Diagnosis,Pathogenesis, Treatment,and Prognosis of Hereditary Fibrinogen Aα-Chain Amyloidosis

Mutations in the fibrinogen Aα-chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom. Previous reports of fibrinogen Aα-chain amyloidosis have been in isolated kindreds, usually in the context of a novel amyloidogenic mutation. Here, we describe 71 patients with fibrinogen amyloidosis, who were prospectively studied at the UK National Amyloidosis Centre. Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases. Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare. Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid. We discovered four amyloidogenic mutations in fibrinogen (P552H, E540V, T538K, and T525fs). A family history of renal disease was frequently absent. Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr. Among 44 patients who reached ESRD, median survival was 9.3 yr. Twelve renal transplants survived for a median of 6.0 (0–12.2) yr. Seven grafts had failed after median follow up from transplantation of 5.8 yr, including three from recurrent amyloid after 5.8, 6.0, and 7.4 yr; three grafts failed immediately for surgical reasons and one failed from transplant glomerulopathy after 5.8 yr with no histological evidence of amyloid. At censor, the longest surviving graft was 12.2 yr. In summary, fibrinogen amyloidosis is predominantly a renal disease characterized by variable penetrance, distinctive histological appearance, proteinuria, and progressive renal impairment. Survival is markedly better than observed with systemic AL amyloidosis, and outcomes with renal replacement therapy are comparable to those for age-matched individuals with nondiabetic renal disease.Hereditary non-neuropathic systemic amyloidosis, first described by Ostertag in 1932,¹ is a rare autosomal dominant condition in which progressive amyloid deposition in the viscera, especially the kidneys, frequently leads to organ failure. Mutations in the genes encoding apoAI,^2–12 apoAII,¹³ fibrinogen Aα-chain,^14–17 and lysozyme¹⁸ have been identified as the cause of the disease in different kindreds. The clinical amyloidosis syndromes that accompany the various mutations in these different genes are diverse with respect to age of onset, mode of presentation, pattern of organ distribution, rate of progression, and prognosis.Hereditary fibrinogen amyloidosis (AFib) was first characterized in 1993 in a Peruvian kindred.¹⁴ Patients with AFib present with renal disease and typically progress to ESRD. The natural history and clinical outcome of the disease has been little characterized, previous reports having been only of isolated kindreds, usually in the context of discovery of a novel amyloidogenic fibrinogen mutation.^15–17,19Here we report the clinical presentation, histologic features, molecular basis (including four novel causative fibrinogen Aα-chain gene mutations), and outcome among 71 patients with AFib who were diagnosed and prospectively studied at the U.K. National Amyloidosis Center (NAC) between 1992 and 2007.     

Neonatal chlamydial infection induces mixed T-cell responses that drive allergic airway disease

RATIONALE: Chlamydial lung infection has been associated with asthma in children and adults. However, how chlamydial infection influences the development of immune responses that promote asthma remains unknown. OBJECTIVES: To determine the effect of chlamydial infection at various ages on the development of allergic airway disease (AAD). METHODS: Mouse models of chlamydial lung infection and ovalbumin-induced AAD were established in neonatal and adult BALB/c mice. Neonatal or adult mice were given a chlamydial infection and 6 weeks later were sensitized and subsequently challenged with ovalbumin. Features of AAD and inflammation were compared between uninfected or unsensitized controls. MEASUREMENTS AND MAIN RESULTS: Mild Chlamydia-induced lung disease was observed 10-15 days after infection, as evidenced by increased bacterial numbers and histopathology in the lung and a reduction in weight gain. After 6 weeks, infection and histopathology had resolved and the rate of weight gain had recovered. Neonatal but not adult infection resulted in significant decreases in interleukin-5 production from helper T cells and by the numbers of eosinophils recruited to the lung in response to ovalbumin exposure. Remarkably, the effects of early-life infection were associated with the generation of both type 1 and 2 ovalbumin-specific helper T-cell cytokine and antibody responses. Furthermore, although neonatal infection significantly attenuated eosinophilia, the generation of the mixed T-cell response exacerbated other hallmark features of asthma: mucus hypersecretion and airway hyperresponsiveness. Moreover, infection prolonged the expression of AAD and these effects were restricted to early-life infection. CONCLUSIONS: Early-life chlamydial infection induces a mixed type 1 and 2 T-cell response to antigen, which differentially affects the development of key features of AAD in the adult.     

Age shall not weary them: mental health in the middle-aged and the elderly

OBJECTIVE: The prevalence of mental disorders in the elderly is disputed. The debate in this area can be informed by data from large population surveys that contain sufficient elderly participants. The aim of the present paper was to provide the first direct comparison of the prevalence and demographic correlates of ICD-10 anxiety and affective disorders in the middle-aged and the elderly. METHOD: The 12 month prevalence and demographic correlates of affective and anxiety disorders were compared in a community sample of middle-aged and elderly Australian residents who took part in the Australian National Mental Health and Well-being Survey (NMHWS). RESULTS: One in seven middle-aged participants and one in 16 elderly participants experienced symptoms consistent with any anxiety or affective disorder in the preceding 12 months. Compared to the middle-aged participants, the elderly had lower rates for most affective and anxiety disorders, and for the combined presence of any disorder. Demographic correlates of mental disorder, especially marital status, were different for the two groups. CONCLUSIONS: Community-dwelling elderly in Australia have lower rates of mental disorder compared to the middle-aged. Differences in demographic correlates between groups support the notion that the determinants of mental disorder in the elderly differ substantially from those in middle age.     

Metabolomic investigation of CLN6 neuronal ceroid lipofuscinosis in affected South Hampshire sheep

The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are a group of fatal inherited neurodegenerative diseases in humans and animals distinguished by a common clinical pathology, characteristic storage body accumulation in cells, and gross brain atrophy. An (1)H NMR spectroscopy- and GC-MS-based metabolomic investigation of changes in the cerebellum, frontal and occipital lobes, and cerebrospinal fluid (CSF) of CLN6 NCL affected South Hampshire sheep charted changes from the preclinical state to advanced disease. Glutamine and succinate concentrations increased in all brain regions in affected sheep relative to controls, whereas concentrations of aspartate, acetate, glutamate, N-acetyl aspartate (NAA), and gamma-aminobutyric acid (GABA) decreased. Changes in the concentrations of inositols, NAA, and GABA were consistent with glial cell activation and neurodegeneration beginning in the frontal and occipital lobes, in agreement with previous histopathological data. Further metabolic deficits were defined in all regions at earlier time points, including the cerebellum, where very little neurological degeneration has been reported. Biochemical abnormalities in the CSF of affected sheep at 18-31 months include relative increases in lactate, acetate, tyrosine, and creatine/creatinine concentrations and decreases in myo- and scyllo-inositol and citrate concentrations. The changes detected in the CSF and brain tissue mirrored those previously apparent in NCL mouse models, suggesting that they are common to all NCLs. However, the changes in glutamate and glutamine concentrations in CSF occurred after clinical disease, indicating that any changes in glutamate/glutamine cycling occur as a consequence of the primary deficits associated with the NCLs.     

Chirurgische Koronarrevaskularisation am schlagenden Herzen

Since the introduction of off-pump coronary artery bypass grafting (OPCAB) for coronary multivessel disease there was growing interest to evaluate the impact of OPCAB surgery compared to conventional coronary artery bypass grafting (CCAB) with cardiopulmonary bypass and cardioplegic arrest. However, subsequent prospective randomized studies and meta-analyses comparing OPCAB and CCAB surgery were performed on low-risk patients or mixed-risk populations. They usually failed to demonstrate a significant benefit of OPCAB surgery on early mortality or perioperative major cardiac and cerebrovascular events. In recent years, efforts were made to analyze the meaning of beating-heart concepts for patients with specific cardiac and extracardiac risks like ischemic cardiomyopathy, older age, renal failure, acute coronary syndrome, left main stenosis and others. For these subsets of patients several mono- and multicenter studies are available today. Even if most of them were nonrandomized and thus failed to reach evidence level A according to the AHA/ACC (American Heart Association/American College of Cardiology) definition, they still allow analyzing interim results for each specific perioperative risk factor. Particularly multi-risk patients and patients with severely reduced left ventricular function seem to benefit in terms of perioperative mortality and major morbidity by avoiding cardiopulmonary bypass and cardioplegic arrest. Analyzing early results and long-term follow-up of 364 patients with severely reduced ejection fraction<20%, the authors found a long-term benefit for patients when using OPCAB strategies particularly due to reduced perioperative mortality. Moreover, for most subsets of patients with significant extracardiac risk factors the incidence or perioperative stroke was reduced. In patients with preoperative renal and pulmonary dysfunction a decrease of corresponding organ failure was found for OPCAB strategy. For most risk populations transfusion requirements were significantly lower in OPCAB compared to CCAB surgery. In none of the patients an unfavorable outcome of beating-heart surgery compared to CCAB was shown. For emergency patients with an acute coronary syndrome presenting stable and unstable hemodynamics the authors found a clinical benefit by using beating-heart strategies. Particularly in patients with cardiogenic shock, cardiopulmonary bypass was often required to guarantee adequate perioperative organ perfusion. However, these patients seemed to benefit from avoiding global cardiac ischemia and maintaining native coronary blood flow. Follow-up results were comparable for these patients. In conclusion, beating-heart coronary artery bypass grafting seems to be advantageous in various risk populations and should be considered for patients with more than average risks for cardiopulmonary bypass and cardioplegic arrest.