Changes in Blood Pressure after the First Dose of Calcitonin (Elcatonin)

We had found previously that calcitonin treatment (elcatonin once a week for 10 weeks) results in significant decreases in blood pressure. The aim of the present study was to determine whether these effects were due to a cumulative effect of elcatonin or could be elicited by treatment with a single dose. To this end, we recruited 62 patients (eight men, 54 women; mean age 83 years; range 67-101 years) with a chief complaint of lower back pain to the present study and examined changes in blood pressure following administration of the first dose of elcatonin. All subjects in the study had been hospitalized either at our institution or an affiliated hospital. After acute phase symptoms had settled, subjects received 1 U (1mL), i.m., elcatonin S20. Blood pressure was measured the day before the first scheduled treatment and on the day of treatment. Both systolic and diastolic blood pressure decreased from 2 h after administration, and dropped significantly 4 and 6 h after administration. Therefore, elcatonin decreased blood pressure without first having to be accumulated in the body. There are several possible explanations for the results, including effects mediated by changes in concentrations of calcitonin gene-related peptide and calcium ions, as well as involvement of the parasympathetic nervous system. In conclusion, calcitonin inhibits bone resorption and pain, lowers blood pressure, and is easy to use in elderly patients who exhibit age-related increases in blood pressure

Epithelial Cell Transforming Sequence 2 in Human Oral Cancer

Epithelial cell transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor for Rho family GTPase, which has been implicated in the malignant phenotype of human cancers. Little is known about the effect of a high level of ECT2 in regulating oral cancer cell behavior. In this study, we investigated the involvement of ECT2 in oral squamous cell carcinoma (OSCC)., and down-regulation of cyclin D1, cyclin E, and CDK4. These data suggested that the elevated Cip/Kip family induced inhibition of the cyclin D1-CDK complex activity leading to cell cycle arrest at the G1 phase.Our results proposed for the first time that ECT2 is an indicator of cellular proliferation in OSCCs and that ECT2 might be a potential therapeutic target for the development of new treatments for OSCCs

The Relationship Between Serum Homocysteine Levels and Vertebral Fractures

Serum homocysteine and pentosidine levels have attracted attention as associated markers of bone quality, which affects bone strength. We examined the relationship of serum homocysteine levels with existing vertebral fractures and renal function. We evaluated 279 of 960 osteoporosis outpatients (12 men, 267 women; mean age, 72 years) whose serum homocysteine levels had been measured in our department. Using a glomerular filtration rate (GFR)-based chronic renal failure severity classification system, we divided patients into three groups: G1/G2, G3a/G3b/G4, and G5. We further divided the patients in the G1/G2 and G3a/G3b/G4 groups into two subgroups on the basis of the presence of fractures. Vertebral fractures were significantly more frequent when serum homocysteine levels were high in the G1/G2 group (P = 0.002). Serum homocysteine levels were lower in patients in the G1/G2 group than the G3a/G3b/G4 group despite the presence or absence of vertebral fractures (P < 0.001). Significant differences in serum homocysteine levels were also seen between patients with and without vertebral fractures in both the G1/G2 and G3a/G3b/G4 groups (P = 0.02). There were also significant correlations between GFR and serum homocysteine levels in both the G1/G2 and G3a/G3b/G4 groups (correlation coefficients, −0.43 and −0.65, respectively; P < 0.001). A negative correlation was observed between serum homocysteine levels and GFR in the G1/G2 and G3a/G3b/G4 groups, and we were able to reaffirm that serum homocysteine levels are affected by renal function. In the G1/G2 group, the prevalence of vertebral fractures was significantly higher in patients with high serum homocysteine levels. Even if renal function was poor, serum homocysteine levels were significantly higher in patients with vertebral fractures. Thus, serum homocysteine is a valid marker of bone quality

Effects of 3 Years of Treatment with a Selective Estrogen Receptor Modulator for Postmenopausal Osteoporosis on Markers of Bone Turnover and Bone Mineral Density

Aim: The aim of the present study was to assess the changes in bone mineral density and bone turnover markers in long-term SERM. Methods: The study was performed on 25 female outpatients with primary osteoporosis treated at the Osteoporosis Department of Showa University School of Medicine. All patients had been on raloxifene (60mg/day) for ≥ 3 years. The mean patient age was 67.1 years and the women were, on average, 18.4 years postmenopausal. Levels of bone turnover markers (urinary naltrexone [NTX] and bone-specific alkaline phosphatase [BAP]) and bone mineral density (BMD; front lumbar vertebrae, three proximal femur sites, and two distal radius sites) were determined before and then annually after starting raloxifene for a period of 3 years. Results: Over the 3-year treatment period, significant decreases were seen in both urinary NTX and BAP levels. Although BMD of the lumbar vertebrae and distal radius was increased over the 3 years after initiation of raloxifene treatment, the difference failed to reach statistical significance. The BMD of the femoral neck decreased, whereas that of the femoral trochanter and femoral intertrochanter area increased. Conclusions: The selective estrogen receptor modulator raloxifene is suitable for the treatment of osteoporosis in postmenopausal patients because it reduces bone turnover while maintaining adequate bone density

Relationships between Markers of Bone Metabolism Used in the Treatment of Osteoporosis

Various markers of bone metabolism are used in the treatment of osteoporosis as they can help assess the condition of bony tissue/bone metabolism and can help predict the likelihood of fractures and bone loss in the near future. We investigated correlations between various bone metabolism markers to ascertain which could be used as a universal marker of bone metabolism and its associated care. Subjects comprised 144 female patients treated for osteoporosis at this facility between January and December 2009, in whom the following bone metabolism markers were measured on the same day: BAP, urine NTX, OC, ucOC, and TRACP-5b. The mean age of the subjects was 71.2 years. All subjects were analyzed as an entire group (total group), and subjects were also divided into 2 groups and analyzed based on whether they were using an osteoporosis drug or not. Subjects currently being treated were included in the treated group (n=113; mean age: 71.9 years). Subjects with no treatment experience were included in the untreated group (n=31; mean age: 68.6 years). In the total group and treated group, significant correlations were revealed between BAP, urine NTX, OC, ucOC, and TRACP-5b. In the untreated group, no correlation was observed between BAP and ucOC, but correlations between BAP, urine NTX, OC, ucOC, and TRACP-5b were observed. ucOC is a marker of bone metabolism, and is also an indicator of the state of vitamin K intake. Based on the correlations with both bone resorption markers and osteoplastic markers found in this study, ucOC was found to be the best universal marker to use in the clinical setting

Circulating T follicular helper 2 cells, T follicular regulatory cells and regulatory B cells are effective biomarkers for predicting the response to house dust mite sublingual immunotherapy in patients with allergic respiratory diseases

The relationships between T follicular helper (Tfh) cells and antigen-specific immunoglobulins (sIgs) in patients with allergic respiratory diseases who are receiving antigen immunotherapy (AIT) have not been fully clarified. Therefore, we started to perform house dust mite sublingual immunotherapy (HDM-SLIT) for 20 patients with atopic asthma comorbid with allergic rhinitis (AA+AR) who were already receiving ordinary treatments including inhaled corticosteroid (ICS). We examined percentages of circulating T follicular helper (cTfh) and regulatory (cTfr) cells and percentages of circulating regulatory T (cTreg) and B (cBreg) cells by FACS and we examined levels of Der-p/f sIgs by ELISA. Based on the symptom score (asthma control questionnaire: ACQ) and medication score ((global initiative for asthma: GINA) treatment step score) in patients with AA, the patients were divided into responders and non-responders. The percentage of cTfh2 cells significantly decreased and the percentage of cTfh1 cells significantly increased within the first year. Der-p/f sIgEs decreased after a transient elevation at 3 months in both groups. Notably, the percentage of cTfh2 cells and the ratio of cTfh2/cBreg cells and Der-p/f sIgEs greatly decreased in responders from 6 months to 12 months. The percentages of cTfr and cTreg cells showed significant negative correlations with the percentage of cTfh2 cells. The percentage of IL-4+ cTfh cells were significantly decreased and the percentage of IFN-γ+ cTfh cells were increased before treatment to 24 months in 6 patients examined (4 responders and 2 non-responders). We performed multi plelogistic regression analysis based on these results, the ratios of cTfh2/cTfr cells and cTfh2/cBreg cells at the start of therapy were statistically effective biomarkers for predicting the response to HDM-SLIT in patients with AA+AR

Efficacy of clarithromycin in patients with mild COVID-19 pneumonia not receiving oxygen administration: protocol for an exploratory, multicentre, open-label, randomised controlled trial (CAME COVID-19 study)

Introduction: The COVID-19 pandemic has emerged worldwide. Although several medications have been approved for treating moderate-to-severe COVID-19, very few treatment strategy has been established for patients with mild COVID-19 who do not require oxygen administration. Clarithromycin is a macrolide antimicrobial agent that has been widely used for bacterial respiratory infectious diseases. Clarithromycin also acts an immunomodulating drug and suppresses cytokine storms in viral respiratory diseases, including influenza. In this study, we aim to evaluate the efficacy of clarithromycin in patients with mild COVID-19.Methods and analysis: This is an exploratory, multicentre, open-label, randomised controlled trial. This study was initiated in May 2021 and will end in July 2022. Patients with mild COVID-19 pneumonia who do not require oxygen administration will be enrolled and randomly assigned in a 1:1:1 ratio to group A (administration of clarithromycin 800 mg/day), group B (administration of clarithromycin 400 mg/day) or group C (standard treatment without clarithromycin). The planned number of enrolled patients is 60 (20 patients × three groups). The primary endpoint is the number of days required to improve the clinical symptoms as measured by the severity score. Secondary endpoints include days for recovery of the body temperature, proportion of patients with oxygen administration, inflammatory cytokines, viral load, serum immunoglobulins, peripheral blood lymphocytes, blood biomarkers and pneumonia infiltrations.Ethics and dissemination: The study protocol was approved by the Clinical Research Review Board of Nagasaki University in accordance with the Clinical Trials Act in Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act and other current legal regulations in Japan. Written informed consent will be obtained from all the participants. The results of this study will be reported as journal publications.Trial registration number: jRCTs071210011

成人T細胞白血病/リンパ腫のクローン構成を評価する新規方法の開発

長崎大学学位論文 [学位記番号]博（医歯薬）甲第1308号 [学位授与年月日]令和3年3月3

ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia-reperfusion injury

Highly adhesive glycoprotein von Willebrand factor (VWF) multimer induces platelet aggregation and leukocyte tethering or extravasation on the injured vascular wall, contributing to microvascular plugging and inflammation in brain ischemia-reperfusion. A disintegrin and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) cleaves the VWF multimer strand and reduces its prothrombotic and proinflammatory functions. Although ADAMTS13 deficiency is known to amplify post-ischemic cerebral hypoperfusion, there is no report available on the effect of ADAMTS13 on inflammation after brain ischemia. We investigated if ADAMTS13 deficiency intensifies the increase of extracellular HMGB1, a hallmark of post-stroke inflammation, and exacerbates brain injury after ischemia-reperfusion. ADAMTS13 gene knockout (KO) and wild-type (WT) mice were subjected to 30-min middle cerebral artery occlusion (MCAO) and 23.5-h reperfusion under continuous monitoring of regional cerebral blood flow (rCBF). The infarct volume, plasma high-mobility group box1 (HMGB1) level, and immunoreactivity of the ischemic cerebral cortical tissue (double immunofluorescent labeling) against HMGB1/NeuN (neuron-specific nuclear protein) or HMGB1/MPO (myeloperoxidase) were estimated 24h after MCAO. ADAMTS13KO mice had larger brain infarcts compared with WT 24h after MCAO (p<0.05). The rCBF during reperfusion decreased more in ADAMTS13KO mice. The plasma HMGB1 increased more in ADAMTS13KO mice than in WT after ischemia-reperfusion (p<0.05). Brain ischemia induced more prominent activation of inflammatory cells co-expressing HMGB1 and MPO and more marked neuronal death in the cortical ischemic penumbra of ADAMTS13KO mice. ADAMTS13 deficiency may enhance systemic and brain inflammation associated with HMGB1 neurotoxicity, and aggravate brain damage in mice after brief focal ischemia. We hypothesize that ADAMTS13 protects brain from ischemia-reperfusion injury by regulating VWF-dependent inflammation as well as microvascular pluggin