Occurrence of two missense mutations in Cu-ATPase of the macular mouse, a Menkes disease model

We have investigated the genetic defect of the Cu-ATPase gene (Atp7a) in the macular mouse, a genetic model of classical Menkes disease. Northern blot analysis showed that its placenta and kidney possess a normal amount of the Cu-ATPase mRNA of the normal size; sequencing analysis revealed two missense mutations, His674Arg and Ser1381 Pro, in a PCR-amplified cDNA for mutant Cu-ATPase. The latter mutation was suspected to affect the function of the ATPase, because it lies in the transmembrane segment that is thought to form a channel for the transportation of copper ions.     

Mutation analysis and expression of the mottled gene in the macular mouse model of Menkes disease

OBJECTIVES: The purpose of this study was to evaluate the ability of two different panoramic imaging systems to produce cross-sectional images with accurate vertical dimensions of the posterior mandible. STUDY DESIGN: Three partially edentulous human cadaver mandibles were used for this study. On each mandible, three potential implant sites were arbitrarily identified in an area between the mental foramen and the ascending ramus. Each site was imaged using two different panoramic machines. Using each image, the mandible's outline, cortical thickness, and position of the mandibular canal were traced on clear acetate film. The mandibles were then sectioned at each site to serve as a gold standard. The cadaver sections and tracings (corrected for magnification) were measured, recording the overall mandibular height, distance from the crest of the ridge to the superior aspect of the mandibular canal, and the thickness of the cortical bone at the most inferior aspect of the mandible. RESULTS: There were no significant differences between either of the system's image measures and the gold standard when considering the distance between the crest and the mandibular canal. Differences were noted between the systems measures and the gold standard in the assessment of the cortical bone thickness and the overall mandibular height. CONCLUSIONS: Both imaging systems can be useful for vertical measurements of a potential implant site in the posterior mandible.     

Fibroblast silver loading for the diagnosis of Menkes disease

Hypotony from an inadvertent filtration bleb developed in the eye of a 66-year-old woman 1 year after phacoemulsification cataract surgery. The hypotony was treated with an autologous blood injection over the previous phacoemulsification incision. This technique successfully treated the hypotony without additional ocular surgery. The authors report an effective alternative treatment for hypotony induced by an inadvertent filtration bleb.     

Efficacy of taxol in the orpk mouse model of polycystic kidney disease

Studies on conscious Sprague-Dawley rats using intracerebral dialysis in live animals combined with high-performance liquid chromatography with electrochemical detection showed that administration of apomorphine into the nucleus accumbens decreased the levels of dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in the extracellular space of the dorsal striatum throughout the observation period and produced a transient reduction in the level of homovanillic acid in the dialysate from this structure. The studies demonstrated that reversible exclusion of the nucleus accumbens with procaine produced a transient increase in the levels of dopamine metabolites, without an increase in serotonin metabolites, in the extracellular space of the dorsal striatum. These results demonstrate that the nucleus accumbens affects dopamine metabolism in the striatum, this being mediated by the dopamine-reactive system in the nucleus accumbens.     

Molecular mechanisms of copper metabolism and the role of the Menkes disease protein

Menkes disease is an X-linked, recessive disorder of copper metabolism that occurs in approximately 1 in 200,000 live births. The condition is characterized by skeletal abnormalities, severe mental retardation, neurologic degeneration, and patient mortality in early childhood. The symptoms of Menkes disease result from a deficiency of serum copper and copper-dependent enzymes. A candidate gene for the disease has been isolated and designated MNK. The MNK gene codes for a P-type cation transporting ATPase, based on homology to known P-type ATPases and in vitro experimentation. cDNA clones of MNK in Menkes patients show diminished or absented hybridization in northern blot experiments. The Menkes protein functions to export excess intracellular copper and activates upon Cu(I) binding to the six metal-binding repeats in the amino-terminal domain. The loss of Menkes protein activity blocks the export of dietary copper from the gastrointestinal tract and causes the copper deficiency associated with Menkes disease. Each of the Menkes protein amino-terminal repeats contains a conserved -X-Met-X-Cys-X-X-Cys- motif (where X is any amino acid). These metal-binding repeats are conserved in other cation exporting ATPases involved in metal metabolism and in proteins involved in cellular defense against heavy metals in both prokaryotes and eukaryotes. An overview of copper metabolism in humans and a discussion of our understanding of the molecular basis of cellular copper homeostasis is presented. This forms the basis for a discussion of Menkes disease and the protein deficit in this disease.     

Glomerulocystic kidney disease: a single entity?

A case of glomerulocystic disease in a young adult with no family history or presence of other extrarenal malformations is described. Histological study revealed the presence of numerous cortical cysts corresponding to dilatations of Bowman's space. The patient had mild stable chronic renal failure for 5 years. In our patient, the disease corresponded to a sporadic adult form of glomerulocystic disease.     

Graves' disease: xenotransplantation model (athymic nude mice)

This study provides the first quantitative indication of the limits of sensitivity of a bone scan with technetium (99Tc-MDP) in detecting skeletal metastases and thereby also helps to explain the fact that bone scans may be negative when metastases are present in the bone marrow. Since 99Tc-MDP remains the least noxious and most widely used isotope for bone scanning, these results have direct clinical relevance in the evaluation of patients with solid tumors and possible metastatic spread.     

Murine gamma-herpesvirus 68 causes severe large-vessel arteritis in mice lacking interferon-gamma responsiveness: a new model for virus-induced vascular disease

Fundamental issues remain unresolved regarding the possible contribution of viruses to vascular pathology, as well as the role of the immune system in regulating these processes. Here we demonstrate that infection of mice with gamma-herpesvirus 68 (gammaHV68) provides a novel model for addressing these issues. Interferon-gamma receptor-deficient (IFNgammaR-/-) mice died weeks to months after gammaHV68 infection from a severe large-vessel panarteritis. GammaHV68-infected B cell-deficient and normal weanling mice exhibited milder large-vessel arteritis. Immunohistochemical analyses demonstrated gammaHV68 antigen in arteritic lesions and revealed a striking tropism of gammaHV68 for smooth muscle cells. These studies demonstrate that IFN-gamma is essential for control of chronic vascular pathology induced by gammaHV68 and suggest gamma-herpesviruses as candidate etiologic agents for human vasculitis.     

Adult polycystic kidney disease: a review of 100 cases

Herein we review 100 cases of adult polycystic kidney disease. Flank pain was the most common presentation in these cases. In 20% of the patients calculi were noted and 10% had obstruction. The average patient age at death was 57 years. The importance of tomography is emphasized with key radiographic features, such as bilateral large kidneys, inhomogeneous nephrogram, caliceal distortion and poorly defined renal margins. Cystic involvement of the liver and spleen may help to confirm the diagnosis. Differential diagnosis includes bilateral multiple simple cysts, angiomyolipomatosis and bilateral renal carcinomas.     

Behaviour of MRL mice: an animal model of disturbed behaviour in systemic autoimmune disease

We studied the relation between various histological types of lung cancer and the number of years of cessation from smoking using data from a recently completed case-control study in Northern Germany. In this context we wanted to answer the question whether smoking cessation is a specific symptom of small cell lung cancer. Defining current smokers as the reference group the odds ratios decreased with years of cessation. Based on the analysis of all male cases and controls in our study, former smokers who stopped smoking 6-10 years ago had an odds ratio of 0.97 (95% confidence interval (C.I.) = 0.65-1.45), ex-smokers with 11-20 years of smoking cessation had a reduced risk of 0.55 (95% C.I. = 0.38-0.79), and for more than 20 years of cessation we found an odds ratio of 0.25 (95% C.I. = 0.16-0.40). Moreover, these calculations are also presented for the major groups of histological types of lung cancer. Our data show that there is no evidence for the presumption that cases with small cell lung cancer stop smoking earlier than cases with other histological types: in no other histological category we found such a big part of current smokers.     

Capsulectomy: a cure for the page kidney

Hypertension is a known complication after renal trauma. The cause of posttraumatic hypertension can be renal scarring, infarction, hydonephrosis, infection, vascular injury, and parenchymal compression. The authors report on the case of a 16-year-old boy who experienced hypertension after blunt renal trauma. He had a dense fibrous pseudocapsule causing renal parenchymal compression, which lead to hypertension, a Page kidney. Evaluation with computed tomographic (CT) scan, radioisotope renal scan, renal Doppler, and angiogram confirmed the diagnosis. Removal of the renal capsule and the constricting fibrous pseudocapsule was curative.     

Correction of the copper transport defect of Menkes patient fibroblasts by expression of the Menkes and Wilson ATPases

Menkes' disease is a fatal, X-linked, copper deficiency disorder that results from defective copper efflux from intestinal cells and inadequate copper delivery to other tissues, leading to deficiencies of critical copper-dependent enzymes. Wilson's disease is an autosomally inherited, copper toxicosis disorder resulting from defective biliary excretion of copper, which leads to copper accumulation in the liver. The ATP7A and ATP7B genes that are defective in patients with Menkes' and Wilson's diseases, respectively, encode transmembrane, P-type ATPase proteins (ATP7A or MNK and ATP7B or WND, respectively) that function to translocate copper across cellular membranes. In this study, the cDNAs derived from a normal human ATP7A gene and the murine ATP7B homologue, Atp7b, were separately transfected into an immortalized fibroblast cell line obtained from a Menkes' disease patient. Both MNK and WND expressed from plasmid constructs were able to correct the copper accumulation and copper retention phenotype of these cells. However, the two proteins responded differently to elevated extracellular copper levels. Although MNK showed copper-induced trafficking from the trans-Golgi network to the plasma membrane, in the same cell line the intracellular location of WND did not appear to be affected by elevated copper.     

Age-related macular disease in rural southern Italy

OBJECTIVE: To report the prevalence of age-related maculopathy (ARM) in Salandra, a small, isolated southern Italian community, to test the hypothesis that an environmental factor, scarce in such a remote community but ubiquitous in modern industrial societies, might modify the risk of developing ARM. DESIGN: Population-based cross-sectional survey. MAIN OUTCOME MEASURES: Prevalence of advanced age-related macular degeneration (ARMD) (geographic atrophy or exudative maculopathy) and ARM (large, soft drusen or retinal pigment epithelium changes, or both) defined by fundus biomicroscopy and 30 degrees stereoscopic, macular photography. Self-sustenance was assessed by interview of participants and local shop retailers. The degree of genetic isolation was computed using a model that fits the genetic population structure with the frequency distribution of surnames in the community. RESULTS: A full ophthalmic examination was undertaken in 366 (63.5%) of 576 eligible participants, 354 (96.7%) of whom had clinical or photographic assessment for the presence of ARMD and 310 (84.6%) of whom had drusen characteristics graded on color transparencies for ARM. The overall prevalence of ARMD was 1.1%. Drusen larger than 50 microns and more numerous than 10 were found in 4.5% of subjects. Salandra was the birthplace of 87.2% of participants and for 77.3% of both parents of each subject. People in the community tended to consume homegrown products. CONCLUSION: The prevalence of ARM may be lower in this self-sustained farming community than elsewhere in the industrialized world.     

Stable chronic disease: a behavioral model

A three-year study was undertaken in the general medical clinic of a private community hospital, to assess the health behavior, health status, and profile of function of stable chronic disease was developed and tested. It was shown that these patients used a disproportionate amount of health care services. Half of the group was treated by a nurse practitioner/physician team and half by a house officer/preceptor team. Patients in both groups behaved similarly. These patients: 1) made frequent demands for outpatient services but did not need more than average hospital care; 2) tended to have problems of socio-economic indigency; 3) were likely to have hypertension, obesity, arthritis, and functional disease; 4) were chiefly women; 5) required special visits 9 percent of the time, usually for exacerbations of illness or intercurrent health problems; 6) made greater demands if they had functional complaints as a primary or secondary health problem; and 7) viewed their health more positively and functioned at a higher level if they were over 65 years of age. It was also found that the nurse practitioner, working in consultation with a physician, was able to provide high-quality health care.