Beta‐amyloid protein (25–35) disrupts hippocampal network activity: Role of Fyn‐kinase

Early cognitive deficit characteristic of early Alzheimer's disease seems to be produced by the soluble forms of β‐amyloid protein. Such cognitive deficit correlates with neuronal network dysfunction that is reflected as alterations in the electroencephalogram of both Alzheimer patients and transgenic murine models of such disease. Correspondingly, recent studies have demonstrated that chronic exposure to βAP affects hippocampal oscillatory properties. However, it is still unclear if such neuronal network dysfunction results from a direct action of βAP on the hippocampal circuit or it is secondary to the chronic presence of the protein in the brain. Therefore, we aimed to explore the effect of acute exposure to βAP_25–35 on hippocampal network activity both in vitro and in vivo, as well as on intrinsic and synaptic properties of hippocampal neurons. We found that βAP_25–35, reversibly, affects spontaneous hippocampal population activity in vitro. Such effect is not produced by the inverse sequence βAP_35–25 and is reproduced by the full‐length peptide βAP_1–42. Correspondingly βAP_25–35, but not the inverse sequence βAP_35–25, reduces theta‐like activity recorded from the hippocampus in vivo. The βAP_25–35‐induced disruption in hippocampal network activity correlates with a reduction in spontaneous neuronal activity and synaptic transmission, as well as with an inhibition in the subthreshold oscillations produced by pyramidal neurons in vitro. Finally, we studied the involvement of Fyn‐kinase on the βAP_25–35‐induced disruption in hippocampal network activity in vitro. Interestingly, we found that such phenomenon is not observed in slices obtained from Fyn‐knockout mice. In conclusion, our data suggest that βAP acutely affects proper hippocampal function through a Fyn‐dependent mechanism. We propose that such alteration might be related to the cognitive impairment observed, at least, during the early phases of Alzheimer's disease. © 2009 Wiley‐Liss, Inc.     

Cingulate gyrus morphology in children and adolescents with fetal alcohol spectrum disorders

Alcohol consumption during pregnancy can lead to a variety of cognitive and other birth defects, collectively termed fetal alcohol spectrum disorders (FASD), and including the Fetal Alcohol Syndrome (FAS). This study examined the impact of gestational alcohol exposure on the morphology of the cingulate gyrus, given this region's role in cognitive control, attention, and emotional regulation, all of which are affected in children with FASD. Thirty-one youth (ages 8–16) with histories of heavy prenatal alcohol exposure (n = 21) and demographically matched comparison subjects (n = 10) underwent structural magnetic resonance imaging. The cingulate gyrus was manually delineated, and parcellated volumes of grey and white matter were compared across groups. Alcohol-exposed individuals had significantly smaller raw cingulate grey matter, white matter, and tissue volumes compared with controls. After adjustment for respective cranial tissue constituents, only white matter volumes remained significantly reduced, and this held regardless of whether or not the child qualified for a diagnosis of FAS. A correlation between posterior cingulate grey matter volume and the WISC-III Freedom from Distractibility Index was also observed in alcohol-exposed children. These data suggest that cingulate white matter is compromised beyond global white matter hypoplasia in alcohol-exposed individuals, regardless of FAS diagnosis. The observed volumetric reductions in the cingulate gyrus may contribute to the disruptive and emotionally dysregulated behavioral profile commonly observed in this population.     

The Role of the Template in Prosthetically Guided Implantology

In prosthetically guided implantology, where ideal placement of implants is determined by the definitive restoration, the use of a radiographic/surgical template plays an essential role. This article describes how to fabricate a radiographic/surgical template to be used for radiographic diagnosis of the selected implant sites and as a guide during surgery for the insertion of the implant with correct angulation.     

Increased risk of tuberculosis in patients with rheumatoid arthritis

OBJECTIVE: To quantify the risk of tuberculosis (TB) in an unselected sample of patients with rheumatoid arthritis (RA) compared to the risk in the general population. METHODS: The incidence of TB in the general population of Spain was obtained from the National Network of Epidemiological Surveillance reports. The incidence of TB was ascertained from a cohort of 788 patients with RA selected randomly from the registries of 34 participating centers throughout Spain. A patient was considered a TB case only if information about disease symptoms, microorganism identification, and TB treatment were confirmed in the clinical records. The relative risk of TB in RA was calculated by dividing the standardized mean incidence of TB from 1990 to 2000 in the RA cohort by the mean incidence of TB in Spain during the same years. RESULTS: The mean incidence of TB in the general population of Spain from 1990 to 2000 was 23 cases per 100,000. Seven cases of TB were identified in the RA cohort, yielding a mean annual incidence (1990-2000) of 134/100,000 patients. The incidence risk ratio of pulmonary TB in patients with RA compared to the general population is 3.68 (95% CI 2.36-5.92). CONCLUSION: We found a 4-fold increased risk of TB infection in patients diagnosed with RA. These results might help to interpret the magnitude of the problem attributable to the introduction of new therapies in RA.     

Power Doppler ultrasonographic monitoring of response to anti-tumor necrosis factor therapy in patients with rheumatoid arthritis

OBJECTIVE: To evaluate the validity, responsiveness, and predictive value of power Doppler ultrasonography (PDUS) monitoring of response to tumor necrosis factor (TNF) blocking agents in rheumatoid arthritis (RA). METHODS: Three hundred sixty-seven RA patients were prospectively recruited at 25 Spanish centers; complete clinical, laboratory, and PDUS data were obtained on 278 patients. The patients underwent clinical, laboratory, and PDUS assessment at baseline and after 1, 3, 6, and 12 months of anti-TNF treatment, and radiographic assessment of the hands and feet at baseline and 12 months. The Disease Activity Score in 28 joints (DAS28) was recorded at each visit. PDUS examination included 86 intraarticular and periarticular sites in 28 joints. US synovial fluid (SF), synovial hypertrophy (SH), and PD signal were scored in all synovial sites. US count and index for SF, SH, and PD signal were obtained. Sensitivity to change of the PDUS variables was assessed by estimating the smallest detectable difference (SDD) from the intraobserver variability. RESULTS: A significant parallel improvement in DAS28 and PDUS parameters was found at followup assessment (P < 0.0005 for within-subject between-visit changes). The SDD for PDUS parameters was lower than the mean changes throughout followup. Time-integrated values of US joint count for PD signal and rheumatoid factor (RF) showed predictive value in relation to progression of radiographic erosion (R = 0.64), and time-integrated values of US joint count for PD signal, RF, and erythrocyte sedimentation rate were predictors of progression of the total radiographic score (R = 0.59). CONCLUSION: These findings indicate that PDUS is a valid method for monitoring response to anti-TNF therapy in RA; results obtained by PDUS are reproducible and sensitive to change. PDUS findings may have predictive value in relation to radiologic outcome.     

HLA-haploidentical blood progenitor cell transplantation in osteopetrosis

Infantile osteopetrosis (OP) carries an extremely poor prognosis unless treated early by hematopoietic stem cell transplantation. We explored the use of purified blood progenitor cells from HLA-haploidentical parents in 7 patients lacking suitable matched donors. Blood progenitor cells were purified by positive selection and by additional T-cell depletion using rosette formation. For conditioning, patients received busulfan, thiotepa, and either cyclophosphamide (5 patients) or fludarabine (2 patients). Stable donor engraftment developed in 6 of 7 patients. Graft-versus-host disease was not observed. Three of the 7 patients had no major complications and 4 of 7 had both veno-occlusive disease and respiratory failure. Five of 7 patients survive with complete cure of OP at a median of 4 years. Patients with OP lacking HLA-matched donors can be successfully treated by transplantation of purified blood progenitor cells from HLA-haploidentical donors.     

Probability of liver cancer and survival in HCV-related or alcoholic-decompensated cirrhosis. A study of 377 patients.

BACKGROUND: Although chronic alcohol intake and chronic hepatitis C may progress to cirrhosis and hepatocellular carcinoma (HCC), few data are available about survival and probability of developing HCC in decompensated cirrhosis of both aetiologies. METHODS: This study identified factors related with probability of developing HCC and survival in a cohort of 377 consecutive patients with decompensated HCV-related cirrhosis (200 cases) or alcoholic cirrhosis (177 cases) without known HCC, hospitalized for their first hepatic decompensation, as well as to evaluate differences between both aetiologies. Patients were followed for a mean period of 39 +/- 2 months. RESULTS: During follow-up, 42 patients (11.1%) developed HCC (16.5% vs 5.1%) in groups HCV and alcohol, respectively; p = 0.0008), and 131 patients (34.7%) died (42% vs 26.6% in groups HCV and alcohol, respectively; p = 0.002). Age and HCV-cirrhosis were independently related to HCC development, while baseline age and Child-Turcotte-Pugh score were independently correlated with survival. CONCLUSION: Survival in decompensated HCV-related or alcoholic cirrhosis is influenced by age and baseline Child-Turcotte-Pugh score, without differences in cirrhosis aetiology. The risk of developing HCC is greater in HCV-related cirrhosis than in alcoholic cirrhosis.     

Influenza vaccination in patients with end-stage renal disease

Introduction: Patients with end-stage renal disease (ESRD) are considered at higher risk of influenza-related complications and are listed worldwide among the subjects for whom yearly influenza vaccination is strongly recommended. However, influenza vaccination coverage of patients with ESRD is significantly lower than desired.

Areas covered: This paper explores why compliance with official recommendations for influenza vaccination is poor in patients with ESRD and analyzes the true risk of infection as well as the immunogenicity, the effectiveness and the safety of influenza vaccination in these patients.

Expert opinion: Epidemiological and clinical data support the importance of influenza in conditioning clinical deterioration of patients with ESRD, particularly in relation to their level of immunosuppression. However, the variable levels of immunodeficiency detected in patients with ESRD may reduce the immune response to influenza vaccination, which appears to be lower than that usually found in healthy subjects. However, few studies are available, and they are difficult to compare for several reasons. Additionally, limited data have been collected on influenza vaccine effectiveness, although the available studies support positive results of vaccination on outcomes of severe disease. Despite such limitations, it is important to highlight that all the available studies have confirmed the good safety and tolerability of inactivated influenza vaccines. These findings, together with the risks associated with influenza in these patients, support annual influenza vaccination in patients with ESRD as well as vaccination of their close contacts and should be presented in educational programs organized for nephrologists and patient associations.     

Optimization of azathioprine dose in combined treatment with anti-TNF-alpha in inflammatory bowel disease

IntroductionThe dose of thiopurine drugs in combined treatments with anti-TNF in inflammatory bowel disease (IBD) has not been clearly established. The purpose of this study is to assess whether the dose of azathioprine influences clinical and biochemical response/remission rates, and anti-TNF drug levels/antibody formation.Material and methodsPatients with IBD on combined maintenance treatment with azathioprine and infliximab or adalimumab were selected. Based on the dose of azathioprine, two groups were defined (standard: 2–2.5 mg/kg/day; and decreased: less than 2 mg/kg/day).ResultsIn the IFX group, there were no statistically significant differences (p = 0.204) in the rates of remission (39% vs 41.3%), response (10% vs 21.7%) or failure (51.5% vs 37%) depending on the dose of thiopurine drugs. No differences were found between AZA-dose dependent IFX levels (2.46 vs 3.21 μg/mL; p = 0.211). In the adalimumab group, there were no statistically significant differences (p = 0.83) in the rates of remission (66% vs 56%), response without remission (15.38% vs 25%) or failure (18% vs 18%) depending on the dose of thiopurines. With respect to ADA-levels, no differences were found in both groups (7.69 vs 8.23 μg/mL; p = 0.37).ConclusionIn our experience, no statistically significant differences were found in either anti-TNF levels or clinical-biological response/remission rates based on doses of azathioprine.