121 research outputs found
Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine
Background
Non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion.
Methodology/Principal Findings
A single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion.
Conclusions/Significance
The present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ
Heritability of a skeletal biomarker of biological aging
Changes in the skeletal system, which include age-related bone and joint remodeling, can potentially be used as a biomarker of biological aging. The aim of the present study was to investigate the extent and mode of inheritance of skeletal biomarker of biological agingâosseographic score (OSS), in a large sample of ethnically homogeneous pedigrees. The investigated cohort comprised 359 Chuvashian families and included 787 men aged 18â89Â years (mean 46.9) and 723 women aged 18â90Â years (mean 48.5). The TOSS - transformed OSS standardized in 5-year age groups for each sex, was analyzed as a BA index. We evaluated familial correlations and performed segregation analysis. Results of our study suggest the familial aggregations of TOSS variation in the Chuvashian pedigrees. In a segregation analysis we found a significant major gene (MG) effect in the individualâs TOSS with a dominant most parsimonious model (H2Â =Â 0.32). Genetic factors (MG genotypes) explained 47% of the residual OSS variance after age adjustment and after including sex-genotype interaction, they explained 52% of the residual variance. Results of our study also indicated that the inherited difference in the skeletal aging pattern in men lies mostly in the rate of aging, but in women in the age of the onset of the period of visible skeletal changes
Photographic mark-recapture analysis of clustered mammal-eating killer whales around the Aleutian Islands and Gulf of Alaska
International Consensus Statement on Rhinology and Allergy: Rhinosinusitis
Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICARâRS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICARâRSâ2021 as well as updates to the original 140 topics. This executive summary consolidates the evidenceâbased findings of the document. Methods: ICARâRS presents over 180 topics in the forms of evidenceâbased reviews with recommendations (EBRRs), evidenceâbased reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICARâRSâ2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidenceâbased management algorithm is provided. Conclusion: This ICARâRSâ2021 executive summary provides a compilation of the evidenceâbased recommendations for medical and surgical treatment of the most common forms of RS
Noradrenergic Abnormalities in the Central Nervous System of Seizure-Naive Genetically Epilepsy-Prone Rats
Can generalism help revive the primary healthcare vision?
It is more than 30 years since the World Health Organization (WHO) called for a paradigm-shift to a model of primary healthcare: a vision of creating âHealth for Allâ through âputting people at the centre of health careâ.1 Since then, we have seen significant advances in health and healthcare. People are âhealthier, wealthier and liver longer today than 30 years agoâ.2 Economic growth, increased resources, and rapid expansion of scientific knowledge and technological advancement have all contributed.2 But we see growing concerns that the primary healthcare vision is being lost, with a worrying impact on our current systems of healthcare.2 The burden of care on individual patients is increasing.3 An excessive focus on disease, fragmentation of care and unregulated commercialization2 has been linked to inefficiency, ineffectiveness and inequity.4 All against a background of changing health needs, notably a rise in the burden of chronic, complex illness.2,5 WHO calls for a revival and strengthening of the primary healthcare vision to meet modern needs, refocusing health services around people.2 Generalism describes an approach to care which is person-, not disease-focused; continuous, not episodic; integrates biotechnical and biographical understanding of illness; and promotes health as a resource for living, and not an end in itself.6 So can generalism help revive the primary healthcare vision
Identification and characterization of novel parathyroid-specific transcription factor Glial Cells Missing Homolog B (GCMB) mutations in eight families with autosomal recessive hypoparathyroidism.
GCMB is a member of the small transcription factor family GCM (glial cells missing), which are important regulators of development, present in vertebrates and some invertebrates. In man, GCMB encodes a 506 amino acid parathyroid gland-specific protein, mutations of which have been reported to cause both autosomal dominant and autosomal recessive hypoparathyroidism. We ascertained 18 affected individuals from 12 families with autosomal recessive hypoparathyroidism and have investigated them for GCMB abnormalities. Four different homozygous germline mutations were identified in eight families that originate from the Indian Subcontinent. These consisted of a novel nonsense mutation R39X; a missense mutation, R47L in two families; a novel missense mutation, R110W; and a novel frameshifting deletion, I298fsX307 in four families. Haplotype analysis, using polymorphic microsatellites from chromosome 6p23-24, revealed that R47L and I298fsX307 mutations arose either as ancient founders, or recurrent de novo mutations. Functional studies including: subcellular localization studies, EMSAs and luciferase-reporter assays, were undertaken and these demonstrated that: the R39X mutant failed to localize to the nucleus; the R47L and R110W mutants both lost DNA-binding ability; and the I298fsX307 mutant had reduced transactivational ability. In order to gain further insights, we undertook 3D-modeling of the GCMB DNA-binding domain, which revealed that the R110 residue is likely important for the structural integrity of helix 2, which forms part of the GCMB/DNA binding interface. Thus, our results, which expand the spectrum of hypoparathyroidism-associated GCMB mutations, help elucidate the molecular mechanisms underlying DNA-binding and transactivation that are required for this parathyroid-specific transcription factor
Identification and characterization of novel parathyroid-specific transcription factor Glial Cells Missing Homolog B (GCMB) mutations in eight families with autosomal recessive hypoparathyroidism.
GCMB is a member of the small transcription factor family GCM (glial cells missing), which are important regulators of development, present in vertebrates and some invertebrates. In man, GCMB encodes a 506 amino acid parathyroid gland-specific protein, mutations of which have been reported to cause both autosomal dominant and autosomal recessive hypoparathyroidism. We ascertained 18 affected individuals from 12 families with autosomal recessive hypoparathyroidism and have investigated them for GCMB abnormalities. Four different homozygous germline mutations were identified in eight families that originate from the Indian Subcontinent. These consisted of a novel nonsense mutation R39X; a missense mutation, R47L in two families; a novel missense mutation, R110W; and a novel frameshifting deletion, I298fsX307 in four families. Haplotype analysis, using polymorphic microsatellites from chromosome 6p23-24, revealed that R47L and I298fsX307 mutations arose either as ancient founders, or recurrent de novo mutations. Functional studies including: subcellular localization studies, EMSAs and luciferase-reporter assays, were undertaken and these demonstrated that: the R39X mutant failed to localize to the nucleus; the R47L and R110W mutants both lost DNA-binding ability; and the I298fsX307 mutant had reduced transactivational ability. In order to gain further insights, we undertook 3D-modeling of the GCMB DNA-binding domain, which revealed that the R110 residue is likely important for the structural integrity of helix 2, which forms part of the GCMB/DNA binding interface. Thus, our results, which expand the spectrum of hypoparathyroidism-associated GCMB mutations, help elucidate the molecular mechanisms underlying DNA-binding and transactivation that are required for this parathyroid-specific transcription factor
- âŠ