Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions.

BACKGROUND: Psychiatric medications are widely prescribed in the USA. Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling both induces cell differentiation and suppresses apoptosis. It is controversial whether these antipsychotics increase breast cancer risk. METHODS: We investigated the impact of several antipsychotics on mammary tumorigenesis initiated by retrovirus-mediated delivery of either ErbB2 or HRas or by transgenic expression of Wnt-1. RESULTS: We found that the two hyperprolactinemia-inducing antipsychotics, risperidone and pimozide, prompted precancerous lesions to progress to cancer while aripiprazole, which did not cause hyperprolactinemia, did not. We observed that risperidone and pimozide (but not aripiprazole) caused precancerous cells to activate STAT5 and suppress apoptosis while exerting no impact on proliferation. Importantly, we demonstrated that these effects of antipsychotics on early lesions required the STAT5 gene function. Furthermore, we showed that only two-week treatment of mice with ruxolitinib, a JAK1/2 inhibitor, blocked STAT5 activation, restored apoptosis, and prevented early lesion progression. CONCLUSIONS: Hyperprolactinemia-inducing antipsychotics instigate precancerous cells to progress to cancer via JAK/STAT5 to suppress the apoptosis anticancer barrier, and these cancer-promoting effects can be prevented by prophylactic anti-JAK/STAT5 treatment. This preclinical work exposes a potential breast cancer risk from hyperprolactinemia-inducing antipsychotics in certain patients and suggests a chemoprevention regime that is relatively easy to implement compared to the standard 5-year anti-estrogenic treatment in women who have or likely have already developed precancerous lesions while also requiring hyperprolactinemia-inducing antipsychotics.

Compression socks and the effects on coagulation and fibrinolytic activation during marathon running.

PURPOSE: Compression socks are frequently used in the treatment and prevention of lower-limb pathologies; however, when combined with endurance-based exercise, the impact of compression socks on haemostatic activation remains unclear. OBJECTIVES: To investigate the effect of wearing compression socks on coagulation and fibrinolysis following a marathon. METHODS: Sixty-seven participants [43 males (mean ± SD: age: 46.7 ± 10.3 year) and 24 females (age: 40.0 ± 11.0 year)] were allocated into a compression (SOCK, n = 34) or control (CONTROL, n = 33) group. Venous blood samples were obtained 24 h prior to and immediately POST-marathon, and were analyzed for thrombin-anti-thrombin complex (TAT), tissue factor (TF), tissue factor pathway inhibitor (TFPI), and D-Dimer. RESULTS: Compression significantly attenuated the post-exercise increase in D-Dimer compared to the control group [median (range) SOCK: + 9.02 (- 0.34 to 60.7) ng/mL, CONTROL: + 25.48 (0.95-73.24) ng/mL]. TF increased following the marathon run [median (range), SOCK: + 1.19 (- 7.47 to 9.11) pg/mL, CONTROL: + 3.47 (- 5.01 to 38.56) pg/mL] in all runners. No significant post-exercise changes were observed for TAT and TFPI. CONCLUSIONS: While activation of coagulation and fibrinolysis was apparent in all runners POST-marathon, wearing compression socks was shown to reduce fibrinolytic activity, as demonstrated by lower D-Dimer concentrations. Compression may reduce exercise-associated haemostatic activation when completing prolonged exercise.

A Qualitative Study Exploring Parental Perceptions of Telehealth in Early Intervention.

Using telehealth as a mode of service delivery has the potential to address some long-standing challenges in early intervention (EI) services such as waiting lists to access services. Yet, little is known about parent perceptions of telehealth in EI based on their lived experiences partnering with EI practitioners. The purpose of this study was to explore parent perceptions on using telehealth, especially on family-professional partnerships and coaching. Interviews were conducted with 15 parents of children receiving EI services via telehealth from June to August of 2021. Almost half of the participants reflected under-represented racial and ethnic backgrounds. Constant comparative analysis and emergent coding were used for data analysis. The findings showed that the advantages outnumbered the disadvantages regarding telehealth. Participants reported that telehealth provided a safe and flexible option and eliminated the wait to access EI services. However, participants identified some disadvantages to telehealth including telehealth precluded substantive interactions with therapists and limited access to technology. The findings also indicated that telehealth enhanced family-professional partnerships. Nearly all participants valued coaching during telehealth. Participants suggested initial supports to facilitate EI via telehealth, including stable internet access, telehealth training, and an initial in-person visit. Implications for research and practice are discussed. Supplementary Information: The online version contains supplementary material available at 10.1007/s10882-022-09853-w.

Investigation of the association between gall bladder wall thickness and hypoalbuminaemia in dogs.

OBJECTIVES: To assess the correlation between gallbladder wall thickness and serum/plasma albumin concentrations in dogs. MATERIALS AND METHODS: Retrospective searches of digital medical record databases were conducted to identify dogs that had either severely low serum/plasma albumin concentration (<1.5 g/dL) or ultrasonographic evidence of gallbladder wall thickening (>2 mm). Analysis of covariance models were used to analyze gallbladder wall thickness with sample type (serum vs plasma), age, etiology, albumin, and albumin ' etiology as the covariates. RESULTS: A total of 216 dogs met inclusion criteria. One-hundred and forty-six dogs had a thickened gallbladder wall (Group 1). Median serum/plasma albumin concentration for dogs in this group was 2.2 g/dL (1 to 5 g/dL), and 84 dogs (57.5%) had hypoalbuminemia (<2.5 g/dL). The search for dogs with severe hypoalbuminemia (< 1.5 g/dL) identified 70 dogs (Group 2). In this group, median gallbladder wall thickness was 1.3 mm (0.2 to 6.1 mm) and 17 dogs (24.3%) had a thickened gallbladder wall. Serum/plasma albumin concentration and gallbladder wall thickness were not significantly correlated for Group 1 (r = 0.0044, p = 0.9580) or Group 2 (r = -0.1137, p = 0.3487). A moderate negative correlation (-0.64) was identified between gallbladder wall thickness and albumin concentration in dogs with immune-mediated diseases (p = 0.03). CLINICAL SIGNIFICANCE: Gallbladder wall thickness and serum/plasma albumin concentration are independent variables in dogs.

Effects of anesthetic agents on socially transmitted olfactory memories in mice.

Mice can learn a food preference from odor cues transmitted on the breath of a conspecific, even if the "demonstrator" is anesthetized. To our knowledge there are no studies examining the effect of anesthetizing the "observer" on development of memory for socially transmitted food preferences (STFP). In Experiment 1 we found that 2-4 month-old F2 C57Bl/6x129sv male and female mice demonstrated a STFP after a 5min exposure to an anesthetized demonstrator mouse when tested 24h later. In Experiment 2, observer mice anesthetized with Sagatal (60 mg/kg) prior to the "social interaction" preferentially avoided the cued food when tested 24h later. This aversion was not due to any overt aversive effects of this dose of Sagatal because mice that ate the food and were then anesthetized, or could only smell the food for 5 min while anesthetized, showed no preference or aversion. In a third experiment we found that the Sagatal-induced aversion was not a general property of anesthesia because there were varied results produced by observer mice treated with anesthetic drugs with different mechanisms of action. Vetalar (200mg/kg) and Rompun (10 mg/kg) treated animals ate similar amounts of cued and non-cued food at test, indicating an absence of learning. Hypnorm (0.5 ml/kg) treated animals showed a preference for the cued food whereas those treated with Hypnovel (2.5 ml/kg) showed an aversion to the cued food. These results show that the food aversion observed with Sagatal is not a general property of anesthetic agents, but appears to be restricted to those acting primarily on the GABAergic system. Thus, we have shown that under certain conditions it is possible for an anesthetized observer mouse to learn a preference or aversion of a socially-linked olfactory cue.

Emergency nurses' knowledge and understanding of their role in recognising and responding to patients with sepsis: A qualitative study.

AIM: Sepsis is a significant and time-sensitive clinical concern for patients who present to Emergency Departments (EDs). Existing guidelines do not define nurses' roles in managing sepsis. This study explored ED nurses' experiences and perceptions around recognising and responding to patients with sepsis, and their awareness of sepsis screening and prognostic tools. The knowledge and insights gained from this study may be used to inform local and international ED policies, and enrich nursing educational packages that may be used to improve quality of patient care and patient outcomes. METHODS: Qualitative design incorporating semi-structured interviews with 14 ED nurses was undertaken. Thematic and consensus-based content analyses were used to explore transcripts. FINDINGS: Six key themes were identified; (1) contribution of the organisation, (2) appreciation of knowledge, (3) appreciation of clinical urgency, (4) appreciation of importance of staff supervision, (5) awareness of the importance of staff experience, and (6) awareness of the need to seek advice. CONCLUSION: ED nurses' identified deficits in their capacity to recognise and respond to patients with sepsis, despite their vital role within the multidisciplinary team that cares for patients with sepsis. The knowledge and insights gained from this study can be used to inform ED policies, to enrich context-specific educational packages that aim to improve quality of patient care and outcomes and identify areas for further research. Development and implementation of a nurse-inclusive sepsis pathway may address many deficits identified in this study.

Light experience and the development of behavioural lateralization in chicks III. Learning to distinguish pebbles from grains.

Chicks searching for food grains against a background of unfamiliar pebbles usually peck pebbles less when using the right eye (RE), or both eyes, than when using the left eye (LE), provided that the embryo's RE has been exposed to light (Li), as is normal. When pecking is fast this right/left difference is mainly due to a heightened ability of RE chicks to inhibit premature pecks (and inappropriate responses in general). Dark incubation (Da) abolishes this ability in RE chicks, and RE and LE chicks show similar frequent pebble pecks. We show now that, under conditions that cause cautious pecking, both Li and Da chicks show a new effect: in both cases LE chicks peck pebbles more than RE chicks, probably because of the novelty of pebbles. Interest in novelty in LE chicks is known to be unaffected by light in incubation. Age-dependent effects are also important. RE and LE chicks, which had either the LE or RE exposed to light before hatching, were tested on days 3, 5, 8 or 12 post-hatching, under conditions giving normal fast pecking. Artificial exposure of the embryo's LE to light reversed the lateralization: in general, chicks using the light-exposed eye performed well at all ages. Irrespective of which eye system had heightened ability to inhibit pebble pecks, RE performance differed from usual on 2 days, whereas LE chicks showed no age-dependent changes. Changes confined to the RE system, therefore, affect behaviour independently of lateralization of the ability to inhibit inappropriate response.

Enhancing OSCE preparedness with video exemplars in undergraduate nursing students. A mixed method study.

BACKGROUND: Objective structured clinical examinations (OSCEs) are designed to assess clinical skill performance and competency of students in preparation for 'real world' clinical responsibilities. OSCEs are commonly used in health professional education and are typically associated with high levels of student anxiety, which may present a significant barrier to performance. Students, including nursing students, have identified that flexible access to exemplar OSCEs might reduce their anxiety and enable them to better prepare for such examinations. AIM: To implement and evaluate an innovative approach to preparing students for OSCEs in an undergraduate (registration) acute care nursing course. METHOD: A set of digitized OSCE exemplars were prepared and embedded in the University-based course website as part of usual course learning activities. Use of the exemplars was monitored, pre and post OSCE surveys were conducted, and qualitative data were collected to evaluate the approach. OSCE grades were also examined. FINDINGS: The online OSCE exemplars increased self-rated student confidence, knowledge, and capacity to prepare and provided clarity around assessment expectations. OSCE exemplars were accessed frequently and positively received; but did not impact on performance. CONCLUSION: Video exemplars aid student preparation for OSCEs, providing a flexible, innovative and clear example of the assessment process. Video exemplars improved self-rated student confidence and understanding of performance expectations, leading to increased engagement and reduced anxiety when preparing for the OSCE, but not overall OSCE performance. Such OSCE exemplars could be used to increase staff capacity and improve the quality of the student learning experience.

ENGAGING STUDENTS IN ACUTE MENTAL HEALTHCARE.

Mental health is an increasing component of the burden of disease worldwide, providing challenges in healthcare and health systems (World Health Organization, 2013); it is widespread, and not limited to dedicated mental health facilities.

Evaluation of capsule endoscopy to detect mucosal lesions associated with gastrointestinal bleeding in dogs.

OBJECTIVE: The objective of this study was to examine the utility of capsule endoscopy to detect mucosal abnormalities in dogs with gastrointestinal haemorrhage. METHODS: Capsules were administered to 2 healthy controls and 8 patients with gastrointestinal haemorrhage. Images were evaluated for quality, gastric emptying time, small intestinal transit time and presence of lesions. RESULTS: There were no adverse effects of capsule endoscopy in dogs weighing from 7·7 to 58 kg. The capsule traversed the entire gastrointestinal tract in 5 of 8 patients, with high quality images obtained in the stomach and small intestine. Gastric emptying time and small intestinal transit time ranged from 1 to 270 and 15 to 180 minutes, respectively. In 3 of 8 patients, the capsule remained in the stomach despite pro-kinetics. Gastric lesions included mild haemorrhage and pinpoint erosion (4 of 8), a mass (1) and thickened bleeding pyloric mucosa (2). Two of 3 dogs with capsule retention had gastric lesions. Intestinal lesions included a healing duodenal ulcer, abnormal villi, ileal ulceration and colonic bleeding. Lesions identified by capsule endoscopy were considered a significant source of haemorrhage in 4 of 7 dogs with active bleeding. The relevance of pinpoint gastric mucosal erosions to blood loss is unclear. CLINICAL SIGNIFICANCE: Capsule endoscopy can enable the non-invasive detection of gastric and small intestinal mucosal lesions in dogs presenting for evaluation of gastrointestinal bleeding.

Luminal epithelial cells within the mammary gland can produce basal cells upon oncogenic stress.

In the normal mammary gland, the basal epithelium is known to be bipotent and can generate either basal or luminal cells, whereas the luminal epithelium has not been demonstrated to contribute to the basal compartment in an intact and normally developed mammary gland. It is not clear whether cellular heterogeneity within a breast tumor results from transformation of bipotent basal cells or from transformation and subsequent basal conversion of the more differentiated luminal cells. Here we used a retroviral vector to express an oncogene specifically in a small number of the mammary luminal epithelial cells and tested their potential to produce basal cells during tumorigenesis. This in-vivo lineage-tracing work demonstrates that luminal cells are capable of producing basal cells on activation of either polyoma middle T antigen or ErbB2 signaling. These findings reveal the plasticity of the luminal compartment during tumorigenesis and provide an explanation for cellular heterogeneity within a cancer.

Student learning styles in anatomy and physiology courses: Meeting the needs of nursing students.

Anatomy and Physiology is a core course in pre-registration nursing programs, yet many students have difficulty successfully negotiating the large volume of content and the complex concepts in these bioscience courses. Typically students perform poorly in these 'threshold' courses', despite multiple interventions to support student engagement. Investigation of the shortcomings in these courses, based on feedback from students indicated several key areas of difficulty in the course, especially focused around a relative lack of hands-on 'concrete' activities in laboratories and tutorials. To attempt to address this, academic and technical staff developed activities for students that promoted discussion and allowed students to interact easily and repetitively with content. Interactive tables and posters that needed to be labelled or 'filled-in' using pre-prepared Velcro dots, as well as pre-prepared flash cards to promote group work, were some examples of the activities used to enhance student experiences and promote hands-on learning. Over the academic year of 2013 these activities were introduced into the laboratory and tutorial classes for first year Bachelor of Nursing anatomy and physiology students. Staff and student participants positively rated implementation of these new activities on surveys, as they allowed them to explore the difficult aspects of anatomy and physiology, utilising various learning styles that may have been neglected in the past.

Role of brain-derived neurotrophic factor and presynaptic proteins in passive avoidance learning in day-old domestic chicks.

The consolidation of a one-trial passive avoidance learning task in the day-old chick involves a number of transient and longer-term biochemical processes, including increased release of glutamate. This study demonstrated that brain-derived neurotrophic factor, a proposed modulator of synaptic transmission and neurotransmitter release, is involved in the cascade associated with memory consolidation in the chick and that its actions were linked to modulation of expression of SNAP-25, syntaxin and synaptophysin, required for exocytosis. Intracerebral injections of 5 microl of antibodies to brain-derived neurotrophic factor into the left and right intermediate medial hyperstriatum ventrale resulted in a dose-dependent reduction in avoidance of an "aversive" bead by 3 h after training. Neurotrophin antibodies (0.5 microg/chick) administered between 1 h before, and up to 30 min after, training induced amnesia by 3 h which was sustained for at least 24 h. Injections of recombinant brain-derived neurotrophic factor (50 microg/ml; 0.5 microg/chick) just before training maintained avoidance in birds trained with a weaker aversant (10% methylanthranilate), such that chicks showed enhanced recall at times (24 h) beyond that when shorter-term forms of memory have decayed. In lysed synaptosomal membranes prepared from chicks injected with antibodies to brain-derived neurotrophic factor there was a decrease in expression of SNAP-25 and syntaxin in the left, but not the right, intermediate medial hyperstriatum ventrale, a region known to be associated with memory formation, which correlated with the decrease in neurotrophin concentration. Thus, these data indicate that brain-derived neurotrophic factor is involved in the formation of a long-term memory for an aversive stimulus and may function as a modulator of presynaptic proteins associated with exocytosis, enabling increases in neurotransmitter release.

Dehydroepiandosterone and its sulphate enhance memory retention in day-old chicks.

We report the presence of dehydroepiandosterone (DHEA) and DHEA sulphate (DHEA-S) in the day-old-chick brain, and their possible role in memory formation. DHEA and DHEA-S were present in the brain at higher concentrations than in the plasma. Radioimmunoassay examination of the intermediate medial hyperstriatum ventrale 5 or 30 min after training or the lobus parolfactorius 60 or 120 min after training on the passive avoidance task did not show learning-related differences in absolute levels of DHEA or DHEA-S. However, bilateral intracerebral injections of DHEA or DHEA-S before or after training on the weak passive avoidance task enhanced recall 24 h after training. Memory retention was enhanced by administration of DHEA and DHEA-S 15 min before training or 30 and 60 but not 180 min after training. Neurosteroids are present in high concentrations in regions of the chick brain known to be associated with learning and memory for an aversive one-trial task. Our study demonstrates that memory retention for this task is enhanced by administration of the neurosteroids DHEA-S and DHEA. These findings provide additional evidence that these neurosteroids have memory-enhancing properties and, thus, if common to other tasks and species, that DHEA-S and DHEA may constitute potential therapeutic tools for the treatment of cognitive deficits.

Memory consolidation in day-old chicks requires BDNF but not NGF or NT-3; an antisense study.

Neurotrophins have been implicated in memory consolidation and recall as well as in other forms of neural plasticity. This study examined the effects of Brain-Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF) and Neurotrophin-3 (NT-3) on consolidation of memory for a one-trial passive avoidance task in day-old chicks. In this task chicks, having pecked once at a bitter tasting bead, avoid a similar but dry bead subsequently. Intracerebral administration of antisense ODNs to BDNF 6-12 h prior to training induced amnesia for the avoidance response by 3 h after training. Administration of a "control" scrambled sequence or saline had no effect on recall; chicks continued to avoid the bead. Treatment with BDNF-AS did not inhibit shorter-term recall; amnesia was not present 1 h after training, but prevented longer-term recall, as amnesia was still present 24 h after training. Treatment with BDNF-antisense reduced both BDNF mRNA and BDNF protein in the chick brain, but did not alter mRNA levels of glyceraldehyde-3-phosphate dehydrogenase. By contrast, no effect of antisense to NGF or NT-3 on behaviour was observed, even though administration reduced the mRNA for each. There were no significant effects of any antisense on other behavioural measures at the doses used. Thus we conclude that BDNF has a specific role in memory consolidation for the passive avoidance task.

Isolation-stress-induced facilitation of passive avoidance memory in the day-old chick.

This study showed that facilitation of recall of a weak version of the 1-trial passive avoidance learning task could be achieved by behavioral "stressing" of day-old chicks after training. Recall, usually retained for less than 9 hr, was extended by socially isolating the chicks for 1 hr immediately after training. There was a brief 3-fold increase in plasma corticosterone levels 10 min after isolation. Facilitated recall was not evident when chicks were isolated 2 hr after training, and it was blocked by intracerebral administration of 2-ng RU 38486, a specific glucocorticoid receptor antagonist, per chick. Male chicks responded more to isolation than did female chicks, presumably a consequence of the additional stress of the injection procedure.

Light exposure of chick embryo influences lateralized recall of imprinting memory.

Environmental cues, such as light during the later part of incubation, are known to establish lateralization of some forms of visually guided behaviors in birds. The authors investigated the effect of light on lateralized recall of imprinting memory in chicks. On Day E19 of incubation, one eye was occluded for 24 hr. The other eye received stimulation by light. Chicks were imprinted and then tested for their imprinting preferences after administration of a low dose (500 ng) of glutamate into either hemisphere. Chicks that had the right eye exposed to light during incubation showed recall of the imprinting stimulus after injection of the left hemisphere but not after injection into the right hemisphere. The reverse was found for chicks that had the left eye exposed to light. Hence, the hemisphere ipsilateral to the eye exposed to light before hatching became essential for recall of imprinting memory. The hemisphere used in recall of imprinting memory received indirect visual inputs and was determined by environmental stimulation (asymmetrical light input).

Glutamate and imprinting memory: the role of glutamate receptors in the encoding of imprinting memory.

Glutamate-sensitive receptors have been implicated in many forms of neural plasticity and learning, including imprinting of chicks. Previous studies have indicated that glutamate binding levels in the left intermediate medial hyperstriatum ventrale (IMHV) region of the chick forebrain increase as a correlate of the acquisition of an imprinting memory; however, it has not been determined whether this is due to an increase in the number of glutamate receptors or to increased receptor affinity. The area specificity of these changes, within the left and right hemisphere, was also unexplored. We have performed Scatchard displacement binding analyses to examine changes in both the number and affinity of glutamate receptors in the left and right hyperstriatum ventrale (HV) and also the left and right archistriatal/lobus parolfactorius (AS/LPO) areas from imprinted and non-imprinted chicks. The results of this study demonstrate lateralised increases in both the number and affinity of glutamate receptors in the left HV area at 7-8 h after imprinting. Significant increases in the affinity, but not the number, of glutamate receptors were found in the left AS/LPO. This suggests that the left AS/LPO, which has previously been shown to be involved in the acquisition of a passive avoidance memory, may also be involved in the formation of an imprinting memory.

Exposure to light prior to hatching induces asymmetry of receptor binding in specific regions of the chick forebrain.

This paper describes neurochemical asymmetries present in forebrain regions of the newly hatched chick that result from environmental conditions; specifically from asymmetrical exposure of the chick embryo to light prior to hatching. Quantitative autoradiography was used to determine GABA and glutamate receptor subtype binding in a number of regions of the left and right forebrain hemispheres of chicks that had either the left (LES), or the right (RES), eye system exposed to light prior to hatching. On day 19 of incubation the embryo's head was withdrawn from the egg and the left or the right eye was occulded until hatching. [3H]MK-801, [3H]AMPA and [3H]muscimol binding assays were performed on frozen sections from 2 different coronal regions of the forebrain, sampled on day-1 posthatching. Significant [3H]MK-801, [3H]AMPA and [3H]muscimol binding asymmetries were determined in forebrain regions from chicks that had their RES exposed to light prior to hatching, particularly in forebrain regions which are known to receive afferent visual input. The reverse pattern of asymmetry was found for all 3 ligands in regions such as the ectostriatum of chicks that had their LES exposed to light, while asymmetry of muscimol and AMPA binding, present in many regions in right eye system chicks was not present in chicks that had the left eye system exposed to light during incubation. Thus, the presence and pattern of experience-dependent neurochemical asymmetries in the chick forebrain are specific to both region and receptor type.

[3H]MK-801 binding asymmetry in the IMHV region of dark-reared chicks is reversed by imprinting.

Glutamate NMDA-type receptor binding in the intermediate medial hyperstriatum ventrale (IMHV) of dark-hatched chicks is lateralized. This lateralization was found to be markedly influenced by imprinting. In dark-reared chicks the binding of the selective ligand [3H]MK-801 was two-fold higher in the right IMHV than in the left IMHV. In contrast, imprinted chicks have significantly higher levels of [3H]MK-801 binding in the left IMHV region than in the right IMHV. Imprinting results in 2a learning-related increase in NMDA-type receptor binding levels in the left IMHV, whereas [3H]MK-801 binding levels in the right IMHV remain unchanged by imprinting. Thus, the plasticity present in the NMDA-type receptor system and associated with imprinting appears to occur in the left hemisphere only.