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It is usually assumed that proprioceptive feedback comes to motoneurons too late to contribute to the initial activity of agonist muscles during fast arm movements, leading to the suggestion that this feedback is only efficient in slow movements and postural control. The argument does not take into account that the changes in the motoneuronal membrane potentials and the associated changes in the state of spinal neurons preceding the initial activity of muscles deeply affect, in a forward way, the state of reflex systems by shifting their thresholds, as suggested in the lambda model for motor control. As a result, the initial muscle activity emerges with full contribution of these systems so that the effects of reflex delays become negligible. We tested the hypothesis that threshold control of muscle activation may be instrumental in preventing destabilizing effects of proprioceptive delays in spinal and trans-cortical pathways to motoneurons. The analysis was made by recording fast elbow movements (peak velocity approximately 300-500 degrees/s) and simulating them in a dynamic model that incorporates the notion of threshold control of intrinsic and reflex muscle properties. The model was robust in reproducing experimental movement patterns (R (2)>0.95). It generated stable output despite substantial proprioceptive (up to 100 ms) and electromechanical (40 ms) delays. Stability was thus ensured for delays not only in segmental (about 25-50 ms) but also in trans-cortical loops (50-70 ms). Our study illustrates that a natural physiological process--threshold control--may manifest feed-forward properties hitherto attributed to hypothetical internal neural models.

Purpose This study aims to explore the dynamics enabling strategic account management (SAM) to function as a value co-creation selling model in the pharmaceutical industry. Design/methodology/approach Using an inductive qualitative research design, data are collected within 11 industry customers in Canada. This work focuses on hospitals as strategic accounts of pharmaceutical companies, exploring SAM value co-creation in the “hospital-pharmaceutical company” relationship. Findings The findings suggest the presence of two key dimensions that can enable a value co-creation SAM model in the hospital-pharmaceutical relationship: “customer-tailored value-added initiatives” and “relationship enhancers”. Customer-tailored value-added initiatives explain the activities that are central to the hospital-pharmaceutical company relationship and can lead to the provision of value added that is unique to the hospital. Relationship enhancers explain the activities that can help strengthen hospital-pharmaceutical company relations in the pursuit of enhanced value-added interactions between the two parties. The research demonstrates a cyclical relationship between “customer-tailored value-added initiatives” and “relationship enhancers”, leading to value co-creation through a SAM model. Practical implications The study informs pharmaceutical industry practitioners on how to improve their value proposition through new, more sustainable selling practices. It offers information on implementing a value co-creation SAM model, which can enable pharmaceutical companies to sustain long-lasting value-added relationships with key accounts such as hospitals. Originality/value The study contributes to the field of SAM by conceptualizing SAM as a value co-creation system. It introduces new knowledge in pharmaceutical marketing by offering empirical insight on the applicability and use of SAM in the hospital-pharmaceutical company dyad.

The grip force holding an object between fingers usually increases before or simultaneously with arm movement thus preventing the object from sliding. We experimentally analyzed and simulated this anticipatory behavior based on the following notions. (1) To move the arm to a new position, the nervous system shifts the threshold position at which arm muscles begin to be recruited. Deviated from their activation thresholds, arm muscles generate activity and forces that tend to minimize this deviation by bringing the arm to a new position. (2) To produce a grip force, with or without arm motion, the nervous system changes the threshold configuration of the hand. This process defines a threshold (referent) aperture (R(a)) of appropriate fingers. The actual aperture (Q(a)) is constrained by the size of the object held between the fingers whereas, in referent position R(a), the fingers virtually penetrate the object. Deviated by the object from their thresholds of activation, hand muscles generate activity and grip forces in proportion to the gap between the Q(a) and R(a). Thus, grip force emerges since the object prevents the fingers from reaching the referent position. (3) From previous experiences, the system knows that objects tend to slide off the fingers when arm movements are made and, to prevent sliding, it starts narrowing the referent aperture simultaneously with or somewhat before the onset of changes in the referent arm position. (4) The interaction between the fingers and the object is accomplished via the elastic pads on the tips of fingers. The pads are compressed not only due to the grip force but also due to the tangential inertial force (\"load\") acting from the object on the pads along the arm trajectory. Compressed by the load force, the pads move back and forth in the gap between the finger bones and object, thus inevitably changing the normal component of the grip force, in synchrony with and in proportion to the load force. Based on these notions, we simulated experimental elbow movements and grip forces when subjects rapidly changed the elbow angle while holding an object between the index finger and the thumb. It is concluded that the anticipatory increase in the grip force with or without correlation with the tangential load during arm motion can be explained in neurophysiological and biomechanical terms without relying on programming of grip force based on an internal model.

My wife, who by choice has stayed at home with our children, was deeply touched...

Pathological neovascularization in age-related macular degeneration (nvAMD) drives the principal cause of blindness in the elderly. While there is a robust genetic association between genes of innate immunity and AMD, genome-to-phenome relationships are low, suggesting a critical contribution of environmental triggers of disease. Possible insight comes from the observation that a past history of infection with pathogens such as Chlamydia pneumoniae, or other systemic inflammation, can predispose to nvAMD in later life. Using a mouse model of nvAMD with prior C. pneumoniae infection, endotoxin exposure, and genetic ablation of distinct immune cell populations, we demonstrated that peripheral infections elicited epigenetic reprogramming that led to a persistent memory state in retinal CX3CR1+ mononuclear phagocytes (MNPs). The immune imprinting persisted long after the initial inflammation had subsided and ultimately exacerbated choroidal neovascularization in a model of nvAMD. Single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) identified activating transcription factor 3 (ATF3) as a central mediator of retina-resident MNP reprogramming following peripheral inflammation. ATF3 polarized MNPs toward a reparative phenotype biased toward production of proangiogenic factors in response to subsequent injury. Therefore, a past history of bacterial endotoxin-induced inflammation can lead to immunological reprograming within CNS-resident MNPs and aggravate pathological angiogenesis in the aging retina.

Background Aneurysmal subarachnoid hemorrhage (SAH) is a catastrophic disease with devastating consequences, including a high mortality rate and severe disabilities among survivors. Inflammation is induced following SAH, but the exact role and phenotype of innate immune cells remain poorly characterized. We investigated the inflammatory components of the early brain injury in an animal model and in SAH patients. Method SAH was induced through injection of blood in the subarachnoid space of C57Bl/6 J wild-type mice. Prospective blood collections were obtained at 12 h, days 1, 2, and 7 to evaluate the systemic inflammatory consequences of SAH by flow cytometry and enzyme-linked immunosorbent-assay (ELISA). Brains were collected, enzymatically digested, or fixed to characterize infiltrating inflammatory cells and neuronal death using flow cytometry and immunofluorescence. Phenotypic evaluation was performed at day 7 using the holding time and footprint tests. We then compared the identified inflammatory proteins to the profiles obtained from the plasma of 13 human SAH patients. Results Following SAH, systemic IL-6 levels increased rapidly, whereas IL-10 levels were reduced. Neutrophils were increased both in the brain and in the blood reflecting local and peripheral inflammation following SAH. More intracerebral pro-inflammatory monocytes were found at early time points. Astrocyte and microglia activation were also increased, and mice had severe motor deficits, which were associated with an increase in the percentage of caspase-3-positive apoptotic neurons. Similarly, we found that IL-6 levels in patients were rapidly increased following SAH. ICAM-1, bFGF, IL-7, IL-12p40, and MCP-4 variations over time were different between SAH patients with good versus bad outcomes. Moreover, high levels of Flt-1 and VEGF at admission were associated with worse outcomes. Conclusion SAH induces an early intracerebral infiltration and peripheral activation of innate immune cells. Furthermore, microglia and astrocytic activation are present at later time points. Our human and mouse data illustrate that SAH is a systemic inflammatory disease and that immune cells represent potential therapeutic targets to help this population of patients in need of new treatments.

From January 2003 to December 2013, sexual transmission of 2 clades of Campylobacter jejuni subspecies jejuni isolates resulted in a prolonged outbreak among men who have sex with men living in Quebec, Canada. The outbreak isolates were acquired locally and were resistant to erythromycin and ciprofloxacin.

Age‐related macular degeneration (AMD) in its various forms is a leading cause of blindness in industrialized countries. Here, we provide evidence that ligands for neuropilin‐1 (NRP1), such as Semaphorin 3A and VEGF‐A, are elevated in the vitreous of patients with AMD at times of active choroidal neovascularization (CNV). We further demonstrate that NRP1‐expressing myeloid cells promote and maintain CNV. Expression of NRP1 on cells of myeloid lineage is critical for mitigating production of inflammatory factors such as IL6 and IL1β. Therapeutically trapping ligands of NRP1 with an NRP1‐derived trap reduces CNV. Collectively, our findings identify a role for NRP1‐expressing myeloid cells in promoting pathological angiogenesis during CNV and introduce a therapeutic approach to counter neovascular AMD. Synopsis A population of innate immune myeloid cells expressing NRP1 receptor invades the retina where it drives and maintains pathological neovascularization during age‐related macular degeneration (AMD). A recombinant NRP1‐derived trap prevents choroidal neovascularization‐associated pathological angiogenesis. NRP1 ligands were elevated in patients with neovascular AMD and in a mouse model of choroidal neovascularization (CNV). NRP1‐expressing mononuclear phagocytes rose in the retina upon injury and promoted CNV. CNV was reduced in mice by therapeutic intravitreal administration of soluble NRP1. Graphical Abstract A population of innate immune myeloid cells expressing NRP1 receptor invades the retina where it drives and maintains pathological neovascularization during age‐related macular degeneration (AMD). A recombinant NRP1‐derived trap prevents choroidal neovascularization‐associated pathological angiogenesis.

Based on promising results from laboratory studies, we hypothesized that pneumococcal vaccination would protect patients from myocardial infarction. We conducted a hospital-based case—control study that included patients considered to be at risk of myocardial infarction. We used health databases to obtain hospital diagnoses and vaccination status. We compared patients who had been admitted for treatment of myocardial infarction with patients admitted to a surgical department in the same hospital for a reason other than myocardial infarction between 1997 and 2003. We found a total of 43 209 patients who were at risk; of these, we matched 999 cases and 3996 controls according to age, sex and year of hospital admission. Cases were less likely than controls to have been vaccinated (adjusted odds ratio [OR] 0.53, 95% confidence interval [CI] 0.40–0.70). This putative protective role of the vaccine was not observed for patients who had received the vaccine up to 1 year before myocardial infarction (adjusted OR 0.85, 95% CI 0.54–1.33). In contrast, if vaccination had occurred 2 years or more before the hospital admission, the association was stronger (adjusted OR 0.33, 95% CI 0.20–0.46). Pneumococcal vaccination was associated with a decrease of more than 50% in the rate myocardial infarction 2 years after exposure. If confirmed, this association should generate interest in exploring the putative mechanisms and may offer another reason to promote pneumococcal vaccination.

Pakistan is considered by the World Health Organization to currently have a \"concentrated\" HIV-1 epidemic due to a rapid rise in infections among people who inject drugs (PWID). Prevalence among the country's nearly 105,000 PWID is estimated to be 37.8% but has been shown to be higher in several large urban centers. A lack of public health resources, the common use of professional injectors and unsafe injection practices are believed to have fueled the outbreak. Here we evaluate the molecular characteristics of HIV-1 sequences (n = 290) from PWID in several Pakistani cities to examine transmission dynamics and the association between rates of HIV-1 transmission with regards to regional trends in opioid trafficking. Tip-to-tip (patristic) distance based phylogenetic cluster inferences and BEAST2 Bayesian phylodynamic analyses of time-stamped data were performed on HIV-1 pol sequences generated from dried blood spots collected from 1,453 PWID as part of a cross-sectional survey conducted in Pakistan during 2014/2015. Overall, subtype A1 strains were dominant (75.2%) followed by CRF02_AG (14.1%), recombinants/unassigned (7.2%), CRF35_AD (2.1%), G (1.0%) and C (0.3%). Nearly three quarters of the PWID HIV-1 sequences belonged to one of five distinct phylogenetic clusters. Just below half (44.4%) of individuals in the largest cluster (n = 118) did seek help injecting from professional injectors which was previously identified as a strong correlate of HIV-1 infection. Spikes in estimated HIV-1 effective population sizes coincided with increases in opium poppy cultivation in Afghanistan, Pakistan's western neighbor. Structured coalescent analysis was undertaken in order to investigate the spatial relationship of HIV-1 transmission among the various cities under study. In general terms, our analysis placed the city of Larkana at the center of the PWID HIV-1 epidemic in Pakistan which is consistent with previous epidemiological data.