Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists

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Muscle sympathetic nerve activity at rest compared to exercise tolerance

Cardiovascular autonomic function is associated with physical performance and exercise training adaptation. The association between physical performance and sympathetic regulation is not well known. We hypothesized that sympathetic nervous system activity is associated with physical performance among male runners. The study population included 26 healthy male club runners [age 33 ± 5 years, body mass index (BMI) 24 ± 1 kg/m², VO_2max 58 ± 5 ml kg⁻¹ min⁻¹; mean ± SD]. Muscle sympathetic nerve activity (MSNA) was assessed from the peroneal nerve by the microneurography technique during 5 min of supine rest. Physical performance was assessed by time to exhaustion during treadmill running. The mean resting MSNA was 20 ± 6 bursts min⁻¹ (range 6–34). The mean time to exhaustion was 1,005 ± 136 s (range 720–1260). When the study group was divided into tertiles according to their running performance (866 ± 69, 994 ± 30 and 1154 ± 71 s in time to exhaustion, P < 0.0001 between the groups), MSNA was lower (P = 0.032) in the group with the best running performance (16 ± 5 bursts min⁻¹) compared to those with the worst running performance (23 ± 7 bursts min⁻¹). In conclusion, baseline sympathetic activity, measured by a microneurography at rest, may be associated with the maximal running performance of healthy subjects.     

Type I interferons as vaccine adjuvants against infectious diseases and cancer

Presently, new attention is given to type I interferons (IFNs) as essential factors linking innate and adaptive immunity. Several studies provided evidence about the importance of IFN-alpha in the differentiation of the Th1 subset, in the generation and activity of cytotoxic T lymphocytes, in the enhancement of a primary antibody response and in the activation of dendritic cells. Owing to their immunomodulatory properties, type I IFNs can represent good candidates to be used as adjuvants for vaccination. In the present review, we summarize recent studies in humans and in animal models, suggesting a possible application of type I IFNs as adjuvants for the development of more effective vaccines against infectious diseases and cancer.     

Intense cytoplasmic ezrin immunoreactivity predicts poor survival in colorectal cancer

Ezrin is a membrane-cytoskeleton anchor, which, in experimental models, regulates tumor cell invasion and metastatic ability. We carried out immunohistochemical analysis of ezrin in 74 advanced colorectal cancer patients and correlated it to clinicopathologic variables and disease outcome. In contrast to the predominantly membraneous immunoreactivity of normal colorectal epithelium, ezrin expression in the colorectal cells was typically cytoplasmic. Altogether, 16.2% (12/74) of the tumors showed negative/weak ezrin staining, 35.1% (26/74) had moderate staining, and 48.6% (36/74) had intense staining. The expression was more intense in colon than in rectal carcinomas (P = .003). Increased ezrin expression was associated with adverse outcome, that is, shorter disease-specific survival; 48.3 months and 36.6 months for negative-weak versus intense expression (P = .041) as well as shorter survival with metastases at 36 months (P = .030); the metastases₃₆ rates in ezrin_neg/weak, ezrin_moderate, ezrin_intense are 58.3%, 25.0%, and 18.4%, respectively. In univariate survival analysis, dichotomized (negative/weak versus moderate/strong) ezrin expression significantly predicted both the 5-year disease specific survival (P = .035) and 5-year metastases (P = .018) but lost this predictive power in multivariate (Cox) analysis. High ezrin expression was also related to high E-cadherin (cytoplasmic) expression, DNA aneuploidy, and high thymidylate synthase expression (P = .046, P = .042, P = .046, respectively). These results suggest that ezrin may play a role in colorectal cancer progression and that ezrin expression might provide clinically valuable information in predicting the biological behavior of colorectal cancer.     

T-cell reactivity to insulin peptide A1-12 in children with recently diagnosed type 1 diabetes or multiple beta-cell autoantibodies

Insulin-specific immune responses appear early in preclinical type 1 diabetes (T1D), and bovine insulin in cow's milk-based infant formulas has been suggested to be of importance in induction of the primary response to insulin in humans. To characterize insulin-specific T-cell reactivity we studied T-cell responses to 10 insulin peptides derived from bovine (BI) and human insulin (HI) in 42 children with recently diagnosed T1D, 47 children with multiple autoantibodies and 111 autoantibody-negative control children with risk-associated HLA alleles. Proliferation responses detected in antigen-stimulated peripheral blood mononuclear cells did not differ between the three groups when the comparison was performed without considering HLA genotypes. However, significant differences were observed, when children with the high-risk genotype HLA (DRB1*03)-DQA1*05-DQB1*02/DRB1*0401-DQA1*03-DQB1*0302 were analyzed separately. The responses to the peptides including amino acids A1-12 derived from B1 and H1 were significantly higher in children with T1D (P=0.008, P=0.004, for B1 and H1, respectively) and in children with diabetes-associated autoantibodies (P=0.002 and P=0.001, respectively) than in control children. Positive responses (stimulation indices SI>/=3) were seen more frequently in T1D children than in controls (4/7 vs 2/19; P=0.03 and 4/7 vs 1/19; P=0.01 for B1 and H1, respectively). T-cell response to the insulin peptide A1-12 is enhanced in clinical and preclinical T1D associated with the high-risk HLA-genotype emphasizing the importance of this epitope.     

Serum matrix metalloproteinases in patients resuscitated from cardiac arrest. The association with therapeutic hypothermia

Aim

To study the systemic levels of matrix metalloproteinases (MMP) -7, -8 and -9 and their inhibitor TIMP-1 in cardiac arrest patients and the association with mild therapeutic hypothermia treatment on the serum concentration of these enzymes.

Methods

MMP-7, -8 and -9 and tissue inhibitor of metalloproteinases-1 (TIMP-1) were analysed in blood samples obtained from 51 patients resuscitated from cardiac arrest. The samples were taken at 24 and 48 h from restoration of spontaneous circulation (ROSC). The biomarker levels were compared between patients (N = 51) and healthy controls (N = 10) and between patients who did (N = 30) and patients who did not (N = 21) receive mild therapeutic hypothermia.

Results

MMP-7 (median 0.47 ng/ml), MMP-8 (median 31.16 ng/ml) and MMP-9 (median 253.00 ng/ml) levels were elevated and TIMP-1 levels suppressed (median 78.50 ng/ml) in cardiac arrest patients as compared with healthy controls at 24 h from ROSC. Hypothermia treatment associated with attenuated elevation of MMP-9 (p = 0.001) but not MMP-8 (p = 0.02) or MMP-7 (p = 0.69). Concentrations of MMPs -7, -8 and -9 correlated with the leukocyte count but not with C-reactive protein (CRP) or neurone-specific enolase (NSE) levels.

Conclusion

We demonstrated that the systemic levels of MMP-7, -8 and -9 but not TIMP-1 are elevated in cardiac arrest patients in the 48 h post-resuscitation period relative to the healthy controls. Patients who received therapeutic hypothermia had lower MMP-9 levels compared to non-hypothermia treated patients, which generates hypothesis about attenuation of inflammatory response by hypothermia treatment.     

Toll‐like receptors 3, 7, and 9 in Juvenile nasopharyngeal angiofibroma

Juvenile nasopharyngeal angiofibroma (JNA) is a rare, benign tumor affecting adolescent males. The etiology of JNA as well as the causes determining the variable growth patterns of individual tumors remains unknown. Toll‐like receptors (TLRs) are part of the innate immune response to microbes; by recognition of distinct features, they link to induction of pro‐inflammatory signaling pathways. We immunostained TLR 3, 7, and 9 in 27 JNA specimens of patients treated at the Helsinki University Central Hospital, Helsinki, Finland, during the years 1970–2009. Results: TLR 3, 7, and 9 expressions were found in stromal and endothelial cells of JNA, and their expression levels varied from negative to very strong positive. TLR 3 expression was found to have a significant correlation with the clinical stage of JNA. Conclusions: The present results propose a putative role of TLRs in the growth process of JNA.