Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment

The classic pathogenesis of secondary hyperparathyroidism (SHPT) began with the trade‐off hypothesis based on parathyroid hormone hypersecretion brought about by renal failure resulting from a physiological response to correct metabolic disorder of calcium, phosphorus, and vitamin D. In dialysis patients with failed renal function, physiological mineral balance control by parathyroid hormone through the kidney fails and hyperparathyroidism progresses. In this process, many significant genetic findings have been established. Abnormalities of Ca‐sensing receptor and vitamin D receptor are associated with the pathogenesis of SHPT, and fibroblast growth factor 23 has also been shown to be involved in the pathogenesis. Vitamin D receptor activators (VDRAs) are widely used for treatment of SHPT. However, VDRAs have calcemic and phosphatemic effects that limit their use to a subset of patients, and calcimimetics have been developed as alternative drugs for SHPT. Hyperphosphatemia also affects progression of SHPT, and control of hyperphosphatemia is, therefore, thought to be fundamental for control of SHPT. Currently, a combination of a VDRA and a calcimimetic is recognized as the optimal strategy for SHPT, and for other outcomes such as reduced cardiovascular disease and improved survival. The latest findings on the pathogenesis and treatment of SHPT are summarized in this review.     

Prophylactic indomethacin in extremely premature infants between 23 and 24 weeks gestation

Background: In extremely premature infants, the presence of a left‐to‐right shunt through a patent ductus arteriosus (PDA) increases the risks of pulmonary hemorrhage, intraventricular hemorrhage, necrotizing enterocolitis, renal failure, and chronic lung disease. Conservative management induces spontaneous ductus closure in <20% of extremely premature infants (infants born at <25 weeks of gestation). The aim of the present study was to determine the efficacy and safety of prophylactic indomethacin (INDO) administration for PDA closure in extremely premature infants born between 23 and 24 weeks of gestation. Methods: A historical case–control study of 30 infants born between 23 and 24 weeks of gestation was carried out. In the prophylactic INDO group, a 12 h‐long, 0.01 mg/kg per h dose of INDO was administered within 6 h of life. During the historical control period, only infants with symptomatic PDA were treated with INDO for 1 h. The incidence of symptomatic PDA, mortality and early neonatal morbidity was compared between the two groups on Fisher's exact test and Mann–Whitney rank–sum test. Results: None of the infants in the prophylactic INDO group had symptomatic PDA, while 11 of the 15 infants in the control group showed symptomatic PDA (P < 0.001). There were no significant differences between the mortality rates and the early neonatal morbidities in the two groups. Conclusions: Prophylactic INDO administration to extremely premature infants born between 23 and 24 weeks of gestation decreased the incidence of symptomatic PDA without increasing the incidence of adverse effects.     

Oridonin induced autophagy in human cervical carcinoma HeLa cells through Ras, JNK, and P38 regulation

In this study, we investigated autophagy induced by oridonin in HeLa cells. HeLa cells were exposed to oridonin, and the fluorescent changes, autophagic levels, and protein expressions were evaluated. Oridonin induced autophagy in HeLa cells in vitro in a dose- and time-dependent manner. Oridonin-treated HeLa cells, which had been prelabeled with the autophagosome-specific dye monodansylcadervarine (MDC), recruited more MDC-positive particles and had a significantly higher fluorescent density; and simultaneously, expressions of autophagy-related proteins, MAP-LC3 and Beclin 1, were increased by oridonin. In oridonin-induced Hela cells, pretreatment with 3-methyladenine (3-MA, the specific inhibitor of autophagy) dose-dependently decreased the autophagic ratio accompanied with downregulation of the protein expressions of MAP-LC3 and Beclin 1. Furthermore, when a Ras inhibitor was applied, the autophagic levels were augmented, whereas P38 and JNK inhibitors decreased the autophagic ratio significantly, indicating that this oridonin-induced autophagic process was negatively regulated by Ras, but positively regulated by P38 and JNK MAPKs. Raf-1 and ERK1/2 had no obvious correlation to these signaling pathways.     

Long-survivors of glioblatoma treated with boron neutron capture therapy (BNCT)

The purpose of this study was to compare the radiation dose between long-survivors and non-long-survivors in patients with glioblatoma (GBM) treated with boron neutron capture therapy (BNCT). Among 23 GBM patients treated with BNCT, there were five patients who survived more than three years after diagnosis. The physical and weighted dose of the minimum gross tumor volume (GTV) of long-survivors was much higher than that of non-long survivors with significant statistical differences.     

Down-regulation of MDR1 by Ad-DKK3 via Akt/NFκB pathways augments the anti-tumor effect of temozolomide in glioblastoma cells and a murine xenograft model

Background

Glioblastoma multiforme (GBM) is the most malignant of brain tumors. Acquired drug resistance is a major obstacle for successful treatment. Earlier studies reported that expression of the multiple drug resistance gene (MDR1) is regulated by YB-1 or NFκB via the JNK/c-Jun or Akt pathway. Over-expression of the Dickkopf (DKK) family member DKK3 by an adenovirus vector carrying DKK3 (Ad-DKK3) exerted anti-tumor effects and led to the activation of the JNK/c-Jun pathway. We investigated whether Ad-DKK3 augments the anti-tumor effect of temozolomide (TMZ) via the regulation of MDR1.

Methods

GBM cells (U87MG and U251MG), primary TGB105 cells, and mice xenografted with U87MG cells were treated with Ad-DKK3 or TMZ alone or in combination.

Results

Ad-DKK3 augmentation of the anti-tumor effects of TMZ was associated with reduced MDR1 expression in both in vivo and in vitro studies. The survival of Ad-DKK3-treated U87MG cells was inhibited and the expression of MDR1 was reduced. This was associated with the inhibition of Akt/NFκB but not of YB-1 via the JNK/c-Jun- or Akt pathway.

Conclusions

Our results suggest that Ad-DKK3 regulates the expression of MDR1 via Akt/NFκB pathways and that it augments the anti-tumor effects of TMZ in GBM cells.

     

The cardiothoracic ratio and all-cause and cardiovascular disease mortality in patients undergoing maintenance hemodialysis: results of the MBD-5D study

Background

The cardiothoracic ratio (CTR) is a non-invasive left ventricular hypertrophy index. However, whether CTR associates with cardiovascular disease (CVD) and mortality in hemodialysis (HD) populations is unclear.

Methods

Using a Mineral and Bone disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D Study) subcohort, 2266 prevalent HD patients (age 62.8 years, female 38.0%, HD duration 9.4 years) with secondary hyperparathyroidism (SHPT) whose baseline CTR had been recorded were selected. We evaluated associations between CTR and all-cause death, CVD death, or composite events in HD patients.

Results

CTR was associated significantly with various background and laboratory characteristics. All-cause death, CVD-related death, and composite events increased across the CTR quartiles (Q). Adjusted hazard risk (HR) for all-cause death was 1.4 (95% confidential interval, 0.9–2.1) in Q2, 1.9 (1.3–2.9) in Q3, and 2.6 (1.7–4.0) in Q4, respectively (Q1 as a reference). The corresponding adjusted HR for CVD-related death was 1.8 (0.8–4.2), 3.1 (1.4–6.8), and 3.5 (1.6–7.9), and that for composite outcome was 1.2 (1.0–1.6), 1.7 (1.3–2.2), and 1.8 (1.5–2.3), respectively. Exploratory analysis revealed that there were relationships between CTR and age, sex, body mass index, comorbidity of CVD, dialysis duration, dialysate calcium level and intact parathyroid hormone, phosphorus, hemoglobin, and usage of phosphate binder.

Conclusion

CTR correlated with all-cause death, CVD death, and composite events in HD patients with SHPT.

     

Research on kidney and mineral metabolism in Japan: past,present, and future

Since the identification of the kidney was the main site for the synthesis of calcitriol (1α, 25-dihydroxycholecalciferol), research on chronic kidney disease (CKD)-associated mineral metabolism disorders and their management has made rapid progress. Various active analogues of calcitriol have clinically become available for treating secondary hyperparathyroidism (SHPT), which is a representative mineral metabolism abnormality in CKD patients. A calcimimetic compound cinacalcet hydrochloride has also been developed for the medical management of SHPT through a different mechanism involving the calcium-sensing receptor. The concept of CKD-mineral and bone disorder (CKD-MBD) was proposed in 2006 to provide a comprehensive understanding of a disorder related to mineral metabolism abnormalities of CKD, based on the fact that these abnormalities are closely associated with cardiovascular disease as well as bone disorders (renal osteodystrophy). There has been a recent surge in the development of phosphate binders for CKD-MBD, focused on an effort to improve mortality. In Japan, high-quality basic and clinical research on CKD-MBD has led to the development of novel therapeutic drugs, such as maxacalcitol, falecalcitriol, and bixalomer. New practice guidelines have been published and are widely adapted in clinical practice.     

Human invariant Valpha24+ natural killer T cells acquire regulatory functions by interacting with IL-10-treated dendritic cells

Glycolipid-reactive Valpha24(+) invariant natural killer T (iNKT) cells have been implicated in regulating a variety of immune responses and in the induction of immunologic tolerance. Activation of iNKT cells requires interaction with professional antigen-presenting cells, such as dendritic cells (DCs). We have investigated the capacity of distinct DC subsets to modulate iNKT cell functions. We demonstrate that tolerogenic DCs (tolDCs), generated by treatment of monocyte-derived DC with interleukin (IL)-10, induced regulatory functions in human iNKT cells. tolDCs, compared with immunogenic DCs, had reduced capacity to induce iNKT-cell proliferation, but these cells produced large amounts of IL-10 and acquired an anergic phenotype. These anergic Valpha24(+) iNKT cells were able to potently inhibit allogeneic CD4(+) T-cell proliferation in vitro. Furthermore, the anergic Valpha24(+) iNKT cells could suppress DC maturation in vitro. We conclude that the interaction of iNKT cells with tolDCs plays an important role in the immune regulatory network, which might be exploited for therapeutic purposes.     

Effect of mazindol on free fatty acid metabolism in the brain of rats

The effects of mazindol which is known as a anorexigenic agent on the free fatty acid metabolism in the brain were studied. One-half mg of mazindol was orally administered to rats weighing 500 g for 5 days. Body weight was reduced by 10%, compared to the control. Serum levels of free fatty acid, triglyceride, total cholesterol and phospholipid were decreased. The effect of mazindol on the incorporation of [1-14C] palmitic acid into various lipids in the brain were studied. When mazindol (5 mg) was administered one hr before injection of [1-14C] palmitic acid to the internal carotid artery of rats ad libitum, incorporation of [1-14C] palmitic acid into free fatty acids in the cerebrum and diencephalon was lower than that of the control, but incorporation into phospholipid and triglyceride were higher than that of the control. When mazindol was injected into fasting rats, incorporation into free fatty acid in cerebrum and diencephalon was increased compared with the control, and the incorporations into phospholipid and triglyceride were decreased.