Sevelamer reverses liver fibrosis by deactivation of hepatic stellate cells.

Liver fibrosis is a chronic liver disease characterized by a progressive wound healing response caused by chronic liver injury. Currently, there are no approved clinical treatments for liver fibrosis. Sevelamer is used clinically to treat hyperphosphatemia and has shown potential therapeutic effects on liver diseases. However, there have been few studies evaluating the therapeutic effects of sevelamer on liver fibrosis, and the specific mechanisms are still unclear. In this study, we investigated the antifibrotic effects of sevelamer-induced low inorganic phosphate (Pi) stress in vitro and in vivo and analyzed the detailed mechanisms. We found that low Pi stress could inhibit the proliferation of activated hepatic stellate cells (HSCs) by promoting apoptosis, effectively suppressing the migration and epithelial-mesenchymal transition (EMT) of hepatic stellate cells. Additionally, low Pi stress significantly increased the antioxidant stress response. It is worth noting that low Pi stress indirectly inhibited the activation and migration of HSCs by suppressing transforming growth factor ß (TGF-ß) expression in macrophages. In a rat model of liver fibrosis, oral administration of sevelamer significantly decreased blood phosphorus levels, improved liver function, reduced liver inflammation, and increased the antioxidant stress response in the liver. Our study revealed that the key mechanism by which sevelamer inhibited liver fibrosis involved binding to gastrointestinal phosphate, resulting in a decrease in blood phosphorus levels, the downregulation of TGF-ß expression in macrophages, and the inhibition of HSC migration and fibrosis-related protein expression. Therefore, our results suggest that sevelamer-induced low Pi stress can attenuate hepatic stellate cell activation and inhibit the progression of liver fibrosis, making it a potential option for the treatment of liver fibrosis and other refractory chronic liver diseases.

Can vitamin B6 alleviate the adverse reactions of quadruple anti-Helicobacter pylori regimen? : randomized controlled trial.

BACKGROUND: Vitamin B6 is an essential water-soluble vitamin for humans. It is often used to prevent a variety of neuropathies, relieve vomiting, and relieve symptoms such as hand and foot neuritis. AIM: To evaluate whether vitamin B6 can alleviate the adverse reactions caused by the quadruple anti-Helicobacter pylori treatment regimen containing minocycline and metronidazole. METHODS: In this randomized controlled trial, 280 patients with H. pylori infection were randomly placed into one of two treatment groups-the conventional treatment group and the vitamin B6 supplement treatment group-for 2 weeks. The primary endpoint was the total incidence of adverse reactions up to 2 weeks after treatment initiation. The study was designed according to CONSORT Medicinal Interventions. And it was registered with Chinese Clinical Trial Registry under the number ChiCTR2100053833. RESULTS: In terms of efficacy, vitamin B6 does not affect the efficacy of conventional regimen. In the vitamin B6 supplement treatment group, the incidence of adverse reactions was 56.92%, which was significantly lower than the 74.62% observed in the conventional treatment group. In addition, the severity of adverse reactions was also significantly reduced. The proportion of moderate to severe central nervous system symptoms decreased from 58.7 to 14.63%. And, the proportion of moderate to severe gastrointestinal reactions decreased from 33.33 to 0%. We speculate that the mechanism of vitamin B6 of reducing adverse reaction may be related to the production of GABA in the brain. CONCLUSIONS: Vitamin B6 can alleviate adverse reactions of the quadruple anti-H. pylori regimen containing minocycline and metronidazole.

Assessing the effectiveness of camrelizumab plus apatinib versus sorafenib for the treatment of primary liver cancer: a single-center retrospective study.

Although the effectiveness of camrelizumab plus apatinib has been confirmed in a phase II clinical study, the efficacy of camrelizumab plus apatinib versus sorafenib for primary liver cancer (PLC) remains unverified. We retrospectively collected the data of 143 patients with PLC who received camrelizumab plus apatinib or sorafenib as the first-line treatment at The First Affiliated Hospital of Anhui Medical University from April 2018 to November 2021. Of these, 71 patients received an intravenous injection of camrelizumab 200 mg (body weight ≥ 50 kg) or 3 mg/kg (body weight < 50 kg) followed by an oral dosage of apatinib 250 mg/day every 3 weeks and 72 patients received sorafenib 400 mg orally, twice a day in 28-day cycles. The primary outcomes were overall survival and progression-free survival. The secondary outcomes were objective response rate, disease control rate, and safety. The median median progression-free survival and median overall survival with camrelizumab plus apatinib and sorafenib were 6.0 (95% confidence interval (CI) 4.2-7.8) and 3.0 months (95% CI 2.3-3.7) and 19.0 (95% CI 16.4-21.6) and 12.0 months (95% CI 8.9-15.1), respectively (death hazard ratio: 0.61, P = 0.023). Grade 3/4 treatment-related adverse events were noted in 50 (70.4%) patients in the camrelizumab plus apatinib group and 19 (26.4%) patients in the sorafenib group. Two treatment-related deaths were recorded. Clinically significant improvements were observed in overall survival and progression-free survival with camrelizumab plus apatinib versus sorafenib. Although the side effects of camrelizumab plus apatinib are relatively high, they can be controlled.

Emergence of Antifungal Resistant Subclades in the Global Predominant Phylogenetic Population of Candida albicans.

Candida albicans remains the most common species causing invasive candidiasis. In this study, we present the population structure of 551 global C. albicans strains. Of these, the antifungal susceptibilities of 370 strains were tested. Specifically, 66.6% of the azole-nonsusceptible (NS)/non-wild-type (NWT) strains that were tested belonged to Clade 1. A phylogenetic analysis, a principal components analysis, the population structure, and a loss of heterozygosity events revealed two nested subclades in Clade 1, namely, Clade 1-R and Clade 1-R-α, that exhibited higher azole-NS/NWT rates (75.0% and 100%, respectively). In contrast, 6.4% (21/326) of the non-Clade 1-R isolates were NS/NWT to at least 1 of 4 azoles. Notably, all of the Clade 1-R-α isolates were pan-azole-NS/NWT that carried unique A114S and Y257H double substitutions in Erg11p and had the overexpression of ABC-type efflux pumps introduced by the substitution A736V in transcript factor Tac1p. It is worth noting that the Clade 1-R and Clade 1-R-α isolates were from different cities that are distributed over a large geographic span. Our study demonstrated the presence of specific phylogenetic subclades that are associated with antifungal resistance among C. albicans Clade 1, which calls for public attention on the monitoring of the future spread of these clones. IMPORTANCE Invasive candidiasis is the most common human fungal disease among hospitalized patients, and Candida albicans is the predominant pathogen. Considering the large number of infected cases and the limited alternative therapies, the azole-resistance of C. albicans brings a huge clinical threat. Here, our study suggested that antifungal resistance in C. albicans could also be associated with phylogenetic lineages. Specifically, it was revealed that more than half of the azole-resistant C. albicans strains belonged to the same clade. Furthermore, two nested subclades of the clade exhibited extremely high azole-resistance. It is worth noting that the isolates of two subclades were from different cities that are distributed over a large geographic span in China. This indicates that the azole-resistant C. albicans subclades may develop into serious public health concerns.

Penta-therapy for severe acute hyperlipidemic pancreatitis.

INTRODUCTION: The purpose of our study is to evaluate the efficacy of penta-therapy for HL-SAP in a retrospective study. METHODS: Retrospective study between January 2007 and December 2016 in a hospital intensive care unit. HL-SAP patients were assigned to conventional treatment alone (the control group) or conventional treatment with the experimental protocol (the penta-therapy group) consists of blood purification, antihyperlipidemic agents, low-molecular weight heparin, insulin, covering the whole abdomen with Pixiao (a traditional Chinese medicine). Serum triglyceride, serum calcium, APACHE II score, SOFA score, Ranson score, and other serum biomarkers were evaluated. The hospital length of stay, local complications, systematic complications, rate of recurrence, overall mortality, and operation rate were considered clinical outcomes. RESULTS: 63 HL-SAP patients received conventional treatment alone (the control group) and 25 patients underwent penta- therapy combined with conventional treatment (the penta-therapy group). Serum amylase, serum triglyceride, white blood cell count, C-reactive protein, and blood sugar were significantly reduced, while serum calcium was significantly increased with penta-therapy. The changes in serum amylase, serum calcium were significantly different between the penta-therapy and control group on 7th day after the initiation of treatment. The reduction in serum triglyceride in the penta-therapy group on the second day and 7th day were greater than the control group. Patients in the penta-therapy group had a significantly shorter length of hospital stay. CONCLUSION: This study suggests that the addition of penta-therapy to conventional treatment for HL-SAP may be superior to conventional treatment alone for improvement of serum biomarkers and clinical outcomes.

Novel approaches to global mining of aberrantly methylated promoter sites in squamous head and neck cancer.

OBJECTIVE: Promoter hypermethylation is emerging as a promising molecular strategy for early detection of cancer. We examined promoter methylation status of 1143 cancer-associated genes to perform a global but unbiased inspection of methylated regions in head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Laboratory-based study. SETTING: Integrated health care system. SUBJECTS AND METHODS: Five samples, two frozen primary HNSCC biopsies and three HNSCC cell lines, were examined. Whole genomic DNA was interrogated using a combination of DNA immunoprecipitation (IP) and Affymetrix whole-genome tiling arrays. RESULTS: Of the 1143 unique cancer genes on the array, 265 were recorded across five samples. Of the 265 genes, 55 were present in all five samples, and 36 were common to four of five samples, 46 to three of five, 56 to two of five, and 72 to one of five samples. Hypermethylated genes in the five samples were cross-examined against those in PubMeth, a cancer methylation database combining text mining and expert annotation (http://www.pubmeth.org). Of the 441 genes in PubMeth, only 33 are referenced to HNSCC. We matched 34 genes in our samples to the 441 genes in the PubMeth database. Of the 34 genes, eight are reported in PubMeth as HNSCC associated. CONCLUSION: This pilot study examined the contribution of global DNA hypermethylation to the pathogenesis of HNSCC. The whole-genome methylation approach indicated 231 new genes with methylated promoter regions not yet reported in HNSCC. Examination of this comprehensive gene panel in a larger HNSCC cohort should advance selection of HNSCC-specific candidate genes for further validation as biomarkers in HNSCC.

Functional MR imaging of the cervical spinal cord by use of 20Hz functional electrical stimulation to median nerve.

PURPOSE: Functional MR imaging of the human cervical spinal cord was carried out on volunteers by 20Hz functional electrical stimulation to median nerve, in order to detect signal changes arising concomitant to neuronal activity. METHODS: Functional MR imaging data were acquired in six subjects with single-shot fast spin-echo sequence (SSFSE) on a 1.5T GE Clinical System. Cervical spinal cord activation was measured both in the sagittal and transverse imaging planes. Postprocessing was performed by AFNI (Analysis of Functional Neuroimages) software system. RESULTS: Activation correlated with the time course of stimulation was consistently detected in both sagittal and transverse imaging planes of the cervical spinal cord. Regions of the spinal cord associated with motor and pain response were observed by 20Hz functional electrical stimulation to the median nerve. CONCLUSION: The functional MR imaging signal can be detected in the human cervical spinal cord with functional electrical stimulation. Investigating the FES response in the spinal cord using the spinal fMRI will be helpful for the further discussion on the diagnosis and functional recovery to spinal cord diseases.

[Prospective study of effect of recombinant human growth hormone on nutritional status and immune function in early postoperative stage of liver transplantation].

OBJECTIVE: To evaluate influence of recombinant human growth hormone (rhGH) on nutritional status and immune function in early postoperative stage of liver transplantation including hepatic function, acute rejection and infection rate, in order to assess its safety in clinical use. METHODS: Sixty patients with non-malignant diseases of the liver in terminal stages were randomly divided into two groups: treatment group (rhGH treatment n=30) and control group (n=30). All the patients received the same nutritional support and immunodepressant treatment regimes. The patients in treatment group received rhGH 10 U hypodermically daily for 10 days 24 hours after liver transplantation. The following parameters including siderophilin, prealbumin, albumin, urea nitrogen, CD4/CD8, immunoglobulin G (IgG), IgM, IgA, growth hormone (GH), insulin-like growth factor-1 (IGF-1), aspartate aminotransferase (AST), alanine aminotransferase (ALT), dosage of insulin to control blood sugar (8-10 mmol/L) were determined on 1st, 4th, 8th, 14th days after the operation, and acute rejection rate after 28 days of operation (confirmed by liver acupuncture biopsy), and infection rate were also assessed. RESULTS: Compared with control group, levels of siderophilin, prealbumin, CD4/CD8, GH, IGF-1 within 14 days in treatment group were increased significantly 14 days after the operation (all P<0.05), and level of urea nitrogen was decreased significantly (P<0.05). The level of albumin in treatment group was lower than that in control group 14 days after operation (P<0.05), while dosages of exogenous insulin were higher on 4th and 8th days after operation than that in control group (both P<0.05). There were no significant differences in levels of AST, ALT within 14 days, or acute rejection rate and infection rate within 28 days between two groups (all P>0.05). CONCLUSION: rhGH can accelerate recovery of nutritional status in the early liver transplantation period. It does not show superiority in improving immune function and influence on recovery of hepatic function, acute rejection or infection rate. The safety has been challenged by inducing high blood sugar as a side effect.

Vitamin E status and its dietary determinants in Taiwanese--results of the Nutrition and Health Survey in Taiwan 1993-1996.

BACKGROUND: A large proportion of Taiwanese are considered to have inadequate vitamin E intake according to Taiwanese RDA. AIM OF THE STUDY: To evaluate the vitamin E status in Taiwan using biochemical indicators, and to examine the influences of dietary factors. METHODS: The Nutrition and Health Survey in Taiwan 1993-1996 was conducted using a multi-stage sampling scheme. Data of 3614 subjects (1728 males, and 1886 females) aged 4 years and above were included in the current analysis. RESULTS: Females had higher levels of serum alpha-tocopherol than males. Serum level of alpha-tocopherol significantly increased with age and blood lipids (p < 0.001). The prevalence rate of deficiency, assessed by the ratio of serum alpha-tocopherol to cholesterol+triglyceride(TG) < 1.59 micromol/mmol, was 1.4 % for Taiwanese aged 4 and above. The prevalence was 1.02 % for adults. This biochemical profile was superior in women compared to men. The age-serum vitamin E status was U-shaped, being poorest in teenagers. Geographical variation in vitamin E/cholesterol+TG ratio was not apparent across regions. An association was observed between serum vitamin E status and frequency of vitamin E supplements, fresh fruits, and 100 % fruit juices. An association was also seen with dietary intakes of vitamin C and vitamin E assessed by 24-hour recall. CONCLUSION: The prevalence rate of vitamin E deficiency in Taiwan was low. An association was observed between serum vitamin E status and dietary vitamins E and C intakes either from foods or supplements.

[Effects of enflurane on myocardial reperfusion injury during cardiac surgery with cardiopulmonary bypass].

OBJECTIVE: To study the effects of inhalation enflurane (Enf) before aortic clamping on myocardial reperfusion injury in cardiac surgery with cardiopulmonary bypass (CPB). METHODS: hirty patents undergoing selective cardiac valve replacement were randomly allocated to three groups. Group I and group II inhaled 1.0 MAC and 0.5 MAC Enf before clamping aorta, respectively. Group III was the control group interval administration with Fentanyl. RESULTS: Immediately upon aortic clamp release (T2), the value of CK-MB, MDA and SOD of all the groups was significantly increased, however,their concentration did not peak significantly until T3 and T4(10 and 30 min after clamp aorta release). The levels at 60 min (T5) and 24 hours (T6) aorta were lower than T4 but still higher than T(0). At T3 and T4, CK-MB levels in group I were significantly higher than those in II and III groups (P=0.0220, 0.0108 and 0.0202, 0.0295). At T6, the CK-MB level of group II was significantly higher than that of group III (P<0.0001). At T4 and T5, the MDA value of group I was higher than that of group II (P=0.0060 and 0.0364). Meanwhile, the SOD level in group I was also higher than that of group II and group III at the T4 point (P<0.0001 and 0.0084). There was a correlation between the CK-MB value and the aorta clamping time,correlation coefficient range being 0.55 - 0.81,(P<0.05). However, there was no correlation between the CK-MB and MDA, SOD. CONCLUSION: There is ischemia reperfusion injury during cardiac surgery CPB with the increase of OFR production and elevation of the antioxidant reserve. Inhalation of large dose of enflurane may result in increased myocardial ischemia reperfusion injury manifested by elevated levels of myocardial enzymes and OFR production.

Effects of enflurane on myocardial reperfusion injury during cardiac surgery with cardiopulmonary bypass / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To study the effects of inhalation enflurane (Enf) before aortic clamping on myocardial reperfusion injury in cardiac surgery with cardiopulmonary bypass (CPB).</p><p><b>METHODS</b>hirty patents undergoing selective cardiac valve replacement were randomly allocated to three groups. Group I and group II inhaled 1.0 MAC and 0.5 MAC Enf before clamping aorta, respectively. Group III was the control group interval administration with Fentanyl.</p><p><b>RESULTS</b>Immediately upon aortic clamp release (T2), the value of CK-MB, MDA and SOD of all the groups was significantly increased, however,their concentration did not peak significantly until T3 and T4(10 and 30 min after clamp aorta release). The levels at 60 min (T5) and 24 hours (T6) aorta were lower than T4 but still higher than T(0). At T3 and T4, CK-MB levels in group I were significantly higher than those in II and III groups (P=0.0220, 0.0108 and 0.0202, 0.0295). At T6, the CK-MB level of group II was significantly higher than that of group III (P<0.0001). At T4 and T5, the MDA value of group I was higher than that of group II (P=0.0060 and 0.0364). Meanwhile, the SOD level in group I was also higher than that of group II and group III at the T4 point (P<0.0001 and 0.0084). There was a correlation between the CK-MB value and the aorta clamping time,correlation coefficient range being 0.55 - 0.81,(P<0.05). However, there was no correlation between the CK-MB and MDA, SOD.</p><p><b>CONCLUSION</b>There is ischemia reperfusion injury during cardiac surgery CPB with the increase of OFR production and elevation of the antioxidant reserve. Inhalation of large dose of enflurane may result in increased myocardial ischemia reperfusion injury manifested by elevated levels of myocardial enzymes and OFR production.</p>