Oxygen supply by photosynthesis to an implantable islet cell device.

Transplantation of islet cells is an effective treatment for type 1 diabetes with critically labile metabolic control. However, during islet isolation, blood supply is disrupted, and the transport of nutrients/metabolites to and from the islet cells occurs entirely by diffusion. Adequate oxygen supply is essential for function/survival of islet cells and is the limiting factor for graft integrity. Recently, we developed an immunoisolated chamber system for transplantation of human islets without immunosuppression. This system depended on daily oxygen supply. To provide independence from this external source, we incorporated a novel approach based on photosynthetically-generated oxygen. The chamber system was packed sandwich-like with a slab of immobilized photosynthetically active microorganisms (Synechococcus lividus) on top of a flat light source (LEDs, red light at 660 nm, intensity of 8 µE/m(2)/s). Islet cells immobilized in an alginate slab (500-1,000 islet equivalents/cm(2)) were mounted on the photosynthetic slab separated by a gas permeable silicone rubber-Teflon membrane, and the complete module was sealed with a microporous polytetrafluorethylene (Teflon) membrane (pore size: 0.4 µm) to protect the contents from the host immune cells. Upon illumination, oxygen produced by photosynthesis diffused via the silicone Teflon membrane into the islet compartment. Oxygen production from implanted encapsulated microorganisms was stable for 1 month. After implantation of the device into diabetic rats, normoglycemia was achieved for 1 week. Upon retrieval of the device, blood glucose levels returned to the diabetic state. Our results demonstrate that an implanted photosynthetic bioreactor can supply oxygen to transplanted islets and thus maintain islet viability/functionality.

A novel device for islet transplantation providing immune protection and oxygen supply.

Islet transplantation as a biological ß-cell replacement therapy has emerged as a promising option for achieving restoration of metabolic control in type 1 diabetes patients. However, partial or complete loss of islet graft function occurs in relatively short time (months to few years) after implantation. The high rate of early transplant dysfunction has been attributed to poorly viable and/or functional islets and is mediated by innate inflammatory response at the intravascular (hepatic) transplant site and critical lack of initial nutrient/oxygen supply prior to islet engraftment. In addition, the diabetogenic effect of mandatory immunosuppressive agents, limited control of alloimmunity, and the recurrence of autoimmunity limit the long-term success of islet transplantation. In order to abrogate instant blood-mediated inflammatory reaction and to provide oxygen supply for the islet graft, we have developed an extravascular (subcutaneous) transplant macrochamber (the 'ßAir' device). This device contains islets immobilized in alginate, protected from the immune system by a thin hydrophilized teflon membrane impregnated with alginate and supplied with oxygen by daily refueling with oxygen-CO (2) mixture. We have demonstrated successful utilization of the oxygen-refueling macrochamber for sustained islet viability and function as well as immunoprotection after allogeneic subcutaneous transplantation in healthy minipigs. Considering the current limitations of intraportal islet engraftment and the restricted indication for islet transplantation mainly due to necessary immunosuppressive therapy, this work could very likely lead to remarkable improvements in the procedure and moreover opens up further strategies for porcine islet cell xenotransplantation.

Effect of polymorphism in insulin locus and HLA on type 1 diabetes in four ethnic groups in Israel.

This study examined a possible association of the insulin (INS) gene with type 1 diabetes (T1D) in patients and controls from four ethnic groups in Israel. We analyzed the distribution of -23HphI single nucleotide polymorphism (SNP) T/A alleles that correspond to INS variable number of tandem repeat short class I alleles (26-63 repeats) and class III alleles (141-209 repeats), respectively. The -23HphI T/T genotype was found to be positively associated with T1D in three Jewish groups (Yemenites: 93.9% patients vs 68.8% controls, P = 0.0002; Ashkenazi: 80.6% vs 50.8%, P < 10(-4); Ethiopians: 75% vs 40.5%, P = 0.002). The Yemenite healthy controls have the highest frequency of T allele from all Jewish groups studied (83.5% vs 68.8% in Ashkenazi and 64.3% in Ethiopians). The high frequency of a susceptibility allele in the Yemenites is in line with the high incidence of T1D in this population. No association was observed between T1D and the INS gene in Israeli Arabs studied (70.6% vs 66.7%). Variable incidence of T1D among different ethnicities in Israel is largely attributed to heterogeneous genetics. Human leukocyte antigen (HLA) results of our previous studies describing the susceptibility and protective haplotypes were used for combined analysis to determine possible interaction between the HLA and INS loci. Only in the Ashkenazi group such interaction was presented with statistical significance.

Immunohistochemical evaluation of hepatic oval cell activation and differentiation toward pancreatic beta-cell phenotype in streptozotocin-induced diabetic mice.

Oval cell (OvCs) involvement in regeneration is a well known phenomenon in models of liver injury, however, the activation of these cells following streptozotocin (STZ)-induced diabetes has not been studied yet. Differentiation of liver cells toward insulin-producing cells in diabetes has been reported, but the cell phenotype is still unclear. The aim of the present study was to confirm by immunohistochemical analysis, the activation of OvCs and their ability to express pancreatic beta-cell phenotype in STZ-induced diabetic mice. Using specific anti-A6 antibodies for mouse OvCs, we found a three-fold increase in periportal number and two-fold higher density of OvCs in diabetic livers, when compared to controls. Unlike non-diabetic controls, double staining technique showed co-localization of A6 and proinsulin in the cytoplasm of OvCs of diabetic animals, but no insulin staining was detected, probably reflecting the premature character of OvCs differentiation toward beta-cell-like phenotype. These data add valuable information concerning the nature and the stage of functional maturity of liver cells undergoing differentiation toward beta-cell phenotype in STZ-induced diabetic animals.

Evidence for oligogenic inheritance of type 1 diabetes in a large Bedouin Arab family.

Based on a genomic search for linkage, a locus contributing to type 1 diabetes in a large Bedouin Arab family (19 affected relatives) maps to the long arm of chromosome 10 (10q25; nonparametric linkage = 4.99; P = 0.00004). All affected relatives carry one or two high-risk HLA-DR3 haplotypes that are rarely found in other family members. One chromosome 10 haplotype, the B haplotype, was transmitted from a heterozygous parent to 13 of 13 affected offspring compared to 10 of 23 unaffected siblings. Recombination events occurring on this haplotype place the susceptibility locus in an 8-cM interval between markers D10S1750 and D10S1773. Two adjacent markers, D10S592 and D10S554, showed evidence of linkage disequilibrium with the disease locus. A 273-bp allele at D10S592 was transmitted to 8 of 10 affected offspring compared to 3 of 14 unaffected siblings, and a 151-bp allele at D10S554 was transmitted to 15 of 15 affected offspring compared with 10 of 24 unaffected siblings. D10S554 and D10S592 and the closest flanking markers are contained in a 1,240-kb yeast artificial chromosome, a region small enough to proceed with positional cloning.

Clinical characteristics and diabetes associated autoantibodies in patients with both type 1 diabetes mellitus and asthma.

OBJECTIVE: Type 1 diabetes mellitus (DM1) and asthma are mediated by opposite arms of the cellular immune system, namely T helper (Th)1 and Th2 CD4+ cells, respectively. It is not known whether their coexistence affects their clinical manifestations. METHODS: The number of asthma exacerbations, frequency of hypoglycemic events, HbA1c levels, diabetes associated autoantibody status and diabetes associated late complications were determined in three paired groups of patients (n = 11) matched by gender and age: DM1 and asthma, asthma only, and DM1 only. RESULTS: Patients with both diseases had a higher prevalence of hypoglycemic events per month compared to patients with DM1 only: 5.67 +/- 4.27 vs 1.45 +/- 2.06, respectively (p = 0.008). The co-existence of the two diseases did not modify the remaining clinical and laboratory parameters. CONCLUSION: Patients with both DM1 and asthma have similar clinical characteristics to patients with only one of these diseases apart from a higher rate of hypoglycemic events compared to patients with DM1 without asthma.

Selective localization of factor VIII antigenicity to islet endothelial cells and expression of class II antigens by normal human pancreatic ductal epithelium.

We evaluated the expression of factor VIII and class II histocompatibility antigens on frozen sections of normal human and rat pancreases. The immunohistologic studies were performed with directly fluoresceinated anti-human factor VIII and monoclonal antibodies A2B5, 3G5 (anti-islet), L-243, I-2, OK1 (anti-human Ia-DR), Leu-10 (anti-human HLA-DQ), anti-human HLA-DP, and OX6 (anti-rat Ia). Islet endothelial cells of humans and Wistar, CD, and BB diabetes-prone rats could be distinguished from intra-acinar endothelial cells by markedly enhanced factor VIII immunoreactivity. Factor VIII-antibody staining of islet endothelial cells was specifically absorbed by prior incubation of anti-human factor VIII antibody with normal human plasma but not by incubation with factor VIII-deficient plasma. By double indirect immunofluorescence, normal human pancreatic ductal epithelium expressed Ia in five of six pancreases studied.

Life-table analysis of progression to diabetes of anti-insulin autoantibody-positive relatives of individuals with type I diabetes.

Cytoplasmic islet cell antibody-negative (ICA-; less than 20 Juvenile Diabetes Foundation units, n = 1670) and ICA+ (n = 42) first-degree relatives of type I (insulin-dependent) diabetic individuals were studied for competitive insulin autoantibodies (CIAAs) with a radioassay. Overall, 3.7% of first-degree relatives (64 of 1712) were CIAA+. Of ICA- relatives, 2.7% (45 of 1670) exceeded the upper limit of our normal CIAA range (greater than 39 nU/ml), and 45% (19 of 42) of ICA+ relatives exceeded this normal range. Follow-up serums for repeat CIAA determination have been obtained from 16 of the nondiabetic CIAA+/ICA- individuals (time between samples, 0.4-5.8 yr). Fourteen of these 16 (87%) CIAA+/ICA- relatives were found to still be positive on follow-up, and 2 of the relatives who were positive on the first determination were negative on their follow-up test. With a mean follow-up of approximately 2 yr, 4 of 45 (9%) of the CIAA+/ICA- relatives, 5 of 23 (22%) of the ICA+/CIAA- relatives, and 12 of 19 (63%) of the CIAA+/ICA+ relatives developed diabetes. Life-table analysis indicated that, overall, 53% of CIAA+ relatives become diabetic after 5 yr of follow-up versus 65% of ICA+ relatives. Also by life-table analysis, the predicted risk after 5 yr of follow-up for progression to diabetes is 17% for CIAA+/ICA- relatives, 42% for ICA+/CIAA- relatives, and 77% for CIAA+/ICA+ relatives. The highest rate of progression to diabetes was found in ICA+ relatives with CIAA levels greater than 150 nU/ml (100% projected to be diabetic within 5 yr, P less than .008 vs. ICA+/CIAA- relatives).

Radioassay determination of insulin autoantibodies in NOD mice. Correlation with increased risk of progression to overt diabetes.

In an initial cross-sectional study, 29 female and 25 male nondiabetic weaned nonobese diabetic (NOD) mice of various ages (age range 30-300 days, mean 108 +/- 10 days) and 11 unweaned NOD pups were evaluated for competitive insulin autoantibodies (CIAAs) with a fluid-phase radioassay. Eleven of 54 (20%) weaned NOD mice had CIAA levels above the range (greater than 39 nU/ml) of 81 control mice. The group of NOD mice that progressed to diabetes had a significantly higher level of CIAAs than NOD mice that did not progress to diabetes (NOD mice progressing to diabetes: CIAA 63 +/- 12 nU/ml; NOD mice not progressing to diabetes: CIAA 8 +/- 4 nU/ml; P less than .02). Seven of 11 (64%) NOD mice having CIAA concentrations exceeding the normal range progressed to diabetes, whereas only 4 of 43 (9%) NOD mice progressed to diabetes without detection of elevated CIAAs (Fisher's exact test, P less than .0005). The relative risk of progressing to overt diabetes with CIAA levels greater than 39 nU/ml was therefore 17 (P less than .005), giving a positive predictive value of 64%, a negative predictive value of 91%, and an overall accuracy of 85%. None of 11 unweaned NOD pups had CIAA levels above the normal range (mean -9.4 +/- 4.9 nU/ml). At 6 wk of age, 37% of female NOD mice were CIAA+, whereas none of the male animals exceeded the normal range at this age (38 +/- 13 vs. 5 +/- 6 nU/ml, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Competitive insulin autoantibody assay. Prospective evaluation of subjects at high risk for development of type I diabetes mellitus.

A quantitative fluid-phase radioassay for autoantibodies reacting with insulin (competitive insulin autoantibody assay, CIAA) was developed. The assay's features include 1) use of a physiologic amount of 125I-labeled insulin, 2) parallel incubations with supraphysiologic cold insulin (competitive), and 3) an incubation time of 7 days and a single-step multiple-wash polyethylene glycol separation. Mean +/- SE CIAA levels in 50 controls were 8 +/- 1.4 nU/ml (range -16-33.3). In 36 cytoplasmic islet cell antibody (ICA)-positive nondiabetic first-degree relatives of type I (insulin-dependent) patients less than 30 yr of age, CIAA levels exceeded the normal range in 20 (55.6%) of 36 (mean 86.8 +/- 17.1 nU/ml). In 26 ICA-positive relatives greater than 30 yr of age, only 5 (19.2%) of 26 exceeded the normal range (mean 26.1 +/- 9.4 nU/ml); P less than .001 compared with younger ICA-positive relatives). Six ICA-negative HLA-identical siblings of type I diabetic patients had normal CIAA levels (mean 3.6 +/- 5.8 nU/ml), and only 2 of 13 ICA-negative identical twins discordant for diabetes (mean 15.4 +/- 6.6 nU/ml) exceeded the normal range. Nine (50%) of 18 ICA-positive schoolchildren exceeded the normal range (mean 105.3 +/- 36.7 nU/ml). Genetically susceptible subjects negative for CIAA (with only 3 exceptions) remained negative for CIAA on multiple determinations (3 conversions observed), and CIAA levels of positive subjects were relatively stable. Linear regression of the first CIAA level versus last (interval between sampling 1 mo to 10 yr) in genetically susceptible individuals showed a highly significant correlation (r = .95, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Functional activity of insulinoma cells (INS-1E) and pancreatic islets cultured in agarose cryogel sponges.

Here, we describe the preparation, structure, and properties of cryogel sponges, which represent a new type of macroporous biomaterial for tissue engineering. Cryogels were produced through freeze-thawing techniques, either from agarose alone or from agarose with grafted gelatin. The aim of this study was to evaluate agarose cryogel sponges as scaffolds for culturing both isolated pancreatic islets and insulinoma cells (INS-1E). In order to evaluate the effect of cell entrapment in artificial scaffolds, cell function reflected by insulin secretion and content was studied in cells cultivated for a 2-week period either in culture plastic plates or in cryogel sponge disks. Our results show that tumor-derived INS-1E cells grown either on plastic or on cryogels do not differ in their proliferation, morphology, insulin release, and intracellular insulin content. However, isolated pancreatic islets cultivated on cryogels sponge show 15-fold higher basal insulin secretion at 3.0 mM glucose than islets cultivated on plastic plates and fail to respond to stimulation with 16.7 mM glucose. In addition, these islets have about 2-fold lower insulin content compared to those grown in plastic plates. It is possible that the cell dysfunction noted in these in vitro experiments is due to the effect of the limited oxygen supply to the islets cultivated in cryogel sponge. Further in vivo studies are needed to clarify the nature of such an observation since according to previous reports, agarose and gelatin induce new vessel formation supporting enhanced oxygen supply.

Islet cell autoantibodies: pathobiology and clinical applications.

Autoimmunity directed against pancreatic islet cells results in slowly progressing beta-cell destruction, culminating over years in clinically manifested insulin-dependent diabetes mellitus (IDDM). Circulating serum autoantibodies directed against the endocrine cells of the islets of Langerhans are an important hallmark of this disease. Assays for these islet cell antibodies (ICA) have facilitated the investigation and understanding of several facets in the pathogenesis of autoimmune diabetes. Their applications have begun to extend into clinical practice and have opened new avenues for early preclinical prediction and preventive prophylaxsis in IDDM.

The prevalence of cutaneous manifestations in IDDM patients and their association with diabetes risk factors and microvascular complications.

OBJECTIVE: The aim of our study was to evaluate the frequency of skin manifestations, including the diabetic hand syndrome, in young IDDM patients. In addition, we studied the relation of the cutaneous manifestations to diabetes duration, glycemic control, and microvascular complications. RESEARCH DESIGN AND METHODS: The frequency of skin manifestations, including the diabetic hand syndrome, were examined in 238 IDDM patients (disease duration > 5 years) and 122 healthy control subjects in a cross-sectional study. In addition, we studied the relation of the cutaneous manifestations with diabetes duration, glycemic control, BMI, microvascular complications, and stratum corneum hydration using a stepwise logistic regression. RESULTS: Diabetic skin manifestations were detected in 168 of 238 (71%) IDDM patients and in 18 of 122 (14%) of the control subjects. Ichthyosiform skin changes of the shins, scleroderma-like skin changes, tinea pedis, and dry scaly palms were detected in 48 vs. 7%, 39 vs. 0%, 32 vs. 7%, and 21 vs. 0.8% of the patients and control subjects, respectively. In the diabetic patients, a significant association was found between ichthyosis of the shins and scleroderma-like skin changes of the hand (P < 0.001) and between scleroderma-like skin changes and the skin dryness of the palms (P < 0.0001). When diabetic risk factors were considered, diabetes duration was significantly associated with scleroderma-like skin changes and ichthyosis of the shins (P < 0.0001). The latter was also found to be related to diabetic retinopathy (P < 0.0001). Keratosis pilaris was present in 21% of the patients versus 9% in control subjects and was found to be exclusively associated with high BMI. CONCLUSIONS: Acquired ichthyosis is a common finding and the most prevalent skin manifestation in young IDDM patients. The development of several skin manifestations in insulin-dependent patients seems to be related to duration of diabetes and to development of diabetic microvascular complications.

Type 1 diabetes environmental factors and correspondence analysis of HLA class II genes in the Yemenite Jewish community in Israel.

OBJECTIVE: The Israeli Yemenite Jewish community has displayed an exceptionally rapid increase in the frequency of type 1 diabetes, having the highest rate of all Israeli ethnic groups. We studied the role of the environment, in relation to the nature and frequency of HLA class II genes, to evaluate its possible involvement in the development of diabetes. RESEARCH DESIGN AND METHODS: We interviewed 196 elderly Yemenite women, who had immigrated to Israel as adults, in programmed encounters about signs and symptoms of type 1 diabetes, infant feeding customs, and infectious diseases in Yemen. We also performed HLA oligotyping of DRB1, DQA1, and DQB1 genes in 120 unrelated Yemenite Jews, including 44 type 1 diabetic patients and 76 healthy control subjects, and used these data in correspondence analysis comparing Yemenites with different Israeli ethnic groups. RESULTS: Interviews indicated that early exposure to cow's milk was very common in Yemen. However, none of the women could recall classical presentations of diabetes. HLA oligotyping showed that gene frequencies of non-Asp-57 (of the HLA-DQB chain) in the patients (0.94) and control subjects (0.6) were similar to those of other populations with a known high incidence of type 1 diabetes. Correspondence analysis revealed that Yemenite Jews are genetically distinct from other ethnic groups in Israel. CONCLUSIONS: The genetic distinctiveness of Yemenite Jews may explain their unusually high incidence of type 1 diabetes in Israel. Despite the presence of highly susceptible diabetogenic HL4 class II genes in this community, early exposure to cow's milk did not cause phenotypic expression of diabetes in Yemen. This finding suggests that in this population, either cow's milk does not play a crucial role in triggering diabetes, or environmentally conferred protection, such as frequent infectious disease in Yemen, was dominant.

Does 1,25-dihydroxyvitamin D participate in the regulation of hormone release from endocrine glands?

The presence of receptors for 1,25-dihydroxyvitamin D3 in the pituitary, pancreas, testis, and ovary has raised the question of a possible direct role for 1,25-dihydroxyvitamin D (1,25(OH)2D) in the regulation of hormone synthesis and secretion. To evaluate this problem, six children with the syndrome of resistance to 1,25(OH)2D with rickets and alopecia underwent dynamic tests of insulin, TSH, PRL, GH, and testosterone secretion. Oral glucose loading resulted in normal glucose curves, subnormal peak insulin responses of 12-20 microU/ml in three hypocalcemic patients, and normal peak serum insulin values of 30-40 microU/ml in two normocalcemic patients. Basal serum, TSH, PRL, T4, and T3 concentrations were normal in all patients. Peak serum TSH values after TRH were 11-17 and 16-32 microU/ml in the hypo- and normocalcemic patients, respectively. The PRL response to TRH stimulation in either hypocalcemic or normocalcemic patients was normal [mean 26.2 +/- 5.1 (SD) ng/ml]. Peak serum GH levels were greater than 8 ng/ml in all five patients studied after one or more of the various stimuli. Serum testosterone concentrations after hCG stimulation were normal in the three patients studied (4.1-8.0 ng/ml). Thus, in children with resistance to 1,25(OH)2D, we could find no significant abnormalities in hormone secretion from the pituitary, pancreas, and testis apart from those presumably due to the hypocalcemia itself.

1,25-Dihydroxyvitamin D resistance, rickets, and alopecia.

Two unrelated kindreds with four affected children having 1,25-dihydroxyvitamin D resistance, rickets, and alopecia are described. The children exhibited early onset of severe rickets with hypocalcemia, hypophosphatemia, elevated serum alkaline phosphatase levels, and secondary hyperparathyroidism. Radiography showed diffuse demineralization and classic changes of rickets. All affected children had total-body alopecia. Serum levels of 1,25-dihydroxyvitamin D3 were elevated and rose to extremely high values during treatment, with no apparent change in the mineral disorder. However, secondary hyperparathyroidism and hypophosphatemia did remit during treatment despite persistently low calcium levels. Skin biopsy was performed in the parents and affected children in one kindred. Analysis of 1,25-dihydroxyvitamin D3 receptors in cultured fibroblasts indicated apparent normal receptors in the parents and undetectable receptors in both affected children. After long periods of treatment with vitamin D metabolites and mineral replacement, healing took place in the older child in each kindred. These data suggest that the healing occurred spontaneously as the children reached seven to nine years of age rather than as a result of the treatment. The biochemical lesion in these children appeared to be a genetically transmitted defect in the 1,25-dihydroxyvitamin D3 receptor. The mechanisms by which healing was initiated and maintained remain to be elucidated.

Neonatal pig islets induce a lower T-cell response than adult pig islets in IDDM patients.

BACKGROUND: Pancreatic pig islets may provide a substitute in the future for difficult to obtain human islets for transplantation in insulin-dependent diabetes millitus (IDDM) patients. However, the immune response to xenografts may significantly hamper this approach. Because neonatal tissue is believed to be less immunogenic, we examined whether the T-cell response to neonatal pig islets differs from the response to adult islets. METHODS: The T-cell proliferative response to different concentrations of sonicated neonatal and adult pig islets, as well as to insulin and mitogens, was tested in 21 recent onset IDDM patients and 21 healthy controls. We determined the presence of various circulating islet autoantibodies and their association with the T-cell response in IDDM patients. RESULTS: In the IDDM patients, sonicated adult pig islets (at 1 microg protein/ml) induced a significantly higher frequency (12 of 21 vs. 1 of 21, p<0.001) and magnitude (2.58+/-0.44 vs. 1.38+/-0.13, p<0.02) of positive T-cell responses than neonatal islets at the same concentration. Similar results were obtained with a 10-fold higher concentration of islet sonicate. There was no significant association between the individual T-cell responses and the presence of circulating autoantibodies in IDDM patients. CONCLUSION: These results indicate that neonatal pig islets induce a lower T-cell reactivity than adult islets, suggesting that the neonatal tissue may be immunologically more suitable for future islet xenotransplantation.

Clinical-echocardiographic correlations in acute rheumatic fever.

Thirty-three children with acute rheumatic fever were studied using echocardiography to characterize heart involvement in this disease. Among 26 subjects with a first episode of acute rheumatic fever, 18 had a clinical diagnosis of carditis and six had heart failure. Heart failure usually resulted from valvular incompetence rather than from myocardial failure in these patients. Conversely, among seven subjects with recurrent rheumatic fever, five had a clinical diagnosis of carditis and four had heart failure. Severe left ventricular dysfunction noted on echocardiography probably contributed significantly to the appearance of heart failure in two of these four subjects. Ten patients were initially believed not to have carditis: a diagnosis of mitral valvulitis was made in two of these ten on the basis of the results of the echocardiographic examination. Echocardiography, which provides important information on the cardiac status of patients with acute rheumatic fever, may help in assessing the prognosis and may be useful in the therapy of these patients.

The heart in acute glomerulonephritis: an echocardiographic study.

Patients with acute glomerulonephritis often are seen with signs suggesting heart failure. Whether these signs are due to fluid overload secondary to kidney damage only, or whether there is associated myocardial damage has not been elucidated. Fourteen children with acute glomerulonephritis were studied by echocardiography during the edematous phase of the disease and five months later to evaluate cardiac function in this disease. Left ventricular size and function remained normal in all children throughout the study. The most consistent finding was enlargement of the left atrium during the edematous phase with a return toward normal values five months later. There was no correlation between blood pressure and the echocardiographic findings. This study suggests that signs of heart failure in acute glomerulonephritis are not due to myocardial damage but probably reflect fluid overload.

Immunogenetics of HLA class II in Israeli Ashkenazi Jewish, Israeli non-Ashkenazi Jewish, and in Israeli Arab IDDM patients.

The distribution of HLA class II alleles and genotypes in IDDM patients was examined in the three main Israeli ethnic groups: Ashkenazi Jews, non-Ashkenazi Jews, and Arabs. Molecular sequence specific oligonucleotide probe analysis was performed for DRB1, DQA1, and DQB1 genes. The DRB1*03011, DQA1*05 DQB1*02/DRB1*0402, DQA1*03, DQB1*0302 genotype was found to be the main susceptibility genotype in all three groups, with differences in the degree of association. In addition to DRB1*0402 (more frequent among Ashkenazi Jews), DRB1*0405, another subtype of DRB1*04, was found to be more prevalent among non-Ashkenazi Jews and Arabs. Many alleles were found to be negatively associated with insulin dependent diabetes mellitus (IDDM). This could be a result of the high frequency of susceptible alleles, or of linkage disequilibrium to a primary negatively associated allele. The strongest negative association was observed for DQB1*0301 in all three ethnic groups. The alleles DRB1*1401, DRB1*1501, DQB1*05031, DQB1*0602, and DQB1*0609 were not detected in any of the 202 IDDM patients, and are probably either strongly protective or in linkage with such alleles. Despite the differences found between the three ethnic groups, an overall analysis shows that the DRB1*04 alleles that account for susceptibility to IDDM in the Israeli population (DRB1*0402 and *0405) are the same as those responsible for susceptibility to IDDM in a number of other Mediterranean populations. In contrast, the susceptible allele in most Caucasian populations is DRB1*0401. It is noteworthy that the susceptible alleles DRB1*0402/05 for Mediterranean and DRB1*0401 for Caucasian populations are also frequent in the respective healthy populations. These findings support the results obtained in other studies, which point to a genetic relationship between the Israeli and Mediterranean populations.