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Biochemical basis of cystic fibrosis
25
CLINICAL CHEMISTRY
DETECTION OF ANTICARDIOLIPIN ANTIBODIES ART
THE
-
STATE OF
Russell RC Buchanan, University of Melbourne, Department of Medicine, Austin Hospital, Heidelberg, Vic, 3084. The solid phase assay for the measurement of anti-phospholipid antibodies was first described 8 years ago. Since then it has undergone a number of modifications which have improved its sensitivity, specificity and reproducibility. The assay is best standardised against a 4 or 5 point standard curve but despite this it still remains a semi-quantitative assay, being able to differentiate sera with high from those with medium and low antibody levels. It does however retain the inherent advantages of a solid phase assay including the ability to control the antigen used, the ability to measure isotype, and ease of measuring total antibody level. The recent description of a serum co-factor which assists in optimal antibody binding may explain some of the discrepancies previously seen in the literature.
B1I)ChEI’iICAL BASiS IrF iYSTiC FiBRUSiS T r e v o r L . W i l l i a m s , Department o f d e s p i r a t o r y i,iedicine, A l f r e d riospi t a l , i:!el>ourne. C y s i i c f i b r o s i s i s a common autosornal r e c e s s i v e disease w i t h a 1 i n c i d e n c e o f a p p r o x i m a t e l y one i n 2,000 l i v e b i r t i i s i n t.he Caucasian p o p u l a t i o n . i t a f f e c t s [nany organs w i t h i n t h e body however t h e commonest l e t h a l e f f e c t i s t h e developnent o f p r o g r e s s i v e b r o n c h i e c t a s i s . A b i o c h e m i c a l b a s i s f o r c y s t i c f i b r o s i s was c o n f i r m e d i n 1953 by d i Sant’Agnese who demonstrated abnormally h i g h sweat c h l o r i d e and sodium l e v e l s i n s u b j e c t s w i t h c y s t i c fibrosis. Presently, a q u a n t i t a t i v e p i l o c a r j i n e ionotophoresis technique i s t h e corner stone o f diagnosis o f cystic fibrosis. The l a s t f i v e y e a r s have seen an e x p l o s i o n i n knowledge i n c y s t i c f i b r o s i s culminating i n the i d e n t i f i c a t i o n o f t h e c y s t i c f i b r o s i s gene on chromosome 7. 70% o f d e f e c t i v e genes have B base p a i r d e l e t i o n d e s i g n a t e d d e l t a 508. At l e a s t another 30 gene d e f e c t s a r e thr,.ight t o e x i s t . The c y s t i c f i b r o s i s gene i s t h o u g h t t o code f o r a c y s t i c f i d r o s i s t r a n s membrane r e g u l a t i n g p r o t e i n (CFT2) which p r o b a b l y r e g u l a t e s i o n conductance ecross t h e c e l l imei~5rane. The d e l t a 508 d e f e c t l e a d s t o a d e l e t i o n o f phenyl a1 a n i ne f r o m t h i s p r o t e i n .
Presenter:
D r T r e v o r W i l l i a m s , Department. o f k e s p i r a t o r y Medicine, A l f r e d H o s p i t a l , irelbourne.
C H E M I C A L P A T H O L O G Y OF G R O W T H DISORDERS
J. Coakley, Department of Clinical Chemistry, Royal Alexandra Hospital for Children, N.S.W. APOLIPOPROTEIN (a) AND ATHEROGENESIS E.D.Janus, Department of Chemical Pathology and Lipid Clinic, St.Vincent’s Hospital, Fitzroy, Victoria 3065. Lp(a) is an independent risk factor for macrovascular disease and is a hybrid of low density lipoprotein (LDL) and apo(a), a protein which is homologous with plasminogen. Plasma levels are genetically determined and reflect the phenotype. Adult levels are reached by age 2 years and remain remarkably constant over time in a given individual. They vary widely from 0 - 3000 UIL. In normal individuals levels are log normally distributed. The physiological role of apo(a) and the mechanism of arterial damage is unknown. This protein adheres t o plasminogen receptors and might interfere with fibrinolysis. It is a major contributor t o family history of premature coronary heart disease. Measurement is by immunological techniques (nephelometry or radioimmunoassay). In patients undergoing coronary artery grafting apo(a) levels (n = 40, geometric mean 193 UIL, 95% confidence intervals 126 - 298) were higher than in healthy controls (n = 140, 107, 85 - 134, P = 0.016. Other groups of patients with coronary artery disease showed similar high levels. Levels were also higher in insulin dependent and non insulin dependent patients with macrovascular disease than those without. Diabetic patients of both groups with microalbuminuria or albuminuria had elevated apo(a) levels resembling those in the patient UndergOing coronary artery graft surgery. In diabetics without microalbuminuria levels were similar to those in normal controls. Raised apo(a) levels in diabetic patients may contribute to their increased macrovascular disease and early mortality.
Growth disorders are characterized by two parameters - the absolute height measurement and the height velocity. The causes of growth failure can be classified as follows : endocrine, psychological, iatrogenic, chromosomal, nutritional, intrauterine, chronic disease and skeletal. I shall concentrate on the endocrine causes of disordered growth, in particular, abnormalities in the production of growth hormone (GH). Other endocrine abnormalities causing short stature include deficiency of thyroxine, excess cortisol and delay in the production of sex steroids at puberty. G H is released from the anterior pituitary in a pulsatile fashion, with the greatest secretion occurring about one hour after the onset of sleep. Secretion of G H is stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin, both these peptides being released from the hypothalamus. G H exerts its growth promoting effects principally by acting on tissues, such as cartilage and muscle, to produce insulin-like growth factor I (IGFI) which probably acts locally in a paracrine fashion to stimulate growth. The clinical features of severe G H deficiency are relatively easy to recognize, but are less apparent in the child with partial lack of GH. The approach to the diagnosis of abnormal secretion of G H must include a complete clinical assessment, with appropriate auxological data and bone age. Provocation tests, to establish either partial or complete deficiency of G H , are based on either pharmacological or physiolo::ical stimuli. Other tests, used mainly for research, include measurement of the G H pulses over 24 hours, G H R H stimulation test and urinary G H excretion. IGFl measurement is of limited value in G H deficiency, but useful in states of G H excess. The introduction of biosynthetic G H has resulted in a broader spectrum of patients with growth disorders receiving treatment, and there is no longer the risk of trnnsniissio:i of slow virus infection, as occurred with t h e use of G H extracted from human pituitaries.
CLINICAL CHEMISTRY
DETECTION OF ANTICARDIOLIPIN ANTIBODIES ART
THE
-
STATE OF
Russell RC Buchanan, University of Melbourne, Department of Medicine, Austin Hospital, Heidelberg, Vic, 3084. The solid phase assay for the measurement of anti-phospholipid antibodies was first described 8 years ago. Since then it has undergone a number of modifications which have improved its sensitivity, specificity and reproducibility. The assay is best standardised against a 4 or 5 point standard curve but despite this it still remains a semi-quantitative assay, being able to differentiate sera with high from those with medium and low antibody levels. It does however retain the inherent advantages of a solid phase assay including the ability to control the antigen used, the ability to measure isotype, and ease of measuring total antibody level. The recent description of a serum co-factor which assists in optimal antibody binding may explain some of the discrepancies previously seen in the literature.
B1I)ChEI’iICAL BASiS IrF iYSTiC FiBRUSiS T r e v o r L . W i l l i a m s , Department o f d e s p i r a t o r y i,iedicine, A l f r e d riospi t a l , i:!el>ourne. C y s i i c f i b r o s i s i s a common autosornal r e c e s s i v e disease w i t h a 1 i n c i d e n c e o f a p p r o x i m a t e l y one i n 2,000 l i v e b i r t i i s i n t.he Caucasian p o p u l a t i o n . i t a f f e c t s [nany organs w i t h i n t h e body however t h e commonest l e t h a l e f f e c t i s t h e developnent o f p r o g r e s s i v e b r o n c h i e c t a s i s . A b i o c h e m i c a l b a s i s f o r c y s t i c f i b r o s i s was c o n f i r m e d i n 1953 by d i Sant’Agnese who demonstrated abnormally h i g h sweat c h l o r i d e and sodium l e v e l s i n s u b j e c t s w i t h c y s t i c fibrosis. Presently, a q u a n t i t a t i v e p i l o c a r j i n e ionotophoresis technique i s t h e corner stone o f diagnosis o f cystic fibrosis. The l a s t f i v e y e a r s have seen an e x p l o s i o n i n knowledge i n c y s t i c f i b r o s i s culminating i n the i d e n t i f i c a t i o n o f t h e c y s t i c f i b r o s i s gene on chromosome 7. 70% o f d e f e c t i v e genes have B base p a i r d e l e t i o n d e s i g n a t e d d e l t a 508. At l e a s t another 30 gene d e f e c t s a r e thr,.ight t o e x i s t . The c y s t i c f i b r o s i s gene i s t h o u g h t t o code f o r a c y s t i c f i d r o s i s t r a n s membrane r e g u l a t i n g p r o t e i n (CFT2) which p r o b a b l y r e g u l a t e s i o n conductance ecross t h e c e l l imei~5rane. The d e l t a 508 d e f e c t l e a d s t o a d e l e t i o n o f phenyl a1 a n i ne f r o m t h i s p r o t e i n .
Presenter:
D r T r e v o r W i l l i a m s , Department. o f k e s p i r a t o r y Medicine, A l f r e d H o s p i t a l , irelbourne.
C H E M I C A L P A T H O L O G Y OF G R O W T H DISORDERS
J. Coakley, Department of Clinical Chemistry, Royal Alexandra Hospital for Children, N.S.W. APOLIPOPROTEIN (a) AND ATHEROGENESIS E.D.Janus, Department of Chemical Pathology and Lipid Clinic, St.Vincent’s Hospital, Fitzroy, Victoria 3065. Lp(a) is an independent risk factor for macrovascular disease and is a hybrid of low density lipoprotein (LDL) and apo(a), a protein which is homologous with plasminogen. Plasma levels are genetically determined and reflect the phenotype. Adult levels are reached by age 2 years and remain remarkably constant over time in a given individual. They vary widely from 0 - 3000 UIL. In normal individuals levels are log normally distributed. The physiological role of apo(a) and the mechanism of arterial damage is unknown. This protein adheres t o plasminogen receptors and might interfere with fibrinolysis. It is a major contributor t o family history of premature coronary heart disease. Measurement is by immunological techniques (nephelometry or radioimmunoassay). In patients undergoing coronary artery grafting apo(a) levels (n = 40, geometric mean 193 UIL, 95% confidence intervals 126 - 298) were higher than in healthy controls (n = 140, 107, 85 - 134, P = 0.016. Other groups of patients with coronary artery disease showed similar high levels. Levels were also higher in insulin dependent and non insulin dependent patients with macrovascular disease than those without. Diabetic patients of both groups with microalbuminuria or albuminuria had elevated apo(a) levels resembling those in the patient UndergOing coronary artery graft surgery. In diabetics without microalbuminuria levels were similar to those in normal controls. Raised apo(a) levels in diabetic patients may contribute to their increased macrovascular disease and early mortality.
Growth disorders are characterized by two parameters - the absolute height measurement and the height velocity. The causes of growth failure can be classified as follows : endocrine, psychological, iatrogenic, chromosomal, nutritional, intrauterine, chronic disease and skeletal. I shall concentrate on the endocrine causes of disordered growth, in particular, abnormalities in the production of growth hormone (GH). Other endocrine abnormalities causing short stature include deficiency of thyroxine, excess cortisol and delay in the production of sex steroids at puberty. G H is released from the anterior pituitary in a pulsatile fashion, with the greatest secretion occurring about one hour after the onset of sleep. Secretion of G H is stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin, both these peptides being released from the hypothalamus. G H exerts its growth promoting effects principally by acting on tissues, such as cartilage and muscle, to produce insulin-like growth factor I (IGFI) which probably acts locally in a paracrine fashion to stimulate growth. The clinical features of severe G H deficiency are relatively easy to recognize, but are less apparent in the child with partial lack of GH. The approach to the diagnosis of abnormal secretion of G H must include a complete clinical assessment, with appropriate auxological data and bone age. Provocation tests, to establish either partial or complete deficiency of G H , are based on either pharmacological or physiolo::ical stimuli. Other tests, used mainly for research, include measurement of the G H pulses over 24 hours, G H R H stimulation test and urinary G H excretion. IGFl measurement is of limited value in G H deficiency, but useful in states of G H excess. The introduction of biosynthetic G H has resulted in a broader spectrum of patients with growth disorders receiving treatment, and there is no longer the risk of trnnsniissio:i of slow virus infection, as occurred with t h e use of G H extracted from human pituitaries.