestinal diverticulosis is illustrated, providing supportive functional and morphologic evidence for the ICC being the cell of origin of GISTs. Skin hyperpigmentation was not observed. Analysis of a 17-cm malignant GIST in the index patient revealed that it was hemi/homozygous for the germline D820Y mutation, indicating loss of the remaining wild-type KIT allele with tumor progression. Two smaller lesions from this patient were heterozygous for the mutation. This phenomenon has been observed in up to 8% of sporadic malignant GISTs but has not been documented in familial disease.     

New Alström syndrome phenotypes based on the evaluation of 182 cases

BACKGROUND: Alstr?m syndrome is a recessively inherited genetic disorder characterized by congenital retinal dystrophy that leads to blindness, hearing impairment, childhood obesity, insulin resistance, and type 2 diabetes mellitus. We provide new details on cardiologic, hepatic, gastrointestinal, urologic, pulmonary, and neurobehavioral phenotypes in Alstr?m syndrome and describe the histopathologic findings in 5 individuals. METHODS: We obtained data on 182 patients from clinical examinations, medical record reviews, standardized questionnaires, and personal interviews with physicians and parents. RESULTS: Dilated cardiomyopathy occurred in 60% of patients. Age at onset was either during infancy, often before vision disturbances were noted, or in adolescence or adulthood. There is a risk of recurrence of infantile cardiomyopathy. Hyperinsulinemia (92%) developed in early childhood and progressed to type 2 diabetes mellitus in 82% of those older than 16 years. Hypertriglyceridemia (54%) precipitated pancreatitis in 8 patients. Urologic dysfunction and gastrointestinal disturbances occurred in 48% and 35% of patients, respectively. Fifty-three percent of patients had persistent pulmonary symptoms. Neurologic symptoms in 20% of patients included clonic tic and absence seizures. Developmental motor or language delays were observed in 46% of patients. Fibrotic infiltrations of multiple organs, that is, kidney, heart, liver, lung, urinary bladder, gonads, and pancreas, were observed. CONCLUSIONS: The wide-ranging and complex spectrum of phenotypes reported herein broadens those previously described for Alstr?m syndrome. These findings will aid physicians in making an early and accurate diagnosis and will help effect appropriate monitoring and treatment.     

Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of Vasopressin antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST)

BACKGROUND: Hospitalizations for worsening heart failure due to fluid overload (congestion) are common. Agents that treat congestion without causing electrolyte abnormalities or worsening renal function are needed. Tolvaptan is an oral vasopressin (V 2 ) antagonist that decreases body weight and increases urine volume without inducing renal dysfunction or hypokalemia. The Efficacy of Vasopressin antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial is evaluating mortality, morbidity, and patient-assessed global clinical status in patients treated with tolvaptan compared with standard care. METHODS AND RESULTS: Patients are eligible for inclusion if they have a reduced left ventricular ejection fraction and are hospitalized for worsening heart failure with evidence of systemic congestion. Patients are randomized 1:1 to tolvaptan 30 mg/day or matching placebo for a minimum of 60 days. Time to all-cause mortality and time to cardiovascular mortality or heart failure hospitalization are the coprimary end points. Patient-assessed global clinical status and quality of life are also evaluated. EVEREST will be continued until 1065 deaths occur. As of April 18, 2005, 2260 patients have been enrolled. CONCLUSION: Tolvaptan has been shown to reduce body weight in patients with worsening heart failure without inducing renal dysfunction or causing hypokalemia. The results of EVEREST will determine whether these effects translate into improved clinical outcomes.     

Non-Invasive Cardiac Evaluation in Heart Failure Patients Using Magnetic Resonance Imaging: A Feasibility Study

Background: To assess the feasibility of a fast, flow-insensitive magnetic resonance imaging (MRI) protocol in heart failure patients for the evaluation of cardiac function, cardiovascular anatomy, and myocardial viability. Methods and Results: Thirty-two consecutive patients with left ventricular (LV) systolic dysfunction and 13 control subjects were prospectively evaluated with MRI. The exam consisted of cine imaging with a steady-state free precession sequence, followed by time-resolved, three-dimensional angiography and delayed, contrast-enhanced imaging. Multiple LV parameters were evaluated, and the heart failure and control results were compared. In 12 patients, MRI-determined ejection fractions were compared to echocardiographic values. Additionally, a qualitative analysis of the cine images was performed. The cardiac MR evaluation yielded diagnostic-quality images in all subjects. Mean imaging time was 37 min. MRI demonstrated significant differences between the heart failure and control subjects in all parameters assessed (p < 0.05). MRI-determined ejection fractions correlated strongly with echocardiographic values (R = 0.75), although the limits of agreement were wide (−17.3%–18.3%). Conclusions: Using fast, flow-insensitive imaging techniques, MRI is feasible in heart failure for the derivation of more independent indices of cardiac status than any other non-invasive test. Although further investigation is warranted, MRI may prove uniquely helpful in heart failure diagnosis and management.     

Autoimmune hepatitis: new diagnostic and therapeutic approach

Autoimmune hepatitis is a self-perpetuating hepatocellular inflammation. The diagnosis is established by a number of diagnostic criteria, defined by the International Autoimmune Hepatitis Group, and the exclusion of other causes of chronic hepatitis. There are two fundamental goals in therapy: induction of remission and maintenance of remission. The standard initial treatment is prednisone monotherapy or combination therapy with prednisone and azathioprine, which induce a clinical, biochemical and histologic remission in 65-87% of patients within 3 years. Other typical treatment endpoints in autoimmune hepatitis are an incomplete response, treatment failure and intolerance of the administrated drugs. If the treatment results are unsatisfactory, liver transplantation and alternative drugs such as Cyclosporin A, tacrolimus, cyclophosphamide, mycophenolate mofetil, budesonide, ursodeoxycholic acid should be considered; however, efficacy in clinical trials has not been shown. Future investigations must focus on the clarification of pathogenic mechanisms, characterization of target autoantigens, identification of host susceptibility factors, and assessment of alternative treatment strategies.