Transcriptional Signatures of Hippocampal Tau Pathology in Primary Age-Related Tauopathy and Alzheimer's Disease.

Background: Tau pathology is common in age-related neurodegenerative diseases. Tau pathology in primary age-related tauopathy (PART) and in Alzheimer's disease (AD) has a similar biochemical structure and anatomic distribution, which is distinct from tau pathology in other diseases. However, the molecular changes associated with intraneuronal tau pathology in PART and AD, and whether these changes are similar in the two diseases, is largely unexplored. Methods: Using GeoMx spatial transcriptomics, mRNA was quantified in CA1 pyramidal neurons with tau pathology and adjacent neurons without tau pathology in 6 cases of PART and 6 cases of AD, and compared to 4 control cases without pathology. Transcriptional changes were analyzed for differential gene expression and for coordinated patterns of gene expression associated with both disease state and intraneuronal tau pathology. Results: Synaptic gene changes and two novel gene expression signatures associated with intraneuronal tau were identified in PART and AD. Overall, gene expression changes associated with intraneuronal tau pathology were similar in PART and AD. Synaptic gene expression was decreased overall in neurons in AD and PART compared to control cases. However, this decrease was largely driven by neurons lacking tau pathology. Synaptic gene expression was increased in tau-positive neurons compared to tau-negative neurons in disease. Two novel gene expression signatures associated with intraneuronal tau were identified by examining coordinated patterns of gene expression. Genes in the up-regulated expression pattern were enriched in calcium regulation and synaptic function pathways, specifically in synaptic exocytosis. These synaptic gene changes and intraneuronal tau expression signatures were confirmed in a published transcriptional dataset of cortical neurons with tau pathology in AD. Conclusions: PART and AD show similar transcriptional changes associated with intraneuronal tau pathology in CA1 pyramidal neurons, raising the possibility of a mechanistic relationship between the tau pathology in the two diseases. Intraneuronal tau pathology was also associated with increased expression of genes associated with synaptic function and calcium regulation compared to tau-negative disease neurons. The findings highlight the power of molecular analysis stratified by pathology in neurodegenerative disease and provide novel insight into common molecular pathways associated with intraneuronal tau in PART and AD.

Seasonality, clinical types and prognostic factors of Vibrio vulnificus infection.

INTRODUCTION: Vibrio vulnificus infection, an uncommon but life-threatening illness, manifests as two main types, primary septicemia and primary wound infections.  Little information regarding the seasonality of V. vulnificus infections in tropical areas and prognostic factors of primary V. vulnificus wound infections is available. METHODOLOGY: This retrospective study was conducted to include 159 V. vulnificus-infected admissions at our institution in southern Taiwan, 63 with primary septicemia (Group 1) and 96 with primary wound infections (Group 2), from 1999 to 2008, for analysis. RESULTS: The case-fatality rate was 24%. Eighty-eight percent of these cases occurred during April to November. During December to March, patients in Group 2 were less likely to have acquired the infection compared with those in Group 1. Group 1 was more likely to have comorbidities and a higher case-fatality rate compared to Group 2. In multivariate analysis, hemorrhagic bullous skin lesions/necrotizing fasciitis (P=0.024), lesions involving two or more limbs (P=0.043), and shock on admission (P=0.015) were related to an increased mortality risk, while surgery < 24 hours after admission (P=0.001) was related to a decreased mortality risk in Group 1; however, hemorrhagic bullous skin lesions/necrotizing fasciitis (P=0.045) was the only prognostic factor in Group 2. CONCLUSION: The presence of hemorrhagic bullous lesion/necrotizing fasciitis is the main prognostic factor for primary septicemia or primary wound infections caused by V. vulnificus. Persons with an underlying immunocompromised status should avoid consuming raw/undercooked seafood or exposing wounds to seawater and should wear clothing during handling of seafood/fishing, especially in warmer months.

Pyogenic liver abscess in the elderly: clinical features, outcomes and prognostic factors.

BACKGROUND: pyogenic liver abscess (PLA) is a potentially life-threatening disease in middle-to-old aged persons. OBJECTIVE: to compare the differences in clinical features and outcomes between older and younger PLA patients, and to identify predictors of outcomes in older patients. DESIGN: retrospective chart review of all PLA patients between July 1999 and June 2007. SETTING: a 1,600-bed primary and tertiary care centre. SUBJECTS: in total, 339 patients were enrolled and included 118 > or =65 years of age (the elderly group) and 221 patients <65 years of age (the non-elderly group). METHODS: clinical features, laboratory, imaging and microbiologic findings, treatment and outcomes for each of the included patients were collected. The predictor of outcome was determined using logistic regression and purposeful selection of covariates. RESULTS: the elderly group had a higher APACHE II score on admission, a biliary abnormality, a malignancy, a pleural effusion, polymicrobial, anaerobic or multi-drug-resistant isolates, inappropriate initial antibiotics, a longer hospitalisation and a longer parenteral antibiotic treatment period than the non-elderly group, whereas the non-elderly group was more likely to be alcoholic men with cryptogenic origin of abscess and Klebsiella pneumoniae infection. There was no difference in case fatality between the elderly (13.6%) and non-elderly (8.6%) groups despite the elderly group having a poorer host status on admission. In multivariate analysis, age (P = 0.028) and APACHE II score at admission > or =15 (P = 0.001) were risk factors, but K. pneumoniae infection (P = 0.012) was a protective factor for fatality in older PLA patients. CONCLUSIONS: these data suggest that older PLA patients would have a fair outcome compared to younger patients, but require longer hospitalisations.

Comparison of Escherichia coli and Klebsiella pneumoniae liver abscesses.

BACKGROUND: Escherichia coli and Klebsiella pneumoniae are the most common causative pathogens of pyogenic liver abscesses. The objective of this study was to compare outcome between patients with liver abscesses due to E coli and those with liver abscesses caused by K pneumoniae; we also aimed to identify separately the predictors of mortality in the 2 groups. METHODS: We conducted a retrospective study of 202 patients who presented with pyogenic liver abscesses caused by either E coli or K pneumoniae from July 2000 to June 2005. Outcome of the patients was analyzed by exact logistic regression with adjustment for baseline and clinical covariates. Significant predictors of mortality in the E coli and the K pneumoniae groups were investigated by multivariate analysis of demographic and clinical variables in each group. RESULTS: Of the 202 patients (128 men and 74 women; age range, 19 to 89 years), pyogenic liver abscess was due to E coli infection in 55 patients and K pneumoniae in 147 patients. In contrast to patients with K pneumoniae, patients with E coli liver abscess were more likely to be older and female, have a biliary abnormality or malignancy, pleural effusion, polymicrobial infection with anaerobic or multi-drug-resistant organisms, a higher APACHE II score, and to have been treated initially with ineffective antibiotics; they were also less likely to have diabetes mellitus. The cause of K pneumoniae liver abscess was often cryptogenic. The sensitivity, specificity, positive predictive value, and likelihood ratio of the presence of biliary disorders and coexisting malignancy as a predictive parameter of E coli liver abscess were 25%, 96%, 67%, and 5.45/1, respectively. The sensitivity, specificity, positive predictive value, and likelihood ratio of the presence of diabetes mellitus with an abscess of cryptogenic origin as a predictive parameter of K pneumoniae liver abscess were 39%, 84%, 81%, and 2.36/1, respectively. There was no significant difference in mortality between patients with E coli and those with K pneumoniae infections (26% vs 4%; adjusted OR, 4.2; 95% CI, 0.63 to 27; P = 0.105). However, for patients with liver abscess caused by E coli, the APACHE II score at admission (OR, 1.7; 95% CI, 1.1 to 2.6; P = 0.021), malignancy (OR, 26; 95% CI, 1.8 to 370; P = 0.016), and right-lobe abscess (OR, 0.0029; 95% CI, 0.00010 to 0.15; P = 0.004) were significant predictors of death, whereas uremia (OR, 52; 95% CI, 3.5 to 750; P = 0.004) and multi-drug-resistant isolates (OR, 26; 95% CI, 2.3 to 290; P = 0.009) were significant predictors of death in the K pneumoniae group. CONCLUSIONS: A higher APACHE II score at admission and a higher frequency of coexisting malignancy may have contributed to the higher, although not significant, mortality rate in patients with liver abscess caused by E coli infection. Clinicians should begin with broad antibiotic coverage such as a second-generation cephalosporin and an aminoglycoside with metronidazole when treating liver abscesses with E coli as the likely pathogen due to the high frequency of multi-drug-resistant isolates among E coli isolates.

Epidemiology of hepatitis B virus infection among young adults in Taiwan, China after public vaccination program.

BACKGROUND: The public vaccination program of hepatitis B virus (HBV) was launched during 1984 in Taiwan, China. However, the long-lasting protective efficacy of HBV vaccination among adolescents older than 15 years of age was seldom recorded. METHODS: A seroepidemiological survey was conducted among 4575 first-year university students in Taiwan, China during 2000 to 2003, including the serological data of HBV by testing HBV surface antigen (HBsAg), surface antibody (anti-HBs), HBV core antibody (anti-HBc) and demographic information. RESULTS: HBsAg carrier rate among male university students born before the initiation of the HBV vaccination program decreased from 12.8% to 4.8% among those born after the vaccination program (P < 0.001, chi(2) test for linear trend). Similarly, HBsAg carrier rate among female university students born before the initiation of the HBV vaccination program decreased from 8.1% to 2.7% among those born after the vaccination program (P < 0.001, chi(2) test for linear trend). Both male and female students in eastern Taiwan had the highest HBsAg carrier rate compared with the other places. Using multiple logistic regression analysis, compared with students born after July 1984, the adjusted OR of HBsAg carrier rate decreased from 3.10 for students born before June 1981 to 1.56 for students born from July 1983 to June 1984 (95% CI 1.96 - 4.91, P < 0.001; 95% CI 1.06 - 2.28, P = 0.024; respectively). CONCLUSIONS: Public vaccination provides long-lasting protection again HBV infection among the university students in Taiwan, China older than 18 years of age. There is a geographic variation of HBV infection among young adults in Taiwan, China.

Spinal cord compression caused by extradural arachnoid cysts. Clinical examples and review.

Most spinal arachnoid cysts are asymptomatic and detected incidentally during magnetic resonance imaging or myelography. The etiology of intraspinal arachnoid cyst is not yet clear. We present two children with three spinal extradural arachnoid cysts and each cyst protruded from a separate dura defect. In both patients, plain radiographs demonstrated widening of the interpedicular distance, which suggested progressive widening of the spinal bony canal. Limited laminectomy was performed to remove the intraspinal cysts. Separate dura defects, the apparent predisposing factors, were also found and repaired. The patients completely recovered neurologically. Radical cyst removal and dura defect closure are the surgical intervention of choice in patients with symptomatic extradural arachnoid cyst.

Fluid shear regulates the kinetics and molecular mechanisms of activation-dependent platelet binding to colon carcinoma cells.

This study was undertaken to investigate the kinetics and molecular requirements of platelet binding to tumor cells in bulk suspensions subjected to a uniform linear shear field, using a human colon adenocarcinoma cell line (LS174T) as a model. The effects of shear rate (20-1000 s(-1)), shear exposure time (30-300 s), shear stress (at constant shear rate by adjusting the viscosity of the medium from 1.3-2.6 cP), cell concentration, and platelet activation on platelet-LS174T heteroaggregation were assessed. The results indicate that hydrodynamic shear-induced collisions augment platelet-LS174T binding, which is further potentiated by thrombin/GPRP-NH(2). Peak adhesion efficiency occurs at low shear and decreases with increasing shear. Intercellular contact duration is the predominant factor limiting heteroaggregation at shear rates up to 200 s(-1), whereas these interactions become shear stress-sensitive at > or = 400 s(-1). Heteroaggregation increases with platelet concentration due to an elevation of the intercellular collision frequency, whereas adhesion efficiency remains nearly constant. Moreover, hydrodynamic shear affects the receptor specificity of activation-dependent platelet binding to LS174T cells, as evidenced by the transition from a P-selectin-independent/Arg-Gly-Asp (RGD)-dependent process at 100 s(-1) to a P-selectin/alpha(IIb)beta(3)-dependent interaction at 800 s(-1). This study demonstrates that platelet activation and a fluid-mechanical environment representative of the vasculature affect platelet-tumor cell adhesive interactions pertinent to the process of blood-borne metastasis.

Present-day thrombolytic therapy: therapeutic agents--pharmacokinetics and pharmacodynamics.

Various thrombolytic agents have been studied as activators of the plasminogen-plasmin system for thrombolysis of thrombus formation. They include streptokinase, urokinase, tissue plasminogen activators, single-chain urokinase plasminogen activator, and anisoylated or acylated plasminogen-streptokinase activator complex (APSAC), only some of which are commercially available. All thrombolytic agents, including APSAC (not commercially available), recombinant tissue plasminogen activator, and prourokinase, generate great quantities of degradation products of fibrinogen or fibrin. All of the second-generation thrombolytic agents induce systemic activation of the entire fibrinolytic system, and none are capable of specifically activating the fibrinolytic system at the site of thrombus formation. The most systemically active agent known at the present time is APSAC. Trials show that bleeding occurs as frequently with the second-generation agents as with the older agents, and further studies may even find that the newer agents are associated with more bleeding than urokinase and streptokinase have been. With knowledge of the properties of the various thrombolytic agents available today, the physician can intelligently select the optimal agent for a given patient problem.