Cognitive Task Domain Influences Cognitive-Motor Interference during Large-Magnitude Treadmill Stance Perturbations.

Reactive balance is postulated to be attentionally demanding, although it has been underexamined in dual-tasking (DT) conditions. Further, DT studies have mainly included only one cognitive task, leaving it unknown how different cognitive domains contribute to reactive balance. This study examined how DT affected reactive responses to large-magnitude perturbations and compared cognitive-motor interference (CMI) between cognitive tasks. A total of 20 young adults aged 18-35 (40% female; 25.6 ± 3.8 y) were exposed to treadmill support surface perturbations alone (single-task (ST)) and while completing four cognitive tasks: Target, Track, Auditory Clock Test (ACT), Letter Number Sequencing (LNS). Three perturbations were delivered over 30 s in each trial. Cognitive tasks were also performed while seated and standing (ST). Compared to ST, post-perturbation MOS was lower when performing Track, and cognitive performance was reduced on the Target task during DT (p < 0.05). There was a larger decline in overall (cognitive + motor) performance from ST for both of the visuomotor tasks compared to the ACT and LNS (p < 0.05). The highest CMI was observed for visuomotor tasks; real-life visuomotor tasks could increase fall risk during daily living, especially for individuals with difficulty attending to more than one task.

The Effect of Cognitive Task, Gait Speed, and Age on Cognitive-Motor Interference during Walking.

Dual-tasking can cause cognitive-motor interference (CMI) and affect task performance. This study investigated the effects of age, gait speed, and type of cognitive task on CMI during gait. Ten younger and 10 older adults walked on a pressure-sensitive GAITRite walkway which recorded gait speed and step length. Participants walked at a slow, preferred, or fast speed while simultaneously completing four cognitive tasks: visuomotor reaction time (VMRT), serial subtraction (SS), word list generation (WLG), and visual Stroop (VS). Each combination of task and speed was repeated for two trials. Tasks were also performed while standing. Motor and cognitive costs were calculated with the formula: ((single-dual)/single × 100). Higher costs indicate a larger reduction in performance from single to dual-task. Motor costs were higher for WLG and SS than VMRT and VS and higher in older adults (p < 0.05). Cognitive costs were higher for SS than WLG (p = 0.001). At faster speeds, dual-task costs increased for WLG and SS, although decreased for VMRT. CMI was highest for working memory, language, and problem-solving tasks, which was reduced by slow walking. Aging increased CMI, although both ages were affected similarly by task and speed. Dual-task assessments could include challenging CMI conditions to improve the prediction of motor and cognitive status.

Slip-Fall Predictors in Community-Dwelling, Ambulatory Stroke Survivors: A Cross-sectional Study.

BACKGROUND AND PURPOSE: Considering the multifactorial nature and the often-grave consequences of falls in people with chronic stroke (PwCS), determining measurements that best predict fall risk is essential for identifying those who are at high risk. We aimed to determine measures from the domains of the International Classification of Functioning, Disability and Health (ICF) that can predict laboratory-induced slip-related fall risk among PwCS. METHODS: Fifty-six PwCS participated in the experiment in which they were subjected to an unannounced slip of the paretic leg while walking on an overground walkway. Prior to the slip, they were given a battery of tests to assess fall risk factors. Balance was assessed using performance-based tests and instrumented measures. Other fall risk factors assessed were severity of sensorimotor impairment, muscle strength, physical activity level, and psychosocial factors. Logistic regression analysis was performed for all variables. The accuracy of each measure was examined based on its sensitivity and specificity for fall risk prediction. RESULTS: Of the 56 participants, 24 (43%) fell upon slipping while 32 (57%) recovered their balance. The multivariate logistic regression analysis model identified dynamic gait stability, hip extensor strength, and the Timed Up and Go (TUG) score as significant laboratory-induced slip-fall predictors with a combined sensitivity of 75%, a specificity of 79.2%, and an overall accuracy of 77.3%. DISCUSSION AND CONCLUSIONS: The results indicate that fall risk measures within the ICF domains-body, structure, and function (dynamic gait stability and hip extensor strength) and activity limitation (TUG)-could provide a sensitive laboratory-induced slip-fall prediction model in PwCS.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A323).

Intracellular Activation of Complement 3 Is Responsible for Intestinal Tissue Damage during Mesenteric Ischemia.

Intestinal ischemia followed by reperfusion leads to local and remote organ injury attributed to inflammatory response during the reperfusion phase. The extent to which ischemia contributes to ischemia/reperfusion injury has not been thoroughly studied. After careful evaluation of intestinal tissue following 30 min of ischemia, we noticed significant local mucosal injury in wild-type mice. This injury was drastically reduced in C3-deficient mice, suggesting C3 involvement. Depletion of circulating complement with cobra venom factor eliminated, as expected, injury recorded at the end of the reperfusion phase but failed to eliminate injury that occurred during the ischemic phase. Immunohistochemical studies showed that tissue damage during ischemia was associated with increased expression of C3/C3 fragments primarily in the intestinal epithelial cells, suggesting local involvement of complement. In vitro studies using Caco2 intestinal epithelial cells showed that in the presence of LPS or exposure to hypoxic conditions the cells produce higher C3 mRNA as well as C3a fragment. Caco2 cells were also noted to produce cathepsins B and L, and inhibition of cathepsins suppressed the release of C3a. Finally, we found that mice treated with a cathepsin inhibitor and cathepsin B-deficient mice suffer limited intestinal injury during the ischemic phase. To our knowledge, our findings demonstrate for the first time that significant intestinal injury occurs during ischemia prior to reperfusion and that this is due to activation of C3 within the intestinal epithelial cells in a cathepsin-dependent manner. Modulation of cathepsin activity may prevent injury of organs exposed to ischemia.

Work Related Post Traumatic Stress Disorder in Medicine Residents.

OBJECTIVE: This study sought to screen for the burden of work-related posttraumatic stress disorder (PTSD) symptoms in internal medicine residents. METHODS: A cross-sectional survey of internal medicine residents from three academic institutions was conducted using the PCL-5 screening tool. RESULTS: Off all residents surveyed, 5.2% screened positive for PTSD symptoms (N = 194). 86.1% of all trainees identified stressors during training. Positive PTSD screens were significantly higher in PGY3 residents (X2 = 15.24, p = 0.0005). Of all PGY3 residents, 9.8% (N = 4) and 14.6% (N = 6) of residents screened positive for PTSD symptoms based on absolute and cluster score criteria, respectively. Verbal/physical assault by patients/families/colleagues were triggers for the most cases of positive screens. CONCLUSIONS: Self-reported stressors are highly prevalent in internal medicine trainees. Verbal/physical assault by patients and families appear to be the triggering event for most positive screens. These observations will help with future study designs to quantify the burden of work related PTSD in internal medicine trainee physicians so that appropriate supportive measures can be provided.

Prevalence of Cardiac Arrhythmias in Hypothyroid and Euthyroid Patients.

The thyroid functions as a regulator of cardiac function and rhythm through genomic and nongenomic actions of triiodothyronine (T3) in cardiac myocytes. Atrial fibrillation is a common complication of thyrotoxicosis. Hypothyroidism is not considered a risk factor for arrhythmias despite well-known EKG changes in this condition. This case control study was conducted to analyze the differences, if any, in the prevalence of cardiac arrhythmias between hypothyroid patients and euthyroid controls. Three hundred and four consecutive patients admitted at our medical center for a period of one year were included in the study. The study population was divided into 2 groups (age, gender and race matched): patients with hypothyroidism and euthyroid subjects as a control group. Major arrhythmia data were obtained from telemetry recordings and from known past medical history. There were 152 subjects in each arm of the study. The mean age was 61.9 years. Mean TSH in hypothyroid group was 40.4 mIU/l (95% CI 33.3-47.5) (range 10.09-304, SE 3.62) and in euthyroid group was 0.89 mIU/l (95% CI 0.82-0.96). Chi-square analysis revealed a higher prevalence of ventricular tachycardia (p=0.04) and any ventricular arrhythmia in the hypothyroid group (p=0.007). This relatively large case control study revealed a statistically higher prevalence of ventricular arrhythmias in hypothyroidism. Our study has thrown light on the prevalence of arrhythmias in hypothyroidism and the observation of increased ventricular arrhythmias necessitates future large scale prospective studies to better define the risk of such ventricular arrhythmias and the effects of thyroid supplementation on this risk.

R-spondin3 prevents mesenteric ischemia/reperfusion-induced tissue damage by tightening endothelium and preventing vascular leakage.

Inflammation and vascular injury triggered by ischemia/reperfusion (I/R) represent a leading cause of morbidity and mortality in a number of clinical settings. Wnt and its homolog partners R-spondins, in addition to regulating embryonic development have recently been demonstrated to serve as wound-healing agents in inflammation-associated conditions. Here we ask whether R-spondins could prevent inflammation-associated tissue damage in ischemic disorders and thus investigate the role of R-spondin3 (R-spo3) in a mouse model of mesenteric I/R. We demonstrate that R-spo3 ameliorates mesenteric I/R-induced local intestinal as well as remote lung damage by suppressing local and systemic cytokine response and deposition of IgM and complement in intestinal tissues. We also show that decreased inflammatory response is accompanied by tightening of endothelial cell junctions and reduction in vascular leakage. We conclude that R-spo3 stabilizes endothelial junctions and inhibits vascular leakage during I/R and thereby mitigates the inflammatory events and associated tissue damage. Our findings uniquely demonstrate a protective effect of R-spo3 in I/R-related tissue injury and suggest a mechanism by which it may have these effects.

C4d deposits on the surface of RBCs in trauma patients and interferes with their function.

OBJECTIVE: Complement system is activated in patients with trauma. Although complement activation is presumed to contribute to organ damage and constitutional symptoms, little is known about the involved mechanisms. Because complement components may deposit on RBCs, we asked whether complement deposits on the surface of RBC in trauma and whether such deposition alters RBC function. DESIGN: A prospective experimental study. SETTING: Research laboratory. SUBJECTS: Blood samples collected from 42 trauma patients and 21 healthy donors. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: RBC and sera were collected from trauma patients and control donors. RBCs from trauma patients (n = 40) were found to display significantly higher amounts of C4d on their surface by flow cytometry compared with RBCs from control (n = 17) (p < 0.01). Increased amounts of iC3b were found in trauma sera (n = 27) (vs 12 controls, p < 0.01) by enzyme-linked immunosorbent assay. Incubation of RBC from universal donors (type O, Rh negative) with trauma sera (n = 10) promoted C4d deposition on their surface (vs six controls, p< 0.05). Complement-decorated RBC (n = 6) displayed limited their deformability (vs six controls, p < 0.05) in two-dimensional microchannel arrays. Incubation of RBC with trauma sera (n = 10) promoted the phosphorylation of band 3, a cytoskeletal protein important for the function of the RBC membrane (vs eight controls, p < 0.05), and also accelerated calcium influx (n = 9) and enhanced nitric oxide production (n = 12) (vs four and eight controls respectively, p < 0.05) in flow cytometry. CONCLUSIONS: Our study found the presence of extensive complement activation in trauma patients and presents new evidence in support of the hypothesis that complement activation products deposit on the surface of RBC. Such deposition could limit RBC deformability and promote the production of nitric oxide. Our findings suggest that RBC in trauma patients malfunctions, which may explain organ damage and constitutional symptoms that is not accounted for otherwise by previously known pathophysiologic mechanisms.

Perturbation-based dual task assessment in older adults with mild cognitive impairment.

Background: Dual tasking (i.e., concurrent performance of motor and cognitive task) is significantly impaired in older adults with mild cognitive impairment (OAwMCI) compared to cognitively intact older adults (CIOA) and has been associated with increased fall risk. Dual task studies have primarily examined volitionally driven events, and the effects of mild cognitive impairment on reactive balance control (i.e., the ability to recover from unexpected balance threats) are unexplored. We examined the effect of cognitive tasks on reactive balance control in OAwMCI compared to CIOA. Methods: Adults >55 years were included and completed the Montreal Cognitive Assessment (MoCA) to categorize them as OAwMCI (MoCA: 18-24, n = 15) or CIOA (MoCA: ≥25, n = 15). Both OAwMCI [MoCA: 22.4 (2.2), 65.4 (6.1) years, 3 females] and CIOA [MoCA: 28.4 (1.3), 68.2 (5.5) years, 10 females] responded to large magnitude stance slip-like perturbations alone (single task) and while performing perceptual cognitive tasks targeting the visuomotor domain (target and tracking game). In these tasks, participants rotated their head horizontally to control a motion mouse and catch a falling target (target game) or track a moving object (track). Margin of stability (MOS) and fall outcome (harness load cell >30% body weight) were used to quantify reactive balance control. Cognitive performance was determined using performance error (target) and sum of errors (tracking). A 3 × 2 repeated measures ANOVA examined the effect of group and task on MOS, and generalized estimating equations (GEE) model was used to determine changes in fall outcome between groups and tasks. 2 × 2 repeated measures ANOVAs examined the effect of group and task on cognitive performance. Results: Compared to CIOA, OAwMCI exhibited significantly deteriorated MOS and greater number of falls during both single task and dual task (p < 0.05), and lower dual task tracking performance (p < 0.01). Compared to single task, both OAwMCI and CIOA exhibited significantly deteriorated perceptual cognitive performance during dual task (p < 0.05); however, no change in MOS or fall outcome between single task and dual task was observed. Conclusion: Cognitive impairment may diminish the ability to compensate and provide attentional resources demanded by sensory systems to integrate perturbation specific information, resulting in deteriorated ability to recover balance control among OAwMCI.

Atypical Hemolytic Uremic Syndrome in a Pregnant Patient with a Thrombomodulin Gene Variant Treated with Plasma Exchange and Eculizumab.

BACKGROUND Hemolytic uremic syndrome (HUS) includes the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The atypical form of HUS is a rare disease characterized by complement overactivation, and it can be from genetic or acquired causes. Genetic causes involve mutation in one of the factors in the alternative complement pathway or inhibitors. Malignant hypertension and pregnancy are the most important acquired causes. The optimal management of patients with aHUS is with eculizumab, which is recombinant antibody against human complement component C5. CASE REPORT This report describes the case of a 25-year-old woman with frequent hospitalizations for poorly controlled hypertension who presented at 20 weeks of gestation with headache, vomiting, and a blood pressure of 230/126 mmHg. The patient had acute kidney injury with hematuria and proteinuria, and kidney biopsy showed hypertensive arteriolar nephrosclerosis and fibrinoid arteriolar necrosis consistent with thrombotic microangiopathy. Further work-up with a genetic panel showed heterozygosity for the thrombomodulin (THBD) gene. She was started on treatment with plasma exchange and eculizumab, a recombinant monoclonal antibody that inhibits terminal complement activation at the C5 protein. The patient responded well to the treatment at the time of her initial outpatient follow-up. CONCLUSIONS This case shows the potential of severe renal manifestation of aHUS, and the need for a kidney biopsy in cases of severe uncontrolled hypertension presenting with kidney injury. If evidence of aHUS is found, prompt treatment with plasma exchange and eculizumab should be initiated.

Overlapping Syndromes: Drug-Induced Vasculitis From Hydralazine With Positive Antinuclear Antibodies.

Hydralazine is an antihypertensive medication that has been associated with drug-associated autoimmune syndromes like interstitial lung disease, pauci-immune glomerulonephritis, and hypocomplementemia. Hydralazine-induced ANCA-associated vasculitis and hydralazine induced positive antinuclear antibodies are rare. Clinical manifestations range from arthralgia, petechiae, or rash to multiorgan involvement. When presented as pulmonary-renal syndrome, it can be rapidly progressive and fatal. Here, we describe a case of hydralazine-associated vasculitis with rapidly progressive glomerulonephritis and highlight the importance of early diagnosis and prompt treatment.

A Case Series of Uncommon Sodium Disorders in Common Clinical Scenarios.

Dysnatremias or sodium disorders (either hyponatremia or hypernatremia) are the most common electrolyte problems in clinical medicine. They pose diagnostic and therapeutic challenges and have high mortality. Even mild changes in sodium levels from normal are associated with worse outcomes and considerable morbidity and mortality. We present a series of four patients with either hypo- or hypernatremia in different clinical scenarios requiring immediate treatment with close monitoring to avoid overcorrection. This case series shows that uncommon or unusual sodium disorders can happen in an otherwise usual situation.

Atrial fibrillation gut syndrome: severe gastroparesis with pyloric spasm following radiofrequency catheter ablation of drug resistant symptomatic atrial fibrillation: a case report.

BACKGROUND: Atrial fibrillation is the most common cardiac arrhythmia, and cardiac ablation is one of the treatment modalities for persistent symptomatic atrial fibrillation. Gastroparesis is a rare complication of radiofrequency catheter ablation for atrial fibrillation, which may be associated with high morbidity. CASE PRESENTATION: We present a 44-year-old Caucasian male with persistent atrial fibrillation who presented with nausea, vomiting, bloating, and constipation after radiofrequency catheter ablation. He was found to have gastroparesis due to pyloric spasm that was treated with botulinum toxin injection. CONCLUSION: This case signifies the importance of identifying gastric complications after radiofrequency catheter ablation atrial fibrillation, and the need for prompt diagnosis and treatment of gastroparesis with botulinum toxin injection.

Cerebello-cortical functional connectivity may regulate reactive balance control in older adults with mild cognitive impairment.

Background: Older adults with mild cognitive impairment (OAwMCI) experience a two-fold increased risk of falling compared to their cognitively intact counterparts. This increased risk could be attributed to impairments in balance control mechanisms (both volitional and reactive), however, the exact neural substrates contributing to the balance impairments remain unclear. While changes in functional connectivity (FC) networks in volitional balance control tasks have been well highlighted, the relationship between these changes and reactive balance control has not been examined. Therefore, this study aims to explore the relationship between FC networks of the brain obtained during resting state fMRI (no visualization or active task performed) and behavioral measures on a reactive balance task in OAwMCI. Methods: Eleven OAwMCI (< 25/30 on MoCA, > 55 years) underwent fMRI and were exposed to slip-like perturbations on the Activestep treadmill. Postural stability, i.e., dynamic center of mass motion state (i.e., its position and velocity) was computed to determine reactive balance control performance. The relationship between reactive stability and FC networks was explored using the CONN software. Results: OAwMCI with greater FC in default mode network-cerebellum (r2 = 0.43, p < 0.05), and sensorimotor-cerebellum (r2 = 0.41, p < 0.05) network exhibited lower reactive stability. Further, people with lower FC in middle frontal gyrus-cerebellum (r2 = 0.37, p < 0.05), frontoparietal-cerebellum (r2 = 0.79, p < 0.05) and cerebellar network-brainstem (r2 = 0.49, p < 0.05) exhibited lower reactive stability. Conclusion: Older adults with mild cognitive impairment demonstrate significant associations between reactive balance control and cortico-subcortical regions involved in cognitive-motor control. Results indicate that the cerebellum and its communications with higher cortical centers could be potential substrates contributing to impaired reactive responses in OAwMCI.

Purple urine in a patient with UTI and constipation.

Purple urine bag syndrome (PUBS) is a visually striking and a rare side effect in a patient with urinary tract infection where urine in the catheter bags and tubing turn purple. The urine in PUBS gets its color from the combination of two pigments, indirubin and indigo, which are breakdown products of tryptophan. The most important risk factors include long-term catheterization, female gender, chronic constipation, old age and being bed bound. Here, we present a case of PUBS in an elderly female with a history of bladder cancer that needed catheterization along with constipation.

Motor adaptation and immediate retention to overground gait-slip perturbation training in people with chronic stroke: an experimental trial with a comparison group.

Background: Perturbation-based training has shown to be effective in reducing fall-risk in people with chronic stroke (PwCS). However, most evidence comes from treadmill-based stance studies, with a lack of research focusing on training overground perturbed walking and exploring the relative contributions of the paretic and non-paretic limbs. This study thus examined whether PwCS could acquire motor adaptation and demonstrate immediate retention of fall-resisting skills following bilateral overground gait-slip perturbation training. Methods: 65 PwCS were randomly assigned to either (i) a training group, that received blocks of eight non-paretic (NP-S1 to NP-S8) and paretic (P-S1 to P-S8) overground slips during walking followed by a mixed block (seven non-paretic and paretic slips each interspersed with unperturbed walking trials) (NP-S9/P-S9 to NP-S15/P-S15) or (ii) a control group, that received a single non-paretic and paretic slip in random order. The assessor and training personnel were not blinded. Immediate retention was tested for the training group after a 30-minute rest break. Primary outcomes included laboratory-induced slip outcomes (falls and balance loss) and center of mass (CoM) state stability. Secondary outcomes to understand kinematic contributors to stability included recovery strategies, limb kinematics, slipping kinematics, and recovery stride length. Results: PwCS within the training group showed reduced falls (p < 0.01) and improved post-slip stability (p < 0.01) from the first trial to the last trial of both paretic and non-paretic slip blocks (S1 vs. S8). During the mixed block training, there was no further improvement in stability and slipping kinematics (S9 vs. S15) (p > 0.01). On comparing the first and last training trial (S1 vs. S15), post-slip stability improved on both non-paretic and paretic slips, however, pre-slip stability improved only on the non-paretic slip (p < 0.01). On the retention trials, the training group had fewer falls and greater post-slip stability than the control group on both non-paretic and paretic slips (p < 0.01). Post-slip stability on the paretic slip was lower than that on the non-paretic slip for both groups on retention trials (p < 0.01). Conclusion: PwCS can reduce laboratory-induced slip falls and backward balance loss outcomes by adapting their post-slip CoM state stability after bilateral overground gait-slip perturbation training. Such reactive adaptations were better acquired and retained post-training in PwCS especially on the non-paretic slips than paretic slips, suggesting a need for higher dosage for paretic slips. Clinical registry number: NCT03205527.

Adverse Events Related to Tirzepatide.

Context: Tirzepatide is a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved by the US Food and Drug Administration in May 2022 for patients with type 2 diabetes mellitus (T2DM). Objective: We aimed to determine the rates of individual adverse events (AEs) related to 3 studied doses of tirzepatide. Methods: We performed a systematic review with meta-analysis including 5 databases (PubMed, Embase, CINAHL, Scopus, and Web of Science) for all clinical trials reporting AEs related to tirzepatide. The safety data from individual studies were extracted and analyzed through meta-regression to assess rates of individual AEs. Study quality assessment was performed using the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Results: Ten trials (6836 participants) were included. Gastrointestinal (GI) AEs were the most commonly reported AEs and were dose dependent 39% (95% CI, 35%-43%), 46% (95% CI, 42%-49%), and 49% (95% CI, 38%-60%) for the 5, 10, and 15 mg dose, respectively. Among all GI AEs, nausea and diarrhea were most frequent at any dose of tirzepatide. Drug discontinuation due to AEs was highest with the 15 mg dose of tirzepatide (10%). Incidence of mild hypoglycemia (blood glucose < 70 mg/dL) was highest with tirzepatide 10 mg dose 22.6% (9.2%-39.8%). Rates of fatal AEs, severe hypoglycemia, acute pancreatitis, cholelithiasis, and cholecystitis were extremely low (≤ 1%) across all doses of tirzepatide. Conclusion: Tirzepatide is associated with a dose-dependent increase in incidence of GI AEs and AEs leading to drug discontinuation. Severe hypoglycemia, fatal AEs, acute pancreatitis, cholelithiasis, and cholecystitis are rare with this medication.

Platelets orchestrate remote tissue damage after mesenteric ischemia-reperfusion.

Ischemia-reperfusion (I/R) injury is a leading cause of morbidity and mortality. A functional role for platelets in tissue damage after mesenteric I/R is largely unknown. The hypothesis that mesenteric I/R local and remote injury are platelet dependent was tested. Using a murine mesenteric I/R model, we demonstrate that platelets orchestrate remote lung tissue damage that follows mesenteric I/R injury and also contribute, albeit to a lesser degree, to local villi damage. While lung damage is delayed compared with villi damage, it increased over time and was characterized by accumulation of platelets in the pulmonary vasculature early, followed by alveolar capillaries and extravasation into the pulmonary space. Both villi and lung tissues displayed complement deposition. We demonstrate that villi and lung damage are reduced in mice made platelet deficient before I/R injury and that platelet transfusion into previously platelet-depleted mice before I/R increased both villi and lung tissue damage. Increased C3 deposition accompanied platelet sequestration in the lung, which was mostly absent in platelet-depleted mice. In contrast, C3 deposition was only minimally reduced on villi of platelet-depleted mice. Our findings position platelets alongside complement as a significant early upstream component that orchestrates remote lung tissue damage after mesenteric I/R and strongly suggest that reperfusion injury mitigating modalities should consider the contribution of platelets.

Inhibition of Syk activity by R788 in platelets prevents remote lung tissue damage after mesenteric ischemia-reperfusion injury.

Tissue injury following ischemia-reperfusion (I/R) occurs as a consequence of actions of soluble factors and immune cells. Growing evidence supports a role for platelets in the manifestation of tissue damage following I/R. Spleen tyrosine kinase has been well documented to be important in lymphocyte activation and more recently in platelet activation. We performed experiments to evaluate whether inhibition of platelet activation through inhibition of spleen tyrosine kinase prevents tissue damage after mesenteric I/R injury. Platelets isolated from C57BL/6J mice fed with R788 for 10 days were transfused into C57BL/6J mice depleted of platelets 2 days before mesenteric I/R injury. Platelet-depleted mice transfused with platelets from R788-treated mice before mesenteric I/R displayed a significant reduction in the degree of remote lung damage, but with little change in the degree of local intestinal damage compared with control I/R mice. Transfusion of R788-treated platelets also decreased platelet sequestration, C3 deposition, and immunoglobulin deposition in lung, but not in the intestine, compared with control groups. These findings demonstrate that platelet activation is a requisite for sequestration in the pulmonary vasculature to mediate remote tissue injury after mesenteric I/R. The use of small-molecule inhibitors may be valuable to prevent tissue damage in remote organs following I/R injury.