Recommendations for the management of cystic thyroid nodules

BACKGROUND: The management of cystic thyroid nodules has not been standardized with respect to an initial fine-needle aspiration cytology (FNAC) cystic change result, which is defined as fluid aspiration and a smear with numerous macrophages but scant or no follicular cells. In the present study the physical characteristics of cystic thyroid nodules predictive of the pathology were investigated, and recommendations made on their management. METHODS: The aspiration results of 1436 thyroid nodules managed between 1998 and 2000 were investigated. A total of 157 patients who had a subsequent operation or follow-up data with reaspiration were the subjects of the present study. Age, sex, nodule characteristics and others were examined as possible predictors of cancer risk. RESULTS: The malignancy rate was 8.9%. Ten cases (71%) of malignancy were not cytologically diagnosed. Male sex and a nodule size of > or = 4 cm were found to be statistically significant predictors of malignancy. The malignancy rate was highest (100%) when a cystic lesion had malignant cytology on reaspiration and local invasion on radiology. CONCLUSIONS: When a cystic change is observed by initial FNAC of thyroid nodules, nodules of > or = 4 cm must be reaspirated and a firm cytologic diagnosis made to rule out malignancy. Nodules should be considered for surgery having taken into account other characteristics, in particular male sex and radiologic findings of local invasion.     

GABA receptors on horizontal cells in the goldfish retina

We investigated the localization of GABA(A) and GABA(C) receptors in horizontal cells (HCs) and HC axon terminals (ATs) dissociated from goldfish retina, using whole-cell patch-clamping recordings. Applications of GABA on HCs induced two groups with inward currents at the holding potential of -50 mV: One was a sustained inward current in the H1 cell, with one type of HCAT (AT1), and the other was a transient inward current in other HC soma and HCAT (AT2). Co-application of GABA with bicuculline or SR95531, GABA(A) receptor antagonists, showed a non-blocking effect in the sustained current, but a blocking effect in the transient current. The sustained current was evoked by cis-4-aminocrotonic acid (CACA), a GABA(C) receptor agonist, while the transient current was not induced by CACA, but mimicked by muscimol, a GABA(A) receptor agonist. Both the sustained and transient currents were completely blocked by picrotoxin and not mimicked by baclofen, a GABA(B) receptor agonist. Thus H1 cell and AT1 have GABA(C) receptors, while H2, H3 cells and AT2 have GABA(A) receptors.     

Suppression of dextran sodium sulfate-induced colitis in mice by zerumbone, a subtropical ginger sesquiterpene, and nimesulide: separately and in combination

Ulcerative colitis (UC) and Crohn's disease are inflammatory disorders of unknown cause and difficult to treat, though some synthetic chemicals, including ligands for peroxisome proliferator-activated receptors (PPARs), are anticipated to be useful drugs. In contrast, few food phytochemicals have been reported to suppress colitis in animal models. The present study was undertaken to explore the suppressive efficacy of zerumbone (ZER), a sesquiterpenoid present in the rhizome of Zingiber zerumbet Smith that is used as a condiment in Southeast Asian countries and known to be a potent suppressant of cyclooxygenase (COX)-2 and inducible nitric oxide synthase expression in cell culture systems. Acute colitis was induced by exposing female ICR mice to 5% DSS in drinking water for 1 week. One week prior to DSS administration, the experimental mice were fed ZER alone, nimesulide (NIM, a selective COX-2 inhibitor) alone, or both in combination (1000 ppm each) for a total of 2 weeks. Inflammatory biomarkers, i.e. interleukin (IL)-1alpha and IL-1beta, tumor necrosis factor (TNF)-alpha, and prostaglandin (PG)E(2) and PGF(2alpha) in colonic mucosa were quantified by an enzyme-linked immunosorbent assay in conjunction with histological alterations. Oral feeding of ZER significantly lowered the levels of IL-1beta [inhibitory rate (IR)=34%], TNF-alpha (IR=29%), and PGE(2) (IR=73%) and suppressed DSS-induced colitis, whereas NIM suppressed the histological changes induced by DSS without affecting inflammatory biomarkers. However, their treatment in combination was most effective for suppressing these biomarkers. Our results suggest that ZER is a novel food factor for mitigating experimental UC and that use of a combination of agents, with different modes of actions, may be an effective anti-inflammatory strategy.     

The opposing effects of endothelin-1 and C-type natriuretic peptide on apoptosis of neonatal rat cardiac myocytes

C-type natriuretic peptide (CNP) and endothelin-1 are paracrine peptides with opposing effects on cardiac myocyte contraction and intracellular cGMP production. Elevated levels of both endothelin-1 and CNP are found in patients with congestive heart failure. These factors may be related to positive and negative regulation of cell apoptosis in the failing heart. To evaluate the effect of CNP and endothelin-1 on apoptosis of cardiac myocytes and the possible mechanisms involved, primary cardiac myocytes were prepared from neonatal Sabra rats. Cardiomyocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Annexin V in situ staining. The TUNEL method was used to measure the apoptotic index. CNP and the cGMP derivative, 8-br-cGMP, induced apoptosis of cardiac myocytes. CNP-induced apoptosis could be blocked by HS 142-1 (a mixture of 20-30 kinds of linear beta-1, 6-glucan esterified by capronic acid, an antagonist of type A and B natriuretic peptide receptors), and KT 5823 (C29H25N3O5), the inhibitor of cGMP-dependent protein kinase). Alpha-difluoromethylornithine (DFMO), the irreversible inhibitor of ornithine decarboxylase, also induced apoptosis to a similar extent. CNP and 8-br-cGMP caused a marked reduction of intracellular ornithine decarboxylase expression, as determined by Western blot analysis and immunohistochemical assay. Preincubation with endothelin-1 attenuated CNP- and 8-br-cGMP-induced cardiomyocyte apoptosis. Endothelin-1 also antagonized the CNP- and 8-br-cGMP-induced reduction of intracellular ornithine decarboxylase expression. These results suggest that CNP has a proapoptotic effect on neonatal rat cardiac myocytes. The effect is mediated via natriuretic peptide receptors and is due to an elevation of intracellular cGMP, which reduces the expression of intracellular ornithine decarboxylase and probably the production of polyamines. Endothelin-1 protects cardiac myocytes against CNP-induced apoptosis by influencing the cGMP-dependent pathway, and this effect is probably mediated through both a reduction of cGMP and antagonism of the CNP-induced reduction of intracellular ornithine decarboxylase expression.     

A multicentre phase II trial of bryostatin-1 in patients with advanced renal cancer

Protein kinase C (PKC) has a critical role in several signal transduction pathways, and is involved in renal cancer pathogenesis. Bryostatin-1 modulates PKC activity and has antitumour effects in preclinical studies. We conducted a multicentre phase II clinical trial in patients with advanced renal cancer to determine the response rate, immunomodulatory activity and toxicity of bryostatin-1 given as a continuous 24 h infusion weekly for 3 out of 4 weeks at a dose of 25 mug m(-2). In all, 16 patients were recruited (11 males and five females). The median age was 59 years (range 44-68). Patients had been treated previously with nephrectomy (8) and/or interferon therapy (9) and/or hormone therapy (4) and/or radiotherapy (6). Eight, five and three patients had performance statuses of 0, 1 and 2, respectively. A total of 181 infusions were administered with a median of 12 infusions per patient (range 1-29). Disease response was evaluable in 13 patients. Three patients achieved stable disease lasting for 10.5, 8 and 5.5 months, respectively. No complete responses or partial responses were seen. Myalgia, fatigue, nausea, headache, vomiting, anorexia, anaemia and lymphopenia were the commonly reported side effects. Assessment of biological activity of bryostatin-1 was carried out using the whole-blood cytokine release assay in six patients, two of whom had a rise in IL-6 levels 24 h after initiating bryostatin-1 therapy compared to pretreatment values. However, the IL-6 level was found to be significantly lower at day 28 compared to the pretreatment level in all six patients analysed.     

Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy

BACKGROUND: The current study was performed to determine the impact of the presence of retroperitoneal lymphadenopathy on the survival and response to immunotherapy of patients with metastatic renal cell carcinoma (RCC). METHODS: A retrospective cohort study was performed with outcome assessment based on the chart review of demographic, clinical, and pathologic data from 1087 patients. Patients with RCC who did not present with metastatic disease, who did not undergo nephrectomy as part of their cancer treatment, and those in whom either the lymph node (N) or metastatic (M) status was unknown, were excluded. A total of 322 M1 patients who met these criteria and who underwent nephrectomy for unilateral RCC formed the principal study population. RESULTS: Two hundred thirty-six patients presented with N0M1 disease and 86 patients presented with N+M1 disease. In M1 patients, the presence of positive regional lymph nodes was associated with larger sized, higher grade, locally advanced primary tumors that were more commonly associated with sarcomatoid features. N0M1 patients were more likely to achieve an objective response to systemic immunotherapy compared with N+M1 patients (P = 0.01). N+M1 patients overall had worse short-term and long-term survival compared with N0M1 patients, with a median survival of 10.5 months compared with 20.4 months, respectively. The median survival of N0M1 patients was improved to 28 months in those who received adjunctive immunotherapy (P = 0.0008), whereas the median survival of patients with N+M1 disease was the same in those treated with and those treated without adjunctive immunotherapy (P = 0.18). CONCLUSIONS: Even in the modern era of systemic immunotherapy, the presence of regional lymphadenopathy exerts a detrimental effect on the survival of patients with metastatic RCC. Lymph node status is a strong predictor of the failure to achieve either an objective immunotherapy response or an improvement in survival when immunotherapy is given as an adjunctive treatment after cytoreductive nephrectomy. However, in multivariate analysis, including both clinical and pathologic variables, lymph node status was found to have less of an impact on survival than primary tumor stage and grade and patient performance status.     

Cytotoxic constituents of Isodon rubescens var. lushiensis

Five new ent-kaurane diterpenoids, ludongnins F-J (1-5), along with 10 known compounds, guidongnins A-C (6-8), angustifolin (9), 6-epiangustifolin (10), sculponeatin J (11), gardenin D, 5,3',4'-trihydroxy-6,7,8-trimethoxyflavone, pedalitin, and quercetin, were isolated from the leaves of Isodon rubescens var. lushiensis. The structures of 1-5 were determined by spectroscopic analysis, as well as X-ray crystallographic analysis of 1. Compounds 1-11 were evaluated against K562 leukemia cells for their cytotoxic effects.     

Anti-obesity action of Salix matsudana leaves (Part 2). Isolation of anti-obesity effectors from polyphenol fractions of Salix matsudana

Previously, it was reported that polyphenol fractions prepared from the leaves of Salix matsudana reduced the elevation of the rat plasma triacylglycerol level at 3 and 4 h after oral administration of a lipid emulsion containing corn oil, at a dose of 570 mg/kg. Moreover, body weights at 2-9 weeks and the fi nal parametrial adipose tissue weights were significantly lower in mice fed the high-fat diet with 5% polyphenol fractions of S. matsudana leaves than in those fed the high-fat diet alone. The polyphenol fractions of S. matsudana leaves also significantly reduced the hepatic total cholesterol content, which was elevated in mice fed the high-fat diet alone. In addition, the polyphenol fractions of S. matsudana leaves inhibited palmitic acid uptake into brush border membrane vesicles prepared from rat jejunum and alpha-amylase activity, and their fractions enhanced norepinephrine-induced lipolysis in fat cells. To clarify the active substances inhibiting the palmitic acid uptake into small intestinal brush border membrane, the alpha-amylase activity or enhancing the norepinephrine-induced lipolyis in fat cells, the isolation of the active substances from polyphenol fraction was attempted using the above three assay systems. Compounds 1, 2 and 3 were isolated from the polyphenol fractions and identified as apigenin-7-O-d-glucoside, luteolin-7-O-d-glucoside and chrysoeriol-7-O-d-glucoside, respectively. Among three flavonoids, apigenin-7-O-d-glucoside inhibited alpha-amylase activity, and luteolin-7-O-d-glucoside and chrysoeriol-7-O-d-glucoside inhibited palmitic acid uptake into small intestinal brush border membrane. Furthermore, three flavonoid glucosides enhanced norepinephrine-induced lipolysis in fat cells.