The burden of atopic dermatitis in Australia: Medical care, treatment satisfaction, financial impact, long-term control and quality of life.

Atopic dermatitis patients and caregivers experience a high physical, mental and financial burden in Australia. We outline how the current care model impacts disease management and patients' quality of life via a survey of 265 Australian patients and caregivers to capture the experience of managing atopic dermatitis (AD) in Australia. Patients report an unsatisfactory quality of life and a high burden of disease with poor long-term control and low treatment satisfaction. They also reported changing spending and saving patterns to fund medical care. Patient experience improves with more specialised care that incorporates shared decision-making and patient/caregiver training beyond the clinic visit. These results highlight the need for improved general practitioner (GP) education, expedited access to medical specialists, greater patient involvement in treatment choices and more financial assistance to improve the experience of Australian patients and caregivers.

Patients' and Caregivers' Experiences Navigating the Burden of Atopic Dermatitis in Argentina.

Background and Objectives: Little is known about patients' and caregivers' experiences with atopic dermatitis (AD) in Argentina, so a survey was administered to learn more. Materials and Methods: A 53-item anonymous survey was administered in Spanish to adult AD patients (n = 334) and caregivers (n = 339) of pediatric AD patients in Argentina (total n = 673). Demographics, healthcare provider information, financial burden, disease severity, disease burden, level of disease-specific education, and experience with shared physician/patient decision making were collected. Linear and logistic regression models were used for statistical comparisons. Results: Survey respondents were overwhelmingly female (90.8%), as was the overall patient population (72.8%). Patients were seen mostly by healthcare specialists (66.8% dermatologists, 13.5% pediatricians, 7.7% allergists, and 7.2% general practitioners). Only 2.8% of respondents reported no symptoms, while 33.3%, 52.4%, and 11.5% reported mild, moderate, and severe AD disease, respectively. Anxiety/depression and pain/discomfort were the most impactful on respondents' quality of life. Caregivers of children with moderate to severe AD and adult patients with severe AD reported a significant financial burden, including using savings or not purchasing food or other essentials to afford medical care. Few people reported receiving disease-specific education or having their own treatment priorities taken into consideration. For adult patients, receiving disease education and being asked about treatment priorities were associated with higher treatment satisfaction and AD control. Discussion: Mental health, pain/discomfort, and financial worries are the most important burdens for adult AD patients and caregivers of children with AD in Argentina. We recommend prioritizing disease-specific education and shared decision making to improve AD care in Argentina.

Management of patients with epilepsy and Intellectual disabilities in group homes vs. Family Homes: Insights into polypharmacy and seizure characteristics.

OBJECTIVES: This study aimed to investigate the differences in ASMs prescription, seizure characteristics and predictors of polypharmacy in patients with epilepsy and Intellectual disabilities (IDs) residing in group homes versus family homes. METHODS: This nine-year retrospective study analyzed patients with epilepsy and IDs who were admitted to the EMU, epilepsy clinics at LHSC and rehabilitation clinics for patients with IDs at Parkwood Institution. The study included individuals aged 16 years and older residing in either group homes or family homes. Data on demographics, epilepsy characteristics, and ASMs use were collected and analyzed using the Statistical Package for Social Sciences. The study utilized binary logistic regression to identify predictors of polypharmacy in patients with epilepsy and IDs. RESULTS: The study enrolled a total of 81 patients, of which 59.3 % resided in family homes. Group home residents were significantly older (41 vs. 24.5 years; p = 0.0001) and were prescribed more ASMs (3 vs. 2; p = 0.002). Specific ASMs were more common in group homes, including valproic acid (54.5 % vs. 25.0 %), lacosamide (54.5 % vs. 22.9 %), topiramate (33.3 % vs. 14.6 %), and phenytoin (30.3 % vs. 6.2 %). Admission to the EMU was more prevalent in group homes (93.9 % vs. 52.1 %; p = 0.0001). Living in a group home increased the risk of polypharmacy (OR = 10.293, p = 0.005), as did older epilepsy onset age (OR = 1.135, p = 0.031) and generalized or focal & generalized epilepsy (OR = 7.153, p = 0.032 and OR = 10.442, p = 0.025, respectively). SIGNIFICANCE: Our study identified notable differences in the demographic and clinical characteristics of patients with epilepsy and IDs living in group homes versus family homes. Age of epilepsy onset, EMU admissions, epilepsy types, and residency setting were significant predictors of polypharmacy. These findings highlight the need for personalized care strategies and increased awareness of the potential risks associated with polypharmacy.

Patients' and Caregivers' Experiences With Atopic Dermatitis-Related Burden, Medical Care, and Treatments in 8 Countries.

BACKGROUND: Previous studies have documented the high patient and caregiver burden associated with atopic dermatitis (AD). Less is known about the factors-especially those related to treatment options and the delivery of medical care-that may relate to burden and unmet needs among patients and their caregivers. OBJECTIVE: Our primary aim was to characterize and compare health-related quality of life, long-term control of symptoms, satisfaction with treatments, the financial burden, and the prevalence of patient-centered care among adult and pediatric patients with AD in 8 developed nations. METHODS: We developed a 53-item anonymous online survey for adult patients and caregivers of children with AD (N = 3171; self-reported disease severity: 8.2% clear, 33.2% mild, 41.1% moderate, 17.6% severe). The survey included questions across 7 domains selected by a steering committee of 11 patient organizations that advocate for patients with AD in the 8 countries. We used validated instruments when available including the 5-level EuroQol five-dimensional questionnaire and the Atopic Dermatitis Control Tool. The survey was offered in 5 languages and promoted through social media and other communication channels of the patient organizations. RESULTS: The health-related quality-of-life scores for adult patients with AD (driven by 2 domains: pain/discomfort and anxiety/depression) were worse than those reported for asthma and type 2 diabetes in previous studies (0.72; 95% CI, 0.65-0.78). Patients and caregivers reported substantial financial impacts even in countries with government-funded health care systems, though the greatest impact was in the United States. In all countries, adults reported better control of symptoms than children, but neither group nor any nationality reported adequate control on average (rescaled mean, 57.5; 95% CI, 56.1-58.9), and control correlated negatively with disease severity. Similarly, satisfaction with treatments, which was moderate across countries on average, was much lower for respondents with more severe disease symptoms (F(3,3165) = 5.5; P < .001). Patients who saw a specialist (a dermatologist or an allergist) instead of a general practitioner for AD care indicated better long-term control of symptoms (by 4 points on average on the 100-point scale; 95% CI, 2.6-5.4; P < .001). Finally, self-management training and shared decision making were uncommonly reported by patients in all countries except by respondents from the United States, but both were associated with better long-term control of symptoms and higher satisfaction. CONCLUSIONS: The burden of AD, evaluated as health-related quality-of-life detriments, financial impacts, and uncontrolled symptoms, is significant and highest for patients with more severe atopic dermatitis who report greater challenges in achieving symptom resolution with existing treatments and approaches to care. The better outcomes associated with respondents who saw specialists suggest that patients, especially those with more severe AD, might benefit from medical care that is guided by providers with more in-depth knowledge of this complex condition. Finally, wider use of patient-centered care practices (specifically, self-management training and shared decision making) could improve outcomes and boost satisfaction with treatments for AD, though more research on this topic is warranted.

RHOA, a small G-protein, signals to mitophagy through regulation of PINK1 protein stability and protects cardiomyocytes against ischemia.

RHOA (ras homolog family member A) is a small G-protein that regulates a range of cellular processes including cell growth and survival. RHOA is a proximal downstream effector of G protein-coupled receptors coupling to GNA12/Gα12-GNA13/Gα13 proteins, and is activated in response to stretch and oxidative stress, functioning as a stress-response molecule. It has been demonstrated that RHOA signaling provides cardioprotection through inhibition of mitochondrial death pathways. Mitochondrial integrity is preserved not only by inhibition of mitochondrial death pathways but also by mitochondrial quality control mechanisms including mitophagy. One of the most well-established mechanisms of mitophagy is the mitochondrial membrane depolarization-dependent PINK1-PRKN/Parkin pathway. However, depolarization of the mitochondrial membrane potential is a late-stage event that occurs just before cell death, and additional intracellular mechanisms that enhance the PINK1-PRKN pathway have not been fully determined. We recently discovered that RHOA activation engages a unique mechanism to regulate PINK1 protein stability without inducing mitochondrial membrane depolarization, leading to increased mitophagy and protection against ischemia in cardiomyocytes. Our results suggest regulation of RHOA signaling as a potential strategy to enhance protective mitophagy against stress without compromising mitochondrial functions.

RhoA signaling increases mitophagy and protects cardiomyocytes against ischemia by stabilizing PINK1 protein and recruiting Parkin to mitochondria.

Mitophagy, a mitochondria-specific form of autophagy, removes dysfunctional mitochondria and is hence an essential process contributing to mitochondrial quality control. PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin are critical molecules involved in stress-induced mitophagy, but the intracellular signaling mechanisms by which this pathway is regulated are unclear. We tested the hypothesis that signaling through RhoA, a small GTPase, induces mitophagy via modulation of the PINK1/Parkin pathway as a protective mechanism against ischemic stress. We demonstrate that expression of constitutively active RhoA as well as sphingosine-1-phosphate induced activation of endogenous RhoA in cardiomyocytes result in an accumulation of PINK1 at mitochondria. This is accompanied by translocation of Parkin to mitochondria and ubiquitination of mitochondrial proteins leading to recognition of mitochondria by autophagosomes and their lysosomal degradation. Expression of RhoA in cardiomyocytes confers protection against ischemia, and this cardioprotection is attenuated by siRNA-mediated PINK1 knockdown. In vivo myocardial infarction elicits increases in mitochondrial PINK1, Parkin, and ubiquitinated mitochondrial proteins. AAV9-mediated RhoA expression potentiates these responses and a concurrent decrease in infarct size is observed. Interestingly, induction of mitochondrial PINK1 accumulation in response to RhoA signaling is neither mediated through its transcriptional upregulation nor dependent on depolarization of the mitochondrial membrane, the canonical mechanism for PINK1 accumulation. Instead, our results reveal that RhoA signaling inhibits PINK1 cleavage, thereby stabilizing PINK1 protein at mitochondria. We further show that active RhoA localizes at mitochondria and interacts with PINK1, and that the mitochondrial localization of RhoA is regulated by its downstream effector protein kinase D. These findings demonstrate that RhoA activation engages a unique mechanism to regulate PINK1 accumulation, induce mitophagy and protect against ischemic stress, and implicates regulation of RhoA signaling as a potential strategy to enhance mitophagy and confer protection under stress conditions.

Dissociation of mitochondrial HK-II elicits mitophagy and confers cardioprotection against ischemia.

Preservation of mitochondrial integrity is critical for maintaining cellular homeostasis. Mitophagy is a mitochondria-specific type of autophagy which eliminates damaged mitochondria thereby contributing to mitochondrial quality control. Depolarization of the mitochondrial membrane potential is an established mechanism for inducing mitophagy, mediated through PINK1 stabilization and Parkin recruitment to mitochondria. Hexokinase-II (HK-II) which catalyzes the first step in glucose metabolism, also functions as a signaling molecule to regulate cell survival, and a significant fraction of cellular HK-II is associated with mitochondria (mitoHK-II). We demonstrate here that pharmacological interventions and adenoviral expression of a mitoHK-II dissociating peptide which reduce mitoHK-II levels lead to robust increases in mitochondrial Parkin and ubiquitination of mitochondrial proteins in cardiomyocytes and in a human glioblastoma cell line 1321N1, independent of mitochondrial membrane depolarization or PINK1 accumulation. MitoHK-II dissociation-induced mitophagy was demonstrated using Mito-Keima in cardiomyocytes and in 1321N1 cells. Subjecting cardiomyocytes or the in vivo heart to ischemia leads to modest dissociation of mitoHK-II. This response is potentiated by expression of the mitoHK-II dissociating peptide, which increases Parkin recruitment to mitochondria and, importantly, provides cardioprotection against ischemic stress. These results suggest that mitoHK-II dissociation is a physiologically relevant cellular event that is induced by ischemic stress, the enhancement of which protects against ischemic damage. The mechanism which underlies the effects of mitoHK-II dissociation can be attributed to the ability of Bcl2-associated athanogene 5 (BAG5), an inhibitor of Parkin, to localize to mitochondria and form a molecular complex with HK-II. Overexpression of BAG5 attenuates while knockdown of BAG5 sensitizes the effect of mitoHK-II dissociation on mitophagy. We suggest that HK-II, a glycolytic molecule, can function as a sensor for metabolic derangements at mitochondria to trigger mitophagy, and modulating the intracellular localization of HK-II could be a novel way of regulating mitophagy to prevent cell death induced by ischemic stress.

Calcium signaling in skeletal muscle development, maintenance and regeneration.

Skeletal muscle-specific stem cells are pivotal for tissue development and regeneration. Muscle plasticity, inherent in these processes, is also essential for daily life activities. Great advances and efforts have been made in understanding the function of the skeletal muscle-dedicated stem cells, called muscle satellite cells, and the specific signaling mechanisms that activate them for recruitment in the repair of the injured muscle. Elucidating these signaling mechanisms may contribute to devising therapies for muscular injury or disease. Here we review the studies that have contributed to our understanding of how calcium signaling regulates skeletal muscle development, homeostasis and regeneration, with a focus on the calcium dynamics and calcium-dependent effectors that participate in these processes.

Spatiotemporal integration of developmental cues in neural development.

Nervous system development relies on the generation of neurons, their differentiation and establishment of synaptic connections. These events exhibit remarkable plasticity and are regulated by many developmental cues. Here, we review the mechanisms of three classes of these cues: morphogenetic proteins, electrical activity, and the environment. We focus on second messenger dynamics and their role as integrators of the action of diverse cues, enabling plasticity in the process of neural development.

Spontaneous calcium transients manifest in the regenerating muscle and are necessary for skeletal muscle replenishment.

Tissue regeneration entails replenishing of damaged cells, appropriate cell differentiation and inclusion of regenerated cells into functioning tissues. In adult humans, the capacity of the injured spinal cord and muscle to self-repair is limited. In contrast, the amphibian larva can regenerate its tail after amputation with complete recovery of muscle, notochord and spinal cord. The cellular and molecular mechanisms underlying this phenomenon are still unclear. Here we show that upon injury muscle cell precursors exhibit Ca(2+) transients that depend on Ca(2+) release from ryanodine receptor-operated stores. Blockade of these transients impairs muscle regeneration. Furthermore, inhibiting Ca(2+) transients in the regenerating tail prevents the activation and proliferation of muscle satellite cells, which results in deficient muscle replenishment. These findings suggest that Ca(2+)-mediated activity is critical for the early stages of muscle regeneration, which may lead to developing effective therapies for tissue repair.

The extent of myelin pathology differs following contusion and transection spinal cord injury.

Demyelination is a prominent feature of spinal cord injury (SCI) and is followed by incomplete remyelination, which may contribute to physiological impairment. Demyelination has been documented in several species including humans, but the extent of demyelination and its functional consequence remain unknown. In this report, we document and compare the extent of tissue pathology, white matter apoptosis, demyelination, and remyelination 2 months following injury in rat contusion and transection models of SCI. Moreover, we document and compare the macrophage response 3 and 14 days post contusion and transection SCI. Contusion injury resulted in widespread tissue pathology, white matter apoptosis, demyelination, incomplete remyelination, and robust macrophage response extending several millimeters cranial and caudal to the epicenter of injury. In contrast, transection injury resulted in focal tissue pathology with white matter apoptosis, demyelination, incomplete remyelination, and robust macrophage response at the epicenter of injury, and little pathologic features at a distance from the epicenter of injury, as indicated by the lack of apoptosis and demyelination. These data indicate for the first time that myelin pathology differs substantially following contusion and transection SCI.