Mineralocorticoid receptor antagonists for chronic heart failure: a meta-analysis focusing on the number needed to treat.

Aims: Recent studies have shown that mineralocorticoid receptor antagonists (MRAs) can decrease mortality in patients with heart failure; however, the application of MRAs in current clinical practice is limited because of adverse effects such as hyperkalemia that occur with treatment. Therefore, this meta-analysis used the number needed to treat (NNT) to assess the efficacy and safety of MRAs in patients with chronic heart failure. Methods: We meta-analysed randomized controlled trials (RCTs) which contrasted the impacts of MRAs with placebo. As of March 2023, all articles are published in English. The primary outcome was major adverse cardiovascular events (MACE), and secondary outcomes included all-cause mortality, cardiovascular death, myocardial infarction (MI), stroke, and adverse events. Results: We incorporated seven studies with a total of 9,056 patients, 4,512 of whom received MRAs and 4,544 of whom received a placebo, with a mean follow-up period of 2.1 years. MACE, all-cause mortality, and cardiovascular mortality were all reduced by MRAs, with corresponding numbers needed to treat for benefit (NNTB) of 37, 28, and 34; as well as no impact on MI or stroke. MRAs increased the incidence of hyperkalemia and gynecomastia, with the corresponding mean number needed to treat for harm (NNTH) of 18 and 52. Conclusions: This study showed that enabling one patient with HF to avoid MACE required treating 37 patients with MRAs for 2.1 years. MRAs reduce MACE, all-cause mortality, and cardiovascular death; however, they increase the risk of hyperkalemia and gynecomastia.

Recent advance of small-molecule drugs for clinical treatment of multiple myeloma.

Multiple myeloma (MM) is a hematologic neoplasm of plasma cells that is currently deemed incurable. Despite the introduction of novel immunomodulators and proteasome inhibitors, MM remains a challenging disease with high rates of relapse and refractoriness. The management of refractory and relapsed MM patients remains a formidable task, primarily due to the emergence of multiple drug resistance. Consequently, there is an urgent need for novel therapeutic agents to address this clinical challenge. In recent years, a significant amount of research has been dedicated to the discovery of novel therapeutic agents for the treatment of MM. The clinical utilization of proteasome inhibitor carfilzomib and immunomodulator pomalidomide has been successively introduced. As basic research continues to advance, novel therapeutic agents, including panobinostat, a histone deacetylase inhibitor, and selinexor, a nuclear export inhibitor, have progressed to the clinical trial and application phase. This review aims to furnish a comprehensive survey of the clinical applications and synthetic pathways of select drugs, with the intention of imparting valuable insights for future drug research and development geared towards MM.

Comparison of three different surgical approaches for treatment of thoracolumbar burst fracture.

OBJECTIVE: The main treatment method used for thoracolumbar fractures is open reduction and internal fixation. Commonly there are three surgical approaches: anterior, posterior and paraspinal. We attempt to compare the three approaches based on our clinical data analysis. METHODS: A group of 94 patients with Denis type A or B thoracolumbar burst fracture between March 2008 and September 2010 were recruited in this study. These patients were treated by anterior-, posterior- or paraspinal-approach reduction with or without decompression. The fracture was fixed with titanium mesh and Z-plate via anterior approach (24 patients), screw and rod system via posterior approach (38 patients) or paraspinal approach (32 patients). Clinical evaluations included operation duration, blood loss, incision length, preoperative and postoperative Oswestry disability index (ODI). RESULTS: The average operation duration (94.1 min +/- 13.7 min), blood loss (86.7 ml +/-0.0 ml), length of incision (9.3 mm +/- 0.7 mm) and postoperative ODI (6 +/- 0.5) were significantly lower (P less than 0.05) in paraspinal approach group than in traditional posterior approach group (operation duration 94.1 min +/- 13.7 min, blood loss 143.3 ml +/-28.3 ml, length of incision 15.4 cm +/- 2.1 cm and ODI 12 +/- 0.7) and anterior approach group (operation duration 176.3 min +/- 20.7 min, blood loss 255.1 ml +/- 38.4 ml, length of incision 18.6 cm +/- 2.4 cm and ODI 13 +/- 2.4). There was not statistical difference in terms of Cobb angle on radiographs among the three approaches. CONCLUSION: The anterior approach surgery is convenient for resection of the vertebrae and reconstruction of vertebral height, but it is more complicated and traumatic. Hence it is mostly used for severe Denis type B fracture. The posterior approach is commonly applied to most thoracolumbar fractures and has fewer complications compared with the anterior approach, but it has some shortcomings as well. The paraspinal approach has great advantages compared with the other two approaches. It is in accordance with the concept of minimally invasive surgery and can replace most posterior approach operations.

[Detection and of peripheral blood B cell activating factor in warm autoimmune hemolytic anemia patients and its implication.].

OBJECTIVE: To detect the B cell activating factor (BAFF) and explore its significance in patients with warm autoimmune hemolytic anemia (WAIHA). METHODS: The levels of serum soluble BAFF (sBAFF) and BAFF mRNA in peripheral blood mononuclear cells (PBMCs) in 30 healthy volunteers (control group) and 43 patients with WAIHA were measured by ELISA and real-time quantitative polymerase chain reaction (RT-qPCR) respectively. RESULTS: The levels of serum sBAFF and BAFF mRNA in PBMCs in pretreatment group \[2311 (825 approximately 6523) ng/L and 884 (463 approximately 2346) ng/L\] was significanly higher than those in posttreatment group\[1205(358 approximately 5014) ng/L and 446(138 approximately 2699) ng/L\] and control group\[1128 (590 approximately 3201) ng/L and 341 (102 approximately 965) ng/L\] (both P < 0.01), the difference between the posttreatment group and control group was not statistically significant. There was no significant difference between therapy responsive and nonresponsive groups before treatment. There was a significant difference between the pre- and post-treatment resuets in responsive group (P < 0.01), but not in nonresponsive group (P > 0.05). The serum levels of sBAFF was positively correlated with the levels of the BAFF mRNA in PBMCs both in pre- and post therapy group (both P < 0.05). CONCLUSION: The levels of serum sBAFF and BAFF mRNA in PBMCs are increased in patients with WAIHA, their dynamic alterations may contribute to the development of WAIHA.

Screening and evaluation of human single-chain fragment variable antibody against hepatitis B virus surface antigen.

BACKGROUND: Phage display technology has become a vital tool in studies aimed at identifying molecules binding to a specific target. It enables the rapid generation and selection of high affinity, fully human antibody product candidates to essentially any disease target appropriate for antibody therapy. In this study, we prepared the recombinant single-chain fragment variable (ScFv) antibody to hepatitis B virus surface antigen (HBsAg) by the phage display technology for obtaining a virus-targeting mediator. METHODS: mRNA was isolated from B-lymphocytes from a healthy volunteer and converted into cDNA. The fragment variables of heavy and light chain were amplified separately and assembled into ScFv DNA with a specially constructed DNA linker by polymerase chain reaction. The ScFv DNA was ligated into the phagmid vector pCANTAB5E and the ligated sample was transformed into competent E.coli TG1. The transformed cells were infected with M13K07 helper phage to form a human recombinant phage antibody library. The volume and recombinant rate of the library were evaluated by bacterial colony count and restriction analysis. After two rounds of panning with HBsAg, the phage clones displaying ScFv of the antibody were selected by enzyme-linked immunosorbant assay (ELISA) from the enriched phage clones. The antigen binding affinity of the positive clone was detected by competition ELISA. HB2151 E.coli was transfected with the positive phage clone demonstrated by competition ELISA for production of a soluble form of the anti-HBsAg ScFv. ELISA assay was used to detect the antigen binding affinity of the soluble anti-HBsAg ScFv. Finally, the relative molecular mass of soluble anti-HBsAg ScFv was measured by SDS-PAGE. RESULTS: The variable heavy (VH) and variable light (VL) and ScFv DNAs were about 340 bp, 320 bp and 750 bp, respectively. The volume of the library was up to 2 x 10(6) and 8 of 10 random clones were recombinants. Two phage clones could strongly compete with the original HBsAb for binding to HBsAg. Within 2 strong positive phage clones, the soluble anti-HBsAg ScFv from one clone was found to have the binding activity with HBsAg. SDS-PAGE showed that the relative molecular weight of soluble anti-HBsAg ScFv was 32 kDa. CONCLUSION: The anti-HBsAg ScFv successfully produced by phage antibody technology may be useful for broadening the scope of application of the antibody.

[Study of effects of drugs on myocardial hypertrophy due to overload].

OBJECTIVE: To study the relation of expression change of tumor necrosis factor-alpha (TNF-alpha), angiotensin II (Ang II), and endothelin-1 (ET-1), and the effect of imidapril on myocardial hypertrophy due to overload. METHODS: Sixty-three rats were randomly divided into four groups: sham operation (n=15), overload group (n=16), imidapril group (n=16), and Caweidiluo group (n=16). Hypertrophic myocardium was reproduced in rats by constricting abdominal aorta. Blood samples and heart were harvested 12 weeks after aorta constriction, and myocardial hypertrophy index, the contents of Ang II, ET-1 in the myocardium and plasma were determined by radioimmunoassay and TNF-alpha in the myocardium and plasma were determined by enzyme linked immunoadsorbent assay. RESULTS: Left ventricle showed obvious hypertrophy 12 weeks after operation. The contents of TNF-alpha, Ang II and ET-1 in the myocardium, and the content of TNF-alpha in serum, Ang II and ET-1 in plasma were increased compared with those of controls (all P<0.01). The treatment of imidapril and Caweidiluo could restrain the development of left ventricle hypertrophy after operation, and imidapril decreased the contents of TNF-alpha, Ang II and ET-1 in myocardium compared with overload group (all P<0.01). Imidapril lowered the contents of TNF-alpha in serum, Ang II and ET-1 in plasma, compared with overload group (all P<0.01), but not ET-1. Caweidiluo lowered the contents of TNF-alpha, Ang II and ET-1 in myocardium, the contents of TNF-alpha in serum, Ang II and ET-1 in plasma (all P<0.01) compared with overload group (both P<0.01). CONCLUSION: The activation of rennin-angiotensin system (RAS) by over load results to an elevation of TNF-alpha contents in plasma and myocardium, and it is probably one of the major regulatory pathways of myocardial hypertrophy.

A case of deficiency of plasma plasminogen activator inhibitor-1 related to Ala15Thr mutation in its signal peptide.

The patient was a 34-year-old man with life-long bleeding episodes, whose hemorrhage problem was characterized predominantly by prolonged bleeding at surgical or traumatic sites. All routine coagulation parameters were within normal ranges. The patient's bleeding tendency was not caused by factor XIII deficiency, alpha2-antiplasmin deficiency, or tissue type-plasminogen activator increase. His characteristic abnormalities of fibrinolysis included shortened euglobulin clot lysis time, low plasminogen activator inhibitor-1 (PAI-1) activity and antigen in plasma, which were remarkably reduced to only about 10% of control. An operation was performed in order to clear two hematomas in the patient's left leg and hip, and subsequent bleeding episodes were well controlled with adjuvant administration of intravenous aminomethylbenoic acid after surgery. PAI-1 gene analysis by polymerase chain reaction product sequencing revealed that the patient had a heterozygous missense mutation G to A transition at nucleotide position 4497 in exon 2, causing replacement of alanine 15 (GCC) to threonine (ACC) at signal peptide. The restriction endonuclease analysis showed that this gene mutation also existed in the patient's father, but not in his mother and 60 normal subjects. The wild-type and mutant plasmids were constructed and transiently transfected into Chinese hamster ovary cell lines; the levels of PAI-1 activity and antigen in the media of the mutant were approximately 70% of the wild type, and the levels of PAI-1 protein in cell lysates were almost equal in wild-type and mutant plasmids. These results indicate that the mutation in signal peptide may partly impair the secretion of PAI-1.