Positive affect and fatigue as predictors of anti-inflammatory IL-10 concentrations among colorectal cancer patients during adjuvant chemotherapy.

OBJECTIVES: (1) To examine the relationships of positive and negative affect and symptoms of depression, anxiety, and fatigue at baseline with the anti-inflammatory cytokine IL-10 concentrations in serum at three points in colorectal cancer patients; and (2) to assess the relationship between these factors and disease recurrence or mortality after a median follow-up of 24 months. METHODS: In a prospective trial, 92 stage II or III colorectal cancer patients scheduled to receive standard chemotherapy were enrolled. Blood samples were collected prior to start of chemotherapy onset (T0), 3 months later (T1), and upon chemotherapy completion (T2). RESULTS: IL-10 concentrations were similar across the time points. Linear mixed-effects model analysis showed that controlling for confounders, higher positive affect and lower fatigue pretreatment (T0) predicted IL-10 concentrations across the time points (estimate = 0.18, SE = 0.08, 95% CI = 0.03, 0.34, p < .04 and estimate = -0.25, SE = 0.12, 95% CI = -0.50, 0.01, p < .04, respectively). Depression at T0 significantly predicted higher disease recurrence and mortality (estimate = 0.17, SE = 0.08, adjusted OR = 1.18, 95% CI = 1.02, 1.38, p = .03). CONCLUSIONS: We report on associations not previously assessed between positive affect and fatigue and the anti-inflammatory cytokine IL-10. Results add to previous findings suggesting that positive affect and fatigue could have a role in anti-inflammatory cytokine dysregulation.

Low physical activity, fatigue and depression in breast cancer survivors: Moderation by levels of IL-6 and IL-8.

BACKGROUND AND AIMS: Although previous studies suggested that depressed mood and fatigue among cancer survivors are associated with chronic inflammation, the effect of cytokines on the relation between physical activity and fatigue and depressed mood is characterized by inconsistent results. The aim was to examine levels of pro-inflammatory (IL-6, IL-8, TNFα, IL-12) and anti-inflammatory (IL-10) cytokines in relation to the effects of physical activity on fatigue and depressed mood. METHODS: Breast cancer survivors (n = 108; stages I-III), aged >20 and who were 1-6 months postchemotherapy were recruited consecutively. Participants completed the Fatigue Symptom Inventory and Center for Epidemiologic Studies Depression Scale and reported physical activity details; 10 cc of blood were drawn for assessment of levels of IL-6, IL-8, IL-10, Il-12, and TNFα in serum. RESULTS: Only IL-6 and IL-8 were associated with fatigue and depressed mood. Controlling for background variables, physical activity and IL-6 were significantly associated with fatigue, but only physical activity was significantly associated with depressed mood. A moderated effect of IL-6 and IL-8 was found in the association of physical activity and fatigue, indicating that this association is significant only in individuals with lower levels of IL-6 or IL-8. CONCLUSIONS: Fatigue and depressed mood are differently associated with pro-inflammatory cytokines. In addition, IL-6 and IL-8 are main cytokines affected by physical activity. The study stresses the need to provide information and tailored guidance for cancer survivors for maintaining an active lifestyle into survivorship and the importance of allocating resources for programs to encourage active lifestyles among cancer survivors. Caution should be exercised in the interpretation of the results due to the cross-sectional design and possibility of bidirectional associations between the study variables.

Wheatgrass Juice Administration and Immune Measures during Adjuvant Chemotherapy in Colon Cancer Patients: Preliminary Results.

Adjuvant chemotherapy is recommended in high-risk stage II-III colorectal cancer (CC). We examine the effect of daily wheatgrass juice (WGJ) intake in addition to chemotherapy on immune parameters, including IL-6, IL-8, IL-10, IL-12, and white blood cells (WBCs) among CC patients. In a controlled prospective trial, 100 stage II-III CC patients were enrolled. According to patient preference, they were divided into two subgroups, control group and intervention group, 50 patients each, all of whom received the same standard postoperative adjuvant chemotherapy, plus consumption of 60 cc WGJ daily in the intervention group. Blood samples were collected at baseline (T0) and upon treatment termination, 5-6 months later (T1). Cytokine concentrations were assessed using ELISA kits. Anti-inflammatory cytokine IL-10 concentrations were significantly higher in the WGJ group than in the control group at T1. The decline in WBC counts between T0 and T1 was significantly lower in the WGJ group. No significant differences were observed in IL-6, IL-8, and IL-12 concentrations between the study groups. The higher levels of IL-10 and the attenuating of WBC decline during chemotherapy may constitute preliminary evidence of the beneficial effects of WGJ on immune parameters, when given as a supplement to standard care. In light of these preliminary results, WGJ supports immunological parameters during adjuvant chemotherapy. Nevertheless, future studies are needed in order to translate those results to clinical recommendations for cancer survivors.

Validation of two commercial real-time PCR assays for rapid screening of the HLA-B*57:01 allele in the HIV clinical laboratory.

The pharmacogenetics approach to screen for the presence of the HLA-B*57:01 allele in HIV-1 infected patients is mandatory to prevent the potential development of hypersensitivity reaction to abacavir treatment. Given the limitations of current genotype methodologies, commercial real-time PCR assays were specifically developed for this purpose, but have not been sufficiently validated and are still not widely used. Here, in the context of the HIV laboratory, we assessed the ability of two commercial kits, the LightSNiP rs2395029 HPC5 assay (TIB Molbiol) and the DuplicαReal-TimeHLA-B*5701 Genotyping kit (Euroclone), to retrospectively detect HLA-B*57:01 positive and negative samples of Israeli HIV-1 infected patients. The LightSNiP rs2395029 HPC5 assay had false-positive results, whereas the DuplicαReal-Time HLA-B*5701 Genotyping kit was highly accurate and could be readily implemented into clinical practice. It is hoped that this study will facilitate the assessment of additional commercial kits for HLA-B*57:01 detection and expand their use in the clinical laboratory. Such studies can likely help the use of abacavir treatment in HIV-1 infected patients.

Human amnion membrane as a substrate for the detection of autoantibodies in pemphigus vulgaris and bullous pemphigoid.

BACKGROUND: Human amnion membrane (HAM) was suggested to be a superior antigenic substrate for immunoblotting in detecting autoantibodies of autoimmune bullous skin diseases. OBJECTIVES: To determine the properties of HAM as an antigenic substrate for the detection of autoantibodies in pemphigus vulgaris and bullous pemphigoid. METHODS: Immunomapping and tandem liquid chromatography mass spectrometry were used to delineate the antigenic structure of HAM. Immunoblotting and indirect immunofluorescence were used to study the diagnostic utility of HAM in 25 pemphigus patients, 41 pemphigoid patients, and 36 controls, and the results were compared to those of indirect immunofluorescence on monkey esophagus, immunoblotting using normal human skin, and enzyme-linked immunosorbent assay. RESULTS: Immunomapping demonstrated the presence of all the antigens known to be targeted in autoimmune bullous skin diseases, in both normal human skin and HAM, except for the absence of BP230, and low threshold levels of Dsg1, Dsg3 and Dsc3 in HAM. HAM indirect immunofluorescence demonstrated anti-basement membrane zone antibodies in 48.7% of the pemphigoid patients, and anti-intercellular space antibodies in 72.0% of the pemphigus patients. HAM immunoblotting did not demonstrate anti-BP230 antibodies, but detected anti-BP180 antibodies in 53.7% of the pemphigoid patients. It did not demonstrate anti-Dsg1 and/ or anti-Dsg3 antibodies in any of the pemphigus patients. These results were inferior to those of ELISA and monkey esophagus indirect immunofluorescence. CONCLUSIONS: Compared to other studied methods, HAM does not offer advantages in detecting autoantibodies in bullous pemphigoid and pemphigus vulgaris.

Cytokine levels (IL-4, IL-6, IL-8 and TGFß) as potential biomarkers of systemic inflammatory response in trauma patients.

PURPOSE: Much research is now being conducted in order to understand the role of cytokines in the development of the inflammatory response following trauma. The purpose of this study was to evaluate whether serum levels of certain cytokines, measured immediately after initial injury, can be used as potential biomarkers for predicting the development and the degree of severity of the systemic inflammatory response (SIRS) in patients with moderate and severe trauma. METHODS: We conducted a prospective study with 71 individuals of whom 13 (18.3 %) were healthy controls and 58 (81.7 %) were traumatized orthopaedic patients who were categorized into two groups: 31 (43.6 %) with moderate injuries and 27 (38.1 %) patients with severe orthopaedic trauma. Thirty cc of heparinized blood were drawn from each individual within a few hours after the injury. Serum levels of pro-inflammatory, regulatory and anti-inflammatory cytokines were measured in each individual participant. RESULTS: High levels of pro-inflammatory cytokines IL-1ß,-6,-8,-12, tumour necrosis factor alpha and interferon gamma were found in all injured patients compared to healthy controls. Only IL-6 and IL-8 were significantly higher in the injured patients. Levels of the regulatory cytokines, transformed growth factor beta (TGF-ß) and IL-10 were higher in the injured patients, but significant only for TGF-ß. Levels of IL-4 were significantly lower in the injured groups as compared to the controls. CONCLUSIONS: Secretion of large amounts of pro-inflammatory cytokines and decreased level of anti-inflammatory cytokines during the acute phase of trauma may lead to the development of systemic inflammatory response syndrome (SIRS) in unstable polytraumatized patients. SIRS may result in life threatening conditions as acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF). High levels of IL-6, IL-8, TGFß and low levels of IL-4 were found to be reliable markers for the existence of immune reactivity in trauma patients. More research is needed to study pattern of cytokine levels along the acute period of injury, after surgical interventions and during recovery.

Possible association of Toll-like receptor 9 polymorphisms with cytokine levels and posttraumatic symptoms in individuals with various types of orthopaedic trauma: early findings.

BACKGROUND: Although TLR9 polymorphisms may be associated with cytokine dysregulation, its role in regulation of cytokines due to bodily trauma or in relation to acute stress symptoms or posttraumatic stress symptoms (ASS/PTS) has not been evaluated. AIMS: To assess serum cytokine levels and levels of ASS and PTS in relation to four common TLR9 single-nucleotide polymorphisms (SNPs) in individuals with various types of orthopaedic trauma. METHODS: Forty-eight accident-injured individuals, aged 20-60 years were studied. Serum cytokine levels and TLR9 SNPS (1486T/C, 1237T/C, 1174G/A and 2848G/A) were assessed together with intensity of ASS and PTS symptoms. RESULTS: Statistically significant higher serum levels of IL-12 and IL-1ß (p<.05) were found in individuals heterozygous for TLR9-1237 (TC) than in individuals expressing the most common TLR9-1237 type (TT), while differences in levels of IL-6 were not significant. Also, marginally significant levels of IL-6 were found in individuals expressing the common TLR9-1174 (GG) compared with individuals homozygous (AA) or heterozygous (GA) for this SNP. They also had non-significant higher intensity of ASS symptoms. A trend of higher PTS levels in individuals expressing the most common type TLR9-1174 (GG) was found, contrary to homozygous (AA) and heterozygous individuals (GA). CONCLUSIONS: The results of this pilot study suggest that accident-injured individuals with certain TLR9 polymorphisms express higher levels of pro-inflammatory cytokines (IL-1ß, IL-6 and IL-12). The associations of TLR9 SNPSs with increased risk of ASS or PTS should be further studied in larger groups of such patients.

Urinary concentration of cytokines in children with acute pyelonephritis.

Urinary tract infection (UTI) is a common bacterial infection among infants and children. Predicting which children with upper UTI will develop long-term sequelae remains difficult. We aimed at evaluating the predictive value of urine concentrations of interleukin-6 (UIL-6) and interleukin-8 (UIL-8) in subsequent renal scarring. In the current observational prospective study, urine samples for UIL-6 and UIL-8 were obtained from two groups: 31 children with first episode of febrile UTI and 22 febrile children of other origin. UIL-6 and UIL-8 were increased in children with febrile UTI, compared to children with fever of other origin [median and range (picograms per milliliter): (1) UIL-6, 74.46 (0-168) vs. 10.51 (0-47.50), respectively, p = 0.0001; (2) UIL-8, 2,660.38 (0-13,801) vs. 0, respectively, p = 0.0001]. Renal scarring was found in 5/31 (16 %) children with acute pyelonephritis. Initial median UIL-8 values were significantly higher in children with later renal scarring than in those without renal scarring [median and range (picograms per milliliter): 6,163 (2,021-13,801) vs. 1,490.5 (0-5,737), respectively, p = 0.018]. In conclusion, UIL-8 might serve as a predictive biomarker for renal scarring after an acute episode of pyelonephritis. Since UIL-8 emerges as a renal-specific diagnostic and prognostic marker, it may be suitable as a selective screening tool for children with febrile UTI.

The acute effects of water-pipe smoking on the cardiorespiratory system.

OBJECTIVE: There are limited data on the acute effects of water-pipe tobacco smoking, commonly known as water-pipe smoking (WPS), on cardiopulmonary parameters. This study evaluated the acute effects of a single 30-min session of WPS on carboxyhemoglobin (COHb) levels, pulmonary function test results, vital signs, fractional exhaled nitric oxide (Feno) levels, and exhaled breath condensate (EBC) cytokine levels in volunteers in a domestic, open-air, group smoking setting. METHODS: This prospective study evaluated the above-noted outcome parameters before and after 30 min of WPS. The primary outcome parameter was the change in COHb levels. RESULTS: Forty-five volunteers (30 men, 15 women), aged 32.35 ± 15.33 years, were recruited. After one session of WPS, the COHb levels rose significantly, from 1.47% ± 0.57% (median 1.4) to 9.47% ± 5.52% (median 7.4), P < .001. Systolic and diastolic BP levels significantly increased after smoking (systolic, 119.52 ± 12.07 mm Hg vs 131.98 ± 17.8 mm Hg; diastolic, 74.84 ± 7.89 mm Hg vs 82.98 ± 12.52 mm Hg, respectively; P < .001). Heart rates increased from 80.39 ± 9.92 beats/min to 95.59 ± 17.41 beats/min, P < .001; and respiratory rates increased from 14.36 ± 1.63 breaths/min to 16.68 ± 2.24 breaths/min, P < .001. There were decreases in forced expiratory flow between 25% and 75% of FVC, peak expiratory flow rate, Feno levels, percentage of eosinophils in peripheral blood, and 8-isoprostane levels in EBC. CONCLUSIONS: This study shows that one session of WPS causes acute biologic changes that might result in marked health problems. It adds to the limited evidence that WPS is harmful and supports interventions to control the continuing global spread of WPS, especially among youth. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01157832; URL: www.clinicaltrials.gov.

Tissue transglutaminase antibodies are a useful serological marker for the diagnosis of celiac disease in patients with Down syndrome.

BACKGROUND: Celiac disease (CD) is overrepresented among patients with Down syndrome (DS), who frequently lack any typical symptoms. Therefore, screening for CD is recommended in this high-risk group. The aim of the study was to determine the prevalence of CD in Arab children with DS and evaluate the contribution of immunoglobulin (Ig) A and IgG anti-gliadin antibodies (AGA), IgA and IgG tissue transglutaminase (TTG) antibodies, and IgA anti-endomysial antibodies (EMA) to screen for CD in children with DS. PATIENTS AND METHODS: A total of 52 Arab patients with DS and 52 healthy Arab control subjects were studied for CD using various serological markers. Data on age, sex, weight, height, gastrointestinal symptoms, and endocrine abnormalities were recorded. Human leukocyte antigen (HLA) was studied in patients undergoing small intestinal biopsy. RESULTS: Five patients with DS were IgA TTG-positive and only 1 patient with DS was IgG TTG-positive. EMA was negative in all patients with DS. TTG (IgA and IgG) and EMA were negative in all control children. IgA AGA was positive in 12 patients with DS and 3 control subjects (P = 0.02), whereas IgG AGA was positive in 41 patients with DS and 26 control subjects (P = 0.004). Only children testing positive for TTG underwent upper endoscopy with duodenal biopsy. Two children with DS were diagnosed with CD. Both patients were IgA TTG-positive. One was HLA DQ2-positive and another was negative for HLA DQ2 and DQ8. CONCLUSIONS: CD is prevalent (3.8%) in Arab patients with DS. Based on our cohort, IgA TTG is useful in diagnosing patients with CD and DS.

Fatal varicella associated with selective natural killer cell deficiency.

A 2-year-old girl with recurrent severe varicella infections had a fatal outcome. Studies of cellular and humoral immunity were normal. No natural killer (NK) cells were detected, and NK activity was markedly decreased. The interleukin (IL)15/IL15R signaling pathway was intact. This case emphasizes the role of NK cells in controlling herpes viral infection.

Splicing defect in RFXANK results in a moderate combined immunodeficiency and long-duration clinical course.

MHC class II deficiency provokes a severe immunodeficiency characterized by a lack of antigen-specific immune response. In the absence of bone marrow transplantation (the only curative treatment), patients affected by this genetic recessive disease die in early childhood. However, others and we have recently described cases of mild or asymptomatic immunodeficiencies with defects in either CIITA (class II transactivator) or RFX5, both proteins required for the transcription of HLA-D genes. We describe in this report the first case of moderate immunodeficiency resulting from a defect in RFXANK, another transcription factor essential for HLA-D expression. The patient did not display any detectable expression of MHC class II molecules on B lymphocytes, monocytes or activated T lymphocytes. Accordingly HLA-D transcription was altered in the corresponding B-lymphoblastoid cell line. The defect in RFXANK was observed both at the transcript and protein level. Indeed a homozygous IVS4+5G>A mutation was evidenced in RFXANK, and shown to hamper the splicing of intron 4. However, we had shown previously that a defect in intron 4 can lead to the skipping of exon 4, and that the resulting truncated protein retains the capacity to activate HLA-DR expression. Therefore, like the two cases of moderate immunodeficiencies described previously, we demonstrate that the RFXANK defect presented here is coherent with a residual activity of the mutant protein. We thus propose that the common feature displayed by mildly immunodeficient patients is the leakiness of the mutations, which might allow a local or temporal expression of MHC class II molecules.