Real-Time Cerebral Hemodynamic Response to Tactile Somatosensory Stimulation.

BACKGROUND AND PURPOSE: Recent studies in rodents suggest that somatosensory stimulation could provide neuroprotection during ischemic stroke by inducing plasticity in the cortex-vasculature relationship. While functional magnetic resonance imaging (fMRI) has shown that somatosensory stimulation increases cerebral blood flow (CBF) over several seconds, subsecond changes in CBF in the basal cerebral arteries have rarely been studied due to temporal resolution limitations. This study characterized hemodynamic changes in the middle cerebral arteries (MCAs) during somatosensory stimulation with high temporal resolution (100 samples/s) using functional transcranial Doppler ultrasound (fTCD). METHODS: Pneumotactile somatosensory stimulation, consisting of punctate pressure pulses traversing the glabrous skin of the hand at 25 cm/s, was used to induce CBF velocity (CBFV) response curves. Changes in CBFV were measured in the bilateral MCAs using fTCD. All 12 subjects underwent three consecutive trials consisting of 20 seconds of stimulation followed by 5 minutes of rest. RESULTS: Sharp, bilateral increases in CBFV of about 20% (left MCA = 20.5%, right MCA = 18.8%) and sharp decreases in pulsatility index of about 8% were observed during stimulation. Left lateralization of up to 3.9% was also observed. The magnitude of the initial increase in CBFV showed significant adaptation between subsequent trials. CONCLUSIONS: Pneumotactile somatosensory stimulation is a potent stimulus that can evoke large, rapid hemodynamic changes, with adaptation between successive stimulus applications. Due to its high temporal resolution, fTCD is useful for identifying quickly evolving hemodynamic responses, and for correlating changes in hemodynamic parameters such as pulsatility index (PI) and CBFV.

IL-17 Receptor Signaling in the Lung Epithelium Is Required for Mucosal Chemokine Gradients and Pulmonary Host Defense against K. pneumoniae.

The cytokine IL-17, and signaling via its heterodimeric IL-17RA/IL-17RC receptor, is critical for host defense against extracellular bacterial and fungal pathogens. Polarized lung epithelial cells express IL-17RA and IL-17RC basolaterally. However, their contribution to IL-17-dependent pulmonary defenses in vivo remains to be determined. To address this, we generated mice with conditional deletion of Il17ra or Il17rc in Scgb1a1-expressing club cells, a major component of the murine bronchiolar epithelium. These mice displayed an impaired ability to recruit neutrophils into the airway lumen in response to IL-17, a defect in bacterial clearance upon mucosal challenge with the pulmonary pathogen Klebsiella pneumoniae, and substantially reduced epithelial expression of the chemokine Cxcl5. Neutrophil recruitment and bacterial clearance were restored by intranasal administration of recombinant CXCL5. Our data show that IL-17R signaling in the lung epithelium plays a critical role in establishing chemokine gradients that are essential for mucosal immunity against pulmonary bacterial pathogens.

Dose-Dependent Suppression of Cytokine production from T cells by a Novel Phosphoinositide 3-Kinase Delta Inhibitor.

There remains a significant need for development of effective small molecules that can inhibit cytokine-mediated inflammation. Phosphoinositide 3 kinase (PI3K) is a direct upstream activator of AKT, and plays a critical role in multiple cell signaling pathways, cell cycle progression, and cell growth, and PI3K inhibitors have been approved or are in clinical development. We examined novel PI3Kdelta inhibitors, which are highly selective for the p110delta isoform of in CD3/CD28 stimulated T-cell cytokine production. In vitro generated CD4+ T effector cells stimulated in the presence of a PI3Kdelta inhibitor demonstrated a dose-dependent suppression of cytokines produced by Th1, Th2, and Th17 cells. This effect was T-cell intrinsic, and we observed similar effects on human PBMCs. Th17 cells expressing a constitutively activated form of AKT were resistant to PI3Kdelta inhibition, suggesting that the inhibitor is acting through AKT signaling pathways. Additionally, PI3Kdelta inhibition decreased IL-17 production in vivo and decreased neutrophil recruitment to the lung in a murine model of acute pulmonary inflammation. These experiments show that targeting PI3Kdelta activity can modulate T-cell cytokine production and reduce inflammation in vivo, suggesting that PI3Kdelta inhibition could have therapeutic potential in treating inflammatory diseases.

Dysregulation in lung immunity - the protective and pathologic Th17 response in infection.

Th17 cytokines can play both protective and pathologic roles in the airways. An emerging theme in Th17 cytokine biology is that these responses can mediate tissue pathology when downstream effector cells are dysfunctional, such as neutrophils lacking functional NADPH oxidase in the case of chronic granulomatous disease, or epithelial cells lacking appropriate ion transport as in the case of cystic fibrosis. In this Mini-Review we highlight recent advances in the protective and pathologic roles of Th17 cytokines in the context of infection at the pulmonary barrier.

Compliance of child care centers in Pennsylvania with national health and safety performance standards for emergency and disaster preparedness.

OBJECTIVES: To determine the preparedness of child care centers in Pennsylvania to respond to emergencies and disasters based on compliance with National Health and Safety Performance Standards for Out-of-Home Child Care Programs. METHODS: A questionnaire focusing on the presence of a written evacuation plan, the presence of a written plan for urgent medical care, the immediate availability of equipment and supplies, and the training of staff in first aid/cardiopulmonary resuscitation (CPR) as delineated in Caring for Our Children: National Health and Safety Performance Standards for Out-of-Home Child Care Programs, 2nd Edition, was mailed to 1000 randomly selected child care center administrators located in Pennsylvania. RESULTS: Of the 1000 questionnaires sent, 496 questionnaires were available for analysis (54% usable response rate). Approximately 99% (95% confidence interval [CI], 99%-100%) of child care centers surveyed were compliant with recommendations to have a comprehensive written emergency plan (WEP) for urgent medical care and evacuation, and 85% (95% CI, 82%-88%) practice their WEP periodically throughout the year. More than 20% of centers did not have specific written procedures for floods, earthquakes, hurricanes, blizzards, or bomb threats, and approximately half of the centers did not have specific written procedures for urgent medical emergencies such as severe bleeding, unresponsiveness, poisoning, shock/heart or circulation failure, seizures, head injuries, anaphylaxis or allergic reactions, or severe dehydration. A minority of centers reported having medications available to treat an acute asthma attack or anaphylaxis. Also, 77% (95% CI, 73%-80%) of child care centers require first aid training for each one of its staff members, and 33% (95% CI, 29%-37%) require CPR training. CONCLUSIONS: Although many of the child care centers we surveyed are in compliance with the recommendations for emergency and disaster preparedness, specific areas for improvement include increasing the frequency of practice of the WEP, establishing specific written procedures for external disasters and urgent medical emergencies, maintaining the immediate availability of potentially life-saving medications, and ensuring that all child care center staff are trained in first aid and CPR.