Effects of bile-acid-binding resin (colestimide) on blood glucose and visceral fat in Japanese patients with type 2 diabetes mellitus and hypercholesterolemia: an open-label, randomized, case-control, crossover study

ObjectiveThe objective was to examine the effects of colestimide on blood glucose, visceral fat, adipocytokines, and bile acid conjugate fractions in Japanese patients.MethodsThis study was an open-label, randomized, case–control, crossover study of colestimide 3 g/day in 40 Japanese patients with type 2 diabetes mellitus (T2D) and hypercholesterolemia. Patients were assigned to the colestimide group in which pravastatin and colestimide were administered orally and to the statin group in which pravastatin alone was administered orally. The principal outcome measures were serum lipid levels, fasting plasma glucose level in the early morning, hemoglobin A1c (HbA_1c), visceral fat area (VFA), and serum 1,5-anhydroglucitol (1,5-AG) level.ResultsSerum low-density lipoprotein cholesterol levels significantly decreased from 113±38 mg/dl at baseline to 90±20 mg/dl (P=.009) at week 12 of colestimide administration. HbA_1c significantly decreased from 7.4%±0.9% at baseline to 6.9%±0.9% (P=.001) at week 12 of colestimide administration. Serum 1,5-AG levels increased from 9.4±10.1 μg/ml to 12.4±9.5 μg/ml (P=.05) at week 12 of colestimide administration. The statin group showed no significant changes in lipids and 1,5-AG. However, ΔVFA was inversely correlated with Δcholic acid, and multivariate analysis revealed that ΔVFA was a significant explanatory variable.ConclusionsColestimide holds promise not only for the treatment of hypercholesterolemia but also for the possible improvement of T2D and visceral fat obesity.     

Hyperostosis around the bilateral acetabulum associated with hypoparathyroidism

We report the case of a 57-year-old woman with hyperostosis around the bilateral acetabulum associated with untreated secondary hypoparathyroidism. She presented with gait disturbance and inability to walk. Radiographs showed abnormal ossification around her hips. We resected the ossifications to improve joint function. One year after surgery, radiographs showed no recurrence of ossification. When radiographs show excessive hyperostosis, it is important to exclude presence of metabolic bone disease.     

Synthesis of 1,2,4-azadiphosphole derivatives based on vanadium-catalyzed [2+2+1] cycloaddition reactions of azobenzenes with phosphaalkynes

A new synthetic method is described to construct 1,2,4-azadiphosphole derivatives based on vanadium-catalyzed [2+2+1] cycloaddition reactions. Reactions of azobenzenes as nitrogen sources with phosphaalkynes as phosphorous counterparts in the presence of VCl₂(thf)₂ as a catalyst afford the corresponding 1,2,4-azadiphospholes.

Vanadium-catalyzed [2+2+1] cycloaddition reactions opened a new access to phosphorous-heterocycles.

Phosphorus heterocycles have provided important structural motifs to explore materials science and coordination chemistry.¹ To access diverse skeletons, development of new and efficient synthetic methods is quite important. In addition to the conventional synthetic methods typically forming carbon–phosphorous single bonds, the use of phosphaalkynes as substrates is beneficial to construct phosphorous-containing π-systems.² Stoichiometric reactivity of phosphaalkynes with transition metal complexes has been studied extensively,³ but catalytic reactions of phosphaalkynes under transition metal catalysis have been limited to several sporadic examples.^4,5 Recently, our group has reported catalytic [2+2+2] cycloaddition reactions to produce phosphabenzenes and [3+2] cycloaddition reactions to produce 1,3-azaphospholes based on the use of phosphaalkynes as substrates.⁵ To investigate further utility of phosphaalkynes to prepare aromatic compounds containing phosphorus atoms, we have focused on the synthesis of 1,2,4-azadiphospholes as next targets.Synthetic examples of 1,2,4-azadiphospholes have been limited to only a few reports.^6,7 To the best of our knowledge, the first synthesis of the 1,2,4-azadiphosphole skeleton was reported in 1991, where a 1,2,4-azadiphosphole derivative was prepared based on a thermal dimerization of an amino-substituted phosphaalkyne.^6a Later, other groups reported stoichiometric reactions of titanium- and vanadium-imide complexes as nitrogen sources with phosphaalkynes.^6b–d Although these stoichiometric reactions provided effective synthetic methods of 1,2,4-azadiphospholes, transition metal-catalyzed synthesis of 1,2,4-azadiphospholes has never been achieved until now.Recently, titanium-catalyzed [2+2+1] cycloaddition reactions have been reported by Tonks and co-workers to prepare pyrroles from reactions of azobenzenes with alkynes (Scheme 1a).⁸ In this reaction system, titanium-imide species generated from azobenzenes worked as a key intermediate. More recently, a similar pyrrole synthesis using vanadium-catalyzed reaction system has been reported by Tonks, Mashima, Tsurugi and co-workers.⁹Open in a separate windowScheme 1Catalytic [2+2+1] cycloaddition reactions with azobenzenes as nitrogen sources in heterocycle synthesis.Based on the research background, we have envisaged metal-catalyzed [2+2+1] cycloaddition reactions of azobenzenes with phosphaalkynes to produce 1,2,4-azadiphospholes (Scheme 1b). As a result, we have found that some vanadium complexes worked as effective catalysts toward the formation of 1,2,4-azadiphospholes. Herein, we report experimental results in detail.First, investigation of reaction conditions was carried out with the use of azobenzene (1a) and 1-adamantylphosphaethyne (2a) as typical substrates. When the reaction of 1a (1 equiv.) with 2a (2 equiv.) in the presence of 20 mol% of VCl₃(thf)₃ was carried out in toluene at 110 °C for 16 hours, the desired 1,2,4-azadiphosphole (3a) was obtained in 48% yield (

Synergistic anti-tumor efficacy by combination therapy of a self-assembled nanogel vaccine with an immune checkpoint anti-PD-1 antibody

Therapeutic strategies for cancer involving immune checkpoint inhibitors (ICIs) have been gaining widespread attention, but their efficacy remains limited. Thus, combination of ICI therapies with other therapeutic modalities may be required to improve their outcomes. In this study, we examined the improved efficacy of a CHP nanogel-based vaccine delivery system after combination with ICI therapy. For this, we evaluated the therapeutic efficacy of combining an anti-PD-1 antibody as an ICI with an OVA antigen-complexed CHP nanogel vaccine delivery system in a mouse E.G7-OVA tumor model. Mice were subcutaneously inoculated with E.G7-OVA tumor cells on one side of the back, and subcutaneously injected with OVA or the OVA/CHP nanogel vaccine on the other side of the back. Anti-PD-1 antibody was administered at defined intervals. Tumor volume, immune responses, and tumor-infiltrating cells were evaluated. Mice treated with OVA vaccine alone showed weak tumor suppression compared with untreated control mice. Mice receiving combined OVA/CHP nanogel vaccine and anti-PD-1 antibody therapy exhibited strong tumor growth suppression and markedly improved survival, suggesting that PD-1 signaling blockade by the anti-PD-1 antibody enhanced the anti-tumor efficacy of the OVA vaccine. Furthermore, tumor-infiltrating cells and immune responses were increased in the combined therapy group. No serious side effects were observed for any of the treatments. Taken together, the immune system activation induced by the CHP nanogel vaccine was synergistically enhanced by the anti-PD-1 antibody. The present findings suggest the potential for enhanced therapeutic efficacy by combining the CHP nanogel vaccine delivery system with ICI therapy for various cancer types.

Combination therapy of OVA/CHP nanogel vaccine with anti-PD-1 antibody synergistically improved anti-tumor effect and survival rate without side effects.     

The overexpression of SIRT1 inhibited osteoarthritic gene expression changes induced by interleukin‐1β in human chondrocytes

In this study, we examined the effects of overexpression of SIRT1 on IL‐1β‐induced gene expression changes in human chondrocytes to explore a protective role of SIRT1 in human chondrocytes. SIRT1 was overexpressed in human chondrocytes by expression plasmid under stimulation with IL‐1β. SIRT1 was also inhibited by siRNA under stimulation with IL‐1β. Gene expression changes were examined by real‐time PCR. The interaction of SIRT1 and p65 (NF‐κB) were examined by Western blotting. SIRT1, MMP‐13, and ADAMTS‐5 expressions in human cartilage were examined by immunohistochemistry. IL‐1β stimulation significantly up‐regulated MMP‐1, 2, 9, and 13 and ADAMTS‐5. Overexpression of SIRT1 significantly inhibited the up‐regulation of those genes caused by IL‐1β while the inhibition of SIRT1 further increased them. In addition, the overexpression of SIRT1 markedly reduced the IL‐1β‐induced acetylation of p65. SIRT1 expression was clearly detected in the non‐OA cartilage while MMP‐13 and ADAMTS‐5 were undetectable. In contrast, in the OA cartilage, SIRT1 expression was decreased while MMP‐13 and ADAMTS‐5 were increased. Our observations suggested that SIRT1 can play a protective role by suppressing IL‐1β‐induced expressions of cartilage‐degrading enzymes partially through the modulation of the NF‐κB pathway. SIRT1 overexpression might be a new therapeutic approach for OA. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 531–537, 2013     

Long-term subjective outcomes of computer-assisted total knee arthroplasty

Purpose

This study aimed to clarify the results of computer-assisted total knee arthroplasty (TKA) after ten years using patient-derived scores.

Methods

Thirty posterior-stabilised total knee prostheses implanted using a computed tomography-free navigation system were compared with 30 matched total knee prostheses of the same type implanted using a conventional, manual technique. At an average of ten years after surgery, we investigated patient-reported outcomes using the Knee Society’s new scoring system. The results of 27 patients (14 patients in the navigation group and 13 patients in the manual group) were assessed in this study.

Results

There was no significant difference between the navigation and manual groups for any section of the questionnaire, which consisted of symptoms, patient satisfaction, patient expectation, walking/standing, standard activities, advanced activities, and discretionary activities.

Conclusion

After long-term follow-up, we found no subjective advantages of using a navigation system for patients who undergo TKA though the absolute number of patients was very small. Additional extensive studies are required to validate our result.     

Using intraoperative radiography to detect incomplete seating of Trident acetabular system ceramic liners

Purpose

There have been some reports of incomplete seating of the ceramic liner in the Stryker Trident acetabular system. We sought to prevent incomplete seating through the use of intraoperative radiography.

Method

We retrospectively reviewed 21 hips in 18 patients who had undergone total hip arthroplasty using a posterolateral approach with a Stryker Trident ceramic liner. All procedures included an intraoperative anteroposterior view radiograph to evaluate liner seating. If incomplete seating was recognized we reinserted the liner. We investigated whether this technique made it possible to detect and correct incomplete seating.

Results

Six of the 21 hips evidenced incomplete seating. In four of these hips, the incomplete seating was revealed on the intraoperative radiograph: two were reinserted properly, one was replaced with a polyethylene liner, and in the last one the incomplete seating was missed despite the radiographical evidence. The location of the gap between the socket and liner caused by the incomplete seating was inferior in all these cases. Intraoperative radiography did not indicate incomplete seating in two hips in which the location of the gap was anterior; the problem was revealed by postoperative lateral view radiography.

Conclusion

With a posterolateral approach in a lateral decubitus position, the use of intraoperative radiography was effective when the gaps were superior or inferior. However, this approach made it easy to miss anterior gaps and intraoperative radiography did not reveal them.     

Anterior transpetrosal approach: epidural or subdural?

Neurosurgical Review -