36 research outputs found
Neuropeptide Y is up-regulated and induces antinociception in cancer-induced bone pain
Pain remains a major concern in patients suffering from metastatic cancer to
the bone and more knowledge of the condition, as well as novel treatment
avenues, are called for. Neuropeptide Y (NPY) is a highly conserved peptide
that appears to play a central role in nociceptive signaling in inflammatory
and neuropathic pain. However, little is known about the peptide in
cancer-induced bone pain. Here, we evaluate the role of spinal NPY in the
MRMT-1 rat model of cancer-induced bone pain. Our studies revealed an
up-regulation of NPY-immunoreactivity in the dorsal horn of cancer-bearing rats
17 days after inoculation, which could be a compensatory antinociceptive
response. Consistent with this interpretation, intrathecal administration of
NPY to rats with cancer-induced bone pain caused a reduction in nociceptive
behaviors that lasted up to 150 min. This effect was diminished by both Y1
(BIBO3304) and Y2 (BIIE0246) receptor antagonists, indicating that both
receptors participate in mediating the antinociceptive effect of NPY. Y1 and Y2
receptor binding in the spinal cord was unchanged in the cancer state as
compared to sham-operated rats, consistent with the notion that increased NPY
results in a net antinociceptive effect in the MRMT-1 model. In conclusion, the
data indicate that NPY is involved in the spinal nociceptive signaling of
cancer-induced bone pain and could be a new therapeutic target for patients
with this condition.Comment: 23 pages, 4 figure
Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.The Fenland Study is funded by the Medical Research Council (MC_U106179471) and
Wellcome Trust
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Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming
Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming
Identification of common variants associated with human hippocampal and intracranial volumes
Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease1, 2 and is reduced in schizophrenia3, major depression4 and mesial temporal lobe epilepsy5. Whereas many brain imaging phenotypes are highly heritable6, 7, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7)