Angiotensin II pseudopeptides containing 1,3,5-trisubstituted benzene scaffolds with high AT2 receptor affinity

Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as gamma-turn mimetics have been synthesized and incorporated in five pseudopeptide analogues of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), replacing Val-Tyr-Ile, Val-Tyr, or Tyr-Ile. All the tested compounds exhibited nanomolar affinity for the AT2 receptor with the best compound (3) having a K(i) of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (K(i) = 30.3 nM). This pseudopeptide exerted full agonistic activity in an AT2 receptor induced neurite outgrowth assay but displayed no agonistic effect in an AT1 receptor functional assay. Molecular modeling, using the program DISCOtech, showed that the high-affinity ligands could interact similarly with the AT2 receptor as other ligands with high affinity for this receptor. A tentative agonist model is proposed for AT2 receptor activation by angiotensin II analogues. We conclude that the 1,3,5-trisubstituted benzene rings can be conveniently prepared and are suitable as gamma-turn mimics.     

Screening of congenital heart disease patients using multiplex ligation-dependent probe amplification: early diagnosis of syndromic patients

Recurrent copy number variants (CNVs) are found in a significant proportion of patients with congenital heart disease (CHD) and some of these CNVs are associated with other developmental defects. In some syndromic patients, CHD may be the first presenting symptom, thus screening of patients with CHD for CNVs in specific genomic regions may lead to early diagnosis and awareness of extracardiac symptoms. We designed a multiplex ligation-dependent probe amplification (MLPA) assay specifically for screening of CHD patients. The MLPA assay allows for simultaneous analysis of CNVs in 25 genomic regions previously associated with CHD. We screened blood samples from 402 CHD patients and identified 14 rare CNVs in 13 (3.2%) patients. Five CNVs were de novo and six where inherited from a healthy parent. The MLPA screen led to early syndrome diagnosis in two of these patients. We conclude that the MLPA assay detects clinically relevant CNVs and suggest that it could be used within pediatric cardiology as a first tier screen to detect clinically relevant CNVs and identify syndromic patients at an early stage.     

HLA-DRBeta1, circulating Th1/Th2 cytokines and immunological homunculus in coronary atherosclerosis

Coronary atherosclerotic disease is one of the most endangering health disorder worldwide. This study was designed to investigate the correlation between HLA-DR1 alleles and circulating Th1/Th2 type cytokines in coronary atherosclerosis. By Elisa, Th1/Th2 type cytokines were determined in serum samples of 31 subjects with unstable angina, 27 subjects with chronic stable angina and 24 individuals as normal control. By SSP-PCR, more than 100 alleles of HLA-DRBeta1 were typed in 24 subjects who had skewed serum levels of Th1/Th2 type cytokines. Lipid profiles were determined by the routine methods of clinical laboratory in all subjects. The mean serum concentration of IL-10 in normal control subjects was higher in comparison to the patient groups.0.33±0.59 pg/ml versus 0.064±0.3 pg/ml in unstable angina pectoris group (p<0.028) and 0.22±0.6 pg/ml in chronic stable subjects. There was no statistically significant difference among the groups in serum levels of other desired cytokines (IFN-Gamma, IL-4). 33.33% of normal control subjects were HLA-DR16 positive whereas none of the subjects with chronic stable angina or individuals with unstable angina pectoris was positive for this antigen. The mean concentration of serum LDL-cholesterol in normal control group was high 142.046±35.40 (pg/ml).This preliminary study shows that the atherogenic effect of the LDL- cholesterol may be dampened by HDL-cholesterol through anti inflammatory cytokine IL-10 and HLA-DR16, a phenomenon interpretable via immunological homunculus theory.     

Steroidogenic factor-1 and endometriosis

Endometriosis is a common and chronic disease characterized by persistent pelvic pain and infertility. Estradiol is essential for growth and inflammation in endometriotic tissue. The complete cascade of steroidogenic proteins/enzymes including aromatase is present in endometriosis leading to de novo estradiol synthesis. PGE₂ induces the expression of the genes that encode these enzymes. Upon PGE₂ treatment, coordinate recruitment of the nuclear receptor SF-1 to the promoters of these steroidogenic genes is the key event for estradiol synthesis. SF-1 is the key factor determining that an endometriotic cell will respond to PGE₂ by increased estradiol formation. The presence of SF-1 in endometriosis and its absence in endometrium is determined primarily by the methylation of its promoter. The key steroidogenic enzyme in endometriosis is aromatase encoded by a single gene because its inhibition blocks all estradiol biosynthesis. Aromatase inhibitors diminish endometriotic implants and associated pain refractory to existing treatments in affected women.     

IL-23 Gene Expression in PBMCs of Patients with Coronary Artery Disease

Objective: Both adaptive and innate immune systems are involved in coronary artery disease (CAD). The aim of this study was to evaluate TH17 cytokines expression profiles in un-stimulated peripheral blood lymphocytes (PBMCs) of patients with coronary artery disease. Methods: Expression profiles of IL-17, IL-23, and TGF-β1 were determined in individuals with and without CAD using Real-time PCR. Results: A significant decrease in IL-23 gene expression in un-stimulated PBMCs of patients with CAD compared to those without CAD was found (p=0.003, OR=0.045, 95% CI: 0.006–0.355). Conclusion: Our data reinforce the potential role of the IL-23 as a critical regulatory molecule that bridges the innate and adaptive arms of the immune system in the complex mechanisms associated with the development of atherosclerosis.     

Mobile phone radiation interferes laboratory immunoenzymometric assays: Example chorionic gonadotropin assays

The radiofrequency radiation is of concern in hospital laboratories as the microwaves have many health effects even on immune functions. The aim of this study was, however, to evaluate the effects of cell phone radiation on chorionic gonadotropin immunoassays of human serum. Two cell phones with 0.69 and 1.09W/kg (head SAR) emitting 900MHz radiation were used. Sixty wells with five human serum concentrations (0, 10, 100, 250, 500mIU/mL) were used in three batches. The well heads in each batch were exposed to 900MHz emitted from these phones, and the 0.69, 1.09W/kg exposed batches were compared with the unexposed controls. Radiation exposure from mobile phones altered the measured serum levels especially in the wells with 100, 250, 500mIU/mL hormone concentrations. Exposure at 1.09W/kg SAR caused a significant loss compared to 0.69W/kg SAR exposure. In conclusion, the microwave exposures may require attention in laboratories using immunoassays.     

Uterine leiomyoma causing menometrorrhagia with a concomitant mature teratoma in a 15-year-old child: a case report and review of the literature

Uterine leiomyoma is the most common uterine tumor in adult females but is rare in the pediatric population with only 10 previous cases reported. We describe the unique case of a 15-year-old girl who presented with abdominal pain and menometrorrhagia and was found to have a uterine leiomyoma as well as a mature ovarian teratoma that required surgical resection. We review diagnostic imaging and optimal management for the 2 gynecologic masses in this teenage girl.