Tumor necrosis factor-alpha blockade suppresses BK polyomavirus replication.

PURPOSE: BK Polyomavirus (BKPyV) infection manifests as renal inflammation and can cause kidney damage. Tumor necrosis factor-α (TNF-α) is increased in renal inflammation and injury. The aim of this study was to investigate the effect of TNF-α blockade on BKPyV infection. METHODS: Urine specimens from 22 patients with BKPyV-associated nephropathy (BKPyVN) and 35 non-BKPyVN kidney transplant recipients were analyzed. RESULTS: We demonstrated increased urinary levels of TNF-α and its receptors, TNFR1 and TNFR2, in BKPyVN patients. Treating BKPyV-infected human proximal tubular cells (HRPTECs) with TNF-α stimulated the expression of large T antigen and viral capsid protein-1 mRNA and proteins and BKPyV promoter activity. Knockdown of TNFR1 or TNFR2 expression caused a reduction in TNF-α-stimulated viral replication. NF-κB activation induced by overexpression of constitutively active IKK2 significantly increased viral replication and the activity of the BKPyV promoter containing an NF-κB binding site. The addition of a NF-κB inhibitor on BKPyV-infected cells suppressed viral replication. Blockade of TNF-α functionality by etanercept reduced BKPyV-stimulated expression of TNF-α, interleukin-1ß (IL-1ß), IL-6 and IL-8 and suppressed TNF-α-stimulated viral replication. In cultured HRPTECs and THP-1 cells, BKPyV infection led to increased expression of TNF-α, interleukin-1 ß (IL-1ß), IL-6 and TNFR1 and TNFR2 but the stimulated magnitude was far less than that induced by poly(I:C). This may suggest that BKPyV-mediated autocrine effect is not a major source of TNFα. CONCLUSION: TNF-α stimulates BKPyV replication and inhibition of its signal cascade or functionality attenuates its stimulatory effect. Our study provides a therapeutic anti-BKPyV target.

Experiences of oncology healthcare personnel in international medical service quality: a phenomenological study.

BACKGROUND: With the globalization of medical services on the rise, Asia has ascended to a destination of choice for its high-quality medical services at very reasonable rates. Monitoring the quality of the international medical industry is vital to maintain service demand. The experiences of healthcare personnel (HCP) involved in international medical services (IMS) regarding the provision of services to international cancer patients have not yet been discussed. This study aimed to explore oncology HCP experiences of IMS quality in caring for international cancer patients in Taiwan. METHODS: Descriptive phenomenological method and were analyzed through Colaizzi's seven-step approach. In this study, 19 respondents were collected data by using in-depth semi-structured interviews. An average interview lasted approximately 45 min. RESULTS: Four major themes were identified from the interviews: patient selection, psycho-oncology care, predicaments, and promoting suggestions. Additionally, thirteen subthemes emerged, including necessary selection of patients, reasons for unwillingness to enroll international patients, helpless patients, emotional distress, care with warmth, insufficient manpower, an unfair reward mechanism, poor hardware equipment, the predicaments of oncology care, various publicity strategies, one-on-one service model, design of a designated area, and reasonable benefit distribution. CONCLUSIONS: This study explored oncology HCP experiences of IMS quality in caring for international cancer patients, with implications for hospitals in developing high-quality IMS. Due to the fact that IMS is a global trend, HCPs, administrators, and policy-makers are advised to improve the quality of IMS in the oncology department, which has been the least studied field in IMS quality.

Incidence and Risk of Carpal Tunnel Syndrome in End-Stage Renal Disease Patients on Dialysis: A Nationwide Population-Based Matched Cohort Study.

Carpal tunnel syndrome (CTS) is a common cause of compression neuropathy of the upper extremities. This retrospective nationwide matched cohort study was conducted using the data from the Taiwan National Health Insurance Research Database between January 2003 and December 2012. The incidence rate of CTS was 975.84 and 544.12/100,000 person-years, respectively, yielding an incidence rate ratio of 1.79 (95% confidence interval, 1.68-1.91, P < 0.0001). CTS patients with End-stage renal disease (ESRD) in the dialysis group were more likely to receive surgical intervention than those the control group (62.41% vs 12.89%, P < 0.0001). The risk of CTS was significantly higher in the ESRD on dialysis cohort (10-year cumulative incidence, 8.0%) than in the control cohort (5.1%), which yielded an adjusted hazard ratio of 13.95 (95% confidence interval, 10.95-17.76, P < 0.0001). The high risk of CTS in ESRD patients on dialysis suggests that timely referral to hand surgeons with appropriate treatment should prevent permanent median nerve damage by CTS and may possibly improve patients' quality of life.

Application of the Age, Creatinine, and Left Ventricular Ejection Fraction Score for Patients on Extracorporeal Membrane Oxygenation.

Patients on extracorporeal membrane oxygenation (ECMO) usually have high mortality rate and poor outcome. Age, Creatinine, and Left Ventricular Ejection Fraction (ACEF) score is an easy-calculating score and provides good performance on mortality prediction in patients undergoing cardiac operations or percutaneous coronary intervention, but it has not been applied to patients on ECMO before. In this study, we aimed to use ACEF score obtained within 1 week of ECMO support for in-hospital mortality prediction in patients on ECMO due to severe myocardial failure. This study reviewed the medical records of 306 patients on ECMO at a specialized intensive care unit (CVSICU) in a tertiary-care university hospital between March 2002 and December 2011, and 105 patients on veno-arterial ECMO due to severe myocardial failure were enrolled. Demographic, clinical, and laboratory variables were retrospectively collected as survival predictors. The overall mortality rate was 47.6%. The most frequent condition requiring ICU admission was postcardiotomy cardiogenic shock. Multiple logistic regression analysis indicated that post-ECMO ACEF score, Sequential Organ Failure Assessment score, and troponin I on day 1 of ECMO support were independent risk factors for in-hospital mortality. Using the area under the receiver operating characteristic curve (AUROC), the post-ECMO ACEF score indicated a good discriminative power (AUROC 0.801 ± 0.042). Finally, cumulative survival rates at 6-month follow-up differed significantly (P < 0.001) for an ACEF score ≤ 2.22 versus those with an ACEF score > 2.22. After ECMO treatment due to severe myocardial failure, post-ECMO ACEF score provides an easy-calculating method with a reproducible evaluation tool with excellent prognostic abilities in these patients.

Epidemiology and outcomes of Endophthalmitis in chronic dialysis patients: a 13-year experience in a tertiary referral center in Taiwan.

BACKGROUND: Endophthalmitis is a severe eye infection leading to disabling outcome. Because there were only a few case report illustrating endophthalmitis in chronic dialysis patient, we would like to investigate the epidemiology and clinical features of endophthalmitis in chronic dialysis patient in a tertiary referral center. METHODS: We searched the health information system in the study hospital with ICD9 encoding endophthalmitis during Jan. 2002 to Dec. 2015. A total of 32 episodes of endophthalmitis occurred in chronic dialysis patients. We performed an 1:2 case-control match on propensity score. The demographic features, clinical manifestation, infection focus and visual outcome were recorded. RESULTS: Of the total of 32 patients, 25 were classified as endogenous endophthalmitis and another seven were exogenous. Most patients presented with ophthalmalgia (n = 32, 100%) and periocular swelling (n = 31, 96.8%), whereas half of the patients suffered blurred vision (n = 16, 50%). Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most frequent causative pathogens. Dialysis vascular infection was also a possible unique focus for bacteremia. The visual acuity of the endogenous groups were less likely to improve in the chronic dialysis patients compared with control group. CONCLUSION: This is the first and the largest case series focusing on endophthalmitis in chronic dialysis patients. Our study showed different pathogen spectrum, an unique bacterial origin and worse visual outcome in these group of patients. Prompt referral to ophthalmologists when the patients present with suspicious symptoms (blurred vision, ophthalmalgia and periocular swelling) is crucial.

Infective spondylodiscitis in patients on maintenance hemodialysis: a case series.

Infective spondylodiscitis is a rare disease. This case review describes the clinical course, risk factors, and outcomes of adult patients on maintenance hemodialysis who presented with infective spondylodiscitis at a single medical center in Taiwan. There were 18 cases (mean age: 64.9 ± 10.8 years) over more than 10 years. Analysis of underlying diseases indicated that 50% of patients had diabetes, 55.6% had hypertension, 55.6% had coronary artery disease, 22.2% had congestive heart failure, 22.2% had a cerebral vascular accident, 16.7% had liver cirrhosis, and 11.1% had malignancies. Sixty-one percent of patients had a degenerative spinal disease and the most common symptom was back pain (83.3%). A total of 38.9% of patients had leukocytosis, 99.4% had elevated levels of C-reactive protein, 78.6% had elevated erythrocyte sedimentation rates, and 55.6% had elevated levels of alkaline phosphatase. The average hemodialysis duration was 72.8 ± 87.5 months, and 8 patients (44.4%) started hemodialysis within 1 year prior to infective spondylodiscitis. Four patients (22.2%) had vascular access infection-associated spondylodiscitis. The lumbar region was the most common location of infection (77.8%), 44.4% of patients developed abscesses, and Staphylococci were the most common pathogen (38.9%). The mortality rate was 16.7%, all due to sepsis. Thirty-three percent of the survivors had recurrent infective spondylodiscitis within 1 year. Infective spondylodiscitis should be considered in hemodialysis patients who present with prolonged back pain with or without fever. Non-contrast MRI is an appropriate diagnostic tool for this condition. Vascular access infection increases the risk for infective spondylodiscitis in hemodialysis patients.

Comparison of RIFLE, AKIN, and KDIGO classifications for assessing prognosis of patients on extracorporeal membrane oxygenation.

BACKGROUND/PURPOSE: Acute kidney injury (AKI) developing during extracorporeal membrane oxygenation (ECMO) is associated with very poor outcome. The Kidney Disease: Improving Global Outcomes (KDIGO) group published a new AKI definition in 2012. This study analyzed the outcomes of patients treated with ECMO and identified the relationship between the prognosis and the KDIGO classification. METHODS: This study examined total 312 patients initially, and finally reviewed the medical records of 167 patients on ECMO support at a tertiary care university hospital between March 2002 and November 2011. Demographic, clinical, and laboratory variables were retrospectively collected as survival predicators. RESULTS: The overall mortality rate was 55.7%. In the analysis of the areas under the receiver operating characteristic curves, the KDIGO classification showed relatively higher discriminatory power (0.840 ± 0.032) than the Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal failure (RIFLE) (0.826 ± 0.033) and Acute Kidney Injury Network (AKIN) (0.836 ± 0.032) criteria in predicting in-hospital mortality. Furthermore, multiple logistic regression analysis showed that KDIGO, hemoglobin, and Glasgow Coma Scale score on the first day of patients on ECMO were independent predictors for in-hospital mortality. Finally, cumulative survival rates at 6-month follow-up after hospital discharge differed significantly for KDIGO stage 3 versus KDIGO stage 0, 1, and 2 (p < 0.001); and KDIGO stage 2 versus KDIGO stage 0 (p < 0.05). CONCLUSION: For those patients with ECMO support, the KDIGO classification proved to be a more reproducible evaluation tool with excellent prognostic abilities than RIFLE or AKIN classification.

Developing a measure of medication-related quality of life for people with polypharmacy.

PURPOSE: To develop a measure of medication-related quality of life (MRQoL) and to validate the measure in a hospital-based population of patients with polypharmacy. METHODS: The Medication-Related Quality of Life Scale version 1.0 (MRQoLS-v1.0) included 14 items developed on the basis of interviews with elderly patients with polypharmacy, defined as taking five or more medications simultaneously. This scale was tested in 219 outpatients (99 with polypharmacy and 120 without polypharmacy). Two measures were used to establish construct validity the Psychological Distress Checklist, for convergent validity, and the Medication Adherence Behavior Scale (MABS), for discriminant validity. RESULTS: The 14-item scale was found to be both reliable and valid. Internal consistency reliability evaluated using Cronbach's alpha for this scale was 0.91. Scores on the MRQoLS-v1.0 correlated statistically significantly and negatively with those on the Psychological Distress Checklist. Discriminant validity was demonstrated by low correlation with MABS, indicating that the MRQoLS-v1.0 measured concepts different from medication adherence. Significant differences in the MRQoLS-v1.0 between patients with polypharmacy and those without polypharmacy provided evidence for known-group validity. CONCLUSIONS: The study presents a psychometric evaluation of a measure used to assess MRQoL of patients with polypharmacy. The instrument is practical to administer in clinics and provides a valuable adjunct to the outcome measurement for patients with polypharmacy. Further research on the sensitivity of this instrument to medication change in multi-medicated patients is warranted.

Plate exposure after anterolateral thigh free-flap reconstruction in head and neck cancer patients with composite mandibular defects.

BACKGROUND: This study aimed to identify the risk factors for postoperative plate exposure in head and neck cancer patients with composite mandibular defects undergoing tumor ablation followed by bridging plate and anterolateral thigh (ALT) flap transfer. METHODS: Between January 2007 and June 2012, 1,452 patients who underwent free tissue transfer after head and neck cancer ablation were retrospectively reviewed. Only ALT flap coverage with a bridging plate for segmental mandibular defects was included. The Jewer's classification was used to define the type of mandibular defect. RESULTS: The study enrolled 123 men and 7 women. The incidence of plate exposure was 37.7 % (49/130). The follow-up time ranged from 0.5 to 5.4 years (mean, 2.4 years). The 5-year probability of a plate exposure-free rate was 32.8 % for the patients with postoperative radiotherapy (RT) (n = 33) and 64.3 % for the patients without it (n = 97). Patients reconstructed with a fasciocutaneous or chimeric type of ALT flap had higher rates of plate exposure than those reconstructed with a musculocutaneous type of ALT flap (p = 0.002). As shown by logistic regression, the significant predictive risk factors for postoperative plate exposure still were postoperative RT [adjusted odds ratio (OR) 2.76, 95 % confidence interval (CI) 1.09-6.99, p = 0.031] and intraoperative blood loss (adjusted OR 2.37, 95 % CI 1.13-4.99, p = 0.022). CONCLUSIONS: The type of ALT flap, postoperative RT, and intraoperative blood loss were the predisposing factors for increased risk of postoperative plate exposure in the specific disease group.

Essential calcium-binding cluster of Leptospira LipL32 protein for inflammatory responses through the Toll-like receptor 2 pathway.

Leptospirosis is the most widespread zoonosis caused by the pathogenic Leptospira worldwide. LipL32, a 32-kDa lipoprotein, is the most abundant protein on the outer membrane of Leptospira and has an atypical poly(Asp) motif ((161)DDDDDGDD(168)). The x-ray crystallographic structure of LipL32 revealed that the calcium-binding cluster of LipL32 includes several essential residues Asp(132), Thr(133), Asp(164), Asp(165), and Tyr(178). The goals of this study were to determine possible roles of the Ca(2+)-binding cluster for the interaction of LipL32 and Toll-like receptor 2 (TLR2) in induced inflammatory responses of human kidney cells. Site-directed mutagenesis was employed to individually mutate Ca(2+)-binding residues of LipL32 to Ala, and their effects subsequently were observed. These mutations abolished primarily the structural integrity of the calcium-binding cluster in LipL32. The binding assay and atomic force microscopy analysis further demonstrated the decreased binding capability of LipL32 mutants to TLR2. Inflammatory responses induced by LipL32 variants, as determined by TLR2 pathway intermediates hCXCL8/IL-8, hCCL2/MCP-1, hMMP7, and hTNF-α, were also lessened. In conclusion, the calcium-binding cluster of LipL32 plays essential roles in presumably sustaining LipL32 conformation for its proper association with TLR2 to elicit inflammatory responses in human renal cells.

Polyomavirus BK-encoded microRNA suppresses autoregulation of viral replication.

Polyomavirus BK (BKV) infection is an important cause of renal allograft failure. Viral microRNAs are known to play a crucial role in viral replication. This study investigated the expression of BKV-encoded microRNAs (miR-B1) in patients with polyomavirus-associated nephropathy (PVAN) and their role in viral replication. Following BKV infection in renal proximal tubular cells, the 3p and 5p miR-B1 levels were significantly increased. Cells transfected with the vector containing the miR-B1 precursor (the miR-B1 vector) showed a significant increase in expression of 3p and 5p miR-B1 and decrease in luciferase activity of a reporter containing the 3p and 5p miR-B1 binding sites, compared to cells transfected with the miR-B1-mutated vector. Transfection of the miR-B1 expression vector or the 3p and 5p miR-B1 oligonucleotides inhibited expression of TAg. TAg-enhanced promoter activity and BKV replication were inhibited by miR-B1. In contrast, inhibition of miR-B1 expression by addition of miR-B1 antagomirs or silencing of Dicer upregulated the expression of TAg and VP1 proteins in BKV-infected cells. Importantly, patients with PVAN had significantly higher levels of 3p and 5p miR-B1 compared to renal transplant patients without PVAN. In conclusion, we demonstrated that (1) miR-B1 expression was upregulated during BKV infection and (2) miR-B1 suppressed TAg-mediated autoregulation of BKV replication. Use of miR-B1 can be evaluated as a potential treatment strategy against BKV infection.

p-Cresol sulfate and indoxyl sulfate induce similar cellular inflammatory gene expressions in cultured proximal renal tubular cells.

BACKGROUND: p-Cresol sulfate (PCS) and indoxyl sulfate (IS) have important roles in the kidney injury. The aim of this study was to determine the inflammatory response to PCS and IS. METHODS: Cultured mouse proximal renal tubular cells were treated with PCS or IS and analyzed by polymerase chain reaction array with an inflammation and immune panel. Gene annotation enrichment and functional annotation clustering were analyzed with the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Functional networks of the target genes were analyzed with the algorithm GeneMANIA. RESULTS: PCS and IS increased the expression of inflammation associated genes. Sixteen upregulated gene clusters of cells treated with PCS or IS were found. The major cytokines in the functional networks generated by PCS or IS treatment were Tgfb1, Fasl, Il6/15, Il15, Csf1/3 and Cxcl10. The major intracellular signal triggered by PCS or IS included Stats, Smads, Nfkb2, Ikbkb, Bcl2 and Bax. In both PCS- and IS-treated cells, Col4a5, Cxc10, Fasl, Stat1 and Ikbkb were the target genes in the predicted molecular functional networks connected to Tgfb1. CONCLUSIONS: PCS and IS stimulate significant cellular inflammation. Similar immune and cellular inflammatory responses were induced by PCS or IS on cultured proximal renal tubular cells.

Acute left-arm compartment syndrome due to cephalic arch stenosis in a dialysis patient.

Acute compartment syndrome of the upper limb due to dialysis access-related bleeding is a rare and severe complication of hemodialysis. In most reported cases, this complication is caused by an enlarging hematoma after puncture or perforation of a fistula in combination with the use of heparin. In this case report, we describe a 52-year-old woman presenting with venous hypertension and left-arm swelling that progressed suddenly on the fifth day of presentation to neurological deficits, cyanotic skin changes, and typical clinical symptoms of acute arm compartment syndrome. An angiographic scan confirmed a critical stenosis at the proximal cephalic-axillary venous junction, and balloon angioplasty successfully dilated the lesion. The arm swelling and other symptoms subsided dramatically within 3 days. This case represents a potentially different mechanism for the development of acute arm compartment syndrome in dialysis patients as well as a treatment strategy different from standard fasciotomy to reduce intracompartmental pressure.

Factors associated with the survival of patients with primary small cell carcinoma of the kidney.

BACKGROUND: Primary small cell carcinoma (SCC) of the kidney is rare, and the factors associated with the survival of these patients are yet to be elucidated. PATIENTS AND METHODS: We collected data on patients who were admitted to our hospital for SCC of the kidney in the last 22 years and of those in studies in the literature. Clinical characteristics were summarized using descriptive statistics. The associations of these factors with survival were evaluated using Cox regression models, and the hazard ratio of death was calculated. RESULTS: This study included 45 patients (8 admitted to our hospital and 37 from studies in the literature) with SCC of the kidney. The overall median survival time was 9.9 months (range 6.9-31.6). Data on demographics, clinical symptoms, tumor staging, and tumor characteristics recorded at the time of diagnosis were not associated with survival. Among the different treatment modalities applied, cisplatin-based chemotherapy afforded a strong survival advantage (hazard ratio = 0.35, p = 0.022). However, patients with early local recurrence (hazard ratio = 19.13, p = 0.012) and early distant metastasis (hazard ratio = 10.93, p = 0.003) after primary treatment showed significantly poor survival. CONCLUSIONS: Patients with primary SCC of the kidney generally presented with large, advanced-stage tumors and showed poor survival. Early detection of the tumor, use of cisplatin-based chemotherapy, and careful follow-up for local recurrence or frequent metastasis within 6 months after the primary treatment could be important for improving overall patient survival.

The essential role of the ERK activation in large T antigen of BK polyomavirus regulated cell migration.

Recent studies have suggested that BK polyomavirus (BKPyV) may be associated with the development of urothelial carcinoma. In Merkel cell carcinoma, TAg and tAg are the major viral proteins of Merkel cell polyomavirus with oncogenic potential. In this study, we aimed to distinguish the role of TAg and tAg in cell migration. Our result demonstrated that ERK was phosphorylated in human renal tubular cells expressing its TAg and tAg after BKPyV infection. Treatment with the ERK inhibitor U0126 suppressed BKPyV gene expression and reduced BKPyV replication. Both TAg and tAg induced cell migration via ERK-dependent signaling. Furthermore, the expression of TAg and tAg had a significant regulatory effect on focal adhesion molecules in renal proximal tubular cells, which strongly suggests that alterations in the focal adhesion complexes are critically involved in TAg and tAg-induced cell migration. Gelatin zymography profiling revealed that TAg regulates the expression and activity of MMP-2 and MMP-9, but not tAg. Interestingly, TAg regulates the expression and activity of MMP-9 through ERK signaling, whereas MMP-2 is regulated through an ERK-independent pathway. Unbalanced ERK pathway activity is frequently observed in many cancers, while MMP proteins are usually overexpressed in aggressive tumors. These findings support the view that BKPyV is an oncogenic virus.

Interferon-alpha and MxA inhibit BK polyomavirus replication by interaction with polyomavirus large T antigen.

INTRODUCTION: BK Polyomavirus (BKPyV) infection is a common complication in kidney transplant recipients and can result in poor outcome and graft failure. Currently, there is no known effective antiviral agent. This study investigated the possible antiviral effects of Interferon alpha (IFNα) and its induced protein, MxA, against BKPyV. METHODS: In vitro cell culture experiments were conducted using human primary renal proximal tubular epithelial cells (HRPTECs). We also did animal studies using Balb/c mice with unilateral kidney ischemic reperfusion injury. RESULTS: Our results demonstrated that IFNα effectively inhibited BKPyV in vitro and murine polyomavirus in animal models. Additionally, IFNα and MxA were found to suppress BKPyV TAg and VP1 production. Silencing MxA attenuated the antiviral efficacy of IFNα.We observed that MxA interacted with BKPyV TAg, causing it to remain in the cytosol and preventing its nuclear translocation. To determine MxA's essential domain for its antiviral activities, different mutant MxA constructs were generated. The MxA mutant K83A retained its interaction with BKPyV TAg, and its antiviral effects were intact. The MxA T103A mutant, on the other hand, abolished GTPase activity and lost its protein-protein interaction with BKPyV TAg, and lost its antiviral effect. CONCLUSION: IFNα and its downstream protein, MxA, have potent antiviral properties against BKPyV. Furthermore, our findings indicate that the interaction between MxA and BKVPyV TAg plays a crucial role in determining the anti-BKPyV effects of MxA.

Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens.

BACKGROUND: A previous study in type 2 diabetic patients with high-normal body lead burdens showed that EDTA chelation therapy for 3 months slows progressive diabetic nephropathy during a 12-month follow-up. The effect of a longer course of therapy on kidney function decrease over a longer follow-up is not known. STUDY DESIGN: A 12-month run-in phase, then a randomized single-blind study with a 27-month intervention. SETTING & PARTICIPANTS: University medical center; 50 patients (serum creatinine, 1.5-3.9 mg/dL) with high-normal body lead burden (≥80-<600 µg) were randomly assigned to the treatment and control groups. INTERVENTION: The treatment group received weekly chelation therapy for 3 months to reduce their body lead burden to <60 µg and then as needed for 24 months to maintain this level. The control group received placebo for 3 months and then weekly for 5 weeks at 6-month intervals for 24 months. OUTCOMES: The primary end point was change in estimated glomerular filtration rate (eGFR) over time. A secondary end point was a 2-fold increase in baseline serum creatinine level or the requirement for renal replacement therapy. MEASUREMENTS: Body lead burdens were assessed by EDTA mobilization tests and eGFR was calculated using the equation for Chinese patients with type 2 diabetes. RESULTS: Mean baseline eGFRs in the treatment and control groups were similar. After 3 months of chelation therapy, the change in eGFR in the treatment group (+1.0 ± 4.8 mL/min/1.73 m(2)) differed significantly from that in the control group (-1.5 ± 4.8 mL/min/1.73 m(2); P = 0.04). In the subsequent 24-month intervention, the yearly rate of decrease in eGFR (5.6 ± 5.0 mL/min/1.73 m(2) per year) in the treatment group was slower than that (9.2 ± 3.6 mL/min/1.73 m(2) per year; P = 0.04) in the control group. 17 (68%) control-group patients and 9 (36%) treatment-group patients achieved the secondary end point. LIMITATIONS: Small sample size, not double blind. CONCLUSIONS: A 27-month course of EDTA chelation therapy retards the progression of diabetic nephropathy in type 2 diabetic patients with high-normal body lead burdens.

Therapeutic Potential of Exosomes Derived from Diabetic Adipose Stem Cells in Cutaneous Wound Healing of db/db Mice.

(1) Background: Diabetes impairs angiogenesis and wound healing. Paracrine secretion from adipose stem cells (ASCs) contains membrane-bound nano-vesicles called exosomes (ASC-Exo) but the functional role and therapeutic potential of diabetic ASC-Exo in wound healing are unknown. This study aims to investigate the in vivo mechanistic basis by which diabetic ASC-Exo enhance cutaneous wound healing in a diabetic mouse model. (2) Methods: Topically applied exosomes could efficiently target and preferentially accumulate in wound tissue, and the cellular origin, ASC or dermal fibroblast (DFb), has no influence on the biodistribution pattern of exosomes. In vivo, full-thickness wounds in diabetic mice were treated either with ASC-Exo, DFb-Exo, or phosphate-buffered saline (PBS) topically. ASC-Exo stimulated wound healing by dermal cell proliferation, keratinocyte proliferation, and angiogenesis compared with DFb-Exo and PBS-treated wounds. (3) Results: Diabetic ASC-Exo stimulated resident monocytes/macrophages to secrete more TGF-ß1 and activate the TGF-ß/Smad3 signaling pathway. Fibroblasts activated by TGF-ß1containing exosomes from ASCs initiate the production of TGF-ß1 protein in an autocrine fashion, which leads to more proliferation and activation of fibroblasts. TGF-ß1 is centrally involved in diabetic ASC-Exo mediated cellular crosstalk as an important early response to initiating wound regeneration. (4) Conclusions: The application of diabetic ASC-Exo informs the potential utility of a cell-free therapy in diabetic wound healing.

In-Hospital Outcomes and Recurrence of Infectious Spondylitis in Patients with and without Chronic Hemodialysis: A Nationwide Cohort Study.

Purpose: The incidence of bloodstream infection among end-stage kidney disease (ESKD) patients on chronic hemodialysis (HD) was 26-fold higher than population controls, causing higher morbidity and costs. The aim of this investigation was to clarify the prognostic factors, in-hospital outcomes and recurrence of infectious spondylitis of patients with and without chronic HD. Patients and Methods: This nationwide study analyzed 2592 patients who admitted for first-time infectious spondylitis between January 1, 2003, and December 31, 2015. Patients were classified into the chronic HD or the non-HD group. The logistic regression model and the general linear model were utilized to determine the impact of chronic HD on in-hospital mortality and recurrence. The Cox proportional hazard model was used to estimate the predictive factors of in-hospital mortality and recurrence. Results: Compared to the non-HD group, patients in the chronic HD group had a higher risk of respiratory failure, sepsis, in-hospital mortality, longer hospital stay, and higher medical spending. Chronic HD was an independent risk factor for in-hospital mortality (hazard ratio 2.21, 95% confidence interval 1.34-3.65, p=0.0019), but not for recurrence. Intravascular device implantation or revision was a prognosticator for the mortality of both groups and a predictor for recurrence of the non-HD group. Surgical treatment was associated with a decreased risk of recurrence, whereas treatment with CT-guided abscess drainage was associated with an increased risk of recurrence in both groups. Conclusion: Patients with infectious spondylitis who were receiving chronic HD had a higher in-hospital mortality compared to those without HD. Intravascular device implantations or revision within 6 months was a significant predictor of in-hospital mortality and disease recurrence. Surgical treatment of infectious spondylitis had a lower risk of recurrence than those with CT-guided abscess drainage in both patient groups.

Clinical and visual outcomes following endogenous endophthalmitis: 175 consecutive cases from a tertiary referral center in Taiwan.

BACKGROUND: To elucidate the linkage between organisms and visual outcome in cases of endogenous endophthalmitis. METHODS: Patients who presented with signs of endogenous endophthalmitis between January 2008 and December 2015 and underwent a vitreous tapping were enrolled. The patients' demographics and clinical findings were recorded. The outcomes include visual acuity and enucleation. RESULTS: A total of 175 consecutive patients with endogenous endophthalmitis were enrolled. Forty-four percent of the patients had a known distal focus of infection. The most common focus was liver abscess (24.6%), and the major intravitreal isolate was Klebsiella pneumoniae (34.4%). In this series, 51.4% of the intravitreal cultures were positive. The visual acuity of fungal ophthalmitis were better than in bacterial ophthalmitis. Multivariate logistic regression showed that Gram negative vitreous isolates, compared with the negative vitreous culture, were associated with higher risk of enucleation (Odds ratio [OR]: 10.424, 95% confidence interval [95% CI]: 3.019-35.995). The use of intravitreal antibiotics, compared non-users, was associated with a reduced risk of enucleation (OR:0.084, 95% CI: 0.026-0.268). Trans pars plana vitrectomy was not associated with risk of enucleation (OR: 0.307, 95% CI: 0.035-2.693). The post-treatment VA was positively correlated with the presenting VA (r = 0.718, p = 0.0001). CONCLUSION: Our study demonstrated that liver abscess is the most common source of endogenous endophthalmitis in Taiwan. The visual outcome is good when the presenting visual acuity is relatively well preserved and when the infecting organism is fungus. The use of intra-vitreal antibiotics reduces the risk of enucleation.