Modulation of CD8 T-cell activation events by monocytic and granulocytic myeloid-derived suppressor cells

Myeloid-derived suppressor cells are immature myeloid cells, consisting of a monocytic and a granulocytic fraction, that are known to suppress anti-tumor immune responses. Important targets of the immunosuppressive capacity of MDSC are CD8⁺ T cells, which are crucial cytotoxic effector cells in immunotherapeutic settings. CD8⁺ T-cell activation and differentiation comprises a well-orchestrated series of events, starting from early TCR-mediated signaling and leading to cytokine secretion, the expression of activation markers, proliferation and the differentiation into several subsets of effector and memory cells. In this review, we summarize the available data on how the production of reactive oxygen species, nitric oxide, the arginase-mediated depletion of l-arginine and Cystine depletion by MDSCs interfere with the signaling molecules necessary for normal CTL differentiation and activation.     

Coding variants of TLR2 and TLR4 genes do not substantially contribute to prosthetic joint infection

Objective and design

Prosthetic joint infection (PJI) is a severe complication of total joint arthroplasty (TJA). We conducted a genetic association study that investigated whether selected coding variants of the genes for Toll-like receptors (TLR)2 and TLR4 may contribute to genetic susceptibility for PJI.

Subjects and methods

In total, 350 patients with TJA (98 with PJI/252 without PJI), and 189 unrelated healthy Czech individuals without TJA were enrolled in our study. Three missense polymorphisms of the genes encoding for TLR2 (TLR2 R753Q, rs5743708) and TLR4 (TLR4 D299G, rs4986790 and T399I, rs4986791) were genotyped by “TaqMan” assay.

Results

The frequencies of less common variants for the investigated TLR2/TLR4 polymorphisms in healthy individuals were similar to those observed in other Caucasian populations. Importantly, the distribution of TLR2/TLR4 genotype alleles did not differ between the patients with PJI and the control groups of patients with nonseptic prostheses/healthy individuals.

Conclusion

Our data suggest that structural genetic variants of the receptors TLR2 and TLR4 do not substantially affect the risk of prosthetic joint infection.     

A study of the conditions of the supercritical fluid extraction in the analysis of selected anti-inflammatory drugs in plasma

Supercritical fluid extraction (SFE) was employed to analyze selected anti-inflammatory drugs in plasma. Evaluation of selected drugs (ibuprofen, indomethacin, and flufenamic acid) was performed using the HPLC method on columns with the reverse phase C-18 and detection in the UV region of the spectrum. A study of the conditions of SFE carried out for 30 min at 50 degrees C investigated the magnitude of the pressure of carbon dioxide suitable for drug extraction, the selection of the collecting solvent, and the modification of CO2 with an organic solvent. The results of the study made it possible to determine the optimal procedure for SFE of ibuprofen, indomethacin, and flufenamic acid from plasma, which renders their HPLC quantification possible.     

Relationship of criminality to endogeneity and anxiety in patients with unipolar depression

The relationship between criminal behavior on the one hand and endogeneity and anxiety on the other hand was investigated in a sample of patients with unipolar depression to help elucidate factors influencing the criminality rate in this population. A lower criminality rate in patients with higher ratings of endogeneity and anxiety was predicted. Clinical records of 179 male and 99 female psychiatric inpatients were retrospectively evaluated using the Newcastle Scale II and Hamilton Anxiety Scale. A full account of conviction records served as a measure of criminal behavior. Forty per cent of male patients and 7% of female patients were criminally registered. A lower criminality rate was indeed found in male and female patients with endogenous type of depression and in male patients with higher anxiety ratings. In a multivariate evaluation, however, sociodemographic variables in terms of age and social class seem to be more important predictors of criminality and all variables we assessed contributed only marginally to the explanation of the criminality variance. Thus, in patients with unipolar depression, sociodemographic factors seem to be of a greater even though still limited importance regarding criminal behavior compared with the clinical variables of endogeneity and anxiety.     

Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling

We have developed animal models of breast cancer that allow the direct examination of the behavior of individual green fluorescent protein-expressing carcinoma cells in live nonmetastatic and metastatic primary tumors in situ. We have combined this model with multiphoton microscopy to image differences in cell behavior within the primary tumor. Differences in cell behavior between nonmetastatic and metastatic cells in culture and within live primary tumors were correlated with results from cDNA microarray analyses to identify potentially important genetic determinants for breast cancer invasion and metastasis. Using multiphoton microscopy, we found five major differences in carcinoma cell behavior between the nonmetastatic and metastatic primary breast tumors involving extracellular matrix, cell motility, and chemotaxis. Behavioral differences were correlated with seven categories of molecules that were differentially expressed and related to these behaviors. We have found that extracellular matrix composition, actin nucleation factors, molecules involved in mechanical stability and survival, and cell polarity and chemotaxis showed large and consistent differences in gene expression. We conclude that aligning cell behavior in vivo with patterns of gene expression can lead to new insights into the microenvironment of carcinoma cells in the primary tumor and the molecular mechanisms behind cell behavior.     

Listerial endocarditis in a penicillin-allergic woman successfully treated with a combination of 4 drugs

A 69-y-old woman with bioprosthetic endocarditis due to Listeria monocytogenes developed an allergic reaction after beginning ampicillin treatment. She was cured with the combination of trimethoprim-sulfamethoxazole, rifampicin and teicoplanin. No immune deficiency was found in the patient.     

Treatment of Interictal Depression with Citalopram in Patients with Epilepsy

The purpose of this study is to assess the efficacy and safety of the selective serotonin-reuptake inhibitor (SSRI) citalopram in depressed epileptic patients. We evaluated 43 epileptic patients who suffered from depression and whose total score on the 21 items of the Hamilton Scale for Depression (HAMD 21) exceeded 15 points. These patients were examined by the psychiatrist and scaled before treatment and after 4 and 8 weeks of treatment with citalopram. The dose of citalopram was flexible, related to the actual condition of the patient. In each patient and in the whole group of patients we compared the monthly seizure frequency (total, partial seizures, generalized tonic–clonic seizures) recorded during treatment with citalopram with that recorded during the 2 months preceding the start of citalopram. During treatment we observed a decrease in the total score on the HAMD 21 from a mean initial value of 21.5 ± 2.9 (range, 17–26) prior to therapy 14.5 ± 2.9 (range, 10–19) (P < 0.001) after 4 weeks of treatment and to 9.9 ± 3.1 (range, 4–19) (P < 0.001) after 8 weeks of treatment. There were 9 (20.9%) responders after 4 weeks of treatment and 28 responders (65.1%) after 8 weeks, all of them with decrease on the HAMD 21 greater than 50%. Nausea was the most common adverse event in 7 patients (16.3%) during the first month of treatment and in 3 patients (6.9%) during the second month of treatment. Sexual dysfunction (decrease of libido) was reported in 2 (4.7%) male patients during the entire course of treatment. No seizure worsening was observed in our patients. Monthly seizure frequency did not change significantly: 2.24 (±0.76) seizures before treatment with citalopram, 2.29 (±0.81) seizures in the first month of treatment, 2.21 (±1.00) seizures in the second month of treatment. No occurrence of de novo generalized tonic–clonic seizures was recorded in individual patients. Citalopram is a safe and effective antidepressant in the treatment of depressed epileptic patients.