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Although both kidney and pancreas transplantation can restore renal and pancreatic endocrine functions, the accompanying immunosuppression may cause diminished glucose tolerance in some individuals. Therefore, we determined to what extent pancreas transplantation itself and the triple immunosuppressive therapy used in pancreas transplant recipients have adverse effects on insulin secretory reserve. Beta-cell secretory reserve was assessed by the method of glucose potentiation of arginine-induced insulin secretion in 25 normoglycemic pancreas recipients, 12 nondiabetic kidney recipients using the same immunosuppressive therapy, 3 psoriasis patients treated long term with cyclosporine, 5 arthritis patients treated long term with prednisone, and their respective sex-, age-, and body mass index-matched control subjects. Levels of fasting glucose, HbA1c, and glucose disappearance rates were normal in all subjects. During the glucose potentiation study, pancreas recipients had significantly less insulin secretion than control subjects (maximal acute response [ARmax] = 1,083 +/- 93% vs. 3,938 +/- 355%, P < 0.001). Insulin responses were also decreased in kidney recipients (ARmax = 2,296 +/- 290%) vs. control subjects (4,691 +/- 554%, P = 0.001) and in psoriasis patients treated with cyclosporine (ARmax = 2,153 +/- 390%) vs. control subjects (3,962 +/- 88%, P = 0.011), but not as extreme as that seen in pancreas recipients. No abnormalities were observed in arthritis patients treated with steroids. We conclude that normoglycemic pancreas and kidney transplant recipients receiving triple immunosuppressive therapy have diminished beta-cell secretory reserve. Because this defect was present in psoriasis patients treated long term with cyclosporine, but not in arthritis patients treated long term with prednisone, this adverse effect was probably caused in part by cyclosporine.
Diabetes 1994 Apr
PMID:Diminished insulin secretory reserve in diabetic pancreas transplant and nondiabetic kidney transplant recipients. 813 66

Recent advances in molecular biology have provided geneticists with ever-increasing numbers of highly polymorphic genetic markers that have made possible linkage mapping of loci responsible for many human diseases. However, nearly all diseases mapped to date follow clear Mendelian, single-locus segregation patterns. In contrast, many common familial diseases such as diabetes, psoriasis, several forms of cancer, and schizophrenia are familial and appear to have a genetic component but do not exhibit simple Mendelian transmission. More complex models are required to explain the genetics of these important diseases. In this paper, we explore two-trait-locus, two-marker-locus linkage analysis in which two trait loci are mapped simultaneously to separate genetic markers. We compare the utility of this approach to standard one-trait-locus, one-marker-locus linkage analysis with and without allowance for heterogeneity. We also compare the utility of the two-trait-locus, two-marker-locus analysis to two-trait-locus, one-marker-locus linkage analysis. For common diseases, pedigrees are often bilineal, with disease genes entering via two or more unrelated pedigree members. Since such pedigrees often are avoided in linkage studies, we also investigate the relative information content of unilineal and bilineal pedigrees. For the dominant-or-recessive and threshold models that we consider, we find that two-trait-locus, two-marker-locus linkage analysis can provide substantially more linkage information, as measured by expected maximum lod score, than standard one-trait-locus, one-marker-locus methods, even allowing for heterogeneity, while, for a dominant-or-dominant generating model, one-locus models that allow for heterogeneity extract essentially as much information as the two-trait-locus methods. For these three models, we also find that bilineal pedigrees provide sufficient linkage information to warrant their inclusion in such studies. We also discuss strategies for assessing the significance of the two linkages assumed in two-trait-locus, two-marker-locus models.
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PMID:Two-trait-locus linkage analysis: a powerful strategy for mapping complex genetic traits. 780 44

Vitamin D is absolutely essential for the maintenance of a healthy skeleton. Without vitamin D, children develop rickets and adults exacerbate their osteoporosis and develop osteomalacia. Casual exposure to sunlight is the major source of vitamin D for most people. During exposure to sunlight, ultraviolet B photons photolyze cutaneous stores of 7-dehydrocholesterol to previtamin D3. Previtamin D3 undergoes a thermal isomerization to form vitamin D3. Increased skin pigmentation, changes in latitude, time of day, sunscreen use, and aging can have a marked influence on the cutaneous production of vitamin D3. Once vitamin D3 is formed in the skin or ingested in the diet, it must be hydroxylated in the liver and kidney to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. It is now recognized that a wide variety of tissues and cells, both related to calcium metabolism and unrelated to calcium metabolism, are target sites for 1,25(OH)2D3. 1,25(OH)2D3 stimulates intestinal calcium absorption and mobilizes stem cells to mobilize calcium stores from bone. Noncalcemic tissues that possess receptors for 1,25(OH)2D3 respond to the hormone in a variety of ways. Of great interest is that 1,25(OH)2D3 is a potent antiproliferative and prodifferentiation mediator. As a result, 1,25(OH)2D3 and its analogs have wide clinical application in such diverse clinical disorders as rheumatoid and psoriatic arthritis; diabetes mellitus type I; hypertension; cardiac arrhythmias; seizure disorders; cancers of the breast, prostate, and colon; some leukemias and myeloproliferative disorders; chemotherapy-induced hair loss; and skin rejuvenation as well as skin diseases like psoriasis and ichthyosis.
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PMID:Noncalcemic actions of 1,25-dihydroxyvitamin D3 and clinical applications. 857 91

A large body of clinical experience on the adverse consequences of cytokine administration has accumulated since the last decade. Side-effects reported after the therapeutic use of cytokines has provided evidence that activation of the immune response may sometimes have deleterious consequences. Several effects appeared as a direct consequence of the immune activation induced by cytokines, e.g. flu-like reactions, vascular leak syndrome. Cytokine-induced exacerbation of underlying diseases or immune dysregulation were other complications of growing concern. Interferon-alpha (IFN-alpha) treatment has now been clearly linked with the exacerbation or the occurrence of several types of autoantibodies or autoimmune diseases (thyroiditis, systemic lupus erythematosus, hematologic disorders, insulin-dependent diabetes mellitus) or diseases involving altered cell-mediated immune functions (inflammatory dermatologic diseases, nephritis, pneumonitis, colitis). By contrast immunological side-effects of IFN-beta and IFN-gamma have been seldom reported. However, the extent of clinical experience with both of these cytokines is still very limited. Interleukin-2 (IL-2) has also been implicated in various conditions that may involve immunopathological processes (thyroid disorders, rheumatoid arthritis, dermatological diseases, interstitial nephritis). Growth factors have been more specifically linked with the development or the exacerbation of dermatological inflammatory diseases through neutrophils, monocytes/macrophages or eosinophils activation (e.g. cutaneous vasculitis and generalized cutaneous eruption, Sweet's syndrome, bullous eruption, psoriasis). Exacerbation of autoimmune thyroiditis was described with granulocyte-macrophage colony-stimulating factor (GM-CSF) only. The immunogenicity of cytokines is also of great relevance and the occurrence of antibodies binding IFN-alpha and IFN-beta, IL2 and GM-CSF have been reported. While the clinical significance of non-neutralizing antibodies is not clearly established, an absence of response or reversal of clinical efficacy has been described in patients developing neutralizing antibodies. Finally, several isolated reports have recently suggested that IFN-alpha treatment may be associated with several immunosuppressive effects while IL-2 is clinically associated with an increased incidence of infectious complications.
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PMID:Immune-mediated side-effects of cytokines in humans. 863 83

Immunoconjugates or immunotoxins (ITs) are targeting molecules which consist of a monoclonal antibody together with a toxin--thereby they can selectively kill target cells in a highly efficient manner. The use of ITs as a drug targeting approach is one of the most attractive research fields for tumor therapy; however, the study of ITs for the treatment of autoimmune diseases has been given little attention until recently. It has been shown that ITs could help alleviate the symptoms of myasthenia gravis and rheumatoid arthritis in animal models. In the last 3 yr ITs have been used in clinical trials (phase I and phase II) for the treatment of various autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, insulin-dependent diabetes mellitus and psoriasis. This article reviews the main progress on the application of ITs for the therapies of autoimmune diseases. The preliminary results suggest the future may hold some promise, but side effects, in addition to there being no convincing efficacy, remain unresolved.
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PMID:Are immunoconjugates useful for therapy with autoimmune diseases? 927 78

1. Autoimmune diseases are common conditions which appear to develop in genetically susceptible individuals, with expression of disease being modified by permissive and protective environments. Familial clustering and data from twin studies provided the impetus for the search for putative loci. Both the candidate gene approach in population-based case-control studies and entire genome screening in families have helped identify susceptibility genes in a number of autoimmune diseases. 2. After the first genome screen in type 1 (insulin-dependent) diabetes mellitus it seems likely that most autoimmune diseases are polygenic with no single gene being either necessary or sufficient for disease development. Of the organ-specific autoimmune diseases, genome screens have now been completed in insulin-dependent diabetes mellitus and multiple sclerosis. Furthermore, the clustering of autoimmune diseases within the same individuals suggests that the same genes may be involved in the different diseases. This is supported by data showing that both HLA (human leucocyte antigen) and CTLA-4 (cytotoxic T-lymphocyte-associated-4) appear to be involved in the development of insulin-dependent diabetes mellitus and Graves' disease. 3. Genome screens have also been completed in some of the non-organ-specific autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis. Many candidate genes have also been investigated although these are predominantly in population-based case-control studies. 4. Substantial progress has been made in recent years towards the identification of susceptibility loci in autoimmune diseases. The inconsistencies seen between case-control studies may largely be due to genetic mismatching between cases and controls in small datasets. Family-based association studies are being increasingly used to confirm genetic linkages and help with fine mapping strategies. It will, however, require a combination of biology and genetics, as has been necessary with the major histocompatibility complex in insulin-dependent diabetes mellitus, to identify primary aetiological mutations.
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PMID:Genetic susceptibility to the development of autoimmune disease. 949 84

The aim of this retrospective study was to characterise the clinical presentation and disease associations of Oriental patients with gout seen in our hospital over a six-month period. One hundred patients comprising of 77 males and 23 females [89% Chinese, 7% Malays, 2% Indians and 2% others; mean age was 50.9 years (range 18 to 82 years), mean age at onset of disease was 43.7 years (range 16 to 78 years)] were studied. The disease was familial in 18% and 44% of patients had a history of alcohol ingestion. Co-morbid conditions included hypertension (36%), hyperlipidaemia (25%), renal failure (17%), ischaemic heart disease (13%), diabetes mellitus (4%), systemic lupus erythematosus (3%), psoriasis (2%) and ankylosing spondylitis (1%). The majority of patients (68%) had at least one associated disease. At the onset of disease, the joints commonly involved were the ankles (39%) and knees (27%) whilst the first metatarsophalangeal (MTP) joint was affected in only 26% of cases. Polyarticular onset was uncommon (n = 6). The precipitating factors reported by the patients included food (n = 23), alcohol (n = 12), drugs (n = 4), trauma (n = 3) and surgery (n = 2). Eleven patients had a history of renal calculi and 15% had tophaceous gout. Majority of patients (71%) had been treated with urate-lowering drugs (allopurinol). We concluded that gout in Singapore predominantly affects middle-aged men who often have an accompanying illness.
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PMID:Clinical presentation and disease associations of gout: a hospital-based study of 100 patients in Singapore. 958 67

With the aim to assess the prevalence and the main clinical correlations of skin lesions in diabetes mellitus, 457 diabetic subjects consecutively attending an outpatient clinic underwent a dermatological examination. Neurovascular foot lesions were excluded. Thirty-five of 64 IDDM patients (54%) had skin alterations mainly consisting of vitiligo (9% of all patients), psoriasis (9%) and eczema (8%). The most frequent skin lesions observed in 240/393 NIDDM subjects (61%) were represented by infections (20% of all patients) and diabetic dermopathy (12.5%), while other lesions were not common. NIDDM patients with skin infections had a worse metabolic control, and those with diabetic dermopathy had a greater prevalence of neuropathy and large vessel disease than patients without skin lesions. These data show that the prevalence of skin diseases in a large, unselected diabetic population is higher than expected and indicate that, in most cases, a careful dermatological examination and a better metabolic control are needed in order to improve quality of life in these patients.
Diabetes Res Clin Pract 1998 Feb
PMID:Skin lesions in diabetes mellitus: prevalence and clinical correlations. 959 79

Aggregation and disaggregation kinetics of erythrocytes in samples of whole blood were studied using a backscattering nephelometry technique. Blood was drawn from normal subjects and from patients suffering from different diseases: chronic glomerulonephritis, systemic lupus erythematosus, hereditary hypercholesterolemia, pulmonary hypertension, intestinal tumors preoperatively (age > 60 years), psoriasis, psoriatic arthritis, ischemia and ischemia with diabetes. Blood samples of healthy donors were used as controls. The backscattering signal in the erythroaggregometer was processed according to algorithms yielding quantitative data on the full amplitude of aggregation, characteristic times of spontaneous aggregation, average hydrodynamic strength of all aggregates and, whenever possible, additionally, strength of the largest aggregates. The obtained results confirm that the complexity of erythrocyte aggregation kinetics requires multiparametric description which, when applied to clinical material, enables the differentiation of aggregation characteristics between diseases.
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PMID:Clinical application of the measurement of spontaneous erythrocyte aggregation and disaggregation. A pilot study. 969 29

Human autoimmune diseases are thought to develop through a complex combination of genetic and environmental factors. Genome-wide linkage searches of autoimmune and inflammatory/immune disorders have identified a large number of non-major histocompatibility complex loci that collectively contribute to disease susceptibility. A comparison was made of the linkage results from 23 published autoimmune or immune-mediated disease genome-wide scans. Human diseases included multiple sclerosis, Crohn's disease, familial psoriasis, asthma, and type-I diabetes (IDDM). Experimental animal disease studies included murine experimental autoimmune encephalomyelitis, rat inflammatory arthritis, rat and murine IDDM, histamine sensitization, immunity to exogenous antigens, and murine lupus (systemic lupus erythematosus; SLE). A majority (approximately 65%) of the human positive linkages map nonrandomly into 18 distinct clusters. Overlapping of susceptibility loci occurs between different human immune diseases and by comparing conserved regions with experimental autoimmune/immune disease models. This nonrandom clustering supports a hypothesis that, in some cases, clinically distinct autoimmune diseases may be controlled by a common set of susceptibility genes.
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PMID:Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. 970 86


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