Caveolin-3 in muscular dystrophy

The dystrophin-glycoprotein complex (DGC) serves as a link between cytoplasmic actin, the membrane and the extracellular matrix of striated muscle. Genetic defects in genes encoding a subset of DGC proteins result in muscular dystrophy and a secondary decrease in other DGC proteins. Caveolae are dynamic structures that have been implicated in a number of functions including endocytosis, potocytosis and signal transduction. Caveolin (VIP-21) is thought to play a structural role in the formation of non-clathrin-coated vesicles in a number of different cell types. Caveolin-3, or M-caveolin, was identified as a muscle- specific form of the caveolin family. We show that caveolin-3 co- purifies with dystrophin, and that a fraction of caveolin-3 is a dystrophin-associated protein. We isolated the gene for human caveolin- 3 and mapped it to chromosome 3p25. We determined the genomic organization of human caveolin-3 and devised a screening strategy to look for mutations in caveolin-3 in patients with muscular dystrophy. Of 82 patients screened, two nucleotide changes were found that resulted in amino acid substitutions (G55S and C71W); these changes were not seen in a control population. The amino acid changes map to a functionally important domain in caveolin-3, suggesting that these are not benign polymorphisms and instead are disease-causing mutations.      

Is there a relationship between antipsychotic blood levels and their clinical efficacy? An analysis of studies design and methodology

Summary— There are now more than 50 studies concerning neuroleptic blood levels and clinical outcome relationships. Haloperidol, the most studied, is the only antipsychotic permitting some conclusions. A number of authors suggest that the striking lack of agreement between different studies results from heterogeneity of their quality. Here, we have used a scoring system for assessing the quality of those studies. According to this system, none (0/14) of the studies having a score <0.60 was able to show a therapeutic window, as compared to 53% (10/19) of those having a score ≥0.60 (p = 0.002, Fisher exact test). Also, the studies able to identify the presence of a therapeutic window during haloperidol treatment were those having sample sizes >20 ( p = 0.06) and those whose patients were treated with fixed doses ( p = 0.02). The diagnosis of schizophrenia in the studies seems not to be an exclusive condition, as compared with those also including schizophreniform and schizoaffective disorders (p = 0.12). Our qualitative analysis of haloperidol blood level publications seem to indicate that an upper limit may exist for haloperidol efficacy; values above this limit seem not to provide any supplementary clinical improvement and may even reduce therapeutic effect.     

Thresholds for detection of a target against a background grating suggest visual dysfunction in migraine with aura but not migraine without aura

Square-wave gratings with particular spatial characteristics in visual illusions. Patients with migraine are particularly susceptible to these illusions and report disc. it. Their discomfort tends to be greater when the gratings are illuminated by red light, a tendency 1 known by controls. Gratings that induce illusions have been found to impair the recognition of opt superimposed targets in headache-free control subjects. We measured the impairment of target detection under illuminants of various chromaticities in migraineurs with and without aura and in mat controls. Migraineurs with aura had significantly higher thresholds for target detection than either migraineurs without aura or controls; in addition, the effect of chromaticity was slightly more pronounced in both migraine groups than in the control group. These findings are consistent with a recent suggestion that migraine with aura might give rise to subclinical damage to the primary visual cortex.     

Chronic leukemia with a hybrid surface phenotype (T lymphocytic/myelomonocytic): leukemic cells displaying natural killer activity and antibody-dependent cellular cytotoxicity

A patient with chronic leukemia exhibited uncommon clinical features, such as hypergammaglobulinemia and activation of intravascular coagulation after low-dose irradiation of the enlarged spleen. By light and electron microscopy, the leukemic cells resembled large granular lymphocytes. The following markers were simultaneously expressed on their surface: receptors for sheep erythrocytes and the Fc part of IgG; common T-cell antigens as revealed by a heteroantiserum (HuTLA) and monoclonal antibodies (OKT3, T411); antigens shared by cytotoxic/suppressor T cells (OKT8, T811) as well as myelomonocytic antigens defined by the OKM1 and M522 monoclonal antibodies. The leukemic cells showed both spontaneous (NK) and antibody-dependent (ADCC) cytotoxicity, but they did not suppress B-cell differentiation in vitro.     

Further evidence of the in vivo role of erythropoietin or companion molecules induced by hypoxia on proliferation and continuing differentiation of BFU-e in PCDC

Normal and plethoric bone marrow cells were grown in plasma clot diffusion chambers (PCDC) implanted into the peritoneum of normal mice or mice submitted to 7 her of hypoxia (23,000 ft) daily, on a single day or on 2 consecutive days at different times after implantation of the PCDC's. Daily discontinuous hypoxia (DDH) produced more 6-day bursts than other treatments. Hypoxia on days 1 and 2 after implantation was nearly as effective as DDH on day-6 bursts. Later bouts of hypoxia or a singly hypoxic exposure on day 1 or 2 was less effective. Erythropoietin (Ep) levels were measured by bioassay on both diffusion chamber (DC) contents and serum. Serum Ep levels peaked at 160 mU/ml after a 7-hr hypoxic exposure while the DC content Ep levels were in the nondetectable range (less than 50 mU/ml). The data implies that either higher than normal Ep levels or a companion molecules (s) produced by hypoxia are required for 1-2 days early in the culture period of force an increasing number of BFU-d-e down the erythrocytic pathway and thus increase red cell production at times of need in vivo.     

Thalidomide as salvage therapy for chronic graft-versus-host disease

Thalidomide has been reported to be an effective agent for treatment of chronic graft-versus-host disease (CGVHD). To determine the efficacy of this agent in patients with refractory CGVHD a total of 80 patients who failed to respond to prednisone (PSE) or PSE and cyclosporine (CSA) were treated with thalidomide. Sixteen patients (20%) had a sustained response, 9 with a complete remission and 7 with a partial response. Twenty-nine patients (36%) had thalidomide discontinued because of side effects, which included sedation, constipation, neuritis, skin rash, and neutropenia. Side effects were reversible with drug discontinuation except for mild residual neuritis in one case. Rashes and neutropenia have not previously been reported as thalidomide side effects when used for CGVHD treatment. We conclude thalidomide is immunosuppressive and active in the treatment of CGVHD. A high incidence of reversible side effects limited dose intensity and reduced the number of patients who could benefit from treatment.     

Yearly diagnostic yield of colonoscopy in patients age 80 years or older,with a special interest in colorectal cancer

Aim: A high diagnostic yield of colonoscopy has been reported in elderly patients, but there is no data on the yearly yield. Our aim was to detect the yearly yield of colonoscopy in elderly patients. Methods: All consecutive endoscopies in the years 1992–2009 were included. Important endoscopic diagnoses were defined as colorectal cancer (CRC), polyps, diverticuli and inflammation. Results: In total, 19 569 endoscopies were performed, of which 1706 (8.7%) were in patients age 80 years or older. The number of women was significantly higher (P < 0.001). The percentage of patients who were 80 years or older was higher than in the general population and remained stable during the study period, though there has been a proportional increase of elderly people in the general population. Inconclusive procedures were present in 106 (6.2%) elderly patients compared with 277 (1.6%) patients under 80 years of age (P < 0.001). There were no significant changes in the consecutive years. A procedure revealing no endoscopic diagnosis was observed less often in patients who were 80 years or older (P < 0.001). CRC was diagnosed in 221 (19.6%) older patients. This figure remained more or less constant each year. Polyps were seen in 448 (8.8%) patients 80 years of age or older. The percentage of patients with diverticuli and inflammation was constant. The number of patients 80 years or older with CRC and polyps rose at a lower rate than the number of older people in the general population. Conclusion: The yield of colonoscopy in patients 80 years or older was high and constant over the years. The number of tumors rose less than expected compared to the increase of elderly in the general population. Geriatr Gerontol Int 2012; 12: 298–303.