PROcedure-SPECific postoperative pain management guideline for laparoscopic colorectal surgery: A systematic review with recommendations for postoperative pain management.

Colorectal cancer is the second most common cancer diagnosed in women and third most common in men. Laparoscopic resection has become the standard surgical technique worldwide given its notable benefits, mainly the shorter length of stay and less postoperative pain. The aim of this systematic review was to evaluate the current literature on postoperative pain management following laparoscopic colorectal surgery and update previous procedure-specific pain management recommendations. The primary outcomes were postoperative pain scores and opioid requirements. We also considered study quality, clinical relevance of trial design, and a comprehensive risk-benefit assessment of the analgesic intervention. We performed a literature search to identify randomised controlled studies (RCTs) published before January 2022. Seventy-two studies were included in the present analysis. Through the established PROSPECT process, we recommend basic analgesia (paracetamol for rectal surgery, and paracetamol with either a nonsteroidal anti-inflammatory drug or cyclo-oxygenase-2-specific inhibitor for colonic surgery) and wound infiltration as first-line interventions. No consensus could be achieved either for the use of intrathecal morphine or intravenous lidocaine; no recommendation can be made for these interventions. However, intravenous lidocaine may be considered when basic analgesia cannot be provided.

Association of levels of interleukin 17 and T-helper 17 count with symptom severity and etiology of chronic heart failure: a case-control study.

AIM: To assess the association between the levels of interleukin 17 (IL-17) and T-helper 17 count and symptom severity and etiology of chronic heart failure. METHODS: This single-center prospective case-control study, conducted from December 1, 2015 to January 1, 2017 in Tehran Heart Center, evaluated gene expression of IL-17, relative count of (CD4+IL17+) Th17 cells and CD4+ helper T-cells in peripheral blood mononuclear cells of 42 patients with CHF and 42 matched controls. A multiple regression model assessed the predictors of peripheral IL-17 expression and Th17 count in patients with CHF. RESULTS: IL-17 expression was increased in patients with CHF, both at baseline and after stimulation. IL-17 and Th17 counts were higher in patients with advanced New York Heart Association (NYHA) functional class (class IV) than in controls and patients with class I. Th17 cell population expanded in patients with CHF, more prominently in patients with class IV than in controls and patients with class I, regardless of the ischemic or non-ischemic CHF origin. Multiple regression model showed that NYHA was the only meaningful predictor of IL-17 levels and Th17 count. CONCLUSION: We demonstrated the lymphocytic origin of IL-17 production in advanced CHF and the ability of disease severity to predict IL-17 levels. Oxford Centre for Evidence-based Medicine level of evidence: 3.

Multivariable prediction models for atrial fibrillation after cardiac surgery: a systematic review protocol.

INTRODUCTION: Dozens of multivariable prediction models for atrial fibrillation after cardiac surgery (AFACS) have been published, but none have been incorporated into regular clinical practice. One of the reasons for this lack of adoption is poor model performance due to methodological weaknesses in model development. In addition, there has been little external validation of these existing models to evaluate their reproducibility and transportability. The aim of this systematic review is to critically appraise the methodology and risk of bias of papers presenting the development and/or validation of models for AFACS. METHODS: We will identify studies that present the development and/or validation of a multivariable prediction model for AFACS through searches of PubMed, Embase and Web of Science from inception to 31 December 2021. Pairs of reviewers will independently extract model performance measures, assess methodological quality and assess risk of bias of included studies using extraction forms adapted from a combination of the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies checklist and the Prediction Model Risk of Bias Assessment Tool. Extracted information will be reported by narrative synthesis and descriptive statistics. ETHICS AND DISSEMINATION: This systemic review will only include published aggregate data, so no protected health information will be used. Study findings will be disseminated through peer-reviewed publications and scientific conference presentations. Further, this review will identify weaknesses in past AFACS prediction model development and validation methodology so that subsequent studies can improve upon prior practices and produce a clinically useful risk estimation tool. PROSPERO REGISTRATION NUMBER: CRD42019127329.

Prophylactic and therapeutic implications of toll-like receptor ligands.

The evolutionary conserved Toll-like receptors (TLRs) are the first identified and best characterized pattern recognition receptors (PRRs) which discriminate self from nonself, providing an early and effective immune response against invading pathogens. The ever expanding knowledge of TLR signaling network make it one of the most promising therapeutic strategies to modulate the immune response in various human diseases. Immune modulating strategies based on TLR-specific agonists elicit a potent immune response to adjuvant vaccine immunotherapy, cancers, allergic diseases, and chronic viral infections while minimizing the risk of uncontrolled provocation of systemic inflammatory response. Moreover, the contribution of TLR signaling in the pathogenesis of chronic noninfectious inflammatory and autoimmune diseases provides the rationale for the development and clinical implementation of TLR-specific antagonists. At present, a few TLR-specific agonists have been approved for both prophylactic and therapeutic applications, while the ongoing preclinical and clinical studies show promising results on various novel therapeutic molecules as an adjunctive to conventional pharmacotherapy or stand-alone therapeutic strategy.

Primary hemophagocytic lymphohistiocytosis in Iran: report from a single referral center.

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by fever, hepatosplenomegaly, and cytopenia, and widespread accumulation of lymphocytes and histiocytes, sometimes with hemophagocytosis, primarily involving the spleen, lymph nodes, bone marrow, and liver. HLH can either occur sporadically (secondary HLH) or as part of a familial syndrome (primary HLH), including familial HLH and the distinct immunodeficiency syndromes. Herein the authors report 6 Iranian patients with primary HLH and their outcome from a single tertiary-care center.

Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies.

Primary immunodeficiencies (PIDs) are commonly characterized by an increased susceptibility to specific infections and, in certain instances, a higher than usual incidence of malignancies. Although improved diagnosis and early treatment of PIDs have reduced early morbidity and mortality from infection, the development of cancer remains a significant cause of premature death. The emergence of cancer in patients with PIDs often results from impairments in the immune response that lead to weakened surveillance against oncogenic viruses, premalignant or malignant cells, or both. Here we review the clinical and biologic features of several PIDs associated with enhanced susceptibility to viral infections and cancer, including X-linked lymphoproliferative disease; IL-2-inducible T-cell kinase deficiency; epidermodysplasia verruciformis; warts, hypogammaglobulinemia, infections, and myelokathexis syndrome; autosomal recessive hyper-IgE syndrome; X-linked agammaglobulinemia; and common variable immunodeficiency. It is of importance that we gain in-depth insights into the fundamental molecular nature of these unique PIDs to better understand the pathogenesis of virus-associated malignancies and to develop innovative therapeutic strategies.

Proinflammatory cytokines in heart failure: double-edged swords.

Increased circulating and intracardiac levels of proinflammatory cytokines have been associated with chronic heart failure. Following an initial insult, the increased production of proinflammatory cytokines, including TNF-α, IL-6, IL-1, and IL-18, jeopardizes the surrounding tissue through propagation of the inflammatory response and direct effects on the cardiac myocyte structure and function. Cardiac myocyte hypertrophy, contractile dysfunction, cardiac myocyte apoptosis, and extracellular matrix remodeling contribute enormously to the development and progression of chronic heart failure. Despite the identification of efficacious pharmacological regimens and introduction of mechanical interventions, chronic heart failure remains among the leading causes of mortality worldwide. To introduce novel therapeutic strategies that modulate the inflammatory response in the context of the failing heart, it is of prime importance to determine the contributions of TNF-α, IL-6, IL-1, and IL-18 in mediating cardiac adaptive and maladaptive responses, as well as delineating their downstream intracellular signaling pathways and their potential therapeutic implications.

Gene Expression and Levels of TGF-B in PBMC Is Associated with Severity of Symptoms in Chronic Heart Failure.

BACKGROUND: TGF-ß1 is known to promote cardiac remodeling and fibrosis during Congestive Heart Failure (CHF). In this study, an attempt was made to investigate expression of Transforming Growth Factor beta1 (TGF-ß1) and relative expansion or contraction of regulatory T-cell (Tregs) population in peripheral blood of patients with Chronic Heart Failure (CHF). METHODS: Real-time PCR assay was used to investigate expression and post-stimulation levels of TGF-ß1 in cell culture supernatant of Peripheral Blood Mononuclear Cells (PBMC) of 42 patients with CHF and 42 controls. Flow cytometry was used to identify relative counts of CD4+CD25+FoxP3+ Tregs. RESULTS: PBMCs in patients with CHF expressed higher levels of TGF-ß1 compared to controls. Post-stimulation levels of TGF-ß1 expression were significantly higher in New York Heart Association (NYHA) functional class IV patients compared to stage I patients. Tregs were significantly expanded in PBMC in CHF, while the CD4+ helper T-cells were unchanged. Treg expansion was more significant in NYHA functional class I patients compared to class IV patients. CONCLUSION: Expansion of Treg population in CHF provides an extrinsic source for TGF-ß1 production to induce reactive fibrosis and cardiac remodeling. Relative decrease in Treg population at advanced stages of CHF is indicative of a loss of regulatory characteristics in these cells and unopposed proinflammatory milieu.

Interleukin-10 and Transforming Growth Factor Beta1 Gene Polymorphisms in Chronic Heart Failure.

BACKGROUND: As cytokines, including interleukin-10 (IL-10) and transforming growth factor beta 1(TGF-ß1) seem to contribute towards the pathogenesis of chronic heart failure (CHF), this study was performed to assess the associations of certain single nucleotide polymorphisms (SNPs) of these genes in a case control study. METHODS: This investigation was carried out to determine the frequency of alleles, genotypes and haplotypes of TGF-ß1 and IL-10 single-nucleotide polymorphisms (SNPs) in 57 Iranian patients with CHF compared with 140 healthy subjects using polymerase chain reaction with sequence-specific primers method. RESULTS: Results of the analyzed data divulged a negative association for both TGF-ß1 GC genotype at codon 25 (P=0.047) and CT genotype at codon 10 (P=0.018) and CHF proneness. Although, TGF-ß1 CC genotype at codon 10 was found to be positively associated with CHF (P=0.011). Moreover, the frequency of IL-10 (-1082, -819, -592) ATA haplotype and TGF-ß1 (codon 10, codon 25) TG haplotype were significantly lower in the patients group (P=0.004 and P=0.040, respectively), while TGF-ß1 (codon 10, codon 25) CG haplotype was overrepresented in patients with CHF (P=0.007). CONCLUSIONS: Cytokine gene polymorphisms might affect vulnerability to CHF. Particular genotypes and haplotypes in IL-10 and TGF-ß1 genes could render individuals more susceptible to CHF.

Tumor Necrosis Factor-Alpha and Interleukin-6 Gene Polymorphisms in Iranian Patients with Ischemic Heart Failure.

BACKGROUND: Proinflammatory cytokines have been known to be elevated in patients with Chronic Heart Failure (CHF). Given the importance of proinflammatory cytokines in the context of the failing heart, the prevalence of Tumor Necrosis Factor-α (TNF-α), Interleukin (IL)-6 polymorphisms in patients with CHF was studied due to ischemic heart disease. METHODS: Forty three patients with ischemic heart failure were enrolled in this study and compared with 140 healthy individuals. The allele and genotype frequency of four Single Nucleotide Polymorphisms (SNPs) within the IL-6 (-174, nt565) and TNF-α (-308, -238) genes were determined, using Polymerase Chain Reaction with Sequence-Specific Primers (PCR-SSP) assay. RESULTS: The frequency of the TNF-α (-238) A/A genotype was significantly higher in patients comparing to controls (p=0.043), while TNF-α G/A genotype at the same position decreased significantly, in comparison with controls (p=0.018). The most frequent haplotype for TNF-α was A/A in the patient group in comparison with controls (p=0.003). There was no significant difference in allele and genotype frequencies of IL-6 at positions -174 and nt565, and TNF-α at position -308. CONCLUSION: Certain alleles, genotypes, and haplotypes in TNF-α, but not IL-6, gene were overrepresented in patients with ischemic heart failure, which may, in turn, predispose individuals to this disease.

Interleukin-2 and Interferon-Gamma Single Nucleotide Polymorphisms in Iranian Patients with Chronic Heart Failure.

BACKGROUND: Inflammatory cytokines have been known to be associated with Chronic Heart Failure (CHF). Given the importance of cytokines in the context of the failing heart, the prevalence of Interleukin-2 (IL-2) and Interferon-gamma (IFN-γ) polymorphisms was studied in patients with CHF due to ischemic heart disease in a case-control study. METHODS: Fifty-six Iranian patients with CHF were enrolled in this study as the case group and compared with 139 healthy subjects, using polymerase chain reaction with sequence-specific primers method, so as to determine the frequency of alleles, genotypes and haplotypes of IFN-γ (+874 A/T) and IL-2 (-330 G/T, +166 G/T) SNPs. RESULTS: The GG genotype at IL-2 -330 in patients with CHF was significantly over-represented in comparison with the control group (p=0.013). Such a positive genotypic association was also observed for IL-2 +166/TT (p=0.022). Meanwhile, the GT genotype frequency at IL-2 -330/GT in the patient group was significantly lower than the one in healthy controls (p=0.049). No significant association was detected between the IFN-γ gene polymorphisms and individuals' susceptibility to CHF. CONCLUSION: Certain genotypes in IL-2 gene were overrepresented in patients with CHF, which could render individuals more vulnerable to this disease.

A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton.

Wiskott-Aldrich syndrome (WAS) is associated with mutations in the WAS protein (WASp), which plays a critical role in the initiation of T cell receptor-driven (TCR-driven) actin polymerization. The clinical phenotype of WAS includes susceptibility to infection, allergy, autoimmunity, and malignancy and overlaps with the symptoms of dedicator of cytokinesis 8 (DOCK8) deficiency, suggesting that the 2 syndromes share common pathogenic mechanisms. Here, we demonstrated that the WASp-interacting protein (WIP) bridges DOCK8 to WASp and actin in T cells. We determined that the guanine nucleotide exchange factor activity of DOCK8 is essential for the integrity of the subcortical actin cytoskeleton as well as for TCR-driven WASp activation, F-actin assembly, immune synapse formation, actin foci formation, mechanotransduction, T cell transendothelial migration, and homing to lymph nodes, all of which also depend on WASp. These results indicate that DOCK8 and WASp are in the same signaling pathway that links TCRs to the actin cytoskeleton in TCR-driven actin assembly. Further, they provide an explanation for similarities in the clinical phenotypes of WAS and DOCK8 deficiency.

Association of interleukin-4 gene polymorphisms with ischemic heart failure.

BACKGROUND: As of the potential immunomodulatory effects of interleukin-4 (IL-4) and its importance in inhibiting the production of proinflammatory cytokines by monocytes and activated T cells, the IL-4 gene polymorphisms were investigated in a group of patients with chronic heart failure due to ischemic heart disease. METHODS: Forty three patients with ischemic heart failure (IHF) were enrolled in this study and compared with 139 healthy individuals. The allele and genotype frequency of 3 single nucleotide polymorphisms within the IL-4 gene were determined. RESULTS: The frequency of the IL-4 -590/T allele in the patient group was significantly higher than in the control group (p < 0.0001). The most frequent genotypes in patients with IHF were IL-4 (-590) CC (p < 0.0001), IL-4 (-33) CC (p = 0.021), and IL-4 (-33) TT (p < 0.0001). The frequency of the following genotypes was significantly lower in patients compared to controls: IL-4 (-1098) TG (p = 0.035), IL-4 (-590) TC (p < 0.0001), and IL-4 (-33) TC (p < 0.0001). The most frequent IL-4 haplotypes in the patient group, which were significantly higher than in the control group, were TCC (p < 0.0001), TCT (p = 0.0242), and GCT (p = 0.0108) haplotypes. In contrast, the frequencies of the following haplotypes in the patient group were significantly lower than in the controls: GCC (p = 0.032), TTT (p = 0.0268), and TTC (p = 0.0399). CONCLUSIONS: Certain alleles, genotypes, and haplotypes in IL-4 gene were over represented inpatients with IHF, which may, in turn, predispose individuals to this disease.

Interleukin-23 receptor single nucleotide polymorphisms in ulcerative colitis. A study in Iranian populations.

BACKGROUND/OBJECTIVE: Genetic factors seem to play an important role in the pathogenesis of ulcerative colitis (UC). Genome wide association studies showed a highly significant association between interleukin 23 receptor (IL23R) single nucleotide polymorphisms (SNPs) and Crohn's disease; however, there are contrary results regarding the disease-modifying effects of IL23R variants in UC. This study was performed in a group of patients with UC to test the possible role of IL23R SNPs in conferring susceptibility or protection against the disease. METHODS: The study was performed on 67 Iranian adult patients with UC and 78 healthy controls. Eight IL23R SNPs were genotyped, using real-time polymerase chain reaction (RT-PCR). The frequencies of alleles and genotype at each position were determined and compared between two groups of patients and controls. RESULTS: The frequency of the T allele at position rs1343151 was significantly higher in the patient group, compared to the controls (P=0.018). The TT genotype at the same position was also significantly overrepresented in the patient group (P=0.02). There was no significant difference in alleles and genotype frequencies of other SNPs between patients and controls. CONCLUSIONS: This study identified a new susceptibility locus associated with UC. Our findings provide further insight into the genetics of UC, which might be amenable to future therapeutic intervention.

Effect of low dose ω-3 poly unsaturated fatty acids on cognitive status among older people: a double-blind randomized placebo-controlled study.

BACKGROUND: Cognitive impairment is a prevalent health problem in older people and its global prevalence tends to increase parallel to the extended life expectancy in world. The beneficial effect of ω-3 PUFAs on cognitive impairment has been demonstrated in some experimental and cohort studies. In this study we aimed to assess the effect of low dose docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) supplementation on cognitive status in the elderly. METHODS: In a double-blind, randomized placebo-controlled study, 199 individuals aged ≥65 years with normal or mild to moderate cognition impairment were assigned to receive either 180 mg of DHA plus 120 mg of EPA or placebo for 180 days. Cognitive status was assessed using Mini-Mental State Examination (MMSE) and Abbreviated Mental Test (AMT) score. RESULTS: MMSE and AMT scores were not different at the time of allocation [18.84 (5.37), 18.55 (5.12), (P = 0.70) and 4.81 (2.79) and 4.64 (2.77), (P = 0.67) respectively] and over 6 months between the ω-3 PUFA- and placebo- treated groups [18.57 (5.21), 18.39 (5.10), (P = 0.80) and 4.64 (2.77) and 4.48 (2.69) and (P = 0.67)]. The participants were categorized based on MMSE score into normal cognition, mild and moderate cognitive impairment. After multivariate adjustment, there was no significant difference among categorized groups regarding the ω-3 PUFA effect except in normal cognition group, that amount of decline in AMT in ω-3 poly unsaturated fatty acids (PUFAs) was less than placebo group. CONCLUSIONS: It seems that prescription of low dose ω-3 PUFAs for 6 months had no significant beneficial effects on improvement of cognition or prevention of cognitive decline in older people.

Targeting of Toll-like receptors: a decade of progress in combating infectious diseases.

Toll-like receptors (TLRs) recognise highly conserved molecular structures, collectively known as pathogen-associated molecular patterns. In the past two decades, development and clinical implementation of TLR ligands-ie, chemically modified synthetic derivatives of naturally occurring ligands and fully synthetic small molecules-have been topics of intense research. Targeted manipulation of TLR signalling has been applied clinically to boost vaccine effectiveness, promote a robust T helper 1-predominant immune response against viral infection, or dampen the exaggerated inflammatory response to bacterial infection. Use of these new therapeutic molecules as adjuncts to conventional pharmacotherapy or stand-alone treatments might offer solutions to unmet clinical needs or could replace existing partly effective therapeutic strategies.

In vitro soluble CD30 levels in patients with chronic stable coronary artery disease.

The CD30 antigen seems to play a costimulatory role in maintaining the physiological balance between T-helper (Th)1/Th2 immune responses. In this study, plasma and in vitro soluble CD30 (sCD30) secretion was investigated in patients with coronary artery disease (CAD) as a plausible marker of dysregulated immune response.Twenty one patients with angiographically confirmed CAD and 31 healthy controls took part in this study. The levels of the activation marker sCD30 were determined in plasma and phytohaemagglutinin (PHA)-stimulated and unstimulated peripheral blood mononuclear cell cultures by ELISA. Plasma sCD30 levels did not differ significantly between the patients and controls. However, spontaneous sCD30 secretion was significantly lower in patients with CAD compared to controls (p < 0.001). The soluble CD30 levels were significantly increased in the supernatant of PHA-stimulated PBMCs compared to unstimulated cultures in both groups of patients and controls (p < 0.001). PHA-stimulated sCD30 secretion was found to be lower in patients compared to controls; however, the difference was not statistically significant. Plasma sCD30 levels were not statistically different in patients with chronic stable CAD, a well-known Th1-mediated disease, compared to controls; whereas decreased spontaneous and PHA-stimulated sCD30 secretion in patients with CAD might indicate the progressive shift towards a Th1 immune response.

Lymphocyte cytotoxicity of oxLDL in patients with atherosclerosis.

BACKGROUND: Atherosclerosis, a chronic inflammatory disease of the vessel wall, is characterized by local and systemic immune responses to a variety of antigens. Oxidized low-density lipoprotein (oxLDL) is considered as an important determining factor in the pathogenesis of atherosclerosis. OBJECTIVE: The purpose of this study was to investigate the degree of peripheral blood mononuclear cells (PBMC) vulnerability to in vitro oxLDL-induced cytotoxicity from atherosclerotic patients in comparison to healthy individuals. METHODS: Thirty patients with atherosclerotic lesions, confirmed by angiography, and 30 matched healthy individuals were investigated. PBMC was prepared from individuals' blood samples which were further stimulated with low dose (1 µg/mL) and high dose (50 µg/mL) of extensively oxidized LDL. MTT assay was utilized to measure cell viability and proliferation. Stimulation index (SI) was calculated as mean ratio of optical density (OD) of the stimulated cells divided by OD of untreated cells. RESULTS: Low dose oxLDL treatment caused no significant proliferative or cytotoxic effect in the control group; however, similar treatment caused significant cytotoxic effect in the patients compared to the controls (p=0.026). High dose oxLDL treatment induced more significant cytotoxicity in the patients compared to the controls (p=0.006). Comparison of the SI between the two groups of patients and controls showed significantly lower index by either the low (p=0.03) or the high dose (p<0.001) oxLDL in the patients compared to the controls. CONCLUSIONS: PBMC from patients with atherosclerosis showed increased susceptibility to oxLDL-induced cytotoxicity. Our results imply that prolonged exposure to elevated levels of circulating oxLDL could weaken the cellular defense mechanisms by progressive depletion of the pool of antiapoptotic proteins, rendering the cells more vulnerable to oxLDL-induced cell death.