Short communication: Risk factors associated with Mycobacterium avium ssp. paratuberculosis introduction into dairy herds in Galicia, northwestern Spain.

This study assessed potential risk factors associated with introduction of Mycobacterium avium ssp. paratuberculosis (MAP) into dairy cattle herds in the Galicia region, northwestern Spain. The study was carried out with data collected from 93 dairies enrolled in a voluntary MAP control program. Information on potential risk factors was obtained through personal interviews with the farmers and veterinarians in charge of the control program of each farm. In addition, blood samples were taken annually over 2 years from cows on the farms in the program, and analyzed with a commercial ELISA to detect antibodies to MAP. Fecal samples of all ELISA-positive cows were analyzed using PCR. Based on χ2 test and Fisher's exact test, purchase practices, shared manure truck, shared materials, and visitors per month who contacted animals were found to be significantly associated with farm MAP infection status. Multiple logistic regression indicated that purchase practices and herd size (included as a potential confounder) are the variables that best predict MAP status.

REFINE: a randomized trial comparing cyclosporine A and tacrolimus on fibrosis after liver transplantation for hepatitis C.

REFINE was a 12-month, prospective, open-label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL-2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA-treated patients (71.6%) and 52/77 tacrolimus-treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between-group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid-free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus- and CsA-treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy-proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV-induced liver fibrosis between patients treated with CsA or tacrolimus in steroid-containing regimens, whereas CsA in steroid-free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant.

MicroRNA signature at the time of clinical HCV recurrence associates with aggressive fibrosis progression post-liver transplantation.

Diagnosis and prediction of the severity of hepatitis C virus recurrence (HCVrec) after liver transplantation (LT) remain a challenge. MicroRNAs have been recently recognized as potential disease biomarkers. Archival liver biopsy samples from 43 HCV+ LT recipients were collected at clinical HCVrec time and at 3 years post-LT. Patients were classified as progressors (P = F0/F1) or nonprogressors (NP = F3/F4) according to the severity of fibrosis on the 3-year biopsy. Training (n = 27) and validation (n = 16) sets were defined. RNA was isolated from all biopsies at clinical HCVrec time, labeled and hybridized to miRNA-arrays. Progressors versus nonprogressors were compared using the two-sample t-test. A p-value ≤0.01 was considered significant. The ingenuity pathway analysis tool was used for microRNA and miRNA:mRNA ontology data integration. Nine microRNAs were differentially expressed between groups. A supervised cluster analysis separated samples in two well-defined groups (progressors vs. nonprogressors). Pathway analysis associated those microRNAs with hepatitis, steatosis, fibrosis, cirrhosis and T cell-related immune response. Data integration identified 17 genes from a previous genomic study as 9-microRNAs signature targets. Seven microRNAs were successfully validated in the validation set using QPCR. We have identified a 9-microRNA signature able to identify early post-LT patients at high risk of severe HCVrec during long-term follow-up.

Posterior fossa endoscopic-assisted surgery: A systematization of its surgical corridors.

INTRODUCTION: The use of endoscopic-assisted techniques in neurosurgery has been implemented to improve better visualization and predict extent of resection. We aim to systematize the posterior fossa surgical regions and the endoscopic surgical corridors providing a quick reference of the anatomy and surgical nuances. METHODS: A retrospective review of patients undergoing endoscopic-assisted surgery of the posterior fossa at a single institution between 2019 and 2020 was conducted along with a description of the microsurgical anatomy from cadaveric specimens and surgical cases. RESULTS: The posterior fossa was segmented into three topographic regions, (upper, middle and lower), with three surgical corridors within each of these. Upper region is accessed through a supracerebellar infratentorial approach and comprises the pineal and pericuadrigeminal region constituted by the median corridor, the lateral corridor, and the extreme lateral corridor. Middle region is accessed through a retrosigmoid approach and comprises the cerebellopontine angle region constituted by the supralateral corridor containing the upper neurovascular complex (NVC), the median corridor containing the median NVC, and the infralateral corridor containing the lower NVC. The lower region is accessed through a far-lateral approach and contains the craniocervical junction region constituted by the upper corridor in between the VII-VIII and IX cranial nerves (CNs), the median corridor between the X and XI CNs, and the lower corridor between the cranial and spinal rootlets of the XI CN. CONCLUSION: We propose a simple and concise systematization, dividing the area into three regions with predefined corridors.

Liver transplantation in systemic lupus erythematosus: case report and review of the literature.

Severe liver involvement requiring liver transplantation is a rare complication in systemic lupus erythematosus (SLE), but very few cases have been reported. We describe a 39-year-old woman with SLE who underwent successful liver transplantation due to acute liver failure. The patient persisted without reactivation of SLE and with good long-term survival. Management and diagnosis considerations are reviewed.

Azathioprine in liver transplantation: a reevaluation of its use and a comparison with mycophenolate mofetil.

Calcineurin inhibitors (CNIs) combined with steroids with or without azathioprine (AZA), have been a standard immunosuppression regimen after liver transplantation (LT). Since 2000 many centers have substituted AZA by mycophenolate mofetil (MMF). However, in LT the superiority of MMF over AZA is not clearly demonstrated. Therefore, we questioned the benefit of MMF versus AZA in LT with regard to rejection, renal dysfunction and hepatitis C virus (HCV) recurrence and survival. Using a literature search, relevant randomized controlled trials (RCT) and cohort studies were identified: two RCTs compared MMF to AZA only for acute rejection. Treated rejection was less with MMF in only one RCT (38.5% vs. 47.7%; p = 0.025), with no difference in patient and graft survival. No RCTs compared MMF and AZA in patients with CNI-related chronic renal dysfunction. Among two studies evaluating MMF, with substitution of AZA, one was stopped due to severe rejection. Recurrent HCV was less severe in 5/9 studies with AZA compared with 2/17 using MMF, six of which documented worse recurrence. Published data in LT show little, if any, clinical benefit of MMF versus AZA. RCTs should reevaluate AZA in LT. Evaluation of HCV replication and recurrence will be particularly important as AZA may have advantages over MMF.

Review article: the treatment of hepatitis C virus recurrence after liver transplantation.

BACKGROUND: Recurrent hepatitis C represents a major challenge for the liver transplant community. Given the potentially significant impact that hepatitis C recurrence has on graft and patient survival, several treatment strategies have been utilized to prevent/slow the progression to hepatitis C-related graft failure. AIM: To review the efficacy and applicability of treatment strategies for managing recurrent hepatitis C. METHODS: Search of MEDLINE (1990 to December 2006) and national meeting abstracts. Search terms included hepatitis C, liver transplantation, treatment, sustained virological response (SVR), and end of treatment virological response. An emphasis was placed on randomized trials. RESULTS: The largest study of treatment prior to liver transplantation (n = 124) achieved SVR in 24%. Eight randomized trials (n = 383) examined the efficacy of preemptive therapy with SVR ranging from 0-33%. Eligibility for treatment was low and dose reduction common. Four randomized trials (n = 245; all abstracts) have reported SVR from 33-42% for treating those with histological evidence of recurrent disease. CONCLUSIONS: Therapies for treating hepatitis C recurrence have limited applicability and tolerability, and they have a low SVR. Based on available results, preemptive therapy is not recommended. Pegylated interferon and ribavirin is currently the preferred choice for treating established recurrence. There is an urgent need for safer and more effective anti-viral therapy in this situation.

Early hyponatraemia after pituitary surgery: cerebral salt-wasting syndrome.

Hyponatraemia is a common complication in patients undergoing neurosurgery. It can be caused either by the syndrome of inappropriate secretion of antidiuretic hormone or by the cerebral salt-wasting syndrome (CSWS). CSWS frequently occurs in patients suffering from subarachnoid haemorrhage and brain injury, but it is rare after pituitary tumour surgery. However, this diagnostic possibility should be considered as these disorders require specific treatment and have different prognoses. In this article, we present a case of acute and early hyponatraemia caused by CSWS after pituitary tumour surgery. We also revise the aetiology, mechanisms, differential diagnosis and treatment of hyponatraemia after pituitary surgery.

Long-term outcomes in liver transplant patients with hepatic C infection receiving tacrolimus or cyclosporine.

Choice of calcineurin inhibitor may be a contributing factor to deteriorating patient and graft survival following liver transplantation for hepatitis C virus (HCV). In our multicenter, open-label LIS2T study, de novo liver transplant patients stratified by HCV status were randomized to cyclosporine or tacrolimus. Follow-up data were obtained in an observational study of 95 patients. Mean follow-up was 34 and 37 months, respectively, for cyclosporine-treated (n = 47) and tacrolimus-treated (n = 48) patients. In patients not receiving antiviral therapy, 22 of 31 given cyclosporine (72%) and 24 of 29 given tacrolimus (83%) had biochemical recurrence of HCV. In 68 patients with at least one biopsy, histological evidence of HCV-related hepatitis was present in 27 of 31 (87%) cyclosporine-treated patients and 37 of 37 (100%) tacrolimus-treated patients (P = .02, chi-square test). Three-year actuarial risk of fibrosis stage 2 was 66% with cyclosporine and 90% with tacrolimus; for fibrosis stage 3 or 4 it was 46% and 80%, respectively. Three graft losses were attributed to HCV recurrence in cyclosporine-treated patients and six in tacrolimus-treated patients. Tacrolimus may be associated with increased risk of histological HCV disease recurrence compared to cyclosporine.

Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2).

BACKGROUND: A prospective, open-label, study was conducted at 29 centers in 9 countries, involving 307 de novo liver transplant patients to compare the clinical usefulness of monitoring 2-hr post-dose cyclosporine (CsA) levels (C2) with conventional trough cyclosporine blood levels (pre-dose) (C0). METHODS: Neoral oral therapy was initiated at 15 mg/kg/day and dose adjusted according to predetermined C2 or C0 target level ranges. The primary efficacy variable was treatment failure at 3 months, where evaluation was based on a composite endpoint of biopsy-proven rejection, treatment for rejection, graft loss, death, or premature withdrawal/discontinuation from the study. RESULTS: Baseline characteristics were similar between groups. Graft loss at 12 weeks (retransplantation or death) occurred in 6.8% C2 and in 7.0% C0 patients. Overall incidence of treated acute rejection was lower for C2 (23.6%) than C0 patients (31.6%) (P=0.144, Cochran-Mantel-Haenszel [CMH] test). In hepatitis C virus (HCV)-negative patients, the incidence of rejection in the C2 group was significantly less than in the C0 group (21.2% vs. 33.0%; P<0.05), whereas in HCV-positive patients, the rejection rate was similar in both groups (26.7% for C2 group vs. 27.3% for C0 group: P=0.81). C2 patients (n=16) who reached minimum target CsA levels by day 3 had a notably low incidence of rejection (12.5%), whereas there was no difference in the incidence of rejection in C0 patients, irrespective of time to reach target level. For biopsy-proven acute rejections (21.6% for C2 vs. 30.4% for C0), the incidence of moderate and severe histological diagnosis was significantly lower in the C2 group than in the C0 group (47% vs. 73%; P=0.01). Safety profiles were similar between the two groups, with few patient withdrawals due to adverse events (9.5% for C2; 7.0% for C0). CONCLUSIONS: Using C2 monitoring, the overall incidence of acute cellular rejection was lower compared with the C0 group, and the histological severity of acute rejections was shown to be significantly milder for the C2 group, indicative of good long-term prognosis. These data demonstrate that the use of C2 monitoring is superior to C0 and results in a reduction in the incidence and severity of acute cellular rejection without detrimental effect on the drug safety profile.

Charge selectivity and urine amylase isoenzymes.

The urinary excretions of salivary and pancreatic amylase were studied in 718 type I diabetic patients and 51 control subjects, as part of a multicenter study on diabetic nephropathy in 15 Spanish hospitals. It was found that the urinary ratio of salivary to pancreatic amylase (S/P ratio), that in normal subjects is always below 1, was elevated in 35.4% of diabetic patients, whereas microalbuminuria was present in 19.8%. The prevalence of elevated S/P ratio was also higher than that of microalbuminuria at the first years from the onset of the disease, but the prevalence of microalbuminuria was higher in patients with a long duration of the disease. alpha 1-microglobulin and microalbuminuria paralleled their prevalences during the disease, when measured in a group of patients. Overnight urine samples were obtained on three consecutive weeks from the diabetic patients, and a nested ANOVA analysis showed that the intra-individual variation of the urine parameters measured (albumin, salivary and pancreatic amylase, and beta-NAG) was very small and not statistically significant. All these findings suggest that in type I diabetes mellitus, loss of negative charges of GBM would induce preferential excretion of the anionic salivary amylase over the more cationic pancreatic amylase, and that this phenomenon is more frequent and appears earlier than microalbuminuria. The mechanisms for the increased excretion of salivary amylase and albumin into urine seem to be at least partly different. On the contrary, increase in urinary excretion of albumin and alpha 1-microglobulin in these patients are correlated, suggesting a tubular participation in the mechanisms of production of microalbuminuria.

Utility of filtration markers to monitor the quality of glomerular function.

Diabetes mellitus can lead, along the years of its course, to chronic renal failure in a high proportion of cases. An early risk-indicator of later diabetic nephropathy is the presence of microalbuminuria, but it usually takes about fifteen to twenty years to appear. Before that, no clinical signs can disclose the underlying alterations of glomerular basement membrane that will eventually bring forth overt nephropathy. The usefulness of the altered excretion of isoenzymes of amylase as an early marker of the glomerular charge selectivity was tested in 202 juvenile onset insulin-dependent diabetics, compared with 51 normal subjects matched for age and sex. The diabetic patients studied showed increased excretion of salivary amylase into urine. The salivary to pancreatic amylase ratio of concentrations in urine was always below 1 in normal subjects, and was increased over 1 in 33.2% of diabetics, although microalbuminuria was present only in 26.2% of patients. The excretion of other proteins was within reference values in the majority of cases, indicating that the kidney was not seriously affected in those patients. Moreover, the altered salivary to pancreatic amylase ratio in urine was more prevalent than microalbuminuria (36.6% vs 18%) in the first decade of the evolution of the diabetes. These results indicate that the ratio of excretions of both isoamylases into urine is a more sensible and earlier marker of altered glomerular charge barrier for anionic proteins.

[Treatment of macroprolactinomas with delayed bromocriptine. Effectiveness of a single intramuscular injection]. / Tratamiento de macroprolactinomas con bromocriptina retardada. Eficacia de una sola inyección intramuscular.

The aim of the present study was to evaluate the effectiveness and tolerance of a new pharmaceutical preparation of long acting bromocryptine (bromocryptine depot of L.A.), characterized by the slow release of bromocryptine during 4 or 6 weeks after a deep intramuscular injection. It was administered to 9 patients with macroprolactinoma, 7 of which had visual abnormalities. The tolerance of the drug was excellent, and only one patient had nausea within the first 24 hours. In all cases, PRL values fell between 40% and 97%. All patients with visual abnormalities, including 2 patients with cranial nerve palsy (IIIth and VIIth pairs) returned to normal or improved. In the CT controls carried out after 4 weeks of therapy a reduction in tumor size was observed in 7 of 9 patients. Two patients were operated through the transesphenoidal route, PRL being demonstrated in the immunohistochemical study of the resected specimen. Subsequently, all patients received oral bromocryptine therapy with perfect tolerance. The results show that parenteral long acting bromocryptine is an effective, well tolerated and convenient way to start the therapy of macroprolactinoma, even when severe visual abnormalities are present.

[Long-acting and repeatable dose bromocriptine in the prolonged treatment of prolactinoma]. / Bromocriptina de acción prolongada y de administración repetible en el tratamiento prolongado de los prolactinomas.

BACKGROUND: The presentations of intravenous or depot bromocriptine (bromocriptine LA or long acting, Pariodel LA and bromocriptine LAR or long acting repeatable, Pariodel LAR) have improved the efficacy and the tolerance of oral bromocriptine. In contrast to bromocriptine LA, bromocriptine LAR may be repeatedly administered intramuscularly. METHODS: Five patients with macroprolactinoma and 4 with microprolactinoma were included in the study. A 50 mg bottle of bromocriptine LAR was administered intramuscularly every month, over a minimum period of 6 months. PRL was determined prior to the study, 1, 3, 7, 14, and 28 days following the initial dose of bromocriptine and thereafter with monthly periodicity. RESULTS: The PRL values decreased in those patients with macroprolactinomas following the administration of bromocriptine LAR; in 2 patients the monthly doses of bromocriptine LAR was increased to 100 mg since the month after the initial dose PRL remained greater than 200 ng/ml with serum RPL normalizing in most of the patients at 6 months of treatment. In two of the three patients who presented visual changes a clear improvement was observed and in all the cases a reduction in the size of the macroprolactinoma was found upon CAT control at 6 months. The PRL values also decreased in the patients with microprolactinomas following administration of bromocriptine LAR, although the response was not as homogeneous as in the patients with macroprolactinomas due to that at 6 months 2 patients continued to have slightly elevated serum PRL levels. The microadenoma persisted in the control CAT at 6 months except in one case. Local and general tolerance to bromocriptine LAR was very good. CONCLUSIONS: This study indicates good tolerance to bromocriptine LAR, being a therapeutic option in the treatment of macroprolactinomas.

[Somatostatin in the emergency treatment of upper digestive hemorrhage in patients with portal hypertension]. / Somatostatina en el tratamiento de emergencia de la hemorragia digestiva alta en hipertensos portales.

During a 2-yr period 15 patients (17 episodes) with variceal bleeding (VB) and 7 with cirrhosis and acute gastroduodenal haemorrhage (GDH) received intravenous somatostatin (250 mcg per hr after a bolus of 250 mcg). Initial control of bleeding was achieved in 13 (76%) with VB and in all with GDH. Three of the 4 patients with VB and 2 with GDH who rebled during treatment were controlled increasing the infusion to 500 mcg/hr. Patients with VB received somatostatin for 24 hrs, time selected for initiating injection sclerotherapy, and those with GDH for 48-72 hrs. At 24 hrs 71% of patients with VB and all with GDH were free of bleeding. Combining different therapies VB was controlled in 16 of the 17 episodes (94%) with only one death. No complications were observed in any of the 22 patients treated.