Assessment of radiologic progression in rheumatoid arthritis. A randomized, controlled trial

Radiologic assessment of progressive joint destruction in rheumatoid arthritis is generally considered to be the ultimate standard for evaluation of treatment. We compared alternative radiologic techniques by performing a randomized, controlled trial in which hand films of rheumatoid arthritis patients were read by several skilled observes. The number of joints evaluated (34 versus 18) was found to make relatively little difference, but the number of readers and their experience level was critical. Films should be read in pairs. Joint space narrowing and erosion scores were shown to contribute independent information. Use of recommended techniques can reduce the number of patients required and, thus, can reduce the cost of a clinical trial by more than half and can substantially increase the sensitivity and efficiency of a trial. Therefore, critical selection of the method of assessing study endpoint is of great importance.     

Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1

Many neurodegenerative disorders are caused by abnormal accumulation of misfolded proteins. In spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded (polyQ-expanded) ataxin-1 (ATXN1) causes neuronal toxicity. Lowering total ATXN1, especially the polyQ-expanded form, alleviates disease phenotypes in mice, but the molecular mechanism by which the mutant ATXN1 is specifically modulated is not understood. Here, we identified 22 mutant ATXN1 regulators by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes, respectively. Among them, transglutaminase 5 (TG5) preferentially regulated mutant ATXN1 over the WT protein. TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length–dependent manner, thereby preferentially modulating mutant ATXN1 stability and oligomerization. Perturbing Tg in Drosophila SCA1 models modulated mutant ATXN1 toxicity. Moreover, TG5 was enriched in the nuclei of SCA1-affected neurons and colocalized with nuclear ATXN1 inclusions in brain tissue from patients with SCA1. Our work provides a molecular insight into SCA1 pathogenesis and an opportunity for allele-specific targeting for neurodegenerative disorders.     

Antibody to a synthetic oligopeptide in subjects at risk for human immunodeficiency virus infection.

Detection of antibodies to human immunodeficiency virus (HIV) by enzyme-linked immunosorbent assay (ELISA) is the accepted method to screen blood products at risk to transmit infection. The presence of antibodies to HIV in 565 serum specimens from 274 patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex, symptomatic and asymptomatic subjects at risk for AIDS, and controls was determined with an ELISA that incorporates synthetic peptides (designated E32/E34) representing sequences in the envelope glycoprotein gp41. Of 105 specimens from patients with AIDS or AIDS-related complex, 3 specimens that were negative by commercially licensed ELISA and immunoblot test were similarly unreactive in the E32/E34 ELISA. For homosexual men with generalized lymphadenopathy, 186 specimens were positive by the E32/E34 ELISA and 63 specimens were negative. In comparison, with the licensed ELISA, 184 of these samples were positive and 65 samples were negative. The two samples that were positive in the E32/E34 ELISA but not the commercial kit were also positive by immunoblotting. Sequential sera from one individual who apparently underwent seroconversion according to the commercial assays were all positive by E32/E34 ELISA and immunoblotting. Thus, the ELISA with synthetic peptides is an extremely sensitive and specific test of antibody response to HIV and has not yet yielded a negative result with a Western blot (immunoblot)-confirmed antibody-positive serum.     

Reporting basal cell carcinoma: a survey of the attitudes of histopathologists

AIMS: To investigate the histopathological reporting of basal cell carcinoma. METHODS: Methods of classification and attitudes to excision margins were ascertained from histopathologists in 130 centres; 82 replies were obtained (63% response rate). RESULTS: 24% of those replying did not use any classification system for basal cell carcinoma. The remainder (76%) used a wide variety of different classification systems. A small number (9%) of those questioned felt reporting on completeness of excision was not important. The majority of histopathologists considered the excision margin was worth reporting but there were differences in methods of processing and reporting biopsies. CONCLUSIONS: There is considerable variation in histopathological reporting of basal cell carcinoma. There is a need for uniformity of histopathological reporting to allow both improved management decisions and comparative audit of this extremely common skin cancer.     

Low-dose estrogen therapy for prevention of osteoporosis: working our way back to monotherapy

The risks of low bone mineral density, osteoporosis and fractures, are major concerns in postmenopausal women. Although postmenopausal hormone therapy is effective for reducing these risks, safety issues have been raised by the results of studies such as the Women's Health Initiative. Although there are scientifically valid reasons to be wary of the general applicability of the Women's Health Initiative findings, the study has underscored the continuing need for research into new forms of menopausal hormone therapy. Low-dose transdermal estrogen monotherapy can preserve bone density while relieving vasomotor symptoms. Transdermal administration may offer advantages, including lack of first-pass liver metabolism, which permits the use of lower doses and avoids a negative impact on the lipid profile. Moreover, a recently published 2-year study of ultra-low-dose transdermal estrogen monotherapy in an older population similar to that of the WHI reported significant increases in bone mineral density, accompanied by significant reductions in markers of bone turnover, with no increased risk of endometrial hyperplasia or other side effects. Additional studies are warranted to shed further light on the possible benefits of low-dose estrogen monotherapy for the prevention of bone loss in postmenopausal women.     

Patterns of workplace harassment, gender, and use of services: an update

Using three waves of data from an ongoing study of current and former university employees (N = 1,656), the authors reexamined the roles of sexual (SH) and generalized (GWH) workplace harassment and gender in predicting use of professional services by focusing on patterning (chronic, remission, onset, intermittent, and never harassed). The authors also reexamined whether services moderated relationships between SH and GWH patterns and drinking and mental health outcomes. All patterns of SH, but only chronic GWH, predicted increased odds of services use. Services use did not moderate relationship between SH patterns and outcomes, but was associated with lower alcohol consumption for men with GWH remission or chronicity, reduced escape drinking for those with GWH remission, and reduced hostility for those with intermittent GWH.     

Neurocognitive Functioning in Patients with 22q11.2 Deletion Syndrome: A Meta-Analytic Review

The 22q11.2 deletion syndrome (22q11.2DS) is a known risk factor for development of schizophrenia and is characterized by a complex neuropsychological profile. To date, a quantitative meta-analysis examining cognitive functioning in 22q11.2DS has not been conducted. A systematic review of cross-sectional studies comparing neuropsychological performance of individuals with 22q11.2DS with age-matched healthy typically developing and sibling comparison subjects was carried out. Potential moderators were analyzed. Analyses included 43 articles (282 effects) that met inclusion criteria. Very large and heterogeneous effects were seen for global cognition (d = ? 1.21) and in specific neuropsychological domains (intellectual functioning, achievement, and executive function; d range = ? 0.51 to ? 2.43). Moderator analysis revealed a significant role for type of healthy comparison group used (typically developing or siblings), demographics (age, sex) and clinical factors (externalizing behavior). Results revealed significant differences between pediatric and adult samples, with isolated analysis within the pediatric sample yielding large effects in several neuropsychological domains (intellectual functioning, achievement, visual memory; d range = ? 0.56 to ? 2.50). Large cognitive deficits in intellectual functioning and specific neuropsychological variables in individuals with 22q11.2DS represent a robust finding, but these deficits are influenced by several factors, including type of comparison group utilized, age, sex, and clinical status. These findings highlight the clinical relevance of characterizing cognitive functioning in 22q11.2DS and the importance of considering demographic and clinical moderators in future analyses.     

Severe hypotension after interscalene block for outpatient shoulder surgery: a case report

The case of a 43 year-old woman who underwent successful right interscalene brachial plexus block for arthroscopic shoulder surgery is presented. During the surgery, she subsequently exhibited signs of neuraxial spread of local anesthetic. Bilateral motor block was noted postoperatively. Spontaneous ventilation was maintained throughout the case, and she was successfully discharged home several hours after the procedure with no residual symptoms.     

Spatiotemporal localization of periostin and its potential role in epithelial-mesenchymal transition during palatal fusion

The medial epithelial seam (MES) between the palatal shelves degrades during palatal fusion to achieve the confluence of palatal mesenchyme. Cellular mechanisms underlying the degradation of MES have been proposed, such as apoptosis, epithelial-mesenchymal transition (EMT) and migration of medial edge epithelia (MEE). Extracellular matrix components have been shown to play an important role in EMT in many model systems. Periostin (also known as osteoblast-specific factor-2) is a secreted mesenchymal extracellular matrix component that affects the ability of cells to migrate and/or facilitates EMT during both embryonic development and pathologic conditions. In this study, we evaluated the spatiotemporal expression patterns of periostin during mouse palatal fusion by in situ hybridization and immunofluorescence. Periostin mRNA and protein were present in the palatal mesenchyme, the protein being distributed in a fine fibrillar network and in the basement membrane, but absent from the epithelium. During MES degradation, the protein was strongly expressed in the basement membrane underlying the MES and in some select MEE. Confocal microscopic analysis using an EMT marker, twist1, and an epithelial marker, cytokeratin 14, provided evidence that select MEE were undergoing EMT in association with periostin. Moreover, the major extracellular matrix molecules in basement membrane, laminin and collagen type IV were degraded earlier than periostin. The result is that select MEE establish interactions with periostin in the mesenchymal extracellular matrix, and these new cell-matrix interactions may regulate MEE transdifferentiation during palatal fusion.