A Scoping Review of Dietary Factors Conferring Risk or Protection for Cognitive Decline in APOE ε4 Carriers.

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease. The strongest genetic risk factor for sporadic AD is carriage of the ε4 allele of the Apolipoprotein E (APOE) gene. Strategies to slow the progression of AD, including dietary interventions, may be modified by the pathogenic effect of this polymorphism. Our objective in this review was to determine the extent and quality of the literature investigating how dietary factors and interventions interact with the APOE ε4 genotype to impact cognitive decline in AD. To that end, we performed a systematic scoping review of published English-language articles involving human subjects. We found evidence suggesting that adherence to a Mediterranean diet may reduce cognitive decline among APOE ε4 carriers, whereas ketogenic agents appear to be ineffective. Diets high in saturated fats may be particularly harmful for APOE ε4 carriers. We identified several topics, including the use of ω-3 fatty acid and antioxidant supplements, for which additional high level evidence is needed.

Pitiriasis rubra pilaris: a propósito de un caso / Pityriasis rubra pilaris: case report

RESUMEN Se presenta caso de paciente masculino de 9 años de edad, fototipo VI acude a consulta especializada de Dermatología en el Hospital pediátrico William Soler por lesiones eritematoescamosas dispuestas en placas localizadas en ambas rodillas, acompañadas de queratodermia palmo plantar. Se realizan exámenes complementarios y biopsia de piel concluyéndose caso como pitiriasis rubra pilaris circunscrita juvenil. Esta dermatosis es de infrecuente presentación, desafío terapéutico por ausencia de estandarización internacional y cursa con una evolución impredecible.

ABSTRACT We present the case of a 9-year-ol, phototype 3, who attended a specialized dermatology consultation at the William Soler pediatric hospital due to erythematosquamous lesions arranged in plaques located on both knees accompanied by palmoplantar keratoderma. Laboratory tests and skin biopsies were carried out, concluding case as a juvenile and circumscribed pityriasisrubra pilaris. This is an infrequent dermatosis, a therapeutic challenge because of the absence of international standardized treatments and it has an unpredictable evolution.

Cross-Sectional Characterization of Albumin Glycation State in Cerebrospinal Fluid and Plasma from Alzheimer's Disease Patients.

We determined albumin post-translational modifications (PTMs) by mass spectrometry (MS) in plasma and cerebrospinal fluid (CSF) from 31 Alzheimer's disease (AD) patients (with 27 samples of paired plasma-CSF from the same patients). Results were cross-sectionally compared with healthy controls. For percentage of relative intensity of glycated isoforms, plasma albumin was globally more glycated in AD patients than in healthy controls (P<0.01). MS results in plasma were confirmed by a quantitative enzymatic assay (Lucica GA-L) for albumin early-glycation detection. In CSF there were no global glycation differences detected by MS, although a different pattern of glycated isoforms was observed. Oxidized+glycated and cysteinylated+glycated isoforms were increased in both plasma and CSF of AD patients in comparison with healthy controls (P<0.001). Furthermore, AD patients showed higher glycation in plasma than in CSF (P<0.01). Our data support the role of glycation and oxidative stress in AD.

Fumaric acid ester treatment in cutaneous lupus erythematosus (CLE): a prospective, open-label, phase II pilot study.

OBJECTIVE: The aim of the study was to assess the efficacy and safety of fumaric acid esters (FAEs) in patients with cutaneous lupus erythematosus (CLE). METHODS: In this 24-week, prospective, open-label, phase II pilot study, 11 patients with CLE, refractory to topical corticosteroids, were included. The primary endpoint of the study was the evaluation of the efficacy of FAEs after 24 weeks of treatment as assessed by the Revised Cutaneous Lupus Disease Area and Severity Index (RCLASI). RESULTS: Compared to baseline, significant improvement in the mean total RCLASI activity score and the mean RCLASI activity score for skin lesions was observed in week 12 (p = 0.002, p = 0.002, respectively) and in week 24 (p = 0.009, p = 0.009, respectively). Most common adverse events included abdominal cramps and headache. CONCLUSIONS: FAEs could be an alternative and safe treatment in patients with therapy-refractory CLE; however, randomized controlled trials are warranted to evaluate the efficacy and safety of FAEs in this disease.

Umbilical cord and preeclampsia.

INTRODUCTION: Preeclampsia is associated with abnormalities in the umbilical cord in several ways: morphological, biochemical and functional. Alteration in blood vessels of the placenta, decidua and circulatory system of the fetus might be related to factors that cause preeclampsia and may be associated with alterations of the umbilical cord. OBJECTIVES: This study aimed to analyze the relationship between each type of umbilical cord abnormality and the different subtypes of hypertensive gestational disorders. METHODS: We conducted a prospective study on consecutive autopsies and its placentas, looking for abnormalities in the umbilical cord's features and their clinical associations. RESULTS: Umbilical cord abnormalities including length, diameter, insertion, entanglements, knots and coils were associated with maternal gestational hypertension. CONCLUSION: In women with gestational hypertension, umbilical cord abnormalities are associated with fetal and neonatal consequences.

IL-21 and probiotic therapy improve Th17 frequencies, microbial translocation, and microbiome in ARV-treated, SIV-infected macaques.

Increased mortality in antiretroviral (ARV)-treated, HIV-infected individuals has been attributed to persistent immune dysfunction, in part due to abnormalities at the gastrointestinal barrier. In particular, the poor reconstitution of gastrointestinal Th17 cells correlates with residual translocation of dysbiotic, immunostimulatory microflora across a compromised intestinal epithelial barrier. We have previously demonstrated that oral probiotics promote increased intestinal CD4(+) T-cell reconstitution during ARV treatment in a non-human primate model of HIV infection; however, essential mucosal T-cell subsets, such as Th17 cells, had limited recovery. Here, we sought to promote Th17 cell recovery by administering interleukin (IL)-21 to a limited number of ARV-treated, probiotic-supplemented, Simian Immunodeficiency Virus (SIV)-infected pigtailed macaques. We demonstrate that probiotic and IL-21 supplementation of ARVs are associated with enhanced polyfunctional Th17 expansion and reduced markers of microbial translocation and dysbiosis as compared with infected controls receiving ARVs alone. Importantly, treatment resulted in fewer morbidities compared with controls, and was independent of increased immune activation or loss of viral suppression. We propose that combining ARVs with therapeutics aimed at restoring intestinal stasis may significantly improve disease prognosis of ARV-treated, HIV-infected individuals.

Treatment of Alzheimer disease using combination therapy with plasma exchange and haemapheresis with albumin and intravenous immunoglobulin: Rationale and treatment approach of the AMBAR (Alzheimer Management By Albumin Replacement) study. / Tratamiento de la enfermedad de Alzheimer mediante terapia combinada de aféresis terapéutica y hemoféresis con albúmina e inmunoglobulina intravenosa: fundamentos y aproximación terapéutica al estudio AMBAR (Alzheimer Management By Albumin Replacement).

INTRODUCTION: There is a growing interest in new therapeutic strategies for the treatment of Alzheimer disease (AD) which focus on reducing the beta-amyloid peptide (Aß) burden in the brain by sequestering plasma Aß, a large proportion of which is bound to albumin and other proteins. This review discusses the concepts of interaction between Aß and albumin that have given rise to AMBAR (Alzheimer's Disease Management by Albumin Replacement) project, a new multicentre, randomised, controlled clinical trial for the treatment of AD. DEVELOPMENT: Results from preliminary research suggest that Albutein(®) (therapeutic albumin, Grifols) contains no quantifiable levels of Aß. Studies also show that Albutein(®) has Aß binding capacity. On the other hand, AD entails a high level of nitro-oxidative stress associated with fibrillar aggregates of Aß that can induce albumin modification, thus affecting its biological functions. Results from the phase ii study confirm that using therapeutic apheresis to replace endogenous albumin with Albutein(®) 5% is feasible and safe in patients with AD. This process resulted in mobilisation of Aß and cognitive improvement in treated patients. The AMBAR study will test combination therapy with therapeutic apheresis and haemopheresis with the possible leverage effect of Albutein(®) with intravenous immunoglobulin replacement (Flebogamma(®) DIF). Cognitive, functional, and behavioural changes in patients with mild to moderate AD will be assessed. CONCLUSIONS: the AMBAR study represents a new therapeutic perspective for AD.

Biomarkers predicting a need for intensive treatment in patients with early arthritis.

The heterogeneous nature of rheumatoid arthritis (RA) complicates early recognition and treatment. In recent years, a growing body of evidence has demonstrated that intervention during the window of opportunity can improve the response to treatment and slow- or even stop-irreversible structural changes. Advances in therapy, such as biologic agents, and changing approaches to the disease, such as the treat to target and tight control strategies, have led to better outcomes resulting from personalized treatment to patients with different prognostic markers. The various biomarkers identified either facilitate early diagnosis or make it possible to adjust management to disease activity or poor outcomes. However, no single biomarker can bridge the gap between disease onset and prescription of the first DMARD, and traditional biomarkers do not identify all patients requiring early aggressive treatment. Furthermore, the outcomes of early arthritis cohorts are largely biased by the treatment prescribed to patients; therefore, new challenges arise in the search for prognostic biomarkers. Herein, we discuss the value of traditional and new biomarkers and suggest the need for intensive treatment as a new surrogate marker of poor prognosis that can guide therapeutic decisions in the early stages of RA.

Dermoscopy of acral melanoma: a multicenter study on behalf of the international dermoscopy society.

BACKGROUND: Most studies on dermoscopy of acral lesions were conducted in Asian populations. In this study, we analyzed these features in a predominantly Caucasian population. OBJECTIVE: Estimate the prevalence of dermoscopic features in acral lesions, and assess their level of agreement between observers. METHODS: In this retrospective multicenter study, 167 acral lesions (66 melanomas) were evaluated for 13 dermoscopic patterns by 26 physicians, via a secured Internet platform. RESULTS: Parallel furrow pattern, bizarre pattern, and diffuse pigmentation with variable shades of brown had the highest prevalence. The agreement for lesion patterns between physicians was variable. Agreement was dependent on the level of diagnostic difficulty. CONCLUSION: Lesions with a diameter >1 cm were more likely to be melanoma. We found as well that a benign pattern can be seen in parts of melanomas. For this reason one should evaluate an acral lesion for the presence of malignant patterns first.

Complete filaggrin deficiency in ichthyosis vulgaris is associated with only moderate changes in epidermal permeability barrier function profile.

BACKGROUND: Ichthyosis vulgaris (IV) is caused by loss-of-function mutations in the profilaggrin (FLG) gene. Filaggrin drives complex interrelated functions, with strategic roles in establishing structural and chemical barrier function, hydration of the skin and maintaining epidermal homeostasis. Data on the effect of FLG mutations on epidermal barrier function in IV are very scarce. OBJECTIVES: A primary aim of this study was to determine in vivo characteristics of epidermal permeability barrier function such as transepidermal water loss (TEWL), skin hydration and skin surface pH in homozygous or compound heterozygous (FLG(-/-)) and heterozygous (FLG(+/-)) subjects with IV. METHODS: We evaluated a cohort of 15 patients with IV, analysed epidermal ultrastructure and investigated epidermal barrier function by measurement of TEWL, skin surface pH and skin hydration. Mutations were screened by restriction enzyme analysis and/or complete sequencing. Ten patients were homozygous or compound heterozygous (FLG(-/-)), while five patients were heterozygous (FLG(+/-)). Twenty healthy individuals served as controls. RESULTS: In FLG(-/-) subjects, a moderate increase of TEWL from 5.41 ± 0.32-7.54 ± 0.90 g/m(2) h (P < 0.03) and a moderate decrease of skin hydration from 29.20 ± 1.96 to 20.17 ± 3.60 (P < 0.05) in comparison with the control group were observed. Changes in skin surface pH were not significant. FLG(+/-) subjects did not suffer from significant changes in all variables. CONCLUSIONS: A complete, but not a partial deficiency is associated with moderate changes in TEWL and skin hydration, revealing surprisingly only a mild disturbance of the epidermal permeability barrier function.

Kinetics of the interaction between anti-FVIII antibodies and FVIII from therapeutic concentrates, with and without von Willebrand factor, assessed by surface plasmon resonance.

The presence of VWF in plasma-derived FVIII (pdFVIII/VWF) products has been pointed out as a key difference with recombinant FVIII (rFVIII) products with regard to immunogenicity. A Surface Plasmon Resonance (SPR) study was designed to characterize in detail the interaction between anti-FVIII (IgGs) from a severe haemophilia A patient, and FVIII from concentrates of different sources. Full-length rFVIII (preincubated or not with purified VWF), B domain-deleted (BDD)-rFVIII and pdFVIII/VWF were analysed. To ensure reproducible conditions for accurate determination of kinetic constants, a capture-based assay format was developed using protein G surfaces for specific and reversible coupling of endogenous anti-FVIII antibodies. Concentration ranges (nm) of FVIII products tested were 9-0.03 (rFVIII) and 6-0.024 (pdFVIII/VWF). The association with antibodies was monitored for 3-5 min, whereas dissociation of the complex was followed for 5-20-240 min. A strong interaction of rFVIII and BDD-rFVIII with patient's IgG was detected with the K (D) values in the low picomolar range (5.9 ± 3.0 and 12.7 ± 6.9 pm, respectively) and very slow dissociation rates, while pdFVIII/VWF showed only marginal binding signals. The VWF complexed rFVIII displayed reduced binding signals compared with uncomplexed rFVIII, but the K (D) was still in the picomolar range (4.1 ± 1.9 pm) indicating insufficient complex formation. rFVIII, alone or bound to exogenously added VWF, showed high affinity for anti-FVIII IgGs from a severe haemophilia A patient whereas pdFVIII/VWF did not. These results are in agreement with those studies that point towards rFVIII concentrates to be more immunogenic than pdFVIII concentrates.

Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infection.

Human immunodeficiency virus (HIV) and Simian immunodeficiency virus (SIV) disease progression is associated with multifocal damage to the gastrointestinal tract epithelial barrier that correlates with microbial translocation and persistent pathological immune activation, but the underlying mechanisms remain unclear. Investigating alterations in mucosal immunity during SIV infection, we found that damage to the colonic epithelial barrier was associated with loss of multiple lineages of interleukin (IL)-17-producing lymphocytes, cells that microarray analysis showed expressed genes important for enterocyte homeostasis, including IL-22. IL-22-producing lymphocytes were also lost after SIV infection. Potentially explaining coordinate loss of these distinct populations, we also observed loss of CD103+ dendritic cells (DCs) after SIV infection, which associated with the loss of IL-17- and IL-22-producing lymphocytes. CD103+ DCs expressed genes associated with promotion of IL-17/IL-22+ cells, and coculture of CD103+ DCs and naïve T cells led to increased IL17A and RORc expression in differentiating T cells. These results reveal complex interactions between mucosal immune cell subsets providing potential mechanistic insights into mechanisms of mucosal immune dysregulation during HIV/SIV infection, and offer hints for development of novel therapeutic strategies to address this aspect of AIDS virus pathogenesis.

Factors that affect concentrations of cyclosporine during the induction period of kidney transplantation: multivariate analysis.

OBJECTIVE: The pharmacokinetics of cyclosporine (CsA) depend on numerous factors over the transplantation course. The aim of this study was to evaluate the impact of several clinical variables on CsA concentrations during the induction period after kidney transplantation. METHODS: Potential variables were contrasted with CsA concentrations at 2 hours postdose (C(2)) and with the area under the concentration curve of CsA (AUC) at days 3 and 10 after transplantation. Evaluated variables were: recipient age, gender, body mass index (BMI), type/duration of previous dialysis, pretransplant serum creatinine (sCr), donor type, CsA dose, cold ischemia time, reduction of sCr, and use of other immunosuppressive drugs. RESULTS: This series included 112 patients who displayed an average age of 43 ± 13 years, including 62 men and 31 recipients of living donor organs. The induction dose of CsA was 8.36 ± 1.53 mg/kg. On day 3, the C(2) was related to the reduction of sCr (P = 0.034) and to the BMI (P = 0.033). There was an inverse correlation with pretransplant sCr (P = 0.012). The AUC correlated with BMI (P = 0.027) and living donor category (P = .002). Patients receiving rapamycin or a locally procured kidney showed a trend toward higher AUC values. On day 10, the CsA dose and use of rapamycin showed a trend to higher values of C(2); the AUC was related to the CsA dose (P = .034). None of the other variables showed significant effects. Analysis between variables showed that time on dialysis correlated with the pretransplant sCr (P = .002) and that the CsA dose was negatively associated with BMI (P = .009). CONCLUSION: Pretransplant sCr, BMI, living donor kidney category, better functional recovery, and the dose of CsA were predictors of CsA concentrations of clinical interest during this induction period. The effect of BMI was not related to higher doses of CsA.

Prophylaxis and treatment of Chagas disease in renal transplant donor and recipient: case report.

Chagas disease is a prevalent zoonosis in Latin America, caused by the protozoa Trypanosoma cruzi and transmitted by Triatoma infestans. Part of the infectious cycle consists of chronic subclinical parasitemia, causing in the long term end-organ damage. Amastigotes have been isolated from various organs including native and allograft renal parenchyma; thus, transplantation plus immunosuppression therapy is another mode of disease transmission and reactivation. Herein, we report 2 successful kidney transplantations cases in which either infection or reactivation was averted using prophylactic nitroderivates.

Strategies for prevention of cytomegalovirus infection in renal transplant patients.

OBJECTIVE: Cytomegalovirus (CMV) constitutes the principal viral infection in renal transplant patients. The indirect consequences of CMV infection increase the risks for acute and chronic rejection, secondary infections, lymphoproliferative disorders, atherosclerosis, and cardiovascular deaths. The direct effects depend on the affected organ. There have been strategies to prevent CMV disease: prophylaxis and preemptive strategy. The aim of this study was to compare the incidences of disease and infection due to CMV among our patients. PATIENTS AND METHODS: We performed a retrospective analysis of all our renal transplant patients between January 2000 and January 2008. RESULTS: Four groups were identified among 94 patients: without any preventive strategy; brief prophylaxis; formal prophylaxis; and preemptive treatment. There were no significant differences among the groups in the incidences of CMV disease, acute renal rejection, or survival. The greatest number of infections was registered in the group with brief prophylaxis (P = .006); 50% of the registered infections occurred before 150 days posttransplantation. CONCLUSIONS: We concluded that the preemptive strategy is appropriate for the low-risk patient, while prevention with antiviral drugs should be reserved for intermediate- and high-risk patients. A brief treatment for prevention is an alternative to prevent CMV disease, but it needs to be followed with serial, long-term evaluation of antigenemia for >150 days posttransplantation.

Renal vein extension using gonadal vein: a useful strategy for right kidney living donor harvested using laparoscopy.

INTRODUCTION: Vascular management of the right renal vein during laparoscopic living donor nephrectomy is still an unsolved problem. This short vessel has limited the use of right kidneys. However, the right kidney should be harvested in some instances. Based on experience in open donor nephrectomy, our unit has used the donor gonadal vein to obtain a longer renal vein in this setting. METHODS: Four consecutive living related donors with the indication for laparoscopic right nephrectomy underwent this procedure. Three donors were females and the overall average age was 48.5 years. The renal vein was controlled with a 30-mm stapler and we included 5-6 cm of the ipsilateral gonadal vein during the harvest. The donor kidney was perfused and renal vessels prepared under cold conditions. The gonadal vein was opened longitudinally and sutured to the donor right renal vein as a wide tube in 3 cases and as a spiral tube in 1 case with 6-0 monofilament suture. RESULTS: This procedure extended the bench work between 25 to 40 minutes permitting an 2.5- to 3.5-cm extension of the donor vein. The transplantations were performed in the usual mode and the vein enlargement enormously facilitated the implantation surgery. All recipients displayed immediate graft function; no complications were observed with this strategy. CONCLUSIONS: Vein extension with the gonadal vein was a simple, safe method to enlarge the renal vein among right living donor kidneys procured using laparoscopy.

Abbreviated AUC monitoring of cyclosporine more adequately identified patients at risk for acute rejection during induction of immunosuppressive therapy after kidney transplantation than recommended C2 concentration values.

OBJECTIVE: Monitoring of cyclosporine (CsA) is critical during the induction of immunosuppressive therapy. Although most centers have incorporated C2 levels, our unit still uses an abbreviated AUC model which includes concentrations at C1, C2, and C6 post-dose (AUC(1-6)). The objective of this study was to compare both strategies of CsA monitoring during the first 30 days after kidney transplantation. PATIENTS AND METHODS: The study included 89 recipients induced with CsA microemulsion and steroids. AUC(1-6) profiles were performed around days 3, 10, and 30 after transplantation with a target of 5500 to 6000 ng*h/mL considered therapeutic. For comparison purposes, a value of C2 >/= 1500 ng/mL was also considered therapeutic. Mean C2 and AUC(1-6) values were low dated with biopsy-proven acute rejection episodes (BPAR) during the study period. RESULTS: Twenty patients received living donor kidneys and overall there were 46 females. During this period, 253 AUC(1-6) were performed including 44 (17.4%) below the therapeutic range. When the analysis included only C2, 171 (67.6%) were below the therapeutic target (P < .001). Five patients experience BPAR and only AUC(1-6) at day 10 discriminated rejectors versus nonrejectors (5645 +/- 1390 and 8221 +/- 2502, respectively; P = .008). C2 was not significantly different at any time in either group. CONCLUSIONS: In this study, abbreviated AUC monitoring more adequately identified patients at risk for acute rejection than C2. Recommended C2 concentration levels need to be redefined in our patients.

Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway.

OBJECTIVE: To study the effects of different disease-modifying antirheumatic drugs (DMARD) on different events mediated by IL-15-activated lymphocytes. METHODS: Peripheral blood lymphocytes (PBL) were isolated from healthy donors and activated with IL-15 after exposure to different DMARD: leflunomide, cyclosporin A, methotrexate, mycophenolic acid, FK-506, sulphasalazine and sodium aurothiomalate. The expression of different surface molecules on the PBL was then determined by flow cytometry. Cells were also co-cultured with the monocytic cell line THP-1 and the tumour necrosis factor (TNF) concentration in the supernatant was measured after 24 h using an immunoenzyme assay. The effect of the aforementioned drugs on IL-17 production by IL-15-activated PBL was also studied. RESULTS: Treatment of PBL with leflunomide, cyclosporin A and FK-506 inhibited the IL-15-induced expression of both CD54 and CD69 by PBL, as well as TNF production in co-cultures of activated PBL and THP-1 cells. The downregulation of CD54 and CD69 in PBL was correlated with the inhibition of TNF production. Likewise, leflunomide, cyclosporin A and FK-506 all inhibited IL-17 production in IL-15-activated PBL. Interestingly, the effect of leflunomide was not reverted by the presence of uridine in the medium. In addition, leflunomide inhibited the phosphorylation of STAT6 in vitro. CONCLUSION: Inhibition of the JAK/STAT pathway may represent an additional effect of leflunomide in chronic polyarthritis because it impairs certain events that control proinflammatory TNF and IL-17 cytokine production.

Are the C-reactive protein values and erythrocyte sedimentation rate equivalent when estimating the 28-joint disease activity score in rheumatoid arthritis?

UNLABELLED: A formula for calculating disease activity score with 28 joint counts (DAS28) with C-reactive protein (CRP) instead of the erythrocyte sedimentation rate (ESR) has been proposed. OBJECTIVE: Here we analyze the factors that contribute to the differences in the DAS28 when calculated using either the ESR (DAS28-ESR) or the CRP values (DAS28-CRP). METHODS: We analyzed the data from 587 visits made by 220 patients with early arthritis. The age at the onset of the disease was 51+/-16 years old and 76.3% of the patients were women. The disease evolution at the first visit was 5 months and at each visit information related to several variables was collected, including that necessary to calculate the DAS28-ESR and DAS28-CRP. We defined a new variable DIFDAS=DAS28-ESR-DAS28-CRP to analyze which independent variables account for differences between the two indexes. RESULTS: There was a correlation between the two indexes of 0.91 (p<0.0001), although the DAS28-ESR value obtained was higher than that of DAS28-CRP at approximately 90% of the visits. Significantly, the difference between both indexes was higher than 0.6 in 44% of the visits studied. A multivariate analysis showed that female gender and disease duration were associated with the higher values obtained for DAS28-ESR when compared to those of DAS28-CRP. CONCLUSION: Our data show that DAS28-ESR and DAS28-CRP are not fully equivalent, because the former usually produces higher values. This finding is particularly relevant in females and patients with a long disease duration.