Is there a role for lung surgery in initially unresectable non-small cell lung cancer after tyrosine kinase inhibitor treatment?

BACKGROUND: The role of lung surgery in initially unresectable non-small cell lung cancer (NSCLC) after tyrosine kinase inhibitor (TKI) treatment remains unclear. We aimed to assess the survival benefits of patients who underwent surgery for regressed or regrown tumors after receiving TKI treatment. METHODS: The details of patients diagnosed with unresectable NSCLC treated with TKI followed by lung resection from 2010 to 2020 were retrieved from our database. The primary endpoint was 3-year overall survival (OS), whereas the secondary endpoints were a 2-year progression-free survival (PFS), feasibility, and the safety of pulmonary resection. The statistical tests used were Fisher's exact test, Kruskal Wallis test, Kaplan-Meier method, Cox proportional hazards model, and Firth correction. RESULTS: Nineteen out of thirty-two patients were selected for the study. The patients underwent lung surgery after confirmed tumor regression (17 [89.5%]) and regrowth (two [10.5%]). All surgeries were performed via video-assisted thoracoscopic surgery: 14 (73.7%) lobectomies and five (26.3%) sublobar resections after a median duration of 5 months of TKI. Two (10.5%) postoperative complications and no 30-day postoperative mortality were observed. The median postoperative follow-up was 22 months. The 2-year PFS and 3-year OS rates were 43.9% and 61.5%, respectively. Patients who underwent surgery for regressed disease showed a significantly better OS than for regrowth disease (HR=0.086, 95% CI 0.008-0.957, p=0.046). TKI-adjuvant demonstrated a better PFS than non-TKI adjuvant (HR=0.146, 95% CI 0.027-0.782, p=0.025). CONCLUSION: Lung surgery after TKI treatment is feasible and safe and prolongs survival via local control and directed consequential therapy. Lung surgery should be adopted in multimodality therapy for initially unresectable NSCLC.

Healthcare burden and factors of type 2 diabetes mellitus with Schizophrenia.

This study investigated healthcare utilization and expenditure for patients with type 2 diabetes mellitus and schizophrenia and associated factors. Healthcare utilization (outpatient visits and hospitalization) and expenditure (outpatient, inpatient, and total medical expenditure) between 2002 and 2013 of patients with T2DM with schizophrenia (case group) and without (control group) were examined using the Taiwan National Health Insurance Research Database. (1) The average total numbers of outpatient visits and hospital admissions of the case group were 35.14 outpatient visits and 1.09 hospital admissions significantly higher than those of the control group in the whole study period (based on every 3-year period). Nonpsychiatric outpatient visits and nonpsychiatric hospital admissions were significantly more numerous for the case group. (2) The total outpatient expenditure, total inpatient expenditure, and total medical expenditure of the case group were NT$65,000, NT$170,000, and NT$235,000 significantly higher than those of the control group, respectively. Nonpsychiatric outpatient expenditure was significantly lower for the case group, but the inpatient and total nonpsychiatric medical expenditure were similar between groups. (3) Patients who were elder of low income, with complications, and high diabetes mellitus complication severity index had higher total numbers of outpatient visits and hospitalizations and medical expenditure. (4) Women had a higher number of outpatient visits but a lower number of hospitalization and medical expenditure. Lower non-psychiatric outpatient expenditure despite more visits indicated non-psychiatrist may not understand schizophrenia patients and cannot communicate well with them, leading to neglect of medical evaluation and treatment that should be carried out.

Beneficial effects of preoperative oral nutrition supplements on postoperative outcomes in geriatric hip fracture patients: A PRISMA-compliant systematic review and meta-analysis of randomized controlled studies.

BACKGROUND: Geriatric hip fracture patients often present malnutrition during admission, which leads to higher morbidity and mortality. Protein-based oral nutrition supplements may improve nutritional status. We conducted this systematic review and meta-analysis of randomized controlled trials (RCTs) according to the PRISMA guidelines to elucidate whether preoperative nutrition supplements can improve postoperative outcomes in geriatric hip fracture patients. METHODS: Only RCTs conducted to compare postoperative outcomes between geriatric hip fracture patients (>60 years old) receiving preoperative oral protein-based nutrition supplement (ONS group) and those who receiving regular diet (Control group) were included. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched from inception until August, 2021. Postoperative outcomes, including complications, length of hospital stay, and in-hospital mortality, were assessed. RESULTS: A total of 5 RCTs with 654 geriatric hip fracture patients (ONS group: 320 subjects; Control group 334 subjects) were included. Our data revealed that postoperative complications risk in the ONS group was significantly lower than in the Control group (odd's ratio: 0.48, 95% confidence intervals [CI]: 0.26-0.89, P = .02, I2 = 64%). However, no significant differences in the length of hospital stay (standardized mean difference: -0.35 days, 95% CI: -1.68 to 0.98 days, P = .61, I2 = 0%) and the risk of having postoperative in-hospital mortality (odd's ratio: 1.07, 95% CI: 0.43-2.63, P = .89, I2 = 54%) between these 2 groups were observed. Quality assessment revealed high risk of bias and significant data heterogeneity (I2>50%) in most included RCTs. CONCLUSION: Preoperative protein-based oral nutrition supplements exert beneficial, but limited, effects on postoperative outcomes in geriatric patients with hip fracture undergoing surgery.

Rutaecarpine, an Alkaloid from Evodia rutaecarpa, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3ß Signal Axis through a Cyclic Nucleotides/VASP-Independent Mechanism.

The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1-5 µM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca2+]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3ß (GSK3ß) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3ß pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders.

Bio-inspired zwitterionic polymeric chelating assembly for treatment of copper-induced cytotoxicity and hemolysis.

We developed a hemocompatible, bio-inspired, multivalent, polymeric-chelating assembly based on the poly(2-methacryloyloxyethyl phosphorylcholine)-b-poly(serinyl acrylate) (PMPC-b-PserA) zwitterionic diblock copolymer. Functional PMPC-b-PserA was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization to catch and encapsulate free copper ions (Cu2+) in a solution. PMPC with an identical polar group to phospholipids exhibits high hydrophilicity and fouling resistance against non-specific adsorption, and inertness to the metal ions. On the other hand, PserA with pendant groups of amino acids possesses a strong capability to react with Cu2+ by coordination interaction. Therefore, when PMPC-b-PserA was brought into contact with Cu2+, a hydrophobic core with multiple coordination "bridges" between polymers and Cu2+ was formed, leading to self-assembly of core-shell polymer-metal nanoparticles. As a result, free Cu2+ ions can be removed from the solution to prevent damage to cells and tissues. The synthesis and chemical structure of PMPC-b-PserA were characterized, and the formation of self-assembled polymer-Cu2+ nanoparticles and colloidal stability were analyzed. More importantly, the detoxification of PMPC-b-PserA in presence of Cu2+ with fibroblast cells was demonstrated by increased cell viability >80%. In addition, the hemolysis, which occurred due to disruption of RBC membranes by free Cu2+, was effectively suppressed by adding PMPC-b-PserA. The bio-inspired and biocompatible chelating agent of PMPC-b-PserA provides a new treatment approach to encapsulate and detoxify heavy metals in complex media for chelation therapy.

Therapeutic effect of modulating the NLRP3-regulated transforming growth factor-ß signaling pathway on interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder with complex pathogenesis and lacks effective treatment. Chronic inflammation is the main pathogenesis of Hunner-type IC/BPS. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome-related transforming growth factor-ß (TGF-ß)/Smad signaling pathway plays a crucial role in inflammation-related tissue fibrosis. Lipopolysaccharide (LPS) and protamine sulfate (LPS/PS) were instilled into the mouse bladder twice a week for 5 consecutive weeks to establish a chronic inflammation-induced IC/BPS model (LPS/PS model). Following LPS/PS treatment, curcumin (oral, 100 mg/kg; a potent NLRP3 modulator) was administered for 2 weeks in the curcumin treatment group, and normal saline was used for the sham group. Bladder function was evaluated by performing the voiding spot assay and examining the status of urothelial denudation and fibrosis in bladder tissues. The expression of NLRP3 inflammasome, interleukin-1ß, TGF-ß, Smad, vimentin, and E-cadherin in bladder tissues was evaluated through immunohistochemistry staining. Results revealed that the repeated instillation of LPS/PS leads to voiding dysfunction, bladder urothelium denudation, and detrusor muscle fibrosis through the upregulation of the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway and the increased epithelial-mesenchymal transition process in bladder tissues. The downregulation of the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway in bladder tissues through curcumin effectively mitigated bladder injury in the LPS/PS model. In conclusion, the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway plays a crucial role in bladder injury in the LPS/PS model, and modulation of this pathway, such as by using curcumin, can effectively mitigate the sequelae of chronic inflammation-induced IC/BPS.

Platonin mitigates vascular hyporeactivity of thoracic aorta in septic rats.

BACKGROUND: Vascular hyporeactivity contributes to hemodynamic alterations and circulatory failure in severe sepsis. Among the identified mechanisms, inflammation and oxidative stress are the most crucial ones in mediating the development of vascular hyporeactivity induced by sepsis. Platonin, a photosensitive dye and an antioxidant, possesses potent antiinflammation effects. We elucidated whether platonin could mitigate vascular hyporeactivity of thoracic aorta in septic rats. MATERIAL AND METHODS: Adult male Sprague-Dawley rats were randomized to receive sham operation (Sham), Sham plus platonin (100 µg/kg), cecal ligation and puncture (CLP), or CLP plus platonin (10, 50, or 100 µg/kg) and designated as the Sham, P, CLP, CLP + P(10), CLP + P(50), and CLP + P(100) group, respectively (n = 6 in each group). After maintaining for 12 hours, surviving rats were euthanized and thoracic aorta was isolated and vascular reactivity of aortic rings was determined. RESULTS: Vascular reactivity induced by vasoconstrictors phenylephrine and angiotensin II of the Sham and the P groups (n = 6 in both groups) were similar, whereas vascular reactivity of the CLP group (n = 5) were significantly lower than those of the Sham group (both P < 0.001). Of note, vascular reactivity induced by phenylephrine and angiotensin II of the CLP + P(10) group (n = 5) and the CLP group were not significantly different. In contrast, vascular reactivity induced by phenylephrine and angiotensin II of the CLP + P(50) and the CLP + P(100) groups (n = 6 in both groups) were significantly higher than those of the CLP group (phenylephrine: P = 0.024 and 0.017; angiotensin II: P = 0.031 and 0.036). CONCLUSION: Platonin could mitigate vascular hyporeactivity of thoracic aorta in septic rats.

Hyperlipidemia is associated with an increased risk of clinical benign prostatic hyperplasia.

BACKGROUND: A high fat diet is associated with risk of benign prostatic hyperplasia (BPH). However, whether hyperlipidemia is associated with BPH remains unclear. This population-based cohort study elucidated whether hyperlipidemia is associated with an increased risk of BPH. METHODS: We used a new-exposure design and analyzed data retrieved from the Taiwan National Health Insurance Database between January 1, 2000 and December 31, 2013. The cohort of men with newly diagnosed hyperlipidemia and the age- and index-date-matched (1:3) nonhyperlipidemia cohort were tracked for incidence of BPH during a 1- to 14-year follow-up. Diagnosis of BPH using the International Classification of Diseases, Ninth Revision, Clinical Modification codes, and the occurrence of BPH diagnosis plus the use of alpha-blockers or 5-alpha reductase inhibitors or receipt of transurethral resection of the prostate were the primary and secondary endpoints, respectively. The confounders in this study were diabetes mellitus, hypertension, coronary heart disease, obesity, liver cirrhosis, nonsteroidal anti-inflammatory drugs, metformin, aspirin, and number of urologist visits. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a multivariate Cox proportional hazards regression model adjusted for the propensity score. RESULTS: A total of 35 860 subjects (aged 40-99 years)-including the hyperlipidemia cohort (n = 8,965) and nonhyperlipidemia cohort (n = 26 895)-were identified. Our data revealed that the hyperlipidemia cohort had significantly higher incidences of developing BPH (24.6% vs 12.3%, P < 0.001) and treated BPH (13% vs 5.7%, P < 0.001) compared with the nonhyperlipidemia cohort. The risk of developing BPH in the hyperlipidemia cohort was significantly higher than that in the nonhyperlipidemia cohort (HR = 1.73, 95% CI = 1.63-1.83, P < 0.001) after adjustment for the propensity score. CONCLUSIONS: Hyperlipidemia is associated with an increased risk of clinical BPH.

Non-sticky and antimicrobial zwitterionic nanocomposite dressings for infected chronic wounds.

Zwitterionic poly(sulfobetaine acrylamide) (pSBAA)-based nanocomposite hydrogels impregnated with germicidal silver nanoparticles (AgNPs) were synthesized and implemented for the treatment of infected chronic wounds. The zwitterionic hydrogels exhibited excellent non-sticky properties and had reinforced mechanical properties by the addition of hectorite nanoclay and poly(ethylene glycol)dimethacrylate as physical and chemical crosslinkers, respectively. In addition, AgNPs were grown within the intercalated clay/polymer structure by in situ free radical reduction, as confirmed by UV-vis spectroscopy and transmission electron microscopy (TEM). The silver-containing pSBAA nanocomposite hydrogels (pSBAA/Ag) exhibited germicidal properties against Gram-positive S. epidermidis and Gram-negative P. aeruginosa. The zwitterionic hydrogels show higher water content than 2-hydroxyethyl methacrylate (pHEMA) hydrogels, owing to the strong hydration via ionic solvation. The negligible cytotoxicity of pSBAA/Ag hydrogels was assessed with human fibroblasts by the MTT assay. Moreover, the zwitterionic hydrogels demonstrated excellent resistance to the adsorption of bovine serum albumin (BSA). To evaluate the feasibility of the hydrogels for clinical application as wound dressings, we created infected diabetic rat models and compared with commercial wound dressings. The results show that pSBAA/Ag hydrogels did not adhere to the newly formed tissue, and were readily removed from the wounds after treatment for 3 days. Moreover, the healing recovery was evaluated by visual observation of infected dorsal wounds on rats with induction of diabetes by streptozotocin. The finding indicates complete healing with the pSBAA/Ag hydrogels after 15 days, faster than other dressings. A histological examination also proved that the zwitterionic hydrogels facilitated epithelialization and collagen distribution in the infected diabetic wounds. Consequently, these novel non-sticky and antimicrobial zwitterionic nanocomposite hydrogels can have high potential for the treatment of infected chronic wounds.

Surface modification with zwitterionic cysteine betaine for nanoshell-assisted near-infrared plasmonic hyperthermia.

Nanoparticles decorated with biocompatible coatings have received considerable attention in recent years for their potential biomedical applications. However, the desirable properties of nanoparticles for in vivo uses, such as colloidal stability, biodistribution, and pharmacokinetics, require further research. In this work, we report a bio-derived zwitterionic surface ligand, cysteine betaine (Cys-b) for the modification of hollow gold-silver nanoshells, giving rise to hyperthermia applications. Cys-b coatings on planar substrates and nanoshells were compared to conventional (11-mercaptoundecyl)tri(ethylene glycol) (OEG-thiol) to investigate their effects on the fouling resistance, colloidal stability, environmental tolerance, and photothermal properties. The results found that Cys-b and OEG-thiol coatings exhibited comparable antifouling properties against bacteria of gram-negative Pseudomonas aeruginosa (P. aeruginosa) and gram-positive Staphylococcus epidermidis (S. epidermidis), NIH-3T3 fibroblasts, and bovine serum albumin. However, when the modified nanoshells were suspended at a temperature of 50°C in aqueous 3M NaCl solutions, shifts in the extinction maximum of the OEG-capped nanoshells with time were observed, while the corresponding spectra of nanoshells capped with Cys-b generally remained unchanged. In addition, when the nanoshells were continuously exposed to NIR irradiation, the temperature of the solution containing nanoshells capped with Cys-b increased to a plateau of 54°C, while that of the OEG-capped nanoshells gradually decreased after reaching a peak temperature. Accordingly, the Cys-b nanoshells were conjugated with anti-HER2 antibodies for targeted delivery to HER2-positive MDA-MB-453 breast cancer cells for hyperthermia treatment. The results showed the selective delivery and effective photothermal cell ablation with the antibody-conjugated Cys-b nanoshells. Therefore, this work demonstrated the promise of bio-derived zwitterionic Cys-b as a stable and biocompatible surface coating for materials in nanomedicine.

The association between participation in a pay-for-performance program and macrovascular complications in patients with type 2 diabetes in Taiwan: A nationwide population-based cohort study.

OBJECTIVE: Diabetes and diabetes-related complications are major causes of morbidity and mortality worldwide and contribute substantially to health care costs. Proper care can prevent or delay vascular complications in people with type 2 diabetes. We sought to examine whether a diabetes pay-for-performance (P4P) program under Taiwan's National Health Insurance program decreased risk of macrovascular complications in type 2 diabetes patients, and associated risk factors. RESEARCH DESIGN AND METHOD: We conducted a longitudinal observational case and control cohort study using two nationwide population-based databases in Taiwan, 2007-2012. Type 2 diabetes patients with a primary diabetes diagnosis in year 2007 and 2008 were included. We excluded patients with any diabetes complications within 2years before the index date. A propensity score matching approach was used to determine comparable P4P and non-P4P groups. We followed each P4P and non-P4P patient until December 31, 2012. Complication incidence rates per 1000 person-years for each complication were calculated. RESULTS: Overall, our results indicated that P4P patients had lower risk of macrovascular complications than non-P4P patients. Specifically, hazard ratios (95% confidence intervals) were 0.84 (0.80-0.88) for stroke, 0.83 (0.75-0.92) for myocardial infarction, 0.72 (0.60-0.85) for atrial fibrillation, 0.93 (0.87-0.98) for heart failure, 0.61 (0.50-0.73) for gangrene, and 0.83 (0.74-0.93) for ulcer of lower limbs. CONCLUSIONS: Compared with patients not enrolled in the P4P program, P4P patients had lower risk of developing serious vascular complications. Our empirical findings provide evidence for the potential long-term benefit of P4P programs in reducing risks of macrovascular complications.

Salutary Effects of Cepharanthine against Skeletal Muscle and Kidney Injuries following Limb Ischemia/Reperfusion.

Limb ischemia/reperfusion (I/R) causes oxidation and inflammation and subsequently induces muscle and kidney injuries. Cepharanthine, a natural plant alkaloid, possesses anti-inflammatory and antioxidative properties. We elucidated the salutary effects of cepharanthine against muscle and kidney injuries following limb I/R. Adult male rats were randomized to receive I/R or I/R plus cepharanthine. I/R was achieved by applying tourniquet high around each thigh for 3 hours followed by reperfusion for 24 hours. Cepharanthine (10 mg/kg, intraperitoneal) was injected immediately before reperfusion. After euthanization, degrees of tissue injury, inflammation, and oxidation were examined. Our data revealed that the I/R group had significant increases in injury biomarker concentrations of muscle (creatine kinase and lactate dehydrogenase) and kidney (creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1). Histological assays revealed moderate muscle and kidney injury characteristics in the I/R group. The I/R group also had significant increases in concentrations of inflammatory molecules (interleukin-6, macrophage inflammatory protein-2, and prostaglandin E2) and reactive nitrogen species (nitric oxide) as well as lipid peroxidation (malondialdehyde). Of note, these effects of limb I/R could be mitigated by cepharanthine. These data confirmed that cepharanthine attenuated muscle and kidney injuries induced by limb I/R. The mechanisms may involve its anti-inflammatory and antioxidative capacities.

Cepharanthine mitigates lung injury in lower limb ischemia-reperfusion.

BACKGROUND: Oxidation and inflammation caused by lower limb ischemia-reperfusion (I/R) readily induce lung injury. We elucidated whether cepharanthine, a potent antioxidative and anti-inflammatory drug, can mitigate lung injury induced by lower limb I/R. Role of heme oxygenase 1 (HO-1) was also investigated. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were randomized to receive I/R, I/R plus cepharanthine, or I/R plus cepharanthine plus the HO-1 activity inhibitor tin protoporphyrin (SnPP; n = 12 in each group). Sham control groups were run simultaneously. I/R was induced by applying rubber band tourniquets high around each thigh for 3 h followed by reperfusion for 24 h. RESULTS: Rats receiving I/R had significant increases in concentrations of nitric oxide, malondialdehyde (lipid peroxidation marker), and inflammatory molecules (including interleukin 6, macrophage inflammatory protein 2, and prostaglandin E2) in plasma, and the lungs, indicating that I/R caused significant oxidation and inflammation in rats. Rats receiving I/R also had significant increases in concentration of phosphorylated inhibitor-κB, indicating that I/R caused significant nuclear factor κB activation. Assays of arterial blood gas, biochemistry, and histopathology confirmed that I/R-induced significant lung injury in rats. Cepharanthine significantly reduced the oxidation, inflammation, nuclear factor κB activation, and lung injury induced by I/R. Of note, cepharanthine significantly enhanced pulmonary HO-1 expression after I/R. Moreover, these previously mentioned effects of cepharanthine were partially reversed by inhibiting the activity of HO-1. CONCLUSIONS: Cepharanthine mitigates lung injury induced by bilateral lower limb I/R in rats. The mechanisms may involve its effects on reducing oxidation and inflammation. The mechanisms may also involve enhancing HO-1 expression.

Health care utilization and expenditures of persons with diabetes comorbid with anxiety disorder: a national population-based cohort study.

OBJECTIVE: The aim of this study was to investigate and compare health care utilization and expenditures between persons with diabetes comorbid with and without anxiety disorder in Taiwan. METHODS: Health care utilization and expenditures among persons with diabetes with and without comorbid anxiety disorder in the period 2000-2004 were examined using the Taiwan's National Health Insurance claims data. Health care utilization included outpatient visits and use of hospital inpatient services, while expenditures included outpatient, inpatient and total medical expenditures. General estimation equation (GEE) models were used to analyze the factors associated with outpatient visits and expenditures, and multiple logistic regression analysis was applied to identify factors associated with hospitalization. RESULTS: In the study period, the average number of annual outpatient visits was 43.11-50.37 and 29.82-31.42 for persons with diabetes comorbid with anxiety disorder and for those without anxiety disorder, respectively. The average annual total expenditure was NT$74,875-92,781 and NT$63,764-81,667, respectively. Controlling for covariates, the GEE models revealed that age and time were associated with outpatient visits. Income and time factor were associated with total expenditure. CONCLUSIONS: Health care utilization and expenditures for persons with diabetes with comorbid anxiety disorder are significantly higher than those without anxiety disorder. The factors associated with health care utilization and expenditures are age, income and time.

FTY720 mitigates torsion/detorsion-induced testicular injury in rats.

BACKGROUND: FTY720, a sphingosine-1-phosphate (S1P) receptor agonist, possesses potent anti-inflammation capacity. We evaluated the therapeutic potentials of FTY720 against testicular injury induced by testicular torsion and/or detorsion (T/D). MATERIALS AND METHODS: Young adult male Sprague-Dawley rats were allocated to receive T/D (the T/D group) and T/D plus FTY720 (4 mg/kg, the T/D-FTY group, n = 6 in each group). To investigate the possible roles of the S1P receptors, another group of rats received T/D plus FTY720 plus the potent S1P receptor antagonist VPC23019 (1 mg/kg, the T/D-FTY-VPC group, n = 6). FTY720 was administered immediately before testicular detorsion, and VPC23019 was administered 30 min before FTY720. Another set of rats that received sham operation, immediately followed by injection of normal saline, FTY720, or FTY720 plus VPC23019, served as control groups. Sham control groups were run simultaneously. After euthanization, levels of testicular injury were measured. RESULTS: Histologic findings revealed severe testicular injury changes in both the T/D and T/D-FTY-VPC groups and moderate testicular injury changes in the T/D-FTY group. In addition, malondialdehyde activity (oxidative status), concentration of interleukin-1ß (inflammation index), myeloperoxidase activity (neutrophil infiltration index), and wet-to-dry weight ratio (tissue edema index) of both the T/D and T/D-FTY-VPC groups were significantly higher than those of the T/D-FTY group. These data confirmed the protective effects of FTY720 against testicular T/D. Moreover, antagonizing the S1P receptors could reverse the protective effects of FTY720. CONCLUSIONS: FTY720 significantly mitigated testicular injury induced by testicular T/D. The mechanisms may involve activating the S1P receptors.

Simvastatin attenuates sepsis-induced blood-brain barrier integrity loss.

BACKGROUND: Systemic inflammation and oxidative stress are crucial in mediating blood-brain barrier (BBB) integrity loss during sepsis. Simvastatin possess potent anti-inflammation and antioxidation capacity. We sought to elucidate whether an acute bolus of simvastatin could mitigate BBB integrity loss in a rodent model of polymicrobial sepsis. METHODS: A total of 96 adult male rats (200-250 g) were randomized to receive cecal ligation and puncture (CLP), CLP plus simvastatin, sham operation, or sham operation plus simvastatin (n = 24 in each group). After maintaining for 24 h, BBB integrity in the surviving rats was determined. RESULTS: CLP significantly induced BBB integrity loss, as grading of Evans blue staining of the brains, BBB permeability to Evans blue dye, and brain edema levels in rats receiving CLP were significantly higher than those receiving sham operation. In contrast, grading of Evans blue staining (P = 0.020), BBB permeability to Evans blue dye (P = 0.031), and brain edema levels (P = 0.009) in rats receiving CLP plus simvastatin were significantly lower than those receiving CLP alone. Tight junction proteins claudin-3 and claudin-5 in endothelial cells are major structural components of BBB. Our data revealed that concentrations of claudin-3 and claudin-5 in rats receiving CLP were significantly lower than those receiving CLP plus simvastatin (P = 0.010 and 0.007). Immunohistochemistry further revealed significant fragmentation of claudin-3 and claudin-5 in rats receiving CLP. Moreover, levels of claudin-3 and claudin-5 fragmentation in rats receiving CLP plus simvastatin were significantly lower than those receiving CLP. CONCLUSIONS: Simvastatin mitigates BBB integrity loss in a rodent model of polymicrobial sepsis.

High-lipid enteral nutrition could partially mitigate inflammation but not lung injury in hemorrhagic shock rats.

BACKGROUND: Loss of gut barrier function is crucial in mediating lung injury induced by hemorrhagic shock/resuscitation (HS). High-lipid enteral nutrition (HL) can preserve gut barrier function. We hypothesized that HL could also mitigate HS-induced lung injury. MATERIALS AND METHODS: Forty-eight adult male rats were randomly assigned to one of four experimental groups: HS; HS-HL; Sham; Sham-HL. HS was induced by blood drawing and mean blood pressure was maintained at 40-45 mmHg for 120 min followed by resuscitation with re-infusion of exsanguinated blood/saline mixtures. HL gavage was performed at 45 min before blood drawing and at the end of resuscitation. RESULTS: Intestinal permeability of the HS group was significantly higher than that of the Sham group (P < 0.001). Pulmonary concentrations of malondialdehyde (lipid peroxidation) and inflammatory molecules, including prostaglandin E2, tumor necrosis factor-α, interleukin-6, and macrophage inflammatory protein-2, of the HS group were significantly higher than those of the Sham group. Histologic analyses, including histopathology, wet/dry weight ratio, and neutrophil infiltration revealed moderate lung injury in the HS group. In contrast, intestinal permeability (P < 0.001) and pulmonary concentrations of tumor necrosis factor-α and macrophage inflammatory protein-2 (P = 0.021 and 0.01) of the HS-HL group were significantly lower than those of the HS group. However, pulmonary concentrations of malondialdehyde, prostaglandin E2, and interleukin-6 of the HS-HL and HS groups were comparable. Moreover, histologic analyses also revealed moderate lung injury in the HS-HL group. CONCLUSIONS: High-lipid enteral nutrition significantly mitigated gut barrier loss and partially mitigated lung inflammation but not oxidation and lung injury in hemorrhagic shock/resuscitation rats.

Effects of antrodia camphorata on viability, apoptosis, and [Ca2+]i in PC3 human prostate cancer cells.

Antrodia camphorata (AC) has been used as a health supplement in Asia to control different cancers; however, the cellular mechanisms of its effects are unclear. The effect of AC on cultured human prostate cancer cells (PC3) has not been explored. This study examined the effect of AC on viability, apoptosis, mitogen-activated protein kinases (MAPKs) phosphorylation and Ca2+ handling in PC3 cells. AC at concentrations of 5-50 microg/ml did not affect cell viability, but at 100-200 microg/ml decreased viability and induced apoptosis in a concentration-dependent manner. AC at concentrations of 25-200 microg/ml did not alter basal [Ca2+]i, but at a concentration of 25 microg/ml decreased the [Ca2+]i increases induced by ATP, bradykinin, histamine and thapsigargin. ATP, bradykinin and histamine increased cell viability whereas thapsigargin decreased it. AC (25 microg/ml) pretreatment inhibited ATP-, bradykinin-, and histamine-induced enhancement on viability, but reversed thapsigargin-induced cytotoxicity. Immunoblotting showed that AC (200 microg/ml) did not induce the phosphorylation of ERK, JNK, and p38 MAPKs. Collectively, in PC3 cells, AC exerted multiple effects on viability and [Ca2+]i, caused apoptosis via pathways unrelated to [Ca2+]i signal and phosphorylation of ERK, JNK and p38 MAPKs.

Catheter-assisted transurethral resection of the prostate: a novel approach.

INTRODUCTION: The aim of the study was to compare the safety and efficacy of catheter-assisted transurethral resection of the prostate (TURP) with traditional TURP in the treatment of benign prostatic hyperplasia. MATERIALS AND METHODS: A total of 61 men were randomized to either catheter-assisted TURP (30 patients) or traditional TURP (31), both performed with a monopolar device. Measurements included the duration of Foley catheterization, length of hospital stay, symptom score and urinary flow rate. All patients were followed for at least 1 year after surgery. RESULTS: The catheter-assisted group had a significantly shorter operative time, duration of postoperative catheterization and length of stay. There were no significant differences in changes in serum sodium and hemoglobin level on postoperative day 1. At 1 year postoperatively, none of the patients suffered from urethral stricture and the 2 groups did not differ significantly in terms of prostatic volume, peak flow rate or International Prostate Symptom Score. CONCLUSIONS: Catheter-assisted TURP is safe and produced results at 1 year similar to traditional TURP. This new method for TURP appears to be a better and more effective approach than the traditional method, although a longer period of observation is needed to assess the durability of the results.

Reproducibility of morning blood pressure surge and its relation to blood pressure reactivity.

This study examined the stability of the morning blood pressure surge (MBPS) and its relation to blood pressure (BP) reactivity in untreated hypertensives. Thirty-six participants completed a stress task at baseline. Ambulatory BP monitoring was carried out three times on a weekday. The MBPS demonstrated small reproducibility and large coefficient of variation. The MBPS correlated with nighttime BP (p = 0.001) but not morning BP or BP reactivity. Dippers had greater MBPS than did nondippers (p < 0.05). The MBPS provides distinct information that is different from the BP response to mental stress.