Clinical findings, underlying pathogenetic processes and treatment of vascular dysfunction in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by the development of fluid-filled cysts in the kidneys. The primary cause of ADPKD is mutations in the PKD1 (polycystic kidney disease 1) or PKD2 (polycystic kidney disease 2) gene. Patients with ADPKD often develop a variety of vascular abnormalities, which have a major impact on the structure and function of the blood vessels and can lead to complications such as hypertension, intracranial aneurysm (ICAN), and atherosclerosis. The progression of ADPKD involves intricate molecular and cellular processes that lead to the development of these vascular abnormalities. Our understanding of these processes remains incomplete, and available treatment options are limited. The aim of this review is to delve into the underlying mechanisms of these vascular abnormalities and to explore potential interventions.

Mechanosensitive channel MscL induces non-apoptotic cell death and its suppression of tumor growth by ultrasound.

Mechanosensitive channel of large conductance (MscL) is the most thoroughly studied mechanosensitive channel in prokaryotes. Owing to its small molecular weight, clear mechanical gating mechanism, and nanopore forming ability upon opening, accumulating studies are implemented in regulating cell function by activating mechanosensitive channel of large conductance in mammalian cells. This study aimed to investigate the potentials of mechanosensitive channel of large conductance as a nanomedicine and a mechano-inducer in non-small cell lung cancer (NSCLC) A549 cells from the view of molecular pathways and acoustics. The stable cytoplasmic vacuolization model about NSCLC A549 cells was established via the targeted expression of modified mechanosensitive channel of large conductance channels in different subcellular organelles. Subsequent morphological changes in cellular component and expression levels of cell death markers are analyzed by confocal imaging and western blots. The permeability of mitochondrial inner membrane (MIM) exhibited a vital role in cytoplasmic vacuolization formation. Furthermore, mechanosensitive channel of large conductance channel can be activated by low intensity focused ultrasound (LIFU) in A549 cells, and the suppression of A549 tumors in vivo was achieved by LIFU with sound pressure as low as 0.053 MPa. These findings provide insights into the mechanisms underlying non-apoptotic cell death, and validate the nanochannel-based non-invasive ultrasonic strategy for cancer therapy.

Hydrazinocurcumin Induced Autophagy and Affected Cell Proliferation by Downregulating the JAK/STAT3 Signaling Pathway in Skin Squamous Cell Carcinoma.

This study aims to investigate the relevant mechanism by which hydrazinocurcumin (HC) interferes with A431 cell autophagy by inhibiting the STAT3 signaling pathway. Different concentrations of HC are used to treat A431 cells to study the effects of HC on A431 cell proliferation and apoptosis. Real-time fluorescent quantitative polymerase chain reaction (PCR) is used to further explore the relationship of HC with the JAK signaling pathway and autophagy. Double immunofluorescence staining is used to detect the fluorescence localization of LC3 and STAT3 after HC treatment. With increasing HC concentrations, A431 cell viability decreases in a dose-dependent manner, and the apoptosis rate increases significantly. Laser confocal colocalization reveals that the fluorescence of labeled LC3 protein is significantly increased, and the fluorescence of labeled STAT3 is significantly reduced in this study. HC may induce autophagy in A431 cells and affect cell proliferation by downregulating the JAK/STAT3 signaling pathway.

Do patient-specific guides improve coronal alignment in total knee arthroplasty?

BACKGROUND: Coronal alignment may impact clinical outcome and survivorship in TKA. Patient-specific instrumentation has been developed to restore mechanical or kinematic axis and potentially reduce component malpositioning. Although it is clear these instruments add cost, it is unclear whether they improve alignment. QUESTIONS/PURPOSES: We determined whether the mean coronal alignment after TKA performed with conventional versus patient-specific instrumentation better restored the mechanical and kinematic axes and whether there were more outliers with one of the two methods. METHODS: We retrospectively evaluated 150 primary TKAs performed for osteoarthritis: Group 1 (n = 50) conventional instrumentation; Group 2 (n = 50) patient-specific instrumentation restoring the mechanical axis; Group 3 (n = 50) patient-specific instrumentation restoring the kinematic axis, and measured femorotibial angle, hip-knee-ankle angle, and the zone of the mechanical axis from scout CT images taken 0 to 6 weeks postoperatively. RESULTS: The mean femorotibial angle differed between the groups: Group 1 had the greatest varus mean alignment and most varus outliers. The mean hip-knee angle was similar between Groups 1 and 2, with Group 3 having greater valgus mean alignment and the most valgus outliers. For the zone of the mechanical axis, Groups 1 and 2 had similar percentages of outliers (40% versus 32%), whereas Group 3 had a greater number of outliers (64%) that were valgus. CONCLUSIONS: TKAs with patient-specific instrumentation restoring the mechanical axis had a similar number of outliers as conventional instrumentation with both groups having more varus outliers than TKAs with patient-specific instrumentation restoring kinematic axis, which had more valgus outliers. Therefore, additional studies are needed to determine whether patient-specific instrumentation improves clinical function or patient satisfaction and whether their routine use can be justified in primary TKA. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Aspirin decreases heterotopic ossification after hip resurfacing.

BACKGROUND: Heterotopic ossification (HO) is a concern for patients undergoing hip surgery, especially surface replacement arthroplasty (SRA) who tend to be younger, more active, and anticipate good motion. It is unclear, however, whether HO occurs more frequently after SRA than traditional total hip arthroplasty (THA) and whether aspirin influences the risk. QUESTIONS/PURPOSES: We therefore determined the incidence of HO after hip resurfacing compared with THA and determined whether aspirin influenced the incidence or severity of HO. METHODS: Retrospectively we compared three patient cohorts: SRA with aspirin (176 hips; 160 patients), SRA with warfarin (60 hips; 57 patients), and THA with warfarin (240 hips; 222 patients). All patients satisfied the same selection criteria and all surgeries were performed through the posterolateral approach using spinal anesthesia. HO was classified using the technique of Brooker et al. comparing the preoperative, immediate postoperative, and 6- to 12-month followup radiographs (minimum, 1 year; mean, 2.7 years). RESULTS: In the SRA with aspirin group, HO was detected in four of 151 hips (2.6%; two Grade I; one Grade II; one Grade III); in the SRA with warfarin group, eight of 46 hips (17.4%) had HO with four hips (8.7%) having severe HO (Grade III). All 12 patients with HO in both SRA groups were male. The HO incidence and severity was less for the SRA patients treated with aspirin compared with those treated with warfarin. In the THA with warfarin control group, HO was detected in five of 189 hips (2.6%; two Grade I; three Grade II). The HO incidence and severity were the same between the THA with warfarin and the SRA with aspirin cohorts. CONCLUSIONS: The risk of HO is greater in SRA than in THA in patients treated with warfarin postoperatively; aspirin appears to decrease the incidence and severity of HO after hip resurfacing surgery to a similar level as total hip arthroplasty.

Quantification of pelvic tilt in total hip arthroplasty.

UNLABELLED: In THA, anterior or posterior tilt of the pelvis changes the position of the acetabular component on the coronal plane of the body as compared with its anatomic position in the pelvic bone. To understand the occurrence and clinical importance for patients with pelvic tilt on an operating room table in the lateral decubitus position, we studied 436 patients (477 hips) undergoing primary THA using an imageless computer navigation system that measured tilt. We determined the distribution and magnitude of pelvic tilt, especially tilt of 10 degrees or greater. The distribution of tilt had a range of 25 degrees posterior to 20 degrees anterior. Twenty-nine of 477 (6.1%) hips had zero tilt; 251 (52.6%) had tilt of 1 degrees to 5 degrees; 120 (25.2%) had tilt of 6 degrees to 9 degrees; and 77 (16.1%) had tilt of 10 degrees or greater. The conversion factor for acetabular anteversion has been determined by a mathematical formula by Lembeck et al. and was confirmed by us in practice. Measurement of pelvic tilt during the performance of THA will improve the accuracy of cup position, especially allowing anteversion to be measured on the coronal plane. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Outpatient total hip arthroplasty.

Patients younger than 65 years were studied to determine what percentage of patients would enroll in a study of outpatient total hip arthroplasty, its safety, and benefits of the program. Of 192 eligible patients, 69 (36%) enrolled, and 53 (77%) of these went home the same day of surgery. Of 53, 44 maintained a diary for the first 3, weeks and 52 completed a satisfaction questionnaire at 6 weeks. Patients were followed for 6 months for occurrence of complications. There were no medical readmissions. Of 52 patients who completed a 6 week questionnaire, 50 (96%) were satisfied with the decision to have outpatient total hip arthroplasty. There were no objective physical benefits identified. This study reports the distribution of acceptance and completion of same day discharge for patients with total hip arthroplasty in a metropolitan population. It confirms safety in selected patients.

A comparison of surgeon estimation and computed tomographic measurement of femoral component anteversion in cementless total hip arthroplasty.

BACKGROUND: The intraoperative estimation of the anteversion of the femoral component of a total hip arthroplasty is generally made by the surgeon's visual assessment of the stem position relative to the condylar plane of the femur. Although the generally accepted range of intended anteversion is between 10 degrees and 20 degrees, we suspected that achieving this range of anteversion consistently during cementless implantation of the femoral component was more difficult than previously thought. METHODS: We prospectively evaluated the accuracy of femoral component anteversion in 109 consecutive total hip arthroplasties (ninety-nine patients), in which we implanted the femoral component without cement. In all hips, we measured femoral stem anteversion postoperatively with three-dimensional computed tomography reconstruction of the femur, using both the distal femoral epicondyles and the posterior femoral condyles to determine the femoral diaphyseal plane. The bias and precision of the measurements were calculated. RESULTS: The surgeon's estimate of femoral stem anteversion was a mean (and standard deviation) of 9.6 degrees +/- 7.2 degrees (range, -8 degrees to 28 degrees). The anteversion of the stem measured by computed tomography was a mean of 10.2 degrees +/- 7.5 degrees (range, -8.6 degrees to 27.1 degrees) (p = 0.324). The correlation coefficient between the surgeon's estimate and the computed tomographic measurement was 0.688; the intraclass coefficient was 0.801. Anteversion measured by computed tomography found that forty-nine stems (45%) were between 10 degrees and 20 degrees of anteversion; forty-three stems (39%) were between 0 degree and 9 degrees of femoral anteversion; eight stems (7%) were in anteversion of >20 degrees; and nine stems (8%) were in retroversion. CONCLUSIONS: The surgeon's estimation of the anteversion of the cementless femoral stem has poor precision and is often not within the intended range of 10 degrees to 20 degrees of anteversion. The implications of this finding increase the importance of achieving a safe range of motion by evaluating the combined anteversion of the stem and the cup.

The p33ING1b tumor suppressor cooperates with p53 to induce apoptosis in response to etoposide in human osteosarcoma cells.

p33ING1b induces cell cycle arrest and stimulates DNA repair, apoptosis and chemosensitivity. The magnitude of some p33ING1b effects may be due to activation of the tumor suppressor p53. To investigate if the p33ING1b protein affected chemosensitivity of osteosarcoma cells, we overexpressed p33ING1b in p53+/+ U2OS cells or in p53-mutant MG63 cells, and then assessed for growth arrest and apoptosis after treatment with etoposide. p33ING1b increased etoposide-induced growth inhibition and apoptosis to a much greater degree in p53+/+ U2OS cells than in p53-mutant MG63 cells. Moreover, ectopic expression of p33ING1b markedly upregulated p53, p21WAF1 and bax protein levels and activated caspase-3 protein kinase in etoposide-treated U2OS cells. Together, our data indicate that p33ING1b prominently enhances etoposide-induced apoptosis through p53-dependent pathways in human osteosarcoma cells. p33ING1b may be an important marker and/or therapeutic target in the prevention and treatment of metastatic osteosarcoma.

The tumor suppressor p33ING1b enhances taxol-induced apoptosis by p53-dependent pathway in human osteosarcoma U2OS cells.

p33ING1b can stimulate cell cycle arrest, DNA repair, apoptosis and chemosensitivity. The actions of p33ING1b involve p53-dependent and p53-independent mechanisms. To investigate if the p33ING1b isoform is involved in the chemosensitivity of osteosarcoma cells, p33ING1b was overexpressed in p53+/+ U2OS cells or p53-mutant MG63 cells, and then cell growth arrest and apoptosis were assessed after treatment with taxol. The results showed that p33ING1b markedly increased taxol-induced growth inhibition and apoptosis in p53+/+ U2OS cells, but not in p53-mutant MG63 cells. Moreover, ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. p33ING1b may be an important marker and/or therapeutic target in the prevention and treatment of osteosarcoma.

[p33(ING1b) enhances chemosensitivity of osteosarcoma cell U2OS to etoposide].

BACKGROUND & OBJECTIVE: As a new tumor suppressor gene, ING1 shared many biological functions with p53, such as cell cycle arrest, DNA repair, apoptosis, and chemosensitivity. The aim of this study was to investigate the effect of p33(ING1b) on chemosensitivity of osteosarcoma cells and its mechanism. METHODS: p33(ING1b) was overexpressed in osteosarcoma cell line U2OS through transient transfection. After transfection, U2OS cells were treated with etoposide for 24 hours, then cell growth inhibitory rates were detected by trypan blue exclusion assay, and apoptosis was assessed using flow cytometry analysis and fluorescent microscopy. Furthermore, the protein expression of p53, p21(WAF1), MDM2 and Bax were determined by Western blot analysis. RESULTS: After transient transfection with p33(ING1b) vector for 24 hours, U2OS cells were treated with 20 microg/ml VP-16 for 24 hours. The results showed that the cell growth inhibitory rates strongly increased [(63.1+/-5.1)%], and etoposide- induced apoptosis was increased(62.7%). Ectopic overexpression of p33(ING1b) increased the protein expression of p53 and strongly enhanced the expression of endogenous p21(WAF1) and Bax. Moreover, after transfection and treatment with 20 microg/ml VP-16, the protein expression of p53, p21(WAF1), and Bax strongly increased compared with other groups. The protein expression of MDM2 showed no significant difference. CONCLUSION: These observations suggest that p33(ING1b) up-regulates p53 protein, and cooperate with p53 in stimulating expression of p21(WAF1) and Bax gene, thus to enhance etoposide-induced apoptosis via p53-dependent pathways.