Nonenzymatic glycosylation of serum IgG and its effect on antibody activity in patients with diabetes mellitus.

Susceptibility to infection is assumed to be increased in diabetic patients, although its mechanism is unknown. The purpose of this study was to determine whether glycosylation of circulating immunoglobulins is related to the decrease of antibody activity in diabetic patients. Thirty-five patients with type II (non-insulin-dependent) diabetes and 14 age-matched normal controls were examined. Nonenzymatic glycosylation of serum immunoglobulin G (IgG) in vivo was measured by two different techniques, colorimetry and affinity chromatography. The levels of glycosylated IgG were significantly higher in diabetic patients than in normal controls. To evaluate the antibody activity of glycosylated IgG, anti-streptolysin O (ASO) titers after in vitro glycosylation of IgG and antibody titers before and after in vivo immunization with influenza vaccine were determined. IgG specific for streptolysin O purified by affinity chromatography decreased ASO titers after in vitro glycosylation. In diabetic patients, serum titers of hemagglutinin-inhibiting antibody against influenza viruses 4 wk after initial immunization were significantly lower than those in normal controls. These results indicate that serum IgG in diabetic patients was nonenzymatically glycosylated, and this modification in vivo might be associated with its functional alteration.

Abnormal glucose tolerance in patients with chronic glomerulonephritis without renal failure.

An oral glucose tolerance test and an assay of insulin receptor activity were performed in patients with chronic glomerulonephritis (CGN) to elucidate the aberration of glucose metabolism in such patients. Ninety of 123 patients with CGN without renal failure showed abnormal glucose tolerance, including 72.6% with IgA nephropathy, 81% with benign recurrent hematuria, 87% with chronic proliferative glomerulonephritis, 100% with membranoproliferative glomerulonephritis, and 80.0% with membranous nephropathy. Insulin responses in CGN patients during oral glucose tolerance tests showed lower levels of basal insulin and significantly higher levels after 90, 120, and 180 min compared with those of normal controls. The binding of radiolabeled insulin to blood mononuclear cells in 22 CGN patients with abnormal glucose tolerance was significantly (P = 0.0023) decreased in comparison with 5 normal controls. However, plasma obtained from such patients showed no significant (P = 0.4761) inhibition of the binding of insulin to normal mononuclear cells. It was concluded that glucose tolerance capacity was impaired in 80.4% of patients with CGN without renal failure. Such impairment of glucose metabolism might be due to decreased activity of insulin receptors on cells in CGN patients.

Localized pleural mesothelioma with elevation of high molecular weight insulin-like growth factor II and hypoglycemia.

Recurrent hypoglycemia occurred in a 48-year-old woman with a localized pleural mesothelioma. During hypoglycemia, serum high molecular weight insulin-like growth factor II (IGF-II) was elevated. The tumor also contained a high level of high molecular weight IGF-II. We propose that the primary cause of the hypoglycemia in this patient was the high molecular weight IGF-II produced by the tumor.

Determination of LDL receptors on cultured lymphocytes using fluorescein-labeled LDL.

A rapid, sensitive procedure for the detection of LDL receptors on cell surface without using radioisotopes is described. Fluorescein-isothiocyanate (FITC) labeled LDL bound with cultured human lymphocytes, and the degree of that binding was compatible with that of 125 I-labeled LDL. The staining of cells with FITC-LDL allows identification and enumeration of LDL-binding cells using fluorescence microscopy or a fluorescence activated cell sorter (FACS). It is suggested that FITC-LDL can be applied for screening of patients with various degrees of activity in LDL receptors on their cell surfaces.

Immunofluorescence staining of renal biopsy samples in patients with diabetic nephropathy in non-insulin-dependent diabetes mellitus using monoclonal antibody to reduced glycated lysine.

This is the first report on immunofluorescence staining of renal biopsy samples in human diabetic nephropathy (DN) using monoclonal antibodies to reduced glycated lysine. In order to detect the localization of glycated lysine in the mesangial matrix and/or the glomerular basement membrane (GBM), we examined immunofluorescence staining using antibodies against reduced glycated lysine in the glomeruli of 16 patients with DN and ten age-matched patients with diffuse mesangial proliferative glomerulonephritis without IgA deposition (DPGN) as controls. In the early stage of DN, immunofluorescence microscopy revealed the presence of intense staining for reduced glycated lysine in the GBM as well as in part of the tubular basement membrane, but not in the mesangial area. In contrast, immunofluorescence microscopy revealed less staining for glycated lysine in the GBM in the advanced stage of DN, and no reaction with any part of the renal tissue in patients with DPGN. It was concluded that detection of reduced glycated lysine in GBM in the early stage of DN might be associated with the initial pathogenesis of this disease.

The effects of long term Tranilast administration on bronchial hypersensitivity in asthmatics.

Tranilast is an oral antiallergic agent developed in Japan. This study investigated the effect of prolonged administration of Tranilast on the bronchial sensitivity of 18 asthmatic subjects. They were treated for either less than 3 months or more than 3 months continuously. Methacholine loading testing was used to assess bronchial reactivity, and the respiratory parameters were recorded on an Astograph. Patients treated for longer than 3 months showed a significant decrease in bronchial sensitivity (p less than 0.05). The anticholinergic and bronchodilatory properties of Tranilast were also investigated in 8 subjects. No significant anticholinergic or bronchodilatory effects were observed following a single oral dose of 100 mg of Tranilast.

Increase of IgA in pharyngeal washings from patients with IgA nephropathy.

The levels of IgA and total proteins in pharyngeal washings were examined in patients with IgA nephropathy and other glomerular diseases in order to determine whether secretory IgA, IgA1 and IgA2 were increased in these patients. Thirty patients with IgA nephropathy, 21 patients with other glomerular diseases and 15 healthy adults were examined. The levels of IgA were quantitated by radial immunodiffusion and laser nephelometry. The levels of total proteins in pharyngeal washings were quantitated by Tonein-TP. It was demonstrated that the levels of IgA in pharyngeal washings were significantly increased in patients with IgA nephropathy compared to those with other glomerular diseases and healthy adults. The levels of total proteins in pharyngeal washings were increased in patients with IgA nephropathy, and the ratio of IgA and total proteins in the washings from patients with IgA nephropathy was not significantly different from those healthy adults. There was a significant correlation between the levels of IgA in pharyngeal washings and those of IgA in sera from patients with IgA nephropathy. The IgA observed in pharyngeal washings contained secretory components, IgA1 and IgA2, in patients with IgA nephropathy. It is suggested that the increase of IgA in the pharyngeal washings in parallel with the increase of total proteins might be associated with local inflammation.

[A clinical experience of ofloxacin in patients with respiratory infection].

To a total of 31 patients (18 in- and 13 out-patients) having respiratory infections, we administered ofloxacin (OFLX) orally at a daily dose of 300 to 600 mg and examined its clinical effect. The clinical effect in the 31 cases was as good as 83.9%. Among these cases, 6 cases showed Pseudomonas aeruginosa, thereby indicating the effective rate of OFLX at 50%. In the present examination, we experienced cases in which OFLX-resistant P. aeruginosa appeared in the cases of long-term administration of OFLX. Therefore, our clinic carried out the sensitivity test of P. aeruginosa against OFLX, gentamicin (GM) and imipenem (IPM) in 1987, using clinically-segregated strains of P. aeruginosa obtained by sputum tests. The sensitive strains, which were 100% sensitive to OFLX, GM, IPM respectively in 1985, showed, in segregated strains in 1987, sensitivity of OFLX 57.1%, GM 85.7% and IPM 100%, thus indicating the high resistance-acquiring frequency of P. aeruginosa against OFLX.

A case of IgA nephropathy associated with marked hematuria after upper respiratory tract infections.

IgA nephropathy is characterized by recurrent hematuria which is occasionally associated with upper respiratory infections. Since serial follow-up of IgA nephropathy has not been reported, a 43 year old patient who showed a typical course of this disease is described. Hematuria was markedly increased each time after upper respiratory infections. Renal biopsy revealed typical features of IgA nephropathy by light and immunofluorescent microscopy. Marked hematuria subsided after administration of antibiotics. Upper respiratory tract infections might be a risk factor in some patients with IgA nephropathy. In some patients upper respiratory tract infections may exacerbate IgA nephropathy.

Selective IgM deficiency: a case study.

We experienced an 85-year-old male patient with selective IgM deficiency. The average levels of his serum immunoglobulins were as follows: IgG, 1,165 mg/dl, IgA 280 mg/dl, and IgM 17 mg/dl. The subpopulations of peripheral blood lymphocytes in this patient were normal, including normal numbers of IgM-bearing lymphocytes. Normal amounts of cells with cytoplasmic IgM were induced by in vitro addition of pokeweek mitogen, and no inhibitory cells or inhibitory factors for in vitro production of IgM were demonstrated in his blood. These results suggest that some defects similar to those in patients with selective IgA deficiency may play a role in the development of selective IgM deficiency.

Effect of cisapride on gastric emptying in diabetic patients without gastrointestinal symptoms.

The long-team effects of cisapride on gastric emptying and hormonal interaction in diabetic patients without gastrointestinal symptoms was evaluated. Gastric emptying was determined by the N-acetyl-p-amino-phenol (APAP) method before and after cisapride treatment. Gastric emptying improved significantly, from 5.95 to 8.04 micrograms/ml, after 6 weeks of treatment. Plasma concentrations of immunoreactive insulin (IRI), after 30 and 45 minutes in the gastric emptying test, increased significantly after treatment. It appeared that improvement of gastric emptying after loading with cisapride might be related to improved insulin secretion in diabetic patients without subjective symptoms of gastroparesis.

IgA nephropathy associated with myasthenia gravis and scleritis.

A 29-year-old male patient with IgA nephropathy developed scleritis and myasthenia gravis during the follow-up period. No lymphocytic infiltration or atrophy in muscle fibers was observed in muscle biopsy specimens. However, an immunofluorescent study on the same specimens showed deposits of immunoglobulin A in muscular vessels. The development of scleritis and myasthenia gravis in a patient with IgA nephropathy suggests a common immunologic basis for these disorders.

Immunofluorescent studies on acute phase reactants in patients with various types of chronic glomerulonephritis.

A study on immunofluorescent staining of so-called "acute phase reactants" (haptoglobin, alpha 1-acid glycoprotein and alpha 1-antitypsin) and beta-lipoprotein in patients with various types of chronic glomerulonephritis is described. Eight patients with IgA nephropathy, eleven patients with proliferative glomerulonephritis, six patients with benign recurrent hematuria, four patients with membranous nephropathy and one patient with Henoch-Schönlein purpura nephritis (HSP nephritis) were examined. Deposition of haptoglobin was observed in patients with IgA nephropathy and HSP nephritis, and that of beta-lipoprotein was observed in various types of chronic glomerulonephritis. There was a significant correlation between the degree of deposition of haptoglobin and that of hematuria in patients with IgA nephropathy and HSP nephritis. It is suggested that deposition of haptoglobin and beta-lipoprotein may be related to "hemolysis" in glomeruli and increased permeability of glomerular capillary walls in kidneys with various types of chronic glomerulonephritis.

Prevalence of IgAl deposits in Henoch-Schoenlein purpura (HSP) nephritis.

A study on the detection of IgA1, IgA2 and the J("joining") chain in glomeruli from renal biopsy specimens in patients with Henoch-Schoenlein purpura (HSP) nephritis is described. Renal biopsy specimens from five patients with HSP nephritis were stained with FITC-labelled anti-human IgA1, IgA2 and J chain, and then examined with a fluorescent microscope. IgA1 was detected in glomeruli from all patients with HSP nephritis examined in this study. IgA2 was not observed in any patients. These findings were similar to those for IgA nephropathy reported previously. Histopathological findings of glomeruli in HSP nephritis were almost identical to those in IgA nephropathy. The levels of serum IgA in patients with HSP nephritis increased as observed in IgA nephropathy. It is suggested that there are some immunopathological similarities between HSP nephritis and IgA nephropathy.

Impaired granulocyte function in patients with diabetes mellitus.

Phagocytosis and intracellular killing of Staphylococcus aureus by granulocytes were examined in diabetic patients. There was no significant difference in the phagocytic activity of granulocytes between control and diabetic-subjects. However, intracellular killing by granulocytes was significantly reduced in insulin-treated diabetic patients compared with control subjects. No significant difference was observed between controls and diet-treated diabetic patients. It is suggested that decreased activity of intracellular killing of bacteria in granulocytes is one of the mechanisms of increased susceptibility to infection in patients with advanced stages of diabetes mellitus.

Detection of immunoglobulins and/or complement in kidney tissues from non-obese diabetic (NOD) mice.

Immunofluorescent studies were performed on kidney tissues from non-obese diabetic (NOD) mice. Tissues from twenty-two NOD mice ranging in age from 8 to 33 weeks were examined by immunofluorescence and light microscopy. It was shown that the immunofluorescent pattern of immunoglobulins and complement deposition in glomeruli from NOD mice were changed from diffuse linear, focal and/or local fine granular to diffuse coarse granular depending on the age. These findings in NOD mice were consistent with those in human diabetic nephropathy. It was suggested that the immunofluorescent studies in NOD mice are useful for evaluation of the pathogenesis of renal involvement in patients with diabetes mellitus.

Focal segmental glomerulosclerosis associated with a pheochromocytoma.

A 22-year-old male patient with focal segmental glomerulosclerosis(FSGS) associated with a pheochromocytoma is reported. Immunofluorescence study of the kidney biopsy specimen demonstrated segmental depositions of IgM, C3 and fibrinogen. Alteration of glomerular basement membrane(GBM) with fibrin strands and platelet aggregates was observed by electron microscopic examination. Administration of prednisolone had no effect on massive proteinuria, but surgical removal of the tumor promptly reduced proteinuria. It was suggested that FSGS can develop in patients with pheochromocytomas, and local hypercoagulation might be responsible for the development of this lesion.

Eosinophilic peritonitis responding to treatment with glycyrrhizin.

A 63-year-old man with diabetes mellitus for 15 years was admitted to our hospital in 1990 because of end-stage renal failure. Five days after beginning continuous ambulatory peritoneal dialysis (CAPD) he developed an eosinophilic peritonitis (EP). With protein loss in the dialysate and a decreased serum albumin level, the patient developed ankle edema. The patient was treated with glycyrrhizin, and his EP resolved. It is suggested that an allergic background may play an important role in the development of EP in patients on CAPD.

A case of insulin-secreting tumor successfully treated with diazoxide.

A 72-year-old patient was referred to our hospital because of a hypoglycemic crisis possibly due to an insulin secreting-tumor. Although its localization was assumed to be at the head of the pancreas as assessed by transhepatic venography with sampling, no mass lesion was detected by selective angiography, ultrasound, computerized axial tomography, magnetic resonance imaging and 67Ga-citrate scan. The patient was treated with diazoxide, because of poor localization and his age, insulin secretion was improved after both 30 and 60 min in the 75 g oral glucose tolerance test. The total amount of urinary C-peptide excretion decreased from 70.8 to 29.2 mcg/day. Thereafter, no hypoglycemic symptoms were observed during his admission. No side effects except mild liver damage were observed.

Genetic predisposing factors in non-insulin dependent diabetes with persistent albuminuria.

We designed this study to elucidate a possible involvement of genetic factors which influence the progression of renal dysfunction in patients with non-insulin dependent diabetes mellitus (NIDDM). A total of 328 patients was randomly selected in the Tokai University Hospital. They had been cared for in our hospital as NIDDM for the past five years, until April, 1989. Fifty-six patients with persistent albuminuria, and an equal number of patients without persistent albuminuria were included in this study. No significant differences were observed between the two groups in terms of age, estimated period of illness, blood pressure, body-mass index, HbAlc, blood glucose, total cholesterol, triglyceride level and mean blood pressure. The family histories obtained by questionnaires revealed that there might be some genetic predisposing factors leading to the onset of nephropathy in patients with NIDDM, especially in cases with paternal high blood pressure. It is suggested that paternal hypertension might be related to the development of nephropathy in patients with NIDDM.