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Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma having a poor overall survival that is in need for the development of new therapeutics. In this study, we report the identification and expression of a new isoform splice variant of the tyrosine kinase receptor AXL in MCL cells. This new AXL isoform, called AXL3, lacks the ligand-binding domain of the commonly described AXL splice variants and is constitutively activated in MCL cells. Interestingly, functional characterization of AXL3, using CRISPR inhibition, revealed that only the knock down of this isoform leads to apoptosis of MCL cells. Importantly, pharmacological inhibition of AXL activity resulted in a significant decrease in the activation of well-known proproliferative and survival pathways activated in MCL cells (ie, β-catenin, Ak strain transforming, and NF-κB). Therapeutically, preclinical studies using a xenograft mouse model of MCL indicated that bemcentinib is more effective than ibrutinib in reducing the tumor burden and to increase the overall survival. Our study highlights the importance of a previously unidentified AXL splice variant in cancer and the potential of bemcentinib as a targeted therapy for MCL., (© 2023 by The American Society of Hematology.)

Density-dependent prey depletion around breeding colonies has long been considered an important factor controlling the population dynamics of colonial animals. 1-4 Ashmole proposed that as seabird colony size increases, intraspecific competition leads to declines in reproductive success, as breeding adults must spend more time and energy to find prey farther from the colony. 1 Seabird colony size often varies over several orders of magnitude within the same species and can include millions of individuals per colony. 5 , Using tracking data from murres (Uria spp.), the world's most densely breeding seabirds, we show that the distribution of foraging-trip distances scales to colony size 6 during the chick-rearing stage, consistent with Ashmole's halo theory. 6 This pattern occurred across colonies varying in size over three orders of magnitude and distributed throughout the North Atlantic region. The strong relationship between colony size and foraging range means that the foraging areas of some colonial species can be estimated from colony sizes, which is more practical to measure over a large geographic scale. Two-thirds of the North Atlantic murre population breed at the 16 largest colonies; by extrapolating the predicted foraging ranges to sites without tracking data, we show that only two of these large colonies have significant coverage as marine protected areas. Our results are an important example of how theoretical models, in this case, Ashmole's version of central-place-foraging theory, can be applied to inform conservation and management in colonial breeding species.0 .33 during the chick-rearing stage, consistent with Ashmole's halo theory. 1 , 2 This pattern occurred across colonies varying in size over three orders of magnitude and distributed throughout the North Atlantic region. The strong relationship between colony size and foraging range means that the foraging areas of some colonial species can be estimated from colony sizes, which is more practical to measure over a large geographic scale. Two-thirds of the North Atlantic murre population breed at the 16 largest colonies; by extrapolating the predicted foraging ranges to sites without tracking data, we show that only two of these large colonies have significant coverage as marine protected areas. Our results are an important example of how theoretical models, in this case, Ashmole's version of central-place-foraging theory, can be applied to inform conservation and management in colonial breeding species., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that remains incurable with the treatment options available today. In the present study, we have identified the dihydroorotate dehydrogenase (DHODH), an essential enzyme for the  de novo  biosynthesis of pyrimidine-based nucleotides, to be overexpressed in MCL in comparison to healthy peripheral blood mononuclear cells (PBMC). In vitro inhibition of the DHODH activity using a newly developed DHODH inhibitor, namely ( R )-HZ05, can induce MCL cell death in the nanomolar range independently than the P53 status of the investigated cell lines. Moreover, the combination of ( R )-HZ05 with tyrosine kinase inhibitor shows the synergistic activity on cell death. Pre-clinical investigation on the efficacy of ( R )-HZ05 shows that it can be prolonged animal lifespan similar to ibrutinib. ( R )-HZ05 use in combination with tyrosine kinase inhibitor demonstrated a superior efficacy on tumor burden reduction and survival than either drug alone. We have demonstrated that the depletion of the pyrimidine nucleotide pool, using DHODH inhibitor, represents a new therapeutic strategy that may benefit MCL patients., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

The timing of annual events such as reproduction is a critical component of how free-living organisms respond to ongoing climate change. This may be especially true in the Arctic, which is disproportionally impacted by climate warming. Here, we show that Arctic seabirds responded to climate change by moving the start of their reproduction earlier, coincident with an advancing onset of spring and that their response is phylogenetically and spatially structured. The phylogenetic signal is likely driven by seabird foraging behavior. Surface-feeding species advanced their reproduction in the last 35 years while diving species showed remarkably stable breeding timing. The earlier reproduction for Arctic surface-feeding birds was significant in the Pacific only, where spring advancement was most pronounced. In both the Atlantic and Pacific, seabirds with a long breeding season showed a greater response to the advancement of spring than seabirds with a short breeding season. Our results emphasize that spatial variation, phylogeny, and life history are important considerations in seabird phenological response to climate change and highlight the key role played by the species' foraging behavior., (© 2019 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

A high percentage of patients with borderline personality disorder (BPD) are prescribed psychotropic medications. Recent meta-analyses of randomized controlled trials suggested evidence of effects of antiepileptics on impulsivity and anger and of atypical antipsychotics on cognitive-perceptual symptoms and anger. Antidepressants had no or negligible effect. Total BPD severity was not significantly reduced by pharmacotherapy. Longitudinal studies suggest that BPD tends to improve, but it is not clarified whether long-term pharmacotherapy make the naturalistic recovery occur more rapidly.

Delirium is a common neuropsychiatric complication to acute physical illness in older, hospitalized patients. It is associated with a poor outcome. The pathophysiogenesis is unknown. The neurochemical and neuroinflammatory hypotheses are supported increasingly. Short-term, low-dose haloperidole is still the best choice of treatment in controlling symptoms in hyperactive delirium, but atypical antipsychotics are probably equally efficacious. Antipsychotics also appear to have a beneficial role in hypoactive delirium, but the evidence is weak. There is a weak evidence of effect of prophylactic, non-pharmacological interventions.

In the County of Funen (population 460,000) 120 homeless people resided in shelters for homeless people during week 49, 1996. Of these homeless persons, 94 (or 78%) were examined using ICD-10 and the Addiction Severity Index. Ninety percent were men, 90% were aged 20-59 years, 98% were unmarried or separated/divorced. Seventy-one percent had lived alone during the past three years, only 2% were employed, and sources of income for 83% were public assistance or disability pensions. The population of homeless people was divided into three groups: 1) Psychoses were found in 13 cases or 14%--schizophrenia (4%), paranoid psychosis (4%) and affective disorder (5%). About 2/3 had double disorder, psychosis plus substance abuse. 2) Sixty-four or 68% were non-psychotic homeless people, who had alcohol/substance abuse (53 or 83%) and/or personality disorder (57 or 89%). 3) Seventeen or 18% had no mental illness. About 60% had been sentenced to prison at least once. About 20% needed psychiatric treatment.

The question has been raised whether the change from hospital to community psychiatry is accompanied by an increasing number of the mentally ill in institutions for homeless people. During week 49, 1996, the residents in institutions for homeless people in the County of Funen were interviewed and diagnosed according to ICD-8, and the results were compared with a similar study from week 47, 1990. The prevalence of psychoses was 11% in 1990 and 14% in 1996. This difference was not significant. Significantly fewer psychotic homeless people were treated for their psychotic disorders in 1996 compared with 1990. The prevalence of alcoholics had fallen by 35%, while the prevalence of narcotics and cannabis addicts had risen by 78% and 110%, respectively. These changes were statistically significant. There was still a high prevalence of personality disorders, 70% in 1990 and 60% in 1996. Even though the deinstitutionalization of the psychiatric service has not been accompanied by more psychotic patients in institutions for the homeless, the clientele is still heavily strained with psychosis, personality disorder and substance abuse.

The present study covers 375 consecutive patients referred to the three outpatient clinics at the Psychiatric Department of Odense University Hospital from November 1995 to February 1997. The aim of the study was to describe differences in problem profiles for men and women. All patients were assessed by means of the Addiction Severity Index at admission. All patients needed treatment for alcohol problems. Significantly more female alcoholics, however, had problems with mental health, physical health, drug use and family/social life. More men than women had legal problems. Almost half of the women had previously attempted to commit suicide, and almost one third of the women suffered from anxiety disorder at the time of admission. Significantly more women than men had partner who also had an alcohol problem.

Of 181 alcoholics who consecutively sought treatment as out- or inpatients, 68 (37.6%) had attempted suicide at least once. Compared with non-attempters, the suicide attempters were significantly more likely to be female, have had a chaotic upbringing and to have known suicide attempts in the family and social circle. Significantly more attempters suffered from depressive disorder, feelings of hopelessness, anxiety attacks, agoraphobia, substance abuse or cluster B personality disorders (dissocial, impulsive, borderline, and histrionic). Also significantly more suicide attempters had committed crimes and received early pension. Assessment of coping showed that suicide attempters had a significantly lower tendency to make plans or to make the best of a stressful situation by growing from it. They were significantly more likely to show mental disengagement, to resort to denial and drink alcohol or take drugs when faced with stressful events or difficulties. When evaluated on the Addiction Severity Index Scale, the suicide attempters were found to have a significantly greater need of treatment.

Three hundred and thirty individuals (80% of the total staff members at a Department of Psychiatry) completed a questionnaire concerning their exposure to patient violence. It was found that over 90% of physicians, nurses and nursing aides had been subjected to patient violence at least once during the entire course of their employment in departments of psychiatry. The following percentages were found for incidents of patients violence occurring during a one year period towards staff while employed in departments of psychiatry: residents (17%), nurses (36%), and nursing aides (52%). The highest frequency was found for nursing staff working in closed wards (75%). Length of employment, and thereby the staff's experience, was not related to exposure to patient violence. Neither sex nor age of the nursing staff were significantly associated with their exposure to patient violence. About 1/3 of the nurses and nursing aides had considered changing their job because of patient violence.

The purpose of the study was to investigate whether deinstitutionalization of psychiatric patients had produced a clientele of homeless mentally ill people which is not treated. During week 47, 1990, 94 of the 129 residents 73%) in the institutions for homeless people in the County of Funen (population 459,000) were examined for mental illness by a psychiatrist. Diagnoses were made using the ICD-8 classification. Social data were recorded. Eighty-nine per cent were men, 59% were aged 30-49 years, 93% were single, and source of incomes for 80% were public assistance or disability pensions. More than half had been sentenced for crime at least once. The majority suffered from severe psychosocial strain. In 91% a psychiatric diagnosis was established, the most frequent being alcoholism (73%) and personality or character disorder (70%). Psychoses were found in 10 cases or 11%. About 29% required psychiatric treatment. The conclusion was that deinstitutionalization in the County of Funen had not resulted in influx of psychotic persons to institutions for the homeless people.

The circumstances of life and the need for social support were investigated in 142 patients with prolonged psychiatric illness who sought help consecutively in the psychiatric casualty department or who were referred to the psychiatric department of Odense Hospital during the period 11 Sep. 1989-31 Dec. 1989. 80% of these were psychotic and 20% were borderline psychotic. Approximately 90% were young adults (20-49 years). Schizophrenic men predominated. More than 40% of all the patients had some form of addiction as a contributory diagnosis and 71% of the patients with borderline psychoses were addicts. Approximately 3/4 of the patients lived alone in flats. The level of occupational training was low as compared with the remainder of the population. The majority received early pensions. The majority lived in social isolation from the remainder of the community. Only a single patient had no fixed abode but suitable forms of residence where social support could be given were insufficient. Similarly, the requirements for possible employment and leisure activities were great.

During the period 23.11.1987-22.11.1989, a total of 7,906 patients attended the psychiatric outpatient department and observation section on 12,469 occasions. Sixty patients (0.8%) behaved violently on 85 occasions. None of these episodes of violence resulted in injuries to persons requiring medical attention. 90% of the violent patients were men and 70% were in the age group 20-39 years. Approximately 1/5 were psychotic and, of these, approximately half suffered from schizophrenia. Comparison with the non-violent patient revealed that the probability of violence was greater if the patient was a man under the influence of alcohol and who had the diagnoses of narcomania, drug abuse or personality disorders. Significantly fewer violent patients were admitted than non-violent patients. Over 80% of the violent patients had previously been admitted to psychiatric departments. Approximately 60% had behaved violently on previous consultations with the psychiatric outpatient department.

The majority of psychiatric patients are not violent during hospitalisation. A minority behave violently during hospitalisation on repeated occasions but violent episodes are mainly concerned and these do not result in corporeal injuries. Gross violence rarely occurs. Violence involves the caring staff most frequently and, more rarely, fellow patients. The patients who are most frequently violent are the most severely ill and untreated psychotic patients. The commonest diagnosis among the violent patients is schizophrenia. Younger patients are often violent. No sex differences exist for violent behaviour. Manic patients are rarely violent and depressive illness is negatively correlated with violence. Approximately 1/5 of the demented patients show violent behaviour. The review demonstrates many methodological deficiencies in the investigations mentioned and presents recommendations concerning the design of investigations in future investigations.

Violence is commonest in emergency and closed departments. Lack of structure in the department and inactivity together with an authoritarian staff attitude may increase the frequencies of violent episodes. Too much therapeutic activity may also cause violence in the department. In order to reduce the frequency of episodes of violence, the staff must be adequate in number. Good contact with the patients may have a preventative effect on violence. The experience of the care staff in the treatment of psychiatric patients is of considerable significance. Massive staff changes with appointment of less experienced care staff and many temporary staff members in the department may increase the extent of violence. Training of the staff in the technique of controlling aggression may improve their ability to cope with violent situations. The effect of staff training may depend upon the content of the training programme. Medical assistance may increase the staff capacity to manage difficult situations such as violent episodes. Leaders have considerable influence on the factors which can reduce the extent of violence. Previous investigations show many methodological defects and new investigations are necessary.

The frequency of depressive illness was investigated in 195 patients who had been referred consecutively after attempted suicide during the period 15. February 1989-15, October 1989. A total of 130 of these patients were admitted to hospital while the remainder were treated in the psychiatric emergency room or admission department. Registration of depressive symptoms on admission revealed that 85% had depressed mood and other depressive symptoms. According to the criteria established by Feighner et al. 51% suffered from definite depressive disease on admission. According to Zung's Depression Scale, 60% were depressed. On the basis of observations during hospitalization, 25% suffered from depressive disease according to the criteria established by Feighner et al. 19% of these patients suffered from endogenic depression according to the Newcastle I scale which corresponds to 5% of all the hospitalized patients with attempted suicide. Approximately 10% were treated with antidepressives. Only 8% were discharged with the diagnoses of endogenic or reactive psychoses (ICD-8). It is concluded that depressive symptoms occur in the majority of patients with attempted suicide but that slight non-endogenic depressive states are most commonly concerned and that many of these improve rapidly during hospitalization without medicinal treatment. Restraint should be observed in prescription of antidepressive medicine to patients with attempted suicide until the diagnosis of depressive disease is verified.

All patients attending the psychiatric emergency clinic at Odense University Hospital in the period 2.9-6.10.1985 were interviewed by a psychiatric nurse and physician in order to determine disease pattern and social circumstances. The present investigation deals with sex distribution of alcoholics in the data collected. In the period, 141 patients with alcoholic problems were registered; of these 97 were men and 44 women. It was found that more female alcoholics than male were married/cohabiting. Unemployment was very high for both groups; almost 80 per cent being unemployed. A great number of the women had interpersonal conflicts, but apart from that the sex difference for amount of psychosocial strain was not significant. Drug abuse and affective reactions were significantly more frequent in women. More women than men were found to suffer from character neuroses, and more men than women were deviants, but this may be a reflection of a diagnostic tradition. It must be concluded that more similarities than differences were found between male and female alcoholics attending the psychiatric emergency department.

The frequency of psychosocial strain was systematically registered concerning 330 consecutive patients in the psychiatric emergency unit in Odense. Psychosocial strain was found in 211 patients (63.9%). In all, 551 stressful events were reported, which corresponds 2.5 per patient. Distribution of psychosocial strain by age, sex and civil status revealed no statistically significant correlation at the level of p less than 0.05, but there was a tendency towards greater strain among young persons, women and married/cohabiant patients. All those seeking education had psychosocial strain, while there were significantly fewer patients with psychosocial strain among early retirees and old age pensioners. The investigation showed that there were significantly fewer schizophrenic patients with psychosocial strain, and significantly more patients with strain were found among those with affective reactions and attempted suicides compared with the other patient categories. The most frequently occurring form of strain in all diagnosis groups was interpersonal conflict with a close person. In most cases the strain was not the result of an external catastrophe, and often the patient may himself have contributed in causing the psychosocial strain. This opens the possibility for socialpsychiatric intervention.