Use of Nicergoline as Adjunctive Treatment of Neurotrophic Keratitis in Routine Clinical Practice: A Case Series.

PURPOSE: To describe the effectiveness and safety of nicergoline in patients with epithelial corneal defect or corneal ulcer due to neurotrophic keratitis (NK). METHODS: A prospective case series review was performed in 14 patients with NK who started treatment with nicergoline as an off-label prescription from January to November 2020. Patients with a epithelial defect or corneal ulcer due to NK were treated with oral nicergoline. RESULTS/SERIAL CASES: Complete corneal healing was observed in 10 (71.4%) of the 14 patients after 25.6 ± 26.60 days (range 7-90) with nicergoline. In three (21.5%) patients wound healing was not achieved, and one patient (7.1%) was lost to follow-up. The mean time between diagnosis and the starting of nicergoline was 10.92 ± 8.85 days (0-28). No adverse effects of nicergoline were observed. CONCLUSION: Nicergoline as an adjunctive treatment for NK showed a potential use in the healing of epithelial defect in real-life clinical practice.

Trends in corneal transplantation in a single center in Barcelona, Spain. Transitioning to DMEK.

PURPOSE: To observe trends in surgical techniques for corneal transplantation and main indications in our hospital over the past five years. METHODS: Retrospective descriptive study, including all keratoplasties performed at the Hospital Clinic of Barcelona, Spain, between January 2014 and December 2018. RESULTS: In total, 332 keratoplasties were performed. In total, 127 (38.25%) were penetrating keratoplasties (PK), and 205 (61.75%) were lamellar keratoplasties (LK). In 2014, a total of 48 keratoplasties were carried-out, whereas in 2018, the total was 93, which represents a 93.75% increase in corneal transplantation surgeries. Eye bank-delivered precut tissue for DMEK was introduced in 2016, and 3 cases (6.25%), were carried out that year. In 2018, DMEK became the leading technique with 56 cases (60.22%). Fuchs' dystrophy was the leading indication for corneal transplant (37.63%) in 2018. CONCLUSION: Introduction of DMEK in a single center can be implemented in a relatively short period of time, becoming the most popular surgical procedure in corneal transplantation. A possible factor encouraging this change is the availability of eye bank-delivered precut tissue, and standardization of donor preparation and host surgical steps, optimizing surgical time in the operating room. This trend should lead to better visual outcomes, faster recovery times, and eventually to a higher surgical volume per year.

The efficacy of a medication review programme conducted in an emergency department.

Background Older age and inappropriate prescribing is related to a greater rate of emergency department visits and hospitalisations. Objective To assess the efficacy of an interprofessional collaboration programme in which a review of the medication of older patients seen in the emergency observation unit was carried out. Setting Emergency departments at four Spanish hospitals. Method Randomised, controlled study. Patients over 65 years of age presenting to the emergency department were randomised to a control or an intervention group. In the intervention group, a pharmacist reviewed the patients' chronic medication and identified any potentially inappropriate prescriptions based on the STOPP/START criteria. Each case was discussed with the emergency specialist and a recommendation to modify the treatment was sent to the general practitioner. Main outcome measure Rate of emergency visits and hospital admissions. Results The adjusted rate ratio of emergency visits and hospital admissions was 0.808 (95% CI 0.617 to 1.059) at 3 months, 0.888 (95% CI 0.696 to 1.134) at 6 months and 0.954 (95% CI 0.772 to 1.179) at 12 months. There was a statistically significant reduction at 3 months in two of the hospitals that participated in the study [adjusted rate ratio at 3 months was 0.452 (95% CI 0.222 to 0.923) in hospital 3 and 0.567 (95% CI 0.328 to 0.983) in hospital 4]. Conclusion Overall, the intervention did not reduce the number of emergency visits and hospital admissions. However, a significant effect was observed in centres were a high acceptance rate of treatment recommendations was achieved.

Data on genotypic distribution and linkage disequilibrium of several ANRIL polymorphisms in hemodialysis patients.

A long non-coding RNA called ANRIL located on chromosome 9p21.3 has been identified as a novel genetic factor associated with cardiovascular disease. Investigation of several single nucleotide polymorphisms (SNPs) of Noncoding Antisense RNA in the INK4 Locus (ANRIL) gene are of particular interest. This article reports data related to the research article entitled: "Association of ANRIL gene polymorphisms with major adverse cardiovascular events in hemodialysis patients" (Arbiol-Roca et al. [1]). Data presented show the genotypic distribution of four selected ANRIL SNPs: rs10757278, rs4977574, rs10757274 and rs6475606 in a cohort constituted by 284 hemodialysis patients. This article analyzes the Hardy-Weinberg disequilibrium of each studied SNP, and the linkage disequilibrium between them.

Association of ANRIL gene polymorphisms with major adverse cardiovascular events in hemodialysis patients.

BACKGROUND: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). Single nucleotide polymorphisms (SNPs) in ANRIL gene have been associated with higher cardiovascular morbidity and mortality in general population. The main objective was to ascertain whether ANRIL polymorphisms could identify risk of major adverse cardiovascular event (MACE) in patients starting on hemodialysis (HD). METHODS: This was a prospective observational cohort study. 284 CKD patients starting on HD were included in the study and followed until achievement of the primary end-point (MACE) or end of the study. All patients were genotyped for four ANRIL SNPs (rs10757278, rs4977574, rs10757274 and rs6475606). Kaplan-Meier curves and multivariate Cox survival analyses, together with multiple logistic regression were used to analyze the association between ANRIL SNPs and MACE. RESULTS: We found that ANRIL SNP rs10757278 was a representative SNP of a strong linkage disequilibrium block and showed significant genotypic associations with MACE in hemodialysis patients. Homozygous patients for the risk allele (GG) showed 2.17 (1.05-4.49) fold increased risk of MACE during hemodialysis than carriers of the protective allele (AA or AG). Diabetes mellitus was a strong enhancer of this effect. CONCLUSIONS: Our results indicate that ANRIL polymorphisms may confer risk to development of MACE in incident patients on hemodialysis.

Contribution of Population Pharmacokinetics to Dose Optimization of Ganciclovir-Valganciclovir in Solid-Organ Transplant Patients.

Treatment of solid-organ transplant (SOT) patients with ganciclovir (GCV)-valganciclovir (VGCV) according to the manufacturer's recommendations may result in over- or underexposure. Bayesian prediction based on a population pharmacokinetics model may optimize GCV-VGCV dosing, achieving the area under the curve (AUC) therapeutic target. We conducted a two-arm, randomized, open-label, 40% superiority trial in adult SOT patients receiving GCV-VGCV as prophylaxis or treatment of cytomegalovirus infection. Group A was treated according to the manufacturer's recommendations. For group B, the dosing was adjusted based on target exposures using a Bayesian prediction model (NONMEM). Fifty-three patients were recruited (27 in group A and 26 in group B). About 88.6% of patients in group B and 22.2% in group A reached target AUC, achieving the 40% superiority margin (P< 0.001; 95% confidence interval [CI] difference, 47 to 86%). The time to reach target AUC was significantly longer in group A than in group B (55.9 ± 8.2 versus 15.8 ± 2.3 days,P< 0.001). A shorter time to viral clearance was observed in group B than in group A (12.5 versus 17.6 days;P= 0.125). The incidences of relapse (group A, 66.67%, and group B, 9.01%) and late-onset infection (group A, 36.7%, and group B, 7.7%) were higher in group A. Neutropenia and anemia were related to GCV overexposure. GCV-VCGV dose adjustment based on a population pharmacokinetics Bayesian prediction model optimizes GCV-VGCV exposure. (This study has been registered at ClinicalTrials.gov under registration no. NCT01446445.).

The anterior hanging-approach improves postoperative course after right hepatectomy in patients with colorectal liver metastases. Results of a prospective study with propensity-score matching comparison.

PURPOSE: To establish the role of the anterior approach with liver hanging maneuver for right hepatectomy in patients with colorectal liver metastases (CRLM). SUMMARY BACKGROUND DATA: The indications for hepatectomy in patients with CRLM are expanding. The liver remnant must be protected to avoid morbidity. METHODS: We prospectively enrolled all patients with the diagnosis of CRLM requiring right hepatectomy from 2009 to 2012. In all cases right hepatectomy with an anterior-hanging maneuver approach was attempted. We compared the group of patients who underwent this procedure with a group of patients who had previously undergone a conventional right hepatectomy. To minimize selection bias, propensity score matching was performed, based on baseline patient characteristics. RESULTS: A right hepatectomy was planned in 57 cases. The anterior-hanging approach was feasible in 85% of cases. Overall morbidity was similar. In-hospital mortality due to hepatic insufficiency was 2.3% in anterior-hanging group compared to 9% in the conventional group (p = 0.30). The incidence of ascites was significantly greater in the conventional group (AH: 18% vs Conv: 54%; p = 0.002), and hospital stay was longer (AH: 10.9 ± 5.7 vs Conv: 14.4 ± 8.1 days; p = 0.05). Bilirubin levels were significantly lower in anterior-hanging group in day 1 and 3. There were no differences on recurrence nor survival. CONCLUSIONS: The anterior-hanging approach for right hepatectomy in patients with CRLM can be used safely with a high feasibility rate. Its use contributes to improve postoperative course.

Use of mycophenolate in ANCA-associated renal vasculitis: 13 years of experience at a university hospital.

INTRODUCTION: Standard therapy with corticosteroids (CS) and cyclophosphamide (CYC) followed by azathioprine has been shown to improve renal and patient survival in ANCA-associated renal vasculitis (rAAV). Mycophenolate mofetil (MF) has been progressively introduced for the treatment of rAAV in the last years because of its immunosuppressive efficacy combined with a lower toxicity profile. In this study, we retrospectively analyse the results of the introduction of MF for maintenance and induction therapy in rAAV in our institution from 2001 to 2013. RESULTS: We reported 67 patients treated with MF as a maintenance treatment, divided by baseline serum creatinine (>500 µmol/L: Group 1 and <500 µmol/L: Group 2) and treatment schedule. Twenty-nine of the 67 patients were also treated with MF as induction treatment, mostly in Group 2. During the follow-up (2 years after the diagnosis) creatinine levels for serum glomerular filtration rate, ANCA titres, C-reactive protein and percentage of haematuria decreased in all groups. In Group 2, parameters and also relapse rates were similar at 24 months in patients treated with CYC or MF as an induction treatment (Subgroups 2a and 2b, respectively). Median dose of MF in maintenance treatment was 1000 mg daily and prednisone dose was tapered to 10 mg daily from Month 3. After 24 months, 82% of patients remained on MF therapy, 18% had discontinued the treatment, seven of them due to medical indication and two because of gastrointestinal intolerance. The percentage of patients that started renal replacement therapy was irregular in Group 1 depending on the subgroup (25-100%), and 10% in Group 2. Adverse effects, such as neutropenia, infections and neoplasia, were more prevalent in groups treated with CYC. CONCLUSION: In conclusion, in our patients with rAAV, MF demonstrated to be an effective and well-tolerated option for maintenance treatment. As an induction treatment, MF seems to be similar to CYC for patients with moderate renal failure in the diagnosis.

Sterile leukocyturia is associated with interstitial fibrosis and tubular atrophy in kidney allograft protocol biopsies.

Kidney allograft interstitial fibrosis and tubular atrophy (IF/TA) is associated with a poorer renal function and outcome. In the current clinical practice, an early diagnosis can only be provided by invasive tests. We aimed to investigate the association of sterile leukocyturia with Banff criteria histological findings in kidney allograft protocol biopsies. We studied 348 allograft biopsies from two different European countries performed at 8.5 + 3.5 months after transplantation. In these cases, the presence of sterile leukocyturia (Leuc+, n = 70) or no leukocyturia (Leuc-, n = 278) was analyzed and related to Banff elementary lesions. Only IF/TA was significantly different between Leuc+ and Leuc- groups. IF/TA was present in 85.7% of Leuc+ and 27.7% of Leuc- patients (p < 0.001). IF/TA patients had higher serum creatinine and presence of proteinuria (p < 0.05). Independent predictors of IF/TA were donor age, donor male sex, serum creatinine and Leuc+ (hazard ratio 18.2; 95% confidence interval, 8.1-40.7). The positive predictive value of leukocyturia for predicting IF/TA was 85.7% whereas the negative predictive value was 72.3%. These studies suggest that leukocyturia is a noninvasive and low-cost test to identify IF/TA. An early diagnosis may allow timely interventional measures directed to minimize its impact and improve graft outcome.

Pretransplant immediately early-1-specific T cell responses provide protection for CMV infection after kidney transplantation.

Cytomegalovirus (CMV) infection is still a major complication after kidney transplantation. Although cytotoxic CMV-specific T cells play a crucial role controlling CMV survival and replication, current pretransplant risk assessment for CMV infection is only based on donor/recipient (IgG)-serostatus. Here, we evaluated the usefulness of monitoring pre- and 6-month CMV-specific T cell responses against two dominant CMV antigens (IE-1 and pp65) and a CMV lysate, using an IFN-γ Elispot, for predicting the advent of CMV infection in two cohorts of 137 kidney transplant recipients either receiving routine prophylaxis (n = 39) or preemptive treatment (n = 98). Incidence of CMV antigenemia/disease within the prophylaxis and preemptive group was 28%/20% and 22%/12%, respectively. Patients developing CMV infection showed significantly lower anti-IE-1-specific T cell responses than those that did not in both groups (p < 0.05). In a ROC curve analysis, low pretransplant anti-IE-1-specific T cell responses predicted the risk of both primary and late-onset CMV infection with high sensitivity and specificity (AUC > 0.70). Furthermore, when using most sensitive and specific Elispot cut-off values, a higher than 80% and 90% sensitivity and negative predictive value was obtained, respectively. Monitoring IE-1-specific T cell responses before transplantation may be useful for predicting posttransplant risk of CMV infection, thus potentially guiding decision-making regarding CMV preventive treatment.

Dendritic cells phenotype fitting under hypoxia or lipopolysaccharide; adenosine 5'-triphosphate-binding cassette transporters far beyond an efflux pump.

This study examines adenosine 5'-triphosphate-binding cassette (ABC) transporters as a potential therapeutic target in dendritic cell (DC) modulation under hypoxia and lipopolysaccharide (LPS). Functional capacity of dendritic cells (DCs) (mixed lymphocyte reaction: MLR) and maturation of iDCs were evaluated in the presence or absence of specific ABC-transporter inhibitors. Monocyte-derived DCs were cultured in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). Their maturation under hypoxia or LPS conditions was evaluated by assessing the expression of maturation phenotypes using flow cytometry. The effect of ABC transporters on DC maturation was determined using specific inhibitors for multi-drug resistance (MDR1) and multi-drug resistance proteins (MRPs). Depending on their maturation status to elicit T cell alloresponses, the functional capacity of DCs was studied by MLR. Mature DCs showed higher P-glycoprotein (Pgp) expression with confocal microscopy. Up-regulation of maturation markers was observed in hypoxia and LPS-DC, defining two different DC subpopulation profiles, plasmacytoid versus conventional-like, respectively, and different cytokine release T helper type 2 (Th2) versus Th1, depending on the stimuli. Furthermore, hypoxia-DCs induced more B lymphocyte proliferation than control-iDC (56% versus 9%), while LPS-DCs induced more CD8-lymphocyte proliferation (67% versus 16%). ABC transporter-inhibitors strongly abrogated DC maturation [half maximal inhibitory concentration (IC50 ): P-glycoprotein inhibition using valspodar (PSC833) 5 µM, CAS 115104-28-4 (MK571) 50 µM and probenecid 2·5 µM], induced significantly less lymphocyte proliferation and reduced cytokine release compared with stimulated-DCs without inhibitors. We conclude that diverse stimuli, hypoxia or LPS induce different profiles in the maturation and functionality of DC. Pgp appears to play a role in these DC events. Thus, ABC-transporters emerge as potential targets in immunosuppressive therapies interfering with DCs maturation, thereby abrogating innate immune response when it is activated after ischaemia.

Surgical treatment of biliary tract complications after liver transplantation.

OBJECTIVE: Biliary strictures are the most common biliary tract complication after liver transplantation. There are scarce data on the results of hepaticojejunostomy (HJ) in the management of biliary complications after orthotopic liver transplantation (OLT). Thus, the role of surgery in this setting remains to be established. The aim of this study was to evaluate the results of surgical treatment of patients with biliary complications at our institution. PATIENTS AND METHODS: We reviewed 1000 consecutive liver transplantations performed at our institution from 1984 to 2007. We used a prospectively recorded database to identify patients who underwent HJ to treat any biliary tract complication. RESULTS: Overall, 62 patients (6.2%) underwent HJ, 40 for an anastomotic and 7 for a non-anastomotic stricture as well as 15 for biliary leaks. Postoperative morbidity was 16%, and postoperative mortality 1.6%. There were 7 cases of anastomotic stenosis (11.3%). Four patients (5%) required retransplantation. CONCLUSIONS: HJ is a safe procedure to manage biliary complications after OLT. It may be the first treatment choice especially for cases with anastomotic strictures.

Long-term results of biopsy-guided selection and allocation of kidneys from older donors in older recipients.

In our old-for-old program, we discard or allocate older extended criteria donor kidneys to single (SKT) or dual kidney transplantation (DKT) depending on histological Remuzzi's score in recipients older than 60 years. Here, we analyze the long-term results of this program and try to identify independent predictors of patient and graft survival. Between December 1996 and January 2008, we performed 115 SKT and 88 DKT. Discard rate was 15%. Acute rejection incidence was higher in SKT than in DKT (22.6% vs. 11.4%, p = 0.04). Renal function was better in DKT than in SKT up to 5 years after transplantation. Surgical complications were frequent in DKT. Ten-year cumulative graft survival was significantly lower in the SKT group (31% vs. 53%, p = 0.03). In SKT, histological score 4 provided similar graft survival than 3 or less, whereas in DKT score 4, 5 or 6 displayed similar outcome. Finally, independent predictors of graft survival were history of major adverse cardiac event and 1-year serum creatinine, rather than SKT or DKT. In conclusion, this biopsy-guided old-for-old strategy resulted in acceptable long-term graft survival. Our results suggest that DKT should be considered for scores of 5 or 6 only.

Hepatocyte growth factor gene therapy enhances infiltration of macrophages and may induce kidney repair in db/db mice as a model of diabetes.

AIMS/HYPOTHESIS: We previously demonstrated hepatocyte growth factor (HGF) gene therapy was able to induce regression of glomerulosclerosis in diabetic nephropathy through local reparative mechanisms. The aim of this study was to test whether bone-marrow-derived cells are also involved in this HGF-induced reparative process. METHODS: We have created chimeric db/db mice as a model of diabetes that produce enhanced green fluorescent protein (EGFP) in bone marrow cells. We performed treatment with HGF gene therapy either alone or in combination with granulocyte-colony stimulating factor, in order to induce mobilisation of haematopoietic stem cells in these diabetic and chimeric animals. RESULTS: We find HGF gene therapy enhances renal expression of stromal-cell-derived factor-1 and is subsequently associated with an increased number of bone-marrow-derived cells getting into the injured kidneys. These cells are mainly monocyte-derived macrophages, which may contribute to the renal tissue repair and regeneration consistently observed in our model. Finally, HGF gene therapy is associated with the presence of a small number of Bowman's capsule parietal epithelial cells producing EGFP, suggesting they are fused with bone-marrow-derived cells and are contributing to podocyte repopulation. CONCLUSIONS/INTERPRETATION: Altogether, our findings provide new evidence about the therapeutic role of HGF and open new opportunities for inducing renal regeneration in diabetic nephropathy.

Peginterferon alfa-2b plus weight-based ribavirin for 24 weeks in patients with chronic hepatitis C virus genotype 1 with low viral load who achieve rapid viral response.

In chronic hepatitis C (CHC), treatment duration may be individualized according to time to first undetectable hepatitis C virus (HCV) RNA, with patients who attain undetectable HCV RNA early in treatment being candidates for shorter regimens. The aim of this study was to determine the relapse rate in patients with CHC genotype (G) 1 infection and low baseline viral load who achieved undetectable HCV RNA by week 4 [rapid virologic response (RVR)] when treated for 24 weeks. This was an open-label, multicentre, noninterventional study. Adult patients with G1 CHC infection and baseline viral load <600,000 IU/mL who attained RVR were treated with peginterferon alfa-2b (1.5 µg/kg/week) plus ribavirin (800-1200 mg/day) for 24 weeks, then followed for a further 24 weeks. The primary endpoint was relapse rate, defined as the proportion of patients with undetectable HCV RNA at treatment week 24 and detectable HCV RNA at week 24 follow-up. The secondary efficacy endpoint was sustained virologic response (SVR). Overall, 170 patients were included in the efficacy-evaluable population. The relapse rate was 9.7% (16/165, 95% confidence interval: 0.06-0.15), and SVR was attained by 149 of 170 patients (87.6%). Virologic outcomes were consistent regardless of age, gender, body weight and genotype. Seven patients reported treatment-emergent serious adverse events (AEs), and four patients discontinued treatment because of an AE. This study further demonstrates that peginterferon alfa-2b plus weight-based ribavirin for 24 weeks is an effective treatment strategy for treatment-naive patients with G1 CHC and low viral load who attain RVR.

Determination of ganciclovir in human plasma by ultra performance liquid chromatography-UV detection.

OBJECTIVES: Implement a sensitive UHPLC method for the assay of ganciclovir in human plasma. DESIGN AND METHODS: We developed and validated a chromatographic method coupled to ultraviolet detection for quantification of ganciclovir, with a short run time using a small volume of human plasma. Comparison of system performance was made with respect to analysis time, efficiency and sensitivity. RESULTS: Correlation coefficients (r) of the calibration curves ranged from 0.999744 to 0.999784. Within-day and between-day imprecision and inaccuracy, specificity and recovery were also evaluated for validation. The method was precise and accurate and the retention time was 0.7 min. The calibration curves were linear between 0.5 and 30 µg/mL. There was a good correlation between HPLC and UHPLC techniques. CONCLUSIONS: We developed a method that is currently applied in a clinical study assessing GCV plasma concentration variability after ganciclovir and valganciclovir administration.