The Diabetes Prevention Program: recruitment methods and results

The Diabetes Prevention Program (DPP) is a multicenter randomized controlled trial designed to test whether diet and exercise or medication can prevent or delay the onset of type 2 diabetes in persons with impaired glucose tolerance, who are at increased risk of the disease. This paper describes DPP recruitment methods, strategies, performance, and costs. The DPP developed an organizational structure for comprehensive management and continuous monitoring of recruitment efforts. The DPP utilized a variety of recruitment strategies, alone or in combination, and a stepped informed consent procedure leading to randomization. Studywide and clinic-specific recruitment data were monitored, analyzed, and used to modify recruitment approaches. DPP recruitment was completed slightly ahead of schedule, meeting goals for the proportion of women enrolled and nearly meeting goals for the proportion of racial/ethnic minorities. Clinics varied widely in the recruitment strategies they used, and these strategies also varied by participant age, gender, and race/ethnicity. Staff time devoted to recruitment averaged 86.8 hours per week per clinic, with the majority of effort by staff specifically assigned to recruitment. The number of staff hours required to recruit a participant varied by recruitment strategy. Recruitment cost (excluding staff cost) was about 1075 US dollars per randomized participant. The DPP experience offers lessons for those planning similar efforts: (1) a method for ongoing assessment and revision of recruitment strategies is valuable; (2) a range of recruitment strategies may be useful; (3) the most effective methods for recruiting potential subjects may vary according to the gender, age, and race/ethnicity of those individuals; (4) recruitment strategies vary in the amount of staff time required to randomize a participant; and (5) a stepped screening may make it easier to identify and recruit volunteers who understand the requirements of the study.     

Prevention of pathology in mdx mice by expression of utrophin: analysis using an inducible transgenic expression system

Duchenne muscular dystrophy results from the absence of dystrophin, a cytoskeletal protein. Previously, we have shown in a transgenic mouse model of the disease (mdx) that high levels of expression of the dystrophin-related protein, utrophin can prevent pathology. We developed a new transgenic mouse model where muscle specific utrophin expression was conditioned by addition of tetracycline in water. Transgene expression was turned on at different time points: in utero, at birth, 10 and 30 days after birth. We obtained moderate levels of expression, variable from fibre to fibre (mosaicism) but sufficient to induce a correct localization of the dystro-sarcoglycan complex. Histology revealed a reduction of necrotic foci and of the percentage of centronucleated fibres, which remained still largely above the normal level. Isometric force was not improved but the resistance to eccentric contractions was significantly stronger. When utrophin expression was activated 30 days after birth, improvements were marginal, suggesting that the age at which utrophin therapy is initiated could be an important factor. Our results also provide an unexpected insight into the pathogenesis of the dystrophinopathies. We observed a complete normalization of the characteristics of the mechano-sensitive/voltage-independent Ca(2+) channels (occurrence, open probabilities and Ca(2+) currents), while the classical markers of dystrophy were still abnormal. These observations question the role of increased Ca(2+) channel activity in initiating the dystrophic process. The new model shows that utrophin therapy, initiated after birth, can be effective, but the extent of correction of the various symptoms of dystrophinopathy critically depends on the amount of utrophin expressed.     

An evaluation of the risk for latex allergy in prehospital EMS providers

Hospital health care providers are increasingly being diagnosed as latex sensitive or allergic. Little is established on incidence or risks to prehospital health care providers. A written survey of EMT-DCs and EMT-Ps was done anonymously using established risk stratification questions to identify factors that indicate higher potential for developing latex allergies. There were 666 surveys distributed with 580 (87%) returned completed. Of the respondents, 533 were male (91%) with 510 (87%) reporting more than 5 years of field experience. Of the survey participants, 435 (75%) were EMT-DC level and 145 (25%) were EMT-P level. We found that latex sensitivities and allergies are present in our population, with an 8% incidence of latex allergies in EMT-DCs and 18% in EMT-Ps. A greater number of respondents report having factors that have been established to be associated with increased risk for latex allergies, indicating the need for more vigilant monitoring for the development of such reactions.     

Medical care inconsistent with patients' treatment goals: association with 1-year Medicare resource use and survival

OBJECTIVES: To describe how frequently seriously ill persons perceive that the care they receive is inconsistent with treatment preferences and the effect on 1-year resource utilization. SETTING: Five U.S. teaching hospitals. DESIGN: Secondary analysis of interview data. PARTICIPANTS: Seriously ill Medicare beneficiaries. MEASUREMENTS: Interviews about patients' preferred approaches to care and whether they perceived care was consistent with these preferences. Part A and B costs for up to 1 year, adjusted for cost differences across hospitals and over time and for 1-year survival. RESULTS: Forty percent of the 1,185 study patients expressed a preference for treatment to focus on extending life, whereas 60% expressed a preference for comfort care. Eighty-six percent of the patients who wanted aggressive treatment reported that care was consistent with their preferences, but only 41% of those who preferred comfort care reported that care was consistent with their preferences. More than one-third of those with a preference for comfort care (35%) reported that the medical care that they received was inconsistent with their goals; 24% were unsure of treatment goals. Those who preferred comfort care but believed that their care was inconsistent with their wishes had higher estimated mean 1-year costs than those who believed that their care was consistent with their wishes (92,442 US dollars vs 52,098 US dollars, P < .001). Even after adjusting for differences in disease severity, age, gender, race, functional status, income, and years of education, adjusted costs were 1.4 times (95% confidence interval = 1.2-1.6) higher. However, 1-year survival was lower in these patients who stated that care was consistent with their preference to focus on comfort care than for those who wished to receive comfort care and stated that care was not consistent with their preference (38% vs 55% 1-year survival, P < .001). CONCLUSION: More than one in three seriously ill persons who prefer comfort care believe that their medical care is at odds with their preference that treatment focus on palliation. Such discord was associated with higher 1-year healthcare costs and increased survival.     

Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease

In the current study, we examined whether ligation of CB2 receptors would lead to induction of apoptosis in tumors of immune origin and whether CB2 agonist could be used to treat such cancers. Exposure of murine tumors EL-4, LSA, and P815 to delta-9-tetrahydrocannabinol (THC) in vitro led to a significant reduction in cell viability and an increase in apoptosis. Exposure of EL-4 tumor cells to the synthetic cannabinoid HU-210 and the endogenous cannabinoid anandamide led to significant induction of apoptosis, whereas exposure to WIN55212 was not effective. Treatment of EL-4 tumor-bearing mice with THC in vivo led to a significant reduction in tumor load, increase in tumor-cell apoptosis, and increase in survival of tumor-bearing mice. Examination of a number of human leukemia and lymphoma cell lines, including Jurkat, Molt-4, and Sup-T1, revealed that they expressed CB2 receptors but not CB1. These human tumor cells were also susceptible to apoptosis induced by THC, HU-210, anandamide, and the CB2-selective agonist JWH-015. This effect was mediated at least in part through the CB2 receptors because pretreatment with the CB2 antagonist SR144528 partially reversed the THC-induced apoptosis. Culture of primary acute lymphoblastic leukemia cells with THC in vitro reduced cell viability and induced apoptosis. Together, the current data demonstrate that CB2 cannabinoid receptors expressed on malignancies of the immune system may serve as potential targets for the induction of apoptosis. Also, because CB2 agonists lack psychotropic effects, they may serve as novel anticancer agents to selectively target and kill tumors of immune origin.     

Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin's lymphoma

Rituximab has significant activity as a single agent in the treatment of follicular non-Hodgkin's lymphoma (NHL). Interleukin 2 (IL-2) is a lymphokine that increases effector cell number. In an effort to augment antibody-dependent cell-mediated cytotoxicity (ADCC) associated with rituximab therapy, low-dose IL-2 was added to a standard rituximab regimen and patients were evaluated for safety and efficacy. Twenty patients with relapsed or refractory follicular NHL were treated with IL-2 (1.2 MIU/m(2)/d for 56 d subcutaneously) as outpatients. Rituximab (375 mg/m(2)) was given on d 15, 22, 29 and 36. The regimen was well tolerated and only three patients required dose adjustments in IL-2. Infusional toxicity associated with rituximab was not exacerbated by IL-2. Peripheral blood immunophenotyping demonstrated significant increases in circulating CD8+ and CD56+ lymphocytes in all evaluable patients (P = 0.0002). Increases in total eosinophil number were observed in all patients. Eleven patients responded to therapy, for an overall response rate of 55%. Four additional patients had stable disease. For these 15 patients, the median time to progression exceeded 13 months. We conclude concomitant cytokine therapy to enhance ADCC with monoclonal antibody therapy was well tolerated and did not exacerbate antibody-related infusional toxicity. Further studies of this rational combination are warranted and ongoing.     

Familial pseudohyperkalaemia Cardiff: a mild version of cryohydrocytosis

We have investigated a Welsh pedigree showing the 'familial pseudohyperkalaemia' phenotype of dominantly inherited, red-cell-based, temperature-dependent pseudohyperkalaemia associated with normal haematology. The 'passive leak' to K across the membrane of these abnormal red cells showed a 'U-shaped' temperature dependence, with a minimum at about 23 degrees C, qualitatively similar to that seen in the frankly haemolytic 'cryohydrocytosis' variant of the hereditary stomatocytosis group. Like three previous pedigrees with cryohydrocytosis, these patients show an excess of ether lipids in the membrane. However, these patients differ from other 'familial pseudohyperkalaemia' pedigrees, in which the leak showed different temperature profiles.