Immune complexes containing factor V in a patient with an acquired neutralizing antibody

An 82-year-old woman presented with extensive hematomas and melena associated with markedly decreased plasma factor V coagulant activity (FV:C). Using a competitive enzyme-linked immunosorbent assay developed in our laboratory, we made serial measurements of factor V antigen (FV:Ag) in plasma and found it to be normal or elevated. The patient's plasma was demonstrated to contain an IgG antibody that could neutralize FV:C in normal plasma. The antibody was of restricted heterogeneity (IgG1, IgG2,kappa). Circulating immune complexes containing antibody to factor V and FV:Ag were demonstrated directly in the plasma by immunoelectrophoresis with polyclonal monospecific antibody and with a monoclonal antibody using an enzyme-linked immunosorbent assay. Presence of neutralizing antibody could be demonstrated in vitro even at times when FV:C was within normal limits by heat inactivation of FV:C. Treatment with plasma and platelet transfusions as well as plasmapheresis induced definite but transient elevation of FV:C. Steroid therapy lowered the neutralizing antibody concentration and produced a rapid and persistent elevation of FV:C during two separate hospitalizations. This report describes a patient in whom levels of FV:Ag have been serially measured, and the presence of circulating immune complexes consisting of factor V and a neutralizing antibody have been directly demonstrated.     

Crotalocytin: characterization of the timber rattlesnake platelet activating protein

Crotalocytin, a platelet activating protein from timber rattlesnake venom, was studied to characterize its nature and to investigate its action on platelets. It exhibited proteolytic activity on the substrate azocoll and amidolytic activity on several peptide p-nitroanilides. The platelet activating and amidolytic activity of Crotalocytin was inhibited by diisopropylfluorophosphate. In addition, phenylmethylsulfonyl fluoride inhibited Crotalocytin's ability to stimulate platelets. Active site titration with p-nitrophenyl guanidobenzoate indicated that 52% of Crotalocytin's molecules were active and that the enzyme could also hydrolyze the titrant. These studies showed that Crotalocytin is a serine protease. Like thrombin and collagen, Crotalocytin induced simultaneous platelet aggregation and adenosine triphosphate (ATP) secretion. EDTA and prostaglandin E (PGE1) blocked Crotalocytin's ability to activate platelets; hirudin and antithrombin III did not. Crotalocytin stimulated the secretion of serotonin from dense granules and low affinity platelet factor 4 and fibrinogen from alpha-granules. Crotalocytin did not cause platelet lactic dehydrogenase loss or agglutinate formalin-fixed platelets, but it did aggregate chymotrypsin-treated platelets. Studies with antimycin A and 2 deoxy- D-glucose showed that Crotalocytin-induced platelet secretion was dependent on metabolic energy. Furthermore, Crotalocytin's induction of platelet secretion was prevented by eliminating exogenous ADP and blocking activation of the arachidonate pathway. Timber rattlesnake venom contains a serine protease that is unique, potent platelet activator.     

Higher prevalence of left ventricular hypertrophy in two Māori cohorts: findings from the Hauora Manawa/Community Heart Study

Objectives: Cardiovascular disease (CVD) is the leading cause of mortality in New Zealand with a disproportionate burden of disease in the Māori population. The Hauora Manawa Project investigated the prevalence of cardiovascular risk factors and CVD in randomly selected Māori and non‐Māori participants. This paper reports the prevalence of structural changes in the heart. Methods: A total of 252 rural Māori, 243 urban Māori; and 256 urban non‐Māori underwent echocardiography to assess cardiac structure and function. Multivariable logistic regression was used to determine variables associated with heart size. Results: Left ventricular (LV) mass measurements were largest in the rural Māori cohort (183.5,sd 61.4), intermediate in the urban Māori cohort (169.7,sd 57.1) and smallest in the non‐Māori cohort (152.6,sd 46.7; p<0.001). Similar patterns were observed for other measurements and indexation had no impact. One‐third (32.3%) met the gender‐based ASE criteria for LV hypertrophy (LVH) with higher prevalence in both Maori cohorts (highest in the rural cohort). There were three significant predictors of LVH: rural Māori (p=0.0001); age (p<0.0001); and gender (p=0.0048). Conclusion: Structural and functional heart abnormalities are more prevalent in Māori compared to non‐Māori, and especially rural Māori. Early identification should lead to better management, ultimately improving life expectancy and quality of life.     

Conservatively treated massive prolapsed discs: a 7-year follow-up

INTRODUCTION

The natural history of a lumbar hernia of the nucleus pulposus (HNP) is not fully known and clear indications for operative intervention cannot be established from the literature. Several studies have shown that the largest discs appear to have the greatest tendency to resolve. The aim of this study was to investigate whether massive prolapsed discs can be safely managed conservatively once clinical improvement has occurred.

PATIENTS AND METHODS

Thirty-seven patients were studied by clinical assessments and serial magnetic resonance imaging (MRI) over 2 years. Patients had severe sciatica at first, but began to show clinical improvement despite the large disc hernia-tions. Clinical assessment included the Lasegue test and neurological appraisal. The Oswestry Disability Index was used to measure function and changes in function. Serial MRI studies allowed measurement of volume changes of the herniated disc material over a period of time.

RESULTS

Initial follow-up at an average of 23.2 months revealed that 83% had a complete and sustained recovery at the initial follow-up. Only four patients required a discectomy. The average Oswestry disability index improved from 58% to 15%. Volumetric analysis of serial MRI scans found an average reduction of 64% in disc size. There was a poor correlation between clinical improvement and the extent of disc resolution.

CONCLUSIONS

A massive disc herniation can pursue a favourable clinical course. If early progress is shown, the long-term prognosis is very good and even massive disc herniations can be treated conservatively.     

Management of constrictive pericarditic in the 21st century

Definitive treatment for constrictive pericarditis is surgical pericardiectomy. Because constriction may be transient in a small proportion of patients, particularly those with exudative effusions, the initial treatment for constrictive pericarditis should be conservative, with loop diuretic therapy to manage volume expansion and edema and the use of colchicine, nonsteroidal anti-inflammatory agents, or, if necessary, glucocorticoid therapy for active inflammation. For subjects with persisting evidence of constriction, symptomatic management is advised for those with only minimal symptoms. Surgical pericardiectomy is advised for subjects with New York Heart Association class II or III symptoms and persisting evidence of constriction at echocardiography and cardiac catheterization and with associated pericardial abnormality on CT or MRI. Complete resection of the pericardium and, where possible, the diseased epicardium via a midline sternotomy is the favored approach, although a video-assisted thoracoscopic approach may be suitable in some subjects. Lateral thoracotomy should be used for suppurative pericarditis to avoid sternal infection. Because of higher mortality, increased complication rates, and suboptimal clinical outcomes, pericardiectomy should be avoided in older patients or those with radiation-induced disease, very advanced symptoms, or evidence of myocardial fibrosis.     

Target setting in intensive insulin management is associated with metabolic control: the Hvidoere Childhood Diabetes Study Group Centre Differences Study 2005

Swift PGF, Skinner TC, de Beaufort CE, Cameron FJ, Åman J, Aanstoot H‐J, Castaño L, Chiarelli F, Daneman D, Danne T, Dorchy H, Hoey H, Kaprio EA, Kaufman F, Kocova M, Mortensen HB, Njølstad PR, Phillip M, Robertson KJ, Schoenle EJ, Urakami T, Vanelli M, Ackermann RW, Skovlund SE for the Hvidoere Study Group on Childhood Diabetes. Target setting in intensive insulin management is associated with metabolic control: the Hvidoere Childhood Diabetes Study Group Centre Differences Study 2005. Objective: To evaluate glycaemic targets set by diabetes teams, their perception by adolescents and parents, and their influence on metabolic control. Methods: Clinical data and questionnaires were completed by adolescents, parents/carers and diabetes teams in 21 international centres. HbA1c was measured centrally. Results: A total of 2062 adolescents completed questionnaires (age 14.4 ± 2.3 yr; diabetes duration 6.1 ± 3.5 yr). Mean HbA 1c = 8.2 ± 1.4% with significant differences between centres (F = 12.3; p < 0.001) range from 7.4 to 9.1%. There was a significant correlation between parent (r = 0.20) and adolescent (r = 0.21) reports of their perceived ideal HbA1c and their actual HbA1c result (p < 0.001), and a stronger association between parents' (r = 0.39) and adolescents' (r = 0.4) reports of the HbA1c they would be happy with and their actual HbA1c result. There were significant differences between centres on parent and adolescent reports of ideal and happy with HbA1c (8.1 < F > 17.4;p < 0.001). A lower target HbA1c and greater consistency between members of teams within centres were associated with lower centre HbA1c (F = 16.0; df = 15; p < 0.001). Conclusions: Clear and consistent setting of glycaemic targets by diabetes teams is strongly associated with HbA1c outcome in adolescents. Target setting appears to play a significant role in explaining the differences in metabolic outcomes between centres.     

Differing thresholds for modulatory effects of adrenomedullin infusion on haemodynamic and hormone responses to angiotensin II and adrenocorticotrophic hormone in healthy volunteers.

Experimental data indicate that adrenomedullin (AM) interacts at various levels with the renin-angiotensin-aldosterone system and the hypothalamic-pituitary-adrenal axis, but data from humans are scant. We examined the effects of intermediate-dose, short-term AM infusion on angiotensin II- and adrenocorticotrophic hormone (ACTH)-mediated hormone and haemodynamic responses in healthy subjects. Seven normal volunteers (age 18-25 years) completed a placebo-controlled crossover study. Each subject was studied on day 4 of two periods of a low-salt diet (40 mmol of sodium and 80 mmol of potassium daily), receiving incremental infusions of angiotensin II in the morning and ACTH in the afternoon of each study day, on a background infusion of AM (4 pmol.min(-1).kg(-1)) or vehicle (hemaccel). Achieved plasma AM levels (23+/-6 pmol/l) and peak angiotensin II levels (160 pmol/l) were similar on the two experimental days. While the pressor action of angiotensin II was attenuated by AM (P<0.01) and noradrenaline levels rose (P<0.05), the aldosterone response was unaltered. During ACTH infusion, AM increased heart rate (P<0.01), plasma adrenaline (P<0.01) and plasma noradrenaline (P<0.05), and augmented the cortisol response (P<0.01), but was without effect on aldosterone levels and blood pressure. We conclude that the threshold for the effects of AM on aldosterone secretion in humans is set higher than for other biological responses to this hormone, namely blood pressure, heart rate, sympathetic activity and cortisol secretion, under these experimental conditions.