Empowering industrial research with shared biomedical vocabularies

The life science industries (including pharmaceuticals, agrochemicals and consumer goods) are exploring new business models for research and development that focus on external partnerships. In parallel, there is a desire to make better use of data obtained from sources such as human clinical samples to inform and support early research programmes. Success in both areas depends upon the successful integration of heterogeneous data from multiple providers and scientific domains, something that is already a major challenge within the industry. This issue is exacerbated by the absence of agreed standards that unambiguously identify the entities, processes and observations within experimental results. In this article we highlight the risks to future productivity that are associated with incomplete biological and chemical vocabularies and suggest a new model to address this long-standing issue.     

Laparoscopic intersphincteric resection with coloplasty and coloanal anastomosis for mid and low rectal cancer

BACKGROUND: The feasibility of laparoscopic rectal resection in patients with mid or low rectal cancer was studied prospectively with regard to quality of mesorectal excision, autonomic pelvic nerve preservation and anal sphincter preservation. METHODS: Laparoscopic rectal excision was performed in 32 patients (21 men) with rectal carcinoma located 5 cm from the anal verge. Most patients had T3 disease and received preoperative radiotherapy. The surgical procedure was performed 6 weeks after radiotherapy and included total mesorectal excision, intersphincteric resection, transanal coloanal anastomosis with coloplasty and loop ileostomy. RESULTS: Three patients needed conversion to a laparotomy. Postoperative morbidity occurred in ten patients, related mainly to coloplasty. Macroscopic evaluation showed an intact mesorectal excision in 29 of 32 excised specimens; microscopically, 30 of the 32 resections were R0. Sphincter preservation was achieved in 31 patients. The hypogastric nerves and pelvic plexuses were identified and preserved in 24 of the 32 patients. Sexual function was preserved in ten of 18 evaluable men. CONCLUSION: A laparoscopic approach can be considered in most patients with mid or low rectal cancer.     

Mapping the Barriers and Facilitators of HCV Treatment Initiation in Methadone Maintenance Therapy Patients: Implications for Intervention Development

An estimated 70–90% of current methadone users have Hepatitis C (HCV). Current treatments have few side effects and can cure infection in 8–12 weeks, but less than 10% of methadone patients initiate treatment. Engaging this group in treatment is an important strategy to lower both morbidity and mortality from liver disease and eliminate a significant reservoir of HCV in communities. To understand how to address this treatment gap we used commercial marketing techniques called perceptual mapping and vector message modeling to analyze survey data from 100 HCV+ methadone patients from four centers in Philadelphia. Results were used to understand barriers and facilitators to treatment initiation and to devise targeted message strategies to adapt to a mobile health communication intervention. Results indicate that focusing on how treatment can make one feel “in charge”, positive interactions with healthcare providers, the positive attributes of the new vs. old HCV treatments, and providing strategies to address tangible barriers to getting treatment, would be important to address in a communication intervention. These marketing methods allow for focusing on specific variables to “move” the group toward a treatment decision, making them an innovative technique to use in developing highly targeted health communication messages.     

Mitochondrial development in Trypanosoma brucei brucei transitional bloodstream forms.

Intermediate and short stumpy bloodstream forms of Trypanosoma brucei brucei are transitional stages in the differentiation of mammal-infective long slender bloodstream forms into the procyclic forms found in the midgut of the tsetse vector. Although the mitochondria of the proliferative long slender forms do not accumulate rhodamine 123, the mitochondria of the transitional forms attain this ability thus revealing the development of an electromotive force (EMF) across the inner mitochondrial membrane. The EMF is inhibited by 2,4-dinitrophenol, rotenone and salicylhydroxamic acid but not by antimycin A or cyanide. Consequently, NADH dehydrogenase, site I of oxidative phosphorylation, is the source of the EMF and the plant-like trypanosome alternative oxidase (TAO) supports the electron flow serving as the terminal oxidase of the chain. Although the TAO is present in the long slender forms as well, it serves only as the terminal oxidase for electrons from glycerol-3-phosphate dehydrogenase. The data presented here, combined with older data, lead to the conclusion that the mitochondria of transitional intermediate and short stumpy forms likely produce ATP. This putative production is either by F1F0 ATPase driven by the complex I proton pump or by mitochondrial substrate level phosphorylation, or most likely by both. These conclusions contrast with the previously held dogma that all bloodstream form mitochondria are incapable of ATP production.     

Follow-up of ventilatory lung function in a group of cement workers.

In a group of 160 active cement workers and 80 control workers selected on the basis of having or not having symptoms of chronic bronchitis, forced vital capacity (FVC) and one second expiratory volume (FEV 1-0), both corrected for age and height, and ratio of one second forced expiratory volume to forced vital capacity (FEV 1-0/FVC (%)) were measured on two occasions with an interval of four and eight years respectively.     

Combination chemotherapy of drug-resistant Trypanosoma brucei rhodesiense infections in mice using DL-alpha-difluoromethylornithine and standard trypanocides.

Combinations of DL-alpha-difluoromethylornithine (DFMO; eflornithine; Ornidyl) with either suramin or melarsen oxide were found to be effective against acute laboratory model infections with Trypanosoma brucei rhodesiense. We used clinical isolates known to be resistant to these drugs when used singly. An infection with a melarsen oxide-refractory isolate was cured by a combination of low-dose DFMO (0.5% in the drinking water) plus low-dose suramin (1 mg/kg of body weight given intraperitoneally). Another strain, moderately resistant to arsenical drugs, was cured with combinations of 4% DFMO with 5 mg of melarsen oxide per kg. Furthermore, a combination of DFMO (2% in the drinking water) and suramin (20 mg/kg) provided a 100% cure rate in a central nervous system model, although the same doses of these drugs used singly were completely ineffective. The synergism of DFMO and suramin against an acute infection was improved when suramin was given at the end of the DFMO administration. No adverse interactions were observed when high doses of DFMO combined with high doses of suramin were administered to uninfected mice. These results suggest that combinations of DFMO and suramin should be examined clinically for activity in arsenical-drug-refractory cases of East African sleeping sickness.     

Biological pacemakers: characterization in an in vitro coculture model

Background

Biological pacemakers could be an alternative or complement to electronic pacemakers. Embryonic stem cells (ESCs) can be differentiated in vitro to spontaneously active cells. Although numerous studies show that ESC-derived cardiomyocytes (ESC-CMs) and other cell types are capable to exert pacemaker function in vivo, detailed analyses of pattern and safety of conduction on a tissue level are rare.

Methods

Murine ESCs (mESCs) expressing enhanced green fluorescent protein and puromycin resistance under control of the promoter of α-myosin (heavy chain) were differentiated to cardiomyocytes (mESC-CMs) and purified by negative antibiotic selection. Ventricles of mouse embryonic hearts (embryonic day 16.5) were embedded in agarose and sliced along the short axis. Clusters of mESC-CMs and the murine, vital heart slices were cocultured on multielectrode arrays for 4 days. Field potentials and videos were recorded daily to investigate beating behavior and excitation spreading within the slice.

Results

On the first day of coculture, the mean beating rate of the tissue slices cocultured with mESC-CMs (n = 19) did not differ significantly from the beating rate of control slices (n = 19) (37 ± 10 versus 19 ± 7 bpm, P = .133). After 4 days of coculture, beating rates were significantly higher in cocultures than in control slices (154 ± 22 versus 49 ± 8 bpm, P < .001). On day 4, 1:1 coupling could be found in 1 of 19 preparations; 2:1, 3:1, or 4:1 coupling in another 4 of 19 preparations; 14 of 19 propagation patterns were irregular.

Conclusion

In this in vitro model, the increase of the beating rate suggests that purified mESC-CMs can pace native heart tissue, albeit with low efficiency.