Increased levels of C‐reactive protein and interleukin‐6 in hyperhomocysteinemic subjects

Objective. Elevated plasma homocysteine concentration is considered to be an independent risk factor for cardiovascular disease. However, the mechanisms by which hyperhomocysteinemia are related to vascular disease are unclear. High‐sensitivity C‐reactive protein (CRP), a marker of inflammation, has been reported to be an independent predictor of future myocardial infarction among clinically healthy individuals. Interleukin (IL)‐6 is a regulator of CRP and has a key role in initiation of inflammation. The aim of this study was to investigate whether individuals with increased plasma homocysteine concentrations have altered levels of serum CRP and IL‐6. Material and methods. Serum concentrations of CRP and IL‐6 were measured in 39 individuals with hyperhomocysteinemia and in 39 control subjects matched for gender, age and body mass index (BMI). In addition, the inflammatory effect of IL‐6 on peripheral blood mononuclear cells was measured. Results. Compared to controls, hyperhomocysteinemic subjects have elevated serum levels of CRP and IL‐6 (p?0.001 and p<0.005, respectively). Importantly, this raised level of IL‐6 was also seen in hyperhomocysteinemic individuals without accompanying hypercholesterolemia or cardiovascular disease. IL‐6 increased the release of monocyte chemoattractant protein‐1 from peripheral blood mononuclear cells, with particularly enhancing effects in cells from patients with hyperhomocysteinemia. Conclusions. These data suggest that enhanced inflammation may be associated with homocysteine‐related cardiovascular disease, possibly involving IL‐6‐related mechanisms.     

Imbalance of interleukin-18 and interleukin-18 binding protein in children with Henoch-Schönlein purpura

The balance between interleukin-18 (IL-18) and its endogenous antagonist, IL-18 binding protein (IL-18BP), was evaluated in children with Henoch-Sch?nlein purpura (HSP). Plasma IL-18 and IL-18BP levels and peripheral blood mononuclear cell IL-18 mRNA expression were significantly higher in patients with active HSP (n = 30) than in healthy controls (n = 20); IL-18BP mRNA expression was similar in active HSP and controls. Plasma levels and mRNA expression of IL-18 and IL-18BP in patients in remission (n = 19) were similar to those in controls. The ratios of IL-18 / IL-18BP plasma levels and IL-18 / IL-18BP mRNA levels in active HSP were significantly higher than in patients in remission and healthy controls. Thus, adequate IL-18BP to block the proinflammatory activity of IL-18 may not be present in active HSP and regulation of the IL-18 / IL-18BP balance might provide a potential therapeutic strategy.     

Monocyte chemoattractant protein‐1 and CC‐chemokine receptor‐2 in severe hypercholesterolaemia

Objectives: To investigate whether plasma concentrations of monocyte chemoattractant protein‐1 (MCP‐1) and the gene expression of its receptor on the monocyte cell surface CCR‐2 were elevated above normal in subjects with asymptomatic, isolated hypercholesterolaemia and if statin treatment could influence this cytokine. Methods: The investigation was designed as a cross sectional study followed by a single, blind, treatment study of patients receiving pravastatin 80?mg/day for 8 weeks. The study included 23 patients with severe hypercholesterolaemia (LDL>5.2?mmol/L) and 39 normocholesterolaemic controls. Blood samples were obtained from patients and controls at baseline and from patients at end of the study and analysed for lipoproteins and inflammatory mediators: MCP‐1, high‐sensitivity C‐reactive protein (HS‐CRP). Isolated peripheral mononuclear cells were analysed for CCR‐2 gene expression. Results: Mean plasma LDL‐C was significantly higher in patients than in controls. No difference in plasma MCP‐1 levels or CCR‐2 gene expression was seen between the groups at baseline, nor were there any differences in plasma concentrations of CRP. After treatment with pravastatin, LDL‐C decreased by 31%. Treatment did not significantly affect the levels of MCP‐1 or CCR‐2 gene expression, nor was CRP affected by treatment with pravastatin. Conclusions: Our study does not support the view that MCP‐1 plasma levels and CCR‐2 gene expression in circulating monocytes are directly responsible for the monocyte recruitment into the arterial intima in patients with severe asymptomatic hypercholesterolaemia. In addition, the inflammatory response of a high concentration of LDL‐C in isolated asymptomatic hypercholesterolaemia is minute.     

Ultrasonography in suspected acute appendicitis in childhood—report of 1285 cases

Objective: For the assessment of the diagnostic value of real-time ultrasonography (US) in children with suspected acute appendicitis (a.A.) the results of graded compression US are compared with clinical and histological final diagnoses. Methods: In a prospective study over nearly 9 years we examined 1285 children aged 1–15 years (m=514, f=771). Using a 5-MHz curved array transducer the right lower quadrant was examined in a graded compression technique. Results: Prevalence of histologically proven a.A. was remarkably low (9%). In diagnosis of acute appendicitis in childhood US achieves a sensitivity of 92%, specificity of 98%, a positive predictive value of 90% and a negative predictive value of 98%. The overall accuracy was 98%. Mesenteric lymphadenitis was seen in 181 cases (prevalence 12%) and terminal ileitis occasionally accompanied by mesenteric lymphadenitis was seen in 116 cases (prevalence 9%). Conclusion: In children with suspected appendicitis US of the abdomen gives great diagnostical value for differential diagnosis of a.A. and other more frequent inflammatory diseases of the ileocoecal region. Thus US provides further reliable information to the referring physician. Consequently it is necessary to perform US in each child with acute abdominal pain, even if clinical diagnosis seems to be well established.     

Correlations between serum amyloid A protein and C‐reactive protein in infectious diseases

Serum amyloid A (SAA) protein is an acute phase reactant that has recently become of increasing interest as a marker for disease and treatment monitoring. We have correlated SAA levels to those of C‐reactive protein (CRP) in sera from 98 patients admitted to an infectious diseases clinic because of viral and bacterial infections, including hepatitis A and B, cytomegalovirus infection, varicellae‐zoster, infectious mononucleosis, influenza A, bacterial pneumonia, streptococcal pharyngitis, bacterial sepsis and severe bacterial sepsis. The study population was chosen from the clinical setting as representatives of these frequently encountered patient groups. SAA levels correlated significantly with CRP levels (r²=0.757, p<0.001) for the entire studied population. Furthermore, positive correlations were found in viral (r²=0.572, p<0.001) and bacterial (r²=0.666, p<0.001) infections. Positive correlations were also observed when the values were compared in accordance with CRP levels higher and lower than 100?mg/L (r²=0.689, p<0.001; CRP>100; r²=0.397, p<0.001; CRP<100). Because SAA is more sensitive than CRP for the detection of minor inflammatory stimuli, as in the viral and low CRP groups, we conclude that SAA can be of use in several viral infections, as well as in non‐invasive and early invasive bacterial infections.     

A Study of The Relationship between The Interleukin‐6 Gene and Obstructive Sleep Apnea

Because obstructive sleep apnea (OSA) is associated with increased levels of inflammatory cytokines, we examined the relationship between OSA and polymorphisms for interleukin‐6 (IL6). Six single nucleotide polymorphisms (SNPs) within IL6 were genotyped in 259 African Americans from the Cleveland Family Study with replication conducted in the Cardiovascular Health Study (n= 124). OSA was dichotomized into apnea hypopnea index (AHI) > 15, or on treatment versus absent: AHI < 5. Logistic regression was conducted, adjusting for age and sex in models with and without body mass index (BMI). SNP IL6–6021 was associated with a decreased risk of OSA after adjusting for BMI (Odds Ratio for T allele 0.24, 95%CI [0.09–0.67], p= 0.006, q= 0.07) under an additive model. This same allele was associated with increased BMI. The results from the replication sample were consistent in direction though not statistically significant (p= 0.23). The SNPs were studied in European‐ Americans, although, the minor allele frequency in IL6–6021 was too low (4%) for meaningful comparisons. A synonymous SNP within the IL6 coding region was protective of OSA in African Americans; with qualitatively similar findings observed in another cohort. This suggests that variants in IL6 may influence the risk of OSA in a pathway that is not explained by obesity. Clin Trans Sci 2010; Volume 3: 337–339     

Insulin‐like growth factor (IGF)‐I,IGF‐II and IGF‐binding protein (IGFBP)‐3 levels in Arab subjects with coronary heart disease

Objective. Insulin‐like growth factors (IGF‐I, IGF‐II) and their binding protein (IGFBP‐3) may be risk markers for coronary heart disease (CHD). This study aimed to assess the levels and determinants of the serum levels of IGF‐I, IGF‐II and IGFBP‐3 in Arab patients with established CHD. Material and methods. Two groups of subjects were matched for age, gender, BMI and waist–hip ratio (WHR): (i) CHD (n = 105), median age 51.0 (range 40.0–60.0) years; (ii) controls (n = 97) aged 49.0 (range 37.0–60.0) years. We measured fasting serum levels of glucose and lipoproteins (total cholesterol, triglycerides, LDL, HDL, apo B), insulin, HOMA‐IR, IGF‐I, IGF‐II and IGFBP‐3 and compared the results between groups. The effects of body mass and the metabolic syndrome (MS) on IGF levels were also examined, and linear correlations were sought between the various parameters. Results. The levels of IGF‐I, IGF‐II and IGFBP‐3 were significantly lower (all p<0.01) for the CHD group than for the control group. These differences were not influenced by BMI or with the presence of MS. In CHD, there were no significant correlations between levels of IGF‐I and IGF‐II and age, BMI, WHR, lipoprotein concentrations and insulin sensitivity, although IGFBP‐3 had weakly significant relationships with some of the lipoproteins. Conclusions. Levels of IGF‐I, IGF‐II and IGFBP3 are reduced in male Arab patients with CHD, and did not appear influenced by traditional CHD risk factors such as age, BMI, insulin sensitivity and presence of MS. Perturbations in the IGF/IGFBP‐3 axis may be potential additional targets for pharmacological manipulation in CHD.     

Pregnancy‐associated plasma protein A: A biomarker in acute ST‐elevation myocardial infarction (STEMI)

Background. Elevated circulating levels of pregnancy‐associated plasma protein A (PAPP‐A), a novel marker of atherosclerotic plaque instability, are associated with increased risk of future cardiac events in patients with acute coronary syndromes (ACS). However, little is known of the kinetics or clinical significance of circulating PAPP‐A after plaque rupture in acute ST‐elevation myocardial infarction (STEMI).

Aim. To evaluate the 48‐hour release of pregnancy‐associated plasma protein A (PAPP‐A) and its association with 12‐month outcome in patients with acute ST‐elevation myocardial infarction (STEMI).

Methods. Sixty‐two consecutive STEMI patients were included (40 men and 22 women, median age 67.5 years (range 34–84)), of whom 54 (87.1%) received reperfusion therapy. PAPP‐A was measured at admission and 6–12, 24 and 48 hours thereafter. In 14 patients, samples were obtained also at 1, 2 and 4 hours.

Results. There was an early peak of circulating PAPP‐A during the first 12 hours from symptom onset, followed by rapid normalization. A second, late PAPP‐A elevation was noticed in 20/62 patients (32.3%). Admission PAPP‐A >10.0?mIU/L (highest tertile) was associated (P = 0.049) with increased 12‐month risk of cardiovascular death or non‐fatal myocardial infarction. Moreover, the combination of failed early reperfusion together with late PAPP‐A elevation was strongly (7/13 versus 10/49 patients, P = 0.016) associated with adverse outcome. Admission PAPP‐A did not correlate with admission C‐reactive protein or cardiac troponin I.

Conclusions. PAPP‐A is elevated early in STEMI and then declines rapidly, a pattern consistent with release from the ruptured plaque. The variability of PAPP‐A kinetics at 48 hours reflects the success of reperfusion. This study also shows that PAPP‐A may have prognostic value in STEMI.     

Circulatory responses to hypoglycaemia in diabetic and non‐diabetic children

The purpose of this study was to investigate the circulatory responses to hypoglycaemia in diabetic and non‐diabetic children and to determine whether these changes were associated with hormone levels or clinical variables. Plasma glucose levels in 18 diabetic and 15 control children were gradually lowered to 2.5 (0.3)?mmol/L (mean (SD)) and 2.9 (0.2)?mmol/L, respectively. Blood pressure and heart rate were recorded at 10‐min intervals, and blood samples were taken for hormone analysis. Systolic pressure increased from 110.1 (10.0) to 115.0 (11.2)?mmHg (p=0.008) in the diabetic children and from 116.9 (12.0) to 121.6 (12.7)?mmHg (p=0.049) in the controls. Diastolic pressure decreased from 61.9 (6.7) to 55.5 (7.6)?mmHg (p<0.001) in the diabetic children and from 66.5 (6.3) to 55.1 (5.1)?mmHg (p<0.001) in the controls. The increase in pulse pressure during hypoglycaemia was significantly smaller in the diabetic children (10.6 (5.5) vs. 15.7 (7.7)?mmHg, p=0.04). The final systolic and pulse pressure correlated with the final adrenaline level in the controls (r=0.66, p=0.008 and r=0.70, p=0.003, respectively). In the non‐diabetic as well as the diabetic group, the increase in pulse pressure correlated with the increase in adrenaline (r=0.66, p=0.008 and r=0.50, p=0.03, respectively). It is concluded that systolic pressure increases and diastolic pressure decreases during hypoglycaemia in children. The smaller increase in pulse pressure observed in the diabetic children is probably related to a significantly smaller increase in adrenaline in this group.     

Does morphine change the physical examination in patients with acute appendicitis?

The objective of this study was to determine if judicious dosing of morphine sulfate can provide pain relief without changing important physical examination findings in patients with acute appendicitis. We conducted a prospective, randomized, double-blind crossover design. Patients scheduled for appendectomy were randomized to two groups. Group A received 0.075 mg/kg intravenous morphine sulfate and 30 minutes later received placebo. The sequence of medication was reversed in group B. Patients were examined by a surgical resident and an EM attending before and after receiving medication. Six explicit physical examination findings were documented as absent, indeterminate, or present. Physicians were also asked if they felt overall examination findings had changed after medication. Patient's visual analog scale (VAS) was recorded before each medication and at study completion. Thirty-four patients were enrolled and full data were available for 22 patients. Neither morphine nor placebo caused a significant change in individual examination findings. Three patients in both groups were judged to have a change in their examination after medication. The median change in VAS was 20 mm after morphine and 0 mm after placebo (P =.01). In this pilot study, patients with clinical signs of appendicitis were treated with morphine and had significant improvement of their pain without changes in their physical examination.     

Is endoscopic retrograde appendicitis therapy a better modality for acute uncomplicated appendicitis? A systematic review and meta-analysis

BACKGROUNDPrevious studies had shown endoscopic retrograde appendicitis therapy (ERAT) is an effective treatment for acute appendicitis. However, different studies reported conflicting outcomes regarding the effectiveness of ERAT in comparison with laparoscopic appendectomy (LA).AIMTo compare the effectiveness of ERAT with LA. METHODSRandomized controlled trials (RCTs) and retrospective studies of ERAT for acute uncomplicated appendicitis were searched in PubMed, Cochrane Library, Web of Science, Embase database, China National Knowledge Infrastructure (CNKI), the WanFang Database, and Chinese Scientific Journals Database (VIP) from the establishment date to March 1 2021. Heterogeneity was assessed using the I-squared statistic. Pooled odds ratios (OR), weighted mean difference (WMD), and standard mean difference (SMD), with 95% confidence intervals (CI) were calculated through either fixed-effects or random-effects model. Sensitivity analysis was also performed. Publication bias was tested by Egger''s test, and Begg’s test. The quality of included RCT were evaluated by the Jadad scale, while Newcastle-Ottawa scale is adopted for assessing the methodological quality of case-control studies. All statistical analysis was performed using Stata 15.1 statistical software. All statistical analysis was performed using Stata 15.1 statistical software. This study is registered with PROSPERO, CRD42021243955. RESULTSAfter screening, 10 RCTs and 2 case-control studies were included in the current systematic review. Firstly, the length of hospitalizations [WMD = -1.15, 95%CI: -1.99, -0.31; P = 0.007] was shorter than LA group. Secondly, the level of post-operative CRP [WMD = -10.06, 95%CI: (-17.39, -2.73); P = 0.007], TNF-α [WMD = -7.70, 95%CI: (-8.47, -6.93); P < 0.001], and IL-6 Levels [WMD = -9.78, 95%CI: (-10.69, -8.88); P < 0.001; P < 0.001] in ERAT group was significantly lower than LA group. Thirdly, ERAT group had a lower incidence of intestinal obstruction than LA group. [OR = 0.19, 95%CI: (0.05, 0.79); P = 0.020]. Moreover, the quality of 10 RCTs were low with 0-3 Jadad scores, while the methodological quality of two case-control studies were fair with a score of 2 (each). CONCLUSIONCompared with LA, ERAT reduces operation time, the level of postoperative inflammation, and results in fewer complications and shorter recovery time, with preserving the appendix and its immune and biological functions.     

C‐reactive protein and tumor necrosis factor‐alpha in relation to insulin‐mediated glucose uptake,smoking and atherosclerosis

Objectives. To examine the hypothesis that serum concentration of C‐reactive protein (CRP) is inversely associated with insulin sensitivity and obesity, and that this may by mediated by tumor necrosis factor‐α (TNFα) and interleukin‐6 (IL‐6). Material and methods. Cross‐sectional, one‐center study of a population‐based sample of 58‐year‐old Swedish men (n = 98). Exclusion criteria were cardiovascular disease, clinical diabetes mellitus and/or continuous cardiovascular medication. Glucose infusion‐rate (euglycemic hyperinsulinemic clamp), adjusted for fat‐free mass, which together with total body fat was measured by dual‐energy X‐ray absorptiometry. Serum concentrations of CRP, TNFα, soluble TNFα receptor 2 (sTNFAR2), IL‐6 determined by ELISA. Ultrasound was used to measure intima‐media thickness (IMT) in both common carotid arteries, carotid bulbs and in the right femoral artery. Results. CRP was inversely associated with insulin sensitivity (r = ?0.28, p<0.01) and with total body fat (r = 0.31, p<0.01), but not independently of the TNFα and sTNFAR2 product. Serum CRP, TNFα, sTNFAR2, but not IL‐6, were associated with low insulin sensitivity, total body fat, abdominal obesity, hyperinsulinemia, hypertriglyceridemia, low HDL cholesterol and small LDL particles, i.e. the metabolic syndrome. These associations were independent of smoking and carotid and femoral artery IMT. Conclusions. Serum concentrations of CRP were related to insulin sensitivity and accompanying factors constituting the metabolic syndrome. The results indicate that this association may be mediated by adipose tissue and TNFα effects, the latter measured as the product of TNFα and sTNFAR2. This was a cross‐sectional study and causality cannot be proven.     

A FABP-ulous 'rule out' strategy? Heart fatty acid binding protein and troponin for rapid exclusion of acute myocardial infarction

Objective

Many Emergency Departments (EDs) utilise ‘triple marker’ testing with CK-MB, myoglobin and troponin I (cTnI) to exclude acute myocardial infarction (AMI) within hours of presentation. We evaluated the ability of 8 biomarkers to rapidly exclude AMI at the point of presentation and investigated whether ‘triple marker’ testing represents the optimal multimarker strategy.

Methods

We recruited patients who presented to the ED with suspected cardiac chest pain occurring within 24 h. Blood was drawn at the time of presentation. Diagnostic value was assessed by calculating the area under the ROC curve (AUC) and a multivariate model was constructed by logistic regression. The primary outcome was a diagnosis of AMI, established by ≥12-h troponin testing in all patients.

Results

705 included patients underwent venepuncture a median of 3.5 h after symptom onset. Heart fatty acid binding protein (H-FABP) had an AUC of 0.86 (95% CI 0.82-0.90), which was significantly higher than any other biomarker including cTnI. While no single biomarker could enable exclusion of AMI, multivariate analysis identified cTnI and H-FABP as the optimal biomarker combination. Combined with clinical risk stratification, this strategy had a sensitivity of 96.9%, specificity of 54.7%, PPV 32.4% and NPV 98.8%.

Conclusions

We have derived an algorithm that would enable AMI to be immediately excluded in 315 (44.7%) patients at the cost of missing 6 AMIs per 1000 patients treated. While the risk is likely to be unacceptable for clinical implementation, we have highlighted an area for future development using serial testing and increasingly sensitive assays.     

Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

Most single-gene diseases, including muscular dystrophy, display a nonuniform phenotype. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. We employed an unbiased mapping approach to search for genes that modify muscular dystrophy in mice. In a genome-wide scan, we identified a single strong locus on chromosome 7 that influenced two pathological features of muscular dystrophy, muscle membrane permeability and muscle fibrosis. Within this genomic interval, an insertion/deletion polymorphism of 36 bp in the coding region of the latent TGF-β–binding protein 4 gene (Ltbp4) was found. Ltbp4 encodes a latent TGF-β–binding protein that sequesters TGF-β and regulates its availability for binding to the TGF-β receptor. Insertion of 12 amino acids into the proline-rich region of LTBP4 reduced proteolytic cleavage and was associated with reduced TGF-β signaling, decreased fibrosis, and improved muscle pathology in a mouse model of muscular dystrophy. In contrast, a 12-amino-acid deletion in LTBP4 was associated with increased proteolysis, SMAD signaling, and fibrosis. These data identify Ltbp4 as a target gene to regulate TGF-β signaling and modify outcomes in muscular dystrophy.     

The connection between C‐reactive protein and atherosclerosis

The connection between C‐reactive protein (CRP) and atherosclerosis lies on three grounds. First, the concentration of CRP in the serum, which is measured by using highly sensitive (a.k.a. ‘hs’) techniques, correlates with the occurrence of cardiovascular disease. Second, although CRP binds only to Fcγ receptor‐bearing cells and, in general, to apoptotic and damaged cells, almost every type of cultured mammalian cells has been shown to respond to CRP treatment. Many of these responses indicate proatherogenic functions of CRP but are being reinvestigated using CRP preparations that are free of endotoxins, sodium azide, and biologically active peptides derived from the protein itself. Third, CRP binds to modified forms of low‐density lipoprotein (LDL), and, when aggregated, CRP can bind to native LDL as well. Accordingly, CRP is seen with LDL and damaged cells at the atherosclerotic lesions and myocardial infarcts. In experimental rats, human CRP was found to increase the infarct size, an effect that could be abrogated by blocking CRP‐mediated complement activation. In the Apob^100/100Ldlr^‐/‐ murine model of atherosclerosis, human CRP was shown to be atheroprotective, and the importance of CRP‐LDL interactions in this protection was noted. Despite all this, at the end, the question whether CRP can protect humans from developing atherosclerosis remains unanswered.     

Signaling through NO and cGMP‐dependent protein kinases

The gaseous molecule nitric oxide (NO) modulates a large variety of physiological functions including vascular tone, intestinal motility, platelet aggregation, proliferation, apoptosis, and neurotransmission. NO initiates diverse cellular signaling cascades which comprise nitrosylation of proteins, adenosine 5′‐diphosphate (ADP)‐ribosylation, or stimulation of soluble guanylyl cyclases which catalyze intracellular guanosine 3′,5′‐cyclic monophosphate (cGMP) synthesis. cGMP activates cGMP‐dependent protein kinases (cGK) which mediate localized and global signaling. Furthermore, cGMP regulates the activity of phosphodiesterases (PDE) which modulate the duration and amplitude of cyclic nucleotide signaling. Two different types of cGK are expressed in mammals, cGKI and cGKII. Activation of the NO/cGMP/cGKI pathway induces relaxation of smooth muscle by lowering the cytosolic calcium level and/or by calcium desensitization of the contractile elements.