46 research outputs found
Historical Study on the Irrigation Reservoirs in Sasayama District
(1)江戸時代において極めて米作率の高かつた篠山藩の灌漑水源は, その7割余が溜池に依存し, その造営は江戸初頭から中期にかけて過半が完成された。斯る短期間に幕藩制のもとで造営が急がれたのは, 庄園制以来隷属下におかれていた耕作農民に独立の機会を与え, 本百姓化して直接的に彼らから領主が生産物地代を確保するに外ならなかつた。そしてその当初の目的は達せられ, 近世村落の成立によつて農業生産上の諸計劃が, その成員の自律性によつて或る程度維持されていた。(2)池の位置は造営の容易性から山腹の谷に多く散在し, 且池元たる山村の耕地に導水の優先権があつたゝめに, 水田の多くを有し水を特に要する盆地内が常に旱損に見舞れ, 江戸時代を通じておくれた技術によつて農業が支えられていた。(3)盆地内は水に窮乏し乍らも, 溜池が農業の発展に果した役割は大であつた。(溜池のない湧水灌漑による地域に比し)そして江戸中期以後藩経済の窮乏に乗じ, 小作料取得の土地所有者の中から藩に代り池を造営する者があらわれ, 或は村方所有の池を集中して, この地方での大地主に成長した
Palliative treatment of uncontrollable hypercalcemia due to parathyrotoxicosis: denosumab as rescue therapy
Parathyroid carcinoma is a rare disease leading to severe hypercalcemia due to hyperparathyroidism. Surgery is the primary treatment option. A more progressive form of the disease is characterized by parathyrotoxicosis, and subsequent hypercalcemia is the most common cause of death. We report a case presenting with severe hypercalcemia due to parathyrotoxicosis from parathyroid carcinoma treated for the first time using the monoclonal antibody denosumab as a rescue therapy and present long-term follow-up data. The 71-year-old patient presented with severe hypercalcemia due to metastatic parathyroid carcinoma. Despite undergoing treatment with bisphosphonates, cinacalcet hydrochloride, and forced diuresis, the patient's condition deteriorated rapidly due to resistant hypercalcemia. Surgery performed because of spinal metastasis and forced diuresis lowered calcium levels, albeit they remained in the hypercalcemic range and significantly increased when forced diuresis was stopped. Considering a palliative situation to overcome hypercalcemia, we decided to administer denosumab, a monoclonal antibody that binds to the receptor activator of nuclear factor-kappa B ligand. After a single subcutaneous administration of 60 mg denosumab, calcium levels normalized within one day. Subsequent denosumab injections led to permanent control of serum calcium for more than 2 years despite rising parathyroid hormone levels and repeated surgeries. Together with recent cases in the literature supporting our observation, we believe that denosumab is relevant for future trials and represents an effective tool to control hypercalcemia in patients with advanced stages of parathyroid cancer
Blockade of the growth hormone (GH) receptor unmasks rapid GH-releasing peptide-6-mediated tissue-specific insulin resistance
The roles of GH and its receptor (GHR) in metabolic control are not yet
fully understood. We studied the roles of GH and the GHR using the GHR
antagonist pegvisomant for metabolic control of healthy nonobese men in
fasting and nonfasting conditions. Ten healthy subjects were enrolled in a
double blind, placebo-controlled study on the effects of pegvisomant on
GHRH and GH-releasing peptide-6 (GHRP-6)-induced GH secretion before and
after 3 days of fasting and under nonfasting conditions (n = 5). Under the
condition of GHR blockade by pegvisomant in the nonfasting state, GHRP-6
(1 microg/kg) caused a increase in serum insulin (10.3 +/- 2.1 vs. 81.3
+/- 25.4 mU/L; P < 0.001) and glucose (4.2 +/- 0.3 vs. 6.0 +/- 0.6 mmol/L;
P < 0.05) concentrations. In this group, a rapid decrease in serum free
fatty acids levels was also observed. These changes were not observed
under GHR blockade during fasting or in the absence of pegvisomant. We
conclude that although these results were obtained from an acute study,
and long-term administration of pegvisomant could render different
results, blockade of the GHR in the nonfasting state induces
tissue-specific changes in insulin sensitivity, resulting in an increase
in glucose and insulin levels (indicating insulin resistance of
liver/muscle), but probably also in an increase in lipogenesis (indicating
normal insulin sensitivity of adipose tissue). These GHRP-6-mediated
changes indicate that low GH bioactivity on the tissue level can induce
changes in metabolic control, which are characterized by an increase in
fat mass and a decrease in lean body mass. As a mechanism of these
GHRP-6-mediated metabolic changes in the nonfasting state, direct
nonpituitary-mediated GHRP-6 effects on the gastroentero-hepatic axis seem
probable
Activation of chimeric and full-length growth hormone receptors by growth hormone receptor monoclonal antibodies: A specific conformational change may be required for full-length receptor signaling
Signal transduction by the growth hormone receptor (GHR) occurs through growth hormone (GH)-induced dimerization of two GHRs to form a trimeric complex, It is thought that dimerization alone is sufficient for signaling, since monoclonal antibodies (mAbs) against the extracellular domain of the GHR elicit proliferation of FDC-P1 cells transfected with a chimeric receptor comprising the extracellular domain of the GHR and the fibronectin and cytoplasmic domains of the murine granulocyte colony-stimulating factor receptor, We have screened 14 GHR mAbs for proliferative activity against characterized FDC-P1 and BaF-B03 cell lines stably expressing the full-length human, rabbit, or rat GHR, or the chimeric human GHR/granulocyte colony-stimulating factor receptor, and for transactivation of the c-fos promoter and STAT activation. With the chimeric receptor, eight mAbs were able to elicit proliferation, although there was no correlation between inhibition of hormone binding and agonist activity. In contrast, no mAbs were able to act as agonists with the full-length GHR FDC-P1 cell lines, although nine competed with GH for binding, A weak proliferative response was observed in the BaF-B03 cell lines with two of the mAbs (263 and 1C9), and the addition of anti-mouse F(ab)(2) resulted in increased signaling in the hGHR BaF-B03 cell line to a plateau of 28 +/- 4% of the GH maximum for mAb 263. These data could indicate considerable stringency in the ability of mAbs to correctly dimerize the full-length GI-IR. However, the ability of mAb 263 to stimulate a mutant hGHR altered in the F'-G' loop of domain 2 was nearly abolished, concurrent with an increased affinity of this mAb for the receptor. Since the F'-G' loop undergoes a conformational change on GH binding and is necessary for full proliferative signaling, we propose that in addition to promoting receptor dimerization, mAb 263 may induce specific changes in receptor conformation similar to GH, which are required for the biological response
Ghrelin drives GH secretion during fasting in man
OBJECTIVES: In humans, fasting leads to elevated serum GH concentrations.
Traditionally, changes in hypothalamic GH-releasing hormone and
somatostatin release are considered as the main mechanisms that induce
this elevated GH secretion during fasting. Ghrelin is an endogenous ligand
of the GH secretagogue receptor and is synthesized in the stomach. As
ghrelin administration in man stimulates GH release, while serum ghrelin
concentrations are elevated during fasting in man, this increase in
ghrelin levels might be another mechanism whereby fasting results in
stimulation of GH release. DESIGN AND SUBJECTS: In ten healthy non-obese
males we performed a double-blind placebo-controlled crossover study
comparing fasting with and fasting without GH receptor blockade. GH,
ghrelin, insulin, glucose and free fatty acids were assessed. RESULTS:
While ghrelin levels do not vary considerably in the fed state, fasting
rapidly induced a diurnal rhythm in ghrelin concentrations. These changes
in serum ghrelin concentrations during fasting were followed by similar,
profound changes in serum GH levels. The rapid development of a diurnal
ghrelin rhythm could not be explained by changes in insulin, glucos
MPOWERED trial open-label extension: long-term efficacy and safety data for oral octreotide capsules in acromegaly
Context The MPOWERED core trial (NCT02685709) and open-label extension (OLE) phase investigated long-term efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly. Core trial primary endpoint data demonstrated noninferiority to injectable somatostatin receptor ligands (iSRLs). Core trial completers were invited to participate in the OLE phase. Objective To assess long-term efficacy and safety of OOC in patients with acromegaly who previously responded to and tolerated both OOC and injectable octreotide/lanreotide and completed the core phase. Methods The unique study design of transitioning between OOC and iSRLs allowed within-patient evaluations. The proportion of biochemical responders (insulin-like growth factor I < 1.3 x upper limit of normal) at end of each extension year who entered that year as responders was the main outcome measure. Results At year 1 extension end, 52/58 patients from both the monotherapy and the combination therapy groups were responders (89.7%; 95% CI 78.8-96.1), 36/41 (87.8%; 95% CI 73.8-95.9) in year 2, and 29/31 (93.5%; 95% CI 78.6-99.2) in year 3. No new or unexpected safety signals were detected; 1 patient withdrew owing to treatment failure. Patients who transitioned from iSRLs in the core trial to OOC in the OLE phase reported improved treatment convenience/satisfaction and symptom control. Conclusion Patient-reported outcome data support for the first time that transitioning patients randomized to iSRL (who previously responded to both OOC and iSRLs) back to OOC had a significant effect on patients' symptoms score in a prospective cohort. The MPOWERED OLE showed long-term maintenance of response and sustained safety with OOC.Metabolic health: pathophysiological trajectories and therap
Oral octreotide capsules for the treatment of acromegaly: comparison of 2 phase 3 trial results
Purpose Results are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly. Methods CH-ACM-01 was an open-label trial (N = 155) and CHIASMA OPTIMAL was a double-blind placebo-controlled (DPC) trial (N = 56), both investigating OOC as maintenance therapy for patients with acromegaly who were biochemical responders receiving iSRLs. Results Baseline characteristics in both trials reflected those expected of patients with acromegaly responding to treatment and were similar between trials, despite differences in inclusion criteria. OOC demonstrated a consistent degree of biochemical response across trials, with 65% of patients in CH-ACM-01 maintaining response during the core period and 64% of patients in CHIASMA OPTIMAL at the end of the DPC. Mean insulin-like growth factor I (IGF-I) levels remained within inclusion criteria at the end of treatment in both trials. Of 110 patients entering the fixed-dose phase in CH-ACM-01, 80% maintained or improved acromegaly symptoms from baseline to the end of treatment. Over 85% of patients in both trials elected to continue into the extension phases. OOC were found to be well tolerated across both trials, and no dose-related adverse events were observed. Conclusions OOC demonstrated remarkably consistent results for biochemical response, durability of response, and preference to continue with oral treatment across these 2 complementary landmark phase 3 trials, despite differences in the design of each.Diabetes mellitus: pathophysiological changes and therap
Oral octreotide capsules for the treatment of acromegaly: comparison of 2 phase 3 trial results (June, 10.1007/s11102-021-01163-2, 2021)
Diabetes mellitus: pathophysiological changes and therap
Diabetes in patients with acromegaly treated with pegvisomant: observations from acrostudy
Purpose: To explore the effects of pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study. Methods: Patients were retrospectively divided into two cohorts, with (DM group) or without diabetes mellitus (no-DM). Parameters of glucose metabolism and IGF-I values were analyzed yearly both cross-sectionally for 4 years (yrs) and longitudinally at 1 and 4–5 yrs of PEGV treatment. Results: Among 1762 patients, 510 (28.9%) had DM before PEGV start. At cross-sectional analyses, in the DM group mean blood glucose was 140.0 ± 58.7 mg/dl at baseline, 116.4 ± 44.8 mg/dl at year 1 and 120.0 ± 44.3 mg/dl at yr 4. Mean HbA1c was 6.6 ± 1.2 % at yr 1 vs. 7.0 ± 1.4 % at baseline. HbA1c was above 6.5% in 61.9% at baseline and ranged from 45.4 to 53.8% at subsequent yearly time points. At the 4-yr longitudinal analysis, in the DM group (n = 109), mean blood glucose decreased by 20.2 mg/dl at yr 4, mean HbA1c was 7.0 ± 1.5% at baseline vs. 6.8 ± 1.4%. Patients achieved IGF-I normalization in 52.1% and 57.4% of cases in the DM and no-DM groups, respectively at 1 year. The mean daily PEGV dose (mg/day) was higher in the DM group (18.2 vs. 15.3) while the absolute change of IGF-I values from baseline was similar in both groups. PEGV was well tolerated in both groups without any unexpected AEs. Conclusions: Patients with DM had a moderate decrease in mean fasting glucose values during PEGV treatment