Genetic and environmental determinants of hepatocyte growth factor levels and their association with obesity and blood pressure

Background: Hepatocyte growth factor (HGF) is a member of the adipocytokine family; it is implicated in tissue repair, regeneration, and angiogenesis. Several studies have reported that the HGF plays important role in obesity and cardiovascular disease.

Aim: This study examines whether HGF and its phenotypic correlations with obesity and blood pressure (BP), in healthy individuals, are due to shared genetic or common environmental factors.

Subjects and methods: Body mass index (BMI), waist-to-hip ratio (WHR), BP, and HGF plasma concentrations were measured in a sample of 733 individuals belonging to 248 pedigrees.

Results: The most significant phenotypic correlations were found among HGF, WHR, and systolic BP (p < 0.001). Analysis of the familial aggregation revealed that parent–offspring and sibling correlations in HGF levels, adjusted for age, age², and sex, were statistically highly significant (p < 0.001). Variance decomposition analysis showed that when adjusted for potential covariates, 48.4% of the HGF variation was due to putative genetic factors. The genetic correlations between all pairs of studied traits (HGF, WHR, and SBP) were statistically significant (p < 0.02) and ranged between 0.23 ± 0.07 and 0.40 ± 0.07. However, correlation between WHR and BP becomes non-significant after adjustment for HGF.

Conclusions: The results provide evidence that putative genetic factors involved in regulation of HGF variation contribute also significantly to variation of the obesity and BP. It is possible that the familial resemblance for WHR and the SBP correlation in the studied sample is affected substantially by genetic factors regulating circulating HGF levels.     

Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.     

Liver injury associated with the use of selective androgen receptor modulators and post-cycle therapy: Two case reports and literature review

BACKGROUNDMuscle growth promoters are being developed for the treatment of disease-induced loss of muscle mass. Ligandrol and ostarine are selective androgen receptor modulators (SARMs) with a non-steroidal structure and a presumably more favorable side effect profile. In recent years, these substances with or without “post-cycle therapy” (PCT) are often misused by amateur athletes aiming to promote muscle growth. At the same time, reports on their toxic effects on organ systems are emerging.CASE SUMMARYWe report two cases of liver injury in young men who used ligandrol and/or ostarine for a few weeks followed by the use of substances for PCT. Acute liver injury occurred in both cases after stopping SARMs while on PCT. The clinical picture was dominated by jaundice and fatigue. The biochemical pattern showed a mixed type of injury with normal alkaline phosphatase and high concentrations of bilirubin and serum bile acids. Histological evidence showed predominantly cholestatic injury with canalicular bile plugs, ductopenia, and mild hepatocellular damage without significant fibrosis. The patients recovered from the condition after 3 mo. The off target effects of SARMs were likely idiosyncratic, but our report highlights the yet unrecognized effects of other toxic substances used for PCT, supra-therapeutic doses, and the complete absence of monitoring for adverse effects.CONCLUSIONAmong muscle-building amateur athletes, SARMs (ligandrol or ostarine) and/or substances in PCT may cause cholestatic liver injury with prolonged recovery.     

Mosquitoes of Anopheles hyrcanus (Diptera,Culicidae) Group: Species Diagnostic and Phylogenetic Relationships

Herein, we report the results of study of Anopheles species in Primorsk and Khabarovsk regions of Russia. Three species of the Anopheles hyrcanus group: An. kleini, An. pullus, and An. lesteri were identified by molecular taxonomic diagnostics for the first time in Russia. Surprisingly, An. sinensis, which earlier was considered the only species of Anopheles in Russian Far East, was not observed. We analyzed nucleotide variation in the 610-bp fragment of the 5′ end of the cytochrome c oxidase subunit I (COI) region. All species possessed a distinctive set of COI sequences. A maximum likelihood phylogenetic tree was constructed for members of the hyrcanus group. The examined Anopheles hyrcanus group members could be divided into two major subgroups: subgroup 1 (An. hyrcanus and An. pullus) and subgroup 2 (An. sinensis, An. kleini, and An. lesteri), which were found to be monophyletic.     

Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis

BACKGROUND AND AIM OF THE STUDY: Calcific aortic stenosis, the major heart valve disease encountered in the elderly, leads to massive calcium deposition in the valve leaflets that morphologically resembles bone formation. Recent studies have demonstrated the expression of various bone-associated proteins in stenotic valves, suggesting that valvular calcification may be an actively regulated process. Bone sialoprotein (BSP), a non-collagenous bone matrix protein, and bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor cytokine superfamily, are known to participate in the regulation of bone development and maturation. Their pathogenetic role in calcific aortic stenosis is unknown. METHODS: Using an immunoperoxidase technique and antibodies against BSP and BMP-2, the expression of BSP and BMP-2 was examined in 16 human aortic valves with calcific aortic stenosis obtained at valve replacement, and in seven normal autopsy controls without signs of aortic stenosis. RESULTS: By semiquantitative scoring, stenotic valves showed a significantly increased staining of BSP in cells and extracellular matrix as compared to control valves (2.7 +/- 0.1 versus 0.6 +/- 0.2 score units, p <0.001). Marked BMP-2 expression was detected in stenotic valves, mostly in cell-rich areas associated with focal calcium deposits, but no specific staining for BMP-2 was detected in control valves (1.5 +/- 0.2 versus 0.0 +/- 0.0 score units, p <0.001). CONCLUSION: These results demonstrate for the first time that BSP and BMP-2 are differentially expressed in normal aortic valves and in aortic stenosis, thereby supporting the concept that valvular calcification might be based on an actively regulated process involving BSP and BMP-2.     

Relationships between uterus and eggs in cestodes from different taxa, as revealed by scanning electron microscopy

Uterine organization and interaction with developing eggs in Tetrabothrius erostris (Tetrabothriidea), Nippotaenia mogurndae (Nippotaeniidea), Arostrilepis tenuicirrosa, and Monocercus arionis (Cyclophyllidea), cestodes belonging to three different orders, were investigated by scanning electron microscopy. The interactions were traced from sexually mature to gravid proglottids for all species. Pieces of evidence of interactions among these species include specific tight contacts between microlamellae of the uterine epithelium and the egg capsule, networks of fibrils between eggs and uterus, or numerous branched diverticula of the uterine wall that surround eggs or combinations of these. The contacts between uterine epithelium and eggs take place in mature and post-mature proglottids, at a period of development when eggs are newly formed and the embryos are rapidly developing. The eggs grow and develop actively in tight contact with the uterine wall. The maximum diameter of eggs increases 1.5–2 times (or 3.5–4 times in M. arionis) during development. In all species, the intimate contacts between uterus and eggs have weakened or disappeared by the time the proglottids have become gravid. The association between uterus and eggs thus appears as strong evidence of active trophic interaction (or matrotrophy) between the parent organism and developing eggs.     

Exposure to dexamethasone reduces pituitary volume and gonadotropic cell number in rat fetuses

Overexposure to glucocorticoids during the fetal period induces changes in developmental processes in various fetal tissues. The aim of this study was to investigate the effects of the synthetic glucocorticoid, dexamethasone (Dx), on pituitary volume and gonadotropic cells during a critical period of pituitary development. The effects of Dx on stereological parameters of the pituitary gland and FSH and LH cells were investigated in 19 and 21-day old fetuses. On day 16 of pregnancy, the experimental dams received 1.0 mg Dx/kg b.w. subcutaneously, followed by 0.5 mg Dx/kg b.w./day on days 17 and 18 of gestation. The control gravid females received the same volume of saline. FSH and LH cells were stained immunohistochemically by the peroxidase–antiperoxidase method (PAP). In 19-day old fetuses, exposure to Dx caused a significant decrease of pituitary volume, estimated by Cavalieri's principle. Also, the total number of FSH and LH cells per pituitary, determined by physical fractionator counting technique, was significantly reduced. These changes persisted until fetal day 21. Volume densities and numerical densities of FSH and LH cells after exposure to Dx in 19 and 21-day old fetuses remained unaffected. Our results suggest that altered stereological parameters in pituitary gland after exposure to dexamethasone in fetal period could be long-lasting.