Body mass index and vaccine responses following influenza vaccination during pregnancy

Background and AimsInfluenza vaccination is recommended by the World Health Organisation for pregnant women, offering the dual benefit of protecting pregnant women and their newborn infants against influenza infection. Various factors can influence vaccine immunogenicity, with obesity being one factor implicated in varied responses. This study aimed to investigate the impact of body mass index (BMI) on vaccine responses following influenza vaccination during pregnancy.MethodsPregnant women attending the Women’s and Children’s Hospital in South Australia during 2014–2016 were invited to participate. Participant’s clinical and demographic factors were recorded prior to administration of licensed seasonal influenza vaccination. Blood samples were collected before and one month post-vaccination to measure antibody responses by haemagglutination inhibition (HI) assay. Seroprotection was defined as a post-vaccination HI titre ≥ 1:40. Regression models assessed associations with failure to achieve seroprotective antibodies to H1, H3, and B influenza strains.ResultsA total of 96 women were enrolled in the study at a median gestation of 22 weeks with a BMI range of 18–49 kg/m². Paired sera samples were available for 90/96 (94%). Most pregnant women (72/90, 80%) demonstrated seroprotective antibody titres to all three influenza vaccine antigens (A(H1N1)pdm09, A(H3N2), B/Yamagata) following vaccination. Compared with women with BMI < 30 kg/m², those with high BMI were less likely to fail to achieve seroprotective antibodies, however this was not statistically significant (RR 0.42, 95% CI 0.11–1.68; p = 0.22). A greater proportion of women vaccinated during their second (47/53, 93%) or third trimester (18/25, 72%) demonstrated seroprotection to all three vaccine antigens following vaccination compared with women vaccinated during their first trimester (7/12, 58%).ConclusionHigh BMI did not impair seroprotection levels following influenza vaccination in pregnant women. Gestation at vaccination may be an important consideration for optimising vaccine protection for pregnant women and their newborns. Further assessment of first trimester influenza vaccine responses is warranted.     

Versatile applicability of a grid-based CYP3A4 Template to understand the interacting mechanisms with the small-size ligands; part 3 of CYP3A4 Template study

Modes of interactions of small ligands with CYP3A4 have been defined using the Template established in our previous studies (DMPK. 34: 113–125 2019 and 34 351–364 2019). Interactions of polyaromatic hydrocarbons such as benzo[a]pyrene, pyrene and dibenzo[a,j]acridine were refined with the idea of Right-side movement of ligands at Rings A and B of Template. Expected formation of metabolites from the placements faithfully matched with experimentally observed sites of their metabolisms and also with preferred orders of regio-isomeric metabolite abundances in recombinant CYP3A4 system. In comparison of CYP3A4-ligand data with the placements on simulations, a futile sitting of non-substituted and free rotatable phenyl structures was suggested as a cause of poor oxidations of the phenyl parts of CYP3A4 ligands. These data were in turn indicative of the role of the rotation-ceasing action for the function. Typical inhibitors, ketoconazole, nicardipine, mibefradil and GF-I-1 shared mutuality on their sittings, in which the inhibitor molecules hold a CYP3A4 residue from dual sides on Template. In addition, clotrimazole would be stuck between facial- and rear-side walls of CYP3A4 and interact with ferric iron through nitrogen atom of the imidazole part. These data offered structural bases of CYP3A4-inhibitory actions of ligands.     

Investigation of age-related differences in an adapted Hayling task

The Hayling task is traditionally used to assess activation and inhibitory processes efficiency among various populations, such as elderly adults. However, the classical design of the task may also involve the influence of strategy use and efficiency of sentence processing in the possible differences between individuals. Therefore, the present study investigated activation and inhibitory processes in aging with two formats of an adapted Hayling task designed to reduce the involvement of these alternative factors. Thirty young adults (M = 20.7 years) and 31 older adults (M = 69.6 years) performed an adapted Hayling task including a switching block (i.e., unblocked design) in addition to the classical task (i.e., blocked design), and the selection of the response between two propositions. The results obtained with the classical blocked design showed age-related deficits in the suppression sections of the task but also in the initiation ones. These findings can be explained by a co-impairment of both inhibition and activation processes in aging. The results of the unblocked Hayling task, in which strategy use would be reduced, confirmed this age-related decline in both activation and inhibition processes. Moreover, significant correlations between the unblocked design and the Trail Making Test revealed that flexibility is equally involved in the completion of both sections of this design. Finally, the use of a forced-response choice offers a format that is easy to administer to people with normal or pathological aging. This seems particularly relevant for these populations in whom the production of an unrelated word often poses problems.     

Stratifying chronic stroke patients based on the influence of contralesional motor cortices: An inter-hemispheric inhibition study

ObjectiveA recent “bimodal-balance recovery” model suggests that contralesional influence varies based on the amount of ipsilesional reserve: inhibitory when there is a large reserve, but supportive when there is a low reserve. Here, we investigated the relationships between contralesional influence (inter-hemispheric inhibition, IHI) and ipsilesional reserve (corticospinal damage/impairment), and also defined a criterion separating subgroups based on the relationships.MethodsTwenty-four patients underwent assessment of IHI using Transcranial Magnetic Stimulation (ipsilateral silent period method), motor impairment using Upper Extremity Fugl-Meyer (UEFM), and corticospinal damage using Diffusion Tensor Imaging and active motor threshold. Assessments of UEFM and IHI were repeated after 5-week rehabilitation (n = 21).ResultsRelationship between IHI and baseline UEFM was quadratic with criterion at UEFM 43 (95%conference interval: 40–46). Patients less impaired than UEFM = 43 showed stronger IHI with more impairment, whereas patients more impaired than UEFM = 43 showed lower IHI with more impairment. Of those made clinically-meaningful functional gains in rehabilitation (n = 14), more-impaired patients showed further IHI reduction.ConclusionsA criterion impairment-level can be derived to stratify patient-subgroups based on the bimodal influence of contralesional cortex. Contralesional influence also evolves differently across subgroups following rehabilitation.SignificanceThe criterion may be used to stratify patients to design targeted, precision treatments.     

Prenatal immune activation potentiates endocannabinoid-related plasticity of inhibitory synapses in the hippocampus of adolescent rat offspring

There is strong evidence that immune activation from prenatal infection increases the risk for offspring to develop schizophrenia. The endocannabinoid (eCB) system has been implicated in the pathophysiology of schizophrenia while models of cortical dysfunction postulate an imbalance between neuronal excitation and inhibition in the disorder. The current study examined the impact of prenatal immune activation on eCB-mediated inhibitory mechanisms. We compared two forms of eCB-related plasticity of evoked inhibitory postsynaptic currents, namely depolarization-induced suppression of inhibition (DSI) and metabotropic glutamate receptor-induced long term depression (mGluR-iLTD), in both the dorsal and ventral hippocampus between adolescent offspring from rat dams that received either saline or bacterial lipopolysaccharide (LPS) during pregnancy. Compared to prenatal saline offspring, prenatal LPS offspring displayed prolonged DSI and stronger mGluR-iLTD in the dorsal and ventral hippocampus, respectively. The sensitivity of mGluR-iLTD to the CB1 receptor antagonist AM251 was also lower in the dorsal hippocampus of prenatal LPS compared to prenatal saline offspring. Testing whether changes in eCB receptor signaling or levels could contribute to these changes in inhibitory transmission, we found region specific increases in 2-arachidonoylglycerol-stimulated signaling and in basal and mGluR-induced levels of anandamide in prenatal LPS offspring when compared to prenatal saline offspring. Our findings indicate that prenatal immune activation can lead to long-term changes in eCB-related plasticity of hippocampal inhibitory synaptic transmission in adolescent rat offspring. Perturbation of the eCB system resulting from prenatal immune activation could represent a mechanism linking early life immune events to the development of psychopathology in adolescence.     

胆红素代谢酶UGT1A1介导的中药不良反应研究进展

尿苷二磷酸葡萄糖醛酸转移酶1A1（UGT1A1）是哺乳动物体内分布的一种重要的Ⅱ相代谢酶,其不仅介导了大量临床药物、毒物的代谢清除,还是机体参与内源性毒性物质胆红素代谢清除的唯一代谢酶。药物或食品中的化学成分对UGT1A1的强烈抑制会引发多种不良反应,如药物/草药-药物相互作用、高胆红素血症、肝功能异常及神经毒性等。近年来,研究发现许多草药提取物及其化学成分可通过强效抑制UGT1A1引发药物-草药相互作用等不良反应。结合药物代谢及药物毒理学相关领域的新近研究进展,系统总结了UGT1A1抑制剂筛选与评价常用方法,以及中草药化学成分对UGT1A1抑制作用的研究进展。上述信息对于临床安全合理的使用中草药,尤其是在中西药联用或中药方剂使用过程中尽可能避免因UGT1A1抑制引发的不良反应,具有重要指导意义。     

How specific are inhibitory deficits to obsessive-compulsive disorder? A neurophysiological comparison with panic disorder

ObjectiveImpaired inhibition may perpetuate repetitive symptoms in obsessive-compulsive disorder (OCD), however OCD-specific deficits have yet to be established. We investigated neural correlates of inhibition in OCD vs. healthy and anxious controls.MethodsERPs and reaction times (RTs) were compared between participants with OCD (n = 20), panic disorder (PD; n = 20) and healthy controls (HCs; n = 20) during an adapted Go/NoGo task, which manipulated inhibitory difficulty.ResultsA classic P3 NoGo anteriorisation effect occurred across groups. Both clinical groups showed RT impairment, and similar topographical anomalies of several (P2, N2 and P3) ERP components. Notably, both clinical groups lacked the strong frontally maximal N2 component topography seen in the HCs, across stimuli. Additionally, with increasing inhibitory difficulty, N2 latency increased in HCs but not in the clinical groups.ConclusionsUnexpectedly, ERP and behavioural anomalies during inhibition in OCD were not qualitatively different to those in PD, but were generally more severe. Common general and inhibitory deficits may underlie intrusive mental phenomena in both conditions.SignificanceThis first ERP response inhibition study in OCD to include anxious controls disconfirmed hypotheses regarding OCD-specific inhibitory deficits, indicating the importance of comparing OCD to other conditions, to evaluate neurobiological models.     

Distinct profiles of behavioral inhibition and activation system sensitivity in unipolar vs. bipolar mood disorders

Psychiatric outpatients with mood disorders (n=275) and community controls (n=733) completed a measure of Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS) sensitivity; psychiatric outpatients also completed measures of mood symptom severity. All patients scored higher on BIS compared to controls; patients with bipolar disorders scored higher on BAS scales compared to patients with depressive disorders. BIS and BAS demonstrated unique patterns of association with mood symptoms. Results support the clinical utility of the BIS/BAS.     

Hoarding disorder and obsessive–compulsive disorder show different patterns of neural activity during response inhibition

Although hoarding disorder (HD) has been historically conceptualized as a subtype or dimension of obsessive–compulsive disorder (OCD), preliminary evidence suggests that these two disorders have distinct neural underpinnings. The aim of the present study was to compare the hemodynamic responses of HD patients, OCD patients, and healthy controls (HC) during response inhibition on a high-conflict Go/NoGo task that has previously proved sensitive to OCD. Participants comprised 24 HD patients, 24 OCD patients, and 24 HCs who completed a Go/NoGo task during functional magnetic resonance imaging (fMRI). Although behavioral data showed no difference among the groups in Go/NoGo task performance, significant differences in hemodynamic activity were noted. During correct rejects (successful response inhibition), HD patients showed greater right precentral gyrus activation, whereas OCD patients exhibited greater right orbitofrontal activation, as assessed using a region of interest approach. During errors of commission (response inhibition failures), OCD patients, but not HD patients, were characterized by excessive activity in left and right orbitofrontal gyrus. The present results lend further support to the biological distinction between HD and OCD, and they are consistent with previous research suggesting frontal hypoactivity in HD patients during hoarding-unrelated tasks.     

Early markers of neural dysfunction and compensation: A model from minimal hepatic encephalopathy

ObjectiveThe Inhibitory Control Task (ICT) was used to detect minimal hepatic encephalopathy (MHE). ICT assesses attention, working memory and inhibition by evaluating performance in detect, go and nogo trials, respectively. The event-related potentials (ERPs) elicited by the ICT provide insight into neural mechanisms underlying the cognitive alterations associated with MHE.MethodsThe performance and the ERPs elicited by ICT were measured in 31 patients with cirrhosis (13 with and 18 without MHE) and in 17 controls. The latency and amplitude of the N2, P3a, P3b and nogo-P3 were compared among the groups.ResultsPatients with MHE performed worse in all ICT trials compared to patients without MHE and controls. Cirrhotic patients, both with and without MHE, displayed a reduction in P3a amplitude, selectively in the detect trials. Patients without MHE exhibited greater N2 and nogo-P3 amplitudes compared to patients with MHE and controls.ConclusionsBoth patients with and without MHE displayed neural alterations reflecting attentional deficits (i.e., P3a attenuation). However, patients without MHE coped with such dysfunctions by recruiting compensatory neural mechanisms, as suggested by the enhancement of the nogo-P3 and N2 amplitudes coupled with a normal ICT performance.SignificanceThe study suggests how initial brain dysfunction might be compensated for by recruitment of additional neurocognitive resources.