Macrophage migration is differentially regulated by fibronectin and laminin through altered adhesion and myosin II localization.

Macrophages are indispensable for proper immune surveillance and inflammatory regulation. They also exhibit dramatic phenotypic plasticity and are highly responsive to their local microenvironment, which includes the extracellular matrix (ECM). This work demonstrates that two fibrous ECM glycoproteins, fibronectin (FN) and laminin (LAM), elicit distinct morphological and migratory responses from macrophages in two-dimensional environments. LAM 111 inhibits macrophage cell spreading, but drives them to migrate rapidly and less persistently compared with cells on FN. Differential integrin engagement and ROCK/myosin II organization helps explain why macrophages alter their morphology and migration character on these two ECM components. This study also demonstrates that LAM 111 exerts a suppressive effect toward FN, as macrophages plated on a LAM/FN mixture adopt a morphology and migratory character almost identical to LAM alone. This suggests that distinct responses can be initiated downstream of receptor-ECM engagement, and that one component of the microenvironment may affect the cell's ability to sense another. Overall, macrophages appear intrinsically poised to rapidly switch between distinct migratory characters based on their ECM environments. The role of ECM composition in dictating motile and inflammatory responses in three-dimensional and in vivo contexts warrants further study.

Macrophage migration is differentially regulated by distinct ECM components.

Macrophages are indispensable for proper immune surveillance and inflammatory regulation. They also exhibit dramatic phenotypic plasticity and are highly responsive to their local microenvironment, which includes the extracellular matrix (ECM). The present work demonstrates that two fibrous ECM glycoproteins, fibronectin (FN) and laminin (LAM), elicit distinct morphological and migratory responses to macrophages in 2D environments. Laminin 111 inhibits macrophage cell spreading, but drives them to migrate rapidly and less persistently compared to cells on fibronectin. Differential integrin engagement and ROCK/myosin II organization helps explain why macrophages alter their morphology and migration character on these two ECM components. The present study also demonstrates that laminin 111 exerts a suppressive effect toward fibronectin, as macrophages plated on a LAM/FN mixture adopt a morphology and migratory character almost identical to LAM alone. This suggests that distinct responses can be initiated downstream of receptor-ECM engagement, and that one component of the microenvironment may affect the cell's ability to sense another. Overall, macrophages appear intrinsically poised to rapidly switch between distinct migratory modes based on their ECM environments. The role of ECM composition in dictating motile and inflammatory responses in 3D and in vivo contexts warrants further study.

Survival motor neuron protein deficiency alters microglia reactivity.

Survival motor neuron (SMN) protein deficiency results in loss of alpha motor neurons and subsequent muscle atrophy in patients with spinal muscular atrophy (SMA). Reactive microglia have been reported in SMA mice and depleting microglia rescues the number of proprioceptive synapses, suggesting a role in SMA pathology. Here, we explore the contribution of lymphocytes on microglia reactivity in SMA mice and investigate how SMN deficiency alters the reactive profile of human induced pluripotent stem cell (iPSC)-derived microglia. We show that microglia adopt a reactive morphology in spinal cords of SMA mice. Ablating lymphocytes did not alter the reactive morphology of SMA microglia and did not improve the survival or motor function of SMA mice, indicating limited impact of peripheral immune cells on the SMA phenotype. We found iPSC-derived SMA microglia adopted an amoeboid morphology and displayed a reactive transcriptome profile, increased cell migration, and enhanced phagocytic activity. Importantly, cell morphology and electrophysiological properties of motor neurons were altered when they were incubated with conditioned media from SMA microglia. Together, these data reveal that SMN-deficient microglia adopt a reactive profile and exhibit an exaggerated inflammatory response with potential impact on SMA neuropathology.

Advances in chronic traumatic encephalopathy.

Over the past decade, concern for negative outcomes associated with concussive brain trauma has grown immensely. These neuropathologic changes, termed chronic traumatic encephalopathy (CTE), have been linked to patients who exhibit neuropsychiatric symptoms and have experienced repetitive brain trauma. Recent publicity has brought about renewed interest in this progressive neurodegenerative disorder. This article will share the advances that have been made with CTE.

Deprescribing at the end of life in older patients.

In the United States, the adult population that will need hospice and palliative care is expected to double in the next 40 years. In primary care, providers are often faced with tough decisions on how to manage patients' medications at the end of life. This article describes how to deprescribe in the last year of life.

Widespread Distribution of Ceratonova shasta (Cnidaria: Myxosporea) Genotypes Indicates Evolutionary Adaptation to its Salmonid Fish Hosts.

The distribution of the freshwater myxozoan parasite Ceratonova shasta in the Pacific Northwest of North America is limited to overlap in the ranges of its 2 hosts: the polychaete Manyunkia sp., and Pacific salmonids. Studies in the Klamath River (Oregon/California) and Deschutes River (Oregon), showed that the parasite population is comprised of multiple sympatric genotypes, some of which correlate with particular salmonid host species and with differences in clinical disease in those hosts. The 3 primary genotypes O, I, and II are defined by the number of a specific tri-nucleotide repeat in the internal transcribed spacer-1 region. To understand the spatial extent of host-parasite genotype patterns, we sequenced the parasite from 448 salmonid fishes from river basins in California, Oregon, Washington, Idaho, and British Columbia, Canada. We sampled intestinal tissues from 6 species of salmon and trout, both those that exist naturally with the parasite (sympatric) and those that do not naturally co-occur with the parasite and were exposed artificially in cages (allopatric). In most river basins we detected the same primary C. shasta genotypes that were described from the Klamath and Deschutes rivers, and we did not detect any novel primary genotypes. Host-parasite genotype patterns were consistent with previous data: genotype O was found in sympatric trout only; genotype I predominantly in Chinook salmon, and genotype II in all 6 fish species but dominant in coho salmon. Our findings of widespread, consistent host-parasite genotype patterns support the hypothesis that C. shasta has a long evolutionary history with salmonid fishes in the Pacific Northwest, and impels additional studies to determine if these parasite genotypes should be considered different species.

Predicted redistribution of Ceratomyxa shasta genotypes with salmonid passage in the Deschutes River, Oregon.

A series of dams on the Deschutes River, Oregon, act as migration barriers that segregate the river system into upper and lower basins. Proposed fish passage between basins would reunite populations of native potamodromous fish and allow anadromous fish of Deschutes River origin access to the upper basin. We assessed the potential redistribution of host-species-specific genotypes (O, I, II, III) of the myxozoan parasite Ceratomyxa shasta that could occur with fish passage and examined the influence of nonnative fish on genotype composition. To determine the present distribution of the parasite genotypes, we exposed eight salmonid species-three native and five stocked for sport fishing-in present and predicted anadromous salmonid habitats. We monitored fish for infection by C. shasta and sequenced a section of the parasite ribosomal DNA gene from fish and water samples to determine parasite genotype. Genotype O was present in both upper and lower basins and detected only in steelhead Oncorhynchus mykiss. Genotype I was spatially limited to the lower basin, isolated predominantly from Chinook salmon O. tshawytscha, and lethal for this species only. Genotype II was detected in both basins and in multiple species, but only as a minor component of the infection. Genotype III was also present in both basins, had a wide host range, and caused mortality in native steelhead and multiple nonnative species. Atlantic salmon Salmo salar and kokanee O. nerka were the least susceptible to infection by any genotype of C. shasta. Our findings confirmed the host-specific patterns of C. shasta infections and indicated that passage of Chinook salmon would probably spread genotype I into the upper Deschutes River basin, but with little risk to native salmonid populations.

Arthroscopic grafting of greater tuberosity cyst and rotator cuff repair.

Cysts of the greater tuberosity can be a normal finding independent of age and concurrent rotator cuff tear. The presence of a large greater tuberosity cyst can present a challenge at the time of rotator cuff repair. We present a 1-step arthroscopic technique to address these defects at the time of rotator cuff repair using a synthetic graft (OsteoBiologics, San Antonio, TX) originally designed to address osteoarticular defects. With the viewing portal established laterally, a portal allowing perpendicular access to the cyst is established. The cyst is thoroughly debrided, and a drill sleeve is then introduced perpendicular to the surrounding bone, serving as a guide for the matching drill to create a circular socket. A correspondingly sized TruFit BGS cylindrical implant (OsteoBiologics) is then implanted by use of the included instrumentation. The scaffold is placed flush with the surrounding bone. Because our arthroscopic rotator cuff protocol uses a tension-band technique with placement of suture anchors distal and lateral to the rotator cuff footprint, we are subsequently able to proceed with routine rotator cuff repair.