Cytokine production, activation marker, and skin homing receptor in children with atopic dermatitis and bronchial asthma

T cells are known to develop a critical role in the pathogenesis of atopic dermatitis (AD) and bronchial asthma. T cells involved in AD express the skin homing receptor CLA, but no lung homing receptor has been identified in bronchial asthma. We compared different cell markers and the cytokine production in T cells from children with AD or bronchial asthma. We studied the involvement of CLA+ and CLA- T-cell subpopulations in these diseases. We studied 20 children with acute AD lesions, 15 with mild persistent asthma, and 15 non-atopic controls. All patients were sensitized to house dust mite (DP) and evaluated during the acute phase. Total and specific IgE were measured by immunoassay and the expression of different cell markers and the cytokine production was analyzed by flow cytometry in peripheral blood mononuclear cells. Total IgE was significantly higher in AD children and IgE to DP in the asthmatic children. There was a significant increase in CD25+ CD4+ cells in asthmatic children and in HLA-DR+ CD4+ and HLA-DR+ CD8+ cells in AD. In the CD4+ subsets, there was an increase in IL-13, IL-5 and TNF-alpha in AD compared to controls, a decrease in IFN-gamma in asthmatic children compared to controls, and an increase in IL-13, IL5, IL2, TNF-alpha, and IFN-gamma in the AD compared to asthmatic children. Changes in cytokine production were mainly detected in CLA+ cells in AD and in CLA- cells in asthma. Differences exist in total and specific IgE, activation markers, and cytokine patterns between AD children and children with asthma, with the former expressing a Th2 pattern whereas in asthmatic children we only detected a decrease in IFN-gamma. Moreover, the subpopulations (CLA+ vs. CLA-) expressing these changes were different, indicating that the underlying mechanisms in the two diseases are not exactly the same.     

Skin cancers and precancerous lesions in Parkinson's disease patients.

Our objective was to evaluate the frequency of neoplastic and preneoplastic skin lesions in Parkinson's disease (PD) patients when compared with an aged-matched population. We performed a cross-sectional survey in PD patients and in an age-matched control group. Patients and controls were examined by a movement disorder specialist and a dermatologist. 150 PD patients and 146 controls were included. Thirty-five PD patients (23.3%) presented skin lesions that could be classified as neoplastic or preneoplastic vs. 20 subjects in the control group (13.7%) (OR 95%, CI 1.92 [1.05, 3.51]). However, this difference lost statistical significance when adjusted for gender (recruitment of controls was matched just for age with an over representation of males in the PD group). Twenty-nine PD patients (19%) presented actinic keratosis and basal cell carcinoma was diagnosed in 4 patients (3%). Although nonconclusive, our results are in agreement with previous studies suggesting an increased risk of skin cancer in PD patients. The frequency of actinic keratosis in PD patients and the associated risk to develop melanoma recommends its screening in future epidemiological studies.     

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan.

This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.     

A comparision of brain biopsy and CSF-PCR in the diagnosis of CNS lesions in AIDS patients

Twenty patients with AIDS who had intracranial lesions underwent both brain biopsy and cerebro-spinal fluid (CSF) examination to compare histological diagnosis with the polymerase chain reaction (CSF-PCR) for the identification of infectious agents. CSF-PCR was performed for herpes simplex virus, varicella zoster virus, cytomegalovirus (CMV), JC virus (JCV), Epstein-Barr virus (EBV), Toxoplasma gondii and Mycobacterium tuberculosis. A definitive diagnosis was obtained by brain biopsy in 14 patients (2 with astrocytoma, 12 with brain infection). CSF-PCR was positive for EBV DNA in 3 of 3 cases of primary cerebral lymphoma, positive for JCV DNA in 6 of 7 biopsy-proven (and one autopsy-proven) cases of progressive multifocal leukoencephalopathy (PML). CSF-PCR was positive for CMV DNA in one biopsy-proven and one autopsy-proven case of CMV encephalitis (the former also had PML) and positive for M. tuberculosis DNA in one case of tuberculous encephalitis. None of the five toxoplasmic encephalitis cases (one definite, four presumptive) were T. gondii DNA positive. There was close correlation between histology and CSF-PCR for CMV encephalitis, PML and PCL. Antitoxoplasma therapy affected the sensitivity of both histological and CSF-PCR methods. Received: 8 November 1995 Received in revised form: 9 July 1996 Accepted: 19 July 1996     

Genetic analysis of seven Mediterranean families with multiple endocrine neoplasia type 2A

OBJECTIVE   Genetic analysis is now essential for the accurate screening of families with multiple endocrine neoplasia type 2 (MEN2). We present the genetic analyses by both haplotype and direct RET proto-oncogene mutation analysis in seven Mediterranean MEN 2A families and have compared these results with biochemical screening tests and pathological examinations.
DESIGN  Total DNA was extracted from leucocytes. Linkage analysis was performed using five RFLP systems from three loci that flank the MEN2A locus (FNRB, RBP3, D10S15). RET proto-oncogene analysis was carried out by automatic DNA sequencing and adequate digestion of PCR amplified products for exons 10 and 11. Screening for medullary thyroid carcinoma or C-cell hyperplasia was performed by the pentagastrin provocation test. Adrenal medullary function was assessed by measurements of 24-hour urinary excretion of catecholamines and their metabolites. Serum calcium and phosphate measurements were the initial screen for hyperparathyroidism. Serum PTH was determined only if hyperparathyroidism was suggested by the former determinations.
PATIENT   Genetic study was performed in 59 individuals (39 at risk) from seven kindreds of Mediterranean origin with MEN 2A.
RESULTS   Diagnosis by linkage analysis was not possible in 30% of individuals at risk, but RET proto-oncogene analysis identified all these individuals. Mutations of the RET proto-oncogene were detected in exon 10 (codon 618) in one MEN 2A kindred and in exon 11 (codon 634) in the others. The results of direct analysis were concordant with linkage studies in each case. Three individuals from different MEN 2A kindreds, who were subsequently shown not to be gene carriers, had false positive pentagastrin stimulation tests.
CONCLUSION   Biochemical tests can be replaced by direct DNA mutation analysis as the first line screening test in order to identify gene carriers of MEN 2A.     

Spontaneous coronary artery dissection mimicking aortic dissection

A 51-year-old woman suffered rapidly irreversible cardiogenic shock with left hemiparesis. Transesophageal echocardiography, which represents an essential imaging tool in the emergency room, ruled out aortic dissection involving branch vessels but did not allow an in vivo diagnosis of spontaneous coronary dissection. The in vivo diagnosis of spontaneous coronary dissection is rather difficult because of the dramatic clinical presentation and selective coronary angiography requirement.     

The molecular basis of Natural Killer (NK) cell recognition and function

Natural Killer cells are likely to play an important role in the host defenses because they kill virally infected or tumor cells but spare normal self-cells. The molecular mechanism that explains why NK cells do not kill indiscriminately has recently been elucidated. It is due to several specialized receptors that recognize major histocompatibility complex (MHC) class I molecules expressed on normal cells. The lack of expression of one or more HLA class I alleles leads to NK-mediated target cell lysis. Different types of receptors specific for groups of HLA-C, HLA-B, and, very recently, HLA-A alleles have been identified. While in most instances, they function as inhibitory receptors, an activatory form of the HLA-C-specific receptors has been identified in some donors. Molecular cloning of HLA-C-, HLA-B- or HLA-A-specific receptors has revealed new members of the immunoglobulin superfamily with two or three Ig-like domains, respectively, in their extracellular portion. While the inhibitory form is characterized by a long cytoplasmic tail associated with a non-polar transmembrane portion, the activatory one has a short tail asociated with a Lys-containing transmembrane portion. Thus, these human NK receptors are different from the murine Ly49, that is a type II transmembrane protein characterized by a C-type lectin domain. A subset of activated T lymphocytes expresses NK-type class I-specific receptors. These receptors exert an inhibiting activity on T cell receptor-mediated functions and may provide an important mechanism of downregulation of T cell responses.     

An ELISA serum assay for autoantibodies to HSP70 in immune-mediated hearing loss

A Western blot to detect anti-HSP70 autoantibodies has been reported to be of diagnostic value for immune-mediated hearing loss patients. While setting up this Western blot in our lab, we detected two main problems. First, some patients were positive for antibodies to a 70-kDa protein when tested against a whole cell lysate, but negative if the antigen used was purified HSP70. Second, if high amounts of purified HSP70 were loaded on the gel, both patients and healthy controls were positive. We have developed and optimized an ELISA as an alternative to the Western blot. This assay is more appropriate to identify positive and negative individuals because it is semi-quantitative. The ELISA is also more sensitive, requiring very low concentrations of the antigen and thus minimizing false positives. Finally, we demonstrated that immune-mediated hearing loss patients recognize mainly the native form of HSP70, a fact that potentially leads to false negatives when a denaturing Western blot assay is used for diagnosis. To test the diagnostic value of the ELISA, we performed a blind test with 70 hearing loss patients, as well as 30 healthy controls. A sensitivity of 84% and a specificity of 93% were obtained, superior to what has been reported so far for the Western blot.