Innate Immune-Modulatory Activity of Prunella vulgaris in Thyrocytes Functions as a Potential Mechanism for Treating Hashimoto's Thyroiditis.

Prunella vulgaris (PV), a perennial herb, has been used to treat thyroid diseases in China for over 2,000 years. In particular, its therapeutic effect has been described for Hashimoto's thyroiditis, including reducing titers autoantibodies against thyroid peroxidase and thyroglobulin of and T helper 17 (Th17) cells. However, the underlying mechanism for how PV exerts such effects has not been investigated. We examined the effects of PV on innate immune activation, which is thought to be one of the triggers for the development of autoimmune diseases, including Hashimoto's thyroiditis. In cultured thyrocytes, PV reduced mRNA levels of inflammatory cytokines that were originally induced as a result of innate immune activation initiated by transfection of double-stranded DNA (dsDNA) or dsRNA. PV suppressed activation of nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3), and suppressed corresponding promoter activation, which were initially activated by dsDNA or dsRNA. PV also suppressed the mRNA levels of molecules responsible for antigen processing and presentation, and PV protected thyrocytes from apoptosis induced by dsDNA and dsRNA. Additionally, PV suppressed the expression of genes involved in iodide uptake and oxidation. Taken together, these results suggest that PV exerts its protective effect on thyrocytes by suppressing both innate and adaptive immune responses and cell death. PV may also protect cells from iodide-associated oxidative injury. This report is among the first to identify the mechanisms to explain PV's beneficial effects in Hashimoto's thyroiditis.

Tolerability and Adverse Events of Adjuvant Chemotherapy for Rectal Cancer in Patients With Diverting Ileostomy.

BACKGROUND/AIM: The impact of diverting ileostomy on the feasibility of adjuvant chemotherapy (ACT) remains unclear. We retrospectively investigated the tolerability and adverse events of ACT for rectal cancer in patients with diverting ileostomy. PATIENTS AND METHODS: Thirty-three patients who received ACT after curative resection with ileostomy construction for rectal cancer were analyzed. We assessed completion rate, the mean relative dose intensities, and the factors affecting the tolerability of ACT. RESULTS: The completion rate of each chemotherapy regimen was 10 out of 16 patients in oral uracil-tegafur plus leucovorin (UFT/LV), 1 out of 3 patients in oral capecitabine (Capecitabine) and 2 out of 14 patients in capecitabine plus oxaliplatin (CAPOX). The mean relative dose intensities were 77% in UFT/LV, 48% in Capecitabine, and 57% of capecitabine and 42% of oxaliplatin in CAPOX. In multivariate analysis, laparoscopic surgery (Odds ratio=11.6, p=0.021) and receiving preoperative chemoradiotherapy (Odds ratio=32.4, p=0.021) were associated with treatment completion. CONCLUSION: Completion rate of ACT in patients with diverting ileostomy was lower than that of colorectal cancer patients in the previous studies. UFT/LV may be a more tolerable regimen than Capecitabine or CAPOX in colorectal cancer patients with diverting ileostomy.

Temporary loss of consciousness during cetuximab treatment of a patient with metastatic colon cancer: a case report.

BACKGROUND: Anti-epidermal growth factor receptor (EGFR) antibody is widely used for the treatment of patients with metastatic colorectal cancer. Hypomagnesemia is a comparatively frequent adverse event of this drug, which is likely overlooked because it occurs later in treatment without symptoms. Furthermore, hypomagnesemia and hypomagnesemia-induced corrected QT (QTc) prolongation may lead to loss of consciousness (LOC), the onset of which is not generally considered associated with the treatment of anti-EGFR antibody because of its rare occurrence. Here, we present a colorectal cancer patient treated with anti-EGFR antibody, who suffered LOC during treatment while severe hypomagnesemia or QTc prolongation was not observed. CASE PRESENTATION: A 69-year-old man with metastatic colon cancer was treated with cetuximab (anti-EGFR antibody) plus irinotecan as third-line chemotherapy. His serum magnesium level gradually decreased, and grade 2 hypomagnesemia (a serum magnesium level of 0.9 mg/dL) was observed at the 12th administration of cetuximab. In light of this development, intravenous supplementation of 20 mEq magnesium sulfate began with careful blood monitoring despite the lack of clinical symptoms. Electrocardiogram (ECG) showed prolonged QT or corrected QT (QTc) intervals (grade 1). His serum magnesium level remained at 0.9 mg/dL, and no hypomagnesemia symptoms were observed by the 17th administration of cetuximab. After the treatment, however, he suddenly lost consciousness without symptoms related to infusion or allergic reactions. Circulatory collapse following dermatological reactions and respiratory events were not evident. Intravenous supplementation of magnesium sulfate was administered again. He awakened 2 min after the onset of temporary LOC without any other symptoms related to hypomagnesemia, such as lethargy, tremor, tetany, and seizures. No other etiology outside of the low level of serum magnesium was confirmed in further examinations. Cetuximab was discontinued, and his serum magnesium level returned to a level within the normal range after 6 weeks. Because of tumor progression, regorafenib and TAS-102 (trifluridine tipiracil hydrochloride) were introduced sequentially for 6 months. Five months after the final treatment of TAS-102, he died of his primary disease, which reflected a survival period of 4 years and 6 months since the beginning of treatment. CONCLUSIONS: This case report reminds clinicians that LOC can be induced without severe hypomagnesemia or QTc prolongation, during anti-EGFR antibody treatment for metastatic colorectal cancer even while under carefully monitored magnesium supplementation.

Iodine excess as an environmental risk factor for autoimmune thyroid disease.

The global effort to prevent iodine deficiency disorders through iodine supplementation, such as universal salt iodization, has achieved impressive progress during the last few decades. However, iodine excess, due to extensive environmental iodine exposure in addition to poor monitoring, is currently a more frequent occurrence than iodine deficiency. Iodine excess is a precipitating environmental factor in the development of autoimmune thyroid disease. Excessive amounts of iodide have been linked to the development of autoimmune thyroiditis in humans and animals, while intrathyroidal depletion of iodine prevents disease in animal strains susceptible to severe thyroiditis. Although the mechanisms by which iodide induces thyroiditis are still unclear, several mechanisms have been proposed: (1) excess iodine induces the production of cytokines and chemokines that can recruit immunocompetent cells to the thyroid; (2) processing excess iodine in thyroid epithelial cells may result in elevated levels of oxidative stress, leading to harmful lipid oxidation and thyroid tissue injuries; and (3) iodine incorporation in the protein chain of thyroglobulin may augment the antigenicity of this molecule. This review will summarize the current knowledge regarding excess iodide as an environmental toxicant and relate it to the development of autoimmune thyroid disease.

[Global leprosy situation, beginning of 2008].

The epidemiological situation of leprosy is reported by the health division of each country to WHO. The reported data is collected by WHO and is immediately run on the Weekly Epidemiological Record. On this latest edition, data from the beginning of 2008 was reported. In almost all of the highly endemic countries, control activities have been integrated within the general healthcare system. However, maintaining political interest and mobilizing the necessary funds to implement activities in the field are challenges for many national programmes as the burden of disease declines further.

[Present leprosy situation in the world in 2006].

The epidemiological situation of leprosy is reported by the health division of each country to WHO. The reported data is collected by WHO and is immediately run on the Weekly Epidemiological Record. On this latest edition, data from the beginning of 2006 was reported. Early case detection and treatment with multidrug therapy (MDT) remains the cornerstone of leprosy control. The challenge will be to establish these facilities as part of an integrated system that provides referral services for other diseases in the area.

Stomach-specific calpain, nCL-2, localizes in mucus cells and proteolyzes the beta-subunit of coatomer complex, beta-COP.

Calpain is a Ca2+-regulated cytosolic protease. Mammals have 14 calpain genes, half of which are predominantly expressed in specific organ(s); the rest are expressed ubiquitously. A defect in calpains causes lethality/pathogenicity, indicating their physiological indispensability. nCL-2/calpain-8a was identified as a stomach-specific calpain, whose physiological functions are unclear. To elucidate these, we characterized nCL-2 in detail. Unexpectedly, nCL-2 was localized strictly to the surface mucus cells in the gastric epithelium and the mucus-secreting goblet cells in the duodenum. Yeast two-hybrid screening identified several nCL-2-interacting molecules. Of these, the beta-subunit of coatomer complex (beta-COP) occurs in the stomach pit cells and is proteolyzed by nCL-2 in vitro. Furthermore, beta-COP and nCL-2 co-expressed in COS7 cells co-localized in the Golgi, and Ca2+-ionophore stimulation caused the proteolysis of beta-COP near the linker region, resulting in the dissociation of beta-COP from the Golgi. These results strongly suggest novel functions for nCL-2 that involve the membrane trafficking of mucus cells via interactions with coat protein.

[Bladder stone caused by olive oil following TVT operation].

Tension-free vaginal tape (TVT), a less-invasive variation of the suburethral sling, has been rapidly gaining popularity worldwide in the treatment of female stress urinary incontinence. We report on two cases of bladder stones composed of fatty acid calcium following TVT operations. Case 1: A 76-year-old woman with a history of hysterectomy due to cervical cancer was suffering from vault prolapse. The insertion of a ring pessary lead to the development of stress urinary incontinence, and she was referred to our hospital. As she was frail, sexually inactive, and elderly, she underwent partial colpocleisis (Le Fort operation) combined with a TVT operation. One-month postoperative videourodynamics and chain cystourethrography (CUG) using olive oil as the lubricant showed cure of incontinence and mild support of the urethra. Her maximum flow rate was 18.8 ml/s and no residual urine was observed. Six months postoperatively she developed postmiction pain and pyuria that were not improved by antibiotics. Cystoscopy showed a small bladder stone, whose removal cured cystitis. Case 2: A 49-year-old woman, with a history of abdominal hysterectomy due to myoma uteri, visited our hospital complaining of stress urinary incontinence. A periurethral collagen injection was only temporarily effective, and she underwent a TVT operation. A 1-month postoperative evaluation including chain CUG using olive oil as the lubricant showed cure of incontinence, mild support of the urethra, a maximum flow rate of 28.8 ml/s, and no residual urine. Two months postoperatively she developed miction pain and pyuria that were solved by removing a small bladder stone. Anti-incontinence surgery increases the risk of developing bladder stones due to either foreign bodies (bladder erosion) or obstruction. However, neither of our cases had these conditions; instead, both bladder stones were composed of fatty acid calcium that appeared to be related to the olive oil used as the lubricant in chain CUG. Only four cases (including ours) of bladder stones composed of fatty acid calcium have been documented, but they may indicate that care is necessary when using olive oil as a contrast medium or lubricant in the urinary tract. When a woman with a history of anti-incontinence surgery has persisting or recurrent cystitis, cystoscopy should be performed to exclude bladder erosion and stones.

Multi-glycoside of Tripterygium wilfordii Hook f. ameliorates proteinuria and acute mesangial injury induced by anti-Thy1.1 monoclonal antibody.

BACKGROUND/AIMS: Multi-glycoside from Tripterygium wilfordii Hook f. (GTW) is used for various immune and inflammatory diseases including renal diseases represented by mesangial proliferative glomerulonephritis (MsPGN) in China. However, there have been no fundamental studies on the operating mechanism of GTW on MsPGN. The aim of this study is to examine as the first step the effects of GTW on acute injurious process such as mesangial injury and proteinuria in an acute and reversible Thy.1.1 glomerulonephritis (Thy1.1GN) model and then to clarify the action mechanism of GTW at molecular level by examining its effects on various injurious factors in this model. METHODS: Thy1.1 GN was induced in rats by a single intravenous injection with 500 microg of anti-Thy1.1 mAb 1-22-3. Daily oral administration of GTW and vehicle as a control was started from 3 days before injection of mAb to the day of sacrifice in each experiment. Fourteen rats were randomly divided into 2 groups, GTW-treated and vehicle-treated groups, and sacrificed on day 14 in experiment 1 or on day 7 in experiment 2 after induction of Thy1.1 GN. Proteinuria was determined on days 1, 3, 5, 7, 10 and 14 in experiment 1 or on 1, 3, 5 and 7 in experiment 2. From blood and kidneys taken at sacrifice, blood biochemical parameters, mesangial morphological changes, glomerular macrophage infiltration, and glomerular mRNA expression of cytokines were examined. RESULTS: In experiment 1, proteinuria and mesangial matrix expansion were significantly attenuated by GTW treatment. In experiment 2, GTW treatment significantly ameliorated proteinuria, mesangial lesions and macrophage accumulation in glomerulus. In addition, it significantly reduced the glomerular expression of mRNA for PDGF, MCP-1 and IL-2. CONCLUSION: GTW ameliorated not only proteinuria but also mesangial alterations in Thy1.1 GN most likely by reducing expression of injurious cytokines, indicating that GTW has suppressive effects on acute inflammatory changes in glomeruli.

An evaluation of 1-84 PTH measurement in relation to bone alkaline phosphatase and bone Gla protein in hemodialysis patients.

BACKGROUND/AIM: It has been suggested that higher levels of parathyroid hormone (PTH) are required to maintain normal bone turnover in chronic hemodialysis (HD) patients. Serum PTH levels determined by intact PTH (i-PTH) assay may overestimate the actual activity of circulating PTH in HD patients. The aim of the present study was to assess the clinical usefulness of whole PTH assay on the evaluation of bone turnover in HD patients. MATERIALS AND METHODS: We performed measurement of parameters on bone turnover in 179 HD patients (116 men, 63 women; mean age 61.0 +/- 13.1 years). Serum whole PTH levels were determined as cyclase-activating PTH (CAP) by an immunoradiometric assay, and compared with those of i-PTH. Cyclase-inactivating PTH (CIP) was calculated as (i-PTH-CAP). The correlations between serum whole PTH levels and clinical parameters such as serum levels of Ca, P, bone alkaline phosphatase (BAP), bone Gla protein (BGP), total protein (TP), albumin (Alb), urea nitrogen (SUN), and creatinine (Cr) were analyzed using multivariate analysis. RESULTS: The mean values of i-PTH and CAP were 124.1 +/- 97.4 and 86.9 +/- 71.6 pg/ml, respectively, indicating that the serum CAP levels were about 70% of i-PTH levels. The serum CAP levels significantly correlated with that of i-PTH (r = 0.959, p < 0.001). Moreover, a significant positive correlation between serum CAP levels and metabolic bone markers such as BAP (r = 0.400, p < 0.01) and BGP (r = 0.481, p < 0.01) was observed. Stepwise multivariate analysis revealed that serum levels of CAP were significantly determined by serum levels of Ca, P, Alb, and oral dosage of vitamin D (F ratio = 18.81, adjusted r(2) = 0.302). CONCLUSIONS: These data suggest that the biological activity of circulating PTH in HD patients is lower than the levels estimated by conventional i-PTH assay.

Insect diapause-specific peptide from the leaf beetle has consensus with a putative iridovirus peptide.

Diapause and hibernation during periods of environmental adversity are essential features of the life cycle in many organisms, yet the molecular basis for these events differs among animals. We have identified an endogenous diapause/hibernation-specific peptide, from the leaf beetle Gastrophysa atrocyanea. This peptide provides antifungal activity, acts as a N-type voltage-gated Ca2+ channel blocker, and has a new consensus sequence with an unknown polypeptide encoded in the insect iridescent virus. These results indicate that the diapause-specific peptide may be utilized as a probe to analyze and compare functional and evolutional aspects of the life cycles of insects and iridoviruses.

Regulation of transformed state by calpastatin via PKCepsilon in NIH3T3 mouse fibroblasts.

Ca(2+)-activated neutral protease calpain is ubiquitously expressed and may have pleiotropic biological functions. We have previously reported that repeated treatment of NIH3T3 mouse fibroblasts with the calpain inhibitor N-acetyl-Leu-Leu-norleucinal (ALLN) resulted in the induction of transformed foci [T. Hiwasa, T. Sawada, and S. Sakiyama (1990) Carcinogenesis 11, 75-80]. To elucidate further the effects of calpain in malignant transformation of NIH3T3 cells, calpastatin, an endogenous specific inhibitor of calpain, was expressed in NIH3T3 cells by transfection with cDNA. G418-selected calpastatin-expressing clones showed a significant increase in the anchorage-independent growth ability. A similar increase in cloning efficiency in soft agar medium was also observed in calpain small-subunit-transfected clones. On the other hand, reduced expression of calpastatin achieved by transfection with calpastatin antisense cDNA in Ha-ras-transformed NIH3T3 (ras-NIH) cells caused morphological reversion as well as a decrease in anchorage-independent growth. When NIH3T3 cells were treated with ALLN for 3 days, cell growth was stimulated by approximately 10%. This growth stimulation by ALLN was not observed in ras-NIH cells, but recovered by expression of a dominant negative form of protein kinase C (PKC)epsilon but not by that of PKCalpha. Western blotting analysis showed that an increase in PKCepsilon was much more prominent than that of PKCalpha in NIH3T3 cells after treatment with ALLN. These results are concordant with the notion that calpain suppresses malignant transformation by predominant degradation of PKCepsilon.