Increased risk of a herpes zoster attack in patients receiving androgen deprivation therapy for prostate cancer.

This study aimed to examine the association of herpes zoster (HZ) with androgen deprivation therapy (ADT) use among patients with prostate cancer (PC), using a population-based data set. The study sample for this study was retrieved from the Taiwan Longitudinal Health Insurance Database 2005. We selected 877 patients with PC who had received ADT as the study group, while 849 patients with PC who had not received ADT served as the comparison group. Each study patient was individually tracked for a 3-year period to discriminate those who subsequently received a diagnosis of HZ. Of the total 1,726 sampled patients, the incidence rate of HZ per 100 person-years was 1.80 (95% CI: 1.41-2.25) during the 3-year follow-up period. In particular, incidence rates of HZ per 100 person-years were 2.36 (95% CI: 1.75-3.13) and 1.24 (95% CI: 0.81-1.81), respectively, for patients with PC who had and those who had not received ADT. Furthermore, Cox proportional hazard regressions showed that the adjusted hazard ratio for an HZ attack during the 3-year follow-up period for patients with PC who had received ADT was 1.88 (95% CI: 1.13-3.11) than those who had not received ADT. We concluded that patients with PC who had received ADT had an increased risk of HZ.

[Inflammation of the parathyroid glands]. / Entzündungen der Nebenschilddrüsen.

Inflammation of the parathyroid glands is rare when compared to other endocrine organs. This leads to the use of descriptive terms as well as the lack of a generally accepted classification for inflammatory disorders of the parathyroid glands. This review article proposes that parathyroid inflammation be subdivided morphologically into (a) non-specific lymphocytic infiltration, which is more an expression of damage to small vessels, due to e. g. severe systemic inflammation or myocardial infarction, (b) autoimmunogenic lymphocytic parathyroiditis, (c) nonimmunogenic inflammation caused by granulomatous diseases or infections and (d) invasive sclerosing (peri) parathyroiditis. As only parathyroid glands removed due to hyperparathyroidism and normal parathyroid glands incidentally removed during thyroid surgery are seen almost exclusively in routine histopathology, virtually no information about the morphological correlate of hypoparathyroidism is available.

Differential miRNA expression profiles in variants of papillary thyroid carcinoma and encapsulated follicular thyroid tumours.

BACKGROUND: Recent studies showed a significant upregulation of distinct microRNAs (miRNAs) in papillary thyroid carcinoma (PTC). The objective of this study was to explore whether this upregulation could also be assigned to distinct histomorphological variants of PTC, especially the follicular variant and other encapsulated follicular thyroid tumours. METHODS: We used total RNA of 113 formalin-fixed paraffin-embedded tissues of 50 PTCs ((10 conventional type (PTC-CT), 10 tall cell variants (PTC-TCVs), 30 follicular variants (PTC-FVs)), 10 follicular adenomas (FAs), 10 multinodular goitres (MNGs), 21 follicular thyroid carcinomas and 22 well-differentiated tumours of unknown malignant potential (WDT-UMP) to analyse the miRNA expression pattern of five selected miRNAs (146b, 181b, 21, 221 and 222) using RT-PCR TaqMan miRNA assay to explore the diagnostic utility of this method. RESULTS: The mean values of the expression pattern of all miRNAS in PTCs show a statistically significant difference from those in MNG and FA with fold changes up to 90 for miRNA 146b, P<0.001. No differences in expression pattern could be showed between MNG and FA. The PTC-FVs differ significantly from FA in all five miRNAS, from MNG in three and from WDT-UMP in one miRNA with fold changes between 1.7 and 21.2, but failed to be of diagnostic value regarding individual cases with substantial overlaps. CONCLUSION: We conclude that analysis of a set of five selected miRNAS distinguish common variants of PTC from FA/MNG but failed to be a useful diagnostic method in individual and doubtful cases, especially in the differential diagnosis of encapsulated follicular thyroid tumours.

[Familial thyroid carcinomas]. / Familiäre Karzinome der Schilddrüse.

Approximately 5% of differentiated thyroid carcinomas with follicular cell differentiation, papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) and 25-30% of medullary thyroid carcinoma (MTC) are hereditary. They occur either as part of a defined syndrome or are confined to the thyroid gland. Compared to their sporadic non-hereditary counterparts hereditary thyroid carcinomas generally develop earlier and regularly show multifocal tumour growth. With the exception of familial MTC, which is preceded by neoplastic C cell hyperplasia, no precursor lesions of hereditary thyroid carcinoma are known. In strong correlation with the localisation of the germline mutation of the RET protooncogene, familial MTC shows a distinct clinical course which allows precise clinical decision-making for prophylactic thyroidectomy to prevent invasive MTC. According to current knowledge prophylactic thyroidectomy of all other types of hereditary thyroid carcinoma is not justified.

[Multiple endocrine neoplasia type 2]. / Multiple endokrine Neoplasien Typ 2.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited cancer syndrome with the major components medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. Due to the clinical course three distinct subtypes are distinguished, MEN 2A, MEN 2B and familial medullary thyroid carcinoma. The disease is caused by germ-line mutations of the RET proto-oncogene and the localization of these mutations correlates with the onset of the development of medullary thyroid carcinoma, which is crucial for the clinical course and outcome of the disease. It therefore has a substantial influence on the clinical management of the affected patients and their relatives. This review summarizes the morphology and clinic of MEN 2-associated tumors and their respective precursor lesions.

Lack of correlation between BRAF V600E mutational status and the expression profile of a distinct set of miRNAs in papillary thyroid carcinoma.

Recent studies demonstrated a significant upregulation of distinct microRNAs (miRNAs), small endogenous RNAs that regulate gene expression, in papillary thyroid carcinoma (PTC). In the pathogenesis of PTC the T1799A (V600E) BRAF mutation is the most common genetic alteration leading to a constitutive activation of the MAPK pathway. The aim of the present study was to elucidate a possible correlation between BRAF mutational status and a distinct miRNA expression profile. In a series of 221 PTC we determined the BRAF V600E mutational status using DNA-sequencing and correlated the occurrence of the mutation with a variety of clinicopathologcial data. The miRNA expression profile of five selected subtypes (miRNA-146b, -181b, -21, -221, -222) in two matched cohorts of BRAF positive (n=28) and wildtype cases (n=26) was examined by RT-PCR TaqMan miRNA assay. The BRAF V600E mutation was significantly found in PTCs with extrathyroidal extension (p <0.001). Among them, V600E was even significantly associated with smaller tumour size of 1 cm or less (microcarcinomas; p<0.003) and the follicular (p=0.017) and tall cell variant (p=0.015). By calculating relative changes in miRNA gene expression no differences in fold changes could be detected between BRAF positive and wildtype PTC suggesting that BRAF has no regulatory influence on the expression of the five examined miRNAs. However, our study confirmed the diagnostic utility of this distinct set of miRNAs to detect PTC by significant fold changes in at least 3 miRNAs (miRNA-146b, -221, -222) irrespective of its histological variant.

Analysis of deregulated miRNAs is helpful to distinguish poorly differentiated thyroid carcinoma from papillary thyroid carcinoma.

Poorly differentiated thyroid carcinoma (PDTC) is defined as a malignant follicular cell derived neoplasm, both morphologically and biologically intermediate between well differentiated and anaplastic thyroid carcinoma (ATC). In the present study we investigated the expression levels of two distinct sets of miRNAs ('set 1': miRNA-146b, -181b, -21, -221, -222, all shown to be significantly upregulated in papillary thyroid carcinoma [PTC]; 'set 2': miRNA-30d, -125b, -26a, -30a-5p, and let7c, all downregulated in ATC) in a series of 15 PDTC (including 3 mixed PDTC/PTC), 9 'pure' PTC, and 9 ATC. Compared to normal thyroid tissue all 'set 1' miRNAs were significantly upregulated in PTC (p<0.001); in ATC 4/5 miRNAs were upregulated (p<0.001) whereas in PDTC the expression levels of all 5 miRNAs did not differ significantly from normal thyroid. All miRNAs of 'set 2' were significantly upregulated in PTC (p<0.004) and downregulated in ATC (p<0.03); in PDTC only 3/5 were downregulated (p<0.011). All 10 miRNAs investigated differed significantly (p<0.003) between PTC and PDTC. In the histologically differentiated PTC compound of mixed PDTC/PTC cases, however, miRNA expression levels of all 10 miRNAs investigated lacked significant difference from those found in the PDTC compound, whereas 6/10 miRNAs differed significantly from 'pure' PTC. Our results indicate that analysis of distinct sets of miRNAs represent useful tools to distinguish PDTC from 'pure' PTC. Additionally our findings suggest that lack of deregulation of some miRNAs may select a subset of PTC prone to progression to PDTC.

COX-2 expression in highly aggressive thyroid malignancies - indication for a possible therapeutic option?

Both anaplastic thyroid carcinoma (ATC) and angiosarcoma of the thyroid (AST) are highly aggressive malignancies with very limited therapeutic options. Since selective inhibition of COX-2, for example, by celecoxib has been shown to suppress both tumour formation and progression, we investigated COX-2 protein expression in a series of ATC and AST (26 cases each) using immunohistochemistry. COX-2 expression was demonstrated in 13 ATC (50%) and 11 AST (42%); a strong COX-2 expression in more than 50% of vital tumour cells was found in 5 ATC and 5 AST, respectively. Although a recently performed phase II trial applying celecoxib failed overall to halt tumour progression in differentiated thyroid carcinoma, the two cases with partial or complete remission noted in this study were related to tumours with immunohistochemically proven strong COX-2 expression. The strong COX-2 expression observed in approximately 20% of our ATC and AST samples may thus indicate selective patients with a possible therapeutic option for an otherwise fatal disease.

[Giant cell tumors of soft tissue arising in surgical scars]. / Riesenzelltumoren des Weichgewebes (mit niedrig-malignem Potenzial) in Operationsnarben.

Giant cell tumor of soft tissue (GCT-ST) is a rare primary soft tissue tumor with low malignant potential. It is clinically and pathologically similar to the giant cell tumor of the bone. Two cases of GCT-ST in surgical scars are reported. Both tumors were initially regarded as tumor relapses of a leiomyosarcoma of deep soft tissue and a dermal in situ squamous cell carcinoma, respectively. The development of GCT-ST in surgical scars has not been observed previously. These findings suggest chronic inflammation and tissue repair as etiological factors in the development of GCT-ST. The period of time between initial surgical intervention and the development of the GCT-ST seems to be unusually short for the development of a "true" second neoplasm, which may underline the sometimes diffuse border between reactive "pseudosarcomatous" and neoplastic fibro-histiocytic lesions.

Wegener's granulomatosis in the thyroid mimicking a tumour.

Wegener's granulomatosis (WG) is a systemic vasculitis characterised by the presence of necrotizing granulomas and classically manifests as a triad of upper and lower respiratory tract involvement along with glomerulonephritis. Other rather unusual presentations of WG include ocular, salivary gland, cutaneous, gastrointestinal and cardiac involvement. We report a case in a 51-year-old woman suffering from WG with positive antineutrophil cytoplasmic autoantibodies and antibodies directed against proteinase 3. Under maintenance therapy, the patient developed two thyroid nodules suspicious for malignancy which led to thyroidectomy. Postoperative histological examination revealed a tumour-forming WG mimicking a malignant thyroid tumour. We conclude that, although extremely rare, Wegener's. granulomatosis should be added to the list of differential diagnoses of tumours of the thyroid gland.

The effect of platelet-rich fibrin on autologous osteochondral transplantation: An in vivo porcine model.

BACKGROUND: This work aimed to evaluate the efficacy of cartilage transplantation to the medial femoral condyle±platelet-rich fibrin (PRF) augmentation in a porcine model. The hypothesis of the study was that PRF may act as a bioactive cell scaffold to fill defects and enhance cartilage regeneration. METHODS: Thirty-two knees of 16 miniature pigs were randomly assigned to four groups. The critical-size osteochondral defects (8x5mm) in femoral condyle of both knees were treated with one of the following: group 1－untreated controls; group 2－cartilage fragments alone; group 3－PRF alone; group 4－PRFT+cartilage fragments. After completion of the surgical implantation, the periosteal patch harvested from the proximal tibia was sutured onto the cartilage of the medial condyle to cover the implanted defects. Animals were sacrificed at six months after treatment. The regenerated cartilages were assessed by gross inspection and histological examination. RESULTS: The best results were obtained with the repair tissue being hyaline-like cartilage (group 4). The grading score of histological evaluation demonstrated that group 4 had better matrix, cell distribution and cartilage mineralization than group 2 and group 3. PRF showed a positive effect on the cartilage repair; the procedure was more effective when PRF was combined with autologous chondrocytes. CONCLUSIONS: This approach may provide a successfully employed technique to target cartilage defects in vivo. Larger groups and longer periods of study may provide more definitive and meaningful support for using this therapeutic approach as a new way of cartilage regeneration.

Evidence of a new metabolic pathway of 5-fluorouracil in Escherichia coli from in vivo 19F-NMR spectroscopy.

Two distinct metabolic pathways of 5-fluorouracil are proposed in Escherichia coli. The first metabolic pathway is a reductive degradation with the formation of dihydrofluorouracil as the first metabolite. The second metabolic pathway is shown to be a hydroxylating degradation, possibly with the formation of 5-hydro-6-hydroxy-5-fluorouracil as the first metabolite. The metabolites of both pathways undergo subsequent hydrolytic degradation with fluoride ion as the common final product. The chemical structures of these metabolites were partially identified by 19F-NMR. The results show a close resemblance between these two metabolic pathways with in vivo pyrimidine biodegradation. The reductive degradation has been proposed by several laboratories, whereas the hydroxy degradation has not been reported before. Both the reductive and hydroxy pathways are demonstrated in this report, to be independent reactions.

Deletion or alteration of hydrophobic amino acids at the first and the third transmembrane domains of hepatitis B surface antigen enhances its production in Escherichia coli.

To investigate the failure of high-level production of hepatitis B viral (HBV) surface antigen (HBsAg), including three authentic forms, large (L), middle (M) and major/small (S) HBsAg, in Escherichia coli, we employed the high-expression vector pGEX containing the glutathione S-transferase-encoding gene (GST) to study HBsAg production. Different fragments of HBV DNA containing the entire pre-S1/pre-S2/S region (for L protein), or partial pre-S1, pre-S2, pre-S1/pre-S2 and pre-S2/S region (for M protein), were fused downstream from the GST gene, in order to obtain five plasmids which encode GST-HBsAg fusion proteins. SDS-PAGE analyses revealed that cells containing plasmids with a full-length S region (pGLS and pGMS) produced undetectable GST-HBsAg fusion proteins, in contrast to those cells harboring plasmids without the S region (pGS1, pGS2 and pGS1S2), which synthesized fusion proteins in 3-10% of the total cellular protein. Using an immunoblot method to screen HBsAg production in cells which harbored plasmids derived from exonuclease BAL 31-digested pGLS, we obtained eight positive clones. Nucleotide sequence analyses of plasmids from the positive clones revealed that termination, deletion or frameshift occurred at the regions encoding either the first or the third transmembrane domain of the major HBsAg. Correlation between the production level of GST-HBsAg fusion proteins and their constituent and arrangement of amino acids (aa) at the last 20 aa among 15 clones suggested that the fusion protein ended with a longer stretch of or a higher ratio of hydrophobic aa had a lower production in E. coli.

Scavenging effect of benzophenones on the oxidative stress of skeletal muscle cells.

Benzophenone is an ultraviolet (UV)-absorbing agent that has been used in industry and medicine for more than 30 years. Consumers of cosmetics and sunscreens containing UV-absorbers are exposed to benzophenones on a daily basis, owing to the widespread use of these compounds. However, the efficacy of these compounds as scavengers of oxidative stress is still not well established. In the present study, we investigate the antioxidative capacity of six sunscreen benzophenone compounds. A primary myoblast culture was mixed in vitro with 100 microM menadione. The cytotoxic effect by menadione-induced oxidative stress was monitored by the lucigenin- or luminol-amplified chemiluminescence, methylthiotetrazole (MTT) assay, and the antioxidative effects of various benzophenone compounds were evaluated. The results showed that the addition of menadione can induce oxidative stress on myoblasts by superoxide and hydrogen peroxide production, which can be eradicated by superoxide dismutase (SOD) and catalase, respectively, in a dose-dependent mode. The catalase has a protective effect on the cytotoxicity induced by menadione as measured by the MTT assay, while the SOD does not. The selected benzophenones also have a significant scavenging effect on the menadione-induced cell death on the myoblasts. The ortho-dihydroxyl structure and other hydroxy groups in the same ring have a stronger scavenging effect on the superoxide anion on myoblasts; thus, a stable penoxy radical may be formed. The mechanism of this effect remains to be clarified.

Erdheim-Chester disease: case report with multisystemic manifestations including testes, thyroid, and lymph nodes, and a review of literature.

Erdheim-Chester disease is a rare non-Langerhans' cell histiocytosis with characteristic radiological and histological features. This entity is defined by a mononuclear infiltrate consisting of lipid laden, foamy histiocytes that stain positively for CD68. About half of those affected have extraskeletal manifestations, including involvement of the hypothalamus-pituitary axis, lung, heart, retroperitoneum, skin, liver, kidneys, spleen, and orbit. This report describes the case of a 50 year old white man who presented with hypogonadism and diabetes insipidus. At necropsy, extensive organ involvement was found, including the testes, thyroid, and lymph nodes. This is the first report of thyroid and lymph node infiltration in this disease. Because of the endocrinological symptoms, neurosarcoidosis and hypophysitis are important diseases in the differential diagnosis. This report also includes a review of the literature concerning rare organ manifestations and patients presenting primarily with similar symptoms.

Inhibition of xanthine oxidase by hydroxylated anthraquinones and related compounds.

Eighteen anthraquinones and related compounds were tested for their inhibitory effects on xanthine oxidase. The enzyme, xanthine oxidase catalyses the oxidation of hypoxanthine to xanthine and of xanthine to uric acid, which has a lambda max of 295nm, forming the basis for a spectrophotometric assay of the activity of xanthine oxidase. The results showed that anthrarobin and purpurin showed moderate effects on xanthine oxidase inhibition (IC50 = 68.35 and 105.13 microM; Ki = 122.38 and 130.49 microM respectively), and both of them induced mixed type (competitive-non-competitive) inhibition with respect to the substrate xanthine.

Inhibitory effects of plant growth regulators on xanthine oxidase.

Several plant hormones and analogues were tested for their inhibitory effects on xanthine oxidase. The flavoprotein enzyme, xanthine oxidase, catalyses the oxidation of hypoxanthine to xanthine and then xanthine to uric acid which has lambda max 295 nm. Uric acid was thus the basis for a spectrophotometric assay of the activity of xanthine oxidase. The results showed that trans-zeatin displayed the strongest activity (IC50 = 23.5 muM) on xanthine oxidase inhibition, followed by indole-3-acrylic acid (IC50 = 136.0 muM) and then by the mixed isomers of zeatin (trans-zeatin and cis-zeatin) (IC50 = 198.65 muM). Trans-zeatin induced an uncompetitive inhibition of the enzyme with respect to the substrate xanthine and the apparent inhibition constant (Ki) was 5.09 muM. However, zeatin riboside was inactive. Since xanthine oxidase serum levels are increased in hepatitis, mild hepatic intoxication, tumours brain tissues, and DNA damage induced by cytotoxic agents, it is expected that trans-zeatin may be useful for the treatment of these diseases as well as gout which is caused by deposition of uric acid in the joints and oxidative damage of tissue caused by generation of superoxide anion radical.

Inhibition of xanthine oxidase by synthetic cytokinin analogues.

Thirteen synthetic cytokinin analogues were tested for their inhibitory effects on xanthine oxidase. The enzyme, xanthine oxidase catalyses the oxidation of hypoxanthine to xanthine and of xanthine to uric acid, which has a gamma max of 295 nm, forming the basis for a spectrophotometric assay of the activity of xanthine oxidase. The results showed that 8-azaadenine(1), 4-amino-6-hydroxypyrazolo [3,4-d] pyrimidine(4), 4-amino-6-mercaptopyrazolo [3,4-d] pyrimidine(5) and 4-aminopyrazolo [3,4-d] pyrimidine(6) display inhibitory effects on xanthine oxidase with an order of activity of IC50 = 0.54, 5.91, 8.17 and 25.46 microM, respectively. Their apparent inhibition constants (Ki) were 0.66, 1.54, 6.61 and 26.79 microM, and induced mixed(competitive-non-competitive), competitive, mixed (competitive-non-competitive), and competitive types of inhibition respectively, with respect to the substrate xanthine.

Inhibition of xanthine oxidase by cytokinins and related substances.

Fourteen cytokinins were tested for their inhibitory effects on xanthine oxidase. The enzyme, xanthine oxidase catalyses the oxidation of hypoxanthine to xanthine and of xanthine to uric acid which has lambda max of 295 nm, forming the basis for a spectrophotometric assay of the activity of xanthine oxidase. The results showed that adenine-HCl, N6-(2-isopentenyl)-adenine, purine and DL-dihydrozeatin displayed very potent activities (IC50 = 1.92, 10.99, 60.98 and 86.36 microM respectively). Their apparent inhibition constants (Ki) were 2.20, 17.99, 13.59 and 115.62 microM, and induced competitive, uncompetitive, competitive and non-competitive type inhibitions respectively with respect to the substrate xanthine.