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.     

MR imaging of intraspinal tumors—Capability in histological differentiation and compartmentalization of extramedullary tumors

Summary Magnetic resonance (MR) images of 29 consecutive patients with intraspinal neoplasms (9 intramedullary tumors, 20 extramedullary tumors) were reviewed to evaluated the utility of MR imaging in distinguishing the intraspinal compartmental localisation and signal characteristics of each lesion. Compartment and histology of all neoplasms were surgically proven. MR correctly assigned one of three compartments to all lesions, 9 intramedullary, 14 intradural extramedullary (6 schwannomas, 3 neurofibromas, 5 meningiomas), and 6 extradural (3 schwannomas, 1 meningioma, 1 cavernous hemangioma, 1 metastatic renal cell carcinoma). All intramedullary tumors showed swelling of the spinal cord itself. In all five extradural tumors a low intensity band was visualized between the spinal cord and tumor. On the other hand, a low intensity band was demonstrated in no cases with intradural tumors. Visualization of this low intensity band is important in differentiating extradural from intradural-extramedullary lesions. We call this low intensity band, the extradural sign. Signal intensity of intradural tumors varied with histology. In extramedullary tumors, signal intensity of schwannomas was similar to that of the cerebrospinal fluid (CSF) both on T1 weighted (inversion recovery) and T2 weighted spin echo (SE) images. On the other hand, meningiomas tended to be isointense to the spinal cord on both T1 and T2 weighted SE images. We found relatively reliable signal characteristics to discriminate meningioma from schwannoma.     

Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.      

Peritoneal fluid concentrations of interleukin-8 in women with endometriosis: relationship to stage of disease

There is increasing evidence that immunological mechanisms play a role in the pathogenesis and pathophysiology of endometriosis. It was therefore of interest to study interleukin-8 (IL-8), a chemokine, in the peritoneal fluid and peripheral blood of women undergoing laparoscopic procedures. The presence and concentrations of IL-8 in relation to endometriosis, infertility and abdominal pain were evaluated. Samples of peritoneal fluid (n = 49) and peripheral blood (n = 50) were obtained from 50 consecutive patients undergoing laparoscopic surgery for various gynaecological indications (abdominal pain, infertility, sterilization). IL-8 was present in the peritoneal fluid of most women (87%). The concentration of IL-8 in the peritoneal fluid was higher in women with endometriosis compared to women without (P = 0.02). This difference was more pronounced in early (stage 1) endometriosis (P = 0.001). IL-8 concentrations in the peritoneal fluid were also higher in women with early endometriosis compared to women with later stages of the disease (P = 0.003). Peripheral blood concentrations did not correlate with peritoneal fluid concentrations of IL-8 and/or the presence of endometriosis. We conclude that IL-8 is an important factor that may contribute to the pathogenesis of endometriosis possibly by promoting neovascularization. This information can be a guide in the development of new therapeutic approaches for the treatment of endometriosis.      

Primary pulmonary low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type with prominent hyalinosis. A case report

We report a case of primary pulmonary low-grade marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)-type with prominent sclerosis, which morphologically resembled pulmonary hyalinizing granuloma (PHG) or inflammatory pseudotumor (IPT) of the lung. The patient, a 66-year-old Japanese female with a history of Sj?gren's syndrome and primary biliary cirrhosis, presented with a lower left lobe mass 6.8 cm in diameter. Histologically, the lesion is characterized by dense bundles of collagen with scattered plasma cells, mature small lymphocytes, and histiocytes among the collagen bundles. Only the peripheral area of the nodule contained dense lymphoplasmacytoid and histiocytoid infiltrates. A few centrocyte-like cells were obscured by the numerous plasma cells and plasmacytoid cells. In addition, lymphoepithelial lesions and colonalized lymphoid follicles were identified by immunohistochemistry alone. Although PHG and IPT are unlikely to be confused with pulmonary MALT-type lymphomas, the present case suggests that MALT-type lymphoma should be added to the list of differential diagnoses for PHG and IPT.     

Spectral discrimination of Cerenkov radiation in scintillating dosimeters

Radiation therapy accelerators require highly accurate dose deposition and the output must be monitored frequently and regularly. Ionization chambers are the primary tool for this control, but their size, their high voltage needed, and the correction needed for electrons make them unsuitable for use during patient treatment. We have developed a small (1-mm-diam and 1-mm-long active part), flexible, and water-equivalent dosimeter. It is suitable for photon and electron beams without corrections, and performs on line dose measurements. This detector is based on only one scintillating fiber and a CCD camera. A new signal processing is used to remove the effect of Cerenkov radiation background, which only requires a preliminary calibration. Central-axis depth-dose distribution comparisons have been achieved with standard ionization chambers, over a range from 8 to 25 MV photons and from 6 to 21 MeV electrons in order to validate this calibration. Results show a very good agreement, with less than 1% difference between the two detectors.     

An autopsy case of mitochondrial encephalomyopathy (MELAS) with special reference to extra-neuromuscular abnormalities.

An autopsy case of a 37-year-old man with mitochondrial encephalomyopathy is reported. Ragged-red fibers and crystalline inclusions in mitochondria were revealed by biopsy of the striated muscle of the patient. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) was diagnosed clinically. In addition to severe atrophy and degeneration of the generalized striated muscles and many foci of laminar necrosis of the cerebral cortex, the following abnormalities were observed: 1) hypertrophy of the myocardium, 2) fatty change of the liver, 3) focal sclerosis of the glomeruli and dilatation of the tubules of the kidneys, 4) hyalinous degeneration of the Langerhans' islands of the pancreas and 5) wavy change of the smooth muscle fibers of the muscularis propria of the gastrointestinal tract. We suggest that mitochondrial encephalomyopathy affects various organs and tissues, among which susceptibility of the muscular tissues--skeletal muscle, myocardium and smooth muscle--is high.     

Effects of para-substituted beta-adrenoceptor blocking agents and methyl-substituted phenoxypropanolamine derivatives on maximum upstroke velocity of action potential in guinea-pig papillary muscles

Summary The effects of atenolol (2–5 mmol/l), sotalol (1–2 mmol/l) and pamatolol (0.1–1 mmol/l), together with N-tertiary butyl phenoxypropanolamines with o-methyl (D-2T: 50–100 mol/l) m-methyl (D-3T: 50–100 mol/l) and p-methyl (D-4T:100–200 mol/l) group as well as with o,p-methyl groups (D-24T) (50–100 mol/l) on action potentials (APs) were investigated in isolated guinea-pig papillary muscles. All the drugs in these concentrations produced a concentration-dependent reduction of the maximum upstroke velocity (V _max). The reduction ofV _max in premature APs induced by stimuli interpolated between the basic driving rate of 0.25, 0.1 or 0.027 Hz decayed exponentially during diastolic intervals. The time constants of these decay processes for atenolol, pamatolol and sotalol ranged between 260–541 ms, those for D-3T and D-4T between 655–1,166 ms, and D-2T and D-24T between 1,565–1,931 ms. A drug which provided larger values caused the reduction ofV _max in a wider range of the frequency. With respect to the aryloxypropanolamine derivatives so far studied (Sada and Ban 1980, 1981 a, b; Sada et al. 1983) fairly good correlations were found as follows: between logn-octanol/water partition coefficient (logP) and ED₂₀ at 0.25 Hz, ED₃₀ at 1 and 4 Hz for 11–14 compounds; between logP and resting block, between molecular weight and A _o ^c i.e. the value extrapolated to the time of APD₉₀ of the conditioning response relative to the predrugV _max value which may represent a fraction of channels blocked per AP for 100 mol/l of 20–22 compounds. With respect to 8 compounds with methyl substituents in the benzene ring or amine part the ortho methyl group makes a major contribution to increase the resting block and to increase log values.