Association of pyrin mutations and autoinflammation with complex phenotype hidradenitis suppurativa: a case-control study.

BACKGROUND: Hidradenitis suppurativa (HS) is a rare, debilitating neutrophilic dermatosis characterized by chronic inflammation of hair follicles. Many inflammatory conditions may accompany HS. OBJECTIVES: To investigate the association of variants of the MEFV gene with a complex HS phenotype. METHODS: Firstly, we identified the clinical characteristics of 119 patients with HS with a complex phenotype (Hurley stage III disease and/or additional inflammatory symptoms). Then, we searched for MEFV variants among these patients. The odds ratios (ORs) for pathogenic MEFV mutations were calculated using data from these patients with HS and 191 healthy controls. RESULTS: The male/female ratio was higher, and the mean age of onset was earlier, in our complex HS group compared with patients with HS in general. Five of the patients with HS (4·2%) had a diagnosis of familial Mediterranean fever (FMF) with a standardized morbidity ratio of 45 [95% confidence interval (CI) 16·50-99·84, P < 0·001] when compared with the frequency of FMF in the general Turkish population. Of the patients with complex HS, 38% were positive for pathogenic variants of MEFV. The OR for carrying a pathogenic MEFV allele was 2·80 (95% CI 1·31-5·97, P < 0·001). CONCLUSIONS: The frequency of MEFV mutations in the group of patients with complex HS was higher than that in healthy controls, suggesting that MEFV mutations may contribute to the pathogenesis of HS. Understanding the role of autoinflammation in HS is of fundamental importance for the development of novel therapies.

Cathepsin S increases tau oligomer formation through limited cleavage, but only IL-6, not cathespin S serum levels correlate with disease severity in the neurodegenerative tauopathy progressive supranuclear palsy.

Limited cleavage promotes the aggregation propensity of protein tau in neurodegenerative tauopathies. Cathepsin S (CatS) is overexpressed in brains of patients suffering from tauopathies such as Alzheimer's disease (AD). Furthermore, CatS serum levels correlate with survival in the elderly. The current study investigates whether limited cleavage by CatS promotes tau aggregation, and whether CatS serum levels may correlate with disease severity in tauopathies. Oligomer formation of fluorescently labeled protein tau was monitored by single particle fluorescence spectroscopy after coincubation with CatS. Tau cleavage patterns were investigated by SDS-PAGE. For serum analyses, samples were collected from 42 patients with probable progressive supranuclear palsy (PSP) according to NINDS-PSP criteria. Disease severity was assessed by PSP rating scale (PSP-RS), PSP staging system (PSP-S) and Schwab and England Activities of Daily Living (SEADL). CatS, cystatin C (CysC) and interleukin 6 (IL-6) serum levels were determined by ELISA, ECLIA and turbidimetry, respectively. SDS-PAGE demonstrated a distinct cleavage pattern of protein tau after coincubation with CatS. Furthermore, tau oligomer formation was increased 2.4-fold (p < 0.05) after limited cleavage. Serum CatS and CysC levels did not correlate with disease severity in PSP. Of note, IL-6 correlated with PSP-S (r = 0.41; 95% CI 0.11-0.65; p = 0.008), SEADL (r = -0.37; 95% CI -0.61 to -0.06; p = 0.017) and the history and gait/midline subdomains of the PSP-RS. While CatS facilitates tau aggregation in vitro, serum levels of CatS appear not to correlate with disease severity. The observed correlation of IL-6 with disease severity warrants further investigation of inflammatory markers in PSP.

Alteration of Multiple Leukocyte Gene Expression Networks is Linked with Magnetic Resonance Markers of Prognosis After Acute ST-Elevation Myocardial Infarction.

Prognostic relevant pathways of leukocyte involvement in human myocardial ischemic-reperfusion injury are largely unknown. We enrolled 136 patients with ST-elevation myocardial infarction (STEMI) after primary angioplasty within 12 h after onset of symptoms. Following reperfusion, whole blood was collected within a median time interval of 20 h (interquartile range: 15-25 h) for genome-wide gene expression analysis. Subsequent CMR scans were performed using a standard protocol to determine infarct size (IS), area at risk (AAR), myocardial salvage index (MSI) and the extent of late microvascular obstruction (lateMO). We found 398 genes associated with lateMO and two genes with IS. Neither AAR, nor MSI showed significant correlations with gene expression. Genes correlating with lateMO were strongly related to several canonical pathways, including positive regulation of T-cell activation (p = 3.44 × 10-5), and regulation of inflammatory response (p = 1.86 × 10-3). Network analysis of multiple gene expression alterations associated with larger lateMO identified the following functional consequences: facilitated utilisation and decreased concentration of free fatty acid, repressed cell differentiation, enhanced phagocyte movement, increased cell death, vascular disease and compensatory vasculogenesis. In conclusion, the extent of lateMO after acute, reperfused STEMI correlated with altered activation of multiple genes related to fatty acid utilisation, lymphocyte differentiation, phagocyte mobilisation, cell survival, and vascular dysfunction.

[Cardiologic findings in Hauptmann-Thannhauser muscular dystrophy (autosomal dominant Emery-Dreifuss muscular dystrophy)]. / Kardiologische Befunde bei Hauptmann-Thannhauser-Muskeldystrophie (autosomal dominante Emery-Dreifuss-Muskeldystrophie).

HISTORY: A 19-year-old man with congestive heart failure reported recent onset of exercise-induced dyspnea and pitting edema of the face. He also developed increasing muscular weakness. Three years before the diagnosis of autosomal-dominant Emery-Dreifuss muscular dystrophy (EDMD) had been made. FINDINGS: Cardiac and lung auscultation were unremarkable. The heart rate was 102 /min, and the blood pressure 100/70 mmHg. Aspartate aminotransferase (62 U/l) and lactate dehydrogensase (361 U/l) were elevated. The electrocardiogram during telemetric monitoring showed a 2 AV block, Mobitz type II. Echocardiography showed an ejection fraction of 20%. Coronary atherosclerosis was excluded by coronary angiography. A raised pulmonary wedge pressure at rest was recorded through an indwelling Swan-Ganz catheter, but cardiac output was normal. Histopathology revealed findings typical for dilated cardiomyopathy. THERAPY AND COURSE: The patient was already on diuretics when admitted; other medication included an ACE inhibitor, beta-blocker, aldosterone antagonist and digitalis. A cardioverter-defibrillator was implanted prophylactically. Congestive heart failure developed during the subsequent months. Two years later the patient underwent orthotopic heart transplantation. CONCLUSION: In patients with genetically determined neuromuscular diseases it is prognostically important early to recognize cardiomyopathy and cardiac arrhythmias. Subsequent cardiac transplantation may be life-saving.