Association between tryptophan hydroxylase-2 genotype and the antidepressant effect of citalopram and paroxetine on immobility time in the forced swim test in mice

Tryptophan hydroxylase-2 (TPH2) is the rate limiting enzyme of serotonin synthesis in the brain. The 1473G allele of the C1473G polymorphism in mTPH2 gene is associated with reduced enzyme activity and serotonin synthesis rate in the mouse brain. Here, the influence of the 1473G allele on the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs), citalopram (2.5 or 5.0 mg/kg) and paroxetine (5.0 or 10.0 mg/kg), in the forced swim test was studied using B6-1473G and B6-1473C congenic mouse lines with the 1473G (decreased TPH2 activity) or 1473C (normal TPH2 activity) alleles, respectively, transferred to the genome of C57BL/6 mouse strain. Paroxetine (5.0 or 10.0 mg/kg) and citalopram (2.5 or 5.0 mg/kg) decreased immobility time in B6-1473C mice, while both doses of paroxetine and 2.5 mg/kg of citaloprame did not alter immobility time in B6-1473G mice. However, 5.0 mg/kg of citalopram reduced immobility in B6-1473G mice. The results provided genetic evidence of moderate association between 1473G allele and reduced sensitivity to SSRIs in mice.     

Effects of LPS and serotonergic drugs on hygienic behavior in mice

Hygienic self-grooming is a behavioral adaptation for removing litter particles and pathogenic agents from animal fur and skin. We studied contribution of brain serotonin system into mechanisms regulating hygienic behavior in intact mice and mice with LPS(lipopolysaccharide)-induced sickness. A spot of fluorescent dye was applied on the back of a mouse, and the decrease in its fluorescence served as an index of fur cleaning efficiency estimated using original classifier algorithm. Agonist of 5-HT_1A receptor (8-OH-DPAT) or 5-HT_2A/2C receptor (DOI) attenuated fur cleaning at a dose of 1 mg/kg but not of 0.2 mg/kg. MAO-A inhibitor clorgyline decreased hygienic self-grooming at a dose of 10 but not of 5 mg/kg. SSRI paroxetine had no effect while fluoxetine diminished hygienic behavior at the higher dose used (20 mg/kg). Inhibitory effect of LPS treatment (50 μg/kg) on fur cleaning was not altered by administration of p-MPPI (5-HT_1A receptor antagonist, 1 mg/kg) or DOI (1 mg/kg) while 8-OH-DPAT (1 mg/kg) produced additive effect. The results suggest the involvement of 5-HT_1A and 5-HT_2A/2C brain serotonin receptors and MAO-A in the inhibition of hygienic behavior in mice. However, LPS-induced depression of fur cleaning appeared to be mediated via different mechanisms and enhanced by 5-HT_1A receptor activation.     

Application of autologous bone marrow stem cells in the therapy of spinal cord injury patients

We studied the safety and efficiency of transplantation of autologous bone marrow cells in complex therapy of patients with spinal cord injury in the late period of the disease. In control group patients, meningomyeloradiculolis was performed, while in the main group surgical treatment was supplemented by transplantation of autologous bone marrow cells. Transplantation of BM stem cells into the cyst cavity and intravenously was well tolerated, did not cause allergic or inflammatory reactions in the early and delayed periods after surgery, and did not induce the formation of ossification foci in the nervous tissue. Analysis of the neurological status by ASIA, Bartel, and Ashworth scales showed that in the main group the positive clinical dynamics was more often observed than in the control. The decrease in neurological deficit included improvement of sensory and motor activity and conducting sensory function. Thus, transplantation of autologous bone marrow cells can be a novel safe strategy for the treatment of patients in the late period after spinal trauma. __________ Translated from Kletochnye Tehnologii v Biologii i Medicine, No. 2, pp. 109–114, April, 2007     

Short- and long-term results of intensive insulin therapy in patients with severe forms of diabetes mellitus type I

Short- (3-4 week) and long-term (1-4 yrs) results of the use of intensive insulin therapy schemes were used in 37 patients with severe forms of type I diabetes mellitus. Its beneficial effect on metabolism, remaining secretory beta-cell function, the frequency and expression of hypoglycemic reactions, manifestations of peripheral and visceral neuropathy, diabetic encephalopathy was proved.     

Contribution of Dehydroepiandrosterone Sulfate and Progesterone to <Emphasis Type="Italic">In Vitro</Emphasis> Regulation of Tolerogenic Activity of IFN-α-Induced Dendritic Cells

Dehydroepiandrosterone sulfate and progesterone exhibited an immunomodulatory effect on the tolerogenic characteristics of IFN-α-induced dendritic cells. The hormone effects depended on the initial level of allostimulatory activity of dendritic cells in mixed lymphocyte culture. However, dehydroepiandrosterone sulfate signifi cantly more often stimulated allostimulatory activity by attenuating the tolerogenic properties of dendritic cells, while progesterone potentiated their tolerogenic potential. The capacity of the hormones (dehydroepiandrosterone sulfate and progesterone) to attenuate tolerogenic activity of dendritic cells was associated with reduction of FasL expression on these cells, while the increase in tolerogenic activity was associated with the increase in the percentage of CD123⁺ dendritic cells, and under conditions of modifi cation with dehydroepiandrosterone sulfate it was associated with increased B7-H1 expression. Possible contribution of indolamine-2,3-dioxygenase and prostaglandin E2 to stimulation of tolerogenic characteristics of dendritic cells modifi ed with dehydroepiandrosterone sulfate and progesterone, respectively, was demonstrated.     

D-bifunctional protein deficiency caused by splicing variants in a neonate with severe peroxisomal dysfunction and persistent hypoglycemia

D -bifunctional protein (DBP) deficiency is a rare, autosomal recessive peroxisomal enzyme deficiency resulting in a high burden of morbidity and early mortality. Patients with DBP deficiency resemble those with a severe Zellweger phenotype, with neonatal hypotonia, seizures, craniofacial dysmorphisms, psychomotor delay, deafness, blindness, and death typically within the first 2 years of life, although patients with residual enzyme function can survive longer. The clinical severity of the disease depends on the degree of enzyme deficiency. Loss-of-function variants typically result in no residual enzyme activity; however, splice variants may result in protein with residual function. We describe a full-term newborn presenting with hypotonia, seizures, and unexplained hypoglycemia, who was later found to have rickets at follow up. Rapid whole genome sequencing identified two HSD17B4 variants in trans; one likely pathogenic variant and one variant of uncertain significance (VUS) located in the polypyrimidine tract of intron 13. To determine the functional consequence of the VUS, we analyzed RNA from the patient's father with RNA-seq which showed skipping of Exon 14, resulting in a frameshift mutation three amino acids from the new reading frame. This RNA-seq analysis was correlated with virtually absent enzyme activity, elevated very-long-chain fatty acids in fibroblasts, and a clinically severe phenotype. Both variants are reclassified as pathogenic. Due to the clinical spectrum of DBP deficiency, this provides important prognostic information, including early mortality. Furthermore, we add persistent hypoglycemia to the clinical spectrum of the disease, and advocate for the early management of fat-soluble vitamin deficiencies to reduce complications.