Biomedical subjects
Publications and source records attributed to J Goldblatt.
We reviewed the cutaneous manifestations of type I non-neuropathic Gaucher disease in fifty South African patients. Characteristic changes such as diffuse pigmentation, easy tanning and flitting brown macules were found to be useful pointers to the diagnosis. Other cutaneous changes secondary to infiltration of the marrow and liver were common and important findings.
Plasma lipid and serum apoprotein concentrations were determined in twenty-nine individuals with Gaucher type I disease. Plasma total cholesterol, low density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol were all significantly reduced in the patients with Gaucher disease compared to a group of matched control subjects. Total, LDL and HDL cholesterol were lower in males than in females with Gaucher disease. These sex differences appeared to be inversely correlated with the severity of disease manifestations which were greater in the males. Serum levels of apoprotein-B and apoprotein-AI, the major structural apoproteins of LDL and HDL, respectively, were decreased in the subjects with Gaucher disease. Thus, the reductions in LDL and HDL cholesterol were associated with reduced numbers of lipoprotein particles in plasma. In contrast, apoprotein-E, a protein which is secreted by several tissues, including activated macrophages and which may mediate hepatic catabolism of lipoproteins, was elevated in the patients. Since macrophages may also catabolize lipoproteins, Gaucher disease may serve as a model for the effect of activated macrophages upon human lipoprotein metabolism.
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Inhibitors and activators of acid beta-glucosidase activity were used as probes to characterize the components of the active site of the membrane bound enzyme, acid beta-glucosidase. Three components of the active site were defined: (1) a catalytic site, (2) an aglycon binding site, and (3) a hydrophobic binding site (Fig. 5A). Similar studies on the residual acid beta-glucosidase in homozygotes with Type 1 Ashkenazi Gaucher disease suggested that this enzyme's hydrophobic site was more hydrophilic than that of the normal enzyme. The defect in this membranous enzymopathy could have resulted from a single base substitution in the structural gene leading to the insertion of a more hydrophilic amino acid in the hydrophobic domain of the gene product. Alternatively, a base substitution which altered the conformation of the enzyme could render the hydrophobic site more hydrophilic. The following consequences of such a mutation would be expected. The mutation would not affect substrate binding to the catalytic site, since the formation of the enzyme-substrate complex (ie, the Km) would not be altered. If the HS site became more hydrophilic, its efficiency for removing the product would be reduced, resulting in a lower substrate turnover (ie, a "Vmax mutation"). Consequently, the binding of glucosyl psychosine, taurocholate, and phosphatidyl serine to the hydrophobic site would be less efficient, resulting in a greater alpha Ki value. Finally, the binding of taurocholate to the HS would be reduced, and this lipid's enhancement of acid beta-glucosidase inhibition by OBG also would be decreased. Since these results are based on kinetic data, confirmation of the hypothesis will require the preparation of homogenous beta-glucosidase from normal and Type 1 Ashkenazi Gaucher sources for amino acid sequencing of the peptides containing the catalytic site as well as the other components of the active site. Such peptides might be identified by their ability to bind radiolabeled inhibitors and/or activating compounds.
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The mucocutaneous lymph node syndrome, first noted in 1961 by Kawasaki in Japan, is an acute, febrile mucocutaneous condition accompanied by cervical lymphadenopathy, which affects infants and young children. More recently it has been recognized in other countries, but not before 1979 in South Africa.
The chronic non-neuropathic form of Gaucher disease has been encountered in 10 individuals in the Afrikaner population of South Africa. The minimum prevalence in this community is 1 in 200 000 with a gene frequency of 0,0022, a heterozygote rate of 0,0044 and at least 9 000 clinically asymptomatic carriers of the abnormal gene. This gene must be present in about 1 in every 220 Afrikaners. The majority of previously reported patients have been Ashkenazi Jews, in whom the condition is relatively benign. By contrast, the disorder in the Afrikaners is precocious in onset, with serious complications and rapid progression. The occurrence of Gaucher disease in a relatively high frequency in the Afrikaner population is important in terms of differential diagnosis, genetic counselling and prevention.
The non-neuropathic form of Gaucher's disease was diagnosed in 11 children of non-Jewish ancestry in South Africa; all were under the age of 4. None had any neurological involvement and, apart from the precocious presentation and rapid course, the features in each resembled those of the classical 'adult' or chronic non-neuropathic form of Gaucher disease. By contrast, the condition presented after puberty in 24 out of 28 Ashkenazi Jews who were studied during the same investigation. Activity of beta-glucosidase was defective in both groups of patients and they could not be distinguished by histological criteria. Only one child with the infantile neuropathic form of Gaucher disease was identified during the survey. The preponderance of the atypical non-neuropathic form of the disorder in young children is of practical importance from the point of view of differential diagnosis in any child with hepatosplenomegaly.
The adult non-neuropathic form of Gaucher's disease has been identified in 32 patients in 25 Ashkenazi Jewish kindreds in South Africa. The minimum prevalence in this population is 1 in 5000, with a gene frequency of 0.014 and a carrier rate of 1 in 36. On correction for bias resulting from possible under-ascertainment, these minimum figures become 1 in 4000, 0.0166, and 1 in 30, respectively. Confirmation of autosomal recessive inheritance was obtained by segregation analysis by the 'a priori' and 'simple sib' methods. The Ashkenazin of South Africa have their origins in Lithuania and it is evident that the high gene frequency in South Africa is a reflection of the genetic constitution of the immigrant population. The localisation of the Gaucher gene to Lithuania represents a further step in the determination of the early geographic distribution of the genetic disorders of the Jewish race.
BACKGROUND: Increasing evidence suggests that patterns of T-cell immunity to inhalant allergens in genetically diverse human populations are more heterogeneous than previously assumed, and that covert differences in expression patterns might underlie variations in airway disease phenotypes. We tested this proposition in a community sample of children. METHODS: We analysed data from 172 individuals who had been recruited antenatally to a longitudinal birth cohort study. Of the 194 birth cohort participants, data from the 147 probands (age range 8.6-13.5 years) who consented to blood collection were included along with data from 25 consenting siblings (mean age 11 years [range 7.4-17.4]). We ascertained clinical phenotypes related to asthma and allergy. We measured T-cell responses to allergens and mitogens, together with blood eosinophils and IgE/IgG antibodies, and assessed associations between these indices and clinical phenotypes. FINDINGS: Atopy was associated with allergen-specific T-helper (Th)2 responses dominated by interleukin 4, interleukin 5, interleukin 9, interleukin 13, whereas interleukin 10, tumour necrosis factor alpha, and interferon gamma responses were common to both atopics and non-atopics. The wheal size from skin prick with allergen was positively associated with in-vitro interleukin 5 and interferon gamma responses, and negatively associated with interleukin 10. Asthma, especially in atopics, was strongly associated with eosinophilia/interleukin 5, and bronchial hyper-responsiveness (BHR) was associated with eosinophilia plus polyclonal interferon gamma production. BHR in non-atopics was associated with elevated allergen-specific and polyclonal interleukin 10 production. INTERPRETATION: Parallel immunological and clinical profiling of children identified distinctive immune response patterns related to asthma and wheeze compared with BHR, in atopics non-atopics. Immunological hyper-responsiveness, including within the Th1 cytokine compartment, is identified as a hallmark of BHR. RELEVANCE TO PRACTICE: These findings highlight the heterogeneity of immune response patterns in asthmatic children, including those with seemingly homogeneous Th2-driven atopic asthma. Further elucidation of the covert relationships between wheezing phenotypes and underlying immunophenotypes in this age group will potentially lead to more effective treatments for what is an unexpectedly heterogeneous collection of disease subtypes.
We conducted a multicenter evaluation of the analytical and clinical performance of the automated Bayer Immuno 1 complexed PSA (cPSA) assay, and compared assay performance to the Bayer Immuno 1 PSA assay. We sought to determine whether measurements of cPSA could be of clinical utility in the management of patients with prostate cancer. Results of the 10-day imprecision across three evaluation sites produced total CV < 2.50% and an analytical sensitivity of 0.02 microgram/L. There was an increased trend in clinical sensitivity for prostate cancer with increasing stage of disease (71-86%). Clinical specificity for patients with benign urogenital disease was 74.8%, and for other nonprostate diseases ranged from 91.1-100%. Retrospective serial monitoring of 155 patients with prostate cancer demonstrated concordance of cPSA measurements to clinical status for 97% of the patients analyzed. Results from the clinical studies using the Bayer Immuno 1 cPSA assay were comparable to results obtained with the Bayer Immuno 1 PSA assay. The Bayer Immuno 1 cPSA assay demonstrates analytical performance and clinical effectiveness in the management of prostate cancer patients during the course of disease and therapy.
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Orthopedic problems are an important feature of the adult, chronic or non-neuropathic form of Gaucher disease. Thirty-five South African patients have been investigated and of these 29 had significant skeletal complications. Twenty-one had nonspecific bone pains, 14 had episodes of pseudoosteomyelitis and 2 had acute hematogenous osteomyelitis. Twenty experienced collapse of femoral heads and in 9, prosthetic joint replacement had been successfully undertaken. Four had kyphoscoliosis due to wedging of vertebral bodies and three had pathological fractures of tubular bones. Twenty-eight of the patients were of Askhenazi Jewish stock and the minimum prevalence of the disorder in this group in South Africa is one in 4,300. If skeletal problems and splenomegally coexist in a Jewish patient, the diagnosis of Gaucher disease warrants serious consideration.