Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.
Mutations in the doublecortin gene (DCX) in humans cause malformation of the cerebral neocortex. Paradoxically, genetic deletion of Dcx in mice does not cause neocortical malformation. We used electroporation of plasmids encoding short hairpin RNA to create interference (RNAi) of DCX protein in utero, and we show that DCX is required for radial migration in developing rat neocortex. RNAi of DCX causes both cell-autonomous and non-cell autonomous disruptions in radial migration, and creates two disruptions in neocortical development. First, many neurons prematurely stop migrating to form subcortical band heterotopias within the intermediate zone and then white matter. Second, many neurons migrate into inappropriate neocortical lamina within normotopic cortex. In utero RNAi can therefore be effectively used to study the specific cellular roles of DCX in neocortical development and to produce an animal model of double cortex syndrome.
Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon whereby brief ischemic exposure confers tolerance to a subsequent ischemic challenge. IPC has not been studied selectively in CNS white matter (WM), although stroke frequently involves WM. We determined whether IPC is present in WM and, if so, its mechanism. We delivered a brief in vivo preconditioning ischemic insult (unilateral common carotid artery ligation) to 12-to 14-week-old mice and determined WM ischemic vulnerability [oxygen-glucose deprivation (OGD)] 72 h later, using acutely isolated optic nerves (CNS WM tracts) from the preconditioned (ipsilateral) and control (contralateral) hemispheres. Functional and structural recovery was assessed by quantitative measurement of compound action potentials (CAPs) and immunofluorescent microscopy. Preconditioned mouse optic nerves (MONs) showed better functional recovery after OGD than the non-preconditioned MONs (31 Ϯ 3 vs 17 Ϯ 3% normalized CAP area, p Ͻ 0.01). Preconditioned MONs also showed improved axon integrity and reduced oligodendrocyte injury compared with non-preconditioned MONs. Toll-like receptor-4 (TLR4) and type 1 interferon receptor (IFNAR1), key receptors in innate immune response, are implicated in gray matter preconditioning. Strikingly, IPC-mediated WM protection was abolished in both TLR4 Ϫ/Ϫ and IFNAR1 Ϫ/Ϫ mice. In addition, IPC-mediated protection in WM was also abolished in IFNAR1 fl/fl LysM cre , but not in IFNAR1 fl/fl control, mice. These findings demonstrated for the first time that IPC was robust in WM, the phenomenon being intrinsic to WM itself. Furthermore, WM IPC was dependent on innate immune cell signaling pathways. Finally, these data demonstrated that microglial-specific expression of IFNAR1 plays an indispensable role in WM IPC.
In recent years there has been an increase in the use of traditional Asian medicines. It is estimated that 30% of the US population is currently using some form of homeopathic or alternative therapy at a total cost of over $13 billion annually. Herbal medications are claimed and widely believed to be beneficial; however, there have been reports of acute and chronic intoxications resulting from their use. This study characterizes a random sampling of Asian medicines as to the content of arsenic, mercury, and lead. Traditional herbal remedies were purchased in the USA, Vietnam, and China. The Asian remedies evaluated contained levels of arsenic, lead, and mercury that ranged from toxic (49%) to those exceeding public health guidelines for prevention of illness (74%) when consumed according to the directions given in or on the package. Heavy metals contained in Asian remedies may cause illness of unknown origin and result in the consumption of health care resources that are attributable to other causes. The public health hazards of traditional herbal Asian remedies should be identified and disclosed.
Ischemic preconditioning (IPC) is an experimental phenomenon in which a subthreshold ischemic insult applied to the brain reduces damage caused by a subsequent more severe ischemic episode. Identifying key molecular and cellular mediators of IPC will provide critical information needed to develop novel therapies for stroke. Here we report that the transcriptomic response of acutely isolated preconditioned cortical microglia is dominated by marked upregulation of genes involved in cell cycle activation and cellular proliferation. Notably, this transcriptional response occurs in the absence of cortical infarction. We employed ex vivo flow cytometry, immunofluorescent microscopy, and quantitative stereology methods on brain tissue to evaluate microglia proliferation following IPC. Using cellular colocalization of microglial (Iba1) and proliferation (Ki67 and BrdU) markers, we observed a localized increase in the number of microglia and proliferating microglia within the preconditioned hemicortex at 72, but not 24, hours post‐IPC. Our quantification demonstrated that the IPC‐induced increase in total microglia was due entirely to proliferation. Furthermore, microglia in the preconditioned hemisphere had altered morphology and increased soma volumes, indicative of an activated phenotype. Using transgenic mouse models with either fractalkine receptor (CX3CR1)‐haploinsufficiency or systemic type I interferon signaling loss, we determined that microglial proliferation after IPC is dependent on fractalkine signaling but independent of type I interferon signaling. These findings suggest there are multiple distinct targetable signaling pathways in microglia, including CX3CR1‐dependent proliferation that may be involved in IPC‐mediated protection.
Background Poststroke fatigue (PSF) is common, but the biological basis of this fatigue is unknown. We explored the possibility that PSF is related to systemic inflammation by investigating polymorphisms in 2 genes that affect the immune response. Methods In a substudy of a larger trial that evaluated the role of the immune response on stroke outcome, fatigue was assessed at 30, 90, 180, and 365 days after ischemic stroke using the Fatigue Assessment Scale. Subjects were genotyped for 3 single nucleotide polymorphisms, one in the interleukin-1 receptor antagonist gene (IL1RN; rs4251961, a T/C substitution) and two in the in toll-like receptor-4 (TLR4) gene (1063 A/G [Asp299Gly] rs4986790 and 1363 C/T [Thr399Ile] rs4986791). Results Of the 39 participants, 22 (56%) endorsed fatigue during the study. The degree of fatigue was remarkably constant over time and independent of stroke outcome. The C allele of the rs4251961 single nucleotide polymorphism (SNP) in IL1RN was associated with self-reported fatigue (P = .03), whereas the cosegregating polymorphisms in TLR4 were associated with lower levels of fatigue (P = .04). Conclusions SNPs in 2 genes with opposing effects on inflammatory immune responses were significantly, but differentially, associated with PSF. These findings suggest a direct link between immune signaling dysregulation and PSF.
Few studies have followed pregnant women prospectively to examine the impact of violence on birth outcome. We included such an assessment in a prospective study of pregnancy among low-income women. Nurses and social workers interviewed pregnant women (n = 364) and asked if they had been the object of violence since they became pregnant. These prenatal interviews were linked with information from perinatal records and with birth and death information. In total, 15.9% of women in the study indicated they had been abused since they became pregnant. Abused women were more likely to be teenagers and to have partners who were teenagers. Abused women were more likely to be primiparous, to smoke during pregnancy and to have physical problems related to stress. Women battered during pregnancy were more likely to suffer fetal distress or fetal death [Odds Ratio (OR) 3.68; 95% Confidence Interval (CI) 1.36, 9.94], even after adjusting for maternal age and smoking status. Finally the infants of abused women were more likely to remain in hospital after their mother's discharge (OR: 3.75; 95% CI: 1.38, 10.23). Our findings suggest that fetuses may be compromised in utero, as shown by higher rates of fetal distress and fetal death found among women physically abused during pregnancy.
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