Both TLR2 and TLR4 are required for the effective immune response in Staphylococcus aureus-induced experimental murine brain abscess

Toll-like receptors (TLRs) play central roles in the innate reaction to bacterial products and transmit specific immune responses against these pathogens. TLRs are expressed on numerous cell types, including innate immune cells, and on astrocytes, neurons, and microglial cells of the central nervous system (CNS). Lipoproteins and lipopolysaccharides are specifically recognized by TLR2 and TLR4, respectively. We examined the in vivo role of TLR2 and TLR4 in Staphylococcus aureus-induced brain abscess. Phenotypically, 87% of TLR2(-/-) mice and 43% of TLR4(-/-) mice died whereas all wild-type (WT) mice recovered. Clearance of bacteria from the CNS was significantly delayed in TLR2(-/-) mice compared with TLR4(-/-) and WT animals. Recruitment of granulocytes and macrophages to the CNS, as well as microglial activation and expansion, was up-regulated in TLR2(-/-) mice. Although inflammation persisted especially in the CNS of TLR2(-/-) mice, but also of TLR4(-/-) mice, WT mice terminated the infection more effectively. Collectively, these data show that the immune response to experimental S. aureus-induced brain abscess depends crucially on the recognition of S. aureus by TLR2 but that TLR4 is also required for an optimal intracerebral immune response in this disorder.     

A cold shock response triggering acute myocardial infarction

Acute risk factors are activities and events that suddenly and transiently increase the risk of acute cardiac events, as reported recently in International Journal of Cardiology. It has already been reported that sudden submersion in cold water may provoke myocardial infarction in both subjects with atherosclerotic coronary disease and young people with angiographically normal coronary arteries.We report a case of an acute myocardial infarction triggered by sudden exposure to cold air temperature extreme in a young person with acutely occluded proximal part of the left anterior descending coronary artery and normal other coronary arteries who had extreme obesity and cigarette smoking as cardiovascular risk factors.Our report indicates that the sudden cold exposure and the resulting cold shock response may provoke acute myocardial infarction in young susceptible patients.     

Diagnostic and prognostic values of CA 19-9 and CEA in periampullary cancers

BACKGROUND: The roles of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) in periampullary cancers have not been clearly established. Diagnostic and prognostic values of these two tumor markers were clarified in this study. STUDY DESIGN: Preoperative serum levels of CEA and CA 19-9, and clinicopathologic features were retrospectively reviewed in 143 surgical patients with periampullary cancer from 1989 to 1997. RESULTS: There were 86 resectable and 57 unresectable periampullary cancers. CA 19-9 demonstrated significantly higher sensitivity in detecting these cancers than CEA. The cancer with unresectable lesion, total bilirubin >7.3 mg/dL, or tumor size >2 cm tended to associate with higher CA 19-9 level. CEA level was significantly higher in the tumor >2 cm, not in the tumor < or =2 cm. CA 19-9 was a significant prognostic factor in both resectable and unresectable periampullary cancers, but CEA was significant only in the resectable group. Multivariate analysis revealed that independent prognostic factors included CA 19-9, resectability, primary tumor, and stage, and CA 19-9 was the most important one. CONCLUSION: CA 19-9 provided more important diagnostic and prognostic values than CEA in periampullary cancers and was the most important independent prognostic factor for periampullary cancers. This study recommends serum CA 19-9 as an adjunct in detecting periampullary cancers, in evaluating resectability, and in predicting prognosis.     

Increased plasma N-glycome complexity is associated with higher risk of type 2 diabetes

Aims/hypothesis

Better understanding of type 2 diabetes and its prevention is a pressing need. Changes in human plasma N-glycome are associated with many diseases and represent promising diagnostic and prognostic biomarkers. Variations in glucose metabolism directly affect glycosylation through the hexosamine pathway but studies of plasma glycome in type 2 diabetes are scarce. The aim of this study was to determine whether plasma protein N-glycome is changed in individuals who are at greater risk of developing type 2 diabetes.

Methods

Using a chromatographic approach, we analysed N-linked glycans from plasma proteins in two populations comprising individuals with registered hyperglycaemia during critical illness (increased risk for development of type 2 diabetes) and individuals who stayed normoglycaemic during the same condition: AcuteInflammation (59 cases vs 49 controls) and AcuteInflammation Replication (52 cases vs 14 controls) populations. N-glycome was also studied in individuals from FinRisk (37 incident cases of type 2 diabetes collected at baseline vs 37 controls), Orkney Complex Disease Study (ORCADES; 94 individuals with HbA_1c > 6.5% [47.5 mmol/mol] vs 658 controls) and Southall and Brent Revisited (SABRE) cohort studies (307 individuals with HbA_1c > 6.5% [47.5 mmol/mol] vs 307 controls).

Results

Individuals with increased risk for diabetes type 2 development (AcuteInflammation and AcuteInflammation Replication populations), incident cases of type 2 diabetes collected at baseline (FinRisk population) and individuals with elevated HbA_1c (ORCADES and SABRE populations) all presented with increased branching, galactosylation and sialylation of plasma protein N-glycans and these changes were of similar magnitude.

Conclusions/interpretation

Increased complexity of plasma N-glycan structures is associated with higher risk of developing type 2 diabetes and poorer regulation of blood glucose levels. Although further research is needed, this finding could offer a potential new approach for improvement in prevention of diabetes and its complications.

     

Preventive and therapeutic effects of oleuropein against carbon tetrachloride-induced liver damage in mice

Olives and olive products, an inevitable part of the Mediterranean diet, possess various beneficial effects, such as a decreased risk of cardiovascular disease and cancer. Oleuropein is a non-toxic secoiridoid found in the leaves and fruits of olive (Olea europaea L.). In this study, we have investigated the hepatoprotective activity of oleuropein in carbon tetrachloride (CCl(4))-induced liver injury in male BALB/cN mice. Oleuropein in doses of 100 and 200mg/kg was administered intraperitoneally (ip) once daily for 3 consecutive days, prior to CCl(4) administration (the preventive treatment), or once daily for 2 consecutive days 6h after CCl(4) intoxication (the curative treatment). CCl(4) intoxication resulted in a massive hepatic necrosis and increased plasma transaminases. Liver injury was associated with oxidative/nitrosative stress evidenced by increased nitrotyrosine formation as well as a significant decrease in superoxide dismutase activity and glutathione levels. CCl(4) administration triggered inflammatory response in mice livers by inducing expression of nuclear factor-kappaB, which coincided with the induction of tumor necrosis factor-alpha, cyclooxygenase-2 and inducible nitric oxide synthase. In both treatment protocols, oleuropein significantly attenuated oxidative/nitrosative stress and inflammatory response and improved histological and plasma markers of liver damage. Additionally, in the curative regimen, oleuropein prevented tumor necrosis factor-beta1-mediated activation of hepatic stellate cells, as well as the activation of caspase-3. The hepatoprotective activity of oleuropein was, at least in part, achieved through the NF-E2-related factor 2-mediated induction of heme oxygenase-1. The present study demonstrates antioxidant, anti-inflammatory, antiapoptotic, and antifibrotic activity of oleuropein, with more pronounced therapeutic than prophylactic effects.     

Epilepsy and serotonin (5HT): Variations of 5HT-related genes in temporal lobe epilepsy

Several lines of evidence point to the role of serotonin (5HT) neurotransmission in the epileptogenesis. The present preliminary study investigated possible association of the temporal lobe epilepsy (TLE) with the polymorphisms in several 5HT-related genes, including serotonin transporter (5HTT), monoamine oxidase A (MAO-A) and serotonin receptors 5HT-1A, 5HT-1B and 5HT-2C. All participants (101 TLE patients and 170 healthy controls) were unrelated individuals of Croatian origin. 5HT-1B allele 861G was found to be slightly overrepresented in the patient group (p = 0.0385). No significant differences between groups were observed for the other tested polymorphisms. Within the limitations imposed by the size of our sample, negative findings suggest that the respective loci do not make considerable contribution to the etiopathogenesis of TLE. Further examination of 5HT-1B gene, which yielded positive result at a trend level, is possibly warranted.     

Low expression levels of ATM may substitute for CHEK2 /TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer

Introduction

Mutations affecting p53 or its upstream activator Chk2 are associated with resistance to DNA-damaging chemotherapy in breast cancer. ATM (Ataxia Telangiectasia Mutated protein) is the key activator of p53 and Chk2 in response to genotoxic stress. Here, we sought to evaluate ATM's potential role in resistance to chemotherapy.

Methods

We sequenced ATM and assessed gene expression levels in pre-treatment biopsies from 71 locally advanced breast cancers treated in the neoadjuvant setting with doxorubicin monotherapy or mitomycin combined with 5-fluorouracil. Findings were confirmed in a separate patient cohort treated with epirubicin monotherapy. Each tumor was previously analyzed for CHEK2 and TP53 mutation status.

Results

While ATM mutations were not associated with chemo-resistance, low ATM expression levels predicted chemo-resistance among patients with tumors wild-type for TP53 and CHEK2 (P = 0.028). Analyzing the ATM-chk2-p53 cascade, low ATM levels (defined as the lower 5 to 50% percentiles) or mutations inactivating TP53 or CHEK2 robustly predicted anthracycline resistance (P-values varying between 0.001 and 0.027 depending on the percentile used to define "low" ATM levels). These results were confirmed in an independent cohort of 109 patients treated with epirubicin monotherapy. In contrast, ATM-levels were not suppressed in resistant tumors harboring TP53 or CHEK2 mutations (P > 0.5).

Conclusions

Our data indicate loss of function of the ATM-Chk2-p53 cascade to be strongly associated with resistance to anthracycline/mitomycin-containing chemotherapy in breast cancer.     

Tobacco use and cessation among medical students in Croatia – results of the Global Health Professionals Pilot Survey (GHPS) in Croatia, 2005

Summary Objectives: To collect information from third year medical students attending Croatian medical schools on prevalence of cigarette smoking and other tobacco use, exposure to secondhand smoke, desire to quit using tobacco, attitudes and training concerning counselling patients on tobacco cessation. Methods: Global Health Professionals Survey (GHPS) was conducted in 2005 in all four Croatian medical schools with a census of third year medical students (404 out of 409, response rate 98.5 %) using an anonymous, confi dential and self-reported questionnaire. Results: More than two thirds (67.4 %) of medical students in Croatia have ever smoked cigarettes, and over one third (36.6 %) are smoking cigarettes currently. Half of the medical students (50.4 %) report exposure to second hand smoke at home. Less than a third of current smokers (30.9 %) have received cessation assistance when they tried to quit. Conclusions: Our findings indicate significant tobacco use among medical students in Croatia. There is an urgent need to reduce this harmful behaviour through more comprehensive public health initiatives, provision of support for cessation among health professionals who smoke and provision of training to health professionals to assist their patients with cessation. Submitted: 09 February 2007; Revised: 06 June 2007; Accepted: 03 January 2008