Inhibitory p41 isoform of invariant chain and its potential target enzymes cathepsins L and H in distinct populations of macrophages in human lymph nodes

Activation of the CD4(+) T-cell mediated immune response relies on the proteolytic capacity of enzymes involved in modulating major histocompatibility complex (MHC) II-associated antigen presentation in antigen-presenting cells (APC). The MHC II-associated chaperone molecule p41 isoform of invariant chain (inhibitory p41 Ii) has been suggested to regulate stability and activity of cathepsin L in these APC. In the present study the human lymph node distribution of non-inhibitory p31 Ii and inhibitory p41 Ii have been compared by differential labelling, using two specific monoclonal antibodies. The distribution of p41 Ii, but not p31 Ii, matched the distribution of cathepsins L and H in subcapsular and cortical sinuses and germinal centres. Co-localization of p41 Ii with cathepsin H was confirmed in strongly CD68(+) sinus-lining macrophages, acting as APC. Furthermore, p41 Ii was determined together with cathepsins L and H in tingible body macrophages, highly phagocytic, but not antigen-presenting cells inside germinal centres. With respect to the physiological function that these two populations of macrophages have in human lymph nodes, our results support a regulatory function of p41 Ii towards cathepsins L and H in human macrophages, associated with the processes of phagocytosis rather than antigen presentation.     

The influence of cytokine gene polymorphisms on the risk of developing gastric cancer in patients with Helicobacter pylori infection

Background

Helicobacter pylori infection is the main cause of gastric cancer. The disease progression is influenced by the host inflammatory responses, and cytokine single nucleotide polymorphisms (SNPs) may have a role in the course of the disease. The aim of our study was to investigate proinflammatory cytokine polymorphisms, previously associated with the development of gastric cancer, in a Slovenian population.

Patients and methods.

In total 318 patients and controls were selected for the study and divided into three groups: (i) patients with gastric cancer (n = 58), (ii) patients with chronic gastritis (n = 60) and (iii) healthy control group (n = 200). H. pylori infection in patient groups was determined by serology, histology and culture. Four proinflammatory gene polymorphisms were determined (IL-1β, IL-1ra, TNF-α, TLR-4) in all subjects.

Results

We found a statistically significant difference between males and females for the groups (p = 0.025). Odds ratio (OR) for gastric cancer risk for females was 0.557 (95% confidence interval [CI]: 0.233–1.329) and for chronic gastritis 2.073 (95% CI: 1.005–4.277). IL-1B-511*T/T homozygous allele for cancer group had OR = 2.349 (95% CI: 0.583–9.462), heterozygous IL-1B-511*T had OR = 1.470 (95% CI: 0.583–3.709) and heterozygotes in TNF-A-308 genotype for chronic gastritis had OR = 1.402 (95% CI: 0.626–3.139). Other alleles had OR less than 1.

Conclusions

We could not prove association between gastric cancer and chronic gastritis due to H. pylori in any cytokine SNPs studied in Slovenian population. Other SNPs might be responsible besides infection with H. pylori for the progression from atrophy to neoplastic transformation.     

The impact of cholesterol and its metabolites on drug metabolism

INTRODUCTION: Global prevalence of Western-type diet has increased in the last decades resulting in occurrence of certain chronic diseases. This type of diet is also linked to high-cholesterol intake and increase in blood cholesterol. Many of the molecular mechanisms of dealing with increased levels of cholesterol and its metabolites have been elucidated in animal models and humans. It is also evident that cholesterol metabolism is closely connected to drug metabolism. Cholesterol/bile acids and drugs share many transporters, enzymes and regulatory proteins which are key points in the crosstalk. AREAS COVERED: This review presents an overview of the effect of cholesterol and its metabolites on drug metabolism with special emphasis on species-specific differences. The article focuses on the role of nuclear receptors farnesoid X receptor, vitamin D receptor and liver X receptor in the regulation of drug metabolism genes and the role of cholesterol biosynthesis intermediates, oxysterols and bile acids in the induction of drug metabolism through pregnane X receptor. EXPERT OPINION: Studies show that the regulation of drug metabolism by sterols is multileveled. Many species-dependent differences were observed which hinder the transfer of findings from model animals to humans. As of now, there is little evidence available for cholesterol impact on drug metabolism in vivo in humans. There is also the need to confirm the results obtained in animal models and in vitro analyses in human cells but this is very difficult given the current lack of tools.     

Verification of a prolonged untreated natural history of breast cancer by the multigene assay

Individualization of therapy for breast cancer patients has progressed significantly over the last 5 years. A 54-year-old female went over 2 years after her diagnosis of breast cancer with no treatment. The pathologic size, however, indicated that the tumor may not have progressed from diagnosis to operation. Due to the apparent lack of progression over 2 years without treatment, a multigene assay was ordered. The recurrence score was 15, indicating a less than 10% risk of distant recurrence at 10 years. The recurrence score also falls into the “low risk” category. The prolonged natural history of this breast cancer patient suggested an indolent cancer. The “low risk” recurrence score confirmed this history and indicated that adjuvant chemotherapy is probably not beneficial to this patient.     

Small Intestinal Bacterial Overgrowth in Patients with Roux-en-Y Gastric Bypass and One-Anastomosis Gastric Bypass

Obesity Surgery - Small intestinal bacterial overgrowth (SIBO) is defined as an excessive growth and/or changed composition of bacteria in the small bowel. Obese patients are at increased risk of...     

Capnometry in suspected pulmonary embolism with positive D-dimer in the field

Introduction  

Pulmonary embolism (PE) is one of the greatest diagnostic challenges in prehospital emergency setting. Most patients with suspected PE have a positive D-dimer and undergo diagnostic testing. Excluding PE with additional non-invasive tests would reduce the need for further imaging tests. We aimed to determine the effectiveness of combination of clinical probability and end-tidal carbon dioxide (PetCO₂) for evaluation of suspected PE with abnormal concentrations of D-dimer in prehospital emergency setting.     

Mathematical model of tumor volume dynamics in mice treated with electrochemotherapy

The effectiveness of electrochemotherapy, a local treatment using electric pulses to increase the uptake of chemotherapeutic drug, includes several antitumor mechanisms. In addition to the cytotoxic action of chemotherapeutic drug, treatment outcome also depends on antitumor immune response. In order to assess the contribution of different antitumor mechanisms to the observed treatment outcome, we designed a model of tumor volume dynamics, which is able to quantify early and late treatment effects. Model integrates characteristics of both main posttreatment processes, namely removal of lethally damaged cells from tumor volume and tumor–immune interaction. Fitting to individual responses gives the insight into the dynamics of tumor cell elimination. Two more or less clearly separable peaks can be observed from these dynamics. Model was used to quantify responses obtained after chemotherapy and electrochemotherapy with bleomycin and cisplatin in immunocompetent and immunodeficient mice. As expected, electrochemotherapy resulted in higher number of lethally damaged cells as well as in stronger immune response compared to chemotherapy alone. Additionally, bleomycin-treated tumors proved to be more immunogenic than cisplatin-treated tumors in the given range of doses.     

Multiple infections after commercial renal transplantation in India.

Sir, The increased demand for transplantable kidneys has not metwith a corresponding increase in the supply of these organs.Many patients travel to other, mostly developing countries,in search of commercial transplantation. In order to performthe procedure rapidly, standards of transplantation are compromised[1]. Besides the clinical issues, ethical problems are alsoof equal concern. We report the case of a 56-year-old Slovenian male who underwentrenal transplantation for