Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a recessively inherited disorder predisposing to renal amyloidosis and associated with mutations in MEFV, a gene encoding a protein of unknown function. Differences in clinical expression have been attributed to MEFV-allelic heterogeneity, with the M694V/M694V genotype associated with a high prevalence of renal amyloidosis. However, the variable risk for patients with identical MEFV mutations to develop this severe complication, prevented by lifelong administration of colchicine, strongly suggests a role for other genetic and/or environmental factors. To overcome the well-known difficulties in the identification of modifying genetic factors, we investigated a relatively homogeneous population sample consisting of 137 Armenian patients with FMF from 127 independent families living in Armenia. We selected the SAA1, SAA2, and APOE genes-encoding serum amyloid proteins and apolipoprotein E, respectively-as well as the patients' sex, as candidate modifiers for renal amyloidosis. A stepwise logistic-regression analysis showed that the SAA1alpha/alpha genotype was associated with a sevenfold increased risk for renal amyloidosis, compared with other SAA1 genotypes (odds ratio [OR] 6. 9; 95% confidence interval [CI] 2.5-19.0). This association, which was present whatever the MEFV genotype, was extremely marked in patients homozygous for M694V (11/11). The risk for male patients of developing renal amyloidosis was fourfold higher than that for female patients (OR=4.0; 95% CI=1.5-10.8). This association, particularly marked in patients who were not homozygous for M694V (34.0% vs. 11.6%), was independent of SAA1-allelic variations. Polymorphisms in the SAA2 or APOE gene did not appear to influence susceptibility to renal amyloidosis. Overall, these data, which provide new insights into the pathophysiology of FMF, demonstrate that susceptibility to renal amyloidosis in this Mendelian disorder is influenced by at least two MEFV-independent factors of genetic origin-SAA1 and sex-that act independently of each other.

An epidemic of acute postinfectious glomerulonephritis in Armenia.

AIM: To evaluate the presentation and course of acute postinfectious glomerulonephritis (APGN), which has increased dramatically in Armenia after serious deterioration in the living conditions. STUDY DESIGN: Observational study, based on case notes, of a large homogeneous group of patients hospitalised for APGN at one centre over a five year period (1992-6). PATIENTS: 474 patients aged < 16 years with a diagnosis of APGN. RESULTS: The annual number of patients increased tenfold from 19 (average 1992/3) to 196 in 1995. Sixty two per cent were in the age group 4-9 years and 65% were boys. Upper respiratory infections, scarlet fever, and skin infections preceded APGN in 51%, 23%, and 13%, respectively. All patients had haematuria (93% gross), 84% had oedema, and 72% had hypertension. C3 was initially decreased in 95% of the patients examined. Renal function was impaired (serum creatinine > 100 mumol/l) in 29%. Four patients with renal failure had crescentic glomerulonephritis at biopsy; of these, three required temporary haemodialysis. Main extrarenal complications were heart failure (10%) and convulsions (3%). One patient died and five (3%) did not recover completely. CONCLUSIONS: APGN in children is associated with considerable initial morbidity, and long term outcome is not uniformly benign. Outbreaks of APGN may occur anytime in countries such as Armenia that are suffering from a sudden decline in socioeconomic conditions.

The role of middle ear muscles in the development of resistance to noise induced hearing loss.

The role of middle ear muscles (MEMs) in the development of increased resistance to noise induced hearing loss (NIHL) was studied using monaural chinchillas. Animals with severed MEMs as well as those with intact MEMs were exposed to an octave band noise (OBN) centered at 0.5 kHz at 95 dB for six hours/day for ten consecutive days. Results indicated that animals with severed MEMs showed greater initial threshold shifts (TS) than the animals with intact MEMs. Both the groups showed a decrease in TS over the ten days of exposure. The subjects were given five days of recovery and then re-exposed to the same noise at 106 dB for 48 h. Permanent threshold shifts (PTS) in each group was compared against those in a control group exposed to the noise only at the higher level. Interestingly, both the 'conditioned' groups incurred substantially less PTS than the control group exposed only to the higher level.

Aneurysms of the temporal bone.

Aneurysms of the internal carotid artery in the temporal bone are rare lesions which can present clinically as a growth in the middle ear cleft. Hemorrhage, occurring spontaneously or iatrogenically, is a primary concern. This study describes morphological and embryological characteristics of the internal carotid artery in relationship to the protympanum and temporal bone. Concepts of pathogenesis and pathology are discussed, with reference to the neurosurgical and otolaryngologic literature. Clinical characteristics, including methods of surgical repair, are presented using three illustrative case reports. Methods of surgical repair include: 1) reinforcement; 2) ligation; and 3) primary excision and reanastomosis.

Functional differences between manganese and iron superoxide dismutases in Escherichia coli K-12.

Superoxide dismutases are enzymes that defend against oxidative stress through decomposition of superoxide radical. Escherichia coli contains two highly homologous superoxide dismutases, one containing manganese (MnSOD) and the other iron (FeSOD). Although E. coli Mn and FeSOD catalyze the dismutation of superoxide with comparable rate constants, it is not known if they are physiologically equivalent in their protection of cellular targets from oxyradical damage. To address this issue, isogenic strains of E. coli containing either Mn or FeSOD encoded on a plasmid and under the control of tac promoter were constructed. SOD specific activity in the Mn and FeSOD strains could be controlled by the concentration of isopropyl beta-thiogalactoside in the medium. The tolerance of these strains to oxidative stress was compared at equal Mn and FeSOD specific activities. Our results indicate that E. coli Mn and FeSOD are not functionally equivalent. The MnSOD is more effective than FeSOD in preventing damage to DNA, while the FeSOD appears to be more effective in protecting a cytoplasmic superoxide-sensitive enzyme. These data are the first demonstration that Mn and FeSOD are adapted to different antioxidant roles in E. coli.

Analysis of reconstruction for anterior mandibular defects using AO plates.

The functional and cosmetic outcome of 11 patients who had anterior arch mandibulectomy for stage II-IV oral cavity carcinoma and were reconstructed with AO stainless-steel or titanium plates was retrospectively analyzed. Although the complication rate was high, plate removal was uncommon. Patients were afforded good function and cosmesis. Severity of postoperative infection corresponded to a low preoperative absolute lymphocyte count, which suggests that increased preoperative diet supplementation may decrease the incidence of early infections. Improved mandibular function and esthetics may allow future patients to be offered early reconstruction routinely.