Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
784
result(s) for
"Hamilton, Susan"
Sort by:
أنا إنسان : كتاب عن التعاطف
\"أنا إنسان\" هي قصة ما يعنيه أن تكون إنسانا كفرد داخل مجتمعنا الإنساني. كبشر نحن معرضون لارتكاب الكثير من الأخطاء لكننا نمتلك القدرة على اختيار الطريقة التي سنتعامل بها مع تلك الأخطاء للتعلم منها والتغير إلى الأفضل، والتعامل بلطف مع الآخرين، حتى حين يكون ذلك صعبا. قصة \"أنا إنسان\" تؤكد على أننا نمتلك القدرة دائما على الاختيار، واتخاذ القرارات الجيدة، بالحب والرحمة والتعاطف مع بعضنا البعض، ومع أنفسنا أيضا، فحين نجد أرضية مشتركة بيننا وبين الآخر، سنشعر بارتباطنا بهذا العالم العظيم وبكل ما حولنا، وسنسعى جاهدين لنكون أفضل ما لدينا.
Book
Use of Antidepressants During Pregnancy?: What to Consider when Weighing Treatment with Antidepressants Against Untreated Depression
Introduction
Mood disorders impact many pregnant women, particularly those who have experienced symptoms prior to conception, and there are significant barriers, including stigma and access, to seeking and receiving appropriate treatments. Antidepressants are a helpful option in treating perinatal depression, but research on risks and benefits of antidepressant use in pregnancy is difficult given lack of “gold standard” comparative trials.
Methods
This paper summarizes current state of knowledge on the safety of antidepressants during pregnancy by providing a summary of the literature published in the past 3 years (January 2013–October 2015). We identified 21 reviews and meta-analyses that were included in this summary report. This report is meant to provide a user-friendly, yet comprehensive guide summarizing the abundant, and in part contradicting, literature on risks and benefits of antidepressants during pregnancy, in order to assist busy primary care prescribers in educating their patients. Our goal is also to contrast the risks/benefits of untreated depression in pregnancy versus treatment with antidepressant medication in pregnancy, and in such support prescribers in their decision-making.
Results
The past 3 years have yielded an abundance of publications on the topic, in part, with conflicting findings adding to confusion and concern among providers, patients, and their families. Many reported studies have methodological problems limiting their impact. Data on adverse effects of medications on pregnancy and fetal outcomes have to be weighed against the impact of untreated illness and poor health habits associated with untreated illness on the same outcomes.
Discussion
Medical-decision making is often complex and seldom free of risks. Obviously, as providers we cannot guarantee that fetal exposure to antidepressants is totally free of risk, yet this is true for any medicine taken in pregnancy. However, to date, perinatal psychiatry has collected enough evidence to suggest that, if the clinical picture warrants it, the use of many antidepressants, especially the SSRIs, is favorable compared to exposing mother and child to untreated depressive illness.
Journal Article
Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature
The
RYR1
gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and
RYR1
variations that impair calcium homeostasis and increase susceptibility to malignant hyperthermia were first identified in 1991. Since then,
RYR1
-related myopathies (
RYR1
-RM) have been described as rare, histopathologically and clinically heterogeneous, and slowly progressive neuromuscular disorders.
RYR1
variants can lead to dysfunctional RyR1-mediated calcium release, malignant hyperthermia susceptibility, elevated oxidative stress, deleterious post-translational modifications, and decreased RyR1 expression.
RYR1
-RM-affected individuals can present with delayed motor milestones, contractures, scoliosis, ophthalmoplegia, and respiratory insufficiency.
Historically,
RYR1
-RM-affected individuals were diagnosed based on morphologic features observed in muscle biopsies including central cores, cores and rods, central nuclei, fiber type disproportion, and multi-minicores. However, these histopathologic features are not always specific to
RYR1
-RM and often change over time. As additional phenotypes were associated with
RYR1
variations (including King-Denborough syndrome, exercise-induced rhabdomyolysis, lethal multiple pterygium syndrome, adult-onset distal myopathy, atypical periodic paralysis with or without myalgia, mild calf-predominant myopathy, and dusty core disease) the overlap among diagnostic categories is ever increasing. With the continuing emergence of new clinical subtypes along the
RYR1
disease spectrum and reports of adult-onset phenotypes, nuanced nomenclatures have been reported (
RYR1
- [related, related congenital, congenital] myopathies). In this narrative review, we provide historical highlights of
RYR1
research, accounts of the main diagnostic disease subtypes and propose
RYR1
-related disorders (
RYR1
-RD) as a unified nomenclature to describe this complex and evolving disease spectrum.
Journal Article
Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility
Exertional heat illness (EHI) and malignant hyperthermia (MH) are life threatening conditions associated with muscle breakdown in the setting of triggering factors including volatile anesthetics, exercise, and high environmental temperature. To identify new genetic variants that predispose to EHI and/or MH, we performed genomic sequencing on a cohort with EHI/MH and/or abnormal caffeine-halothane contracture test. In five individuals, we identified rare, pathogenic heterozygous variants in
ASPH
, a gene encoding junctin, a regulator of excitation-contraction coupling. We validated the pathogenicity of these variants using orthogonal pre-clinical models, CRISPR-edited C2C12 myotubes and transgenic zebrafish. In total, we demonstrate that
ASPH
variants represent a new cause of EHI and MH susceptibility.
The genetic cause(s) of malignant hyperthermia and exertional heat illness are unknown in approximately 30% of cases. To address this barrier, the authors performed genome sequencing on a large cohort of cases, identifying rare variants in
ASPH
, a gene encoding junctin, and validating them in animal and cell models.
Journal Article
MyoSight—semi-automated image analysis of skeletal muscle cross sections
Background
Manual analysis of cross-sectional area, fiber-type distribution, and total and centralized nuclei in skeletal muscle cross sections is tedious and time consuming, necessitating an accurate, automated method of analysis. While several excellent programs are available, our analyses of skeletal muscle disease models suggest the need for additional features and flexibility to adequately describe disease pathology. We introduce a new semi-automated analysis program, MyoSight, which is designed to facilitate image analysis of skeletal muscle cross sections and provide additional flexibility in the analyses.
Results
We describe staining and imaging methods that generate high-quality images of immunofluorescent-labelled cross sections from mouse skeletal muscle. Using these methods, we can analyze up to 5 different fluorophores in a single image, allowing simultaneous analyses of perinuclei, central nuclei, fiber size, and fiber-type distribution. MyoSight displays high reproducibility among users, and the data generated are in close agreement with data obtained from manual analyses of cross-sectional area (CSA), fiber number, fiber-type distribution, and number and localization of myonuclei. Furthermore, MyoSight clearly delineates changes in these parameters in muscle sections from a mouse model of Duchenne muscular dystrophy (mdx).
Conclusions
MyoSight is a new program based on an algorithm that can be optimized by the user to obtain highly accurate fiber size, fiber-type identification, and perinuclei and central nuclei per fiber measurements. MyoSight combines features available separately in other programs, is user friendly, and provides visual outputs that allow the user to confirm the accuracy of the analyses and correct any inaccuracies. We present MyoSight as a new program to facilitate the analyses of fiber type and CSA changes arising from injury, disease, exercise, and therapeutic interventions.
Journal Article
A chemical chaperone improves muscle function in mice with a RyR1 mutation
Mutations in the
RYR1
gene cause severe myopathies. Mice with an I4895T mutation in the type 1 ryanodine receptor/Ca
2+
release channel (RyR1) display muscle weakness and atrophy, but the underlying mechanisms are unclear. Here we show that the I4895T mutation in RyR1 decreases the amplitude of the sarcoplasmic reticulum (SR) Ca
2+
transient, resting cytosolic Ca
2+
levels, muscle triadin content and calsequestrin (CSQ) localization to the junctional SR, and increases endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and mitochondrial ROS production. Treatment of mice carrying the I4895T mutation with a chemical chaperone, sodium 4-phenylbutyrate (4PBA), reduces ER stress/UPR and improves muscle function, but does not restore SR Ca
2+
transients in I4895T fibres to wild type levels, suggesting that decreased SR Ca
2+
release is not the major driver of the myopathy. These findings suggest that 4PBA, an FDA-approved drug, has potential as a therapeutic intervention for RyR1 myopathies that are associated with ER stress.
Mutations in the RyR1 channel cause core myopathies. Here the authors show that ER stress and the unfolded protein response underlie the pathology caused by a common RyR1 channel mutation, and show that treatment with a chemical chaperone restores muscle function in mice.
Journal Article
Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation
Mutations in the skeletal muscle Ca
2+
release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in
Ryr1
(Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with
RYR1
mutations and YS mice due to Ca
2+
driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with
RYR1
pathogenic variants.
Individuals with malignant hyperthermia susceptibility (MHS) suffer from lifethreatening responses to heat. Here the authors demonstrate that adaptive thermogenesis from brown adipose tissue contributes to this heat sensitivity in a preclinical mouse model of MHS
Journal Article
Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice
Blockade of cholinergic neurotransmission by muscarinic receptor antagonists produces profound deficits in attention and memory. However, the antagonists used in previous studies bind to more than one of the five muscarinic receptor subtypes. Here we examined memory in mice with a null mutation of the gene coding the M
1
receptor, the most densely distributed muscarinic receptor in the hippocampus and forebrain. In contrast with previous studies using nonselective pharmacological antagonists, the M
1
receptor deletion produced a selective phenotype that included both enhancements and deficits in memory. Long-term potentiation (LTP) in response to theta burst stimulation in the hippocampus was also reduced in mutant mice. M
1
null mutant mice showed normal or enhanced memory for tasks that involved matching-to-sample problems, but they were severely impaired in non-matching-to-sample working memory as well as consolidation. Our results suggest that the M
1
receptor is specifically involved in memory processes for which the cortex and hippocampus interact.
Journal Article
Characterization and temporal development of cores in a mouse model of malignant hyperthermia
Malignant hyperthermia (MH) and central core disease are related skeletal muscle diseases often linked to mutations in the type 1 ryanodine receptor (RYR1) gene, encoding for the Ca²⁺ release channel of the sarcoplasmic reticulum (SR). In humans, the Y522S RYR1 mutation is associated with malignant hyperthermia susceptibility (MHS) and the presence in skeletal muscle fibers of core regions that lack mitochondria. In heterozygous Y522S knock-in mice (RYR1Y⁵²²S/WT), the mutation causes SR Ca²⁺ leak and MHS. Here, we identified mitochondrial-deficient core regions in skeletal muscle fibers from RYR1Y⁵²²S/WT knock-in mice and characterized the structural and temporal aspects involved in their formation. Mitochondrial swelling/disruption, the initial detectable structural change observed in young-adult RYR1Y⁵²²S/WT mice (2 months), does not occur randomly but rather is confined to discrete areas termed presumptive cores. This localized mitochondrial damage is followed by local disruption/loss of nearby SR and transverse tubules, resulting in early cores (2-4 months) and small contracture cores characterized by extreme sarcomere shortening and lack of mitochondria. At later stages (1 year), contracture cores are extended, frequent, and accompanied by areas in which contractile elements are also severely compromised (unstructured cores). Based on these observations, we propose a possible series of events leading to core formation in skeletal muscle fibers of RYR1Y⁵²²S/WT mice: Initial mitochondrial/SR disruption in confined areas causes significant loss of local Ca²⁺ sequestration that eventually results in the formation of contractures and progressive degradation of the contractile elements.
Journal Article