Answering the Rehabilitation 2030 Call.

In 2017, the World Health Organization initiated a global effort to improve rehabilitative services by 2030, with the overall goal of helping individuals with disabilities achieve maximal independence and improved well-being. Though more than 1 billion people worldwide live with a disability, a significant portion do not have access to appropriate rehabilitative services. In low-income countries, such as Zambia, where rehabilitative services are greatly lacking, disability can further exacerbate economic disparities in the context of personal, cultural, and environmental factors that limit participation in society. Therefore, expansion of rehabilitative services in low-income countries is a pressing global need, and such efforts must be tailored to the societal and cultural framework in which they are implemented. Community-based rehabilitation programs are uniquely poised to provide services in similar low-to-middle-income countries as they eliminate travel barriers to care, allow for regular follow-up, and address the societal determinants of disability by encouraging greater community engagement and by decreasing cultural stigma around disability. Special Hope Network (SHN), a community-based rehabilitation organization in Lusaka, Zambia that serves families caring for children with physical and cognitive disabilities, represents a cost-effective, sustainable, and culturally practical model to provide rehabilitative care. We propose this organization's model as one that can be reproduced and expanded upon in other low-to-middle-income countries to answer the World Health Organization's call to action.

Belzutifan for treatment of giant retinal hemangioblastoma with extrascleral extension associated with von Hippel-Lindau syndrome.

PURPOSE: To describe the clinical response and safety profile of the novel HIF-2ɑ inhibitor belzutifan in treating a giant retinal hemangioblastoma (RHB) with extrascleral extension associated with von Hippel-Lindau syndrome (VHL). METHODS: A 71-year-old woman with VHL presented with a giant RHB with extrascleral extension in her only remaining eye. She had no light perception OD and intraocular pressure (IOP) was 48. She requested enucleation due to chronic pain, but, due to concern for significant bleeding given the size of the neoplasm, a trial of belzutifan was initiated. RESULTS: Within three months of treatment initiation, the patient reported an 80% reduction in pain. MRI showed 30% reduction in longest tumor diameter. Dose adjustments were guided by serum hemoglobin levels, allowing the patient to remain on the medication for over a year with continued tumor regression on MRI and avoid enucleation. CONCLUSION: RHB with extrascleral extension is exceedingly rare and its treatment is complex, often requiring enucleation or external beam radiotherapy. This report demonstrates the use of belzutifan to safely and successfully reduce ocular tumor burden of complicated RHB with extrascleral extension, ultimately decreasing the need for enucleation.

GABAergic neuronal IL-4R mediates T cell effect on memory.

Mechanisms governing how immune cells and their derived molecules impact homeostatic brain function are still poorly understood. Here, we elucidate neuronal mechanisms underlying T cell effects on synaptic function and episodic memory. Depletion of CD4 T cells led to memory deficits and impaired long-term potentiation. Severe combined immune-deficient mice exhibited amnesia, which was reversible by repopulation with T cells from wild-type but not from IL-4-knockout mice. Behaviors impacted by T cells were mediated via IL-4 receptors expressed on neurons. Exploration of snRNA-seq of neurons participating in memory processing provided insights into synaptic organization and plasticity-associated pathways regulated by immune cells. IL-4Rα knockout in inhibitory (but not in excitatory) neurons was sufficient to impair contextual fear memory, and snRNA-seq from these mice pointed to IL-4-driven regulation of synaptic function in promoting memory. These findings provide new insights into complex neuroimmune interactions at the transcriptional and functional levels in neurons under physiological conditions.

An emerging map of glutamate delta 1 receptors in the forebrain.

Glutamate delta 1 (GluD1) and glutamate delta 2 (GluD2) form the delta family of ionotropic glutamate receptors; these proteins plays widespread roles in synaptic architecture, motor behavior, and cognitive function. Though the role of GluD2 at cerebellar parallel fiber-Purkinje cell synapses is well established, attention now turns to the function of GluD receptors in the forebrain. GluD1 regulates synaptic assembly and modulation in multiple higher brain regions, acting as a postsynaptic cell adhesion molecule with effects on both excitatory and inhibitory transmission. Furthermore, variations and mutations in the GRID1 gene, which codes for GluD1, and in genes which code for proteins functionally linked to GluD1, are associated with mental disorders including autism, schizophrenia, bipolar disorder, and major depression. Cerebellin (Cbln) family proteins, the primary binding partners of delta receptors, are secreted C1q-like proteins which also bind presynaptic neurexins (NRXNs), forming a tripartite synaptic bridge. Published research explores this bridge's function in regions including the striatum, hippocampus, cortex, and cerebellum. In this review, we summarize region- and circuit-specific functions and expression patterns for GluD1 and its related proteins, and their implications for behavior and disease.

Expanded Clinical Phenotype, Oncological Associations, and Immunopathologic Insights of Paraneoplastic Kelch-like Protein-11 Encephalitis.

Importance: Recognizing the presenting and immunopathological features of Kelch-like protein-11 immunoglobulin G seropositive (KLHL11 IgG+) patients may aid in early diagnosis and management. Objective: To describe expanding neurologic phenotype, cancer associations, outcomes, and immunopathologic features of KLHL11 encephalitis. Design, Setting, and Participants: This retrospective tertiary care center study, conducted from October 15, 1998, to November 1, 2019, prospectively identified 31 KLHL11 IgG+ cases in the neuroimmunology laboratory. Eight were identified by retrospective testing of patients with rhomboencephalitis (confirmed by tissue-based-immunofluorescence and transfected-cell-based assays). Main Outcomes and Measures: Outcome variables included modified Rankin score and gait aid use. Results: All 39 KLHL11 IgG+ patients were men (median age, 46 years; range, 28-73 years). Initial clinical presentations were ataxia (n = 32; 82%), diplopia (n = 22; 56%), vertigo (n = 21; 54%), hearing loss (n = 15; 39%), tinnitus (n = 14; 36%), dysarthria (n = 11; 28%), and seizures (n = 9; 23%). Atypical neurologic presentations included neuropsychiatric dysfunction, myeloneuropathy, and cervical amyotrophy. Hearing loss or tinnitus preceded other neurologic deficits by 1 to 8 months in 10 patients (26%). Among patients screened for malignancy (n = 36), testicular germ-cell tumors (n = 23; 64%) or testicular microlithiasis and fibrosis concerning for regressed germ cell tumor (n = 7; 19%) were found in 83% of the patients (n = 30). In 2 patients, lymph node biopsy diagnosed metastatic lung adenocarcinoma in one and chronic lymphocytic leukemia in the other. Initial brain magnetic resonance imaging revealed T2 hyperintensities in the temporal lobe (n = 12), cerebellum (n = 9), brainstem (n = 3), or diencephalon (n = 3). Among KLHL11 IgG+ patients who underwent HLA class I and class II genotyping (n = 10), most were found to have HLA-DQB1*02:01 (n = 7; 70%) and HLA-DRB1*03:01 (n = 6; 60%) associations. A biopsied gadolinium-enhancing temporal lobe lesion demonstrated T cell-predominant inflammation and nonnecrotizing granulomas. Cerebellar biopsy (patient with chronic ataxia) and 2 autopsied brains demonstrated Purkinje neuronal loss and Bergmann gliosis, supporting early active inflammation and later extensive neuronal loss. Compared with nonautoimmune control peripheral blood mononuclear cells, cluster of differentiation (CD) 8+ and CD4+ T cells were significantly activated when patient peripheral blood mononuclear cells were cultured with KLHL11 protein. Most patients (58%) benefitted from immunotherapy and/or cancer treatment (neurological disability stabilized [n = 10] or improved [n = 9]). Kaplan-Meier curve demonstrated significantly higher probability of wheelchair dependence among patients without detectable testicular cancer. Long-term outcomes in KLHL11-IgG+ patients were similar to Ma2 encephalitis. Conclusions and Relevance: Kelch-like protein-11 IgG is a biomarker of testicular germ-cell tumor and paraneoplastic neurologic syndrome, often refractory to treatment. Described expanded neurologic phenotype and paraclinical findings may aid in its early diagnosis and treatment.

Photocontrol of ion permeation in lipid vesicles with amphiphilic dithienylethenes.

The integration of photochromic dithienylethenes (DTEs) with lipid vesicles as photoresponsive membrane disruptors for ion transport applications has been examined. We have synthesized three amphiphilic DTEs 1-3 that incorporate a terminally charged alkyl chain, and contain methyl or phenylethynyl substituents at the reactive carbons. Our photochromic reactivity studies suggest that the inclusion of a single alkyl chain favors the photoactive antiparallel conformation of DTEs, given the significant improvement in the cyclization quantum yield over previous phenylethynyl derivatives. Our ion permeation studies show that the open-ring isomers of these DTEs are more disruptive than the closed-ring isomers in the four lipid vesicle systems studied, regardless of their lamellar phase at room temperature. In addition, a steric effect was clearly observed as DTEs incorporating the comparatively smaller methyl group exhibited lower rates of ion permeation than the bulkier phenylethynyl group. In all cases, UV irradiation led to a reduction in ion permeability. In fact, the methyl analog exhibited a significant reduction in ion permeability in gel-phase lipid vesicles upon UV exposure. Also, the hexyl chain derivatives had a greater effect on membrane permeability than the dodecyl derivative owing to their relative position in the bilayer membrane of lipid vesicles.

Therapeutic home adaptations for older adults with disabilities.

Family physicians commonly care for older patients with disabilities. Many of these patients need help maintaining a therapeutic home environment to preserve their comfort and independence. Patients often have little time to decide how to address the limitations of newly-acquired disabilities. Physicians can provide patients with general recommendations in home modification after careful history and assessment. Universal design features, such as one-story living, no-step entries, and wide hallways and doors, are key adaptations for patients with physical disabilities. Home adaptations for patients with dementia include general safety measures such as grab bars and door alarms, and securing potentially hazardous items, such as cleaning supplies and medications. Improved lighting and color contrast, enlarged print materials, and vision aids can assist patients with limited vision. Patients with hearing impairments may benefit from interventions that provide supplemental visual and vibratory cues and alarms. Although funding sources are available, home modification is often a nonreimbursed expense. However, sufficient home modifications may allow the patient and caregivers to safely remain in the home without transitioning to a long-term care facility.

The effects of an orally administered cholinergic agonist on REM sleep in major depression.

BACKGROUND: Centrally active cholinergic agents such as arecoline and physostigmine shorten rapid eye movement (REM) latency, reduce REM interval times, or both and do so preferentially in patients with depression. We tested an orally administered cholinergic agonist (donepezil HCL 10 mg [Aricept]) to determine whether this agent also alters REM timing in depressed patients (n = 8) compared with age- and gender-matched control subjects (n = 8). METHODS: All subjects were studied for 3 consecutive nights in the sleep laboratory. The design was a fixed-order placebo-donepezil protocol to accommodate the long half-life of donepezil. Night 1 served as an adaptation night. On night 2, placebo was administered at 8:00 PM. On night 3, donepezil was administered at 8:00 PM. RESULTS: The cholinergic challenge distinguished the groups. In depressed patients REM latency was reduced compared with baseline (47.6 vs. 64.4, p =.04) following administration of donepezil. Control subjects showed no response: REM latency after donepezil was virtually identical to baseline REM latency (71.7 vs. 69.3). CONCLUSIONS: These data indicate that donepezil is likely to be useful in testing hypotheses related to cholinergic function in mood disorders.