Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome)

A cross-sectional survey in individuals affected with the lysosomal storage disease Mucopolysaccharidosis VI (MPS VI) was conducted to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of the disease. The survey evaluated 121 bona fide MPS VI-affected individuals over the age of 4 years from 15 countries across the Americas, Europe, and Australasia representing greater than 10% of the estimated world prevalence of the disease. A medical history, complete physical exam, urinary GAG determination, and assessment of several clinical measures related to physical endurance, pulmonary function, joint range of motion, strength, and quality of life were completed for each participant. Although a wide variation in clinical presentation was observed, several general findings were obtained reflecting progression of the disease. Impaired physical endurance, as measured by the distance achieved in a 6-min walk, could be demonstrated across all age groups of MPS VI-affected individuals. High urinary GAG values (>200 mug/mg creatinine) were associated with an accelerated clinical course comprised of age-adjusted short stature and low body weight, impaired endurance, compromised pulmonary function, and reduced joint range of motion. An unexpected result was the predominance of urinary GAG values <100 mug/mg creatinine for those participants over the age of 20 years. Pending the collection of longitudinal data, these results suggest that urinary GAG levels predict clinical morbidity, and longer-term survival is associated with urinary GAG levels below a threshold of 100 mug/mg creatinine.     

Evaluation of the mouse lymphoma tk assay (microwell method) as an alternative to the in vitro chromosomal aberration test

In order to evaluate the utility of the mouse lymphoma assay(MLA) for detecting in vitro clastogens and spindle poisonsand to compare it with the in vitro chromosomal aberration test(CA), we conducted an international collaborative study of theMLA that included 45 Japanese laboratories and seven overseaslaboratories under the cooperation of the Ministry of Healthand Welfare of Japan and the Japanese Pharmaceutical Manufacturer'sAssociation. We examined 40 chemicals; 33 were reportedly positivein the CA but negative in the bacterial reverse mutation assay,six were negative in both assays and one was positive in both.We assayed mutations of the thymidine kinase (TK) locus (tk)of L5178Y tk^+/– mouse lymphoma cells using the microwellmethod. According to our standard protocol, cells were exposedto the chemical for 3 h, cultured for 2 days and TK-deficientmutants were expressed in 96-well plates under trifluorothymidine.Each chemical was coded and tested by two or three laboratories.Among the 34 CA-positive chemicals, positive MLA results wereobtained for 20 and negative results were obtained for nine.The remaining five chemicals were inconclusive or equivocalbecause of discrepant inter-laboratory results or reproduceddiscrepant results, respectively. Among the six CA-negativechemicals, one was negative in the MLA, two were positive andthree were inconclusive. Thus, the MLA could detect only 59%(20/34) of CA-positive chemicals. We concluded that the MLAwas not as sensitive as the CA. Some MLA-negative chemicalsevoked positive responses in the CA only after long continuoustreatment. These might also be genotoxic in the MLA with longcontinuous treatment. Improvement of the MLA protocol, includingalteration of the duration of the treatment, might render theMLA as sensitive as the CA. ⁸ To whom correspondence should be addressed. Tel: +81 3 37009847; Fax: +81 3 3700 2348; Email: sofuni{at}nihs.go.jp     

Acquired factor XII deficiency in a woman with recurrent pregnancy loss: working on a differential diagnosis in a single case

Background  

Antiphospholipid syndrome (APS) has been often associated to RPL since 1980 and some reports in the Literature rarely described antibodies to factor XII in patients with APS.     

BRONCHIAL CARCINOID ACCOMPANIED BY THYROID ADENOMAS AND ADRENAL ADENOMAS

A large tumor massively occupying the left pleural cavity had the Andings of both typical carcinoid and oncocytoma which were thought to be of bronchogenic origin. The ultrastructural observation of the tumor revealed a mixture of rod-shaped granules in addition to usual round neurosecretory ones. In the nuclei of dark cells of the oncocytoma, a latticed or hatched structure was detected. Besides two adenomas and hyperplastic foci of large acidophilic cells in the thyroid, a black adenoma and cortical adenoma in the adrenal gland, were detected. Moreover, there was an ectopic adrenal gland in the retroperitoneum. Briefly it was suggested that the bronchial carcinoid presented may be related to multiple endocrine adenomatosis.     

Thyroid Carcinoma in Japan and the West: Similarities and Differences

Geographic or ethnic differences in the incidence of thyroid carcinoma, as well as in the histologic distribution of thyroid carcinoma between Japan and Western countries, have been described but are still unclear. The recent establishment of histologic criteria for the diagnosis of thyroid carcinoma by the WHO committee has facilitated the comparison of clinicopathological data of patients with thyroid carcinoma all over the world. The aim of the present review article is to clarify the epidemiological and clinicopathological differences of thyroid carcinoma between Japan and Western countries. We found recently no significant differences in the incidence, mortality, and histologic distribution of thyroid carcinoma between Japan and Western countries; this was contrary to our expectation. This is likely attributable to westernization of the Japanese diet, standardized medical levels, and international standardization of histologic criteria of thyroid carcinoma.     

Immune status and uptake of antiretroviral interventions to prevent mother-to-child transmission of HIV-1 in Africa

The aim of this study performed in Abidjan, C?te d'Ivoire, was to describe the distribution of CD4+ T-cell lymphocytes (CD4) in HIV-1-infected (HIV+) pregnant women diagnosed during prenatal voluntary counseling and testing and to assess whether HIV-related immunodeficiency influenced the acceptance of an antiretroviral (ARV) package (zidovudine beginning at 36 weeks of amenorrhea plus intrapartum nevirapine) to prevent mother-to-child transmission. Between April and June 2002, a CD4 count was systematically performed in all HIV+ women (n=221) in 5 antenatal clinics carrying out voluntary counseling and testing. No difference in CD4 count was found in HIV+ women who did not return for their test result (n=50) and those who were informed of their positive serostatus (n=171) (median CD4 count: 389/mm3 vs. 420/mm3; P=0.19). We also found a lack of difference in CD4 count in those who accepted ARV (n=72) and those who did not but knew their HIV status (n=99) (median CD4 count: 405/mm3 vs. 425/mm3; P=0.47). The overall uptake of the intervention (31.9%) appeared to be independent of the maternal immune status.     

Evidence on major gene control of cortical index in pedigree data from Middle Dalmatia,Croatia

It was recently reported that the inheritance of the metacarpal cortical index (CI) in the Chuvashian population can be described in terms of a major gene (MG) model. By applying transmission probability tests, the hypothesis was accepted that not only baseline level of CI but also its sex‐specific dependence on age were under control of the same putative large‐effect gene. Using a pedigree sample from the population of the islands of Middle Dalmatia, Croatia (847 observed individuals in 278 pedigrees), data are presented to support the above findings. The following hypotheses were accepted: (i) inheritance of baseline CI in the Croatian population can be attributed to the effect of a MG responsible for about 42% of the variation; (ii) the same MG takes part in the control of the dependence of CI on age, particularly the age at onset of involutive bone changes (inflection point), and of the rate of decrease in CI with age (slope coefficient). Issues related to the assortative mating effect on CI and the determination of the most parsimonious model are discussed. Am. J. Hum. Biol. 13:398–408, 2001. © 2001 Wiley‐Liss, Inc.     

Suppressive effect of leflunomide metabolite (A77 1726) on metalloproteinase production in IL-1beta stimulated rheumatoid synovial fibroblasts

Leflunomide, an isoxazol derivative structurally unrelated to other immunomodulatory drugs, has proven to be efficacious in the treatment of rheumatoid arthritis (RA). This study was conducted to elucidate the mechanism by which leflunomide mediated antirheumatic effects. We investigated the effects of A77 1726, leflunomide's active metabolite, on mitogen-activated protein kinase (MAPK) activation in IL-1beta-stimulated rheumatoid synovial fibroblasts. The effects of A77 1726 on the secretion of matrix metalloproteinases (MMPs) from rheumatoid synovial fibroblasts were also examined. A77 1726 partially suppressed IL-1beta-induced ERK1/2 and p38 kinase activation. In contrast, A77 1726 efficiently suppressed IL-1beta-stimulated JNK1/2 kinase activation. Although no suppressive effect was demonstrated on MMP-2, A77 1726 markedly inhibited MMP-1, 3, and 13 secretions from IL-1beta-stimulated rheumatoid synovial fibroblasts. Tissue inhibitor of metalloproteinases-1 (TIMP-1) was constitutively produced from rheumatoid synovial fibroblasts and the suppressive effects of A77 1726 on TIMP-1 production were minimal. Our results suggest that the suppression of the MAPK signalling pathway and MMP synthesis in rheumatoid synovial fibroblasts is a possible mechanism for the inhibitory activity of leflunomide against rheumatoid arthritis.     

Implementing a Stratified Vocational Advice Intervention for People on Sick Leave with Musculoskeletal Disorders: A Multimethod Process Evaluation

Journal of Occupational Rehabilitation - Purpose To perform a process evaluation of a stratified vocational advice intervention (SVAI), delivered by physiotherapists in primary care, for people on...