The chloride channel inhibitor NS3736 [corrected] prevents bone resorption in ovariectomized rats without changing bone formation.

Chloride channel activity is essential for osteoclast function. Consequently, inhibition of the osteoclastic chloride channel should prevent bone resorption. Accordingly, we tested a chloride channel inhibitor on bone turnover and found that it inhibits bone resorption without affecting bone formation. This study indicates that chloride channel inhibitors are highly promising for treatment of osteoporosis. INTRODUCTION: The chloride channel inhibitor, NS3736, blocked osteoclastic acidification and resorption in vitro with an IC50 value of 30 microM. When tested in the rat ovariectomy model for osteoporosis, daily treatment with 30 mg/kg orally protected bone strength and BMD by approximately 50% 6 weeks after surgery. Most interestingly, bone formation assessed by osteocalcin, mineral apposition rate, and mineralized surface index was not inhibited. MATERIALS AND METHODS: Analysis of chloride channels in human osteoclasts revealed that ClC-7 and CLIC1 were highly expressed. Furthermore, by electrophysiology, we detected a volume-activated anion channel on human osteoclasts. Screening 50 different human tissues showed a broad expression for CLIC1 and a restricted immunoreactivity for ClC-7, appearing mainly in osteoclasts, ovaries, appendix, and Purkinje cells. This highly selective distribution predicts that inhibition of ClC-7 should specifically target osteoclasts in vivo. We suggest that NS3736 is inhibiting ClC-7, leading to a bone-specific effect in vivo. RESULTS AND CONCLUSION: In conclusion, we show for the first time that chloride channel inhibitors can be used for prevention of ovariectomy-induced bone loss without impeding bone formation. We speculate that the coupling of bone resorption to bone formation is linked to the acidification of the resorption lacunae, thereby enabling compounds that directly interfere with this process to be able to positive uncouple this process resulting in a net bone gain.     

PLATELET STORAGE POOL DEFICIENCY IN PREGNANCY

SUMMARY A case of inherited platelet storage pool deficiency is described which was successfully managed with prophylactic platelet transfusion at delivery.     

PRURITUS AND HLA IN HEMODIALYSIS PATIENTS

Hepatitis C virus (HCV) infection is known to increase morbidity and mortality in the dialysis population. Renal transplantation is an offered treatment option after a careful pretransplant evaluation. This study assessed the impact of HCV infection on patient and allograft survival rates in a selected group of dialysis patients and kidney transplant recipients.
The study included 252 end-stage renal disease patients who were receiving hemodialysis (HD) treatment or who received renal transplantation at our centre in 1995–96. Of the total, 116 [94 HCV (–) and 22 HCV (+)] underwent transplantation and 134 [106 HCV (–) and 30 HCV (+)] remained on HD. We retrospectively investigated 5 years of follow-up findings in the records of these patients. All 22 HCV (+) individuals underwent liver biopsy to ensure there was no advanced liver disease before transplantation. None of the recipients or HD patients showed decompensation related to liver disease during follow up.
The overall 5-year patient survival rates for the kidney recipient and HD groups were 85.2% and 74.5%, respectively. Comparison of outcomes for the HCV (+) recipients had a significantly higher 5-year survival rate than the HCV (+) HD patients ( P <0.04). The 3-year graft survival rates for the HCV (+) and HCV (–) transplant recipients were comparable, but the risks of chronic rejection and graft loss at 5 years were higher in the HCV (+) group ( P <0.02, P <0.006, respectively). In conclusion, renal transplantation should be the preferred therapy in HCV-infected dialysis patients because it improves the survival rates. HCV infection is associated with increased rates of chronic rejection and graft loss at 5 years post-transplantation.     

Effect of moderate-to-severe hepatic steatosis on neutralising antibody response among BNT162b2 and CoronaVac recipients

Background/AimsStudies of hepatic steatosis (HS) effect on COVID-19 vaccine immunogenicity are lacking. We aimed to compare immunogenicity of BNT162b2 and CoronaVac among moderate/severe HS and control subjects.MethodsTwo hundred ninety-five subjects who received BNT162b2 or CoronaVac vaccines from five vaccination centers were categorized into moderate/severe HS (controlled attenuation parameter ≥268 dB/m on transient elastography) (n=74) or control (n=221) groups. Primary outcomes were seroconversion rates of neutralising antibody by live virus Microneutralization (vMN) assay (titer ≥10) at day21 (BNT162b2) or day28 (CoronaVac) and day56 (both). Secondary outcome was highest-tier titer response (top 25% of vMN titer; cutoff: 160 [BNT162b2] and 20 [CoronaVac]) at day 56.ResultsFor BNT162b2 (n=228, 77.3%), there was no statistical differences in seroconversion rates (day21: 71.7% vs. 76.6%; day56: 100% vs. 100%) or vMN geometric mean titer (GMT) (day21: 13.2 vs. 13.3; day56: 91.9 vs. 101.4) among moderate/severe HS and control groups respectively. However, lower proportion of moderate/severe HS patients had highest-tier response (day56: 5.0% vs. 15.5%; P=0.037). For CoronaVac (n=67, 22.7%), there was no statistical differences in seroconversion rates (day21: 7.1% vs. 15.1%; day56: 64.3% vs. 83.0%) or vMN GMT (5.3 vs. 5.8,) at day28. However, moderate/severe HS patients had lower vMN GMT (9.1 vs. 14.8, P=0.021) at day 56 with lower proportion having highest-tier response (21.4% vs. 52.8%, P=0.036).ConclusionsWhile there was no difference in seroconversion rate between moderate/severe HS and control groups after two doses of vaccine, a lower proportion of moderate/severe HS patients achieved highest-tier response for either BNT162b2 or CoronaVac.     

Antimicrobial and antispasmodic activity of leaf extract and fractions of Stachytarpheta cayennensis

ObjectiveTo investigate the antimicrobial activity of the methanol leaf extract (ME), n-hexane fraction (HF), ethylacetate fraction (EF) and methanol fraction (MF), of Stachytarpheta cayennensis C. Rich (verbenaceae) as well as to ascertain the antispasmodic effects of the ME and the various fractions (HF, EF and MF) on acetylcholine (Ach) and histamine (H) induced contractions on isolated guinea pig ileum.MethodsThe in vitro agar well diffusion method was used for the antimicrobial studies while the isolated tissue method was employed for the antispasmodic test. Organisms used were all clinical isolates of Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella paratyphi, Candida albicans and Aspergillus niger.ResultsThe extract and fractions exhibited dose dependent inhibition against all the bacteria tested and also exhibited insignificant antifungal activity against Candida albicans and Aspergillus niger. The minimum inhibitory concentration (MIC) of the extract and fractions (mg/mL) on Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella paratyphi respectively were ME 5.62, 14.12, 22.38, 2.11; EF 1.25, 6.30, 9.40, 9.40 and MF 3.98, 8.81, 39.80, 21.13. The n-hexane fraction exhibited MIC of 1.07 mg/mL against only Bacillus subtilis. The extract and fractions exhibited significant (P< 0.05) dose dependent attenuation of contractions induced by acetylcholine and histamine on isolated guinea pig ileum. Concentrations of the extract and fractions (μg/mL) which evoked 50% inhibition of maximal response exhibited by Ach were ME 0.64, HF 0.16, EF 0.08 and MF 0.15, while that of histamine included ME 5.12, HF 0.16, EF 0.04 and MF 0.64. Preliminary phytochemical studies on the extract and fractions indicated the presence of carbohydrates, alkaloids, saponins, flavonoids, steroids and terpenoids.ConclusionsThe extract and fractions of Stachytarpheta cayennensis possessed both antibacterial and antispasmodic effects confirming the claimed use in folkloric medicine for wound healing and gastrointestinal ulceration.