p35/Cdk5 pathway mediates soluble amyloid-beta peptide-induced tau phosphorylation in vitro

Alzheimer's disease (AD) is pathologically characterized by deposition of amyloid-beta peptides (Abeta) as senile plaques and by the occurrence of neurofibrillary tangles (NFTs) composed primarily of hyperphosphorylated tau protein. Activation of cyclin-dependent kinase 5 (Cdk5) via its potent activator p25 has recently been shown to promote phosphorylation of tau at AD-specific phosphoepitopes, and increased cleavage of p35 to p25 has been demonstrated in AD patients, suggesting that Cdk5 may represent a pathogenic tau protein kinase. We were interested in the potential effect of soluble forms of Abeta on Cdk5-mediated AD-like tau phosphorylation, insofar as previous studies of human biopsies and aged canine and primate brains have shown that dystrophic neurites appear before the formation of neuritic plaques. We transfected N2a cells with a p35 vector (N2a/p35 cells) and, after differentiation, challenged these cells with Abeta(1-42) peptide in soluble form (sAbeta(1-42)). Results show that sAbeta(1-42) at relatively low levels (1-5 microM) dose-dependently increases tau phosphorylation at AD-specific phosphoepitopes in differentiated N2a/p35 cells compared with controls, an effect that is blocked by antisense oligonucleotides against p35. sAbeta(1-42)-induced tau phosphorylation is concomitant with an increase in both p25 to p35 ratio and Cdk5 activity (but not protein levels). Additionally, blockade of L-type calcium channels or inhibition of calpain completely abolishes this effect. Taken together, these data indicate that sAbeta is a potent activator of the p25/Cdk5 pathway, resulting in promotion of AD-like tau phosphorylation in vitro.     

Cost-effectiveness of serotesting compared with universal immunization for varicella in refugee children from six geographic regions

BACKGROUND: It is unknown whether it is more cost-effective to test for varicella antibody or to immunize without testing in immigrant populations. The reliability of history of varicella disease is also unclear. METHODS: The prevalences of varicella antibody in immigrant children from six regions of the world were used in a cost-effectiveness model to calculate the antibody prevalence above which it is more cost-effective to test rather than to immunize. History of varicella disease was obtained from chart review. We calculated the positive and negative predictive values of varicella history by age group and region. RESULTS: The prevalence of varicella antibody above which it is more cost-effective to test than to immunize was 34% for children less than 13 years old and 17% for those aged 13 years and older. Overall, the positive predictive value of varicella history was 93-100% and the negative predictive value of varicella history was 28-66% among the six geographic regions. CONCLUSION: Immunization without serotesting was cost-effective in children <5 years of age. Testing prior to immunization was cost-effective in children 5 years of age and older. History of varicella was a good predictor of the presence of antibody to varicella, whereas a negative history was a poor predictor of the absence of antibody to varicella.     

Bilateral interpleural versus lumbar epidural bupivacaine-morphine analgesia for upper abdominal surgery

This randomized study was designed to compare the effectiveness of bilateral interpleural analgesia with lumbar epidural analgesia, on postoperative pain relief in upper abdominal surgery. The studied patients were randomely allocated into either interpleural group "IP" (n = 15) or epidural group "EP" (n = 15). In "IP" group, preanesthetic bilateral interpleural block was done using a mixture of bupivacaine 0.5% (0.8 mg/kg) and 2 mg morphine diluted to 50 ml saline for each side. In "EP" group, the same mixture-diluted in 20 ml saline-was injected in the epidural space (L2-3). The general anesthetic technique was the same in both groups. Hemodynamic, gasometric, verbal pain score (VPS) values and complications were compared in both techniques. Heart rate (HR) and mean arterial pressure (MAP) readings were in the accepted normal range in the perioperative period although significant lower readings were detected in "EP" group. No significant differences were displayed in blood gasometric variables between the two groups. There were considerable level of analgesia in both groups in the postoperative period although "EP" analgesia was superior to "IP". More pain free patients (9 versus 4) and significant lower consumption of nalbuphine were detected in "EP" group. The results of this study indicate that bilateral "IP" analgesia may offer a satisfactory analgesia for upper abdominal surgery when the use of other analgesic techniques may be contraindicated.     

Acid-base equilibrium during capnoretroperitoneoscopic nephrectomy in patients with end-stage renal failure: a preliminary report

We have studied the acid-base equilibrium in 12 patients with end-stage renal failure (ESRF) during capnoretroperitoneoscopic nephrectomy. Bupivacaine (12 mL, 0.375%) and morphine (2mg) were given in the lumbar epidural space, and fentanyl (0.5 microg kg(-1)) and midazolam (50 microg kg(-1)) were given intravenously. Anaesthesia was induced by thiopental, maintained with halothane carried by oxygen enriched air (inspired oxygen fraction = 0.35), and ventilation was achieved with a tidal volume of 10 mL kg(-1) at a rate of 12 min(-1). This procedure resulted in a mild degree of respiratory acidosis that was cleared within 60 min. We conclude that capnoretroperitoneoscopic nephrectomy can be performed in patients with end-stage renal failure with minimal transient respiratory acidosis that can be avoided by increased ventilation.     

Can we increase hepatic oxygen availability? The role of intentional hypercarbia

Our hypothesis is that hypercarbia produces sympathetic stimulant effect and local vasodilatation. We studied the effect of intentional hypercarbia (IHC) on hepatic venous oxygen saturation. The hepatic vein (HV) was cannulated in 15 patients through either the right internal jugular vein or the femoral vein to measure HV oxygen saturation and calculate oxygen content. The inferior vena cava (IVC) was cannulated in 6 patients above and below drainage of the hepatic veins for oxygen saturation and content difference along the IVC. IHC was achieved in awake patients by breathing oxygen enriched air at a flow rate of 2L/min for 10 min, and during anesthesia by increasing anesthetic dead space and reducing tidal volume. IHC increased HV blood oxygen saturation, decreased the arterio-hepatic vein oxygen content difference and decreased oxygen saturation difference and oxygen content difference along IVC.     

TERT rs2853669 as a predictor for overall survival in patients with acute myeloid leukaemia

Introductionthe aim of the study was to investigate the contribution of TERT rs2736100 and rs2853669 gene polymorphisms in defining the genetic predisposition to acute myeloid leukaemia (AML), their association with different prognostic markers, and their impact on survival, outcome, and the prognosis of affected patients. Also, we investigated the association of TERT SNPs in AML in the presence or absence of DNMT3A (R882), NPM1, and FLT3 mutations.Material and methodsA total of 509 participants were enrolled in our study, consisting of 146 AML patients and 363 healthy participants, with no history of malignancy. TERT rs2736100 and rs2853669 polymorphisms were genotyped by using TaqMan SNP genotyping assay FLT3 (ITD, D835), DNMT3A (R882), and NPM1 c.863_864insTCTG (type A) mutations were analised in each AML case.ResultsTERT rs2736100 and rs2853669 were not associated with AML risk in the codominant, dominant, recessive, or allelic models. Multivariate Cox regression showed that TERT rs2853669 was a significant predictor for overall survival in AML patients. After adjusting for age, gender, cytogenetic risk group, ECOG status, FLT3, DNMT3A, NPM1 mutation, AML subtype, and treatment, the estimated adjusted hazard ratio (HR adjusted = 1.54, 95% CI: 1.01–2.35) showed that the TERT rs2853669 variant genotype had a negative influence on survival time.ConclusionsTERT rs2853669 and rs2736100 polymorphisms were not risk factors for developing AML in the Romanian population, but the TERT rs2853669 variant genotype had a negative effect on AML patients’ overall survival in the presence of other known prognostic factors.     

In situ formation of porous space maintainers in a composite tissue defect

Reconstruction of composite defects involving bone and soft tissue presents a significant clinical challenge. In the craniofacial complex, reconstruction of the soft and hard tissues is critical for both functional and aesthetic outcomes. Constructs for space maintenance provide a template for soft tissue regeneration, priming the wound bed for a definitive repair of the bone tissue with greater success. However, materials used clinically for space maintenance are subject to poor soft tissue integration, which can result in wound dehiscence. Porous materials in space maintenance applications have been previously shown to support soft tissue integration and to allow for drug release from the implant to further prepare the wound bed for definitive repair. This study evaluated solid and low porosity (16.9% ± 4.1%) polymethylmethacrylate space maintainers fabricated intraoperatively and implanted in a composite rabbit mandibular defect model for 12 weeks. The data analyses showed no difference in the solid and porous groups both histologically, evaluating the inflammatory response at the interface and within the pores of the implants, and grossly, observing the healing of the soft tissue defect over the implant. These results demonstrate the potential of porous polymethylmethacrylate implants formed in situ for space maintenance in the craniofacial complex, which may have implications in the potential delivery of therapeutic drugs to prime the wound site for a definitive bone repair.     

Acute Hepatitis B Outbreaks Related to Fingerstick Blood Glucose Monitoring in Two Assisted Living Facilities

OBJECTIVES: To establish the etiology for outbreaks of hepatitis B virus (HBV) infections at two assisted living facilities (ALFs) and devise appropriate control measures. DESIGN: Multisite outbreak investigations, retrospective cohort. SETTING: Two ALFs in Illinois. PARTICIPANTS: Facility A residents (n=120) and Facility B residents (n=105) and nursing staff (n=6). MEASUREMENTS: For Facility A, a retrospective cohort study to identify risk factors for HBV infection through serological testing of all residents and a medical record extraction. For Facility A and B, investigation of fingerstick blood glucose monitoring techniques. For Facility B, serological HBV testing of nurses and residents receiving fingerstick blood glucose monitoring. RESULTS: At Facility A, five confirmed acute, two probable acute, and one probable chronic HBV infections were identified in the 109 residents tested. All of the eight identified residents with HBV infection had diabetes mellitus. HBV deoxyribonucleic acid (DNA) sequences from the chronic and acute cases were identical. Transmission of HBV was associated with fingerstick blood glucose monitoring (relative risk (RR)=28.5, 95% confidence interval (CI)=1.6–498; P<.001) and insulin injections (RR=7.4, 95% CI=1.3–40.8; P=.03). At Facility B, seven of 21 residents (33.3%) receiving fingerstick blood glucose monitoring had evidence of recent HBV infection. CONCLUSION: Nurses probably transmitted HBV infection from resident to resident during fingerstick blood glucose monitoring in two separate ALFs, causing outbreaks. Awareness of the high risk for HBV transmission during procedures for the care of diabetes mellitus was limited. Following established infection control measures is critical to prevent spread of this highly contagious virus.