Genetic determinants of statin intolerance

Background  

Statin-related skeletal muscle disorders range from benign myalgias – such as non-specific muscle aches or joint pains without elevated serum creatinine kinase (CK) concentration – to true myositis with >10-fold elevation of serum CK, to rhabdomyolysis and myoglobinuria. The genetic basis of statin-related muscle disorders is largely unknown. Because mutations in the COQ2 gene are associated with severe inherited myopathy, we hypothesized that common, mild genetic variation in COQ2 would be associated with inter-individual variation in statin intolerance. We studied 133 subjects who developed myopathy on statin monotherapy and 158 matched controls who tolerated statins without incident or complaint.     

The effects of phorbol esters with different biological activities on protein kinase C

The sapintoxins are a series of naturally occurring fluorescent phorbol esters with a range of selective biological activities (e.g. pro-inflammatory but non-tumour promoting). Their ability to activate protein kinase C (PKC) in vitro has been studied. Both tumour promoting and non-promoting phorbol derivatives activate the enzyme in vitro at low concentrations. 12-deoxyphorbol-13-phenylacetate-20 acetate (DOPPA) acts as a partial agonist in the activation of protein kinase C. Structurally distinct phorbol esters may therefore preferentially activate different forms of protein kinase C. α-sapinine, a biologically inactive compound, binds to protein kinase C without stimulating the enzyme and prevents subsequent activation by phorbol esters such as 12-O-tetradecanoyl phorbol-13-acetate (TPA).     

Right superficial femoral artery to superior vena cava graft using a polytetrafluroethylene graft: a new technique in a complicated dialysis access patient.

Sir, The expansion of haemodialysis includes older patients withcomorbidities, poor quality vessels, unsuitable for transplantationor peritoneal dialysis. Vascular access complications accountfor 20% of hospital admissions [1]. With exhausted sites inupper extremities, unusual sites for arteriovenous grafts formationare used [2]. The     

Two cases of hereditary keratoderma with congenital glaucoma

Two cases are reported: a father and son with a new syndrome consisting of a severe congenital glaucoma associated with a form of palmoplantar keratoderma showing features of mutilating palmoplantar keratoderma. Both the glaucoma and keratoderma may be attributed to an autosomal dominantly inherited genetic mutation of a single chromosome affecting two tissues of neural crest origin, the ectodermal tissues of the hands and feet and the cranial mesenchyme from which the tissues of the chamber angle develop. Elucidation of the precise chromosomal abnormality causing these defects may help in understanding the inheritance and aetiology of glaucoma.     

Effects of nisoldipine on coronary collateral perfusion and hemodynamics in chronically instrumented dogs

The effect of a new dihydropyridine slow-channel calcium blocking agent, nisoldipine, on hemodynamics and myocardial blood flow in normal and collateral-dependent areas distal to a chronic coronary artery occlusion were studied in chronically instrumented, conscious dogs. Nisoldipine produced significant and dose-related decreases in arterial blood pressure, an elevation of heart rate and large increases in coronary blood flow velocity. In dogs with an Ameroid constrictor previously implanted to enhance coronary collateral development, this agent produced large increases in perfusion distal to a chronic coronary artery occlusion. In addition, despite a reduction in arterial pressure, nisoldipine preserved renal cortical, intestinal and skeletal muscle blood flow while increasing tissue flow within liver and cerebral cortex. Thus, nisoldipine increases oxygen supply to collateral-dependent myocardium in the presence of reduced driving pressure for collateral perfusion.     

The Development and Teaching of the Ethical Principles and Guidelines for Family Scientists*

This article describes the development of the Ethical Principles and Guidelines for Family Scientists that the National Council on Family Relations Board of Directors unanimously approved. Furthermore, it discusses the importance of ethics education for family professionals and provides suggestions for educators. Finally, the ethical principles and guidelines are delineated. We argue that the development of a scholarship on ethics education is important for current and future family scientists.     

Surgical therapy for thyroid carcinoma: a review of 1249 solitary thyroid nodules

A total of 1249 "cold" solitary thyroid nodules were excised at the Brigham and Women's Hospital from 1948 through 1987. Of these nodules, 241 showed malignant conditions: 123 were papillary, 42 were mixed papillary-follicular, and 43 were pure follicular carcinomas. There were also 23 anaplastic, 8 medullary, and 3 Hürthle cell carcinomas. These patients were followed up from 3 to 31 years, with a mean range of 10 years. Fifty-three patients with well-differentiated tumors underwent total thyroidectomies, and 179 underwent subtotal thyroidectomies (excluding anaplastic, medullary, and Hürthle cell tumors). Regional lymph node involvement was commonly found but appeared not to affect survival; tumor size and local spread and extent of thyroid gland involvement did affect survival. A small percentage of well-differentiated thyroid tumors do, in time, undergo anaplastic change that leads to metastasis and death. There was no 30-day mortality rate. The late mortality rate was 2% for papillary and 14% for follicular carcinomas. Papillary tumors are becoming more common. Older aged patients and male patients appear to carry poorer prognoses for survival. The total thyroidectomy procedure has not improved survival over subtotal thyroidectomy and carries a higher complication rate.     

Cerebellar diaschisis revisited: pontine hypometabolism and dentate sparing.

A unilateral supratentorial lesion may cause hypometabolism in the contralateral cerebellar hemisphere (crossed cerebellar diaschisis). We analyzed glucose metabolism, measured by PET-FDG, in the posterior fossa in 67 patients (78 PET studies) with primary unilateral supratentorial brain tumors selected for visually obvious metabolic asymmetry in the cerebellar hemispheres. We found that glucose utilization was 17% lower in the contralateral cerebellar cortex (compared with the ipsilateral one), consistent with the selection criterion, and 19% lower in the ipsilateral pons, wherein lie the first order synapses of the corticopontocerebellar pathway. This finding helps to validate the prevalent view that cerebellar diaschisis is due to interruption of afferent input from the corticopontocerebellar pathway. However, glucose metabolism in the contralateral dentate nucleus was relatively preserved--only 2% less than the ipsilateral dentate. This "dentate sparing" suggests preservation of afferent input to the largest of the deep cerebellar nuclei from the Purkinje cells in the cortex, despite interruption of the major excitatory input to the Purkinje cells.