Neurodegeneration in the Brain Tumor Microenvironment: Glutamate in the Limelight

Malignant brain tumors are characterized by destructive growth and neuronal cell death making them one of the most devastating diseases. Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer''s and Parkinson''s diseases and amyotrophic lateral sclerosis. Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage. Excessive glutamate release via the glutamate/cystine antiporter xCT (system xc-, SLC7a11) renders cancer cells resistant to chemotherapeutics and create the tumor microenvironment toxic for neurons. In particular the glutamate/cystine antiporter xCT takes center stage in neurodegenerative processes and sets this transporter a potential prime target for cancer therapy. Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release. Yet another important biological feature of the xCT/glutamate system is its modulatory effect on the tumor microenvironment with impact on host cells and the cancer stem cell niche. The EMA and FDA-approved drug sulfasalazine (SAS) presents a lead compound for xCT inhibition, although so far clinical trials on glioblastomas with SAS were ambiguous. Here, we critically analyze the mechanisms of action of xCT antiporter on malignant gliomas and in the tumor microenvironment. Deciphering the impact of xCT and glutamate and its relation to TRP channels in brain tumors pave the way for developing important cancer microenvironmental modulators and drugable lead targets.     

Chemoprevention of colorectal cancer by targeting Janus kinase 3 with a rationally designed small molecule inhibitor

The effects of the rationally designed JAK3 inhibitor JANEX-1 on the development of intestinal tumors in the APC(min) mouse model of familial adenomatous polyposis were examined. At a non-toxic dose level, >4 times lower than its day 30 LD(10), JANEX-1 was highly effective in preventing intestinal tumor development in Min mice, resulting in markedly improved survival outcomes. JAK3 inhibitors may, therefore, be useful in the chemoprevention of colorectal cancer. Here, an overview regarding the potential of JANEX-1 as a chemopreventive agent is provided.     

Assessment of Trace Metal and Metalloid Accumulation and Human Health Risk from Vegetables Consumption through Spinach and Coriander Specimens Irrigated with Wastewater

This study focused on evaluating the metal and metalloid contamination and associated risks in the two vegetables crops, coriander (Coriandrum sativum) and spinach (Spinacia oleracea) treated with three water regimes, canal water, groundwater and municipal wastewater. These vegetables are widely consumed by people and are also used in traditional medicine for treating various disorders. Metal and metalloid accumulation (Zn, Pb, Se, Cu, As, Mo, Fe, Ni) was found higher in vegetables treated with wastewater. Wastewater treated soil had high pollution load index. Fe, Zn, As and Pb had higher values in water, soil and vegetables as compared to other studied metals. Overall, metal correlation for soil and vegetables was significant and positive except for Fe and Cu in spinach. The highest value for daily metal intake was estimated for Fe while Se had the lowest value for the same index. It was thus concluded that trace metal and metalloid accumulation was a major health concern for the public consuming these vegetables.     

Properties of global‐ and local‐ancestry adjustments in genetic association tests in admixed populations

Population substructure can lead to confounding in tests for genetic association, and failure to adjust properly can result in spurious findings. Here we address this issue of confounding by considering the impact of global ancestry (average ancestry across the genome) and local ancestry (ancestry at a specific chromosomal location) on regression parameters and relative power in ancestry‐adjusted and ‐unadjusted models. We examine theoretical expectations under different scenarios for population substructure; applying different regression models, verifying and generalizing using simulations, and exploring the findings in real‐world admixed populations. We show that admixture does not lead to confounding when the trait locus is tested directly in a single admixed population. However, if there is more complex population structure or a marker locus in linkage disequilibrium (LD) with the trait locus is tested, both global and local ancestry can be confounders. Additionally, we show the genotype parameters of adjusted and unadjusted models all provide tests for LD between the marker and trait locus, but in different contexts. The local ancestry adjusted model tests for LD in the ancestral populations, while tests using the unadjusted and the global ancestry adjusted models depend on LD in the admixed population(s), which may be enriched due to different ancestral allele frequencies. Practically, this implies that global‐ancestry adjustment should be used for screening, but local‐ancestry adjustment may better inform fine mapping and provide better effect estimates at trait loci.     

The Effects of Positive End-Expiratory Pressure at Different Levels on Postoperative Respiration Parameters in Patients Undergoing Laparoscopic Cholecystectomy

Purpose/Aim of the study: We investigated the effects of different positive end-expiratory pressure (PEEP) levels on postoperative respiration parameters in patients undergoing laparoscopic cholecystectomy. Materials and Methods: One hundred and five consecutive patients were randomly divided to three groups (n = 35, for each group). Group I did not receive PEEP whereas group II received PEEP as 5 cmH₂O and group III received PEEP as 8 cm H₂O. Measurements with spirometer were taken 1 hour before the operation (T₁) and, 1 (T₂), 6 (T₃), and 24 hours (T₄) after extubation by an anesthetist. Forced expiratory volume (FEV₁), forced vital capacity (FVC), and peak expiratory flow (PEF) were recorded. Results: Group I had higher FVC values measured at T₂ time point compared with other groups (p < 0.05, for both groups). There was a statistically significant difference between group I and group III in terms of the FVC values measured at T₃ and T₄ time points (p = 0.05 and p < 0.05, retrospectively). A statistical difference was found between group I and group II in terms of FEV₁ measured at T₂ time point (p < 0.05). Group I had higher FEV₁ values measured at T₃ and T₄ time points compared to group III (p = 0.05, P<0.05; respectively). Group III had lower PEF values measured at T₄ time point compared to group I and II (p < 0.05). Conclusions: We concluded that PEEP with 5 or 8 cmH₂O has negative effects on lung function tests measured with spirometer during postoperative 1^st, 6^th, and 24^th hours in patients underwent elective laparoscopic cholecystectomy.     

Prognostic factors for the surgical management of peripheral nerve lesions

Although the evaluation and treatment of patients with peripheral nerve injuries has evolved and improved over the years, there are still some arguments on the methods and results of surgery. We reviewed retrospectively the clinical, electrophysiological and surgical characteristics of peripheral nerve lesions for 1,636 nerves in 1,565 patients who had been managed in our department in a 10-year period. The most common cause of injuries was gunshot wound in 56.3% of all patients, followed by sharp lacerations (20.6%), fractures (10.6%) and tractions (5.1%). Among 1,636 cases of nerve injuries, the most frequently wounded nerve was median nerve (32.3%), followed by ulnar (24.1%), radial (12.1%), sciatic (10.7%) and peroneal nerves (7.7%), and brachial plexus (7.7%). Simple decompression was the most preferred technique for nerve repair in 27.8%. The electrophysiological improvement was observed in 66.8%, as assessed by electromyography. Clinical improvement was found in 58.4%, as judged by muscle strength grading. If the nerve is compressed or contused, but remains intact, the improvement is satisfactory after surgery. The type of injury, its time of occurrence, initial deficit, and degree of recovery expected are important issues in establishing the treatment plan, which may range from skilled observation to extensive surgical intervention.     

Lack of experience is a significant factor in the missed diagnosis of perilunate fracture dislocation or isolated dislocation

Objective

The aim of this study was to analyze the risk factors contributing to the misdiagnosis of perilunate injuries.

Evaluation for <Emphasis Type="Italic">Helicobacter pylori</Emphasis> in Meckel’s Diverticulum by Using Real-Time PCR

Background  

Although Helicobacter pylori (H. pylori) has been identified in heterotopic gastric mucosa of Meckel’s diverticulum, controversial results are reported in the pertinent literature.     

Low Pulse Pressure as a Predictor of Death in Patients with Mild to Advanced Heart Failure

The prognostic value of pulse pressure has been investigated in heart-failure patients. Low pulse pressure in advanced heart failure and high pulse pressure in mild heart failure have been separately linked to increased mortality rates. We prospectively investigated an association between pulse pressure and 2-year cardiovascular death in an entire heart-failure population.We prospectively enrolled 225 heart-failure patients (New York Heart Association [NYHA] functional class, I–IV; mean age, 56.5 ± 12.3 yr; 188 men). The patients'' blood pressures were measured in accordance with recommended guidelines. Pulse pressures were calculated as the difference between systolic and diastolic blood pressure values. The patients were monitored for a mean period of 670 ± 42 days for the occurrence of cardiovascular death.All patients were divided into quartiles according to their pulse pressures (<35, 35–45, 46–55, and >55 mmHg). Pulse pressure decreased as NYHA class worsened (P <0.001). Patients in the <35-mmHg quartile had the lowest plasma sodium concentrations, left ventricular ejection fractions, and systolic myocardial velocities upon echocardiography; and the highest left ventricular dimensions, early diastolic/late diastolic filling velocity ratios, and peak early/peak late diastolic myocardial velocity ratios. Pulse pressure independently predicted death in the patients with advanced heart failure and in the entire population. Upon receiver operating characteristic analysis, a 30-mmHg cutoff value for pulse pressure predicted death with 83.7% sensitivity and 79.7% specificity.Pulse pressure is easily calculated and enables the prediction of cardiovascular death in patients with mild to advanced heart failure. Pulse pressure can be used reliably as a prognostic marker in clinical practice.Key words: Blood pressure/physiology, cardiovascular diseases/mortality/physiopathology, epidemiologic methods, heart failure/epidemiology/etiology/physiopathology, multivariate analysis, predictive value of tests, prospective studies, pulse/physiology, reference values, risk factorsPulse pressure (PP) is the difference between systolic and diastolic blood pressure (BP) values. Pulse pressure markedly rises after the 5th decade of life, due to arterial stiffening with increasing age.^1,2 Several studies have shown a close relationship between high PP and the occurrence of cardiovascular (CV) death.^3-5 Furthermore, high PP is a risk factor for the development of coronary heart disease, myocardial infarction, and heart failure in normotensive and hypertensive persons.^6-10Data regarding the prognostic value of PP in patients with heart failure are limited and controversial. The importance of PP was investigated in 2 large studies. The SAVE¹¹ (Survival and Ventricular Enlargement) trial revealed a worse prognosis in patients with high PP and symptomatic or asymptomatic left ventricular (LV) systolic dysfunction. The SOLVD¹² (Studies of Left Ventricular Dysfunction) trial found that high PP independently predicted total and CV death in mild heart failure. However, in both studies, patients in New York Heart Association (NYHA) functional classes I and II constituted most of the population, and few patients had advanced heart failure (NYHA classes III and IV). In other studies involving patients with advanced heart failure, low PP was associated with high CV mortality rates.^13-16 We believed that further study was warranted in order to elucidate the prognostic value of PP in an entire heart-failure population. Accordingly, we investigated the association between PP and 2-year CV death in patients in whom the severity of heart failure ranged from mild to advanced.