Engaging Specialist Palliative Care in the Management of Amyotrophic Lateral Sclerosis: A Patient-, Family-, and Provider-Based Approach.

Objective: To describe key stakeholders' perspectives on specialist palliative care and its integration into the management of amyotrophic lateral sclerosis (ALS). Methods: The study conducted was a qualitative, noninterventional, descriptive study. Data were collected via individual interviews of 42 stakeholders (n = 14 patients, n = 16 family caregivers, and n = 12 health-care providers). Transcribed interviews were analyzed using inductive thematic analysis techniques. Results: Stakeholders' general impressions of specialist palliative care were highly variable. Many expressed limited or inaccurate understandings of palliative care's definition and purpose. Perceptions of palliative care as hospice were common. Stakeholders generally supported the integration of specialist palliative care into ALS management, and many recognized the value of early integration of palliative services in both the community and the clinical setting. Conclusion: Key stakeholders readily identified a meaningful role for specialist palliative care in ALS management. Integration of specialist palliative care into existing systems of support would be facilitated by a more comprehensive understanding of the service among patients, family caregivers, and health-care providers.

Real-Time Noninvasive Bioluminescence, Ultrasound and Photoacoustic Imaging in NFκB-RE-Luc Transgenic Mice Reveal Glia Maturation Factor-Mediated Immediate and Sustained Spatio-Temporal Activation of NFκB Signaling Post-Traumatic Brain Injury in a Gender-Specific Manner.

Neurotrauma especially traumatic brain injury (TBI) is the leading cause of death and disability worldwide. To improve upon the early diagnosis and develop precision-targeted therapies for TBI, it is critical to understand the underlying molecular mechanisms and signaling pathways. The transcription factor, nuclear factor kappa B (NFκB), which is ubiquitously expressed, plays a crucial role in the normal cell survival, proliferation, differentiation, function, as well as in disease states like neuroinflammation and neurodegeneration. Here, we hypothesized that real-time noninvasive bioluminescence molecular imaging allows rapid and precise monitoring of TBI-induced immediate and rapid spatio-temporal activation of NFκB signaling pathway in response to Glia maturation factor (GMF) upregulation which in turn leads to neuroinflammation and neurodegeneration post-TBI. To test and validate our hypothesis and to gain novel mechanistic insights, we subjected NFκB-RE-Luc transgenic male and female mice to TBI and performed real-time noninvasive bioluminescence imaging (BLI) as well as photoacoustic and ultrasound imaging (PAI). Our BLI data revealed that TBI leads to an immediate and sustained activation of NFκB signaling. Further, our BLI data suggest that especially in male NFκB-RE-Luc transgenic mice subjected to TBI, in addition to brain, there is widespread activation of NFκB signaling in multiple organs. However, in the case of the female NFκB-RE-Luc transgenic mice, TBI induces a very specific and localized activation of NFκB signaling in the brain. Further, our microRNA data suggest that TBI induces significant upregulation of mir-9-5p, mir-21a-5p, mir-34a-5p, mir-16-3p, as well as mir-155-5p within 24 h and these microRNAs can be successfully used as TBI-specific biomarkers. To the best of our knowledge, this is one of the first and unique study of its kind to report immediate and sustained activation of NFκB signaling post-TBI in a gender-specific manner by utilizing real-time non-invasive BLI and PAI in NFκB-RE-Luc transgenic mice. Our study will prove immensely beneficial to gain novel mechanistic insights underlying TBI, unravel novel therapeutic targets, as well as enable us to monitor in real-time the response to innovative TBI-specific precision-targeted gene and stem cell-based precision medicine.

Absence of Glia Maturation Factor Protects from Axonal Injury and Motor Behavioral Impairments after Traumatic Brain Injury.

Traumatic brain injury (TBI) causes disability and death, accelerating the progression towards Alzheimer's disease and Parkinson's disease (PD). TBI causes serious motor and cognitive impairments, as seen in PD that arise during the period of the initial insult. However, this has been understudied relative to TBI induced neuroinflammation, motor and cognitive decline that progress towards PD. Neuronal ubiquitin-C-terminal hydrolase- L1 (UCHL1) is a thiol protease that breaks down ubiquitinated proteins and its level represents the severity of TBI. Previously, we demonstrated the molecular action of glia maturation factor (GMF); a proinflammatory protein in mediating neuroinflammation and neuronal loss. Here, we show that the weight drop method induced TBI neuropathology using behavioral tests, western blotting, and immunofluorescence techniques on sections from wild type (WT) and GMF-deficient (GMF-KO) mice. Results reveal a significant improvement in substantia nigral tyrosine hydroxylase and dopamine transporter expression with motor behavioral performance in GMF-KO mice following TBI. In addition, a significant reduction in neuroinflammation was manifested, as shown by activation of nuclear factor-kB, reduced levels of inducible nitric oxide synthase, and cyclooxygenase- 2 expressions. Likewise, neurotrophins including brain-derived neurotrophic factor and glial-derived neurotrophic factor were significantly improved in GMF-KO mice than WT 72 h post-TBI. Consistently, we found that TBI enhances GFAP and UCHL-1 expression and reduces the number of dopaminergic TH-positive neurons in WT compared to GMF-KO mice 72 h post-TBI. Interestingly, we observed a reduction of THpositive tanycytes in the median eminence of WT than GMF-KO mice. Overall, we found that absence of GMF significantly reversed these neuropathological events and improved behavioral outcome. This study provides evidence that PD-associated pathology progression can be initiated upon induction of TBI.

A telephonic single breath count test for screening of exacerbations of myasthenia gravis: A pilot study.

BACKGROUND: Patients with myasthenia gravis (MG) may experience worsening symptoms outside of a clinical setting. A method of diagnosing and triaging such individuals would be valuable. This study gauged the viability of a nurse-administered single breath count test (SBCT) over the telephone for assessing MG exacerbations. METHODS: This was a retrospective, single-center review of a pilot study of 45 telephone calls from patients with MG who had worsening baseline symptoms. SBCTs were administered over the telephone to patients by trained nurses. Patients with a breath count of 25 or less were sent to the emergency department. RESULTS: Using a cutoff count of 25, the nurse-administered telephonic SBCT had a positive predictive value of 71%, sensitivity of 80%, and specificity of 60% in diagnosing an MG exacerbation. CONCLUSIONS: SBCT administered by trained nurses by means of telephone may be a useful screening tool for assessing decreased respiratory function in patients with MG.

Neuroinflammation Mediated by Glia Maturation Factor Exacerbates Neuronal Injury in an in vitro Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) is the primary cause of death and disability affecting over 10 million people in the industrialized world. TBI causes a wide spectrum of secondary molecular and cellular complications in the brain. However, the pathological events are still not yet fully understood. Previously, we have shown that the glia maturation factor (GMF) is a mediator of neuroinflammation in neurodegenerative diseases. To identify the potential molecular pathways accompanying TBI, we used an in vitro cell culture model of TBI. A standardized injury was induced by scalpel cut through a mixed primary cell culture of astrocytes, microglia and neurons obtained from both wild type (WT) and GMF-deficient (GMF-KO) mice. Cell culture medium and whole-cell lysates were collected at 24, 48, and 72 h after the scalpel cuts injury and probed for oxidative stress using immunofluorescence analysis. Results showed that oxidative stress markers such as glutathione and glutathione peroxidase were significantly reduced, while release of cytosolic enzyme lactate dehydrogenase along with nitric oxide and prostaglandin E2 were significantly increased in injured WT cells compared with injured GMF-KO cells. In addition, injured WT cells showed increased levels of oxidation product 4-hydroxynonenal and 8-oxo-2'-deoxyguanosine compared with injured GMF-KO cells. Further, we found that injured WT cells showed a significantly increased expression of glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, and phosphorylated ezrin/radixin/moesin proteins, and reduced microtubule associated protein expression compared with injured GMF-KO cells after injury. Collectively, our results demonstrate that GMF exacerbates the oxidative stress-mediated neuroinflammation that could be brought about by TBI-induced astroglial activation.

Stakeholder Perspectives on the Biopsychosocial and Spiritual Realities of Living With ALS: Implications for Palliative Care Teams.

CONTEXT: Amyotrophic lateral sclerosis (ALS) is an all-encompassing, life-limiting disease, resulting in the eventual paralysis of all voluntary muscles and concurrent loss of independence. As the disease advances, both patients and their family caregivers develop complex biological, psychological, and social needs, leading to increasing calls for the involvement of palliative care teams in the management of ALS. OBJECTIVE: The purpose of this study was to generate a rich description of the realities of living with ALS, equipping palliative care teams with an in-depth understanding of the experiences and needs of patients with ALS and their family caregivers. METHODS: This study employed a mixed-methods design, with quantitative data supplementing a larger body of qualitative data. Semi-structured interviews with 42 key stakeholders, including patients, family caregivers, and health-care providers, were analyzed for themes essential for effective understanding of ALS. RESULTS: Identified themes were organized into 2 broad categories: (1) biopsychosocial needs of patients with ALS and family caregivers and (2) the impact of ALS on spiritual and emotional well-being. Quantitative data supported the recognized themes, particularly with regard to challenges associated with preserving independence, securing sufficient social support, and managing the emotional complexities of the disease. CONCLUSION: Study findings illustrate the intricacies of living with ALS and the importance of eliciting individualized values when caring for patients with ALS and their families. The complex biopsychosocial needs experienced by patients and family caregivers suggest numerous opportunities for meaningful palliative care involvement.