Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age

Background Maternal inflammation during pregnancy increases the risk for offspring psychiatric disorders and other adverse long-term health outcomes. The influence of inflammation on the developing fetal brain is hypothesized as one potential mechanism but has not been examined in humans. Methods Participants were adult women (N = 86) who were recruited during early pregnancy and whose offspring were born after 34 weeks’ gestation. A biological indicator of maternal inflammation (interleukin-6) that has been shown to influence fetal brain development in animal models was quantified serially in early, mid-, and late pregnancy. Structural and functional brain magnetic resonance imaging scans were acquired in neonates shortly after birth. Infants’ amygdalae were individually segmented for measures of volume and as seeds for resting state functional connectivity. At 24 months of age, children completed a snack delay task to assess impulse control. Results Higher average maternal interleukin-6 concentration during pregnancy was prospectively associated with larger right amygdala volume and stronger bilateral amygdala connectivity to brain regions involved in sensory processing and integration (fusiform, somatosensory cortex, and thalamus), salience detection (anterior insula), and learning and memory (caudate and parahippocampal gyrus). Larger newborn right amygdala volume and stronger left amygdala connectivity were in turn associated with lower impulse control at 24 months of age, and mediated the association between higher maternal interleukin-6 concentrations and lower impulse control. Conclusions These findings provide new evidence in humans linking maternal inflammation during pregnancy with newborn brain and emerging behavioral phenotypes relevant for psychiatric disorders. A better understanding of intrauterine conditions that influence offspring disease susceptibility is warranted to inform targeted early intervention and prevention efforts

What Is Causing the Reduced Drug-Placebo Difference in Recent Schizophrenia Clinical Trials and What Can be Done About It?

On September 18, 2007, a collaborative session between the International Society for CNS Clinical Trials and Methodology and the International Society for CNS Drug Development was held in Brussels, Belgium. Both groups, with membership from industry, academia, and governmental and nongovernmental agencies, have been formed to address scientific, clinical, regulatory, and methodological challenges in the development of central nervous system therapeutic agents. The focus of this joint session was the apparent diminution of drug-placebo differences in recent multicenter trials of antipsychotic medications for schizophrenia. To characterize the nature of the problem, some presenters reported data from several recent trials that indicated higher rates of placebo response and lower rates of drug response (even to previously established, comparator drugs), when compared with earlier trials. As a means to identify the possible causes of the problem, discussions covered a range of methodological factors such as participant characteristics, trial designs, site characteristics, clinical setting (inpatient vs outpatient), inclusion/exclusion criteria, and diagnostic specificity. Finally, possible solutions were discussed, such as improving precision of participant selection criteria, improving assessment instruments and/or assessment methodology to increase reliability of outcome measures, innovative methods to encourage greater subject adherence and investigator involvement, improved rater training and accountability metrics at clinical sites to increase quality assurance, and advanced methods of pharmacokinetic/pharmacodynamic modeling to optimize dosing prior to initiating large phase 3 trials. The session closed with a roundtable discussion and recommendations for data sharing to further explore potential causes and viable solutions to be applied in future trials

Patient and prescriber perspectives on long-acting injectable (LAI) antipsychotics and analysis of in-office discussion regarding LAI treatment for schizophrenia

BACKGROUND: The research goal is to better understand prescriber, patient, and caregiver perspectives about long-acting injectable (LAI) antipsychotic therapy and how these perspectives affect LAI use. Addressing these perspectives in the clinic may lead to greater success in achieving therapeutic goals for the patient with schizophrenia. METHODS: Ethnographic information was collected from a non-random sample of 69 prescriber-patient conversations (60 with community mental health center [CMHC] psychiatrists; 9 with nurse-practitioners) recorded during treatment visits from August 2011 to February 2012, transcribed and analyzed. Discussions were categorized according to 11 predetermined CMHC topics. In-person observations were also conducted at 4 CMHCs, including home visits by researchers (n = 15 patients) prior to the CMHC visit and observations of patients receiving injections and interacting with staff. Telephone in-depth interviews with psychiatrists, patients, and caregivers to gather additional information on LAI discussion, prescription, or use were conducted. RESULTS: Antipsychotic treatment decisions were made without patient or caregiver input in 40 of 60 (67%) of psychiatrist-patient conversations. Involvement of patients or caregivers in treatment decisions was greater when discussing LAI (15 of 60 [25%]) vs oral antipsychotic treatment (5 of 60 [8%]). LAIs were not discussed by psychiatrists in 11 of 22 (50%) patients taking oral antipsychotics. When offered, more LAI-naïve patients expressed neutral (9 of 19 [47%]) rather than favorable (3 of 19 [16%]) or unfavorable (7 of 19 [37%]) responses. Prescribers were most concerned about potentially damaging the therapeutic relationship and side-effects when discussing LAIs while patient resistance was often related to negative feelings about injections. Psychiatrists had some success in overcoming patient objections to LAIs by addressing and decomposing initial resistance. More than half (11 of 19 [58%]) of LAI-naïve patients agreed to start LAI treatment following office visits. Patient-described benefits of LAIs vs orals included perceived rapid symptom improvement and greater overall efficacy. CONCLUSIONS: In this study, many psychiatrists did not offer LAIs and most patients and caregivers were not involved in antipsychotic treatment decision making. Opportunities to increase active patient engagement, address resistances, guide patient drug-formulation selection, and provide better LAI-relevant information for more individualized approaches to treating the patient with schizophrenia were present

Reduction in Phencyclidine Induced Sensorimotor Gating Deficits in the Rat Following Increased System Xc − Activity in the Medial Prefrontal Cortex

Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc −, a cystine–glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis. Objectives: Our goal was to determine whether increased system xc − activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating. Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc −, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3–3 mg/kg, sc). N-Acetylcysteine (10–100 μM) and the system xc − inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 μM) were used to increase and decrease system xc − activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc − activity. Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10–100 μM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 μM), indicating an involvement of system xc −. Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc − independent mechanisms, but that increasing cystine–glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine

Dynamic Functional Connectivity Analysis Reveals Transient States of Dysconnectivity in Schizophrenia

Schizophrenia is a psychotic disorder characterized by functional dysconnectivity or abnormal integration between distant brain regions. Recent functional imaging studies have implicated large-scale thalamo-cortical connectivity as being disrupted in patients.However, observed connectivity differences in schizophrenia have been inconsistent between studies,with reports of hyperconnectivity and hypoconnectivity between the same brain regions. Using resting state eyes-closed functional imaging and independent component analysis on amulti-site data that included 151 schizophrenia patients and 163 age- and gender matched healthy controls, we decomposed the functional brain data into 100 components and identified 47 as functionally relevant intrinsic connectivity networks. We subsequently evaluated group differences in functional network connectivity, both in a static sense, computed as the pairwise Pearson correlations between the full network time courses (5.4 minutes in length), and a dynamic sense, computed using slidingwindows (44 s in length) and k-means clustering to characterize five discrete functional connectivity states. Static connectivity analysis revealed that compared to healthy controls, patients show significantly stronger connectivity, i.e., hyperconnectivity, between the thalamus and sensory networks (auditory, motor and visual), as well as reduced connectivity (hypoconnectivity) between sensory networks from all modalities. Dynamic analysis suggests that (1), on average, schizophrenia patients spendmuch less time than healthy controls in states typified by strong, large-scale connectivity, and (2), that abnormal connectivity patterns are more pronounced during these connectivity states. In particular, states exhibiting cortical–subcortical antagonism (anticorrelations) and strong positive connectivity between sensory networks are those that showthe group differences of thalamic hyperconnectivity and sensory hypoconnectivity. Group differences are weak or absent during other connectivity states. Dynamic analysis also revealed hypoconnectivity between the putamen and sensory networks during the same states of thalamic hyperconnectivity; notably, this finding cannot be observed in the static connectivity analysis. Finally, in post-hoc analyses we observed that the relationships between sub-cortical low frequency power and connectivitywith sensory networks is altered in patients, suggesting different functional interactions between sub-cortical nuclei and sensorimotor cortex during specific connectivity states. While important differences between patients with schizophrenia and healthy controls have been identified, one should interpret the results with caution given the history of medication in patients. Taken together, our results support and expand current knowledge regarding dysconnectivity in schizophrenia, and strongly advocate the use of dynamic analyses to better account for and understand functional connectivity differences

КОМБИНИРОВАННЫЕ ЛАБОРАТОРНЫЕ ИССЛЕДОВАНИЯ МАТЕРИАЛОВ РАБОЧИХ ОРГАНОВ НА АБРАЗИВНЫЙ ИЗНОС

Researches of wear of agricultural machines working tools, especially soil cutting elements, in field conditions are complicated because of inconstancy of properties of soil mass. The authors developed the method of a research of materials wear with use of two stands. At the IM-01 stand flat grinded samples were tested. Wear was determined by weighing on analytical scales. The second stand (KPS) represented the circular soil canal in which placed the abrasive weight consisting of the particles of clay, sand and other components existing in real soils. Approximate assessment of coefficient of relative wear resistance for two-layer fragments of soil cutting blades was developed. This coefficient can be determined at the rotary soil stand directly only when comparing monometallic fragments of products (by their linear wear). In case of IM-01 stand the coefficient was calculated according to comparative data of weight wear practically for any materials. «Transfer» of laboratory researches results to real conditions of wear is possible only approximately: in practice the difference in the compared results equals 30-35 percent. Laboratory researches by the IM-01 stand were spent in case of loading 4.85 N during 0.5 h for each sample. steel 65G with the hardness of 40±2 HRC was used as a standard, corundum of fraction of 0.2-0.4 mm was as abrasive material. Rotary soil stand testing was carried out at a speed of rotation of the driving mechanism 40 revolutions per minute that corresponded to the speed of movement of samples 2.2 meters per second. The cutting angle of installation to a furrow bottom is similar to this indicator for a ploughshare and equals to 30 degrees. From the chosen materials and hard alloys the best results has taken a basis steel 50KhFA with hard PR-FBYu-1-4 alloy. In comparison with a reference sample, weight wear resistance increased by 2.9 times, and linear one risened by 3.5 times. Use of new materials with the improved characteristics of wear resistance can raise a resource of working tools, in particular ploughshares, by 2.5-3 times, at the same time efficiency by the principle «price - quality» can increase by 2.1 times.Исследования изнашивания рабочих органов сельхозмашин, особенно почворежущих деталей, в полевых условиях усложнены из-за непостоянства свойств почвенной массы. Разработали метод исследования изнашивания материалов, включающий использование двух стендов. На стенде ИМ-01 испытывали плоские шлифованные образцы, где износ определяли по массе взвешиванием на аналитических весах. Второй стенд (КПС) представлял собой круговой почвенный канал, в который помещали абразивную массу, состоящую из частиц глины, песка и других компонентов, входящих в реальные почвы. Разработали приближенную оценку коэффициента относительной износостойкости для двухслойных фрагментов почворежущих лезвий. Отметили, что этот коэффициент на круговом почвенном стенде может быть определен напрямую только при сравнении монометаллических фрагментов изделий (по их линейному износу). На стенде ИМ-01 коэффициент рассчитали по сравнительным данным весовых износов практически для любых материалов. Установили, что «перенос» результатов лабораторных испытаний на реальные условия изнашивания возможен лишь с некоторым приближением: на практике разница в сравниваемых результатах составляет 30-35 процентов. Лабораторные испытания на стенде ИМ-01 проводили при нагрузке 4,85 Н в течение 0,5 ч для каждого образца. В качестве эталона использовали сталь 65Г твердостью 40±2 HRC, абразивный материал - корунд фракции 0,2-0,4 мм. Испытания на круговом почвенном стенде проводили при скорости вращения приводного механизма 40 оборотов в минуту, что соответствовало скорости движения образцов 2,2 метра в секунду. Угол резания установки ко дну борозды аналогичен этому показателю для плужного лемеха и равен 30 градусам. Показали, что из выбранных материалов и твердых сплавов лучшие результаты имеет взятая за основу сталь 50ХФА с твердым сплавом ПР-ФБЮ-1-4. По сравнению с эталонным образцом, износостойкость увеличилась в 2,9 раза по массе и в 3,5 раза по линейному размеру. Установили, что использование в производстве новых материалов с улучшенными характеристиками по износостойкости может повысить ресурс рабочих деталей, в частности плужных лемехов, в 2,5-3 раза, при этом эффективность по принципу «цена - качество» увеличится в 2,1 раза

Синтез азометинов на основе производных 4-аминобензолсульфамида

Synthesis of (£)-azomethines, derivatives of 4-aminobenzenesulfonamide (Streptocidum), by condensation of substituted vanillin-like benzaldehydes with streptocidum in methanol, has been described.Представлен синтез функционально замещенных ароматических (Е)-азометинов - производных 4-аминобензол-сульфамида (стрептоцида), полученных конденсацией замещенных бензальдегидов ванилинового ряда и стрептоцида в среде метанола с выходом 70-82%