Factors Influencing Palliative and End-of-Life Care for Adults with Intellectual Disabilities: A Scoping Review of Health and Care Workers' Experiences.

In developed countries, there has been an increase in the longevity of adults with intellectual disabilities. In the later stages of their lives, people with intellectual disability have specific needs in terms of palliative and end-of-life care that need to be better understood in order to offer appropriate care. This scoping review aimed to identify the main factors influencing the provision of palliative and end-of-life care from the perspective of health and care workers involved with adults with an intellectual disability at the end of life. Seven databases were systematically searched for relevant articles published between 2002 and 2022. NVivo qualitative research analysis software was used to conduct a thematic analysis of the 50 included studies. Three main factors were identified: the location of care and death, the involvement of the person with intellectual disability, and collaborative practices.

How to recognize and diagnose abusive head trauma in infants.

UNLABELLED: Abusive head trauma (AHT) is complex to define for establishing proper diagnosis criteria. This observation complicates greatly the diagnosis process when faced with an infant in consultation. OBJECTIVE: This study aims at clarifying the main criteria to be considered during the medical examination and interview with the social worker. METHOD: An exhaustive literature survey was conducted to examine carefully the symptoms and signs as risk factors proposed to physicians. RESULTS: An analysis of the data available in the literature was quite difficult due to the various methods and the lack of real controlled studies. However, this analysis did show that the initial clinical signs and symptoms that are most frequently encountered are not very specific and can lead to a large differential diagnosis where AHT is often omitted. CONCLUSION: The presence or combination of symptoms, even not highly specific, associated to a lack of a precise alternative diagnosis, especially in children under the age of one, should bring specialist to ask for additional brain imaging exams. The risk factors should not be taken into account for the diagnosis.

Genetic factors determining the functional organization of neural circuits controlling rhythmic movements the murine embryonic parafacial rhythm generator.

In mammals, fetal movements governed by central pattern generators are essential for the development of adaptive behaviors such as breathing, walking, and chewing, which are vital after birth. Combining targeted mutations and genetic fate mapping can help to define the molecular determinants that control the development of these central pattern generators. In this chapter, recent results are presented on the embryonic parafacial (e-pF) rhythm generator, one of the two oscillators involved in controlling the breathing behavior and chemosensitive responsiveness.

Developmental basis of the rostro-caudal organization of the brainstem respiratory rhythm generator.

The Hox genetic network plays a key role in the anteroposterior patterning of the rhombencephalon at pre- and early-segmental stages of development of the neural tube. In the mouse, it controls development of the entire brainstem respiratory neuronal network, including the pons, the parafacial respiratory group (pFRG) and the pre-Bötzinger complex (preBötC). Inactivation of Krox20/Egr2 eliminates the pFRG activity, thereby causing life-threatening neonatal apnoeas alternating with respiration at low frequency. Another respiratory abnormality, the complete absence of breathing, is induced when neuronal synchronization fails to develop in the preBötC. The present paper summarizes data on a third type of respiratory deficits induced by altering Hox function at pontine levels. Inactivation of Hoxa2, the most rostrally expressed Hox gene in the hindbrain, disturbs embryonic development of the pons and alters neonatal inspiratory shaping without affecting respiratory frequency and apnoeas. The same result is obtained by the Phox2a(+/-) mutation modifying the number of petrosal chemoafferent neurons, by eliminating acetylcholinesterase and by altering Hox-dependent development of the pons with retinoic acid administration at embryonic day 7.5. In addition, embryos treated with retinoic acid provide a mouse model for hyperpnoeic episodic breathing, widely reported in pre-term neonates, young girls with Rett's syndrome, patients with Joubert syndrome and adults with Cheyne-Stokes respiration. We conclude that specific respiratory deficits in vivo are assignable to anteroposterior segments of the brainstem, suggesting that the adult respiratory neuronal network is functionally organized according to the rhombomeric, Hox-dependent segmentation of the brainstem in embryos.

L-carnitine, a diet component and organic cation transporter OCTN ligand, displays immunosuppressive properties and abrogates intestinal inflammation.

Allele variants in the L-carnitine (LCAR) transporters OCTN1 (SLC22A4, 1672 C --> T) and OCTN2 (SLC22A5, -207 G --> C) have been implicated in susceptibility to Crohn's disease (CD). LCAR is consumed in the diet and transported actively from the intestinal lumen via the organic cation transporter OCTN2. While recognized mainly for its role in fatty acid metabolism, several lines of evidence suggest that LCAR may also display immunosuppressive properties. This study sought to investigate the immunomodulatory capacity of LCAR on antigen-presenting cell (APC) and CD4+ T cell function by examining cytokine production and the expression of activation markers in LCAR-supplemented and deficient cell culture systems. The therapeutic efficacy of its systemic administration was then evaluated during the establishment of colonic inflammation in vivo. LCAR treatment significantly inhibited both APC and CD4+ T cell function, as assessed by the expression of classical activation markers, proliferation and cytokine production. Carnitine deficiency resulted in the hyperactivation of CD4+ T cells and enhanced cytokine production. In vivo, protection from trinitrobenzene sulphonic acid colitis was observed in LCAR-treated mice and was attributed to the abrogation of both innate [interleukin (IL)-1beta and IL-6 production] and adaptive (T cell proliferation in draining lymph nodes) immune responses. LCAR therapy may therefore represent a novel alternative therapeutic strategy and highlights the role of diet in CD.

Pre-/post-otic rhombomeric interactions control the emergence of a fetal-like respiratory rhythm in the mouse embryo.

How regional patterning of the neural tube in vertebrate embryos may influence the emergence and the function of neural networks remains elusive. We have begun to address this issue in the embryonic mouse hindbrain by studying rhythmogenic properties of different neural tube segments. We have isolated pre- and post-otic hindbrain segments and spinal segments of the mouse neural tube, when they form at embryonic day (E) 9, and grafted them into the same positions in stage-matched chick hosts. Three days after grafting, in vitro recordings of the activity in the cranial nerves exiting the grafts indicate that a high frequency (HF) rhythm (order: 10 bursts/min) is generated in post-otic segments while more anterior pre-otic and more posterior spinal territories generate a low frequency (LF) rhythm (order: 1 burst/min). Comparison with homo-specific grafting of corresponding chick segments points to conservation in mouse and chick of the link between the patterning of activities and the axial origin of the hindbrain segment. This HF rhythm is reminiscent of the respiratory rhythm known to appear at E15 in mice. We also report on pre-/post-otic interactions. The pre-otic rhombomere 5 prevents the emergence of the HF rhythm at E12. Although the nature of the interaction with r5 remains obscure, we propose that ontogeny of fetal-like respiratory circuits relies on: (i) a selective developmental program enforcing HF rhythm generation, already set at E9 in post-otic segments, and (ii) trans-segmental interactions with pre-otic territories that may control the time when this rhythm appears.

Ontogeny of central rhythm generation in chicks and rodents.

Recent studies help in understanding how the basic organization of brainstem neuronal circuits along the anterior-posterior (AP) axis is set by the Hox-dependent segmentation of the neural tube in vertebrate embryos. Neonatal respiratory abnormalities in Krox20(-/-), Hoxa1(-/-) and kreisler mutant mice indicate the vital role of a para-facial (Krox20-dependent, rhombomere 4-derived) respiratory group, that is distinct from the more caudal rhythm generator called Pre-Bötzinger complex. Embryological studies in the chick suggest homology and conservation of this Krox20-dependent induction of parafacial rhythms in birds and mammals. Calcium imaging in embryo indicate that rhythm generators may derive from different cell lineages within rhombomeres. In mice, the Pre-Bötzinger complex is found to be distinct from oscillators producing the earliest neuronal activity, a primordial low-frequency rhythm. In contrast, in chicks, maturation of the parafacial generator is tightly linked to the evolution of this primordial rhythm. It seems therefore that ontogeny of brainstem rhythm generation involves conserved processes specifying distinct AP domains in the neural tube, followed by diverse, lineage-specific regulations allowing the emergence of organized rhythm generators at a given AP level.

The pre-Bötzinger oscillator in the mouse embryo.

Studies of the sites and mechanisms involved in mammalian respiratory rhythm generation point to two clusters of rhythmic neurons forming a coupled oscillator network within the brainstem. The location of these oscillators, the pre-Bötzinger complex (preBötC) at vagal level, and the para-facial respiratory group at facial level, probably result from regional patterning schemes specifying neural types in the hindbrain during embryogenesis. Here, we report evidence that the preBötC oscillator (i) is first active at embryonic stages, (ii) originates in the post-otic hindbrain neural tube and (iii) requires the glutamate vesicular transporter 2 for rhythm generation.

Neural tube patterning by Krox20 and emergence of a respiratory control.

Recent data begin to bridge the gap between developmental events controlling hindbrain neural tube regional patterning and the emergence of breathing behaviour in the fetus and its vital adaptive function after birth. In vertebrates, Hox paralogs and Hox-regulating genes orchestrate, in a conserved manner, the transient formation of developmental compartments in the hindbrain, the rhombomeres, in which rhythmic neuronal networks of the brainstem develop. Genetic inactivation of some of these genes in mice leads to pathological breathing at birth pointing to the vital importance of rhombomere 3 and 4 derived territories for maintenance of the breathing frequency. In chick embryo at E7, we investigated neuronal activities generated in neural tube islands deriving from combinations of rhombomeres isolated at embryonic day E1.5. Using a gain of function approach, we reveal a role of the transcription factor Krox20, specifying rhombomeres 3 and 5, in inducing a rhythm generator at the parafacial level of the hindbrain. The developmental genes selecting and regionally coordinating the fate of CNS progenitors may hold further clues to conserved aspects of neuronal network formation and function. However, the most immediate concern is to take advantage of early generated rhythmic activities in the hindbrain to pursue their downstream cellular and molecular targets, for it seems likely that it will be here that rhythmogenic properties will eventually take on a vital role at birth.

Use of TH-EGFP transgenic mice as a source of identified dopaminergic neurons for physiological studies in postnatal cell culture.

The physiological and pharmacological properties of dopaminergic neurons in the brain are of major interest. Although much has been learned from cell culture studies, the physiological properties of these neurons remain difficult to study in such models because they are usually in minority and are difficult to distinguish from other non-dopaminergic neurons. Here we have taken advantage of a recently engineered transgenic mouse model expressing enhanced green fluorescence protein (EGFP) under the control of the tyrosine hydroxylase promoter to establish a more effective dopaminergic neuron cell culture model. We first evaluated the specificity of the EGFP expression. Although ectopic expression of EGFP was found in cultures derived from postnatal day 0 pups, this decreased over time in culture such that after 2 weeks, approximately 70% of EGFP-expressing neurons were dopaminergic. We next sought to validate this dopaminergic neuron culture model. We evaluated whether EGFP-expressing dopaminergic neurons displayed some of the well-established properties of dopaminergic neurons. Autoreceptor stimulation inhibited the activity of dopaminergic neurons while neurotensin receptor activation produced the opposite effect. Confocal imaging of the synaptic vesicle optical tracer FM4-64 in EGFP-expressing dopaminergic neurons demonstrated the feasibility of high resolution monitoring of the activity of single terminals established by these neurons. Together, this work provides evidence that primary cultures of postnatal TH-EGFP mice currently represent an excellent model to study the properties of these cells in culture.

Genetic and developmental models for the neural control of breathing in vertebrates.

The present paper reviews some of the possible mechanisms that may link gene function in the brainstem and breathing patterns in vertebrates. On one hand, adaptation and acclimatisation of mature breathing to environmental constraints such as hypoxia, involves complex regulation of the gene expression in precise cardiorespiratory sites of the brainstem. On the other hand, targeted inactivation of different genes suggests that postnatal respiratory variables at rest depend on genes controlling the prenatal development of the brainstem. During embryogenesis, neurotrophins (gdnf, bdnf) regulate the survival of specific cellular populations composing the respiratory neuronal network. The expression of developmental genes such as Hox and Krox-20 initiates hindbrain segmentation, the earliest sign of regionalisation in the brainstem. As shown in the chick embryo, segmental specifications allow the establishment of an active embryonic rhythmic network and later insertion of specific neuronal circuits increasing the primordial rhythm frequency to near mature values.

Branchiomotor activities in mouse embryo.

Using a novel isolated hindbrain in vitro preparation, we demonstrate that, in the mouse, branchiomotor activities from trigeminal, facial, glossopharyngeal and vagal nerves start during segmentation, a crucial and conserved period of hindbrain embryogenesis. At embryonic day (E) 10.5, branchiomotor nerves are independently active in bursts, become coactive at a low frequency (about 0.5 min-1) at E12.5, before high frequency (about 15 min-1) fetal breathing starts at E14.5. Comparison with observations in chick reveals a transient episodic rhythmic pattern highly similar in mouse at E13.5 and chick at E7. This pattern is proposed as a marker identifying a phylotypic stage during the development of hindbrain neuronal networks in vertebrates.

Evidence that elevated glucose causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy.

Congenital malformations, including neural tube defects (NTDs), are significantly increased in the offspring of diabetic mothers. We previously reported that in the embryos of a mouse model of diabetic pregnancy, NTDs are associated with reduced expression of the gene Pax-3, which encodes a transcription factor that regulates neural tube development, and that reduced expression of Pax-3 leads to neuroepithelial apoptosis. In this study, we used three approaches to test whether glucose alone could be responsible for these adverse effects of diabetes on embryonic development. First, primary culture of embryo tissue in medium containing 15 mmol/l glucose inhibited Pax-3 expression compared with culture in medium containing 5 mmol/l glucose. Second, inducing hyperglycemia in pregnant mice by subcutaneous glucose administration significantly inhibited Pax-3 expression (P < 0.05), as demonstrated by quantitative reverse transcription-polymerase chain reaction assay of Pax-3 mRNA, and also increased neural tube apoptosis (P < 0.05). NTDs were significantly increased in glucose-injected pregnancies when blood glucose levels were >250 mg/dl (P < 0.002) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.37). Third, phlorizin administration to pregnant diabetic mice reduced blood glucose levels and the rate of NTDs. As seen with glucose-injected pregnancies, the rate of NTDs in phlorizin-treated diabetic pregnancies was related to the severity of hyperglycemia, since NTDs were significantly increased in severely hyperglycemic (>250 mg/dl) diabetic pregnancies (P < 0.001) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.35). These two findings, that elevated glucose alone can cause the changes in Pax-3 expression observed during diabetic pregnancy and that the NTD rate rises with significant increases in blood glucose levels, suggest that congenital malformations associated with diabetic pregnancy are caused by disruption of regulatory gene expression in the embryo in response to elevated glucose.

Segmental specification of GABAergic inhibition during development of hindbrain neural networks.

A primordial rhythm-generating neural network emerges during the segmental period of vertebrate hindbrain development, suggesting a common genetic basis to both the structure and network activity of the region. We show here that segmentation influenced a postsegmental developmental step by which a GABAergic rhythm generator was incorporated into the primordial network and increased rhythm frequency to near mature values. This process depended on specifications in r3 and r5 that controlled, on the basis of a two-segment repeat, later maturation of GABAergic inhibition.

The role of cranial MRI in identifying patients suffering from child abuse and presenting with unexplained neurological findings.

OBJECTIVE: The aim of this study was to demonstrate the usefulness of cerebral MRI to detect possible child abuse in children with unexplained neurologic findings. METHOD: Between 1990 and 1997, 208 children were referred for suspected physical child abuse to the Child Protection Clinic of Ste-Justine Hospital, a tertiary care pediatric hospital. Among them, 39 children presented initially with neurological findings. For 27 of them, the CT Scan results prompted the diagnosis of child abuse. However, in 12 children, even if a CT-Scan was performed, the diagnosis and/or the mechanisms of the neurologic distress remained obscure. Investigation was completed with MRI study in those 12 cases. RESULTS: MRI findings were diagnostic for physical abuse in eight cases. A diagnosis of child abuse was made in two more cases by a combination of MRI and skeletal survey findings. In one case, MRI was suggestive but the diagnosis of child abuse could not be confirmed. One case was misinterpreted as normal. CONCLUSIONS: MRI is the test of choice to rule out child abuse when faced with a child presenting unexplained neurologic signs lasting for few days. The fact that MRI can better differentiate collections of different ages makes this imaging test particularly useful in identifying cases of child abuse. These results, however, always have to be integrated in a well conducted multidisciplinary clinical approach.