BackgroundPre-eclampsia is the most common complication occurring during pregnancy. In the majority of cases, it is concurrent with other pathologies in a comorbid manner (frequent co-occurrences in patients), such as diabetes mellitus, gestational diabetes and obesity. Providing bronchial asthma, pulmonary tuberculosis, certain neurodegenerative diseases and cancers as examples, we have shown previously that pairs of inversely comorbid pathologies (rare co-occurrences in patients) are more closely related to each other at the molecular genetic level compared with randomly generated pairs of diseases. Data in the literature concerning the causes of pre-eclampsia are abundant. However, the key mechanisms triggering this disease that are initiated by other pathological processes are thus far unknown. The aim of this work was to analyse the characteristic features of genetic networks that describe interactions between comorbid diseases, using pre-eclampsia as a case in point.ResultsThe use of ANDSystem, Pathway Studio and STRING computer tools based on text-mining and database-mining approaches allowed us to reconstruct associative networks, representing molecular genetic interactions between genes, associated concurrently with comorbid disease pairs, including pre-eclampsia, diabetes mellitus, gestational diabetes and obesity. It was found that these associative networks statistically differed in the number of genes and interactions between them from those built for randomly chosen pairs of diseases. The associative network connecting all four diseases was composed of 16 genes (PLAT, ADIPOQ, ADRB3, LEPR, HP, TGFB1, TNFA, INS, CRP, CSRP1, IGFBP1, MBL2, ACE, ESR1, SHBG, ADA). Such an analysis allowed us to reveal differential gene risk factors for these diseases, and to propose certain, most probable, theoretical mechanisms of pre-eclampsia development in pregnant women. The mechanisms may include the following pathways: [TGFB1 or TNFA]-[IL1B]-[pre-eclampsia]; [TNFA or INS]-[NOS3]-[pre-eclampsia]; [INS]-[HSPA4 or CLU]-[pre-eclampsia]; [ACE]-[MTHFR]-[pre-eclampsia].ConclusionsFor pre-eclampsia, diabetes mellitus, gestational diabetes and obesity, we showed that the size and connectivity of the associative molecular genetic networks, which describe interactions between comorbid diseases, statistically exceeded the size and connectivity of those built for randomly chosen pairs of diseases. Recently, we have shown a similar result for inversely comorbid diseases. This suggests that comorbid and inversely comorbid diseases have common features concerning structural organization of associative molecular genetic networks.
ObjectiveImmunotherapy of tuberculosis (TB) to shorten treatment duration represents an unmet medical need. Orally delivered, tableted TB vaccine (V7) containing heat-killed Mycobacterium vaccae (NCTC 11659) has been demonstrated in prior clinical studies to be safe and fast-acting immune adjunct.MethodsThe outcome of Phase III trial of V7 containing 10 µg of hydrolyzed M. vaccae was evaluated in 152 patients randomized at 2:1 ratio: V7 (N = 100), placebo (N = 52). Both arms received conventional 1st or 2nd line TB drugs co-administered with daily pill of V7 or placebo.ResultsAfter one month mycobacterial clearance was observed in 68% (P < 0.0001) and 23.1% (P = 0.04) of patients on V7 and placebo. Stratified conversion rates in V7 recipients with drug-sensitive and multidrug-resistant TB were 86.7% and 55.6% vs 27.2% and 15% in placebo. Patients on V7 gained on average 2.4 kg (P < 0.0001) vs 0.3 kg (P = 0.18) in placebo. Improvements in hemoglobin levels, erythrocyte sedimentation rate and leukocyte counts were significantly better than in controls. Liver function tests revealed that V7 can prevent chemotherapy-induced hepatic damage.ConclusionOral M. vaccae is safe, can overcome TB-associated weight loss and inflammation, reduce hepatotoxicity of TB drugs, improve sputum conversion three-fold OR 3.15; 95%CI (2.3,4.6), and cut treatment length by at least six-fold. Longer follow-up studies might be needed to further substantiate our findings (Clinicaltrials.gov: NCT01977768).
Monocyte migration from the peripheral blood to the uterine decidual tissue is essential for the regulation of placental development. We evaluated the phenotypical changes in the peripheral blood monocytes in pregnant women. The peripheral blood counts of monocytes expressing CD11b, CD47, and integrin β7 were elevated in women with normal gestation in comparison with nonpregnant women; the intensity of CD62P, CD11b, CD11c, CD29, CD31, and CD54 expression was higher in pregnancy. The counts of monocytes expressing adhesion molecules were similar in normal pregnancy and gestosis. Gestosis was characterized by higher counts of monocytes expressing IFN-γ receptor (CD119) and more intense expression of this receptor. Changes in the monocyte phenotype can promote their adhesion to the uterine vascular endothelium and further migration of these cells to the decidual tissue.
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