[Applications of Raman Spectroscopy on Quality Control of Hospital Formulations].

Hospital formulation has several advantages, including the flexibility of customization as per the disease state or the patients' precise requirements. However, compared with commercial formulations, hospital formulations are usually not under the same level of quality check. In the present study, we tested mixed powder formulations prepared in a hospital pharmacy using Raman spectroscopy to investigate the feasibility of applying Raman spectroscopy as a quality-control tool of hospital formulations. For this purpose, we first established a numerical evaluation method to determine the uniformity of a powder mixture using Raman chemical imaging data with atropine sulfate/lactose mixture samples and revealed that the mixing uniformity correlated to the experience level of the pharmacist. Next, we developed a content quantification method in a one-dose packaged powder formulation by measuring the Raman spectra from the outside of the package. Because this method allows for quantification of the components inside the package in a non-destructive and non-contact manner, it can be applied for content confirmation after one-dose packaging. Using this method, the content uniformity of the mixed powder formulation in the one-dose package was compared between the formulations prepared by the pharmacists and those prepared by a pharmacy robot. Our study indicates the possibility of applying Raman spectroscopy as a quality-control tool of hospital formulations. Studies on further applications of Raman spectroscopy in the field of clinical pharmacology are expected.

Association of morning fasting blood glucose variability with insulin antibodies and clinical factors in type 1 diabetes.

The fasting blood glucose concentration in type 1 diabetes may vary without being much affected by diet and exercise. This study aimed to identify association of morning fasting blood glucose concentration variability with insulin antibodies and clinical factors. The subjects in this study were 54 patients with type 1 diabetes who had high variation of fasting blood glucose. The insulin antibody level was measured, and correlations of glycemic variability with antibody levels, binding rates, and other clinical factors were investigated. The standard deviation (SD) of the 30-day morning self-monitored fasting blood glucose concentration (FBG SD) was evaluated as an index of glycemic variability. The mean glucose level was 159.8±42.1 mg/dL and the FBG SD was 47.5±22.0 mg/dL. Glycemic variability (FBG SD) was positively correlated with insulin antibody level, but not with insulin antibody binding rate, and had a negative correlation with C-peptide immunoreactivity/plasma glucose (CPR/PG) and positive correlations with diabetes duration, basal insulin dose and bolus insulin dose. Glycemic variability was not correlated with BMI, HbA1c or age. In multiple regression analysis of glycemic variability, CPR/PG was the only significant related factor. The results showed that glycemic variability was mainly influenced by endogenous insulin secretion capacity and was high in patients with high insulin antibody levels. In some patients with a high insulin antibody titer, the antibody may have an effect on the variability of the fasting glucose concentration in type 1 diabetes.

Effects of age on insulin resistance and secretion in subjects without diabetes.

OBJECTIVE: To examine whether aging itself affects insulin resistance (IR) and insulin secretion in the general Japanese population. METHODS: This study included data for 2,324 men and 1,472 women 30-79 years of age without diabetes who participated in a general health checkup program. The effects of age on homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of ß-cell function (HOMA-B) were examined using a linear regression model. Logistic regression models were used to identify clinical characteristics related to age. Multiple regression analyses using a stepwise form were performed to examine factors, including age, possibly affecting HOMA-IR and HOMA-B. RESULTS: The fasting plasma glucose (FPG) levels increased with age in both sexes, whereas the body mass index (BMI) and HOMA-B decreased with increasing age in men and the BMI increased with age in women. The HOMA-IR increased with increasing age in postmenopausal women. The proportion of physically active subjects increased in both sexes, and the proportion of current smokers decreased with age in men and postmenopausal women. The proportion of regular drinkers increased, and the proportion of subjects with a family history of diabetes decreased with age in men. The stepwise multiple regression analysis showed that age was inversely associated with the HOMA-B in both sexes and positively associated with the HOMA-IR in men and postmenopausal women. However, the BMI had the largest impact on the HOMA-IR and HOMA-B in both sexes. CONCLUSION: Age-related increases in the glucose levels in Japanese men and women may be associated with impaired insulin secretion. As a result, a sex difference was observed regarding the impact of aging on IR.

An autopsy case of macroglobulinemia complicated with syndrome of inappropriate secretion of ADH (SIADH) like hyponatremia, hypopituitarism and AL amyloidosis.

An 88-year-old male patient with macroglobulinemia was admitted to our hospital because of severe hyponatremia and unconsciousness. Laboratory findings showed decreased inhibition of antidiuretic hormone (ADH) and he was diagnosed with syndrome of inappropriate secretion of ADH (SIADH). Hyponatremia improved with only limitation of water intake and the patient was followed up on a continuing outpatient basis. However, soon after discharge from hospital, his legs started swelling with edema and hyponatremia worsened. He was re-admitted due to a fall at home. Hyponatremia was observed at re-admission. A CRH challenge test showed partial dysfunction of ACTH secretion. Corticosteroid therapy was performed, but the patient subsequently died from pneumonia. Pathological findings at autopsy revealed invasion of plasma cells and amyloid depositions in multiple organs, including the pituitary, adrenal cortex, heart, liver, kidney, lymph nodes and bone marrow. Consistent with these results, fibrosis was observed in the anterior lobe of the pituitary, suggesting that the autopsy findings were related to the clinical observations and diagnosis. This is the first reported case of macroglobulinemia complicated with multiple hormone dysfunction.

Prevalence of retinopathy and its risk factors in a Japanese population.

AIMS/INTRODUCTION: To determine the prevalence and risk factors of retinopathy and validity of the current diagnostic cut-offs for diabetes by using data of health check-up examinees. MATERIALS AND METHODS: The study comprises 1,864 Japanese who participated in the general health check-up program and did not have a previous history of cardiovascular disease. Non-mydriatic 45° digital fundus photographs were taken twice annually. Multivariate logistic regression model was used to identify risk factors for retinopathy in participants without previously diagnosed diabetes. RESULTS: The overall prevalence of retinopathy in participants with and without previously diagnosed diabetes were 23.3% (28/120) and 4.2% (74/1,744), respectively. Univariate logistic regression analysis identified age, systolic blood pressure (SBP), fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) as risk factors for retinopathy. Multivariate logistic regression analysis showed that FPG or both HbA1c and SBP were significant, positive and independent risk factors for retinopathy. The prevalence of retinopathy increased with deterioration of glucose categories (P < 0.001 for FPG or HbA1c). However, a statistically significant increased risk of retinopathy remained only in participants with FPG ≥ 7.0 mmol/L or HbA1c ≥ 6.5% compared with those with the lowest quartile of glucose in the participants without previously diagnosed diabetes after adjusting for age and SBP. CONCLUSIONS: The prevalence of retinopathy was 4.2%, and FPG or both HbA1c and SBP were positive and independent risk factors for retinopathy in health check-up examinees without previously diagnosed diabetes. The FPG 7.0 mmol/L or HbA1c 6.5% seems to be appropriate to diagnose diabetes in view of its association with retinopathy.

A case of TSH-producing adenoma treated with octreotide in combination with thiamazole for the control of TSH and thyroid hormones after trans-sphenoidal neurosurgery.

While TSH-producing adenoma (TSHoma) is rare, the diagnosis is often delayed because the clinical features are heterogeneous. The patient was a 69-year-old woman who had been referred to the Yachiyo Medical Center in August 2008, because of dyspnea, loss of appetite, weight loss of 10 kg, and diarrhea that lasted 4 years. We diagnosed this patient with pituitary TSH-producing macroadenoma. Thyroid hormone concentration was increasing although the serum TSH level was within a normal range after trans-sphenoidal surgery. We considered that because of enlargement of the thyroid gland due to long-term stimulation by TSH, a low concentration of TSH could stimulate the thyroid gland to produce excess T3 or T4. The somatostatin analogue, octreotide was used to control the TSHoma and serum TSH concentration but not thyroid hormone. The octreotide in combination with thiamazole treatment for 14 months controlled thyroid hormone concentration and decreased the thyroid mass, and ultimately, the thiamazole could be stopped. To date, the use of combination therapy of octreotide with thiamazole in patients with remaining TSH-producing adenoma without Basedow's disease is rare, and we suggest that this treatment is one of the therapeutic means to treat recurrence of TSH-producing adenoma after surgery with progressive complications or large thyroid gland.

Moyamoya disease complicated by Graves' disease and type 2 diabetes mellitus: report of two cases.

The pathogenesis of moyamoya disease remains unknown. Examination of diseases concurrent with moyamoya disease may offer a clue to clarify the pathogenesis. Coexistence of moyamoya disease, Graves' disease, and diabetes mellitus is very rare. We present the first cases in the literature. A 38-year-old man with moyamoya disease and a 43-year-old woman with quasi-moyamoya disease, both concurrent with Graves' disease and type 2 diabetes mellitus, are presented. Both patients underwent antithyroid therapy and revascularization. After normalization of thyroid hormones level and blood glucose level followed by revascularization, the symptoms of cerebral ischemia were improved. The common etiological factors of these diseases are discussed. Genetic and autoimmune factor appeared to be involved in the pathogenesis of the three diseases, which may suggest that these factors play important roles in the pathogenesis of moyamoya disease. Further studies are required to define the pathogenesis of moyamoya disease, especially in cases with comorbidities as in the present patients.

The over 50 year clinical course of a patient with slowly progressive type 1 diabetes (SPIDDM).

Type 1 diabetic patients who have endured their condition for prolonged periods are not uncommon, but there are few well-documented cases of type 2 diabetic patients with duration of over fifty years. In the present case study, we analyzed the history of a diabetic patient whose duration was 53 years. Her case was consequently diagnosed not as the common type 2 diabetes, but as the slowly progressive type 1 diabetes (SPIDDM) identified by Japanese medical researchers. The patient, now 73 years old, was first diagnosed with diabetes in 1953 when she was 17 years of age and started insulin injections. In 1962 she was referred to our hospital, and two years later she vaginally delivered a healthy baby (birth weight 3100 g) at the 40(th) week of gestation. She was the first case of a diabetic mother delivering an infant treated at Tokyo Women's Medical College Hospital. Her data shows that her C-peptide responses by meal tolerance test in 1978 was at least partly preserved though it decreased year by year. Her anti-GAD antibody was found to be positive in 2000 and remained so in 2009. This leads us to conclude that the etiology of her SPIDDM was most likely has insulin secretion exhaustion.