Assessment of the efficacy of intra-articular platelet rich plasma treatment in an ACLT experimental model by dynamic contrast enhancement MRI of knee subchondral bone marrow and MRI T2∗ measurement of articular cartilage.

OBJECTIVE: The vascularization of subchondral bone plays a significant role in the progression of knee osteoarthritis (OA). Treatment with platelet-rich plasma (PRP) has positive effects on cartilage lesions. However, PRP's efficacy for subchondral bone marrow lesions and the relationship of these lesions to cartilage are still undiscovered. Therefore, our aims were first to longitudinally investigate the change in subchondral flow by dynamic contrast enhanced MRI and degeneration of cartilage by MRI T2∗ in an anterior cruciate transection rodent (ACLT) model, and second to examine changes in parameters after intra-articular PRP injection. DESIGN: A 32-week investigation in 18 rats allocated to sham-control, ACLT with normal saline injection (ACLT + NS), and ACLT with PRP injection groups ended with histological evaluation. Another rat was used as a donor of allogenic PRP. RESULTS: Compared to the sham-control group, the ACLT + NS group had higher subchondral blood volume A (0.051, 95% confidence interval: 0.009, 0.092) and lower venous washout kel (-0.030: -0.055, -0.005) from week 4; lower permeability kep from week 18 (-0.954: -1.339, -0.569); higher cartilage T2∗ values (1.803: 1.504, 2.102) reflecting collagen loss beginning at week 10. For the PRP treatment group, subchondral bone marrow A and cartilage T2∗ decreased from week 10. Histological results confirmed and were correlated with the MRI findings. CONCLUSION: Subchondral hyper-perfusion plays a vital role in the pathogenesis of OA and was associated with cartilage degeneration. The efficacy of PRP can be observed from reduced perfusion and MRI T2∗ values.

Risk of post-contrast acute kidney injury in emergency department patients with sepsis.

INTRODUCTION: Although computed tomography (CT) is a useful tool for exploring occult infection in patients with sepsis in the emergency department, the potential nephrotoxicity of contrast media is a major concern. Our study aimed to investigate the association between use of contrast-enhanced CT and the risks of acute kidney injury and other adverse outcomes in patients with sepsis. METHODS: In total, 587 patients with sepsis who underwent CT scan (enhanced CT group: 105, non-enhanced CT group: 482) from January 2012 to December 2016 at a tertiary referral centre were enrolled in this retrospective analysis, and propensity score matching was performed to minimise the selection bias. The length of stay, incidences of acute kidney injury and emergent dialysis, and short-term mortality were compared between the two groups. RESULTS: Compared with patients in the non-enhanced CT group, patients in the contrast-enhanced CT group did not have increased risks of acute kidney injury (odds ratio [OR]=1.38, 95% confidence interval [CI]=0.55-3.43; P=0.489), emergent dialysis (OR=1.31, 95% CI=0.47-3.68; P=0.602), or short-term mortality (OR=0.90, 95% CI=0.48-1.69; P=0.751). In addition, there was no significant difference in the median length of hospital stay between survivors in the two groups (20 vs 19 days, P=0.742). CONCLUSIONS: Intravenous contrast administration during CT scanning was not associated with prolonged length of hospital stay in patients with sepsis in an emergency setting. Moreover, the use of contrast-enhanced CT was not associated with increased risks of acute kidney injury, emergent dialysis, or short-term mortality.

What happens after no contralateral exploration in total extraperitoneal (TEP) herniorrhaphy of clinical unilateral inguinal hernias?

BACKGROUND: While performing unilateral TEP herniorrhaphy, controversy still exists about whether to do contralateral exploration or not. Routine contralateral exploration has been proposed to prevent metachronous contralateral hernias by the repair of incidental contralateral occult hernias. Some surgeons have even proposed to do prophylactic bilateral TEP herniorrhaphy for unilateral hernia patients. To evaluate the appropriateness of not doing contralateral exploration in unilateral TEP herniorrhaphy, we reviewed our experiences under our practice of no contralateral exploration and we also reviewed other published literature. METHODS: A total of 305 patients who underwent 313 TEP herniorrhaphies for inguinal hernias by a single surgeon during August 2012-July 2016 at Chia-Yi Christian Hospital were enrolled in this retrospective study. Demographic, perioperative and follow-up data were obtained for analysis and review. RESULTS: Of the 305 patients, 261 patients had unilateral TEP herniorrhaphy and 44 patients had bilateral TEP herniorrhaphy. The mean operation time for the unilateral TEP herniorrhaphy group was 59.8 min, and for the bilateral TEP herniorrhaphy group it was 85.2 min (p < 0.001). Seven of 261 (2.7%) patients had metachronous contralateral hernia after unilateral TEP herniorrhaphy. There were no statistically significant differences in any of the outcome variables when comparing the sequential and simultaneous primary bilateral TEP herniorrhaphies. CONCLUSIONS: Without routine contralateral exploration, the incidence of metachronous contralateral hernia was 2.7% (7/261) in unilateral hernia patients. This is acceptable as metachronous hernia also occurred in 3.2% of patients with negative contralateral exploration according to our literature review. Sequential and simultaneous bilateral primary TEP herniorrhaphy outcomes were similar. We conclude that no exploration for the other groin is a justified decision for unilateral inguinal hernia patients.

The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients.

This study investigates the incidences and predictors of hepatitis B virus (HBV) relapse after tenofovir disoproxil fumarate (TDF) therapy in hepatitis B e antigen (HBeAg)-positive and -negative patients. We retrospectively recruited 143 chronic hepatitis B (CHB) patients without cirrhosis (39 HBeAg-positive and 104 HBeAg-negative patients) who were previously treated with TDF and had post-treatment follow-up for at least 6 months (median: 55, IQR 36-85 weeks). All the patients fulfilled the stopping criteria of APASL 2012. The virological and clinical relapse rates at 104 weeks in HBeAg-positive patients were 66.6% and 59.1%, while they were 72.3% and 55.9%, respectively, in HBeAg-negative patients. Cox regression analysis revealed that the higher end-of-treatment HBsAg levels were an independent factor of virological relapse in HBeAg-positive and HBeAg-negative patients. The end-of-treatment HBsAg levels of 200 (area under the receiver operating characteristic (AUROC): 0.624) and 80 IU/mL (AUROC: 0.959) were the optimal values for predicting HBV relapse in HBeAg-positive and HBeAg-negative patients, respectively. The virological relapse rate at 78 weeks was 14.3% and 19.6% in HBeAg-positive and HBeAg-negative patients who achieved HBsAg ≤200 IU/mL and HBsAg ≤80 IU/mL, respectively. Two patients experienced hepatic decompensation upon hepatitis flares, and no patient died after timely retreatment. Seven patients experienced off-therapy HBsAg loss. The cumulative rates of HBsAg loss at 104 weeks were 45.5% and 59.3% in patients with end-of-treatment HBsAg ≤80 IU/mL and ≤50 IU/mL, respectively. In conclusions, the end-of-treatment HBsAg levels were a useful marker for predicting HBV relapse in HBeAg-positive and HBeAg-negative CHB patients.

Cartilage MRI T2∗ relaxation time and perfusion changes of the knee in a 5/6 nephrectomy rat model of chronic kidney disease.

OBJECTIVE: Chronic kidney disease (CKD) is characterized by metabolic disturbances in calcium and phosphorus homeostasis as kidney function declines. Alterations in blood perfusion in bone resulting from arteriosclerosis of bone vessels may relate to the progression of CKD. Herein, change in dynamic contrast enhanced (DCE) MRI parameters (A: amplitude, kel: elimination constant, and kep: permeability rate constant) and MRI T2∗ relaxation time of the knee cartilage were measured in a rodent nephrectomy model in order to (1) examine the relationship of peripheral blood perfusion to CKD and (2) demonstrate the feasibility of using DCE-MRI parameters and MRI T2∗ as imaging biomarkers to monitor disease progression. DESIGN: Two groups of male Sprague-Dawley rats received either (1) no intervention or (2) 5/6 nephrectomy. RESULTS: We found that the CKD group (compared with the control group) had lower A and kel values and similar kep value in the lateral and medial articular cartilages beginning at 12 weeks (P < 0.05); statistically significantly higher T2∗ values in the lateral and medial articular cartilages beginning at 18 weeks (P < 0.05); statistically significantly decreased inner luminal diameter of the popliteal artery, and altered structure of the lateral and medial articular cartilages (P < 0.05). CONCLUSION: Perfusion deficiency and CKD may be related. DCE parameters and MRI T2∗ could serve as imaging biomarkers of cartilage degeneration in CKD progression.

Abnormal perfusion in patellofemoral subchondral bone marrow in the rat anterior cruciate ligament transection model of post-traumatic osteoarthritis: a dynamic contrast-enhanced magnetic resonance imaging study.

OBJECTIVE: Although anterior cruciate ligament (ACL) injury is a well-recognized risk factor for developing knee post-traumatic osteoarthritis (PTOA), the process in the patellofemoral (PF) joint after ACL injury is still under-researched. Our aim was to investigate the perfusion changes in PF subchondral bone marrow in the rat ACL transection (ACLX) model of PTOA using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DESIGN: Eighteen male Sprague Dawley rats were randomly separated into three groups (n = 6 each group): a normal control group and groups receiving ACLX and sham-surgery, respectively, in the right knee. Perfusion parameters in the patellar and femoral subchondral bone marrows of all rats were measured on DCE-MRI at 0, 4, 8, and 16 weeks after respective treatment. After the last MRI at week 16, the rats were sacrificed and their right knees were harvested for histologic examination. In addition, to observe the long-term histologic change in PF joints, 9 additional rats (n = 3 in each group) were included and sacrificed at week 32 for histologic examination. RESULTS: In the ACLX group vs the sham and control groups, the perfusion parameters were significantly changed in both patellar and femoral subchondral bone marrows at week 16. Histologic examination revealed cartilage defects in ACLX rats at 32 weeks after surgery. CONCLUSIONS: These data point to a possible functional relationship between subchondral bone marrow perfusion abnormalities and cartilage breakdown in PTOA. Moreover, the perfusion parameters derived from DCE-MRI can potentially serve as biomarkers of early OA.

Targeting post-translational modifications of histones for cancer therapy.

Post-translational modifications (PTMs) on histones including acetylation, methylation, phosphorylation, citrullination, ubiquitination, ADP ribosylation, and sumoylation, play important roles in different biological events including chromatin dynamics, DNA replication, and transcriptional regulation. Aberrant histones PTMs leads to abnormal gene expression and uncontrolled cell proliferation, followed by development of cancers. Therefore, targeting the enzymes required for specific histone PTMs holds a lot of potential for cancer treatment. In this review article, we retrospect the latest studies in the regulations of acetylation, methylation, and phosphorylation of histones. We also summarize inhibitors/drugs that target these modifications for cancer treatment.

Saturated fatty acid induces cancer stem cell-like properties in human hepatoma cells.

Hepatic steatosis has been reported to be a risk factor for the development of liver cancer. The underlying mechanism for carcinogenesis remains to be elucidated. It has been postulated that cancer stem cells (CSCs) within tumor tissues are a subset of cells with stem cell properties of self-renewal and undifferentiation. The purpose of this study was to investigate the effects of a saturated fatty acid, palmitate (PA), on CSC-like properties of human hepatoma HepG2 cells. We investigated the effects of PA on HepG2 cells and primary rat hepatocytes (PRH) by exposing them to PA to induce lipid accumulation. Significant fat accumulation was observed by Oil Red O staining in cells exposed to PA, and it was accompanied by significant increase in NFκB (p65) nuclear translocation in HepG2 cells. Notably, PA significantly enhanced the sphere forming ability of HepG2 cells, but not PRH. Furthermore, PA significantly increased stemness gene expressions of Sox2 and Oct4, and sonic hedgehog (Shh) production. Notably, NFκB inhibitors, N-Acetyl-L-cysteine and pyrollidine dithiocarbamate, and a NOX inhibitor, diphenyleneiodonium, significantly attenuated PA-induced sphere forming ability of HepG2 cells. Our results suggest that lipid accumulation may not only induce pro-inflammatory responses in hepatocytes but may also activate CSC-like properties of hepatoma cells through NFκB activation.

Extreme Hyperlactatemia After Heart Transplantation: One Center's Experience.

INTRODUCTION: Hyperlactatemia may occur early after cardiac surgery and is correlated with prognosis. This study was conducted to analyze the perioperative variables and postoperative outcomes among heart transplant recipients with extremely high lactate levels (>15 mmol/L). METHODS: The single-center medical records of heart transplantation from June 2006 to May 2013 were retrospectively reviewed for patient characteristics, perioperative hemodynamic variables, arterial blood gas analysis data, and postoperative mortality. RESULTS: Among 58 consecutive heart transplant recipients, lactate levels over the detectable upper limit (>15 mmol/L) were identified in 12 patients after intensive care unit admission, with peak time at 1.9 ± 2.0 (range 0-6.1) hours. The maximal preoperative lactate level was 3.1 mmol/L, and most (11/12) postoperative lactate levels returned to <4 mmol/L at 27.5 ± 12.8 hours after surgery (range 15-58, median 24), displaying a trend toward delayed extubation time in 10 recipients (P < .01). Blood glucose levels elevated significantly from preoperative 148.9 ± 45.2 to 375.7 ± 96.9 mg/dL at peak lactate level (P < .01). Four patients died in the ICU (range 5-32 days), 4 died after discharge (range 5-57 months), with 6 in total surviving over 1 year. CONCLUSION: Extreme hyperlactatemia commonly occurred early after heart transplantation and mostly recovered within 30 hours; however, with delayed extubation time after operation.

Slug is temporally regulated by cyclin E in cell cycle and controls genome stability.

The transcriptional repressor Slug is best known to control epithelial-mesenchymal transition (EMT) and promote cancer invasion/metastasis. In this study, we demonstrate that Slug is temporally regulated during cell cycle progression. At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation. Non-phosphorylatable Slug is markedly stabilized at G1/S transition compared with wild-type Slug and greatly leads to downregulation of DNA synthesis and checkpoint-related proteins, including TOP1, DNA Ligase IV and Rad17, reduces cell proliferation, delays S-phase progression and contributes to genome instability. Our results indicate that Slug has multifaceted roles in cancer progression by controlling both EMT and genome stability.

Genetic polymorphisms and tissue expression of interleukin-22 associated with risk and therapeutic response of gastric mucosa-associated lymphoid tissue lymphoma.

Chronic Helicobacter pylori-stimulated immune reactions determine the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. We aimed to explore the genetic predisposition to this lymphoma and its clinical implication. A total of 68 patients and 140 unrelated controls were genotyped for 84 single-nucleotide polymorphisms in genes encoding cytokines, chemokines and related receptors that play important roles in T cell-mediated gastrointestinal immunity. Five genotypes in IL-22, namely CC at rs1179246, CC at rs2227485, AA at rs4913428, AA at rs1026788 and TT at rs7314777, were associated with disease susceptibility. The former four genotypes resided in the same linkage disequilibrium block (r(2)=0.99) that conferred an approximately threefold higher risk. In vitro experiments demonstrated that co-culturing peripheral mononuclear cells or CD4(+) T cells with H. pylori stimulated the secretion of interleukin-22 (IL-22), and that IL-22 induced the expression of antimicrobial proteins, RegIIIα and lipocalin-2, in gastric epithelial cells. Furthermore, patients with gastric tissue expressing IL-22 were more likely to respond to H. pylori eradication (14/22 vs 4/19, P<0.006). We conclude that susceptibility of gastric MALT lymphoma is influenced by genetic polymorphisms in IL-22, the product of which is involved in mucosal immunity against H. pylori and associated with tumor response to H. pylori eradication.

Multidrug overdose-induced myoclonus complicated by rhabdomyolysis: possible role and mechanism of muscle toxicity of risperidone.

WHAT IS KNOWN AND OBJECTIVE: Atypical antipsychotics are considered safe for treating schizophrenia and are rarely reported to induce rhabdomyolysis. CASE SUMMARY: Here is a case of a woman with schizophrenia who developed rhabdomyolysis following overdose of risperidone, trihexyphenidyl and benzodiazepines. There was no recurrence of rhabdomyolysis when above medication was resumed with therapeutic dose. WHAT IS NEW AND CONCLUSION: Multidrug overdose are common but are rarely reported to induce rhabdomyolysis. Overdose risperidone may increase the risk of rhabdomyolysis and need to be kept in mind.

Therapeutic ROS targeting of GADD45γ in the induction of G2/M arrest in primary human colorectal cancer cell lines by cucurbitacin E.

Cucurbitacin E (CuE) or α-elaterin is a natural compound previously shown to be an antifeedant as well as a potent chemopreventive agent against several types of cancer. The present study investigated the anticancer effects of CuE on colorectal cancer (CRC) using primary cell lines isolated from five CRC patients in Taiwan, Specifically, we explored the anti-proliferation and cell cycle G2/M arrest induced by CuE in CRC cells. MPM-2 flow cytometry tests show that CuE-treated cells accumulated in metaphase (CuE 2.5-7.5 µM). Results further indicate that CuE produced G2/M arrest as well as the downregulation of CDC2 and cyclin B1 expression and dissociation. Both effects increased proportionally with the dose of CuE; however, the inhibition of proliferation, arrest of mitosis, production of reactive oxygen species (ROS), and loss of mitochondrial membrane potential (ΔΨm) were found to be dependent on the quantity of CuE used to treat the cancer cells. In addition, cell cycle arrest in treated cells coincided with the activation of the gene GADD45(α, ß, γ). Incubation with CuE resulted in the binding of GADD45γ to CDC2, which suggests that the delay in CuE-induced mitosis is regulated by the overexpression of GADD45γ. Our findings suggest that, in addition to the known effects on cancer prevention, CuE may have antitumor activities in established CRC.

Inducement of mitosis delay by cucurbitacin E, a novel tetracyclic triterpene from climbing stem of Cucumis melo L., through GADD45γ in human brain malignant glioma (GBM) 8401 cells.

Cucurbitacin E (CuE) is a natural compound previously shown to have anti-feedant, antioxidant and antitumor activities as well as a potent chemo-preventive action against cancer. The present study investigates its anti-proliferative property using MTT assay; CuE demonstrated cytotoxic activity against malignant glioma GBM 8401 cells and induced cell cycle G2/M arrest in these cells. CuE-treated cells accumulated in metaphase (CuE 2.5-10 µM) as determined using MPM-2 by flow cytometry. We attempted to characterize the molecular pathways responsible for cytotoxic effects of CuE in GBM 8401 cells. We studied the genome-wide gene expression profile on microarrays and molecular networks by using pathway analysis tools of bioinformatics. The CuE reduced the expression of 558 genes and elevated the levels of 1354 genes, suggesting an existence of the common pathways involved in induction of G2/M arrest. We identified the RB (GADD45ß and GADD45γ) and the p53 (GADD45α) signaling pathways as the common pathways, serving as key molecules that regulate cell cycle. Results indicate that CuE produced G2/M arrest as well as the upregulation of GADD45 γ and binding with CDC2. Both effects increased proportionally with the dose of CuE, suggesting that the CuE-induced mitosis delay is regulated by GADD45γ overexpression. Our findings suggest that, in addition to the known effects on cancer prevention, CuE may have antitumor activity in glioma therapy.

Streptococcus agalactiae infective endocarditis with large vegetation in a patient with underlying protein S deficiency.

We present a case of a patient with underlying protein S deficiency who suffered from infective endocarditis with a large anterior mitral leaflet (AML) mass of approximately 4.5 cm in length. Intraoperative transesophageal echocardiography (TEE) revealed the mass at the AML base and a rupture of the posterior mitral leaflet chordae tendinae. The vegetation's large size may have been caused by one or more of three factors: location, underlying disease, and the microorganism causing infection. Patients with protein S deficiency are prone to thromboembolic events during cardiac surgery. Infective endocarditis caused by Streptococcus agalactiae usually has a poor prognosis, and, thus, early surgery is recommended.

Assessment of cam-type femoroacetabular impingement by ultrasonography: value of anterior femoral distance measurements.

PURPOSE: To retrospectively determine the reproducibility and performance of a quantitative measurement for cam-type femoroacetabular impingement (FAI) designated as the anterior femoral distance (AFD) of the femoral head-neck junction identified at ultrasonography (US). MATERIALS AND METHODS: 72 patients with clinically suspected FAI were retrospectively evaluated, and US studies were performed during a 20-month period. Of these, we selected 53 patients who underwent subsequent magnetic resonance (MR) arthrography and had adequate recorded US images. All the longitudinal US images of the anterior and anterosuperior contours of the femoral head-neck junction were recorded by a radiologist. 33 of these US images were also recorded by a technician. An alpha angle of > 55° on MR arthrography was indicative of cam-type FAI. Two independent radiology residents blinded to the clinical data and MR arthrography measured the maximal femoral head-neck overgrowth defined as the AFD on US (AFD-US). Reproducibility was assessed using intra-class correlation coefficients (ICCs) and Bland-Altman plots, and diagnostic performance was assessed using receiver operating characteristic (ROC) analysis. RESULTS: AFD-US showed high intra- and inter-rater agreement (ICC = 0.913 - 0.968) in all measurements and good reproducibility among different operators in the anterior contour measurements (ICC = 0.881) but not in the anterosuperior contour measurements (ICC = 0.196). An AFD-US cut-off value of 4.0 mm in the anterior contour yielded the greatest sensitivity (80.9 %) and specificity (87.5 %) for the diagnosis of cam-type FAI by ROC analysis. CONCLUSION: AFD-US of the anterior contour of the femoral head-neck junction is helpful in diagnosing cam-type FAI.