Brief research report: Photoplethysmography pulse sensors designed to detect human heart rates are ineffective at measuring horse heart rates

This study sought to evaluate the accuracy of a PPG (photoplethysmography) sensor designed to measure human heart rates in monitoring the distal limb pulse of healthy adult horses. We hypothesized that the PPG sensor is sensitive to placement location and orientation, and that measurement accuracies depend on placement and orientation on the limb. To evaluate this hypothesis, a completely randomized block design with a factorial treatment structure was used. Horses were considered as the block. Limb type (right front, left front, right hind, and left hind) and position of sensor (medial or lateral) were treatments, with levels arranged in a complete (4x2) factorial design. Data were collected by placing the PPG sensor on the limb of each horse (n = 6), with placement location according to the treatment (limb type and location) combination, and taking pulse readings for 60 seconds. Manual heart rates were collected concurrently using a stethoscope. Data were analyzed by calculating root mean square errors (RMSE) for the PPG measurements with the manual heart rates as a gold standard. Variation in RMSE associated with limb and location of sensor were evaluated using a general linear model with fixed effects for limb and location and a random effect for horse. Our results indicated that the PPG sensor was ineffective at measuring horse heart rates, and that the device was insensitive to placement location and orientation. Future work should focus on developing alternative analytics to interpret the data from PPG sensors to better reflect horse heart rates

Sudden acquired retinal degeneration syndrome (SARDS) â a review and proposed strategies toward a better understanding of pathogenesis, early diagnosis, and therapy

Sudden acquired retinal degeneration syndrome (SARDS) is one of the leading causes of currently incurable canine vision loss diagnosed by veterinary ophthalmologists. The disease is characterized by acute onset of blindness due to loss of photoreceptor function, extinguished electroretinogram with an initially normal appearing ocular fundus, and mydriatic pupils which are slowly responsive to bright white light, unresponsive to red, but responsive to blue light stimulation. In addition to blindness, the majority of affected dogs also show systemic abnormalities suggestive of hyperadrenocorticism, such as polyphagia with resulting obesity, polyuria, polydipsia, and a subclinical hepatopathy. The pathogenesis of SARDS is unknown, but neuroendocrine and autoimmune mechanisms have been suggested. Therapies that target these disease pathways have been proposed to reverse or prevent further vision loss in SARDSâ affected dogs, but these treatments are controversial. In November 2014, the American College of Veterinary Ophthalmologists' Vision for Animals Foundation organized and funded a Think Tank to review the current knowledge and recently proposed ideas about disease mechanisms and treatment of SARDS. These panel discussions resulted in recommendations for future research strategies toward a better understanding of pathogenesis, early diagnosis, and potential therapy for this condition.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/122446/1/vop12291.pd

Interleukin 6 Accelerates Mortality by Promoting the Progression of the Systemic Lupus Erythematosus-Like Disease of BXSB. Yaa Mice

IL6 is a multifunctional cytokine that drives terminal B cell differentiation and secretion of immunoglobulins. IL6 also cooperates with IL21 to promote differentiation of CD4(+) T follicular helper cells (TFH). Elevated serum levels of IL6 correlate with disease flares in patients with systemic lupus erythematosus (SLE). We previously reported that IL21 produced by T-FH plays a critical role in the development of the SLE-like disease of BXSB. Yaa mice. To examine the possible contributions of IL6 to disease, we compared disease parameters in IL6-deficient and IL6-competent BXSB. Yaa mice. We report that survival of IL6-deficient BXSB. Yaa mice was significantly prolonged in association with significant reductions in a variety of autoimmune manifestations. Moreover, B cells stimulated by co-engagement of TLR7 and B cell receptor (BCR) produced high levels of IL6 that was further augmented by stimulation with Type I interferon (IFN1). Importantly, the frequencies of T-FH and serum levels of IL21 were significantly reduced in IL6-deficient mice. These findings suggest that high-level production of IL6 by B cells induced by integrated signaling from the IFN1 receptor, TLR7 and BCR promotes the differentiation of IL21-secreting T-FH in a signaling sequence that drives the lethal autoimmune disease of BXSB. Yaa mice.Peer reviewe

Table_1_Brief research report: Photoplethysmography pulse sensors designed to detect human heart rates are ineffective at measuring horse heart rates.docx

This study sought to evaluate the accuracy of a PPG (photoplethysmography) sensor designed to measure human heart rates in monitoring the distal limb pulse of healthy adult horses. We hypothesized that the PPG sensor is sensitive to placement location and orientation, and that measurement accuracies depend on placement and orientation on the limb. To evaluate this hypothesis, a completely randomized block design with a factorial treatment structure was used. Horses were considered as the block. Limb type (right front, left front, right hind, and left hind) and position of sensor (medial or lateral) were treatments, with levels arranged in a complete (4x2) factorial design. Data were collected by placing the PPG sensor on the limb of each horse (n = 6), with placement location according to the treatment (limb type and location) combination, and taking pulse readings for 60 seconds. Manual heart rates were collected concurrently using a stethoscope. Data were analyzed by calculating root mean square errors (RMSE) for the PPG measurements with the manual heart rates as a gold standard. Variation in RMSE associated with limb and location of sensor were evaluated using a general linear model with fixed effects for limb and location and a random effect for horse. Our results indicated that the PPG sensor was ineffective at measuring horse heart rates, and that the device was insensitive to placement location and orientation. Future work should focus on developing alternative analytics to interpret the data from PPG sensors to better reflect horse heart rates.</p

Abrogated AID Function Prolongs Survival and Diminishes Renal Pathology in the BXSB Mouse Model of Systemic Lupus Erythematosus.

Almost a decade has passed since the approval of belimumab, an mAb directed against B lymphocyte stimulation and the first targeted therapy approved for systemic lupus erythematous (SLE) in over 50 y. Although well tolerated, the efficacy of belimumab remains limited and is not labeled for patients suffering from nephritis, the leading cause of patient mortality. We sought to explore alternative targets of autoreactive B lymphocytes through manipulation of affinity maturation. The BXSB/MpJ mouse, a well-established model of human SLE, develops elevated antinuclear Abs and immune complex-mediated nephritis along with other manifestations of SLE-like disease. To limit interfering with critical background genetics, we used CRISPR-Cas9 to disrupt activation-induced cytidine deaminase (AID

Interferon-γ Limits Diabetogenic CD8(+) T-Cell Effector Responses in Type 1 Diabetes.

Type 1 diabetes development in the NOD mouse model is widely reported to be dependent on high-level production by autoreactive CD4(+) and CD8(+) T cells of interferon-γ (IFN-γ), generally considered a proinflammatory cytokine. However, IFN-γ can also participate in tolerance-induction pathways, indicating it is not solely proinflammatory. This study addresses how IFN-γ can suppress activation of diabetogenic CD8(+) T cells. CD8(+) T cells transgenically expressing the diabetogenic AI4 T-cell receptor adoptively transferred disease to otherwise unmanipulated NOD.IFN-γ(null) , but not standard NOD, mice. AI4 T cells only underwent vigorous intrasplenic proliferation in NOD.IFN-γ(null) recipients. Disease-protective IFN-γ could be derived from any lymphocyte source and suppressed diabetogenic CD8(+) T-cell responses both directly and through an intermediary nonlymphoid cell population. Suppression was not dependent on regulatory T cells, but was associated with increased inhibitory STAT1 to STAT4 expression levels in pathogenic AI4 T cells. Importantly, IFN-γ exposure during activation reduced the cytotoxicity of human-origin type 1 diabetes-relevant autoreactive CD8(+) T cells. Collectively, these results indicate that rather than marking the most proinflammatory lymphocytes in diabetes development, IFN-γ production could represent an attempted limitation of pathogenic CD8(+) T-cell activation. Thus, great care should be taken when designing possible diabetic intervention approaches modulating IFN-γ production. Diabetes 2017 Mar; 66(3):710-721

B-lymphocytes expressing an immunoglobulin specificity recognizing the pancreatic ß-cell autoantigen peripherin are potent contributors to type 1 diabetes development in NOD mice.

While the autoimmune destruction of pancreatic ß-cells underlying type 1 diabetes (1D) development is ultimately mediated by T-cells in NOD mice and also likely humans, B-lymphocytes play an additional key pathogenic role. It appears expression of plasma membrane bound immunoglobulin (Ig) molecules that efficiently capture ß-cell antigens allows autoreactive B-lymphocytes bypassing normal tolerance induction processes to be the subset of antigen presenting cells most efficiently activating diabetogenic T-cells. NOD mice transgenically expressing Ig molecules recognizing antigens that are (insulin) or not (hen egg lysozyme; HEL) expressed by ß-cells have proven useful in dissecting the developmental basis of diabetogenic B-lymphocytes. However, these transgenic Ig specificities were originally selected for their ability to recognize insulin or HEL as foreign, rather than autoantigens. Thus, we generated and characterized NOD mice transgenically expressing an Ig molecule representative of a large proportion of naturally occurring islet-infiltrating B-lymphocytes in NOD mice recognizing the neuronal antigen peripherin. Transgenic peripherin autoreactive B-lymphocytes infiltrate NOD pancreatic islets, acquire an activated proliferative phenotype, and potently support accelerated T1D development. These results support the concept of neuronal autoimmunity as a pathogenic feature of T1D, and targeting such responses could ultimately provide an effective disease intervention approach. Diabetes 2016 Jul; 65:1977-87

IL6-deficient BXSB.<i>Yaa</i> mice have reduced disease manifestations.

<p>(A) Sera from 6-month old BXSB.<i>Yaa</i>.<i>Il6</i>^<i>-/-</i>, BXSB.<i>Yaa</i>, BXSB.<i>Il6</i>^<i>-/-</i>, BXSB, BXSB.<i>B6Y</i> and C57BL/6 mice were quantified for the presence of ANA by ELISA (n = 3–10 mice per group). Each dot represents one mouse. Horizontal bars indicate mean ± SEM and p values are calculated by one-way ANOVA with Tukey’s multiple comparison tests. (B) Survival curve analysis of BXSB.<i>Yaa</i>.<i>Il6</i>^<i>+/-</i> (n = 17), BXSB.<i>Yaa</i>.<i>Il6</i>^<i>-/—</i>(n = 41) and archival data of BXSB.<i>Yaa</i> (n = 93) mice. (C-E) IL6-competent and—deficient BXSB.<i>Yaa</i> mice (n = 8–10) were compared for disease manifestations including spleen weight (C), serum IgG1 and IgG2b (D) and serum anti-dsDNA antibody titers (E). Bars represent mean ± SEM of observations from individual mice and p values are calculated using two-way ANOVA. * p<0.05, ** p<0.01, ***p<0.0001.</p

IL6 levels correlate with disease manifestations in BXSB.<i>Yaa</i> mice.

<p>Sera from BXSB.<i>Yaa</i> and BXSB mice of different ages were collected and tested for the levels of (A) IL6 (B) anti-nuclear antibodies (ANA) and anti-dsDNA antibodies, and (C) immunoglobulin isotypes (IgG2b and IgG2c); n = 4–20 mice per age group. Each dot represents one mouse. Horizontal bars represent mean ±SEM. p values are calculated by one-way ANOVA with Tukey’s multiple comparison tests. * p<0.05, ** p<0.01, ***p<0.0001.</p

BXSB.<i>Yaa</i> B cells exhibit an activated phenotype.

<p>(A) Purified CD43^- B cells from 4–5 month old BXSB.<i>Yaa</i> and BXSB mice were stimulated with R837 (50ng/ml) for 24 hours and stained for surface expression of the activation markers—CD40, MHCII, ICOSL and CD86. Data are expressed as mean ± SEM of mean fluorescence intensity (MFI) and are pooled from 4–5 independent experiments. (B) Purified CD43^- B cells from 4–5 month old BXSB.<i>Yaa</i> and BXSB mice were stimulated with graded doses of R837 for 24 hours. ³H thymidine (0.5μCi/well) was added and its incorporation was determined after 16 hours by liquid scintillation counting. Proliferation was determined as counts per minute (CPM). (C-D) CD43^- B cells were stimulated with R837 (50ng/ml) in the presence and absence of anti-BCR antibody. IL6 secretion (C) and B cell proliferation (D) were determined as described earlier. (E) Purified B cells from 4–5 month old BXSB.<i>Yaa</i> and BXSB mice were cultured in the presence or absence of R837 (50ng/ml); IFNα and IFNβ (40U/ml), either alone or in combination, for 24h. Supernatants were collected and quantified for IL6 levels by standard sandwich ELISA. All data (B-E) are expressed as mean ± SEM of triplicate wells and are representative of 2–3 independent experiments. P values are determined by two-way ANOVA. * p<0.05, ** p<0.01, ***p<0.0001.</p