Cinacalcet hydrochloride relieves hypercalcemia in Japanese patients with parathyroid cancer and intractable primary hyperparathyroidism.

Pharmacological treatment of hypercalcemia is essential for patients with parathyroid carcinoma and intractable primary hyperparathyroidism (PHPT). Use of the calcimimetic cinacalcet hydrochloride (cinacalcet) is an option to treat such patients. We investigated the efficacy and safety of cinacalcet in Japanese patients with parathyroid carcinoma and intractable PHPT. Five Japanese patients with parathyroid carcinoma and two with intractable PHPT were enrolled in an open-label, single-arm study consisting of titration and maintenance phases. Cinacalcet doses were titrated until the albumin-corrected serum calcium concentration decreased to 10.0 mg/dL or less or until dose escalation was considered not necessary or feasible. Serum calcium concentration at the baseline was 12.1 ± 1.3 mg/dL (mean ± standard deviation; range 10.4-14.6 mg/dL) and decreased to 10.1 ± 1.6 mg/dL (range 8.6-13.3 mg/dL) at the end of the titration phase with cinacalcet at a dosage of up to 75 mg three times a day. At the end of the titration phase, at least a 1 mg/dL reduction in serum calcium concentration from the baseline was observed in five patients (three with carcinoma and two with PHPT), and it decreased to the normocalcemic range in five patients (three with carcinoma and two with PHPT). Common adverse events were nausea and vomiting. One patient discontinued participation in the study because of an adverse event, liver disorder. Cinacalcet effectively relieved hypercalcemia in 60% of the Japanese patients with parathyroid carcinoma and might be effective in those with intractable PHPT. The drug might be tolerable and safe at a dosage of at most 75 mg three times a day.

Differential changes in blood flow and oxygen utilization in active muscles between voluntary exercise and electrical muscle stimulation in young adults.

The physiological effects on blood flow and oxygen utilization in active muscles during and after involuntary contraction triggered by electrical muscle stimulation (EMS) remain unclear, particularly compared with those elicited by voluntary (VOL) contractions. Therefore, we used diffuse correlation and near-infrared spectroscopy (DCS-NIRS) to compare changes in local muscle blood flow and oxygen consumption during and after these two types of muscle contractions in humans. Overall, 24 healthy young adults participated in the study, and data were successfully obtained from 17 of them. Intermittent (2-s contraction, 2-s relaxation) isometric ankle dorsiflexion with a target tension of 20% of maximal VOL contraction was performed by EMS or VOL for 2 min, followed by a 6-min recovery period. DCS-NIRS probes were placed on the tibialis anterior muscle, and relative changes in local tissue blood flow index (rBFI), oxygen extraction fraction (rOEF), and metabolic rate of oxygen (rMRO2) were continuously derived. EMS induced more significant increases in rOEF and rMRO2 than VOL exercise but a comparable increase in rBFI. After EMS, rBFI and rMRO2 decreased more slowly than after VOL and remained significantly higher until the end of the recovery period. We concluded that EMS augments oxygen consumption in contracting muscles by enhancing oxygen extraction while increasing oxygen delivery at a rate similar to the VOL exercise. Under the conditions examined in this study, EMS demonstrated a more pronounced and/or prolonged enhancement in local muscle perfusion and aerobic metabolism compared with VOL exercise in healthy participants.NEW & NOTEWORTHY This is the first study to visualize continuous changes in blood flow and oxygen utilization within contracted muscles during and after electrical muscle stimulation (EMS) using combined diffuse correlation and near-infrared spectroscopy. We found that initiating EMS increases blood flow at a rate comparable to that during voluntary (VOL) exercise but enhances oxygen extraction, resulting in higher oxygen consumption. Furthermore, EMS increased postexercise muscle perfusion and oxygen consumption compared with that after VOL exercise.

Effects of calcination temperature and acid-base properties on mixed potential ammonia sensors modified by metal oxides.

Mixed potential sensors were fabriated using yttria-stabilized zirconia (YSZ) as a solid electrolyte and a mixture of Au and various metal oxides as a sensing electrode. The effects of calcination temperature ranging from 600 to 1,000 °C and acid-base properties of the metal oxides on the sensing properties were examined. The selective sensing of ammonia was achieved by modification of the sensing electrode using MoO(3), Bi(2)O(3) and V(2)O(5), while the use of WO(3,) Nb(2)O(5) and MgO was not effective. The melting points of the former group were below 820 °C, while those of the latter group were higher than 1,000 °C. Among the former group, the selective sensing of ammonia was strongly dependent on the calcination temperature, which was optimum around melting point of the corresponding metal oxides. The good spreading of the metal oxides on the electrode is suggested to be one of the important factors. In the former group, the relative response of ammonia to propene was in the order of MoO(3) > Bi(2)O(3) > V(2)O(5), which agreed well with the acidity of the metal oxides. The importance of the acidic properties of metal oxides for ammonia sensing was clarified.

Distinct diagnostic criteria for ultrasonographic examination of papillary thyroid carcinoma: a multicenter study.

Recent advances permitting high-resolution ultrasonography have made ultrasonographic examination of nodular thyroid diseases an accessible examination for routine practice. However, diagnostic criteria for ultrasonographic examination of thyroid nodules are not surely established. To identify the optimal strategy for well standardized differential diagnosis of papillary thyroid carcinoma and benign nodules, we evaluated the significance of individual ultrasonographic characteristics of thyroid nodules in a multicenter study. Ten characteristics in ultrasonograms from 53 patients scored by 17 investigators from 15 centers were analyzed by t tests and logistic regression analyses. Between benign and papillary thyroid cancer groups, all characteristics but not size or multiplicity of strong echoes, which suggest calcifications, were significant parameters. Logistic regression analyses showed that border character, shape, and internal echo level are highly significant parameters (p < 0.0005). A multiple logistic regression showed to be the most important predictors of pathologic diagnosis. The diagnostic criterion with border character and internal echo level yielded 93% sensitivity and 92% specificity. In conclusion, univariate and multivariate analyses identified border character, shape, internal echo level, but not strong echoes (calcifications), as important characteristics in differentiating papillary thyroid carcinoma from benign nodules. These results will contribute to standardization of accurate ultrasonographic diagnosis of papillary thyroid carcinoma.

Identification of metallopanstimulin-1 as a member of a tumor associated antigen in patients with breast cancer.

The immunological screening of breast cancer was performed with IgG autoantibodies by the serological analysis of recombinant cDNA expression library methods to explore novel tumor associated antigens. We have focused on a small zinc finger protein metallopanstimulin-1 (MPS-1). MPS-1 mRNA was ubiquitously expressed in normal human tissues except the brain and the placenta. In Western blot analysis, MPS-1 was easily detected strongly in actively proliferating cells and three breast cancer cell lines. In the tissue the protein of MPS-1 in cancer cells was more abundant than that of surrounding normal cells. Screening of tissue specimens by immunohistochemistry revealed 50.4% positive for MPS-1 in 125 cancer patients. These data suggest that MPS-1 could be applicable to the immunotherapy of breast cancer.

Thyroid-stimulating hormone induces interleukin-18 gene expression in FRTL-5 cells: immunohistochemical detection of interleukin-18 in autoimmune thyroid disease.

Interleukin (IL)-18 is a cloned cytokine that was identified originally as a factor having potent interferon (IFN)-gamma-inducing activity on Kupffer cells. First, we analyzed IL-18 gene expression by reverse transcription-polymerase chain reaction (RT-PCR) in rat thyroid FRTL-5 cells and human thyroid tissue samples. The expression of IL-18 mRNA in FRTL-5 cells was enhanced by thryoid-stimulating hormone (TSH) in a dose-dependent manner. 8-Bromo-cyclic adenosine monophosphate (cAMP) also increased in IL-18 mRNA levels. Furthermore, TGCT clones that exhibited an increase in intracellular cAMP accumulation showed an increased IL-18 mRNA signal when compared to controls. Taken together, these data suggested that the effect of TSH on IL-18 gene expression was mediated by activating protein kinase A. Treatment of FRTL-5 cells with the antithyroid drug, methimazole (MMI), suppressed this stimulatory action of TSH on IL-18 gene expression. Next, we examined IL-18 expression in human thyroid tissue derived from patients with autoimmune thyroid diseases (ATD). RT-PCR and immunohistology demonstrated that human thyroid follicular cells expressed IL-18. Especially in thyroid tissue from a patient with Hashimoto's thyroiditis, expression was more diffuse and extensive, generally observed in close relation to a lymphocytic infiltrate. Also, IL-18 protein was distributed in the same follicles that express Fas-L and HLA-DR. This study is the first to demonstrate the detection of IL-18 in the thyroid gland. The frequent expression of IL-18 in thyrocytes suggests that IL-18 itself might be a secreted immunomodulator in ATD.

DAP12 ITAM motif regulates differentiation and apoptosis in M1 leukemia cells.

DAP12 is an immunoreceptor tyrosine-based activation motif (ITAM)-bearing transmembrane adapter molecule that is associated with the NK-activating receptors. DAP12 is expressed not only in NK cells, but also in myeloid cells. Previously, we reported that DAP12 was likely to be involved in monocyte differentiation to macrophage. In this study, we established the mutant DAP12-M1 transfectants (Y76F-M1) that have mutation at their ITAM motifs. We observed that Y76F-M1 cells could not differentiate to macrophages by stimulation via DAP12, whereas wild type DAP12 transfectants (FDAP-M1) could. Furthermore, we demonstrated that the apoptosis signal mediated by LPS was inhibited in Y76F-M1 cells, but was augmented in FDAP-M1 cells. In contrast to the LPS-mediated apoptosis, the combination of LPS and DAP12 stimulation showed good cell viability in FDAP-M1 cells. Collectively our studies demonstrated that DAP12 has a critical role for macrophage differentiation and LPS induced apoptosis in M1 leukemia cells.

Modulation of hepatic granulomatous responses by transgene expression of DAP12 or TREM-1-Ig molecules.

DAP12 (also known as KARAP) is a novel ITAM-bearing transmembrane adapter molecule that is expressed on the cell surface of natural killer cells, monocytes, dendritic cells, and macrophages. Several myeloid cell-specific DAP12-associating receptors, such as TREM receptor family, SIRP-beta1, and MDL-1 have been identified. The in vivo function of DAP12 and its associating molecules in inflammation has remained primarily unknown. To investigate DAP12 signaling during chronic inflammation, we constructed two adenoviral gene transfer vectors to express FLAG/DAP12 (Ad-FDAP12) and the extracellular domain of mouse TREM-1 and the Fc portion of human IgG1 (Ad-TREM-1 Ig), respectively, and observed their modulatory activities in a mouse model of hepatic granulomatous inflammation elicited by zymosan A. Mice were injected with zymosan A intravenously and 24 hours after zymosan A, they were injected with Ad-FDAP12 or Ad-TREM-1 Ig. Zymosan A-induced hepatic granuloma formation peaked at day 7 and markedly declined by day 10. Although adenoviral-mediated DAP12 gene transfer did not enhance granuloma formation by day 7, it sustained and enhanced granuloma formation beyond day 7. However, an anti-FLAG monoclonal antibody used to potentiate the signaling of adenoviral-derived DAP12, enhanced granuloma formation at day 7. In sharp contrast to the effect by Ad-FDAP12, transgene expression in the liver of soluble form of extracellular domain of TREM-1 as an antagonist of DAP12 signaling, remarkably inhibited zymosan A-induced granuloma formation at all time points examined. Our findings thus suggest that both DAP12 and TREM-1 are involved in the development of granulomatous responses in the liver.