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To date, almost all case reports of insulin‐derived amyloidosis described the presence of a subcutaneous mass that was observable on physical examination. This report presents two cases of insulin‐derived amyloidosis without palpable masses at insulin injection sites. In both cases, blood glucose concentrations improved, and the insulin dose could be reduced by an average of 45% after changing the insulin injection sites. The insulin absorption at the site was reduced to at most 40% of that at a normal site in one case. Magnetic resonance imaging and ultrasonography were useful to screen and differentiate insulin‐derived amyloidosis without a palpable mass. This report showed that insulin‐derived amyloidosis without a palpable mass can be present at the insulin injection site, and has similar clinical effects to insulin‐derived amyloidosis with palpable masses., This report showed that insulin‐derived amyloidosis without a palpable mass can be present at the insulin injection site and has similar clinical effects to insulin‐derived amyloidosis with palpable masses. Magnetic resonance imaging and ultrasonography were useful to screen and differentiate insulin‐derived amyloidosis without a palpable mass.

Background Insulin-derived amyloidosis is a skin-related complication of insulin therapy that interferes with insulin therapy. Although toxicities of in vitro-formed insulin amyloid fibrils have been well studied, the toxicity of insulin-derived amyloidosis remains to be clarified. Case presentation A 58-year-old man with type 2 diabetes mellitus underwent a lower limb amputation due to diabetic gangrene. Several antibiotics including minocycline were administered for infection and sepsis. A hard mass at the insulin injection sites in the lower abdomen was discovered by chance four months later. Although no abnormal findings in the surface skin of the mass were observed, necrotic tissue was seen around the mass when a biopsy was performed. Histological and toxicity studies were performed for this patient and four other patients with abdominal masses at insulin injection sites. Histological and immunohistochemical studies showed that the masses had typical characteristics of amyloid deposits in all cases, whereas necrotic findings were seen adjacent to the amyloid deposit only in the case presented. Toxicity studies indicated that the amyloid tissue from the present case had significant cell toxicity compared to the control skin tissue or the amyloid tissues from the other four cases. Conclusions This report showed that toxic insulin-derived amyloidosis can occur. In addition, this report suggested that toxic insulin-derived amyloidosis may cause necrosis in the surrounding tissue. Although the toxic amyloid deposit of insulin-derived amyloidosis was found in only one patient, no structural differences between toxic and non-toxic deposits were seen on histological and immunohistochemical studies. Electronic supplementary material The online version of this article (10.1186/s12902-019-0385-0) contains supplementary material, which is available to authorized users.

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.

Insulin-derived amyloidosis is a complication of insulin therapy. The amyloid fibril protein is derived from the injected insulin and forms an amyloid deposit at the injection site [1,2]. The clini...

Objectives Insulin-derived amyloidosis is a rare skin-related complication of insulin therapy. The purpose of this study was to show the effects of insulin-derived amyloidosis on blood glucose levels, insulin dose requirements, and insulin absorption. Methods Seven patients were found to have insulin-derived amyloidosis at the Tokyo Medical University Ibaraki Medical Center. The clinical characteristics and insulin therapy of the 7 patients were investigated. Insulin absorption was studied by comparing the serum insulin levels after insulin injections into insulin-derived amyloidosis sites versus injections into normal sites in 4 patients. Results When the insulin-derived amyloidosis was discovered, the mean hemoglobin A1c level was 9.3%, and the mean daily insulin dose was 57 units. After changing the injection sites to avoid the insulin-derived amyloidosis, the blood glucose concentrations improved, and the mean daily insulin dose could be reduced to 27 units (P = .035; 53% reduction). The insulin absorption at insulin-derived amyloidosis sites was 34% of that at normal sites (P = .030). Conclusions Insulin-derived amyloidosis caused poor glycemic control and increased insulin dose requirements because of impairments in insulin absorption.

A power spectral analysis of heart rate variability has been applied in order to assess diabetic autonomic neuropathy and high frequency spectra are thus considered to possibly reflect vagal nerve integrity in patients with diabetes mellitus. The purpose of this study was to investigate the relationship between the findings of high frequency spectra analysis and the results of the Ewing battery. We performed 24-hour power spectral analysis using an ambulatory ECG monitoring system and standard tests in order to assess diabetic autonomic neuropathy (Ewing battery) in 18 diabetic patients to compare their diagnostic values for diabetic autonomic neuropathy. We used the high frequency amplitude (high frequency spectra; 0.15-0.40 Hz) as a direct measure of vagal nerve integrity from each hourly spectral plot. All hourly high frequency spectra decreased along with the impaired assessment of the battery, especially during the night when the high frequency spectra showed a manifest increase in patients classified as normal according to the battery. High frequency spectra during the night while asleep (22:00-05:00) and during a 24-hour period significantly correlated with the results of the battery. These values markedly decreased even in patients classified as having early vagal damage when compared with those classified as normal. High frequency spectra during night closely reflected the intrinsic vagal nerve integrity in patients with diabetes mellitus. High frequency spectra during night or a 24-hour period is a simple and sensitive measure of diabetic autonomic neuropathy and is considered to be a useful modality for detecting even early changes in autonomic dysfunction.

A 57-year-old man was referred to our outpatient clinic after interferon-beta (IFN-beta) treatment for 7 weeks. While IFN-beta therapy was continued in our outpatient clinic, his blood glucose level increased gradually, and he was admitted to our hospital for hyperglycemia. The patient was prescribed a 1,600-kcal diet and intensive insulin therapy was performed. GAD antibody became positive 15 months after the start of IFN therapy, and disappeared 27 months after the start of IFN therapy. Insulin secretion was depleted and the patient had HLA-DR4, B54, and DRB1*0405. This appears to be a case of type 1 diabetes mellitus induced by administration of IFN-beta alone.

OBJECTIVE To determine whether hepatocyte growth factor (HGF) is elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR). RESEARCH DESIGN AND METHODS Vitreous fluid samples were obtained at the time of vitreoretinal surgery from 73 eyes of PDR patients and from 17 eyes of nondiabetic patients (control subjects) who had macular hole, rhegmatogenous retinal detachment, or epiretinal membrane (9, 4, and 4 eyes, respectively) but no associated proliferative vitreoretinopathy. Stages of PDR were classified as active or quiescent. Concentrations of HGF and vascular endothelial growth factor (VEGF) in vitreous fluid were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS Intravitreous concentrations of HGF (median [range]) were significantly higher in diabetic patients with PDR (6.00 ng/ml [0.75−22.2]) than in control patients (2.86 ng/ml [0.75−5.80]). Intravitreous concentrations of VEGF were also higher in diabetic patients with PDR (1.62 ng/ml [0.15−7.9]) than in control patients (0.16 ng/ml [0.16−0.29]). Both VEGF and HGF concentrations were significantly higher in patients with active retinopathy than in those with quiescent retinopathy. However, vitreous concentrations of HGF were unrelated to those of VEGF CONCLUSIONS We found that levels of HGF in vitreous fluid of PDR patients are significantly higher than in nondiabetic patients and that the levels of HGF are elevated in the active PDR stage. This suggests that HGF stimulates or perpetuates neovascularization in PDR.

Diabetic retinopathy is characterized by increased vascular permeability, ischemia, and neovascularization. Ischemia in the retina can induce neovascularization via induction of vascular endothelial growth factor (VEGF) expression by the transcription factor hypoxia-inducible factor-1 (1). Hypoxia is also the main stimulus for erythropoietin (EPO) gene expression. It has been reported that EPO may have not only erythropoietic (2) but also neuroprotective (3) and angiogenic (4) effects. EPO is expressed at a number of sites including kidney, liver, brain, uterus (5), and the adult mammalian retina, which also expresses EPO receptors (6). The aim of this study was to investigate whether EPO is elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and whether vitreous EPO levels are related to systemic levels of EPO, anemia, or nephropathy. Vitreous fluid samples were obtained from 59 PDR patients and 16 macular hole patients at the start of the vitrectomy procedure. Concentrations of EPO in vitreous fluid and serum samples were measured by an enzyme-linked immunosorbent assay for EPO (Toyobouseki, Osaka, Japan). Concentrations of VEGF were measured by an enzyme-linked immunosorbent assay for human VEGF (R & D Systems, Minneapolis, MN). Protein in vitreous fluid was determined using the method of Bradford (Bio-Rad, Hercules, CA). The Mann-Whitney U test was used to compare intravitreous concentrations of protein, VEGF, …

Pretreatment of neutrophils with granulocyte colony-stimulating factor (G-CSF) enchanced luminol-dependent chemiluminescence emission by the stimulation of formylmethionylleucylphenylalanine (FMLP), opsonized zymosan, and zymosan. The intensity of the priming effects was in the following order: FMLP > zymosan > opsonized zymosan. However, the priming effect of G-CSF was not detected by the stimulation of phorbol myristate acetate. The reaction curve with the stimulation of FMLP showed a bimodal shape, and the elevation of the first peak by the priming effect was further prominent in comparison with the elevation of the second peak. This indicates that G-CSF mainly enhances the extracellular release of oxygen radicals in response to the stimulation with FMLP. This is the first report investigating intra- and extracellular events in chemiluminescence reaction of neutrophils primed with G-CSF.

Fifty-four diabetic patients with or without clinical evidence of neuropathy and with no clinical evidence of CNS dysfunction were studied by somatosensory-evoked potentials after electrical stimulation of the median nerve at the wrist and recorded from the scalp electrode against a noncephalic reference. Peripheral conduction index, calculated as the distance from the wrist to the C7 spinous process divided by the P9 latency, was significantly decreased (P less than 0.01) in diabetic patients (69.81 +/- 6.47 m/s) compared with 28 age-matched nondiabetic subjects (76.85 +/- 5.65 m/s). The P11-P13 interpeak latency, representative of the transit time from the dorsal column at the level of the sensory input into the cervical cord to the brain stem along the somatosensory pathways (CCT1), and the P13-N19 interpeak latency, representative of the transit time from the brain stem to the somatosensory cortex (CCT2), were significantly increased in diabetic patients (CCT1, 2.51 +/- 0.63 ms; CCT2, 5.76 +/- 0.92 ms) compared with nondiabetic subjects (CCT1, 2.28 +/- 0.36 ms, P less than 0.05; CCT2, 5.18 +/- 0.51 ms, P less than 0.01). We conclude that, in diabetic patients, neurophysiological abnormalities may be present in two distinct parts of the CNS and the peripheral nervous system.

We assessed the hourly coefficient of variance of RR intervals (CVRR) in 29 subjects with non-insulin-dependent diabetes mellitus and 19 age-matched healthy subjects using an ambulatory 24-hour ECG monitoring system. We also evaluated CVRR during 100 beats in both groups in the supine posture at 07:00 and 10:00 in the morning. Hourly CVRR showed an overt diurnal variation in both groups especially in the daytime and at midnight, but was significantly lower (p less than 0.05) in diabetic patients. CVRR during resting 100 beats at 07:00 was significantly higher (p less than 0.05) than that at 10:00 in both groups. These findings indicate that HRV shows an obvious diurnal variation in both groups. As a steep and marked change occurs in the morning, careful consideration is necessary to assess the test performed for a short time span at random times throughout the day, particularly in the morning.

We describe a man without the clinical findings of Cushing's syndrome, but who harbored an incidentally found cortisol-producing adrenal adenoma. On adrenal 131I-adsterol imaging, there was good uptake to the nodule, but no visualization of the contralateral adrenal. No abnormalities were found in the basal plasma cortisol, ACTH, urinary free cortisol and 17OHCS. However, dynamic hormone assessment revealed the existence of abnormal cortisol secretion: no suppression to dexamethasone, incomplete response to human corticotropin-releasing hormone, and lack of diurnal variation in plasma cortisol. Left adrenalectomy was performed with the diagnosis of cortisol-producing adrenal tumor. The pathological finding was an adrenal adenoma, and the perifusion of the excised tissues revealed a negligible response of the tumor tissue to ACTH though the residual normal cortex responded. Postoperative course was uneventful without replacement therapy with cortisol. It is suggested that the tumor autonomously produced a small amount of cortisol not only insufficient to provide clinical Cushing's syndrome, but also to provide typical suppression of hypothalamo-pituitary corticotroph-adrenal system.

In August, 2005, a 62-year-old Japanese man, with a 20-year history of type 1 diabetes, was admitted to our hospital, for investigation of apparent insulin resistance. Since January, 2004, he had been taking insulin in a longacting (glargine) and a shortacting (lispro) form, at a total of 66 units a day. Despite the dose being gradually increased to 94 units a day, his blood glucose concen trations had subsequently been high, and poorly con trolled. Examination showed nothing of note. Blood tests gave a value for glycosylated haemoglobin (HbA1c) of 8∙6% (target value ≤6·5%). The patient’s body-mass index was 21∙1 kg/m2 (weight 57∙5 kg). Although we kept the patient on a strict diet, and increased the total daily dose of insulin to 116 units (lispro 94; glargine 22), his blood glucose concentration, before meals, remained 7∙8–21∙1 mmol/L. Blood tests showed normal concentrations of corticotropin, cortisol, thyroid hormones, glucagon, growth hormone, and carcino-embryonic antigen, and undetectable quantities of antibodies to insulin; urinary concen trations of meta nephrines were normal. Ultrasonography of the abdomen showed nothing of note. However, re-examination of the lower abdomen revealed two lumps, one on each side, under the skin; each contained a hard, irregular nodule, 3–4 cm in diameter. The patient had noticed the lumps several months previously; he routinely injected insulin into the nodules, since they were easily grasped, and injection was less painful than elsewhere. We admin istered insulin via a diff erent part of the abdomen; hypoglycaemia ensued. We rapidly decreased insulin doses. Good blood glucose concentrations were obtained with a total daily dose of 24 units (lispro 18; glargine 6). Abdominal MRI showed the nodules to lie in the fat under the skin; unlike fat, they had low signal intensity on T1-weighted (fi gure) and T2-weighted images. We took a biopsy sample of a nodule; histopathological analysis showed it to consist largely of amorphous, acellular, eosinophilic material. When the material was stained with Congo red, and seen with polarised light, we saw green birefringence, diagnostic of amyloid. On immunohistochemical testing, the amyloid deposit was positively stained by monoclonal antibodies to human insulin. When last seen, in November, 2008, the patient needed 66 units a day of insulin—injected outside the lumps, which were smaller than before. Common causes of insulin resistance include obesity; sever physical stress; prescribed drugs, such as glucocorticoids; and endocrine disorders, such as Cushing’s syndrome, phaeochromocytoma, or acromegaly. Rarer causes include mutations of the insulin receptor gene; antibodies to insulin, or to the insulin receptor; and lipodystrophy syndromes. Doctors should always consider if, and how, the patient is injecting insulin. Amyloid deposits consist of proteins arranged in a cross-β conformation: pathological amyloid deposits can be formed of various proteins, including α-synuclein in Parkinson’s disease, and prions in Creutzfeldt-Jakob disease. For amyloid to consist of insulin is rare. In all reported cases of insulin-induced amyloidosis, of which we are aware, the patient took non-human insulins: we speculate that aminoacid diff erences between endogenous and injected insulin may have contributed to the development of amyloidosis. Partly because use of nonhuman insulin is increasing, and partly because we have seen four cases recently, we speculate that insulininduced amyloidosis may be under diagnosed: for instance, by being mistaken for lipo hypertrophy. Injection into fatty lumps can reduce the eff ectiveness of insulin, though less markedly than does injection into amyloid. Amyloid lumps are typically harder, and more discrete, than fatty lumps of lipo hyper trophy; MRI can assist with diagnosis. We refer to amyloid lumps of insulin as “insulin balls”.

The adsorption and chromatographic properties of hydroxyapatite sorbents for application to different viruses have been investigated. The strong adsorption of viruses was observed on macroporous hydroxyapatite with hydrophilic properties of the sorbent surface. The viruses were purified on this sorbent without loss of biological activity. The column can be used for virus vaccine production.

An experimental model is introduced for the study of liver metastases using intrasplenically injected EL-4 and Lewis lung tumor cells. Fluorinated pyrimidine derivatives, 1-(2-tetrahydrofuryl)-5-fluorouracil and 5-fluorouracil, showed inhibitory effects on the frequencies of liver metastases. Immunosuppressive effects of these drugs were compared at the doses capable of showing 50% inhibition of the development of metastatic nodules. These derivatives strongly suppressed the phagocytic activity and the number of Kupffer cells of the liver and then the humoral response against sheep red blood cells, the delayed hypersensitivity against picryl chloride. On the contrary, combined administration of protein-bound polysaccharide (PSK) and 1-(2-tetrahydrofuryl)-5-fluorouracil showed no inhibitory effect on these activities.

Objective To measure the amount and affinity of insulin antibodies, we performed a trial to establish a new method for quantitative and qualitative analysis of these antibodies by using surface plasmon resonance (BIAcoreTM system).Methods Real-time detection of insulin antibody interaction and kinetic analysis were performed using the BIAcoreTM system.Patients or Materials Eight diabetic patients with insulin antibodies and whose fasting total immunoreactive insulin levels were more than 100 μU/ml were selected. The patients with and without recurrent hypoglycemia were classified into hypoglycemic episode-positive or hypoglycemic episode-negative groups, respectively. Seven diabetic patients without insulin antibodies were selected as controls.Results In the 8 patients, the concentration of insulin antibodies ranged from 2.91 to 16.3 μg/ml and insulin antibodies were not detected in the control group. The apparent KD (dissociation constant) and kd (the dissociation rate constant) values of the patients were much larger than those seen for the anti-human insulin monoclonal antibody. The KD values were significantly higher in the hypoglycemic episode-positive group than in the hypoglycemic episode-negative group (p

We assessed the possibility of using myo-inositol as a marker of glucose intolerance.We measured urinary myo-inositol enzymatically before and 2 h after a 75-g oral glucose tolerance test in 564 volunteers, who were divided into four groups [normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM)]. Furthermore, we classified NGT into NGT-A (2-h blood glucose120 mg/dl and 2-h glucosuria50 mg/dl) and NGT-B (remaining NGT subjects). We then compared deltamyo-inositol (myo-inositol/creatinine ratio: 2-h after glucose load--before load) of each group to investigate the relationship between glucose intolerance and deltamyo-inositol.The glucose tolerance of NGT-B appeared to have deteriorated compared with NGT-A as determined by blood glucose, insulin, and glucosuria. There was very little effect of gender or age on deltamyo-inositol in NGT-A. deltamyo-inositol was significantly higher than that in NGT-A (0.5+/-7.1 mg/g Cr) not only in IFG (8.7+/-19.5 mg/g Cr, P0.0001), IGT (14.8+/-22.9 mg/g Cr, P0.0001) and DM (79.5+/-37.1 mg/g Cr, P0.0001), but in NGT-B (7.4+/-12.7 mg/g Cr, P0.0001). With 2 mg/g Cr as a tentative cut-off for deltamyo-inositol to detect NGT-A, sensitivity and specificity were 68% and 72%, respectively.The deltamyo-inositol can be use of a non-invasive and sensitive marker for glucose intolerance.

Background: To determine myo-inositol more accurately, we improved the enzymatic cycling method. Methods: We screened myo-inositol dehydrogenase (MIDH; EC.1.1.1.18) from Flavobacterium sp., which was highly specific to myo-inositol. We measured urinary myo-inositol/creatinine ratio 2 h after 75-g oral glucose tolerance test (2 h MI) of 71 volunteers, and investigated the relationship between diabetes and urinary myo-inositol concentration. Results: The calibration curve was linear (r=1.00) up to 2000 μmol/l, and the detection limit was 10 μmol/l. Within-run and between-run CVs were 0.5–1.1% and 0.4–1.3%, respectively. The 2 h MI of impaired fasting glycemia (IFG; 65.1±46.6 mg/g Cr, P

A power spectral analysis of heart rate variability has been applied in order to assess diabetic autonomic neuropathy and high frequency spectra are thus considered to possibly reflect vagal nerve integrity in patients with diabetes mellitus. The purpose of this study was to investigate the relationship between the findings of high frequency spectra analysis and the results of the Ewing battery. We performed 24-hour power spectral analysis using an ambulatory ECG monitoring system and standard tests in order to assess diabetic autonomic neuropathy (Ewing battery) in 18 diabetic patients to compare their diagnostic values for diabetic autonomic neuropathy. We used the high frequency amplitude (high frequency spectra; 0.15-0.40 Hz) as a direct measure of vagal nerve integrity from each hourly spectral plot. All hourly high frequency spectra decreased along with the impaired assessment of the battery, especially during the night when the high frequency spectra showed a manifest increase in patients classified as normal according to the battery. High frequency spectra during the night while asleep (22:00-05:00) and during a 24-hour period significantly correlated with the results of the battery. These values markedly decreased even in patients classified as having early vagal damage when compared with those classified as normal. High frequency spectra during night closely reflected the intrinsic vagal nerve integrity in patients with diabetes mellitus. High frequency spectra during night or a 24-hour period is a simple and sensitive measure of diabetic autonomic neuropathy and is considered to be a useful modality for detecting even early changes in autonomic dysfunction.

Matrix metalloproteinases (MMPs) are implicated in tissue destruction during various pathophysiologic conditions. The vitreous body is a gel-like extracellular matrix that undergoes liquefaction during aging and pathological processes. To investigate the pathogenic role of MMPs in proliferative diabetic retinopathy (PDR), we studied 73 eyes from PDR patients and 25 eyes from patients with non-diabetic ocular diseases. Vitreous MMPs were measured by zymography. Retinopathy was assessed by ophthalmoscopy and PDR was classified into 3 stages, 'naked', 'active', and 'quiescent'. Although proMMP-9 was expressed in only 8% (2/25) of non-diabetic patients, it was expressed in more than 80% (38/47) of 'active' PDR patients and still expressed in 60% (9/15) of those with 'quiescent' PDR. Vascular endothelial growth factor (VEGF) in vitreous fluids was undetectable (0.16 ng/ml) in most of the non-diabetic patients, and was maximally elevated in the 'active' PDR patients (mean=2.20 ng/ml, range; 0.16-7.61), declining in patients with 'quiescent' PDR (1.04 ng/ml, 0.16-3.77). These results suggest that MMP-9 is one of the noteworthy factors in relation to the progress of PDR, as well as angiogenic cytokines such as VEGF.

The effect of acarbose, an alpha-glucosidase inhibitor, on postprandial glucose and lipid metabolism was investigated in patients with type 2 diabetes mellitus. Twenty patients (10 men and 10 women) with type 2 diabetes mellitus were studied. A test meal was taken with or without 100 mg of acarbose. The levels of plasma glucose, and serum immunoreactive insulin, lipids, apolipoproteins, and remnant-like particle cholesterol were investigated. Acarbose inhibited the postprandial increase of both plasma glucose and serum immunoreactive insulin. Acarbose also significantly suppressed the increase of serum triglycerides at 60, 90, and 120 min (P < 0.05 to P < 0.01), and the increase of serum remnant-like particle cholesterol at 60 and 120 min (P < 0.05). Acarbose inhibited the postprandial decline of apolipoprotein C-II, and decreased the postprandial serum apolipoprotein C-III level. These results suggest that acarbose may improve postprandial hyperlipidemia as well as postprandial hyperglycemia in patients with type 2 diabetes mellitus.

SUMMARYEffects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) against severe infections in cyclophosphamide (CY)-induced neutropenic mice were investigated by its single use or by its combination with cephem antibiotics. Treatment with rhG-CSF increased the number of peripheral blood leucocytes and strikingly shortened the duration of the neutropenic state. Most of the regained population in the peripheral blood leucocytes were neutrophils. Functions of neutrophils, such as phagocytic activity, superoxide release, and expression of Mac-1 molecules, were remarkably enhanced by administration of rhG-CSF. When rhG-CSF was administered to CY-induced neulropenic mice before infection, protective effects against various kinds of bacteria were remarkable. On the other hand, such remarkable effects were not observed when rhG-CSF was administered after infections. However, even in the case of post-infectious treatment, a combination therapy of rhG-CSF with cephem antibiotics, particularly with Cefodizime (CDZM), showed a significant improvement in the survival rate and a decrease in the number of viable bacteria in the liver. These results suggest that a combination therapy of rhG-CSF with cephem antibiotics, especially with CDZM, is an efficient regime against severe infections in patients with ncutropenia induced by a heavy anti-tumour chemotherapy.

SUMMARYAlthough the standard assays for reactive oxygen species have been based on the measurement of those released into the extracellular environment, the microbicidal capacity to the engulfed microorganisms is mainly dependent on those released into the intracellular environment, such as phagosomes. We studied intracellular oxidative activities of individual phagocytes by dichlorofluorescein (DCFH) oxidation assay to investigate the relationship between the reactive oxygen species released intracellularly and the impaired microbicidal capacity in diabetic patients. Time courses of intracellular production of hydrogen peroxide by polymorphonuclear leucocytes (PMNL) and monocyies were observed at the resting condition and after the stimulation with phorbol myristale acetate (PMA: 160 nm) by flow cytometry. Thirty-four patients with non-insulin-dependent diabetes mellitus (NIDDM) and 23 age-matched healthy volunteers were subjected to the studies. PMNL from patients with NIDDM showed a significantly decreased capacity to produce hydrogen peroxide after the stimulation (P < 0·05 at 15 min, P < 0·01 at 30 and 45 min). By contrast, inlracellular hydrogen peroxide production by monocytes at the resting condition and an early stimulatory phase (8 min after the stimulation) was significantly (P< 0·01) enhanced in patients with NIDDM compared with that in controls. Both the changes of inlracellular hydrogen peroxide production observed in PMNL and monocytes from patients with NIDDM were in association with an increased haemoglobin Alc level in crythrocytes. but did not relate to total cholesterol and triglyceride levels in the serum. The possible mechanisms of these dissociated changes in hydrogen peroxide producing capacity of phagocytes from patients with NIDDM are discussed.

The prognosis of patients with heart disease and prediction of sudden cardiac death can be assessed through heart rate variability, an indirect measure of abnormal autonomic control. The authors have evaluated the heart rate variability by 24-hour ambulatory electrocardiographic monitoring in 25 diabetic patients, 19 ischemic heart disease patients, 18 congestive heart failure patients, and 10 normal subjects. Thirteen diabetic patients had autonomic neuropathy and 12 patients did not. Heart rate variability index (mean SD) in patients with diabetes mellitus, ischemic heart disease, and congestive heart failure was significantly lower (34.5 +/- 12.6 ms, 43.7 +/- 15.4 ms, and 34.6 +/- 15.8 ms vs 65.6 +/- 16.7 ms, p less than 0.05) than that of normal subjects. Mean SD was significantly lower in patients with autonomic neuropathy as compared to patients without autonomic neuropathy (26.4 +/- 6.5 ms vs 44.2 +/- 11.0 ms, p less than 0.05) mean SD as compared to survivors: 49 +/- 7 ms in patients with mild ischemic heart disease, 48 +/- 15 ms in patients with severe ischemic heart disease, and 23 +/- 7 ms in patients who died. Similarly, the mean SD in 4 congestive heart failure patients who died was lower significantly (p less than 0.05) than in those who survived (19.0 +/- 5.6 ms vs 40.0 +/- 14.5 ms). Among congestive heart failure patients, clinical improvement by therapy was associated with a significant increase in mean SD. When the mean SD of 30 ms was used as the cutoff point for detection of autonomic dysfunction or patient death, specificity exceeded 90% and sensitivity was 75%.(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated the metabolic capability of murine peripheral granulocytes after administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) by quantitative flow cytometric assay for H2O2-dependent oxidative product formation. Intraperitoneal administration of a daily dose of 10 micrograms of rhG-CSF for 5 days induced doubling of the leukocyte population. Differential counting of peripheral leukocytes and scattergram by flow cytometry showed an increased mature granulocyte population. After stimulation with phorbol myristate acetate, the granulocytes of the rhG-CSF-administered mice demonstrated some hyperresponsive population and an increased H2O2 production. The hyperresponsive population showed H2O2 production 4-6 times higher than did normal cells. Granulocytes from the G-CSF-treated mice revealed an augmented phagocytic activity and an increased expression of Mac-1 molecules. Moreover, mice treated with G-CSF showed an enhanced resistance against intravenous infection with a lethal dose of E. coli. Granulocytes showing such markedly increased oxidative metabolism may be a significant component of the host defence to various infective organisms.

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH), hypothalamic hypogonadism and alopecia universalis occurred in a 31-year-old female with insulin-dependent diabetes mellitus (IDDM). Despite various clinical investigations and careful observation for 20 months, the cause and pathogenesis of SIADH and hypothalamic hypogonadism were not elucidated. The complex of these disorders had not been described. The presence of IDDM and alopecia universalis, in which an autoimmune process has been assumed to be involved, is interesting in considering the pathogenesis of the SIADH and hypothalamic hypogonadism.

We have developed a simple method for assessing the oxidative metabolic burst of peripheral blood leukocytes with a minute amount of whole peripheral blood by flow cytometry according to the method of Bass et al. with some modification. By this method, we can measure the H2O2 production by both granulocytes and monocytes in the same blood sample. The oxidative product formation by peripheral blood neutrophils can be monitored sequentially in the same mouse infected with E. coli. The mice infected intravenously with 0.1 LD50 of the bacteria showed increased basal activities from an early stage of infection; those infected intraperitoneally with the same dose of the bacteria showed a delayed enhancement. In case of infection with 0.01 LD50, the enhanced basal activities lasted for only a short period of time. The H2O2 production was correlated well with the clearance of the infected bacteria. These results demonstrated that the oxidative-product formation by peripheral blood neutrophils is affected by both the route and the dose of infection.

外傷の既往なく,顔面のほてり,後頭部痛,眩暈および耳鳴などのBarre-Lieou症候群の症状を主訴とし,その症状と平行して尿中カテコラミンの上昇を認めた症例を報告し, Barre-Lieou症候群と全身的交感神経緊張との関連について若干の考察を加えた.症例は46才,男.尿中カテコラミン高値を指摘され入院.検査所見では褐色細胞腫の所見は認めず,頸椎についてもBarsony stone以外の所見は認めなかつた.症状発作と一致して尿中カテコラミン上昇を認め,全身的な交感神経の緊張により症状が出現したものと考えた.本性候群には局所的な因子のみでなく,全身的な交感神経の緊張がその主因となつている例も存在していると考えられた.