Characterization of a Factor H Mutation That Perturbs the Alternative Pathway of Complement in a Family with Membranoproliferative GN

Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.     

Adverse consequences of immediate thrombolysis-related complications: a multi-centre registry-based cohort study of acute stroke

Journal of Thrombosis and Thrombolysis - Complications following thrombolysis for stroke are well documented, and mostly concentrated on haemorrhage. However, the consequences of patients who...     

Smoking and catecholamine and c-AMP concentrations in the coronary circulation of man and the effect of oxprenolol

Summary Changes in catecholamine, c-AMP and lactate concentrations in the coronary circulation of man, during smoking, were studied in 12 patients. The heart rate increased from 63±2 beats/min (control) to 74±3 (smoking) (P<0.01), falling to 70±2 (10 min after smoking) (0.05>P>0.01), whilst coronary sinus c-AMP concentrations rose from 11±0.7 nmol/l (smoking) to 11.9±0.8 nmol/l (after smoing) (0.05>P>0.01; one tailed t test). There was no significant change in blood pressure, catecholamine or lactate concentrations. The study was repeated in eight of the patients following intravenous oxprenolol. Coronary sinus catecholamine concentrations increased from 4.1±0.7 nmol/l (control) to 5.5±1.1 nmol/l (after smoking) (0.05>P>0.01; one tailed t test), but heart rate and c-AMP concentrations remained unchanged, confirming that smoking-induced tachycardia is a result of a -adrenergic mechanism, at least part of which is due to a release of cardiac catecholamines. Arterial lactate concentrations increased only following oxprenolol from 0.74±0.07 mmol/l (control) to 0.83±0.09 mmol/l (smoking).     

Treatment needs and diagnosis awareness in primary care patients with chronic kidney disease

Background

GPs in England are required to keep a register of patients with chronic kidney disease (CKD). National Institute for Health and Clinical Excellence (NICE) guidelines recommend regular follow-up, but patients are perceived to be low risk and not requiring active management.

Aim

To assess treatment needs of CKD stage 3 patients in primary care, as well as their awareness of CKD.

Design and setting

A cross-sectional analysis from a longitudinal prospective study in 32 general practices.

Method

A total of 1741 participants underwent clinical assessment including urine and blood tests. Participants were asked about awareness of their CKD. Results were reviewed and a letter recommending treatment in line with NICE guidelines was sent to their GP.

Results

The mean age of participants was 73 ± 9 years; 60% (n = 1052) were female and diabetes was present in 17%; 67% of participants required further intervention. Most required improved control of hypertension (n = 1576; 33.1% of cohort). Other recommendations included advice to investigate anaemia (n = 1142; 8.2%) or stop nephrotoxic drugs (n = 1120; 7.5%). Less than 6% of participants met NICE criteria for referral to nephrology services and 41% were unaware of their CKD diagnosis. Multivariable analysis identified subjects with formal educational qualifications, age <75 years, estimated glomerular filtration rate (eGFR) 30–44 ml/min/1.73 m², and significant albuminuria as more likely to be aware of their diagnosis.

Conclusion

The study data show that the majority of patients required at least one intervention to improve the management of their CKD. Most interventions could be delivered in primary care and only a minority required nephrology referral. Many patients were unaware of their CKD diagnosis, and efforts should be made to improve this to facilitate involvement in their care.     

Interdisciplinary management recommendations for toxicity associated with interferon‐alfa therapy

Adjuvant interferon‐α (IFN‐α) therapy in patients with melanoma has been established as standard therapy since more than 10 years.During IFN‐α therapy, flu‐like symptoms, gastrointestinal disorders, arthralgias and neuropsychiatric symptoms are the most common side effects. The management and prophylaxis of these side effects have been improved by a more detailed understanding of pathophysiologic mechanisms and increased clinical experience. New insights in the relevance of detection of autoantibodies and development of autoimmunity have influenced the clinical pathway substantially. This review covers the pathomechanisms, incidence and optimized therapy of IFN‐α‐associated side effects.     

Cognitive impairments of alcoholic cirrhotic patients: correlation with endogenous benzodiazepine receptor ligands and increased affinity of platelet receptors.

OBJECTIVES--To determine whether differences in cognitive function between alcoholic and non-alcoholic cirrhotic patients relate to differences in endogenous ligands for the benzodiazepine receptor and/or benzodiazepine binding. METHODS--Seventeen grade-I hepatic encephalopathic patients (nine alcoholic, eight non-alcoholic) were compared with 10 matched controls on plasma concentrations of endogenous ligands for the neuronal benzodiazepine receptor, benzodiazepine binding in platelets, and performance on tests of cognitive function. RESULTS--Both groups of patients were impaired on verbal recall and on reaction time tasks compared with controls; alcoholic patients were also impaired on Reitan's trails test and digit cancellation. Four of the 17 patients had detectable concentrations of endogenous benzodiazepine ligands and they were more impaired than other patients on trails and cancellation tests. The groups did not differ in the density of benzodiazepine platelet receptors, but receptor affinity was higher in alcoholic patients than in controls; furthermore, receptor affinity correlated with the time to complete the cancellation task and with reaction time. CONCLUSION--Alcoholic cirrhotic patients may have enhanced concentrations of ligands for neuronal and peripheral benzodiazepine receptors and these may contribute to cognitive impairments in these patients.