Photoparoxysmal response (PPR) is an EEG trait of spike and spike-wave discharges in response to photic stimulation that is closely linked to idiopathic generalized epilepsy (IGE). In our previous studies we showed that PPR is associated with functional alterations in the occipital and frontal cortices. The aim of the present study was to determine structural changes associated with PPR. For this purpose we analysed the cortical thickness as derived from T1 MRI images in PPR-positive-subjects (n = 12; 15.5 ± 8.6 years; 4 males), PPR-positive-IGE-patients (n = 12; 14.9 ± 2.7 years; 4 males) and compared these groups with a group of PPR-negative-healthy-controls (HC, n = 17; 15.3 ± 3.6 years; 6 males). Our results revealed an increase of cortical thickness in the occipital, frontal and parietal cortices bilaterally in PPR-positive-subjects in comparison to HC. Moreover PPR-positive-subjects presented a significant decrease of cortical thickness in the temporal cortex in the same group contrast. IGE patients exhibited lower cortical thickness in the temporal lobe bilaterally and in the right paracentral region in comparison to PPR-positive-subjects. Our study demonstrates structural changes in the occipital lobe, frontoparietal regions and temporal lobe, which also show functional changes associated with PPR. Patients with epilepsy present changes in the temporal lobe and supplementary motor area. 相似文献
The Arrhenius parameters of the propagation rate coefficient, kp, are determined via the pulsed laser polymerization—size exclusion chromatography (PLP‐SEC) method for five branched acrylates (tert‐butyl (tBA), isobornyl (iBoA), benzyl (BnA), 2‐ethylhexyl (EHA), and 2‐propylheptyl acrylate (PHA)) in 1 m solution in butyl acetate (BuAc) to complete the series, published by Haehnel et al. in 2014, of branched acrylates (isononyl (INA‐A), tridecyl (TDA‐A and TDN‐A), heptadecyl (C17A), and henicosyl acrylate (C21A)) in solution that do not show a trend in kp. Furthermore, the propagation rate coefficients of the branched acrylates in 1 m solution are critically compared with the branched acrylates in bulk as well as branched methacrylates. A summary of the trends and family‐type behavior for the linear and branched (meth)acrylates as well as methacrylates with cyclic ester side chains is provided. For the branched acrylates in 1 m solution, no clear trends of the propagation rate coefficients, kp, or Arrhenius parameters A and EA are detectable and—in contrast to the corresponding methacrylates—there is no family‐type behavior observed in solution as well as in bulk.
Neoliberal ideology champions privatization, personal responsibility, and entrepreneurship, and public health practice under neoliberalism channels this individualized focus. Though this ‘new public health’ may be seen as a liberalizing practice of governance, in which individuals are free to maximize health and autonomy, this privatization also embeds responsibility within the individual without regard to existing or resulting inequalities. This paper examines the presence of neoliberal ideology in the narratives and subjectivities as it relates to HIV prevention in the lives of young gay and bisexual men living in New York City. We also seek to further the critique of neoliberalism in HIV prevention. The men often saw themselves or others as rational, autonomous agents, yet there were also clear instances where social and structural factors were at play. These factors influenced a subjectivity existing outside the narrow, atomistic framework of neoliberalism. Implicit moral hierarchies arose from notions of personal responsibility and recklessness, pitting men against each other and potentially inhibiting social and community prevention efforts. Further, neoliberal ideology obscured the social and structural mechanisms at play, such as racial inequality, economic inequality, homophobia, and sexual shaming. In contrast to the ideology of neoliberal public health, we must explicitly consider the resources, opportunities, and social conditions that shape autonomy and subjectivity among young gay and bisexual men. 相似文献
The antimalarial drug chloroquine has been suggested as a treatment for Ebola virus infection. Chloroquine inhibited virus replication in vitro, but only at cytotoxic concentrations. In mouse and hamster models, treatment did not improve survival. Chloroquine is not a promising treatment for Ebola. Efforts should be directed toward other drug classes. 相似文献
Impulsivity is an important feature of multiple neuropsychiatric disorders, and individual variation in the degree of inherent impulsivity could play a role in the generation or exacerbation of problematic behaviors. Serotonin (5-HT) actions at the 5-HT2AR receptor (5-HT2AR) promote and 5-HT2AR antagonists suppress impulsive action (the inability to withhold premature responses; motor impulsivity) upon systemic administration or microinfusion directly into the medial prefrontal cortex (mPFC), a node in the corticostriatal circuit that is thought to play a role in the regulation of impulsive action. We hypothesized that the functional capacity of the 5-HT2AR, which is governed by its expression, localization, and protein/protein interactions (eg, postsynaptic density 95 (PSD95)), may drive the predisposition to inherent impulsive action. Stable high-impulsive (HI) and low-impulsive (LI) phenotypes were identified from an outbred rodent population with the 1-choice serial reaction time (1-CSRT) task. HI rats exhibited a greater head-twitch response following administration of the preferential 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and were more sensitive to the effects of the selective 5-HT2AR antagonist M100907 to suppress impulsive action relative to LI rats. A positive correlation was observed between levels of premature responses and 5-HT2AR binding density in frontal cortex ([3H]-ketanserin radioligand binding). Elevated mPFC 5-HT2AR protein expression concomitant with augmented association of the 5-HT2AR with PSD95 differentiated HI from LI rats. The observed differential sensitivity of HI and LI rats to 5-HT2AR ligands and associated distinct 5-HT2AR protein profiles provide evidence that spontaneously occurring individual differences in impulsive action reflect variation in the cortical 5-HT2AR system. 相似文献
OBJECTIVE: Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects approximately 40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation-AAU-of a multisystem, inflammatory, genetically complex disease, AS. METHODS: Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined. RESULTS: As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA-B). Strong linkage was seen at a region on chromosome 9p21-9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23-1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS. CONCLUSION: This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21-9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases. 相似文献
Refeeding studies were performed on male Sprague-Dawley rats that had been fasted for 72 hours to characterize the specific effect of carbohydrates on T3 metabolism. Fasting is associated with low serum T3 levels and reduced hepatic T4-5′-deiodinase activity (T4 → T3). Carbohydrate refeeding (20% glucose in H2O) normalized both the serum T3 and hepatic T4-5′-deiodinase activity within 72 hours, whereas fat (10% Intralipid) and amino acids (5.5% Travasol) had no effect after 72 hours of refeeding. Refeeding with a mixed diet (Purina Rodent Chow) occasionally reactivated hepatic T4-5′-deiodinase activity, however, normalization of enzyme activity did not occur within 72 hours. Time-course studies demonstrated that hepatic T4-5′-deiodinase activity was not stimulated until 24 hours of carbohydrate refeeding had elapsed and that 48 to 72 hours were required for normalization. The mechanism of the carbohydrate-refeeding effect was characterized by analyzing the alterations in the kinetics Michaelis constant (Km) and maximal velocity (Vmax) of hepatic T4-5′-deiodinase and the changes in the hepatic content of nonprotein sulfhydryl groups (NP-SH), which are possible enzyme cofactors. There was no relationship between the hepatic enzyme activity and the NP-SH response during the refeeding period. Moreover, homogenate enrichment with the sulfhydryl compound, dithiothreitol (DTT), did not alter the temporal profile of the enzyme recovery consequent to refeeding. Refeeding with carbohydrate had no effect on the Km of hepatic T4-5′-deiodinase but had a significant effect on the Vmax. Refeeding with glucose induced an increase in enzyme Vmax over the time-course, which became significant (P < 0.005) compared with the enzyme Vmax of the fasted group by 72 hours. During carbohydrate refeeding, a positive correlation was noted between the ratio of serum insulin to glucagon and hepatic-T4-5′-deiodinase activity (r = 0.82, P < 0.001), whereas a negative correlation was found between enzyme activity and the ratio of serum glucose to insulin (r = ?0.9, P < 0.001). Furthermore these correlations also applied during refeeding with fat and amino acids. Thus, the carbohydrate-refeeding reactivation of hepatic T4-5′-deiodinase in fasted rats is a delayed process that requires a refeeding period equivalent to the duration of fasting for enzyme normalization to occur. Recovery was due to an increase in the hepatic content of active enzyme rather than an enhancement of cofactor supply. The glucoregulatory hormones, glucagon and insulin, may modulate these carbohydrate induced changes on hepatic T4-5′-deiodinase. Moreover, the differential reaction of hepatic T4-5′-deiodinase to specific nutriments may be mediated by these glucoregulatory hormones. 相似文献
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with continuous neuronal loss. Treatment of clinical progression remains challenging due to lack of insights into inflammation-induced neurodegenerative pathways. Here, we show that an imbalance in the neuronal receptor interactome is driving glutamate excitotoxicity in neurons of MS patients and identify the MS risk–associated metabotropic glutamate receptor 8 (GRM8) as a decisive modulator. Mechanistically, GRM8 activation counteracted neuronal cAMP accumulation, thereby directly desensitizing the inositol 1,4,5-trisphosphate receptor (IP3R). This profoundly limited glutamate-induced calcium release from the endoplasmic reticulum and subsequent cell death. Notably, we found Grm8-deficient neurons to be more prone to glutamate excitotoxicity, whereas pharmacological activation of GRM8 augmented neuroprotection in mouse and human neurons as well as in a preclinical mouse model of MS. Thus, we demonstrate that GRM8 conveys neuronal resilience to CNS inflammation and is a promising neuroprotective target with broad therapeutic implications. 相似文献