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This retrospective cohort study aims to provide a comprehensive account of death in Swedish patients with ALS, including clinical status preceding death, the death setting, as well as symptoms. The study presents detailed information on a cohort of patients with ALS from Stockholm, Sweden, deceased in 2018–2020. In addition, selected information is presented on a larger complementary cohort of ALS patients from all regions of Sweden deceased in 2011–2020. Data were obtained from patient medical records, the Swedish Motor Neuron Disease Quality Registry, and the Swedish Quality Registry of Palliative Care. Ninety-three patients were included in the main cohort and 2224 patients in the complementary cohort. In the main cohort, there was a slow decline in weight and motor function during the 12 months preceding death. Most (93.4%) anticipated/prolonged deaths occurred in a palliative care unit, at home, or in an assisted living facility while 44.8% of precipitous deaths occurred in a hospital ward. Next of kin or health care staff were present at death for most patients (78.7%). In the final week of life, 41.1% experienced at least one symptom (either pain, anxiety, confusion, or dyspnea) that was only partially relieved or not at all. The majority of patients died in their own homes or at a palliative unit in the presence of next of kin and most symptoms were adequately managed. This paper might be used in educating patients, next of kin as well as health professionals, decreasing uncertainty surrounding the end of life. [ABSTRACT FROM AUTHOR]

Objective: To provide a detailed and differentiated description of the path to receiving the correct amyotrophic lateral sclerosis (ALS) diagnosis, including delay times, referrals, alternate diagnoses, and clinical progression. Methods: Medical records until the date of ALS diagnosis were reviewed and linked to the Swedish Motor Neuron Disease Quality Registry. Results: The study included 353 Stockholm ALS patients diagnosed in 2016–2021. Patients were divided into four groups: 117 (33.1%) with lower extremity (LE), 85 (24.1%) with upper extremity (UE), 136 (38.5%) with bulbar, and 15 (4.2%) with respiratory onset. The time from onset to diagnosis was 16.0 (9.4–27.5) months in LE, 12.9 (8.8–17.8) months in UE, 11.7 (7.4–16.0) months in bulbar, and 8.3 (4.7–15.6) months in respiratory onset. Patients with UE or LE onset were often referred to orthopedics or a spinal/hand surgery clinic (29.3% for LE and 41.8% for UE), while bulbar patients were more frequently referred to ENT (66.3%). For those with LE or UE onset, the most common alternate diagnosis was spinal/foraminal stenosis whereas myasthenia gravis and stroke were more common for bulbar onset patients. For the respiratory group, cardiopulmonary diagnoses predominated. The proportion of all patients in King's stage 3 or 4 increased from 11.3% to 46.1% from the initial health care visit to diagnosis. Conclusions: There was great variation in the path to ALS diagnosis according to the onset clinical phenotype. In all groups, the diagnostic delay and clinical progression was substantial. We identified subgroups where the delay was the longest and might be reduced. [ABSTRACT FROM AUTHOR]

Recently, MHC class I molecules have been shown to be important for the retraction of synaptic connections that normally occurs during development [Huh, G.S., Boulanger, L. M., Du, H., Riquelme, P. A., Brotz, T. M. & Shatz, C. J. (2000) Science 290, 2155-2158]. In the adult CNS, a classical response of neurons to axon lesion is the detachment of synapses from the cell body and dendrites. We have investigated whether MHC I molecules are involved also in this type of synaptic detachment by studying the synaptic input to sciatic motoneurons at I week after peripheral nerve transection in [beta]-microglobulin or transporter associated with antigen processing 1-null mutant mice, in which cell surface MHC I expression is impaired. Surprisingly, lesioned motoneurons in mutant mice showed more extensive synaptic detachments than those in wild-type animals. This surplus removal of synapses was entirely directed toward inhibitory synapses assembled in clusters. In parallel, a significantly smaller population of motoneurons reinnervated the distal stump of the transected sciatic nerve in mutants. MHC I molecules, which traditionally have been linked with immunological mechanisms, are thus crucial for a selective maintenance of synapses during the synaptic removal process in neurons after lesion, and the lack of MHC I expression may impede the ability of neurons to regenerate axons. [beta]2-microglobulin | motoneuron | spinal cord | synapse elimination | nerve lesion

Key points: How defects in muscle contractile function contribute to weakness in amyotrophic lateral sclerosis (ALS) were systematically investigated.Weakness in whole muscles from late stage SOD1G93A mice was explained by muscle atrophy as seen by reduced mass and maximal force.On the other hand, surviving single muscle fibres in late stage SOD1G93A have preserved intracellular Ca2+ handling, normal force‐generating capacity and increased fatigue resistance.These intriguing findings provide a substrate for therapeutic interventions to potentiate muscular capacity and delay the progression of the ALS phenotype. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by degeneration and loss of motor neurons, leading to severe muscle weakness and paralysis. The SOD1G93A mouse model of ALS displays motor neuron degeneration and a phenotype consistent with human ALS. The purpose of this study was to determine whether muscle weakness in ALS can be attributed to impaired intrinsic force generation in skeletal muscles. In the current study, motor neuron loss and decreased force were evident in whole flexor digitorum brevis (FDB) muscles of mice in the late stage of disease (125–150 days of age). However, in intact single muscle fibres, specific force, tetanic myoplasmic free [Ca2+] ([Ca2+]i), and resting [Ca2+]i remained unchanged with disease. Fibre‐type distribution was maintained in late‐stage SOD1G93A FDB muscles, but remaining muscle fibres displayed greater fatigue resistance compared to control and showed increased expression of myoglobin and mitochondrial respiratory chain proteins that are important determinants of fatigue resistance. Expression of genes central to both mitochondrial biogenesis and muscle atrophy where increased, suggesting that atrophic and compensatory adaptive signalling occurs simultaneously within the muscle tissue. These results support the hypothesis that muscle weakness in SOD1G93A is primarily attributed to neuromuscular degeneration and not intrinsic muscle fibre defects. In fact, surviving muscle fibres displayed maintained adaptive capacity with an exercise training‐like phenotype, which suggests that compensatory mechanisms are activated that can function to delay disease progression. Key points: How defects in muscle contractile function contribute to weakness in amyotrophic lateral sclerosis (ALS) were systematically investigated.Weakness in whole muscles from late stage SOD1G93A mice was explained by muscle atrophy as seen by reduced mass and maximal force.On the other hand, surviving single muscle fibres in late stage SOD1G93A have preserved intracellular Ca2+ handling, normal force‐generating capacity and increased fatigue resistance.These intriguing findings provide a substrate for therapeutic interventions to potentiate muscular capacity and delay the progression of the ALS phenotype. [ABSTRACT FROM AUTHOR]

Direct electrical recording and stimulation of neural activity using micro-fabricated silicon and metal micro-wire probes have contributed extensively to basic neuroscience and therapeutic applications; however, the dimensional and mechanical mismatch of these probes with the brain tissue limits their stability in chronic implants and decreases the neuron–device contact. Here, we demonstrate the realization of a three-dimensional macroporous nanoelectronic brain probe that combines ultra-flexibility and subcellular feature sizes to overcome these limitations. Built-in strains controlling the local geometry of the macroporous devices are designed to optimize the neuron/probe interface and to promote integration with the brain tissue while introducing minimal mechanical perturbation. The ultra-flexible probes were implanted frozen into rodent brains and used to record multiplexed local field potentials and single-unit action potentials from the somatosensory cortex. Significantly, histology analysis revealed filling-in of neural tissue through the macroporous network and attractive neuron–probe interactions, consistent with long-term biocompatibility of the device., Stem Cell and Regenerative Biology

Abstract: Objectives: Intravital microscopy is a useful tool for studying leukocyte trafficking in atherosclerosis. However, distinction between various subclasses of leukocytes using this technology is lacking. Therefore, we generated ApoE−/−/Lysozyme MEGFP/EGFP mice and investigated whether targeted cell types could be visualized by in vivo microscopy and whether absence of lysozyme M will influence atherosclerosis. Methods: We crossed male ApoE−/− mice with mice homozygous for a knock-in mutation of enhanced green fluorescent protein (EGFP) in the lysozyme M locus (LysEGFP/EGFP) creating ApoE−/−/LysEGFP/EGFP mice. Mice were sacrificed at the age of 26 weeks. Blood was collected for serum lipid analysis, differential white blood cell count and flow cytometry. Lesion area was determined on en face mounted aortas and sections from aortic roots were stained for immunohistochemistry. Atherosclerotic lesions were also studied by confocal- and intravital microscopy. Results: Basic parameters, such as white blood cell count, cholesterol profile, lesion area and plaque composition was unaltered in ApoE−/−/LysEGFP/EGFP mice compared to ApoE−/− mice. Fluorescent neutrophils and monocytes were clearly visualized by intravital fluorescence and confocal microscopy. Fluorescent cells were distributed primarily in the periphery of atherosclerotic lesions indicating a preference for recruitment in these areas. Conclusions: ApoE−/−/LysEGFP/EGFP mice will serve as a useful model to study leukocyte trafficking in atherosclerosis and how different subsets of leukocytes influence atherogenesis. [Copyright &y& Elsevier]

The generation of human pluripotent stem cell (hPSC)-derived ventricular progenitors and their assembly into a 3-dimensional in vivo functional ventricular heart patch has remained an elusive goal. Herein, we report the generation of an enriched pool of hPSC-derived ventricular progenitors (HVPs), which can expand, differentiate, self-assemble, and mature into a functional ventricular patch in vivo without the aid of any gel or matrix. We documented a specific temporal window, in which the HVPs will engraft in vivo. On day 6 of differentiation, HVPs were enriched by depleting cells positive for pluripotency marker TRA-1-60 with magnetic-activated cell sorting (MACS), and 3 million sorted cells were sub-capsularly transplanted onto kidneys of NSG mice where, after 2 months, they formed a 7 mm × 3 mm × 4 mm myocardial patch resembling the ventricular wall. The graft acquired several features of maturation: expression of ventricular marker (MLC2v), desmosomes, appearance of T-tubule-like structures, and electrophysiological action potential signature consistent with maturation, all this in a non-cardiac environment. We further demonstrated that HVPs transplanted into un-injured hearts of NSG mice remain viable for up to 8 months. Moreover, transplantation of 2 million HVPs largely preserved myocardial contractile function following myocardial infarction. Taken together, our study reaffirms the promising idea of using progenitor cells for regenerative therapy., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Intravital microscopy is a useful tool for studying leukocyte trafficking in atherosclerosis. However, distinction between various subclasses of leukocytes using this technology is lacking. Therefore, we generated ApoE(-/-)/Lysozyme M(EGFP/EGFP) mice and investigated whether targeted cell types could be visualized by in vivo microscopy and whether absence of lysozyme M will influence atherosclerosis., Methods: We crossed male ApoE(-/-) mice with mice homozygous for a knock-in mutation of enhanced green fluorescent protein (EGFP) in the lysozyme M locus (Lys(EGFP/EGFP)) creating ApoE(-/-)/Lys(EGFP/EGFP) mice. Mice were sacrificed at the age of 26 weeks. Blood was collected for serum lipid analysis, differential white blood cell count and flow cytometry. Lesion area was determined on en face mounted aortas and sections from aortic roots were stained for immunohistochemistry. Atherosclerotic lesions were also studied by confocal- and intravital microscopy., Results: Basic parameters, such as white blood cell count, cholesterol profile, lesion area and plaque composition was unaltered in ApoE(-/-)/Lys(EGFP/EGFP) mice compared to ApoE(-/-) mice. Fluorescent neutrophils and monocytes were clearly visualized by intravital fluorescence and confocal microscopy. Fluorescent cells were distributed primarily in the periphery of atherosclerotic lesions indicating a preference for recruitment in these areas., Conclusions: ApoE(-/-)/Lys(EGFP/EGFP) mice will serve as a useful model to study leukocyte trafficking in atherosclerosis and how different subsets of leukocytes influence atherogenesis.

The Schwann cell basal lamina (BL) is required for normal myelination. Loss or mutations of BL constituents, such as laminin-2 (alpha2beta1gamma1), lead to severe neuropathic diseases affecting peripheral nerves. The function of the second known laminin present in Schwann cell BL, laminin-8 (alpha4beta1gamma1), is so far unknown. Here we show that absence of the laminin alpha4 chain, which distinguishes laminin-8 from laminin-2, leads to a disturbance in radial sorting, impaired myelination, and signs of ataxia and proprioceptive disturbances, whereas the axonal regenerative capacity is not influenced. In vitro studies show poor axon growth of spinal motoneurons on laminin-8, whereas it is extensive on laminin-2. Schwann cells, however, extend longer processes on laminin-8 than on laminin-2, and, in contrast to the interaction with laminin-2, solely use the integrin receptor alpha6beta1 in their interaction with laminin-8. Thus, laminin-2 and laminin-8 have different critical functions in peripheral nerves, mediated by different integrin receptors.