Differential Responsivity of the Hypothalamic-Pituitary-Adrenal Axis to Glucocorticoid Negative-Feedback and Corticotropin Releasing Hormone in Rats Undergoing Morphine Withdrawal: Possible Mechanisms Involved in Facilitated and Attenuated Stress Responses

Chronic morphine treatment produces profound and long-lasting changes in the pituitary-adrenal responses to stressful stimuli. The purpose of the present study was to explore the mechanisms involved in these altered stress responses. Chronic morphine administration increased basal plasma concentrations of corticosterone and adrenocorticotropic hormone (ACTH), which peaked at 36 h after the final morphine injection and returned to normal levels within 84-h. Whole brain glucocorticoid receptor protein expression was reduced (approximately 70%) in morphine-treated rats 4-h after the final morphine injection and these levels recovered within 16-h. Twelve hours following morphine withdrawal, rats displayed normal ACTH, but potentiated and prolonged corticosterone responses to restraint stress. Both the ACTH and corticosterone responses to restraint in acutely withdrawn rats were insensitive to dexamethasone. Furthermore, acutely withdrawn rats displayed reduced ACTH but prolonged corticosterone responses to peripheral corticotropin releasing hormone (CRH) administration. These findings suggest that the normal ACTH and enhanced corticosterone responses to stress in acutely withdrawn rats involved decreased sensitivity of negative-feedback systems to glucocorticoids, reduced pituitary responsivity to CRH, and enhanced sensitivity of the adrenals to ACTH. Eight days following morphine withdrawal, rats displayed dramatically reduced ACTH, but normal corticosterone responses to restraint stress. These rats displayed enhanced sensitivity to dexamethasone and normal pituitary-adrenal responses to CRH. These data suggest that the reduced ACTH responses to stress in 8-day withdrawal rats involved increased sensitivity of negative-feedback systems to glucocorticoids as well as reduced CRH and/or AVP function in response to stress. Taken together, the results of this study illustrate some of the mechanisms mediating altered stress responsivity in rats that have received chronic morphine treatment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73727/1/j.1365-2826.2001.00714.x.pd

CoV-TI-Net: Transferred Initialization with Modified End Layer for COVID-19 Diagnosis

This paper proposes transferred initialization with modified fully connected layers for COVID-19 diagnosis. Convolutional neural networks (CNN) achieved a remarkable result in image classification. However, training a high-performing model is a very complicated and time-consuming process because of the complexity of image recognition applications. On the other hand, transfer learning is a relatively new learning method that has been employed in many sectors to achieve good performance with fewer computations. In this research, the PyTorch pre-trained models (VGG19\_bn and WideResNet -101) are applied in the MNIST dataset for the first time as initialization and with modified fully connected layers. The employed PyTorch pre-trained models were previously trained in ImageNet. The proposed model is developed and verified in the Kaggle notebook, and it reached the outstanding accuracy of 99.77% without taking a huge computational time during the training process of the network. We also applied the same methodology to the SIIM-FISABIO-RSNA COVID-19 Detection dataset and achieved 80.01% accuracy. In contrast, the previous methods need a huge compactional time during the training process to reach a high-performing model. Codes are available at the following link: github.com/dipuk0506/SpinalNe

Neutrophils Suppress Intraluminal NK Cell-Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells

Immune cells promote the initial metastatic dissemination of carcinoma cells from primary tumors. In contrast to their well-studied functions in the initial stages of metastasis, the specific roles of immunocytes in facilitating progression through the critical later steps of the invasion–metastasis cascade remain poorly understood. Here, we define novel functions of neutrophils in promoting intraluminal survival and extravasation at sites of metastatic dissemination. We show that CD11b+/Ly6G+neutrophils enhance metastasis formation via two distinct mechanisms. First, neutrophils inhibit natural killer cell function, which leads to a significant increase in the intraluminal survival time of tumor cells. Thereafter, neutrophils operate to facilitate extravasation of tumor cells through the secretion of IL1β and matrix metalloproteinases. These results identify neutrophils as key regulators of intraluminal survival and extravasation through their cross-talk with host cells and disseminating carcinoma cells. SIGNIFICANCE: This study provides important insights into the systemic contributions of neutrophils to cancer metastasis by identifying how neutrophils facilitate intermediate steps of the invasion–metastasis cascade. We demonstrate that neutrophils suppress natural killer cell activity and increase extravasation of tumor cells.Human Frontier Science Program (Strasbourg, France) (fellowship LT00728/2008-L)Charles King Trust FoundationMassachusetts Institute of Technology. Ludwig Center for Cancer ResearchCancer Research Institute (New York, N.Y.) (Irvington Fellowship)National Institutes of Health (U.S.) (grant P01 CA080111)National Institutes of Health (U.S.) (grant CA163109

Nutritive value of unconventional fibrous ingredients fed to Guinea pigs in the Democratic Republic of Congo

peer reviewedThe energy and protein value for Guinea pigs (GP) of 9 forages (7 dicots and 2 grasses) and 5 hay-based diets was determined. The apparent faecal digestibility of dry matter, organic matter, crude protein and energy was measured on GP housed in metabolic cages. The forages and the diets were digested in vitro using pepsin and pancreatin hydrolysis and gas fermentation test to simulate stomach, small intestine and large intestine, respectively. Most of the dicots had high digestible crude protein content (152–201 g/kg DM) and the 2 grasses showed lower values (80–85 g/kg DM). Digestible energy content of the forages ranged between 5.79 to 13.08 MJ/kg DM. None of the forage species or hay-based diets provided sufficient energy to supply the 11.7 MJ/kg metabolic energy requirements. The influence of intestinal fermentation on energy and protein values was highlighted by correlations (P<0.05) between in vivo and in vitro data, including gas fermentation. It is the first time that such relationships are reported in single-stomach animals

Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

BACKGROUND Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations. METHODS We conducted a phase 1–2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured. RESULTS A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture–related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], −18 to 27) for the 20-mg dose, −25 percentage points (95% CI, −40 to −5) for the 40-mg dose, −19 percentage points (95% CI, −35 to 2) for the 60-mg dose, and −33 percentage points (95% CI, −47 to −16) for the 100-mg dose. CONCLUSIONS In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture–related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699. opens in new tab; EudraCT number, 2015-004098-33. opens in new tab.

The effects of CRF antagonists, antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats

Exposure to extreme stress has been suggested to produce long-term, detrimental alterations in the hypothalamic–pituitary–adrenal (HPA) axis leading to the development of mental disorders such as depression. Therefore, compounds that block the effects of stress hormones were investigated as potential therapeutics for depression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46365/1/213_2005_Article_2164.pd

Paradoxical Effects of Chronic Morphine Treatment on the Temperature and Pituitary-Adrenal Responses to Acute Restraint Stress: A Chronic Stress Paradigm

Body temperature and pituitary-adrenal responses to restraint (15 min or 4 h) stress were evaluated in nondependent and morphine-dependent rats. Male Sprague-Dawley rats were treated twice daily with increasing doses of morphine (10–100 mg/kg, s.c.) for 16 days. Transmitters were implanted in the peritoneal cavity to monitor body temperature and blood was collected for hormone assays. Acute withdrawal from chronic morphine treatment was associated with reduced body weight, increased adrenal weight and decreased thymus weight. Sixteen days after termination of chronic morphine treatment, rats had recovered normal adrenal size, but still displayed marked thymus involution and reduced body weight. Restraint-induced hyperthermia was attenuated in morphine-dependent rats that had undergone 12-h withdrawal. Sixteen days after withdrawal, rats still had not fully recovered the hyperthermic response to restraint. Chronic morphine treatment resulted in a marked elevation of basal corticosterone concentrations. Despite the negative-feedback effects of elevated basal corticosterone concentrations, morphine-dependent rats that had undergone 12-h withdrawal displayed a potentiated and prolonged corticosterone response to restraint stress. In contrast, rats that had undergone 8-day and 16-day morphine withdrawal had recovered normal basal pituitary-adrenal activity, but displayed significantly reduced and shorter adrenocorticotropic hormone and corticosterone responses to restraint. These results suggest that chronic morphine dependence is a chronic stressor, resulting in profound and long-lasting changes in the temperature and pituitary-adrenal responses to acute restraint stress in a time-dependent manner. This morphine-dependence model may be useful in understanding the role that hormonal stress responses play in the maintenance and relapse to opioid use in humans.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74210/1/j.1365-2826.2001.00713.x.pd

System Modelling to Support Accelerated Fuel Transfer Rate at EBR-II

The Experimental Breeder Reactor-II (EBR-II) ia a 62.5 MW(th) liquid metal reactor operated by Argonne National Laboratory for The United States Department of Energy. The reactor is located near Idaho Falls, Idaho at the Argonne-West site (ANL-W). Full power operation was achieved in 1964,- the reactor operated continuously since that time until October 1994 in a variety of configurations depending on the programmatic mission. A three year program was initiated in October, 1993 to replace the 330 depleted uranium blanket subassemblies (S/As) with stainless steel reflectors. It was intended to operate the reactor during the three year blanket unloading program, followed by about a half year of driver fuel unloading. However, in the summer of 1994, Congress dictacted that EBR-II be shut down October 1, and complete defueling without operation. To assist in the planning for resources needed for this defueling campaign, a mathematical model of the fuel handling sequence was developed utilizing the appropriate reliability factors and inherent mm constraints of each stage of the process. The model allows predictions of transfer rates under different scenarios. Additionally, it has facilitated planning of maintenance activities, as well as optimization of resources regarding manpower and modification effort. The model and its application is described in this paper

Introducing a Dental Caries Marking Software and Evaluate Radiologists’ Disagreement in Caries Detection Using this Software

Statement of Problem: Bitewing radiograph is the main reference for diagnosis of proximal and recurrent caries. There is no software for gathering and analyzing radiologists’ opinion in the field of caries detection on digital bitewing radiograph (DBR). Objectives: The main aim of this study is to introduce the first windows application that could be used for marking caries on DBR. This software is called Dental Caries Marking Software (DCMS). The second aim is to create the first DBR caries dataset to be used for future software development projects in the field of automatic caries detection; also gathering and documenting the disagreements and critiques regarding DCMS. Materials and Methods: DCMS has been designed and implemented by the researchers of this study. This software is divided into two parts. The first part is DCMS writer that is used for gathering the user’s opinion and The second part is DCMS analyzer that is used for reading and analyzing the user’s opinion file. Eight radiologists with different experiences used DCMS for marking dental caries on 200 DBR, 50 of which were repeated twice for assessing the accuracy of each radiologist. Results: A total of 3833 points were marked by 8 users on 150 non repetitive DBR. Only 35 points were marked similarly by 8 users; in other words, 8 users totally agreed with 4% of the caries points. According to 50 repetitive DBR, the maximum accuracy of users was 69% and the minimum was 50%. Conclusions: There is significant debate over the diagnosis of caries on DBR; therefore, for unifying the radiologist’s opinions, the need for intelligent caries detection software is apparent. DCMS is useful software for gathering caries data. Moreover, the use of conventional display monitor has negative impacts on accurate diagnosis of caries on DBR