Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer.

PURPOSE: Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. METHODS: PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. RESULTS: In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. CONCLUSION: Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer

Purpose Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. Methods PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. Results In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. Conclusion Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

Association between predator species richness and human hantavirus infection emergence in Brazil.

Hantavirus infection is a rodent-borne disease (RBD) transmitted by urine or feces (as the natural reservoirs) with an annual estimated worldwide incidence of ~150,000 cases. Previous ecological studies suggested that higher species richness of rodents could decrease the risk of RBDs in humans, because the regulatory pressure of predators could reduce contact among rodents, and between humans and rodents. Using surveillance data, we investigated the association of predator species richness with hantavirus infection emergence in 5562 Brazilian inland municipalities between 2007 and 2017. Multivariable logistic regression models were used for the analyses. Diurnal and non-diurnal predator species were independent explanatory variables in the models. Rodent species richness and demographic, socioeconomic, and environmental factors were used as covariates. During the study period, 1084 cases were reported in 429 municipalities. The results showed a reverse-U-shaped association between diurnal predator species richness and hantavirus infection emergence (odds ratio [OR] 0.463, 0.688, and 0.553 for the first [lowest], third, and fourth [highest] quartiles, respectively, using the second quartile as a reference), while higher non-diurnal predator species richness tended to be associated with higher emergence risk (OR 0.134, 1.065, and 2.708 for the first, third, and fourth quartiles, respectively). The difference in these associations illustrates the complexity of the effects of predator species richness on human RBDs, which require further investigation in follow-up studies. The results showed a close link between environmental factors and public health, emphasizing that the One Health concept should be employed to understand the dynamics of RBDs.

Reversal and Resumption of Antithrombotic Therapy in LVAD-Associated Intracranial Hemorrhage.

BACKGROUND: Little data exist regarding reversal and resumption of antithrombotics after left ventricular assist device (LVAD)-associated intracranial hemorrhage. METHODS: Prospectively collected data of LVAD patients with intracranial hemorrhage were reviewed. Coagulopathy reversal agents, antithrombotic regimens, and thrombotic (venous thromboembolism, ischemic stroke, myocardial infarction) and hemorrhagic (recurrent intracranial hemorrhage, gastrointestinal bleed, anemia requiring transfusion) complications were recorded. RESULTS: Of 405 patients, intracranial hemorrhage occurred in 39 (10%): 23 intracerebral hemorrhages, 10 subarachnoid hemorrhages, and 6 subdural hematomas. Of 27 patients who received antithrombotic reversal, 8 (30%) had inadequate coagulopathy reversal, and 3 of these patients had hemorrhage expansion or died before repeat imaging. One (4%) patient had a thrombotic complication (deep vein thrombosis). Antithrombotic therapy was resumed in 17 (100%) survivors in a median time 8 days for antiplatelet agents and 14 days for warfarin. Recurrent intracranial hemorrhage occurred within a median of 7 days of antithrombotic resumption, while ischemic stroke occurred in a median of 428 days. Patients who resumed antiplatelets alone (n = 4) had a trend toward more thrombotic events (1.37 versus 0.14 events/patient-year [EPPY]; p = 0.08), including more fatal thrombotic events (0.34 EPPY versus 0.08 EPPY; p = 0.89) compared with those resuming warfarin ± antiplatelet (n = 14). Nonfatal hemorrhage event rates were 0.34 EPPY in the warfarin ± antiplatelet versus 0 EPPY in the antiplatelet-alone group (p = 0.16). No fatal hemorrhagic events occurred. CONCLUSIONS: Reversal of anticoagulation appears safe after LVAD-associated intracranial hemorrhage, though inadequate reversal was common. Resumption of warfarin ± antiplatelet was associated with fewer fatal and nonfatal thrombotic events compared with antiplatelets alone, though more nonfatal hemorrhage events occurred.

Damage control of caval injuries in a porcine model using a retrievable Rescue stent.

OBJECTIVE: Early hemorrhage control before the operating room is essential to reduce the significant mortality associated with traumatic injuries of the vena cava. Conventional approaches present logistical challenges on the battlefield or in the trauma bay. A retrievable stent graft would allow rapid hemorrhage control in the preoperative setting when endovascular expertise is not immediately available and without committing a patient to the limitations of current permanent stents. This study details a refined retrievable Rescue stent for percutaneous delivery that was examined in a porcine survival model of penetrating caval hemorrhage. METHODS: A retrievable caval stent was reduced in delivery profile to a 9F sheath using finite element analysis. The final stent was constructed with a "petal and stem" design using nitinol wire followed by covering with polytetrafluoroethylene. Seven Yorkshire pigs (79-86 kg) underwent 22F injury of the infrarenal vena cava with intentional class II hemorrhage (1200 mL). Percutaneous deployment of the Rescue stent was used to temporize hemorrhage for 60 minutes, followed by resuscitation with cell saver blood and permanent caval repair. Hemorrhage control was documented with photography and angiography. Vital signs were recorded and laboratory values were measured out to 48 hours postoperatively. Data were examined with a repeated-measures analysis of variance. RESULTS: The profile of the caval Rescue stent was successfully reduced from 16F to 9F while remaining within fracture and shape memory limits for nitinol. In addition, both rapid deployment and recapture were preserved. Following intentional hemorrhage after caval injury, animals revealed a significant drop in mean arterial pressure (average, 30 mm Hg), acidosis, and elevated lactate level compared with before injury. Compared with uncontrolled hemorrhage, which resulted in death in <9 minutes, the Rescue stent achieved hemorrhage control in <1 minute after venous access in all seven animals. All animals were successfully recovered after permanent repair. There was no significant change in levels of transaminases, bilirubin, creatinine, or hemoglobin at 48 hours compared with preinjury baseline. CONCLUSIONS: A retrievable Rescue stent achieved rapid percutaneous hemorrhage control after a significant traumatic injury of the vena cava and allowed successful recovery of all injured animals. Further development of this approach may have utility in preoperative damage control of caval injuries.

Correlation between overactive bladder symptom score and neuropsychological parameters in Alzheimer's disease patients with lower urinary tract symptom

ABSTRACT Purpose To examine an association between the overactive bladder symptom score (OABSS) and neuropsychological parameters. Moreover, we investigate the factors that affect each item in the questionnaire. Materials and Methods A total of 376 patients (males: 184; females: 192) with probable Alzheimer’s disease (AD) were recruited. Cognitive testing was conducted using the Mini Mental Status Examination (MMSE), Clinical Dementia Rating (CDR) scale, Global Deterioration Scale (GDS), and Barthel Activities of Daily Living (ADL). Lower urinary tract symptom (LUTS) was assessed using OABSS and voiding diary. Results The prevalence of overactive bladder (OAB) (defined as OABSS ≥3 with an urgency score of ≥2) in patients with AD was 72.6%. Among the OAB subjects, the most common severity of symptom was moderate (72.6%), followed by mild (21.2%), and severe (5.8%). It was found that OABSS had a very high correlation with aging (r=0.75; p<0.001). When compared with neuropsychological parameters, it was found that OABSS was highly correlated with the CDR scores (r=0.446; p<0.001). However, no significant correlation was found between the changes in OABSS scores and those in other neuropsychological parameters. Based on the individual symptom scores, urgency incontinence was highly correlated with the CDR scores (r=0.43; p<0.001). Conclusions OABSS is a useful tool in assessing AD patients with LUTS. There was a consistent positive association between OABSS severity, including urgency incontinence, and CDR scores.

Correlation between overactive bladder symptom score and neuropsychological parameters in Alzheimer's disease patients with lower urinary tract symptom.

PURPOSE: To examine an association between the overactive bladder symptom score (OABSS) and neuropsychological parameters. Moreover, we investigate the factors that affect each item in the questionnaire. MATERIALS AND METHODS: A total of 376 patients (males: 184; females: 192) with probable Alzheimer's disease (AD) were recruited. Cognitive testing was conducted using the Mini Mental Status Examination (MMSE), Clinical Dementia Rating (CDR) scale, Global Deterioration Scale (GDS), and Barthel Activities of Daily Living (ADL). Lower urinary tract symptom (LUTS) was assessed using OABSS and voiding diary. RESULTS: The prevalence of overactive bladder (OAB) (defined as OABSS ≥3 with na urgency score of ≥2) in patients with AD was 72.6%. Among the OAB subjects, the most common severity of symptom was moderate (72.6%), followed by mild (21.2%), and severe (5.8%). It was found that OABSS had a very high correlation with aging (r=0.75; p<0.001). When compared with neuropsychological parameters, it was found that OABSS was highly correlated with the CDR scores (r=0.446; p<0.001). However, no significant correlation was found between the changes in OABSS scores and those in other neuropsychological parameters. Based on the individual symptom scores, urgency incontinence was highly correlated with the CDR scores (r=0.43; p<0.001). CONCLUSIONS: OABSS is a useful tool in assessing AD patients with LUTS. There was a consistent positive association between OABSS severity, including urgency incontinence, and CDR scores.

Hemorheological and Glycemic Parameters and HDL Cholesterol for the Prediction of Cardiovascular Events / Parâmetros Hemorreológicos e Glicêmicos e HDL- Colesterol para a Predição de Eventos Cardiovasculares

Abstract Background: Hemorheological and glycemic parameters and high density lipoprotein (HDL) cholesterol are used as biomarkers of atherosclerosis and thrombosis. Objective: To investigate the association and clinical relevance of erythrocyte sedimentation rate (ESR), fibrinogen, fasting glucose, glycated hemoglobin (HbA1c), and HDL cholesterol in the prediction of major adverse cardiovascular events (MACE) and coronary heart disease (CHD) in an outpatient population. Methods: 708 stable patients who visited the outpatient department were enrolled and followed for a mean period of 28.5 months. Patients were divided into two groups, patients without MACE and patients with MACE, which included cardiac death, acute myocardial infarction, newly diagnosed CHD, and cerebral vascular accident. We compared hemorheological and glycemic parameters and lipid profiles between the groups. Results: Patients with MACE had significantly higher ESR, fibrinogen, fasting glucose, and HbA1c, while lower HDL cholesterol compared with patients without MACE. High ESR and fibrinogen and low HDL cholesterol significantly increased the risk of MACE in multivariate regression analysis. In patients with MACE, high fibrinogen and HbA1c levels increased the risk of multivessel CHD. Furthermore, ESR and fibrinogen were significantly positively correlated with HbA1c and negatively correlated with HDL cholesterol, however not correlated with fasting glucose. Conclusion: Hemorheological abnormalities, poor glycemic control, and low HDL cholesterol are correlated with each other and could serve as simple and useful surrogate markers and predictors for MACE and CHD in outpatients.

Resumo Fundamento: Parâmetros hemorreológicos e glicêmicos e o HDL-colesterol são utilizados como biomarcadores da aterosclerose e trombose. Objetivo: Investigar a associação e a relevância clínica da velocidade de hemossedimentação (VHS), fibrinogênio, glicose de jejum, hemoglobina glicada (HbA1c) e HDL-colesterol na predição de eventos adversos cardiovasculares (EAC) importantes em pacientes ambulatoriais. Métodos: 708 pacientes estáveis ambulatoriais foram incluídos no estudo e acompanhados por um período médio de 28,5 meses. Os pacientes foram subdivididos em pacientes sem EAC e pacientes com EAC, que incluíram morte súbita cardíaca, infarto agudo do miocárdio, doença coronariana recém-diagnosticada, e acidente vascular cerebral. Comparamos os parâmetros hemorreológicos, glicêmicos, e perfis lipídicos entre os grupos. Resultados: Pacientes com EAC apresentaram níveis significativamente mais elevados de VHS, fibrinogênio, glicose de jejum, e HbA1c, e níveis mais baixos de HDL-colesterol em comparação a pacientes sem EAC. VHS e níveis de fibrinogênio elevados, e baixos níveis de HDL-colesterol aumentaram significativamente o risco de EAC em análise de regressão multivariada. Além disso, VHS e fibrinogênio correlacionaram-se positivamente com HbA1c e negativamente com HDL-colesterol, mas não se correlacionaram com glicose de jejum. Conclusão: Distúrbios hemorreológicos, baixo controle glicêmico e baixo nível de HDL-colesterol correlacionam-se entre si e podem ser usados como marcadores substitutos simples, úteis, e como preditores de EAC e doença coronariana em pacientes ambulatoriais.

Hemorheological and Glycemic Parameters and HDL Cholesterol for the Prediction of Cardiovascular Events.

BACKGROUND: Hemorheological and glycemic parameters and high density lipoprotein (HDL) cholesterol are used as biomarkers of atherosclerosis and thrombosis. OBJECTIVE: To investigate the association and clinical relevance of erythrocyte sedimentation rate (ESR), fibrinogen, fasting glucose, glycated hemoglobin (HbA1c), and HDL cholesterol in the prediction of major adverse cardiovascular events (MACE) and coronary heart disease (CHD) in an outpatient population. METHODS: 708 stable patients who visited the outpatient department were enrolled and followed for a mean period of 28.5 months. Patients were divided into two groups, patients without MACE and patients with MACE, which included cardiac death, acute myocardial infarction, newly diagnosed CHD, and cerebral vascular accident. We compared hemorheological and glycemic parameters and lipid profiles between the groups. RESULTS: Patients with MACE had significantly higher ESR, fibrinogen, fasting glucose, and HbA1c, while lower HDL cholesterol compared with patients without MACE. High ESR and fibrinogen and low HDL cholesterol significantly increased the risk of MACE in multivariate regression analysis. In patients with MACE, high fibrinogen and HbA1c levels increased the risk of multivessel CHD. Furthermore, ESR and fibrinogen were significantly positively correlated with HbA1c and negatively correlated with HDL cholesterol, however not correlated with fasting glucose. CONCLUSION: Hemorheological abnormalities, poor glycemic control, and low HDL cholesterol are correlated with each other and could serve as simple and useful surrogate markers and predictors for MACE and CHD in outpatients.

Patients lost to follow-up after midurethral sling surgery: How are they?

Purpose To assess the ratio of patients lost to follow-up (FU) after midurethral sling surgery, to evaluate their success rate and current status, and to identify the reasons for FU loss. Materials and Methods Two-hundred thirty-eight patients who received trans-obturator tape (TOT) surgery were reviewed. For patients lost to FU within 3 months, Stamey’s outcome questionnaire and questions regarding the reasons for FU loss were submitted via phone interview. Results One hundred forty-three (60.1%) patients (FU loss group) were lost to FU within 3 months postoperatively. In the FU loss group, phone interviews were conducted with 117 (81.8%) patients. Aside from the urgency rate (59.3% vs. 72.3%, p=0.049), there were no significant statistical differences in preoperative profiles between two group. The success rate of the FU loss group (80.3%, 94 of 117 patients) was lower than that of the FU group (95.8%, 91 of 95 patients) (p=0.001). The success rates in the FU loss group with mixed urinary incontinence (MUI) were significantly lower than in the FU group with MUI. As for the reason for FU loss, 74 patients (62.7%) were lost due to incontinence improvement, 19 patients (16.1%) cited personal problems, and 5 patients forgot the next follow-up date. Only 10 patients gave up further treatment despite their persisting incontinence. Conclusions In our study, more than half of patients were lost to follow-up after midurethral sling surgery. The FU loss group showed a lower surgical success rate, particularly with MUI. Close FU is recommended for better consultation of patients’ incontinence. .

Patients lost to follow-up after midurethral sling surgery: how are they?

PURPOSE: To assess the ratio of patients lost to follow-up (FU) after midurethral sling surgery, to evaluate their success rate and current status, and to identify the reasons for FU loss. MATERIALS AND METHODS: Two-hundred thirty-eight patients who received trans-obturator tape (TOT) surgery were reviewed. For patients lost to FU within 3 months, Stamey's outcome questionnaire and questions regarding the reasons for FU loss were submitted via phone interview. RESULTS: One hundred forty-three (60.1%) patients (FU loss group) were lost to FU within 3 months postoperatively. In the FU loss group, phone interviews were conducted with 117 (81.8%) patients. Aside from the urgency rate (59.3% vs. 72.3%, p=0.049), there were no significant statistical differences in preoperative profiles between two group. The success rate of the FU loss group (80.3%, 94 of 117 patients) was lower than that of the FU group (95.8%, 91 of 95 patients) (p=0.001). The success rates in the FU loss group with mixed urinary incontinence (MUI) were significantly lower than in the FU group with MUI. As for the reason for FU loss, 74 patients (62.7%) were lost due to incontinence improvement, 19 patients (16.1%) cited personal problems, and 5 patients forgot the next follow-up date. Only 10 patients gave up further treatment despite their persisting incontinence. CONCLUSIONS: In our study, more than half of patients were lost to follow-up after midurethral sling surgery. The FU loss group showed a lower surgical success rate, particularly with MUI. Close FU is recommended for better consultation of patients ' incontinence.

Clinical risk factors for Clostridium difficile-associated diseases.

Many factors appear to influence the chance of acquiring Clostridium difficile (C. difficile) infection, and an accurate identification of risk factors could be beneficial in many ways. Thus, in the present study, clinical risk factors for C. difficile-associated disease (CDAD) in Korea were identified. A total of 93 patients who met the inclusion criteria and 186 age/gender/ward/admission period-matched control patients were included in this study. Statistically significant associations were found with presence of chronic lung diseases (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.25-9.32; p = 0.017), presence of ileus (OR, 10.05; 95% CI, 2.42-41.80; p = 0.001), presence of intensive care unit (ICU) stay (OR, 9.79; 95% CI, 3.03-31.68; p < 0.001), use of cephalosphorins (OR, 3.30; 95% CI, 1.13-9.62; p = 0.029), history of surgery (OR, 10.89; 95% CI, 3.96-29.92; p < 0.001), and history of long-term care facility stay (OR, 14.90; 95% CI, 4.02-55.26; p < 0.001). Awareness of CDAD is critical to provide appropriate clinical care. Surveillance of the national incidence rate and multicenter studies are needed, and the potential value of a C. difficile vaccine should be studied.

Clinical risk factors for Clostridium difficile-associated diseases

Many factors appear to influence the chance of acquiring Clostridium difficile (C. difficile) infection, and an accurate identification of risk factors could be beneficial in many ways. Thus, in the present study, clinical risk factors for C. difficile-associated disease (CDAD) in Korea were identified. A total of 93 patients who met the inclusion criteria and 186 age/gender/ward/admission period-matched control patients were included in this study. Statistically significant associations were found with presence of chronic lung diseases (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.25-9.32; p = 0.017), presence of ileus (OR, 10.05; 95% CI, 2.42-41.80; p = 0.001), presence of intensive care unit (ICU) stay (OR, 9.79; 95% CI, 3.03-31.68; p < 0.001), use of cephalosphorins (OR, 3.30; 95% CI, 1.13-9.62; p = 0.029), history of surgery (OR, 10.89; 95% CI, 3.96-29.92; p < 0.001), and history of long-term care facility stay (OR, 14.90; 95% CI, 4.02-55.26; p < 0.001). Awareness of CDAD is critical to provide appropriate clinical care. Surveillance of the national incidence rate and multicenter studies are needed, and the potential value of a C. difficile vaccine should be studied.