Effects of pimecrolimus cream 1% in the treatment of patients with atopic dermatitis who demonstrate a clinical insensitivity to topical corticosteroids: a randomized, multicentre vehicle-controlled trial.

BACKGROUND: Colonization with Staphylococcus aureus in atopic dermatitis (AD) is often associated with worsening of clinical symptoms. Staphylococcus aureus produces superantigens that contribute to cutaneous inflammation and corticosteroid (CS) resistance. OBJECTIVES: To investigate the relationship between CS insensitivity, S. aureus colonization and superantigen production in AD, and to explore the efficacy of pimecrolimus cream in CS-insensitive AD. METHODS: This was a randomized, double-blind, vehicle-controlled, multicentre, parallel-group study. Seventy-three patients with AD, aged 2-49 years, who had a documented clinical insensitivity to topical CS, were recruited. The primary efficacy parameters combined laboratory (including S. aureus colonization, superantigens) and clinical assessments [including Eczema Area and Severity Index (EASI), whole body Investigator's Global Assessment (IGA), pruritus assessment score, patient's assessment score of disease control]. RESULTS: An increase in S. aureus counts correlated with worsening of clinical score (week 6 vs. baseline) when assessed by IGA, pruritus severity and patient assessment. The presence of superantigens correlated with this worsening. During the 6-week double-blind phase, disease improvement in the pimecrolimus cream group was demonstrated by decreasing EASI scores compared with vehicle. Mean EASI scores for the head and neck showed greater improvement in the pimecrolimus cream group than in the vehicle group at all observed time points. CONCLUSIONS: In a cohort of patients with clinical insensitivity to CS there was a significant positive correlation between S. aureus and disease severity. Results suggest that for some of these patients, treatment with pimecrolimus cream 1% is useful, especially in the head/neck area.

Exercise for treating fibromyalgia syndrome.

BACKGROUND: Fibromyalgia (FMS) is a syndrome expressed by chronic widespread body pain which leads to reduced physical function and frequent use of health care services. Exercise training is commonly recommended as a treatment. This is an update of a review published in Issue 2, 2002. OBJECTIVES: The primary objective of this systematic review was to evaluate the effects of exercise training including cardiorespiratory (aerobic), muscle strengthening, and/or flexibility exercise on global well-being, selected signs and symptoms, and physical function in individuals with FMS. SEARCH STRATEGY: We searched MEDLINE, EMBASE, CINAHL, SportDiscus, PubMed, PEDro, and the Cochrane Central Register for Controlled Trials (CENTRAL, Issue 3, 2005) up to and including July 2005. We also reviewed reference lists from reviews and meta-analyses of treatment studies. SELECTION CRITERIA: Randomized trials focused on cardiorespiratory endurance, muscle strength and/or flexibility as treatment for FMS were selected. DATA COLLECTION AND ANALYSIS: Two of four reviewers independently extracted data for each study. All discrepancies were rechecked and consensus achieved by discussion. Methodological quality was assessed by two instruments: the van Tulder and the Jadad methodological quality criteria. We used the American College of Sport Medicine (ACSM) guidelines to evaluate whether interventions had provided a training stimulus that would effect changes in physical fitness. Due to significant clinical heterogeneity among the studies we were only able to meta-analyze six aerobic-only studies and two strength-only studies. MAIN RESULTS: There were a total of 2276 subjects across the 34 included studies; 1264 subjects were assigned to exercise interventions. The 34 studies comprised 47 interventions that included exercise. Effects of several disparate interventions on global well-being, selected signs and symptoms, and physical function in individuals with FMS were summarized using standardized mean differences (SMD). There is moderate quality evidence that aerobic-only exercise training at recommended intensity levels has positive effects global well-being (SMD 0.44, 95% confidence interval (CI 0.13 to 0.75) and physical function (SMD 0.68, 95% CI 0.41 to 0.95) and possibly on pain (SMD 0.94, 95% CI -0.15 to 2.03) and tender points (SMD 0.26, 95% CI -0.28 to 0.79). Strength and flexibility remain under-evaluated. AUTHORS' CONCLUSIONS: There is 'gold' level evidence (www.cochranemsk.org) that supervised aerobic exercise training has beneficial effects on physical capacity and FMS symptoms. Strength training may also have benefits on some FMS symptoms. Further studies on muscle strengthening and flexibility are needed. Research on the long-term benefit of exercise for FMS is needed.

Detection of rare allelic variants of the interferon-alpha 2 gene in human genomic DNA.

We have analyzed human donor DNA for the presence of sequences corresponding to allelic variants of the IFN-alpha 2 locus. Using both restriction enzyme digestion of PCR-amplified fragments and sequence analysis of these fragments, we have identified the three reported allelic variants, IFN-alpha 2a, IFN-alpha 2b, and IFN-alpha 2c, in genomic DNA derived from donors of African or Afro-Caribbean origin. This is the first report of the IFN-alpha 2a and IFN-alpha 2c alleles occurring in human donor DNA and supports the view that these are variants of the predominant IFN-alpha 2b allele rather than arising from mutations occurring in cultured cells.

Cloning and sequence analysis of kappa and gamma cynomolgus monkey immunoglobulin cDNAs.

One gamma heavy chain and 10 kappa light chain cynomolgus monkey (Macaca fascicularis) immunoglobulin cDNAs have been cloned and sequenced. Comparisons of the variable (V) regions to human antibody sequences have revealed extensive identity, exhibiting 93% at the amino acid level for the VH framework regions, and 88-99% for the V kappa frameworks. Identification of very few cynomolgus monkey-specific framework region residues suggests a role for cynomolgus monkey antibodies as donators of variable regions to chimeric monoclonal antibodies for utilisation in human therapy with human constant (C) regions. The cynomolgus monkey C kappa region exhibited 83% amino acid identity to its human counterpart, and the C gamma region was 95, 93, 95, and 95% similar to the human C gamma 1, C gamma 2, C gamma 3, and C gamma 4 regions, respectively. Evolutionary analysis of the C gamma genes, using the silent molecular clock, suggests that the divergence between cynomolgus monkey and human occurred before the time at which the ancestral gamma gene diverged into the multiple isotypes observed in humans.

Maximizing the impact of dairy and beef bulls through breeding technology.

Both biological and monetary considerations influence adoption of new breeding technologies. Therefore, genetic, reproductive, and economic factors that determine productivity of dairy and beef operations are reviewed. Improved sire evaluation programs, more efficient artificial insemination, and effective natural service are discussed and related to the present and future impact of dairy and beef bulls. Potential benefits of heterosis, artificial control of reproduction, improved bull management, computers, and multidiscipline research also are suggested. The dramatic impact of artificial insemination on genetic improvement and profitability of most commercial dairy herds is outlined. The uncertain expansion of beef artificial insemination is examined. Comparisons of dairy and beef industries indicate that expectation of similar results from the same animal breeding technologies are unwarranted. Dairy artificial insemination is and should continue to be economically feasible for commercial operations. Commercial beef producers will use little artificial insemination and rely on natural service bulls until precise human control of conception in the bovine is cost effective.

Allergic contact eczema to phenylephrine.

A female patient developed periorbital eczema and conjunctivitis prior to cataract surgery. Investigations revealed an allergic contact eczema to phenylephrine hydrochloride 10% eyedrops being used preoperatively for mydriasis.

Controversies in obstetrics: dermatologic problems.

Skin disease in pregnancy generally produces increased concern among attending physicians. Not only is the diagnosis often a problem but the safety of the therapy may also be a concern. The author of this article presents three common skin problems and their treatments to illustrate the general principles used in diagnosis and treatment of skin disease during pregnancy.

High-risk workers: the eczematous hand.

The hand is the most commonly involved site in occupation - related skin disease, and contact eczema is the most common diagnosis. The identification of workers at high risk for this condition is possible and will help in their management and assessment.

Neonatal lupus erythematosus: five new cases with HLA typing.

In two of five infants with neonatal lupus erythematosus the signs of the disease did not appear until the children had been exposed to direct sunlight. This suggests that an environmental factor may be required for the development of the disease in some patients. Three of the five patients, together with their mothers, had the HLA (histocompatibility) antigens A1 and B8, which supports the concept that individuals may be genetically susceptible to lupus erythematosus.

Patch and photopatch testing in chronic actinic dermatitis.

Photopatch tests in 47 patients with chronic actinic dermatitis (CAD) showed musk ambrette to be the only significant allergen in our standard photopatch test series. The incidence of positive patch tests to a standard series of contact allergens in this group was compared with 213 men over the age of 50 years with eczema investigated in the contact clinic. Among the photosensitive patients, there was an increased incidence of reaction to thiuram-mix (CAD 10%; controls 3%), carba mix (CAD 6%; controls 1%), nickel sulphate (CAD 6%; controls 2%) and vioform (CAD 10%; controls 0.5%). A decreased incidence of reaction to potassium dichromate (CAD 0%; controls 8%) and balsam of Peru (CAD 4%; controls 10%) was recorded.

Rescue, expression, and analysis of a neutralizing human anti-hepatitis A virus monoclonal antibody.

A human anti-hepatitis A virus mAb was rescued from a hybridoma cell line by conventional cDNA cloning, and expressed in CHO cells. The full nucleotide sequences of the mAb H and L chains were determined, revealing a VHI/V lambda II V region combination. Comparisons with germline V genes suggest that the V regions had undergone somatic mutations characteristic of an Ag-driven immune response. A comparison of the binding to hepatitis A virus between mAb derived from the CHO cells and the original hybridoma cell line using ELISA, radioimmunoprecipitation, and solid-phase competition RIA, indicated that the CHO cell-derived mAb fully retained the specificity of the mAb produced by hybridoma cells. Analysis of viral neutralization using a radioimmunofocus inhibition assay demonstrated the retention of antibody functionality after expression in CHO cells, demonstrating the use of this technique in the rescue and high level expression of unstable efficacious human mAb.

Engineered anti-CD38 monoclonal antibodies for immunotherapy of multiple myeloma.

Multiple myeloma is a malignancy of plasma cells for which there is no effective treatment. To develop an immunotherapeutic agent, we have raised a high affinity mAb (AT13/5) against CD38, one of the few well-characterized surface Ags present on myeloma cells. Since murine monoclonals have many disadvantages as human therapeutics, we prepared two engineered forms of the Ab: a CDR-grafted humanized IgG1 and a chimeric FabFc2 (mouse Fab cross-linked to two human gamma 1 Fc). To retain affinity in the humanized Ab, a number of changes were required to the human framework regions of the heavy chain. In particular, through systematic mutagenesis and computer modeling, we identified a critical interaction between the side chains of residues 29 and 78, which may be important for the humanization of other Abs. The properties of the humanized IgG1 and FabFc2 constructs were compared in a series of in vitro tests. Both constructs efficiently directed Ab-dependent cellular cytotoxicity against CD38-positive cell lines, but C was activated only poorly. Neither construct caused down-modulation of CD38, nor did they affect the NADase activity of CD38. Despite their differing structures, both Abs showed similar activity in most assays, although the humanized IgG1 was more potent at inducing monocyte cytotoxicity. These data represent the first direct comparison of CDR-grafted and chimeric FabFc2 forms of the same Ab, and offer no support for the perceived advantages of the FabFc2. These Abs show promise for therapy of multiple myeloma and other diseases involving CD38-positive cells.

Interferon (IFN)-alpha 2 genotype analysis of Chinese chronic hepatitis B patients undergoing recombinant IFN-alpha 2a therapy.

Sixteen Chinese chronic hepatitis B virus (HBV)-infected patients were treated with recombinant interferon-alpha 2a (rIFN-alpha 2a). Of these, 8 made a response to IFN, with titers of neutralizing antibody of 141-4525 as determined by an antiviral neutralization bioassay. To determine whether the immunogenicity of the IFN was directly linked to the patients' genotype, their genomic DNA was analyzed for the presence of the human IFN-alpha 2a gene. None of the patients possessed the gene for IFN-alpha 2a, but only 50% developed neutralizing antibodies. The hypothesis, therefore, of a direct link between antibody formation and genotype cannot be sustained. Alternative explanations of the immunogenicity of IFN-alpha 2a must be sought.