Synthesis of functionalized tryptamines by Brønsted acid catalysed cascade reactions

An original synthetic protocol has been developed for the preparation of highly functionalized tryptamines from 2-hydroxycyclobutanone and secondary arylamines via a solvent-free Brønsted acid catalysed two-step reaction sequence

Palliative care in Dutch hospitals: A rapid increase in the number of expert teams, a limited number of referrals

Background: Palliative care expert teams in hospitals have positive effects on the quality of life and satisfaction with care of patients with advanced disease. Involvement of these teams in medical care is also associated with substantial cost savings. In the Netherlands, professional standards state that each hospital should have a palliative care team by 2017. We studied the number of hospitals that have a palliative care team and the characteristics of these teams. Methods: In April 2015, questionnaires were mailed to key palliative care professionals in all general, teaching and academic hospitals in the Netherlands. Out of 92 hospitals, 74 responded (80 %). Results: Seventy-seven percent of all participating hospitals had a palliative care team. Other services, such as outpatient clinics (22 %), palliative care inpatient units (7 %), and palliative day care facilities (4 %) were relatively scarce. The mean number of disciplines that were represented in the teams was 6,5. The most common disciplines were nurses (72 %) and nurse practitioners (54 %), physicians specialized in internal medicine (90 %) or anaesthesiology (75 %), and spiritual caregivers (65 %). In most cases, the physicians did not have labeled hours available for their work as palliative care consultant, whereas nurses and nurse practitioners did. Most teams (77 %) were only available during office hours. Twenty-six percent of the teams could not only be consulted by healthcare professionals but also by patients or relatives. The annual number of consultations for inpatients per year ranged from 2 to 680 (median: 77). On average, teams were consulted for 0.6 % of all patients admitted to the hospitals. Conclusion: The number of Dutch hospitals with a palliative care team is rapidly increasing. There are substantial differences between teams regarding the disciplines represented in the teams, the procedures and the number of consultations. The development of quality standards and adequate staffing of the teams could improve the quality and effectiveness of the teams

Preparation of Cyclobutene Acetals and Tricyclic Oxetanes through Photochemical Tandem and Cascade Reactions

We describe a photochemical reaction using two starting materials, a cyclopent-2-enone and an alkene, which are transformed in a controlled manner via the initial [2+2]-photocycloaddition adducts into cyclobutene aldehydes (conveniently trapped as stable acetals) or unprecedented angular tricyclic 4:4:4 oxetane-containing skeletons. These compounds are formed through tandem or triple cascade photochemical reaction processes, respectively. Small libraries of each compound class were prepared, thus suggesting that this photochemistry approach opens new opportunities for synthesis design and for widening molecular diversity

Spectrum of Neuroradiologic Findings Associated with Monogenic Interferonopathies

The genetic interferonopathies are a heterogeneous group of disorders thought to be caused by the dysregulated expression of interferons and are now commonly considered in the differential diagnosis of children presenting with recurrent or persistent inflammatory phenotypes. With emerging therapeutic options, recognition of these disorders is increasingly important, and neuroimaging plays a vital role. In this article, we discuss the wide spectrum of neuroradiologic features associated with monogenic interferonopathies by reviewing the literature and illustrate these with cases from our institutions. These cases include intracerebral calcifications, white matter T2 hyperintensities, deep WM cysts, cerebral atrophy, large cerebral artery disease, bilateral striatal necrosis, and masslike lesions. A better understanding of the breadth of the neuroimaging phenotypes in conjunction with clinical and laboratory findings will enable earlier diagnosis and direct therapeutic strategies

Inappropriate end-of-life cancer care in a generalist and specialist palliative care model: a nationwide retrospective population-based observational study

Objectives To evaluate the impact of provision and timing of palliative care (PC) on potentially inappropriate end-of-life care to patients with cancer in a mixed generalist—specialist PC model. Method A retrospective population-based observational study using a national administrative health insurance database. All 43 067 adults in the Netherlands, who were diagnosed with or treated for cancer during the year preceding their death in 2017, were included. Main exposure was either generalist or specialist PC initiated >30 days before death (n=16 967). Outcomes were measured over the last 30 days of life, using quality indicators for potentially inappropriate end-of-life care. Results In total, 14 504 patients (34%) experienced potentially inappropriate end-of-life care; 2732 were provided with PC >30 days before death (exposure group) and 11 772 received no PC or ≤30 days before death (non-exposure group) (16% vs 45%, p30 days before death were 5 times less likely to experience potentially inappropriate end-of-life care (adjusted OR (AOR) 0.20; (95% CI 0.15 to 0.26)) than those with no PC or PC in the last 30 days. Both early (>90 days) and late (>30 and≤90 days) PC initiation had lower odds for potentially inappropriate end-of-life care (AOR 0.23 and 0.19, respectively). Conclusion Timely access to PC in a mixed generalist—specialist PC model significantly decreases the likelihood of potentially inappropriate end-of-life care for patients with cancer. Generalist PC can play a substantial role.Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Effective connectivity reveals strategy differences in an expert calculator

Mathematical reasoning is a core component of cognition and the study of experts defines the upper limits of human cognitive abilities, which is why we are fascinated by peak performers, such as chess masters and mental calculators. Here, we investigated the neural bases of calendrical skills, i.e. the ability to rapidly identify the weekday of a particular date, in a gifted mental calculator who does not fall in the autistic spectrum, using functional MRI. Graph-based mapping of effective connectivity, but not univariate analysis, revealed distinct anatomical location of “cortical hubs” supporting the processing of well-practiced close dates and less-practiced remote dates: the former engaged predominantly occipital and medial temporal areas, whereas the latter were associated mainly with prefrontal, orbitofrontal and anterior cingulate connectivity. These results point to the effect of extensive practice on the development of expertise and long term working memory, and demonstrate the role of frontal networks in supporting performance on less practiced calculations, which incur additional processing demands. Through the example of calendrical skills, our results demonstrate that the ability to perform complex calculations is initially supported by extensive attentional and strategic resources, which, as expertise develops, are gradually replaced by access to long term working memory for familiar material

The changing face of major trauma in the UK

Aim Major trauma (MT) has traditionally been viewed as a disease of young men caused by high-energy transfer mechanisms of injury, which has been reflected in the configuration of MT services. With ageing populations in Western societies, it is anticipated that the elderly will comprise an increasing proportion of the MT workload. The aim of this study was to describe changes in the demographics of MT in a developed Western health system over the last 20 years. Methods The Trauma Audit Research Network (TARN) database was interrogated to identify all cases of MT (injury severity score >15) between 1990 and the end of 2013. Age at presentation, gender, mechanism of injury and use of CT were recorded. For convenience, cases were categorised by age groups of 25 years and by common mechanisms of injury. Longitudinal changes each year were recorded. Results Profound changes in the demographics of recorded MT were observed. In 1990, the mean age of MT patients within the TARN database was 36.1, the largest age group suffering MT was 0–24 years (39.3%), the most common causative mechanism was road traffic collision (59.1%), 72.7% were male and 33.6% underwent CT. By 2013, mean age had increased to 53.8 years, the single largest age group was 25–50 years (27.1%), closely followed by those >75 years (26.9%), the most common mechanism was low falls (39.1%), 68.3% were male and 86.8% underwent CT. Conclusions This study suggests that the MT population identified in the UK is becoming more elderly, and the predominant mechanism that precipitates MT is a fall from <2 m. Significant improvements in outcomes from MT may be expected if services targeting the specific needs of the elderly are developed within MT centres

The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse

Dominant optic atrophy is a rare inherited optic nerve degeneration caused by mutations in the mitochondrial fusion gene OPA1. Recently, the clinical spectrum of dominant optic atrophy has been extended to frequent syndromic forms, exhibiting various degrees of neurological and muscle impairments frequently found in mitochondrial diseases. Although characterized by a specific loss of retinal ganglion cells, the pathophysiology of dominant optic atrophy is still poorly understood. We generated an Opa1 mouse model carrying the recurrent Opa1(delTTAG) mutation, which is found in 30% of all patients with dominant optic atrophy. We show that this mouse displays a multi-systemic poly-degenerative phenotype, with a presentation associating signs of visual failure, deafness, encephalomyopathy, peripheral neuropathy, ataxia and cardiomyopathy. Moreover, we found premature age-related axonal and myelin degenerations, increased autophagy and mitophagy and mitochondrial supercomplex instability preceding degeneration and cell death. Thus, these results support the concept that Opa1 protects against neuronal degeneration and opens new perspectives for the exploration and the treatment of mitochondrial diseases

Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations