Context can influence the number of responses elicited by a discrete, appetitive conditioned stimulus (CS) but can context control when a CS elicits a response? To test this fundamental question, we ...gave male, Long-Evans rats Pavlovian conditioning sessions in which the same auditory conditioned stimulus (CS, 30 s, 15 trials/session) was presented in 2 different physical contexts on alternating days, according to a within-subjects design. In one context, called the early context, alcohol (15 % ethanol, 0.2 ml/trial) was delivered from the onset of the 5th second until the termination of the 10th second of the 30 s CS. In the second late context, alcohol was delivered from the onset of the 25th second until the termination of the 30th second of the same CS. In a comparison of the last session of training, the probability of making a conditioned response during the first four seconds of the CS was significantly higher in the early context than in the late context. This result shows that context can signal when an unconditioned stimulus occurs in relation to a CS and highlights a role for context in controlling precisely timed alcohol-seeking responses.
Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, ...introduction of newer graft sources (for example, umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, peri- and post-transplant exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplant experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This report provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.
•We studied the role of the medial prefrontal cortex (PFC) in appetitive extinction.•Inactivating the infralimbic PFC facilitated extinction in a Pavlovian assay.•It also increased nonCS responding ...during a Pavlovian conditioning session.•This region may maintain responding when an appetitive CS is withheld.•It may also serve distinct functions when an appetitive US is presented or omitted.
The infralimbic medial prefrontal cortex (IL) has been posited as a common node in distinct neural circuits that mediate the extinction of appetitive and aversive conditioning. However, appetitive extinction is typically assessed using instrumental conditioning procedures, whereas the extinction of aversive conditioning is customarily studied using Pavlovian assays. The role of the IL in the extinction of appetitive Pavlovian conditioning remains underexplored. We investigated the involvement of the IL and prelimbic medial prefrontal cortex (PrL) in appetitive extinction in Pavlovian and instrumental conditioning assays in male, Long-Evans rats. Following acquisition, a gamma-aminobutyric acid agonist solution (0.03nmol muscimol; 0.3nmol baclofen; 0.3μl/side) was bilaterally microinfused into the IL or PrL to pharmacologically inactivate each region before the first extinction session. Compared to saline, PrL inactivation did not affect the acquisition of extinction or the recall of extinction memory 24-h later. IL inactivation caused a more rapid extinction of Pavlovian conditioning, but had no effect on the extinction of instrumental conditioning or extinction recall. IL inactivation during a Pavlovian conditioning session in which conditioned stimulus (CS) trials were paired with sucrose did not affect CS-elicited behaviour, but increased responding during intervals that did not contain the CS. The same manipulation did not impact lever pressing for sucrose. These findings suggest that the IL may normally maintain Pavlovian conditioned responding when an anticipated appetitive CS is unexpectedly withheld, and that this region has distinct roles in the expression of Pavlovian conditioning when an appetitive unconditioned stimulus is either presented or omitted.
Current advances in cancer therapy have increased survival, emphasizing the need for life quality improvement. Fertility loss is common post-chemotherapy. Current guidelines establish embryo and ...oocyte cryopreservation to address premature ovarian insufficiency (POI). Ovarian tissue cryopreservation has also recently become an acceptable option for fertility preservation, particularly as it is the only option for pre-pubertal patients. Few definitions for optimum fertility outcomes, and few systematic reviews comparing embryo, oocyte, and ovarian tissue cryopreservation as a means of fertility preservation (FP) in pre- and post-pubertal female cancer patients exist. This systematic review aims to improve understanding of gonadotoxic effects of chemoradiation therapy in cancer patients, to analyze the different fertility preservation techniques and procedures available to women with chemoradiation induced ovarian insufficiency, and to compare and recognize the benefits of each technique in restoring fertility, sexual hormone function, and quality of life. Searches were conducted electronically on PubMed, Cochrane, and EBSCOHost, including clinical trials, prospective, and retrospective studies of female cancer patients undergoing anti-cancer therapy, with predefined MeSH terminology. Data were collected, analyzed, and compared. Non-randomized clinical studies were evaluated for risk bias through the Newcastle-Ottawa Scale. In total, 23 studies were included. From there, 647 patients opted for oocyte cryopreservation, 267 for embryo cryopreservation, and 1382 for ovarian tissue cryopreservation (OTC). A total of 175, 18, and 121 live births resulted respectively from oocyte, embryo, and OTC, respectively. Studies without live births discussed other fertility markers as indicators of improvement in sexual hormone function and fertility. The gonadotoxic effects of chemotherapy call for FP intervention. Oocyte and embryo cryopreservation/implantation are well-established procedures. With changing trends and life quality consideration, OTC is a promising interventional method for pre-pubertal patients facing the prospect of fertility loss.
Objective: We conduct a secondary analysis on the demographics, tumor characteristics, survival, and risk factors for mortality among patients with prostatic ductal adenocarcinoma (PDA) in the ...Kingdom of Saudi Arabia (KSA).
Methods: This is a registry-based retrospective study that included all patients diagnosed with prostate cancer in the KSA. The data were collected from the Saudi Cancer Registry, which collects tumor data from all private, military, and health ministry hospitals in Saudi Arabia through five regional offices.
Results: Among 3607 prostate cancer patients detected during the specified period, 209 (5.8%) had ductal adenocarcinoma. The median interquartile range age of patients was 72.0 years (64.0-78.0). Adenocarcinoma lesions were malignant among all the patients. Grade III tumors were most frequently apparent lesions (61.2%), followed by Grade II tumors (26.3%), Grade I tumors (7.2%), and Grade VI tumors (5.3%). A total of 33 patients died, representing 15.8% of the whole sample. The 1-year survival rate was 78.1%. More than a third of patients who were residing in the Western region deceased (38.0%), whereas no deaths were reported in other regions with a statistically significant difference based on regions (P < 0.001).
Conclusion: To the best of our knowledge, this is the first registry-based study to investigate PDA in the KSA; these efforts were done to further understand this deadly condition and to further enhance patient care in the KSA.
(1) Background: Mutations in NFκB1, a transcriptional regulator of immunomodulating proteins, are a known cause of inborn errors of immunity. Our proband is a 22-year-old male with a diagnosis of ...common variable immunodeficiency (CVID), cytopenias with massive splenomegaly, and nodular regenerative hyperplasia of the liver. Genetic studies identified a novel, single-point mutation variant in NFκB1, c. T638A p. V213E. (2) Methods: Next-generation panel sequencing of the patient uncovered a novel single-point mutation in the NFκB1 gene that was modeled using the I-TASSER homology-modeling software, and molecular dynamics were assessed using the YASARA2 software (version 20.14.24). (3) Results: This variant replaces valine with glutamic acid at position 213 in the NFκB1 sequence. Molecular modeling and molecular dynamic studies showed altered dynamics in and around the rel homology domain, ankyrin regions, and death domain of the protein. We postulate that these changes alter overall protein function. (4) Conclusions: This case suggests the pathogenicity of a novel variant using protein-modeling techniques and molecular dynamic simulations.
Environmental contexts associated with drug use promote craving in humans and drug‐seeking in animals. We hypothesized that the basolateral amygdala (BLA) itself as well as serial connectivity ...between the BLA and nucleus accumbens core (NAC core) were required for context‐induced renewal of Pavlovian‐conditioned alcohol‐seeking. Male Long‐Evans rats were trained to discriminate between two conditioned stimuli (CS): a CS+ that was paired with ethanol (EtOH, 20%, v/v) delivery into a fluid port (0.2 mL/CS+, 3.2 mL per session) and a CS− that was not. Entries into the port during each CS were measured. Next, rats received extinction in a different context where both cues were presented without EtOH. At test, responding to the CS+ and CS− without EtOH was evaluated in the prior training context. Control subjects showed a selective increase in CS+ responding relative to extinction, indicative of renewal. This effect was blocked by pre‐test, bilateral inactivation of the BLA using a solution of GABA receptor agonists (0.1 mm muscimol and 1.0 mm baclofen; M/B; 0.3 μL per side). Renewal was also attenuated following unilateral injections of M/B into the BLA, combined with either M/B, the dopamine D1 receptor antagonist SCH 23390 (0.6 μg per side) or saline infusion in the contralateral NAC core. Hence, unilateral BLA inactivation was sufficient to disrupt renewal, highlighting a critical role for functional activity in the BLA in enabling the reinstatement of alcohol‐seeking driven by an alcohol context.
Environmental contexts associated with drug use can have a profound impact on drug‐seeking behaviour. The present data reveal that unilateral inactivation of the basolateral amygdala attenuates context‐induced renewal of Pavlovian‐conditioned alcohol‐seeking in rats. This novel result suggests that the capacity of alcohol‐contexts to influence conditioned responses elicited by Pavlovian alcohol cues is highly reliant on the basolateral amygdala.
To evaluate the use of high-dose radiotherapy using carbon ions (C12) on non-adenoid cystic malignant salivary gland tumors (MSGT).
Between 2009 and 2013, patients with biopsy-proven non-ACC MSGT ...histologies of the head and neck received a combined regimen of IMRT plus C12 boost. Treatment toxicity (CTC v3), response (RECIST 1.1), control and survival rates were retrospectively analyzed.
40 patients with pathologically confirmed non-ACC MSGT (T4: 45 %; N+: 40 %; gross residual: 58 %; mucoepidermoid carcinoma (MEC): 45 %; adenocarcinoma: 20 %) were treated with a median of 74 GyE (80 Gy BED). Chemoradiation was given in 5 patients with MEC. Grade III acute toxicity was observed in up to 15 % (mucositis, dermatitis, dysphagia), no higher-grade late toxicity occurred to date. At a follow-up of 25.5 months, LC, and PFS at 2 and 3 years are 81.5 % (LC) and 66.8 % (PFS), OS at 2 and 3 years is 83.6 % and 72.8 %. Most frequent site of disease progression was distant metastasis. Histologic subtype correlated with LC and PFS. Resection status (gross vs microscopic disease) had no significant effect on LC, PFS, or OS.
The treatment is well tolerated, no higher grade late effects were observed. Considering the negative pre-selection, LC, PFS and OS are promising. While histology and site of origin significantly influenced control and survival rates, resection status did not, potentially due to the effect of dose escalation.
Patient registries, frequently referred to as outcome registries, are 'organized systems' that use observational study methods to collect uniform data. Registries are used to evaluate specified ...outcomes for a population defined by a particular disease, condition or exposure that serves one or more predetermined scientific, clinical or policy purposes. Outcome registries were established very early in the development of hematopoietic SCT (HSCT). Currently, myriads of national and international HSCT registries collect information about HSCT activities and outcomes. These registries have contributed significantly to determining trends, patterns, treatment practices and outcomes. There are many different HSCT registries, each with different aims and goals; some are led by professional organizations, others by government authorities, health care providers or third parties. Some registries simply assess activity and others study outcomes. These registries are complementary and are gradually developing interoperability with each other to expand future collaborative research activities. A key development in the last few years was the incorporation of recommendations into the World Health Organization guiding principles on cell, tissue and organ transplantation. The data collection and analysis should be an integral part of therapy and an obligation rather than a choice for transplant programs. This article examines challenges in ensuring data quality and functions of outcome registries, using HSCT registries as an example. It applies to all HSCT-related data, but is predominantly focused on HSCT registries of professional organizations.
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