The impact of icodextrin on the outcomes of incident peritoneal dialysis patients.

OBJECTIVE: The aim of the study is to investigate the effects of icodextrin on the risks of death, technique failure and the first episode of peritonitis in peritoneal dialysis (PD) patients. METHODS: From medical records of a medical center in Taiwan, a total of 725 newly diagnosed end-stage kidney disease patients receiving PD for at least 90 days from January 1, 2007 to December 31, 2018 were identified. These patients were grouped as 190 icodextrin users and 535 non-users. Users were defined as utilization of icodextrin for ≥ 50% of their PD duration. The use of icodextrin was considered a time-varying exposure in the Cox proportional hazard model. The risks of death, technique failure and the first episode of peritonitis were compared between two cohorts by the end of 2018. RESULTS: Compared to the non-users, the icodextrin users had significant lower risks of mortality (6.5 vs.7.2 per 100 person-years; adjusted HR = 0.62, 95% CI = 0.42-0.91) and technique failure (12.7 vs. 15.2 per 100 person-years; adjusted HR = 0.61, 95% CI = 0.47-0.81), and the first peritonitis episode (5.0 vs. 17.0 per 100 person-years; adjusted HR = 0.22, 95% CI = 0.14-0.35). The risk of peritonitis reduced further in icodextrin users with diabetes and with cardiovascular disease. CONCLUSION: Icodextrin was associated with lower risks of mortality, technique failure, and the first episode of peritonitis.

Risk of Diabetic Retinopathy in Patients With Type 2 Diabetes After SGLT-2 Inhibitors: A Nationwide Population Cohort Study.

Diabetic retinopathy (DR) accounts for 80% of cases of vision loss in patients with type 2 diabetes mellitus (T2DM). Interventional treatments are only indicated in advanced DR and are ineffective in some patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are used to attenuate T2DM-associated cardiovascular complications. We conducted the cohort study to investigate the effect of SGLT2is on DR development. Data (May 2016-December 2018) obtained from the Taiwan National Health Insurance Research Database were analyzed in this nationwide retrospective cohort study. After propensity score matching, a total of 31,764 patients receiving SGLT2is and another 31,764 patients receiving dipeptidyl peptidase 4 inhibitors (DPP4is) were included in this study. Multiple Cox proportional-hazards regression models were used to evaluate DR risk. Overall DR incidence among SGLT2i or DPP4i users was 10.9 or 15.6 per 10,000 patient-years, respectively. After covariate adjustment, DR (both early and late stage) risk was substantially lower in SGLT2i users (adjusted hazard ratio: 0.68, 95% confidence interval: 0.6-0.78) than in DPP4i users. DR risk appears to be considerably lower in SGLT2i users than in DPP4i users. Glycemic control measurement with HbA1C level was unavailable in this claim database.

Association of urinary liver-type fatty acid-binding protein with outcomes after adrenalectomy for unilateral primary aldosteronism.

BACKGROUND AND AIMS: This study explored the association between urinary liver-type fatty acid-binding protein to creatinine (uL-FABP-cre) ratio and postoperative clinical failure in unilateral primary aldosteronism (PA) patients undergoing adrenalectomy. MATERIALS AND METHODS: Data from the Taiwan Primary Aldosteronism Investigation Group database were analyzed, including patients with unilateral PA who had adrenalectomy between December 2015 and October 2018. Statistical methods included generalized additive modeling, logistic regression analysis, net reclassification improvement (NRI), and the C statistic. RESULTS: In the study cohort of 131 patients (mean age 52.3 ± 10.8 years; 43.5% male), 117 achieved clinical success, while 14 experienced clinical failure. A uL-FABP-cre ratio ≥5 predicted clinical failure (odds ratio: 6.22, p = 0.005). Subgroup analysis revealed its efficacy in predicting clinical failure in patients with BMI ≥ 24 kg/m2, normokalemia, or <5 years of hypertension. Furthermore, incorporating uL-FABP-cre ratio into the Primary Aldosteronism Surgical Outcome (PASO) score significantly improved predictive ability. The addition increased the C statistic from 0.671 to 0.762 (p < 0.01) and improved category-free NRI by 0.675 (p = 0.014). CONCLUSION: A uL-FABP-cre ratio ≥5 accurately predicted clinical failure post-adrenalectomy in unilateral PA, enhancing PASO score's identification of high-risk patients for postoperative clinical failure.

Denosumab treatment and infection risks in patients with osteoporosis: propensity score matching analysis of a national-wide population-based cohort study.

Introduction: Denosumab demonstrates efficacy in reducing the incidence of hip, vertebral, and nonvertebral fractures in postmenopausal women with osteoporosis. We present a population-based national cohort study to evaluate the infection risks in patients with osteoporosis after long-term denosumab therapy. Methods: We used the Taiwan National Health Insurance Research Database (NHIRD) to identify patients with osteoporosis. The case cohort comprised patients treated with denosumab. Propensity score (PS) matching was used to select denosumab nonusers for the control cohort. The study period was between August 2011 and December 2017. Our study comprised 30,106 pairs of case and control patients. Results: Patients receiving denosumab therapy had high risks of the following infections: pneumonia and influenza (adjusted hazard ratio [aHR]: 1.33; 95% confidence interval [CI]: 1.27 -1.39), urinary tract infection (aHR: 1.36; 95% CI:1.32 -1.40), tuberculosis (aHR: 1.60; 95% CI: 1.36 -1.87), fungal infection (aHR: 1.67; 95% CI:1.46 -1.90), candidiasis (aHR: 1.68; 95% CI: 1.47 -1.93), herpes zoster infection (aHR: 1.27; 95% CI: 1.19 -1.35), sepsis (aHR: 1.54; 95% CI:1.43 -1.66), and death (aHR: 1.26; 95% CI: 1.20 -1.32). However, the longer the duration of denosumab treatment, the lower the risk patients had of developing infections. Discussion: Denosumab therapy is associated with a higher infection risk at the early periods of treatment. Nevertheless, the risk attenuates significantly after the 2nd year of therapy. Clinicians should closely monitor infection status in patients with osteoporosis during the initial stages of denosumab therapy.

Outcomes and Effects of Vaccination on Sars-Cov-2 Omicron Infection in Kidney Transplant Recipients.

BACKGROUND: Kidney transplant recipients (KTRs) are at high risk of COVID-19. Vaccination is significantly effective at preventing infection and reducing infection severity. Omicron infections are less severe than infections by previous strains, but breakthrough disease is more common. Thus, we conducted this study to observe the vaccine efficacy in our KTRs. METHODS: During the surge in the Omicron variant, beginning in May 2022, we retrieved data from 365 KTRs who had received at least one dose of various COVID vaccines until June 30, 2022. Outcomes of the KTRs (n = 168) after at least the 2nd vaccination were assessed until September 30, 2022, before the border was opened for tourism. RESULTS: The antibody response in KTRs after the 1st and 2nd doses of SARS-CoV-2 vaccines demonstrated a significant increase from the 1st dose (median: 0.4; IQR: 0.4-8.4 U/mL, P < .001) to the 2nd dose (median: 57.5; IQR: 0.4-799.2 U/mL), and the response rate rose from 32% to 65% (P < .001). SARS-CoV-2 infection was identified in 14/365 (3.8%) patients after at least the 1st dose and 7/187 (3.7%) patients at least 7 days beyond the 2nd dose. Most KTRs had a mild course, but 3 (17%) were hospitalized due to pneumonia. CONCLUSIONS: Our data demonstrate a lower response rate and anti-S titers after 2nd dose vaccination in KTRs than in the general population, but a lower incidence of SARS-CoV-2 infection after vaccination was observed during the Omicron outbreak. Owing to the breakthrough infections found in ordinarily vaccinated KTRs, we must emphasize the importance of vaccination and boosters to prevent severe illness, hospitalizations, and death among those developing infections.

Diagnosis and Management of Fabry Disease in High-Risk Renal Disease Patients in Taiwan: A Single Center Study.

BACKGROUND: Fabry disease (FD) is an X-linked inborn error of lysosomal storage disorder, a deficiency in lysosomal hydrolase α-galactosidase A activity due to pathogenic variants in the GLA gene. Accumulation of globotriaosylceramide in multiple organs contributes to end-stage kidney disease, heart failure, and cerebrovascular accidents. METHODS: We began the FD screening program by involving male patients older than 20 years of age who were on chronic dialysis, had a post-kidney transplantation, and were part of the Pre-End Stage Renal Disease Program in our hospital. α-galactosidase A activity was detected through an initial dried blood spots screen assay, followed by levels of lyso-globotriaosylceramide and sequencing of the GLA gene when screening patients with suspected FD to confirm their diagnosis. RESULTS: A total of 1812 patients had been FD screened, with the prevalence of FD being approximately 0.16 % (3/1812) up until June 2022. Interestingly, we confirmed a family cluster (2 sons and their mother) of having the c.936+919G>A mutation (designated GLA IVS4) with hypertrophic cardiomyopathy in Taiwan and another with the mutation c.644A>G (p.Asn215Ser), a more common later-onset variant reported in people of European or North American descent. Two patients were confirmed with cardiomyopathy through a cardiac biopsy, with their cardiac function later reversed after enzyme replacement therapy. CONCLUSIONS: The FD screening test detects chronic kidney disease due to an unknown etiology and prevents other organ complications. Early detection of FD is crucial for reversing target organ damage with enzyme replacement therapy.

Adverse Effects of Denosumab in Kidney Transplant Recipients: A 20-Year Retrospective Single-Center Observation Study in Central Taiwan.

BACKGROUND: Bone loss can be noted in kidney transplantation recipients (KTRs) and can be related to fracture events. Denosumab, a potent monoclonal antibody to RANK ligand, increases lumbar bone mineral density. However, safety data for denosumab remain limited regarding transplant recipients. Hypocalcemia and increased genital tract infections have been mentioned as adverse effects in KTRs after being prescribed denosumab. METHODS: We retrospectively analyzed the electronic medical records of KTRs during the recent 20 years who had been prescribed antiresorptive therapy and were >18 years old. Medical records and their clinical data were reviewed and analyzed. We compared the frequency of adverse effects between denosumab with other antiresorptive therapies. RESULTS: A total of 70 KTRs were enrolled, with 46 patients being given denosumab and the first injection being noted on October 31, 2014. No significant differences were seen in mortality rate, opportunistic infection, pneumonia, or genitourinary tract infection. One diagnosis of osteonecrosis of the jaw was noted in the denosumab group (2.2%). A higher incidence of hypocalcemia (<8.4 mg/dL) was noted in the denosumab group (34.8%), and a higher but nonsignificant difference in the incidence of severe hypocalcemia was also noted in the group. CONCLUSIONS: Denosumab may be considered as safe as other antiresorptive therapies for KTRs. However, more hypocalcemia events have been noted, so medical personnel may need to be cautious when prescribing its use.

Comparison of the risks of renal cell carcinoma or urothelial cancer between hemodialysis and peritoneal dialysis patients.

PURPOSE: This study is to compare risks of developing renal cell carcinoma or urothelial cancer between hemodialysis (HD) and peritoneal dialysis (PD) patients. METHODS: The age-, sex-, and index year-matched patients with newly diagnosed end-stage kidney disease (ESKD) undergoing dialysis [HD (N = 22,587) or PD (N = 11,547)] from 2000 to 2015 in Taiwan were identified. Patients were followed until the development of renal cell carcinoma or urothelial cancer, renal transplantation, death, or the end of follow-up (December 31, 2017). The hazard ratio (HR), and sub-hazards ratio (SHR), in which death was considered as a competing risk, of developing renal cell carcinoma or urothelial cancer were compared between the HD and PD patients. RESULTS: The incidence rate of renal cell carcinoma was higher in the PD group than in age-, sex-, and index year-matched HD group (11.5 versus 5.52 per 10,000 person-years), with an adjusted HR of 2.15 (95% confidence interval (CI) = 1.59, 2.92), and an adjusted SHR of 1.97 (95% CI = 1.46, 2.67). The incidence rate of urothelial cancer was also higher in the PD group than in corresponding HD group (40.3 and 34.0 per 10,000 person-years), with an adjusted HR of 1.15 (95% CI = 1.00, 1.33) and an adjusted SHR of 1.08 (95% CI = 0.94, 1.25). These findings were further validated in propensity score-matched dialysis cohorts. CONCLUSIONS: ESKD patients undergoing PD are at a higher risk of developing renal cell carcinoma than those on HD, but risks of developing urothelial cancer are similar among the two groups.

Risk of Severe Alphaherpesvirus Infection after Solid Organ Transplantation: A Nationwide Population-Based Cohort Study.

Patients after solid organ transplantation (SOT) are more susceptible to various viral infections, including alphaherpesviruses. Therefore, the aim of our study was to investigate the risk of alphaherpesvirus infections, including herpes simplex and herpes zoster, after solid organ transplantation. Inpatient records from the Taiwan National Health Insurance Research Database (NHIRD) defined solid organ recipients, including heart, liver, lung, and kidney, hospitalized for alphaherpesvirus infections as a severe case group of transplants and matched them with a nontransplant cohort. We enrolled 18,064 individuals, of whom 9032 were in each group. A higher risk of severe alphaherpesvirus infection was noted in solid organ recipients (aHR = 9.19; p < 0.001) than in the general population. In addition, solid organ transplant recipients had the highest risk of alphaherpesvirus infection within 1 year after transplantation (aHR = 25.18). The comparison found a higher risk of herpes zoster and herpes simplex infections in recipients of kidney (aHR = 9.13; aHR = 12.13), heart (aHR = 14.34; aHR = 18.54), and liver (aHR = 5.90; aHR = 8.28) transplants. Patients who underwent solid organ transplantation had a significantly higher risk of alphaherpesvirus infection than the general population.

Risk of Major Cardiovascular Disease after Exposure to Contrast Media: A Nationwide Population-Based Cohort Study on Dialysis Patients.

Contrast associated kidney injury is caused by side effects of iodinated contrast media (ICM), including inflammation. Chronic inflammation among dialysis patient contributes to atherosclerosis, which leads to simultaneous conditions of the kidney, brain, and vasculature. Data to investigate the pathologic effects of ICM on cardiovascular complications in dialysis patients are lacking. Dialysis patients who had been exposed to ICM from computed tomography (ICM-CT) were allocated as the ICM-CT cohort (N = 3751), whereas dialysis patients without ICM exposure were randomly allocated as the non-ICM cohort (N = 17,196). Furthermore, 540 pairs were selected for analyses through propensity score-matching in terms of age, sex, comorbidities, dialysis vintage, and index date. During a median follow-up of 10.3 years, ICM-CT cohort had significantly higher risks in the following, compared with non-ICM cohort: all-cause mortality (adjusted hazard ratio [aHR], 1.36; 95% confidence interval [CI], 1.26-1.47), cardiovascular events (aHR,1.67; 95% CI, 1.39-2.01), acute coronary syndrome (adjusted HR: 2.92; 95% CI, 1.72-4.94), sudden cardiac arrest (aHR, 1.69; 95% CI, 0.90-3.18), heart failure (aHR, 1.71; 95% CI,1.28-2.27), and stroke (aHR, 1.84; 95% CI,1.45-2.35). The proinflammatory ICM is significantly associated with an increased risk of major cardiovascular events in patients on dialysis.

Necroptosis: A Pathogenic Negotiator in Human Diseases.

Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.

Gender Differences in microRNA Expressions as Related to Long-Term Graft Function in Kidney Transplant Patients.

In recent studies, much has been discussed about biomarkers used in the evaluation of the transplanted graft function. However, there remains a lack of research regarding the long-term effects of microRNAs (miRNAs) on the different genders for kidney transplant (KTx) patients. In this study, we aim to assess the functions of miRNAs on long term outcomes of KTx patients by extracting differently expressed miRNAs between patients of normal graft function and graft dysfunction, while further analyzing their impact on the different genders. We analyzed the data of 40 patients who had received KTx for a period of more than ten years and included data regarding renal function, immuno-related markers and plasma miRNAs. Data were classified by gender for further studies. Twelve out of 17 females and 8 out of 23 males had undergone graft dysfunction. Renal function analysis showed significantly worse outcomes in the female patients. There were five differently expressed miRNAs between the female control group and female dysfunction group: miR-128-3p, miR-21-5p, miR-150-5p, miR-92a-3p and miR-15a-5p, and five between the male control group and male dysfunction group: miR-23a-3p, miR-126-3p, miR-142-3p, miR-223-3p and miR-26a-5p. Gender differences exist in incidences of kidney graft dysfunction, with male patients displaying better preservation in graft functions. Overall, these differently expressed miRNAs either enhance or suppress host immune responses. They can be predictive markers for graft survival and can also be important factors that lead to worse long term kidney graft function in females when compared to males.

Patterns of biopsy-proven renal diseases in geriatric patients: A single medical center experience.

The elderly population is expanding rapidly, and that has become a major healthcare burden in terms of chronic kidney disease. The distribution patterns of kidney diseases in these elderly patients remain largely unclear. Here, we compared biopsy-based renal disease patterns between elderly and nonelderly patients. We performed a single-center, retrospective study (1992-2008) on biopsy-proven renal diseases to compare results between geriatric patients (age ≥ 65 years; n = 254) and nongeriatric patients (18 ≤ age < 65 years; n = 2592). Renal pathology was interpreted by pathologists based on light microscopy, immunofluorescence, and electron microscopy. The ages of the geriatric and nongeriatric groups were 71.8 ±â€…4.5 (65.1-87.3) and 39.7 ±â€…17.6 (18-64.9) years, respectively, and 74% and 41% of them, respectively, were men. In the geriatric group, the most frequent diagnosis was membranous nephropathy (46.1%), followed by minimal change disease/focal segmental glomerulosclerosis (16.9%), diabetic nephropathy (8.3%), hypertensive nephrosclerosis (7.5%), and IgA nephropathy (5.9%). The geriatric group had more membranous nephropathy and less lupus nephritis and IgA nephropathy than the nongeriatric group. Furthermore, the 5-year survival rate of the geriatric group was significantly low. Our results demonstrated the different distributions of renal biopsy patterns in geriatric patients diagnosed with acute or chronic progressive kidney injury and proteinuria through renal biopsy.

A Fatal Case of Chlorfenapyr Poisoning and the Therapeutic Implications of Serum Chlorfenapyr and Tralopyril Levels.

Chlorfenapyr is a new contact and stomach insecticide derived from natural pyrroles secreted by Streptomyces spp. It is a pro-insecticide and acts after metabolic transformation to its active metabolite tralopyril. Tralopyril is an uncoupler of oxidative phosphorylation in the mitochondria of the target insects and of experiment animals, leading to the disruption of adenosine triphosphate synthesis and death. Several fatal human poisonings had been reported and no blood chlorfenapyr or tralopyril measurements were available. The treatment remains supportive. A 32-year-old healthy man ingested 200 mL of 10% chlorfenapyr as a suicide attempt. Unfortunately, he succumbed at 157 h post-ingestion, shortly after having fever and seizures. His serum level of chlorfenapyr at 4 h post-exposure was 77.4 ng/mL, and was undetectable at 113 and 156 h, respectively. The serum levels of tralopyril were 723.6, 14,179, and 9654.2 ng/mL at 4, 113, and 156 h post-ingestion, respectively. The delay in the rise of serum tralopyril levels was noticeable, which seems to correlate with the patient's signs and symptoms. The information may have therapeutic implications in the management of this deadly poisoning.

Risk of Dementia after Exposure to Contrast Media: A Nationwide, Population-Based Cohort Study.

Contrast-medium-associated kidney injury is caused by the infusion of contrast media. Small vessel disease is significantly associated with various diseases, including simultaneous conditions of the kidney and brain, which are highly vulnerable to similar vascular damage and microvascular pathologies. Data to investigate the adverse effect of contrast media on the brain remain extremely lacking. In this study, 11,332,616 NHI enrollees were selected and divided into two groups, exposed and not exposed to a contrast medium during the observation period, from which 1,461,684 pairs were selected for analyses through matching in terms of age, sex, comorbidities, and frequency of outpatient visits during the previous year. In total, 1,461,684 patients exposed to a contrast medium and 1,461,684 controls not exposed to one were enrolled. In multivariable Cox proportional hazard models, patients exposed to a contrast medium had an overall 2.09-fold higher risk of dementia. In multivariable-stratified analyses, the risk of Alzheimer's disease was remarkably high in younger patients without any underlying comorbidity. This study is the first to discover that exposure to contrast media is significantly associated with the risk of dementia. A four-fold increased risk of vascular dementia was observed after exposure to a contrast medium. Further studies on the influence of exposure to contrast media on the brain are warranted.

Early Comprehensive Kidney Care in Dialysis-Requiring Acute Kidney Injury Survivors: A Populational Study.

Background: For patients with Acute Kidney Injury (AKI), a strong and graded relationship exists between AKI severity and mortality. One of the most severe entities of AKI is Dialysis-Requiring Acute Kidney Injury (D-AKI), which is associated with high rates of mortality and end-stage renal disease (ESRD). For this high-risk population group, there is a lack of evidence regarding optimal post-AKI care. We propose that post-AKI care through the combined efforts of the nephrologist and the multidisciplinary care team may improve outcomes. Our aim here is to study for survivors of dialysis-requiring acute kidney injury, the effects of implementing early comprehensive kidney care. Methods: This is a retrospective longitudinal cohort study of Taiwanese through analyzing the National Health Insurance Research Database (NHIRD). We included patients with acute dialysis during hospitalization from January 1, 2015 to December 31, 2018. Propensity match was done at 1:1, including estimated glomerular filtration rate (eGFR) based on CKD-EPI which was performed due to large initial disparities between these two cohorts. Results: After the propensity match, each cohort had 4,988 patients. The mean eGFR based on CKD-EPI was 27.5 ml/min/1.73 m2, and the mean follow-up period was 1.4 years.The hazard ratio for chronic dialysis or ESRD was 0.55 (95% CI, 0.49-0.62; p < 0.001). The hazard ratio for all-cause mortality was 0.79 (95% CI, 0.57-0.88; p < 0.001). Both outcomes favored early comprehensive kidney care. Conclusions: For survivors of dialysis-requiring acute kidney injury, early comprehensive kidney care significantly lowered risks of chronic dialysis and all-cause mortality.

The impact of multidisciplinary pre-dialysis care on the outcomes of incident peritoneal dialysis patients.

BACKGROUND: This study aims to evaluate the impact of multidisciplinary pre-dialysis care (MDPC) on the risks of peritonitis, technique failure and mortality in peritoneal dialysis (PD) patients. METHODS: Incident end-stage kidney disease patients who received peritoneal dialysis (PD) for more than 90 days were recruited in this study from 1 January 1, 2007 to December 31, 2018. Patients were classified into two groups, the MDPC group and the control group, that received the usual care by nephrologists. Risks of the first episode of peritonitis, technique failure and mortality were compared between the two groups. RESULTS: There were 126 patients under the usual care and 546 patients under the MDPC. Patients in the MDPC group initiated dialysis earlier than those in the non-MDPC group. There was no significant difference between these two groups in time to the first episode of peritonitis. Compared to the non-MDPC group, the MDPC group was at similar risks of technique failure (adjusted HR = 0.85, 95% CI = 0.64-1.15) and mortality (adjusted HR = 0.66, 95% CI = 0.42-1.02). Among patients with diabetes, the risk of mortality was significantly reduced in the MDPC group with an adjusted HR of 0.45 (95% CI = 0.25-0.80). CONCLUSIONS: There was no significant difference in time to develop the first episode of peritonitis, and risks of technique failure and mortality between these two groups. Diabetic PD patients under MDPC had a lower risk of mortality than those under the usual care.

Calycosin Alleviates Paraquat-Induced Neurodegeneration by Improving Mitochondrial Functions and Regulating Autophagy in a Drosophila Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder with limited clinical treatments. The occurrence of PD includes both genetic and environmental toxins, such as the pesticides paraquat (PQ), as major contributors to PD pathology in both invertebrate and mammalian models. Calycosin, an isoflavone phytoestrogen, has multiple pharmacological properties, including neuroprotective activity. However, the paucity of information regarding the neuroprotective potential of calycosin on PQ-induced neurodegeneration led us to explore whether calycosin can mitigate PD-like phenotypes and the underlying molecular mechanisms. We used a PQ-induced PD model in Drosophila as a cost-effective in vivo screening platform to investigate the neuroprotective efficacy of natural compounds on PD. We reported that calycosin shows a protective role in preventing dopaminergic (DA) neuronal cell death in PQ-exposed Canton S flies. Calycosin-fed PQ-exposed flies exhibit significant resistance against PQ-induced mortality and locomotor deficits in terms of reduced oxidative stress, loss of DA neurons, the depletion of dopamine content, and phosphorylated JNK-caspase-3 levels. Additionally, mechanistic studies show that calycosin administration improves PQ-induced mitochondrial dysfunction and stimulates mitophagy and general autophagy with reduced pS6K and p4EBP1 levels, suggestive of a maintained energy balance between anabolic and catabolic processes, resulting in the inhibition of neuronal cell death. Collectively, this study substantiates the protective effect of calycosin against PQ-induced neurodegeneration by improving DA neurons' survival and reducing apoptosis, likely via autophagy induction, and it is implicated as a novel therapeutic application against toxin-induced PD pathogenesis.

Risks of central nervous system infections and related mortality in patients undergoing dialysis.

INTRODUCTION: This study aimed to investigate the risks of central nervous system (CNS) infections and related mortality in patients with end-stage renal disease (ESRD) undergoing dialysis. METHODS: Incident dialysis patients were identified from 2000 to 2013. The risks of CNS infection and related mortality were analyzed. RESULTS: The adjusted hazard ratio (HR) of CNS infection in the ESRD group compared with the control group was 3.46 (95% confidence interval [CI] 2.75-4.35). The adjusted odds ratio (OR) of 90-day mortality following CNS infections in the ESRD group in comparison with the control group was 5.99 (95% CI 2.78-12.9). The adjusted HR of overall CNS infection for the peritoneal dialysis (PD) group in comparison with the hemodialysis (HD) group was 1.07 (95% CI 0.63-1.82). Influenza vaccination was associated with a lower risks of CNS infection in dialysis patients (adjusted HR: 0.38, 95% CI 0.30-0.48). The adjusted OR of 90-day mortality following CNS infection for the PD group in comparison with the HD group was 1.01 (95% CI 0.55-1.87). CONCLUSIONS: The risks of CNS infections and related mortality were remarkably high in dialysis patients with no significant difference between patients with ESRD under HD and PD treatment.

Cadmium induces the expression of Interleukin-6 through Heme Oxygenase-1 in HK-2 cells and Sprague-Dawley rats.

Cadmium is toxic to the kidney through mechanisms involving oxidative stress and inflammation. We studied reciprocal crosstalk among the oxidative stress, inflammation, and the nuclear Nrf2 pathway in cadmium-induced nephrotoxicity on HK-2 human renal proximal tubular epithelial cells. Cadmium chloride (CdCl2) caused cell viability loss, Reactive Oxygen Species (ROS) generation, glutathione reduction, and Interleukin-6 (IL-6) expression, accompanied by Nrf2 activation and Heme Oxygenase-1 (HO-1) expression. Pharmacological treatments demonstrated cytotprotective and anti-inflammatory effects of Nrf2 activation. Intriguingly, inhibition of HO-1 activity mitigated cell viability loss and IL-6 expression in CdCl2-treated cells. Parallel attenuation by HO-1 inhibitor was demonstrated in cadmium-induced ROS generation and glutathione reduction. CdCl2-treated cells also increased levels of ferrous iron, cGMP, Mitogen-Activated Protein Kinases phosphorylation, as well as NF-κB DNA-binding activity. These increments were mitigated by antioxidant N-Acetyl Cysteine, HO-1 inhibitor SnPP, and PKG inhibitor KT5823, and were mimicked by the Carbon Monoxide-releasing compound. In the kidney cortex of CdCl2-exposed Sprague-Dawley rats, we found similar renal injury, histological changes, ROS generation, IL-6 expression, and accompanied pro-oxidant and pro-inflammatory changes. These observations indicated that cadmium-induced nephrotoxicity was associated with oxidative stress and inflammation, and HO-1 likely acts as a linking molecule to induce nephrotoxicity-associated IL-6 expression upon cadmium exposure.