Altered kallikrein 7 and 10 concentrations in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia

BACKGROUND: The role of various proteases in the pathogenesis of Alzheimer's disease is well documented. Recently, many members of the human tissue kallikrein family, a group of 15 secreted serine proteases, were found to be highly expressed in the central nervous system (CNS). Some of these enzymes can be measured in cerebrospinal fluid (CSF) by using ELISA-type methodologies. METHODS: We quantified various kallikreins in CSF of 20 patients with Alzheimer's disease (AD), 16 patients with frontotemporal dementia (FTD), and 15 controls. We then correlated the levels of various kallikreins with presence of AD or FTD. Among all kallikreins measured, detectable levels in CSF were identified for kallikreins hK6, hK7, and hK10. Other tested kallikreins (hK5, hK8, hK11, and hK13) were unmeasurable. The most notable differences between kallikrein levels in CSF and the three groups of subjects were seen between controls and FTD patients for hK6 (decrease in FTD; P = 0.017), controls and FTD patients for hK7 (decrease in FTD; P < 0.001), and controls and AD patients for hK7 (decrease in AD; P = 0.019). In addition, significant differences were seen between FTD patients or control subjects and patients with AD patients for hK10 (increase in AD; P < 0.02). Approximately half of the AD patients had CSF hK10 levels that were higher than all patients with FTD except one and all control subjects except two. Various kallikrein concentrations in CSF were correlated, the strongest correlation seen between hK6 and hK7 (r(s) = 0.58). We also observed a statistically significant association between decreasing hK7 concentration in CSF and possession of one or two ApoE4 alleles (P = 0.014). CONCLUSIONS: We demonstrate for the first time significant alterations of hK6, hK7, and hK10 concentration in CSF of patients with AD and FTD. Notably, all three kallikreins (hK6, hK7, and hK10) are decreased in CSF of FTD patients and hK10 is increased in CSF of AD patients, in comparison to control subjects. The possible connection between these enzymes and the pathogenesis and progression of AD and FTD needs to be further investigated.     

The effect of formulations and experimental conditions on in vitro human skin permeation-Data from updated EDETOX database

In vitro methods are commonly used in order to estimate the extent of systemic absorption of chemicals through skin. Due to the wide variability of experimental procedures, types of skin and data analytical methods, the resulting permeation measures varies significantly between laboratories and individuals. Inter-laboratory and inter-individual variations with the in vitro measures of skin permeation lead to unreliable extrapolations to in vivo situations. This investigation aimed at a comprehensive assessment of the available data and development of validated models for in vitro skin flux of chemicals under various experimental and vehicle conditions. Following an exhaustive literature review, the human skin flux data were collated and combined with those from EDETOX database resulting in a dataset of a total of 536 flux reports. Quantitative structure-activity relationship techniques combined with data mining tools were used to develop models incorporating the effects of permeant molecular structure, properties of the vehicle, and the experimental conditions including the membrane thickness, finite/infinite exposure, skin pre-hydration and occlusion. The work resulted in statistically valid models for estimation of the skin flux from varying experimental conditions, including relevant real-world mixture exposure scenarios. The models indicated that the most prominent factors influencing flux values were the donor concentration, lipophilicity, size and polarity of the penetrant, and the melting and boiling points of the vehicle, with skin occlusion playing significant role in a non-linear way. The models will aid assessment of the utility of dermal absorption data collected under different conditions with broad implications on transdermal delivery research.     

Expression of ets-1 is not affected by N-ras or H-ras during oral oncogenesis

PURPOSE: To determine whether ras-activated cascades lead to activation of ets-1 expression in sequential histological stages of oral oncogenesis in an experimental animal model. METHODS: Thirty-seven Syrian golden hamsters were divided into three experimental groups (A, B, C) and one control group. The hamsters' buccal pouches in experimental groups were treated with 0.5% 9, 10-dimethyl-1, 2-benzanthracene (DMBA) for 14 weeks and were excised at 10, 14, 19 weeks, respectively. The biopsies were classified pathologically (normal mucosa, hyperkeratosis, hyperplasia, dysplasia, early invasion, well and moderately differentiated carcinoma) and studied immunohistochemically. The two-tailed Student's t test was performed for each animal group and for each histological category. RESULTS: The ets-1 expression increased in early stages of oral tumor formation and invasion. The expression of N-ras gradually decreased during oral oncogenesis, as previously observed with H-ras. CONCLUSIONS: Neither N-ras nor H-ras affects ets-1 expression in contrast to other types of cancer in which N-ras and ets-1 are implicated in the same signalling pathway. Therefore, the existing pathway implicating these proteins might be somehow altered in oral cancer. It seems that ets-1 is a good prognostic marker for invasiveness and progression of oral cancer.     

Relation between local temperature and C-reactive protein levels in patients with coronary artery disease: effects of atorvastatin treatment

Although previous studies have shown systemic inflammatory activation the relation with the local plaque inflammatory activation has not been extensively studied. The present study investigated the relation between local and systemic inflammatory activation in patients with coronary artery disease and the impact of atorvastatin treatment. We included 215 patients undergoing percutaneous coronary intervention; of them 140 were treated with atorvastatin. Patients with stable angina (SA) and acute coronary syndromes (ACS) were included. Systemic inflammation was assessed by serum C-reactive protein (CRP), soluble adhesion molecules levels and local plaque inflammatory activation by coronary thermography. Temperature difference (DeltaT) was assigned as the difference between the proximal vessel wall temperature from the maximal temperature at the culprit plaque. Patients with ACS (n=78) had increased DeltaT compared to patients with SA (n=137) (0.16+/-0.10 degrees C versus 0.08+/-0.07 degrees C, P<0.001). Patients treated with atorvastatin had lower DeltaT compared to untreated patients (0.10+/-0.07 degrees C versus 0.15+/-0.10 degrees C, P<0.01). DeltaT was less in the treated group compared to the untreated group in patients with SA and ACS (ACS: 0.13+/-0.08 degrees C versus 0.20+/-0.11 degrees C, P<0.01, SA: 0.08+/-0.06 degrees C versus 0.13+/-0.08 degrees C, P=0.03). Although a correlation was found between CRP levels and DeltaT (R=0.29, P<0.01), in certain groups a discrepancy between CRP levels and DeltaT was observed. In 25% of patients with low DeltaT CRP levels were >1mg/dl and in 35.5% of patients with high DeltaT CRP was <2mg/dl. The correlation between soluble adhesion molecules and DeltaT did not reach statistical significance. Although there is a correlation between widespread and local inflammatory activation in patients with coronary artery disease, a discrepancy between culprit plaque and systemic inflammatory activation is observed. Atorvastatin has a parallel effect on systemic and local inflammatory process in patients with coronary artery disease.