A Modular Construction of Epidithiodiketopiperazines.

Epidithiodiketopiperazines (ETPs) possess remarkably diverse biological activities and have attracted significant synthetic attention. The preparation of analogues is actively pursued; however, they are structurally challenging, and more direct and modular methods for their synthesis are desirable. To this end, the utility of a bifunctional triketopiperazine building block for the straightforward synthesis of ETPs is reported. A modular strategy consisting of enolate alkylation followed by site-selective nucleophile addition enables the concise synthesis of (±)-hyalodendrin and a range of analogues.

An enantioselective synthesis of α-alkylated pyrroles via cooperative isothiourea/palladium catalysis.

Herein we describe the direct enantioselective Lewis base/Pd catalysed α-allylation of pyrrole acetic acid esters. This provides high isolated yields of highly enantioenriched products and exhibits broad reaction scope with respect to both reaction partners. The products can be readily elaborated in a manner which points towards potential applications in target directed synthesis.

Sustained upregulation of glial fibrillary acidic protein in Müller cells in pigeon retina following disruption of the parasympathetic control of choroidal blood flow.

Choroidal blood flow in pigeon eyes is light driven and controlled by a parasympathetic input from ciliary ganglion (CG) neurons that receive input from the medial subdivision of the ipsilateral nucleus of Edinger-Westphal (EWM). EWM lesions diminish basal ChBF and irreversibly prevent ipsilateral light-evoked increases in ChBF, presumably rendering the retina mildly ischemic. To characterize the location, severity, and time course of the retinal abnormality caused by an EWM lesion, we quantitatively analyzed the cellular and regional extent of Müller cell glial fibrillary acidic protein (GFAP) immunolabeling up to nearly a year after an EWM lesion. We found that unilateral EWM lesions greatly increased Müller cell GFAP throughout the entire retinal depth and topographic extent of the affected eye, up to nearly a year post lesion. By contrast, destruction of the pupilloconstrictive pretectum or of the pupilloconstrictive part of lateral EW (EWL) did not appreciably increase Müller cell GFAP. Thus, the large increase in Müller cell GFAP following an EW lesion is attributable to an ongoing defect in choroidal vasodilatory function rather than to chronic pupil dilation. The Müller cell GFAP increase was greater ipsilateral than contralateral to the EWM destruction for the retinal territory deep to the heavily CG-innervated superior and temporal choroid, but not for the retinal territory deep to the poorly CG-innervated inferior and nasal choroid. The GFAP increase was light-dependent, since it did not occur in EW-lesioned birds housed in dim illumination. Our results show that the chronic vascular insufficiency caused by the loss of the EWM-mediated parasympathetic control of choroidal blood flow leads to a significant and sustained increase in retinal Müller cell GFAP. This increase could be a sign of a disturbance in retinal homeostasis that eventually leads to retinal injury and impaired visual function.

Non-autoimmune primary hypothyroidism in diabetic and non-diabetic chronic renal dysfunction.

The aim of this study was to investigate the frequency and mechanisms of hypothyroidism observed in diabetic patients with advanced diabetic nephropathy, including outcomes of management for this condition. A controlled study was designed using 32 diabetic and 31 non-diabetic patients not receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) who excreted mean urinary protein greater than 0.5 g/day examined on three consecutive days during admission to our hospital. Thyroid hormones in both serum and urine, anti-thyroid antibodies, renal function and iodine concentrations in serum were measured during admission in all patients included. In particular, in patients who showed overt hypothyroidism, further studies including large-needle biopsies of the thyroid and iodine-perchlorate discharge tests were performed. All patients in the two groups revealed negative antithyroid antibody titers, and the mean serum total iodine levels did not significantly differ between the two groups. Mean serum FT4 levels significantly decreased, and the TSH level was significantly elevated in the diabetic group compared to those in the non-diabetic group (p < 0.005, p < 0.02, respectively). The frequency of overt hypothyroidism in the diabetic group (22%; 7/32) was significantly higher (p < 0.05) than that in the non-diabetic group (3.2%; 1/31). The daily urinary thyroid hormone excretion in both groups did not show any significant correlation with serum thyroid hormone levels. Seven patients who revealed overt hypothyroidism in the diabetic group showed elevated serum total iodine levels during hypothyroidal status, ranging between 177 and 561 microg/l. Also, the iodine-perchlorate discharge tests carried out in six of these patients all showed a positive discharge. After management based on iodine restriction, normalization of serum thyroid hormone levels in accordance with definite decreases in the serum total iodine level was achieved, accompanied by a significant weight reduction. In conclusion, we found a significantly high prevalence of non-autoimmune primary hypothyroidism in patients with advanced diabetic nephropathy compared to those with non-diabetic chronic renal dysfunction, which may partly relate to earlier development of oedematous status. Clinical and laboratory findings suggest that impaired renal handling of iodine resulting in an elevation of serum iodine levels, rather than autoimmune mechanism or urinary hormone loss, may play a principal role in the development of these conditions, probably through a prolongation of the Wolff-Chaikoff effect. The mechanisms by which this phenomenon develops more frequently in diabetic than in non-diabetic renal dysfunction remain to be elucidated.

Painless thyroiditis associated with severe inflammatory reactions in amyloid goiter: a case report.

We report the case of a 64-year-old woman with rheumatoid arthritis (RA) associated with high grade fever, malaise, and painless swelling of thyroid gland. Laboratory findings showed severe systemic inflammatory reactions, including increases in various cytokines such as IL-6. Gallium-67 citrate imaging revealed intense uptake in the painlessly enlarged thyroid gland. Histologically, biopsied specimens of thyroid showed diffuse amyloid infiltrations, which included amyloid A (AA) protein. Biopsies of rectum and stomach revealed similar amyloid depositions, indicating that the amyloid had a secondary origin, potentially due to RA. All clinical symptoms were relieved by intravenous pulsatile administration of methylprednisolone followed by oral prednisone, resulting in prolonged hypothyroid status. To our knowledge, this is the first case report in Japan describing painless thyroiditis with severe inflammatory reactions in amyloid goiter.

The relationship of fasting plasma glucose values and other variables to 2-h postload plasma glucose in Japanese subjects.

OBJECTIVE: To investigate the relationship between fasting plasma glucose (FPG) values and other variables (e.g., age, sex, and BMI) to 2-h post-75-g oral glucose load glycemia (PG) in Japanese subjects. RESEARCH DESIGN AND METHODS: Subjects included 13,694 Japanese subjects between 20 and 83 years of age (10,677 men and 3,017 women) who were undergoing a 75-g oral glucose tolerance test (OGTT) during a health screening performed at our hospital. The influences of age for 2-h PG at a fixed fasting plasma glucose (FPG) level of 126 mg/dl were analyzed. Multiple linear regression analysis was performed using a model in which the dependent variable was 2-h PG using the following explanatory variables: FPG, age, sex, BMI, blood pressure, plasma cholesterol, and triglyceride (TG) levels. RESULTS: The 2-h PG at a fixed FPG of 126 mg/dl increased by 0.94 mg/dl per year in patients aged between 30 and 78 years (r = 0.68, P < 0.0001). In multiple regression, five explanatory variables (FPG, age, BMI, plasma TG levels, and systolic blood pressure levels) were all positively associated with 2-h PG. The percentages of patients with 2-h diabetes (isolated postchallenge hyperglycemia [IPH]) versus fasting plus 2-h diabetes by the World Health Organization criteria significantly (P = 0.005) increased as the patients' decades increased, whereas the impact of BMI on the percentages was significant only in young patients (P = 0.001). CONCLUSIONS: Aging was found to be the second best predictor of 2-h PG on multiple regression. Therefore, OGTT should be performed especially in elderly patients because they show IPH more frequently.

Clinical management of intraductal papillary mucinous tumors of the pancreas based on imaging findings.

The aim of this study was to assess the imaging findings of pathologically proven intraductal papillary-mucinous tumors of the pancreas and the natural history of follow-up cases, and to optimize the therapeutic management of patients with these tumors according to their imaging findings. All nine patients with main duct type tumors were histologically diagnosed as having adenocarcinoma or adenoma, with no hyperplastic lesion. The images failed to discriminate between the two histologic types. In 26 patients with branch duct type tumors, all but one with intraductal mural nodules or tumors of > or = 30 mm had adenocarcinoma or adenoma, regardless of the caliber of the main duct. Of the nine patients with tumors < 30 mm and no mural nodules. three had adenoma, and six had hyperplasia. All of four patients had hyperplasia, with the additional caliber of the main duct being < 6 mm. In a series of 23 cases in which the patient was followed-up, no apparent progression was found in 17 patients who had no mural nodules and tumors of < 30 mm. Given these results, patients with main duct type tumors, and those with branch duct type tumors showing mural nodules or a tumor diameter of > or = 30 mm, are at high risk of developing neoplasms, including adenocarcinoma, for which surgical resection should be considered, whereas those patients with tumors < 30 mm and no mural nodules can be followed.

Use of a catheter with a large side hole for selective catheterization of the inferior phrenic artery.

The authors report the use of a catheter with a large side hole in the catheterization of the right inferior phrenic artery (IPA) arising from the proximal portion of the celiac trunk. A 5-F catheter with a side hole on either the top or the right side of the superior portion near the tip was used in five patients with hepatocellular carcinoma fed by the right IPA, which could not be selected by a conventional coaxial technique. In all patients, a 3-F microcatheter was successfully advanced into the right IPA through the side hole of this catheter introduced into the celiac artery or the common hepatic artery.

K-ras mutations in duodenal aspirate without secretin stimulation for screening of pancreatic and biliary tract carcinoma.

BACKGROUND: K-ras mutations at codon 12 (KRM) have been detected in over 80% of tissues and pure pancreatic juice (PPJ) samples from patients with pancreatic carcinoma (PCa) and are promising genetic tumor markers. Aspirating PPJ not only requires technical skill, but is also exhausting for patients. The authors attempted to evaluate whether the detection of KRM in the duodenal aspirate (DA) obtained immediately after endoscopic retrograde cholangiopancreatography (ERCP), an easier sample-collecting method than collecting PPJ, could be useful for the diagnosis of PCa and biliary tract carcinoma (BTCa). METHODS: DA was collected endoscopically without secretin stimulation immediately after the ERCP procedure from 160 patients: 38 patients with PCa, 38 with chronic pancreatitis (CP), 22 with BTCa, 20 with adenomyomatosis of the gallbladder (AGB), 22 with cholecystolithiasis (CCL), and 20 control subjects. Mutant allele specific amplification (MASA), which is a highly sensitive method for detecting KRM, was performed, with the DNAs extracted from these samples by phenol-chloroform. RESULTS: The incidence of KRM in DA by MASA was 25 (66%) of the 38 PCa cases, 12 (32%) of the 38 CP cases, and 12 (55%) of the 22 BTCa cases. There was no patient with positive KRM in DA among the 20 cases of AGB, 22 of CCL, and 20 control subjects. The sensitivity was 62% and the specificity 88% in this study design. The KRM incidence was found to be relatively high for the patients with PCa and BTCa by MASA, which is a highly sensitive method, although the incidence of KRM in DA from the patients with PCa was not as high as the incidence in their PPJ with secretin stimulation. CONCLUSIONS: MASA showed a relatively high incidence of KRM even in the DA, which was easily obtained from the patients with PCa and BTCa without secretin stimulation immediately after ERCP. These results suggest that the detection of KRM in the DA by MASA is useful for the screening of both PCa and BTCa.

Troglitazone combination therapy in obese type 2 diabetic patients poorly controlled with alpha-glucosidase inhibitors.

The efficacy and safety of treatment with troglitazone combined with an alpha-glucosidase inhibitor, in obese type 2 diabetic patients who were previously administered alpha-glucosidase inhibitors alone, in improving glycaemic control and reducing insulin resistance were studied. Obese type 2 diabetic patients, poorly controlled with alpha-glucosidase inhibitors, were randomized to receive either oral troglitazone 200 mg twice daily (22 patients: group A) or a placebo (20 patients: group B) in addition to their usual alpha-glucosidase inhibitor. In group A, significant decreases in the mean levels of haemoglobin A1c and basal plasma insulin levels were observed 6 months after the start of combined therapy. Serum triglyceride levels significantly decreased but serum lactic acid dehydrogenase and body weight significantly increased. New systemic oedema was observed in six patients. Combined therapy with troglitazone and alpha-glucosidase inhibitors may be effective for diabetic metabolic abnormalities, although the potential development of adverse effects such as body-weight gain and systemic oedema demands vigilance.

Development of Graves' hyperthyroidism from primary hypothyroidism in a case of thyroid hemiagenesis.

We report a 42-year-old female with right thyroid hemiagenesis who initially presented with hypothyroidism and then developed hyperthyroidism. The serum titer of thyroid-stimulating antibody was weakly positive in the initial hypothyroid state, and then markedly increased along with the development of hyperthyroidism, while thyroid stimulation-blocking antibody was continuously negative throughout the observation period. Thyroid histology of biopsied specimens during the hypothyroid state demonstrated diffuse thyroiditis with mononuclear cell infiltrations; however, the histology during the hyperthyroid state showed hyperplasia in follicular epithelial cells accompanied by partial lymphocyte infiltration. This is the first case of thyroid hemiagenesis associated with a conversion from primary hypothyroidism due to Hashimoto's thyroiditis to hyperthyroidism due to Graves' disease.

Diabetic nephropathy accompanied by iodine-induced non-autoimmune primary hypothyroidism: two case reports.

We reported 2 diabetic patients with nephrotic syndrome due to advanced diabetic nephropathy complicated by non-autoimmune primary hypothyroidism. Hypothyroidism developed along with the anasarcous status. Histological examinations of the thyroid gland revealed almost normal thyroid follicles without lymphocytic infiltration. The amounts of thyroid hormone lost into the extravascular space such as in urine and ascites were not sufficient to cause hypothyroidism alone. Serum total iodine levels measured during the hypothyroidal state in both cases were definitely elevated, and the perchlorate discharge test of both cases showed positive discharge (24 and 34%, respectively). The thyroid functions normalized after iodine restriction in the first case and initiating hemodialysis in the second case, in parallel with normalization of serum total iodine levels. These findings suggest that impaired renal handling of iodine resulting in elevation of serum iodine levels, rather than an autoimmune mechanism or extravascular hormone loss, played a principal role in the development of primary hypothyroidism found in these 2 patients, probably through a prolonged Wolff-Chaikoff effect.

Three diabetic cases of acute dizziness due to initial administration of voglibose.

We observed 3 diabetic patients with intolerable dizziness followed by nausea and vomiting immediately after an initial administration of the alpha-glucosidase inhibitor, voglibose. These symptoms did not recur after discontinuation of the drug. Adverse effects as observed in these cases have not been reported previously. Since the 3 patients were relatively old (average age, 72 years old) and had various degrees of micro- and macroangiopathies, these side effects may have been associated with increased micro- and macrocirculatory disturbances in their central nervous systems through alpha-glucosidase inhibition of this agent.

Antibodies to glutamic acid decarboxylase (GAD) in non-obese Japanese diabetics without insulin therapy: a comparison of two commercial RIA kits based on recombinant and pig brain GAD.

To compare the clinical usefulness of commercial radioimmunoassay (RIA) kits based on recombinant and pig brain GAD, we measured glutamic acid decarboxylase autoantibody (GADAb) titers in 125 non-obese (body mass index < 24) Japanese diabetics without insulin therapy using two commercial RIA kits based on recombinant human (rh) GAD65 (GADAb Cosmic) and purified pig brain native GAD (RIP Anti-GAD Hoechst). The frequencies of GADAb positivity using these two RIA kits (normal ranges; < 1.3 and < 4.0 U/ml, respectively) were about 4.8 (6/125) and 3.2% (4/125), respectively. The six patients found to be positive with RIA using GADAb Cosmic demonstrated significantly higher prevalence of NIDDM in their parents (P = 0.04), lower beta-cell function estimated by intravenous glucagon loading tests (P = 0.03) and higher prevalence of progression to insulin therapy (P = 0.0001). Five of these six patients slowly progressed to insulin-requiring status within 34 +/- 11 months of follow-up evaluation, and one of these five patients progressed to a completely insulin-dependent status within 30 months from the onset of diabetes. Of these six patients, two demonstrated chronic pancreatitis, three had chronic thyroiditis, and five showed HLA DR4. Interestingly, two of the six patients demonstrated very low GADAb titers (2.3 and 2.9 U/ml), while RIP Anti-GAD Hoechst showed no positivity with the same sera. Based on the binding study after pre-incubation of unlabeled GADs, these low titrated GADAb were elucidated to be true specific reactions to rh GAD65 alone. Moreover, one of the two patients with chronic thyroiditis and HLA DR4 slowly progressed to insulin-requiring status over a period of 45 months. These findings suggest that the measurement of GADAb using a commercial assay kit with rh GAD65 may be more useful to detect non-insulin-dependent type I diabetics among non-obese patients than using a commercial kit with purified pig brain native GAD, especially among those with low GADAb titers.

Subsegmental transcatheter arterial embolization for hepatocellular carcinoma in the caudate lobe.

PURPOSE: To clarify the effectiveness of transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) in the caudate lobe of the liver. MATERIALS AND METHODS: Thirteen patients with HCC in the caudate lobe underwent TAE. TAE was performed by injection of the mixture of anticancer drugs (mitomycin C and doxorubicin or epirubicin) and iodized oil, followed by gelatin sponge particles. Arterial anatomy of the caudate branch, local recurrence rate, and survival rate were evaluated. RESULTS: From 31 TAEs for the caudate lobe, 22 subsegmental TAEs were successfully performed (71%). Local recurrence in the caudate lobe was seen in 10 patients (77%). Subsegmental TAE for the caudate lobe was repeated one to five times. Cumulative local recurrence rates were 33% and 75% within 3 and 6 months, respectively. Survival rates after first TAE for HCC in the caudate lobe were 89% and 74% for 1 and 3 years, respectively. CONCLUSION: Local recurrence rate after subsegmental TAE for HCC in the caudate lobe was high. However, repeated subsegmental TAE possibly improves the prognosis of HCC in the caudate lobe.

Clinicopathologic studies of immunologic fecal occult blood test for colorectal cancer.

In our hospital, 83 patients with colorectal cancer underwent the immunologic fecal occult blood test (IFOBT). The positive rate for IFOBT in all patients was 87%. Colon cancers more proximal than the transverse colon were 100% positive. Carcinomas of the ulcerative type showed a significantly higher positive rate than those of the non-ulcerative type (94% vs 73%). Carcinomas penetrating the muscularis or beyond showed a significantly higher positive rate, of 96% (52/54 cases) compared to carcinomas confined to the mucosa or submucosa, which gave positive rates of 64% and 60%, respectively. In the investigation of the 7 patients with colorectal cancer who showed negative results on the IFOBT, IFOBT had been performed only once in of these patients. Accordingly, it was considered necessary to perform IFOBT more than once. The cancers in 5 of these 7 patients were found to be carcinomas confined to the mucosa. This result suggests the advisability of annual IFOBTs. It is also considered necessary to manage patients who show undefinable but possibly positive (+/-) results with caution.

Endoscopic resection of large colorectal polyps using a clipping method.

PURPOSE: In conventional endoscopic snare polypectomy, bleeding and perforation are the principal concerns. To prevent these complications, we employ an endoscopic clipping technique using the HX-3L clipping apparatus. METHODS: With this method, clips are used to clamp the base of a polyp. A snare is hung peripheral to the clips. The polyp is then resected by coagulating and cutting with an electric current. RESULTS: Neither bleeding nor perforation during or after polypectomy has occurred, nor have complications related to the use of clips developed. Gigantic polyps were not resected piecemeal, but rather were resected en bloc facilitating a clear determination of cancer on the surface of the resected site. Endoscopic clipping permitted site marking for colonoscopic surveillance. CONCLUSION: We conclude that the clipping method has many advantages and is a useful technique in colonoscopic polypectomy.

The immunohistochemical evaluation of PSP/reg-protein in normal and diseased human pancreatic tissues.

In order to elucidate the characteristics of reg-protein, which is identical to pancreatic stone protein (PSP/reg-protein), and the relationship between the generation and evolution of chronic pancreatitis and the expression of PSP/reg-protein in the pancreas, we investigated the expression of PSP/reg-protein in normal and diseased human pancreatic tissues by immunohistochemistry. The PSP/reg-protein was expressed in all cases with normal pancreas or chronic pancreatitis, and in 70.6% of cases with pancreatic cancer. This protein was present in the cytoplasm of acinar cells and, in some cases, in the intraluminal contents of ductules in nonmalignant tissues. From the view of distribution and cellular localization, PSP/reg-protein was expressed more broadly and densely in chronic pancreatitis with mild to moderate injury than in the normal pancreas. However, the protein was less expressed in severely damaged chronic pancreatitis tissue, such as calcifying pancreatitis, than in the normal pancreas. These findings suggest that mild to moderate injury to pancreatic tissue may stimulate the synthesis of PSP/reg-protein, whereas more severe injury tends to depress it.