Low cytomegalovirus seroprevalence in early multiple sclerosis: a case for the 'hygiene hypothesis'?

BACKGROUND AND PURPOSE: Cytomegalovirus (CMV) infection has recently been associated with a lower multiple sclerosis (MS) susceptibility, although it remains controversial whether it has a protective role or is merely an epiphenomenon related to westernization and early-life viral infections. We aimed to evaluate whether CMV serostatus may differ in patients with early MS as compared with patients with non-early MS, analyzing the putative association of this virus with MS clinical course and humoral immune responses against other herpesviruses. METHODS: Multicentric analysis was undertaken of 310 patients with MS (early MS, disease duration ≤5 years, n = 127) and controls (n = 155), evaluating specific humoral responses to CMV, Epstein-Barr virus and human herpesvirus-6, as well as T-cell and natural killer (NK)-cell immunophenotypes. RESULTS: Cytomegalovirus seroprevalence in early MS was lower than in non-early MS or controls (P < 0.01), being independently associated with disease duration (odds ratio, 1.04; 95% confidence interval, 1.01-1.08, P < 0.05). CMV+ patients with MS displayed increased proportions of differentiated T-cells (CD27-CD28-, CD57+, LILRB1+) and NKG2C+ NK-cells, which were associated with a lower disability in early MS (P < 0.05). CMV+ patients with early MS had an age-related decline in serum anti-EBNA-1 antibodies (P < 0.01), but no CMV-related differences in anti-human herpesvirus-6 humoral responses. CONCLUSIONS: Low CMV seroprevalence was observed in patients with early MS. Modification of MS risk attributed to CMV might be related to the induction of differentiated T-cell and NK-cell subsets and/or modulation of Epstein-Barr virus-specific immune responses at early stages of the disease.

Successful restoration of corneal surface integrity with a tissue-engineered allogeneic implant in severe keratitis patients.

OBJECTIVES: Corneal diseases are among the main causes of blindness, with approximately 4.6 and 23 million patients worldwide suffering from bilateral and unilateral corneal blindness, respectively. The standard treatment for severe corneal diseases is corneal transplantation. However, relevant disadvantages, particularly in high-risk conditions, have focused the attention on the search for alternatives. METHODS: We report interim findings of a phase I-II clinical study evaluating the safety and preliminary efficacy of a tissue-engineered corneal substitute composed of a nanostructured fibrin-agarose biocompatible scaffold combined with allogeneic corneal epithelial and stromal cells (NANOULCOR). 5 subjects (5 eyes) suffering from trophic corneal ulcers refractory to conventional treatments, who combined stromal degradation or fibrosis and limbal stem cell deficiency, were included and treated with this allogeneic anterior corneal substitute. RESULTS: The implant completely covered the corneal surface, and ocular surface inflammation decreased following surgery. Only four adverse reactions were registered, and none of them were severe. No detachment, ulcer relapse nor surgical re-interventions were registered after 2 years of follow-up. No signs of graft rejection, local infection or corneal neovascularization were observed either. Efficacy was measured as a significant postoperative improvement in terms of the eye complication grading scales. Anterior segment optical coherence tomography images revealed a more homogeneous and stable ocular surface, with complete scaffold degradation occurring within 3-12 weeks after surgery. CONCLUSIONS: Our findings suggest that the surgical application of this allogeneic anterior human corneal substitute is feasible and safe, showing partial efficacy in the restoration of the corneal surface.

Serum cholesterol levels and survival after rtPA treatment in acute stroke.

BACKGROUND: According to the reverse epidemiology hypothesis, high cholesterol levels might be protective and associated with greater survival rates under certain conditions. In stroke patients, a clear correlation between lipid levels and mortality after ischaemic and hemorrhagic strokes has been demonstrated. The aim of this study was to analyze the impact of lipid levels on 3-month mortality in patients with ischaemic stroke (IS) homogeneously treated with intravenous rtPA and admitted to a monitored acute stroke unit. METHODS: Retrospective analysis of a prospective cohort of 220 patients with an IS treated with rtPA within the first 4.5 h in a single tertiary hospital from January 2005 to August 2010. RESULTS: Mortality at 3 months was 15.0%. Univariate analysis showed that age, NIHSS at admission, heart failure, and atrial fibrillation were directly related to 3-month mortality; cholesterol, triglycerides, and low density lipoprotein were inversely associated. The death rate by cholesterol level was 5.5% for the highest tertile (>192 mg/dl), 13.7% for the middle (192-155 mg/dl), and 25.7% for the lowest (<155 mg/dl), P = 0.003. Multivariate analysis showed that amongst the lipid determinations, only cholesterol [OR: 0.985 (95% CI: 0.972-0.998), P = 0.021] was inversely associated with 3-month mortality. The 'protective' effect of cholesterol was independent of stroke severity and remained significant in non-lacunar strokes. CONCLUSIONS: Survival of stroke patients receiving current, most effective medical treatment is related to blood cholesterol levels, with an inverse relationship between cholesterol and mortality. The mechanism of this apparently paradoxical situation remains unexplained but merits further research.

Natural killer cell phenotype and clinical response to interferon-beta therapy in multiple sclerosis.

CD56(bright) NK cells, which may play a role in immunoregulation, are expanded in multiple sclerosis (MS) patients treated with immunomodulatory therapies such as daclizumab and interferon-beta (IFNß). Yet, whether this NK cell subset is directly involved in the therapeutic effect is unknown. As NK receptor (NKR) expression by subsets of NK cells and CD8+ T lymphocytes is related to MS clinical course, we addressed whether CD56(bright) NK cells and NKR in IFNß-treated MS patients differ according to the clinical response. IFNß was associated to lower LILRB1+ and KIR+NK cells, and higher NKG2A+NK cell proportions, an immunophenotypic pattern mainly found in responders. After IFNß treatment, a CD56(bright) NK cell expansion was significantly related to a positive clinical response. Our results reveal that IFNß may promote in responders changes in the NK cell immunophenotype, corresponding to the profile found at early maturation stages of this lymphocyte lineage.

Natural killer receptors distribution in multiple sclerosis: Relation to clinical course and interferon-beta therapy.

NK cell receptors (NKR) are expressed in subsets of NK and CD8+ T cells, lymphocytes involved in multiple sclerosis (MS) pathogenesis. Clinical implications of NKR expression in MS are unknown. Here, we show that the proportions of CD8+ T cells displaying LILRB1, an inhibitory NKR expressed at late stages of T cell differentiation, were directly related with age and MS duration, and inversely with the immunomodulatory therapy-dependent increase of CD56(bright) NK cells. Similar associations were found for KIR+ and CD56+ CD8+ T cells, whereas no age-related NKR distribution was perceived in controls. Moreover, active MS had lower LILRB1+ NK cells, and IFN-ß-treated patients exhibited a phenotypic profile related to shorter disease evolution. Progressive accumulation of terminally differentiated T lymphocytes and experienced NK cells in MS, presumably stimulated in response to a persistent challenge and modulated by IFN-ß therapy, may support the analysis of NKR distribution as new biomarkers.

Multiple sclerosis associates with LILRA3 deletion in Spanish patients.

The genetic susceptibility to multiple sclerosis (MS) is only partially explained, and it shows geographic variations. We analyse here two series of Spanish patients and healthy controls and show that relapsing MS (R-MS) is associated with a gene deletion affecting the hypothetically soluble leukocyte immunoglobulin (Ig)-like receptor A3 (LILRA3, 19q13.4), in agreement with an earlier finding in German patients. Our study points to a gene-dose-dependent, protective role for LILRA3, the deletion of which synergizes with HLA-DRB1(*)1501 to increase the risk of R-MS. We also investigated whether the risk of suffering R-MS might be influenced by the genotypic diversity of killer-cell Ig-like receptors (KIRs), located only approximately 400 kb telomeric to LILRA3, and implicated in autoimmunity and defence against viruses. The relationship of LILRA3 deletion with R-MS is not secondary to linkage disequilibrium with a KIR gene, but we cannot exclude some contributions of KIR to the genetic susceptibility to R-MS.

Clustering of vascular risk factors and in-hospital death after acute ischemic stroke.

OBJECTIVE: to evaluate the influence of clustering of vascular risk factors (VRF) on in-hospital mortality in patients with acute ischemic stroke (AIS) developing a risk score for mortality prediction. METHODS: clinical data from 1527 patients admitted to hospital with a first-ever AIS were prospectively evaluated from 1997 to 2005 assessing the presence of six VRF: diabetes, hypertension, hyperlipidemia, ischemic heart disease, atrial fibrillation and peripheral arterial disease. A composite vascular risk score (VRS) was created using five risk factors. Hyperlipidemia was excluded from the score due to its protective impact on mortality. Two modified VRS models were created and assessed for their accuracy as predictors for in-hospital mortality based on the odds ratio for each VRF obtained in the univariate analysis. RESULTS: 197 patients (12.9 %) died during the acute hospitalization period. Stroke severity increased with each additional VRF (p = 0.002). Cox proportional hazards model adjusted for confounders showed an association between the composite VRS and in-hospital mortality (p = 0.045). According to the clustering of VRS, the risk for in-hospital death increased from 1.951 (95 % CI 1.041-3.665) for patients having one VRS to 2.343 (95% CI 1.081-5.076) for those having a VRS > or = 4. ROC curves showed that the modified VRS model based on a given value of one for each accumulated VRF, including the absence of hyperlipidemia, had the highest predictive capability for in-hospital mortality (p < 0.0001). CONCLUSIONS: the presence of multiple VRF in patients with acute ischemic stroke increases the stroke severity and the risk of in-hospital death.

Cladribine in aggressive forms of multiple sclerosis.

Cladribine (2-chlorodeoxyadenosine) is an immunosuppressant drug previously evaluated in multiple sclerosis (MS) with variable results. We report six patients with aggressive relapsing MS who despite a poor response to other therapies had a favourable clinical evolution after cladribine. Four women and two men with a rapid increase in the number and severity of relapses leading to increasing disability [mean Expanded Disability Status Scale (EDSS) 6.42, standard deviation +/- 0.58, mean relapse rate per year in the 2 years prior to study entry 2.67 +/- 0.75] were retrospectively evaluated. Brain magnetic resonance imaging (MRI) performed in five patients showed active disease with gadolinium-enhancing lesions. Cladribine was given at 0.07 mg/kg/day for five consecutive days once monthly with a total of 2- to 4-monthly courses. After 6 months, mean EDSS decreased to 3.75 +/- 1.64 and MRIs showed a decrease or suppression in the number of gadolinium-enhancing lesions. After 1 year from first dose, cladribine dosage was repeated in four patients because of recurrence of relapses with subsequent similar positive clinical results. In the follow-up period (49.33 +/- 39.66 months), the mean relapse rate decreased to 0.71 +/- 0.55 and no unexpected or serious adverse events were observed.

Prevalence of autoimmune thyroid disorders in a Spanish multiple sclerosis cohort.

The aim of the study was to determine the prevalence of thyroid autoimmune disorders in a cohort of untreated multiple sclerosis (MS) patients and compare it with a stratified sample of an adult population. We prospectively studied 93 untreated MS patients. The control group included 401 healthy subjects selected by stratified sampling in a non-iodine-deficient area. Antithyroid antibodies (ATA) (antibodies against peroxidase and thyroglobulin) were considered positive at titres > or =149 IU/ml. Antibodies were positive in 11 MS patients (11.8%; 95% CI 5.3-18.4%). This prevalence was five times higher (P = 0.0001) when compared with that in the control population. We found six cases with subclinical hypothyroidism (6.45%; 95% CI 11.4-1.5) in contrast to 2.24% in the control group. Comparing MS with positive and negative ATA, there was a non-significant, slightly higher frequency of low Expanded Disability Status Scale (EDSS) score in the ATA-positive group (81% vs. 73.2%). One year after start of interferon (IFN) treatment, only one patient developed subclinical thyroid dysfunction. MS patients have a higher prevalence of ATA compared with the general population. An initial ATA and thyroid-stimulating hormone (TSH) determination is recommended in all MS patients. A periodic assessment of thyroid function during IFN treatment only seems to be justified in those cases where positive ATA or dysfunction is present before treatment.

No association of the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) to multiple sclerosis.

Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by neurons and immune cells, promotes neuronal survival and repair during development and after CNS injury. The BDNF-Val66Met polymorphism is functional and induces abnormal intracellular trafficking and decreased BDNF release. Therefore, we investigated the impact of the BDNF-Val66Met polymorphism on the susceptibility and clinical course in a case-control study of 224 multiple sclerosis (MS) Spanish patients and 177 healthy controls. We found no evidence for association to susceptibility or severity of the disease in our population. Moreover, we did not observe, in a subgroup of 12 MS patients, that the methionine substitution at position 66 in the prodomain had negative impact in the capacity to produce BDNF by peripheral blood mononuclear cells (PBMC).

Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure.

PURPOSE: Nonconvulsive status epilepticus is an unusual complication of cephalosporin therapy, with only a few isolated cases reported. SUBJECTS AND METHODS: We reviewed the clinical and electroencephalographic (EEG) characteristics of 10 patients with renal failure in whom developed alteration of consciousness without convulsions associated with continuous epileptiform EEG activity while being treated with cephalosporins. RESULTS: Nonconvulsive status epilepticus developed in 5 men and 5 women, with a mean (+/- SD) age of 69 +/- 14 years, while receiving intravenous cephalosporins (ceftriaxone, 2 patients; ceftazidime, 2; and cefepime, 6). All patients had renal failure; 1 also had hepatic failure. Patients presented with progressive disorientation or agitation, sometimes associated with mild facial or limb myoclonus, that had begun 1 to 10 days (mean, 5 +/- 2 days) after starting cephalosporin treatment. The EEG showed continuous or intermittent bursts of generalized, high-voltage, 1 to 2 Hz sharp wave activity or sharp and slow wave activity that resembled, but could be differentiated from, the triphasic waves seen in metabolic encephalopathies. Intravenous clonazepam suppressed the epileptiform activity completely in 5 patients and partially in the other 5. Cephalosporins were withdrawn, and antiepileptic therapy was started for all patients. All patients improved, 2 in less than 24 hours and the remainder within 2 to 7 days. CONCLUSIONS: Cephalosporins can cause nonconvulsive status epilepticus in patients with renal failure. The clinical picture is difficult to differentiate from a that of metabolic encephalopathy unless an EEG is obtained. Physicians should be aware of this potentially dangerous complication.

Common epithelial tumours of the ovary in cows.

A morphological study of the epithelial tumours diagnosed during examination of 1489 cows slaughtered in León, Spain was carried out. Epithelial neoplasms were observed in four animals which represents an incidence of 0.27 per cent. So far as the authors are aware it is the first time that two serous papillary cystadenomas and one serous superficial papilloma have been described in cows. The fourth neoplasm was a mucinous cystadenoma.

Effect of diethylstilbestrol or zeranol on fetal development, gestation duration, and number of offspring in NMRI mice.

OBJECTIVE: To evaluate the effects of diethylstilbestrol (DES) or alpha-zearalanol (zeranol) on fetal development, gestation duration, and number of offspring. DESIGN: Study effects of prenatal administration of DES or zeranol on various pre- and perinatal variables in an experimental group of mice, compared with effects in a control group. ANIMALS: Pregnant NMRI mice. PROCEDURE: Diethylstilbestrol or zeranol (150 mg/kg of body weight) or vehicle (controls) was administered SC to pregnant mice on days 9 and 10 of gestation. Fetuses from pregnant mice of each group were counted and weighed, and their size and head length were recorded. Additional pregnant mice delivered their fetuses naturally, and pups from each group were counted and their sex was determined. At the end of gestation, abortions were evaluated. All data were statistically analyzed. RESULTS: Mean number of fetuses was significantly lower (P < 0.0001) in DES-treated (4.59 +/- 0.48) than in control mice (8.33 +/- 0.49). Both estrogenic substances significantly reduced fetal size and weight (P < 0.0001), compared with control mice. Diethylstilbestrol significantly increased abortion frequency (P < 0.0001) and gestation duration (P < 0.0001), compared with values for control mice. A reduced number of live pups (P < 0.0001) from pregnant mice administered DES (5.48 +/- 0.38) or zeranol (5.97 +/- 0.49) was observed, compared with control mice (8.52 +/- 0.50), because of reduced number of male offspring (P < 0.0001). CONCLUSIONS: Diethylstilbestrol or zeranol administered during mid-pregnancy leads to decreased fetal weight and size and lower numbers of male offspring at birth. Likewise, DES induced a significant increase in abortions and gestation duration.

[Renal artery calcified aneurysm in a female patient with solitary kidney, rare pathology]. / Aneurisma calcificado de la arteria renal en paciente monorrena, una patología inusual.

Renal artery aneurysm are uncommon. The true prevalence of renal aneurysms in the general population is unknown (less than 0.4%). Because of more widespread use of Angiography and CT as well as improved imaging techniques, they are diagnosed more frecuently. Fibromuscular dysplasia and arteriosclerotic occlusion of the renal artery are believed to be the most frecuent causes. In general, there are no pathognomonic signs and symptoms of renal aneurysm. Nonspecific complaints include flank pain, hematuria, hypertension and hypotension (suspect rupture of aneurysm). We report a case of a woman with a renal artery calcified aneurysm in a solitary kidney.

[Hydatid cyst and horseshoe kidney: an exceptional association]. / Quiste hidatidico y riñón en herradura: una asociación excepcional.

We report on a case of kidney ecchinococosis associated with a horseshoes renal anomaly. The diagnostic procedures used to confirm this association were serological tests, pyelography and computerized tomography. Periquistectomy was done with good recovery of the left renal unit. We believe to report on a pathological association extremely infrequent.

[Cancer and kidney transplantation]. / Cáncer y trasplante renal.

The higher risk of developing malignant tumours in transplanted patients is a fact widely acknowledged over the last decade. This paper includes an analysis of our series and a review of the literature. Cancers developed by the transplanted patient or "de novo" cancers and, within this group skin and lip cancer (58%), are by far the most frequent ones. Their biological behaviour is, in general, more aggressive than similar ones in non-transplanted population. Also, different incidence rates and behaviour have been established depending on the immunosuppressive regime given to the patient. Most common pre-existing carcinoma was renal cancer (one third of cases). When these patients had been adequately treated before the transplant, the minimum disease-free interval that has to elapse to be included in a waiting list will depend on the type of tumour. Transferred tumours are the least frequent but more worrying ones due to both their clinical and legal implications. In view of the existing evidence, it is of particular relevance to insure the primitive nature of any CNS tumour as well as the absence of tumoral disease in young females who die of brain haemorrhage.

Pairs of kidneys transplanted from the same donor: is there any difference?

OBJECTIVES: The aim of this study was to compare the evolution of the first kidney in relation to the second kidney transplanted from the same donor, focusing on the impact that a longer cold ischemia time may have as an independent variable. MATERIAL AND METHODS: The study included 44 pairs of kidneys transplanted from the same donor between February 2008 and October 2010, divided into Groups 1 and 2 according to the graft placement order. The variables analyzed were age, sex, comorbidities, number of transfusions, length of hospital stay, maximum peak PRA, immunologic incompatibility, ischemia time, delayed graft function (DGF), presence of rejection, creatinine clearance at first week, at 3 months and at 1 year, and vascular and tract complications in each group. RESULTS: The mean cold ischemia time was 15.6 hours in Group 1 and 20.1 hours in Group 2 (P < .001). The average recipient age was 52.79 years in Group 1 and 54.52 years in Group 2, with an equal sex ratio in the two groups; an average of 2.06 PRC were transfused prior to transplantation in Group 1 and 0.93 PRC in Group 2; the average length of stay was similar in the two groups. Major DR incompatibility was only found in Group 2 (P < .03). Creatinine clearance at first week, DGF and acute rejection showed worse results in Group 2, but these differences were not significant. Vascular complications were present in 4.5% and 2.3% of Groups 1 and 2, respectively, and tract complications were 6.8% and 11.4%. CONCLUSIONS: A greater tendency to DGF, early rejection and tract complications were found in the group with longer ischemia time, although the difference was not statistically significant. Larger series will be necessary to confirm our results.