Cardiac arrest-induced global brain hypoxia-ischemia during development affects spontaneous activity organization in rat sensory and motor thalamocortical circuits during adulthood

Normal maturation of sensory information processing in the cortex requires patterned synaptic activity during developmentally regulated critical periods. During early development, spontaneous synaptic activity establishes required patterns of synaptic input, and during later development it influences patterns of sensory experience-dependent neuronal firing. Thalamocortical neurons occupy a critical position in regulating the flow of patterned sensory information from the periphery to the cortex. Abnormal thalamocortical inputs may permanently affect the organization and function of cortical neuronal circuits, especially if they occur during a critical developmental window. We examined the effect of cardiac arrest (CA)-associated global brain hypoxia-ischemia in developing rats on spontaneous and evoked firing of somatosensory thalamocortical neurons and on large-scale correlations in the motor thalamocortical circuit. The mean spontaneous and sensory-evoked firing rate activity and variability were higher in CA injured rats. Furthermore, spontaneous and sensory-evoked activity and variability were correlated in uninjured rats, but not correlated in neurons from CA rats. Abnormal activity patterns of ventroposterior medial nucleus (VPm) neurons persisted into adulthood. Additionally, we found that neurons in the entopeduncular nucleus (EPN) in the basal ganglia had lower firing rates yet had higher variability and higher levels of burst firing after injury. Correlated levels of power in local field potentials (LFPs) between the EPN and the motor cortex (MCx) were also disrupted by injury. Our findings indicate that hypoxic-ischemic injury during development leads to abnormal spontaneous and sensory stimulus-evoked input patterns from thalamus to cortex. Abnormal thalamic inputs likely permanently and detrimentally affect the organization of cortical circuitry and processing of sensory information. Hypoxic-ischemic injury also leads to abnormal single neuron and population level activity in the basal ganglia that may contribute to motor dysfunction after injury. Combination of deficits in sensory and motor thalamocortical circuit function may negatively impact sensorimotor integration in CA survivors. Modulation of abnormal activity patterns post-injury may represent a novel therapeutic target to improve neurologic function in survivors

Long-term deficits in cortical circuit function after asphyxial cardiac arrest and resuscitation in developing rats

AbstractCardiac arrest is a common cause of global hypoxic-ischemic brain injury. Poor neurologic outcome among cardiac arrest survivors results not only from direct cellular injury but also from subsequent long-term dysfunction of neuronal circuits. Here, we investigated the long-term impact of cardiac arrest during development on the function of cortical layer IV (L4) barrel circuits in the rat primary somatosensory cortex. We used multielectrode single-neuron recordings to examine responses of presumed excitatory L4 barrel neurons to controlled whisker stimuli in adult (8 ± 2-mo-old) rats that had undergone 9 min of asphyxial cardiac arrest and resuscitation during the third postnatal week. Results indicate that responses to deflections of the topographically appropriate principal whisker (PW) are smaller in magnitude in cardiac arrest survivors than in control rats. Responses to adjacent whisker (AW) deflections are similar in magnitude between the two groups. Because of a disproportionate decrease in PW-evoked responses, receptive fields of L4 barrel neurons are less spatially focused in cardiac arrest survivors than in control rats. In addition, spiking activity among L4 barrel neurons is more correlated in cardiac arrest survivors than in controls. Computational modeling demonstrates that experimentally observed disruptions in barrel circuit function after cardiac arrest can emerge from a balanced increase in background excitatory and inhibitory conductances in L4 neurons. Experimental and modeling data together suggest that after a hypoxic-ischemic insult, cortical sensory circuits are less responsive and less spatially tuned. Modulation of these deficits may represent a therapeutic approach to improving neurologic outcome after cardiac arrest.</jats:p

Cardiomyocyte cohesion is increased after ADAM17 inhibition

A Disintegrin And Metalloprotease (ADAM) family proteins are involved in several cardiac diseases, and some ADAMs have been associated with cardiomyopathies. ADAM17 is known to cleave desmoglein 2 (DSG2), one of the proteins involved in the pathogenesis of arrhythmogenic cardiomyopathy (AC). Desmosomal stability is impaired in AC, an inheritable genetic disease, the underlying causes of which can be mutations in genes coding for proteins of the desmosome, such as DSG2, desmoplakin (DP), plakoglobin (PG), plakophilin 2 or desmocollin 2. Stabilizing desmosomal contacts can therefore be a treatment option. In the heart of the murine Jup−/− AC model, (Jup being the gene coding for PG) mice, elevated levels of p38MAPK, an activator of ADAM17, were found. However, ADAM17 levels were unaltered in Jup−/− mice hearts. Nonetheless, inhibition of ADAM17 led to enhanced cardiomyocyte cohesion in both Jup+/+ and Jup−/− mice, and in HL-1 cardiomyocytes. Further, enhanced cohesion in HL-1 cardiomyocytes after acute inhibition of ADAM17 was paralleled by enhanced localization of DSG2 and DP at the membrane, whereas no changes in desmosomal assembly or the desmosomal complex were observed. In conclusion, acute inhibition of ADAM17 might lead to reduced cleavage of DSG2, thereby stabilizing the desmosomal adhesion, evidenced by increased DSG2 and DP localization at cell borders and eventually cardiomyocyte cohesion. We believe that similar mechanisms exist in AC

Emergency Neurological Life Support: Intracranial Hypertension and Herniation

Sustained intracranial hypertension and acute brain herniation are “brain codes,” signifying catastrophic neurological events that require immediate recognition and treatment to prevent irreversible injury and death. As in cardiac arrest, a brain code mandates the organized implementation of a stepwise management algorithm. The goal of this emergency neurological life support protocol is to implement an evidence-based, standardized approach to the evaluation and management of patients with intracranial hypertension and/or herniation

Thalamocortical dysfunction and thalamic injury after asphyxial cardiac arrest in developing rats

Global hypoxia-ischemia interrupts oxygen delivery and blood flow to the entire brain. Previous studies of global brain hypoxia ischemia have primarily focused on injury to the cerebral cortex and to the hippocampus. Susceptible neuronal populations also include inhibitory neurons in the thalamic Reticular Nucleus. We therefore investigated the impact of global brain hypoxia-ischemia on the thalamic circuit function in the somatosensory system of young rats. We used single neuron recordings and controlled whisker deflections to examine responses of thalamocortical neurons to sensory stimulation in rat survivors of 9 min of asphyxial cardiac arrest incurred on post-natal day 17. We found that 48–72 hours after cardiac arrest, thalamocortical neurons demonstrate significantly elevated firing rates both during spontaneous activity and in response to whisker deflections. The elevated evoked firing rates persist for at least 6–8 weeks after injury. Despite the overall increase in firing, by 6 weeks, thalamocortical neurons display degraded receptive fields, with decreased responses to adjacent whiskers. Nine min of asphyxial cardiac arrest was associated with extensive degeneration of neurites in the somatosensory nucleus as well as activation of microglia in the Reticular Nucleus. Global brain hypoxia-ischemia during cardiac arrest has a long-term impact on processing and transfer of sensory information by thalamic circuitry. Thalamic circuitry and normalization of its function may represent a distinct therapeutic target after cardiac arrest

Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction

The retinoblastoma 1 (RB1) tumor suppressor is a critical regulator of cell cycle progression and development. To investigate the role of RB1 in neural crest–derived melanocytes, we bred mice with a floxed Rb1 allele with mice expressing Cre from the tyrosinase (Tyr) promoter. TyrCre(+);Rb1(fl/fl) mice exhibited no melanocyte defects but died unexpectedly early with intestinal obstruction, striking defects in the enteric nervous system (ENS), and abnormal intestinal motility. Cre-induced DNA recombination occurred in all enteric glia and most small bowel myenteric neurons, yet phenotypic effects of Rb1 loss were cell-type specific. Enteric glia were twice as abundant in mutant mice compared with those in control animals, while myenteric neuron number was normal. Most myenteric neurons also appeared normal in size, but NO-producing myenteric neurons developed very large nuclei as a result of DNA replication without cell division (i.e., endoreplication). Parallel studies in vitro found that exogenous NO and Rb1 shRNA increased ENS precursor DNA replication and nuclear size. The large, irregularly shaped nuclei in NO-producing neurons were remarkably similar to those in progeria, an early-onset aging disorder that has been linked to RB1 dysfunction. These findings reveal a role for RB1 in the ENS

Паллиативное хирургическое лечение с применением фотодинамической терапии больных со злокачественными новообразованиями желчевыводящей системы, осложненными обструктивной желтухой

The article presents the results of a study of survival, markers of hemostasis, proteolysis, and tumor invasion after complex palliative treatment of patients with histologically verified malignant tumors of the bile ducts complicated by obstructive jaundice in two comparable groups of patients. The aim of the study was to evaluate the effectiveness of palliative surgical treatment using photodynamic therapy in patients with malignant tumors of the biliary system complicated by obstructive jaundice. In 10 patients of the main group, palliative surgical treatment was performed using photodynamic therapy; in 20 patients of the comparison group, palliative surgical treatment was performed without photodynamic therapy. In patients of the main group, a statistically significant increase in life expectancy by 104 days (p=0.033) was observed compared to the comparison group. At the same time, a statistically significant effect of tumor necrosis factor α, a marker of tumor invasion, on survival (p = 0.012) and a decrease in its level after photodynamic therapy by 15 pg/ml (p=0.041) was revealed. Thus, palliative treatment using photodynamic therapy of malignant tumors of the bile ducts, complicated by obstructive jaundice, can increase the survival rate of patients by reducing tumor invasion.В работе представлены результаты исследования выживаемости, маркеров гемостаза, протеолиза и опухолевой инвазии после комплексного паллиативного лечения больных с гистологически верифицированными злокачественными новообразованиями желчевыводящих протоков, осложненными обструктивной желтухой в двух сопоставимых группах больных. Целью исследования было оценить эффективность паллиативного хирургического лечения с применением фотодинамической терапии (ФДТ) у больных злокачественными новообразованиями желчевыводящей системы, осложненными обструктивной желтухой. У 10 пациентов основной группы проводилось паллиативное хирургическое лечение с применением ФДТ, у 20 пациентов группы сравнения проводилось паллиативное хирургическое лечение без применения ФДТ. У пациентов основной группы наблюдалось статистически значимое увеличение продолжительности жизни по сравнению с группой сравнения на 104 дня (р=0,033). При этом выявлено статистически значимое влияние маркера опухолевой инвазии – фактора некроза опухоли α на выживаемость (р=0,012) и уменьшение его уровня после ФДТ с 43,53±33,99 пг/мл до 28,33±26,12 пг/мл (p = 0,041). Таким образом, паллиативное лечение с применением ФДТ злокачественных новообразований желчевыводящих протоков, осложненных обструктивной желтухой, позволяет увеличить выживаемость пациентов за счет уменьшения опухолевой инвазии

Damaging effects of ecologically unfavorable environmental factors on the health of descendants

Aim. To determine the possible damaging effects of ecologically unfavorable environmental factors (radiation and chemical) on the health of descendants. Methods. The cross-sectional study included 232 women of the Altai territory, who were divided into three groups: the first group included the descendants of persons who were in the area of radiation exposure, the second one - the descendants of chemical workers, the third group was the control group. As part of the expedition trip to the study areas, the collection of clinical and anamnestic data, the study of extragenital, gynecological morbidity, laboratory and functional methods of research were carried out. Results. The data were obtained confirming the most damaging effect on reproductive health in the descendants of persons who were in the area of radiation exposure. It was the first group where the high frequency of extragenital and gynecological pathology was revealed. At the same time, the reproductive function of women, closely related to functional changes in the immune system, was disordered. The results of the study of a number of parameters of the immune system revealed changes in the functioning of cellular immunity, increase in the level of proinflammatory cytokines (tumor necrosis factor), mainly in the descendants of persons who were in the area of radiation exposure, in contrast to the descendants of workers of chemical production and control group. Conclusion. A comparative assessment of some health parameters of descendants of persons exposed to radiation and chemical factors showed that the most damaging effect on the reproductive health of descendants is caused by radiation factor

Прогнозирование влияния фотодинамической терапии на выживаемость у пациентов с IV стадией злокачественных новообразований поджелудочной железы

The article presents the results of a study of survival after complex palliative treatment of patients with malignant tumors of the pancreas stage IV in two comparable groups of patients. The aim of the study is to determine the prognostic factors affecting survival in patients with stage IV pancreatic cancer who received local and systemic photodynamic therapy. In the main group, which consisted of 19 patients with histologically veried stage IV pancreatic maligant tumor, palliative treatment was performed using photodynamic therapy. In the comparison group, consisting of 28 patients with histologically veried malignant tumor of the pancreas stage IV, palliative treatment was performed without the use of photodynamic therapy. On the background of the use of local and systemic photodynamic therapy in the main group it was observed a statistically significant increase in life expectancy compared with the comparison group. The three-month survival of patients who received local and systemic photodynamic therapy is affected by the level of brinogen before treatment. The level of brinogen above 3.4 g/l makes it possible to predict a decrease in the probability of three-month survival after photodynamic therapy. Thus, complex treatment with the use of photodynamic therapy for stage IV malignant tumors of the pancreas can increase the survival rate of patients.В работе представлены результаты исследования выживаемости в двух сопоставимых группах больных после комплексного паллиативного лечения больных со злокачественными новообразованиями поджелудочной железы IV стадии. Целью исследования было определить прогностические факторы, влияющие на выживаемость у больных IV стадией злокачественного новообразования поджелудочной железы, которым планируется проведение локальной и системной фотодинамической терапии. В основной группе, включавшей 19 пациентов с гистологически верифицированным злокачественным новообразованием поджелудочной железы IV стадии, проводили паллиативное лечение с применением фотодинамической терапии. В группе сравнения, включавшей 28 пациентов с гистологически верифицированным злокачественным новообразованием поджелудочной железы IV стадии, проводили паллиативное лечение без применения фотодинамической терапии. На фоне применения локальной и системной фотодинамической терапии в основной группе наблюдали статистически значимое увеличение продолжительности жизни по сравнению с группой сравнения. Исследования показали, что на трехмесячную выживаемость пациентов, которым планируется проведение локальной и системной фотодинамической терапии, влияет уровень фибриногена до лечения. Уровень фибриногена выше 3,40 г/л позволяет прогнозировать снижение вероятности трехмесячной выживаемости после проведения фотодинамической терапии. Таким образом, комплексное лечение с применением фотодинамической терапии злокачественных новообразований поджелудочной железы IV стадии позволяет увеличить выживаемость пациентов

Роль механизмов воспаления в развитии состояния предрасположенности к тромбозам и тромбоэмболиям у больных хронической обструктивной болезнью легких в сочетании с синдромом обструктивного апноэ сна

The objective: to study the effect of sleep-related breathing disorders on the activation of blood coagulation reactions associated with systemic inflammation in patients with chronic obstructive pulmonary disease and concurrent obstructive sleep apnea.Subjects and methods. An open prospective comparative study analyzed thrombogenic risk factors, markers of inflammation and insulin resistance in 65 patients with chronic obstructive pulmonary disease and concurrent obstructive sleep apnea, 26 of them received non-invasive ventilation as a part of their therapy (main group).Results. The blood levels of homocysteine and prothrombin fragments 1+2 are closely associated with the duration of nocturnal hypoxemia, concentrations of C-reactive protein, C-peptide, and endothelial vascular growth factor and can be managed with CPAP therapy.The authors state that they have no conflict of interests.Цель: изучить влияние расстройств дыхания, связанных со сном, на активацию гемокоагуляционных реакций во взаимосвязи с системным воспалением у больных хронической обструктивной болезнью легких в сочетании с синдромом обструктивного апноэ сна.Материалы и методы. В открытом проспективном сравнительном исследовании проведен анализ факторов тромбогенного риска, маркеров воспаления и инсулинорезистентности у 65 больных хронической обструктивной болезнью легких в сочетании с синдромом обструктивного апноэ сна, 26 из которых получали в комплексном лечении неинвазивную вентиляцию легких (основная группа).Результаты. Показатели содержания в крови гомоцистеина и фрагментов протромбина 1 + 2 находятся в тесной зависимости от продолжительности ночной гипоксемии, концентраций С-реактивного белка, С-пептида, эндотелиального сосудистого фактора роста и могут корригироваться применением CPAP-терапии