Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes

The induction of autoimmunity by viruses has been attributed to numerous mechanisms. In mice, coxsackievirus B4 (CB4) induces insulin-dependent diabetes mellitus (IDDM) resembling the final step of disease progression in humans. The immune response following the viral insult clearly precipitates IDDM. However, the molecular pathway between viral infection and the subsequent activation of T cells specific for islet antigen has not been elucidated. These T cells could become activated through exposure to sequestered antigens released by damaged beta cells, or they could have responded to factors secreted by the inflammatory response itself. To distinguish between these possibilities, we treated mice harboring a diabetogenic T cell repertoire with either the islet-damaging agent streptozotocin (STZ) or poly I:C, which nonspecifically activates T cells. Significantly, only treatment of mice with STZ resulted in IDDM and mimicked the effects observed following CB4 infection. Furthermore, antigen-presenting cells from STZ-treated mice were shown to directly activate autoreactive T cells and induce diabetes. Therefore, the primary role of CB4 in the precipitation of IDDM is to damage tissue, causing release and presentation of sequestered islet antigen. These events stimulate autoreactive T cells and thereby initiate disease.     

Continuing C3 breakdown after bilateral nephrectomy in patients with membrano-proliferative glomerulonephritis

Serum levels of complement components and of C3 nephritic factor (C3NeF) were measured serially in two patients with membrano-proliferative glomerulonephritis who were subjected to bilateral nephrectomy and maintained by peritoneal dialysis for 2 wk before renal transplantation. In both patients, low levels of C3 and high levels of preformed alpha 2D, a C3 breakdown product, were present before nephrectomy and remained essentially unchanged during the anephric period. With transplantation, C3 levels rose towards normal and alpha 2D disappeared from the serum. The serum of both patients contained detectable amounts of C3NeF, a factor which has been shown to react with a cofactor found in normal serum to form an enzyme, designated C3 lytic nephritic factor (C3LyNeF), which will cleave C3 to form the breakdown products, beta1A and alpha 2D. The level of C3NeF was high in one patient before nephrectomy, increased somewhat during the anephric period, and fell after transplantation. In the other patient, the C3NeF level was initially lower, remained relatively constant during the anephric period, and was not significantly affected by transplantation. In both patients, levels of C4 and C5 were either normal or elevated over the period of the study and bore no relationship to the C3 level. The following conclusions can be drawn from the data. The high levels of alpha 2D during the anephric period and the disappearance of this protein as C3 levels approach normal at the time of transplantation indicate that the low C3 levels were largely the result of C3 breakdown rather than diminished synthesis. The presence of C3NeF in detectable amounts in both patients suggest that C3LyNeF, formed by the reaction of C3NeF and cofactor, was responsible for the low C3 levels. Finally, the lack of effect of nephrectomy on C3, alpha 2D, and C3NeF levels indicate that the site of C3 breakdown was extrarenal and that C3NeF and cofactor are at least in large part of extrarenal origin.     

Prevalence of clinical isolates of Escherichia coli and Klebsiella spp. producing multiple extended-spectrum beta-lactamases

Eleven thousand two hundred seventy-two Escherichia coli, 1109 Klebsiella pneumoniae, 1124 Salmonella enterica, and 602 Klebsiella oxytoca unrelated clinical isolates were obtained between 2001 and 2004 in a university hospital in Salamanca, Spain. One hundred thirteen E. coli (1%), 32 K. pneumoniae (2.9%), 4 K. oxytoca (0.66%), and 5 S. enterica (0.44%) isolates produced extended-spectrum beta-lactamases (ESBLs). We obtained 42.2% of the ESBL-producing isolates from outpatients and 57.8% from inpatients. The most commonly detected ESBLs were CTX-M 14 (43.5% of ESBL-producing isolates), TEM-116 (22.1%), and SHV-2 (15.6%). A CTX-M 27-producing E. coli is 1st reported in Spain in this study. Two (20 isolates, 13%) or 3 (7 isolates, 4.5%) ESBLs were produced by 17.5% of ESBL-producing isolates (27 isolates). The most frequent combinations were CTX-M 14 + TEM-116 (5.7%), SHV-12 + TEM-116 (2.6%), and SHV-2 + CTX-M 14 + TEM-116 (2.6%). Clonal diversity was high even between isolates producing the same combinations of 2 or 3 beta-lactamases.     

Association between KISS1 rs5780218 promoter polymorphism and onset of growth hormone secreting pituitary adenoma

Objectives

This study analyzed the KISS1 c.-145delA (rs5780218) promoter polymorphism in a cohort of patients with growth hormone secreting pituitary adenoma (somatotropinoma) and controls, to investigate its role in the incidence of acromegaly and to assess patient/tumor characteristics.Material and methods rs5780218 allelic and genotypic distributions were compared between 49 somatotropinoma patients and 167 healthy controls. rs5780218 was also assessed in relation to patient characteristics and tumor aggressiveness, as characterized by tumor invasion and resistance to conventional therapy. The relationship between KISS1 mRNA expression and the rs5780218 genotype was also assessed in available pituitary tumor samples.

Quantitative analysis of the admission electrocardiogram identifies patients with unstable coronary artery disease who benefit the most from early invasive treatment

OBJECTIVES: The aim of the present study was to evaluate whether the effect of an early invasive treatment strategy differed between patients sub-grouped according to their severity of myocardial ischemia, as evaluated by quantitative electrocardiographic (ECG) analysis at the time of presentation. The present study is a sub-study of the previously published Fast Revascularization during InStability in Coronary artery disease trial (FRISC-II). BACKGROUND: An early invasive treatment strategy has been shown to be the preferable treatment for non-ST-segment elevation acute coronary syndromes (ACS). The population of patients with unstable coronary artery disease is heterogeneous regarding both the underlying pathology and prognosis. Early risk stratification is important to select patient subgroups that will benefit the most from a given treatment. METHODS: In 2,201 patients with non-ST-segment elevation ACS, the ischemic burden at hospital admission was determined by quantitative measurements of ST-T-segment deviations on the ECG. The patients were subsequently sub-grouped in tertiles based on the amount of ST-segment deviation. The primary end point for this analysis was death or myocardial infarction (MI) within one year after study inclusion. RESULTS: The invasive treatment strategy produced a reduction of approximately 50% in death or MI among the patients with intermediate or major ST-segment deviation. The findings were independent of age, gender, or troponin T status. The patients with confounding factors precluding ST analysis had a poor outcome regardless of the treatment strategy. CONCLUSIONS: Ischemic burden on the admission ECG identifies patients with ACS who benefit the most from an invasive treatment strategy. When the standard ECG is scrutinized with complete quantitative measurements, it provides independent information on prognosis and benefit of treatment.     

Hereditary vacuolar internal anal sphincter myopathy causing proctalgia fugax and constipation: a new case contribution

Hereditary anal sphincter myopathy is rare. We present a family with one affected member with proctalgia fugax, constipation and internal anal sphincter hypertrophy. Ultrastructural findings show vacuolization of smooth muscle cells without the characteristic polyglucosan inclusion. Further relief of symptoms was obtained using an oral calcium antagonist. Based on clinical presentation, endosonography and morphological findings, we consider our case is a histological variant of the vacuolar myopathy originally described.     

Lack of effect of metoclopramide and domperidone on esophageal peristalsis and esophageal acid clearance in reflux esophagitis

The acute effects of oral metoclopramide (40 mg/day) and domperidone (80 mg/day) on esophageal motor activity and acid reflux were assessed in a randomized, double-blind, placebo-controlled study in 20 patients with erosive reflux esophagitis. Esophageal motor function was assessed by standard manometry with wet swallows, and reflux events were evaluated by ambulatory 24-hr pH-monitoring. Both drugs caused a significant (P less than 0.05) increase in lower esophageal sphincter pressure lasting at least 120 min. However, neither esophageal body motility, duration of esophageal exposure to acid, nor esophageal clearance were effected by drug administration in comparison to placebo. Side effects were reported in two patients who received metoclopramide, while no adverse effects occurred after domperidone intake. In conclusion, the so-called motility agents metoclopramide and domperidone have few acute effects on esophageal motility in patients with erosive reflux esophagitis.     

Danish multicenter randomized study on fibrinolytic therapy versus acute coronary angioplasty in acute myocardial infarction: rationale and design of the DANish trial in Acute Myocardial Infarction-2 (DANAMI-2)

Background

Randomized trials have indicated that primary coronary angioplasty performed in patients admitted directly to highly-experienced angioplasty centers offers certain advantages over intravenous fibrinolytic therapy. However, the large majority of patients with acute myocardial infarction are submitted to hospitals without a catheterization laboratory. This means that additional transportation will be necessary for many patients if a strategy of acute coronary angioplasty is to be introduced as routine treatment. The delay of treatment caused by transportation might negate (part of) the benefits of primary angioplasty compared to fibrinolytic therapy given immediately at the local hospital.

Study design

The DANish trial in Acute Myocardial Infarction-2 (DANAMI-2) is the first large-scale study to clarify, in a whole community, which of the 2 treatment strategies is best. A total of 1900 patients with ST-elevation myocardial infarction are to be randomized: 800 patients will be admitted to invasive hospitals and 1100 patients will be admitted to referral hospitals. Half of the 1100 patients admitted to referral hospitals will immediately be transferred to an invasive center to be treated with primary angioplasty.

Implications

If acute transfer from a local hospital to an angioplasty center is the superior strategy, primary angioplasty should be offered to all patients as routine treatment on a community basis.     

IgE reactivity to profilin in Platanus acerifolia pollen-sensitized subjects with plant-derived food allergy.

BACKGROUND: The presence of profilin-specific IgE antibodies is a cause of cross-reactivity between botanically-unrelated allergen sources. Recently, the association between Platanus acerifolia pollinosis and plant-derived food allergy has been described. The aim of this study was to ascertain whether the P. acerifolia profilin is involved in such cross-reactivity. METHODS: Twenty-three patients suffering from Platanus acerifolia pollinosis and plant-derived food allergy were evaluated in an allergy department. Specific IgE levels to P. acerifolia pollen, P. acerifolia profilin and food extracts were measured. Molecular masses of IgE-binding proteins were calculated by Western blotting and cross-reactivity studies among P. acerifolia profilin and different food extracts were evaluated by Enzyme AllergoSorbent Test (EAST)-inhibition assays. Also, EAST-inhibition assays with the two known P. acerifolia allergens, Pla a 1 and Pla a 2, were performed. RESULTS: Surprisingly, a high IgE-binding prevalence (90%) of P. acerifolia profilin was found. EAST-inhibition showed high inhibition values when Platanus acerifolia pollen extract was used as free phase and plant-derived food extracts as solid phase, whereas the other way round showed low inhibition values. IgE reactivity to profilin was studied using a pool of patient sera, by EAST-inhibition assays with hazelnut, apple peel, peanut, chickpea and peanut extracts as solid phase and no inhibition was obtained when P. acerifolia profilin was used as inhibitor phase. The same results were obtained when purified Pla a 1 and Pla a 2 were also used as inhibitor phase. CONCLUSIONS: The clinical association observed between Platanus acerifolia pollen and plant-derived food could be explained by the in vitro IgE cross-reactivity detected by EAST-inhibition. However, it appears that neither P. acerifolia profilin nor the two major allergens described (Pla a 1 and Pla a 2) can explain such a strong cross-reactivity.     

Functional capacity impairment in patients with coronary artery disease: prevalence, risk factors and prognosis

BACKGROUND: Some patients developing heart failure and functional capacity impairment have no history of myocardial infarction (MI), and stable angina pectoris is their principal clinical manifestation of coronary artery disease (CAD). The present study was aimed to evaluate the outcome of CAD-related functional capacity impairment in patients with and without a history of MI over a 7.7-year follow-up. METHODS: The study sample comprised 14,283 coronary patients aged 45-74 years, screened for participation in the Bezafibrate Infarction Prevention study. The presence of NYHA functional class II was defined as mild functional capacity impairment and the presence of NYHA functional class III-IV was defined as advanced functional capacity impairment. RESULTS: The patients were divided in two groups: (1) those with a history of MI, 10,307 patients, who formed three subgroups: NYHA I 7,551 patients (73.3%); NYHA II 2,176 patients (21.1%); NYHA III + IV 580 patients (5.6%), and (2) those without a history of MI, 3,976 patients, who also formed three subgroups: NYHA I 2,744 patients (69.0%); NYHA 981 patients (24.7%); NYHA III + IV 251 patients (6.3%). Multivariate analysis identified a history of MI as a consistent predictor of increased all-cause and cardiac mortality for patients with NYHA I, II and III + IV subgroups with escalating significance for patients with advanced functional capacity impairment: hazard ratios of 1.55 (95% CI 1.36-1.75), 1.56 (95% CI 1.30-1.86) and 1.72 (95% CI 1.24-2.40) for all-cause and 1.93 (95% CI 1.60-2.33), 1.73 (95% 1.35-2.20) and 3.22 (95% CI 1.87-5.54) for cardiac mortality, respectively. CONCLUSIONS: The prevalence of low functional capacity is similar among coronary patients with and without a history of MI, but their long-term survival differs substantially in favor of the latter. Therefore, two different types of CAD-related advanced functional capacity impairments (post-MI and non-post-MI) can be distinguished.