Publications

Exogenous sphingosine 1-phosphate (S1P) is an effective cardioprotectant against ischemic injury. We have investigated the hypothesis that S1P is also an important endogenous cardioprotectant released during both ischemic preconditioning (IPC) and ischemic postconditioning (IPOST). IPC of ex vivo rat hearts was instituted by two cycles of 3 min ischemia-5 min reperfusion prior to 40 min of index ischemia and then 40 min of reperfusion. IPC resulted in 70% recovery of left ventricular developed pressure (LVDP) upon reperfusion and a small infarct size (10%). VPC23019 (VPC), a specific antagonist of S1P(1 and 3) G protein-coupled receptors (GPCRs), when present during preconditioning blocked protection afforded by two cycles of IPC. VPC also blocked preconditioning of isolated rat cardiac myocytes subjected to hypoxia-reoxygenation injury. Increased release of S1P from myocytes in response to IPC was also demonstrated. These data indicate that S1P is released from myocytes in response to IPC and protects by binding to S1P GPCRs. In the ex vivo heart, if a third cycle of IPC was added to increase release of endogenous mediators, then the need for any individual mediator (e.g., S1P) was diminished and VPC had little effect. The adenosine antagonist 8-(p-sulfophenyl)-theophylline (8-SPT) likewise inhibited protection by two cycles but not three cycles of IPC, but VPC plus 8-SPT inhibited protection by three cycles of IPC. Similar to IPC, IPOST induced by four postindex ischemia cycles of 15 s reperfusion-15 s ischemia resulted in 66% recovery of LVDP and a 7% infarct size. When VPC was present during postconditioning and reperfusion, LVDP only recovered by 26% and the infarct size increased to 27%. Adding an additional cycle of IPOST reduced the inhibitory effect of VPC and 8-SPT individually, but not their combined effect. These studies reveal that S1P is an important mediator of both IPC and IPOST that is released along with adenosine during each cycle of IPC or IPOST.

Efficient removal of apoptotic cells is essential for resolution of inflammation. Failure to clear dying cells can exacerbate lung injury and lead to persistent inflammation and autoimmunity. Here we show that TNFalpha blocks apoptotic cell clearance by alveolar macrophages and leads to proinflammatory responses in the lung. Compared with mice treated with intratracheal TNFalpha or exogenous apoptotic cells, mice treated with the combination of TNFalpha plus apoptotic cells demonstrated reduced apoptotic cell clearance from the lungs and increased recruitment of inflammatory leukocytes to the air spaces. Treatment with intratracheal TNFalpha had no effect on the removal of exogenous apoptotic cells from the lungs of TNFalpha receptor-1 (p55) and -2 (p75) double mutant mice and no effect on leukocyte recruitment. Bronchoalveolar lavage from mice treated with TNFalpha plus apoptotic cells contained increased levels of proinflammatory cytokines IL-6, KC, and MCP-1, but exhibited no change in levels of anti-inflammatory cytokines IL-10 and TGF-beta. Administration of TNFalpha plus apoptotic cells during LPS-induced lung injury augmented neutrophil accumulation and proinflammatory cytokine production. These findings suggest that the presence of TNFalpha in the lung can alter the response of phagocytes to apoptotic cells leading to inflammatory cell recruitment and proinflammatory mediator production.

Food insecurity is a risk factor for both HIV transmission and worse HIV clinical outcomes. We examined the prevalence of and factors associated with food insecurity among homeless and marginally housed HIV-infected individuals in San Francisco recruited from the Research on Access to Care in the Homeless Cohort. We used multiple logistic regression to determine socio-demographic and behavioral factors associated with food insecurity, which was measured using the Household Food Insecurity Access Scale. Among 250 participants, over half (53.6%) were food insecure. Higher odds of food insecurity was associated with being white, low CD4 counts, recent crack use, lack of health insurance, and worse physical and mental health. Food insecurity is highly prevalent among HIV-infected marginally housed individuals in San Francisco, and is associated with poor physical and mental health and poor social functioning. Screening for and addressing food insecurity should be a critical component of HIV prevention and treatment programs.

WikiPathways is a platform for creating, updating, and sharing biological pathways [1]. Pathways can be edited and downloaded using the wiki-style website. Here we present a SOAP web service that provides programmatic access to WikiPathways that is complementary to the website. We describe the functionality that this web service offers and discuss several use cases in detail. Exposing WikiPathways through a web service opens up new ways of utilizing pathway information and assisting the community curation process.

BACKGROUND

Teleteaching of endoscopy has been limited by the exorbitant cost and time inherent in high-quality digital endoscopy video transmission. The Digital Video Transport System (DVTS) transmitted over advanced networks, such as Internet2 and the Asia-Pacific Advanced Network (APAN), provides a unique infrastructure for sharing uncompressed digital videos of endoscopy. This may allow high-quality, real-time, international training of diagnostic and therapeutic endoscopy techniques at a low cost.

OBJECTIVE

To test the proof of concept of long-distance teaching through live, interactive, high-resolution video transmission by using advanced networks and the DVTS. We used teleteaching of image-enhanced endoscopy techniques as a model.

DESIGN

Prospective multicenter pilot study.

SETTING AND PARTICIPANTS

Trainees, faculty, and staff at 3 international endoscopy units.

INTERVENTION

An image-enhanced endoscopy video lecture with advanced-network technologies.

MAIN OUTCOME MEASUREMENTS

We compared image-based prelecture and postlecture test scores and secondarily assessed technical feasibility and quality.

RESULTS

The DVTS transmitted over advanced networks successfully transmitted uncompressed, high-resolution, digital lectures with endoscopic video (digital video format 720 x 480 pixels). Postsession scores improved. Participants highly rated the technical and informational quality. The majority reported a definite interest in participating in future sessions, with a mean rating (out of 5 [scale 1-5]) of 4.7 +/- 0.5.

LIMITATIONS

Pilot study with a limited number of participants and sessions.

CONCLUSION

The DVTS transmitted over advanced networks such as Internet2 and APAN can provide the infrastructure for transmission of high-resolution, uncompressed video endoscopy for the purpose of teleteaching endoscopy.

BACKGROUND

The fixed dose antimalarial combination of dihydroartemisinin-piperaquine (DP) is a promising new artemisinin-based combination therapy (ACT). We present an individual patient data analysis of efficacy and tolerability in acute uncomplicated falciparum malaria, from seven published randomized clinical trials conducted in Africa and South East Asia using a predefined in-vivo protocol. Comparator drugs were mefloquine-artesunate (MAS3) in Thailand, Myanmar, Laos and Cambodia; artemether-lumefantrine in Uganda; and amodiaquine+sulfadoxine-pyrimethamine and artesunate+amodiaquine in Rwanda.

METHODS AND FINDINGS

In total 3,547 patients were enrolled: 1,814 patients (32% children under five years) received DP and 1,733 received a comparator antimalarial at 12 different sites and were followed for 28-63 days. There was no significant heterogeneity between trials. DP was well tolerated with 1.7% early vomiting. There were less adverse events with DP in children and adults compared to MAS3 except for diarrhea; ORs (95%CI) 2.74 (2.13 to 3.51) and 3.11 (2.31 to 4.18), respectively. DP treatment resulted in a rapid clearance of fever and parasitaemia. The PCR genotype corrected efficacy at Day 28 of DP assessed by survival analysis was 98.7% (95%CI 97.6-99.8). DP was superior to the comparator drugs in protecting against both P.falciparum recurrence and recrudescence (P = 0.001, weighted by site). There was no difference between DP and MAS3 in treating P. vivax co-infections and in suppressing the first relapse (median interval to P. vivax recurrence: 6 weeks). Children under 5 y were at higher risk of recurrence for both infections. The proportion of patients developing gametocytaemia (P = 0.002, weighted by site) and the subsequent gametocyte carriage rates were higher with DP (11/1000 person gametocyte week, PGW) than MAS3 (6/1000 PGW, P = 0.001, weighted by site).

CONCLUSIONS

DP proved a safe, well tolerated, and highly effective treatment of P.falciparum malaria in Asia and Africa, but the effect on gametocyte carriage was inferior to that of MAS3.