A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852).

Background: Preclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy. Patients and methods: Women with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled. Patients had to have received concurrent chemotherapy and radiation as well as possible consolidation chemotherapy; have adequate organ function. The trial utilized a standard 3 + 3 phase I dose escalation with patients receiving paclitaxel 175 mg/m2 on day 1, cisplatin 50 mg/m2 on day 2, and escalating doses of veliparib ranging from 50 to 400 mg orally two times daily on days 1-7. Cycles occurred every 21 days until progression. Dose-limiting toxicities (DLTs) were assessed at first cycle. Fanconi anemia complementation group D2 (FANCD2) foci was evaluated in tissue specimens as a biomarker of response. Results: Thirty-four patients received treatment. DLTs (n = 1) were a grade 4 dyspnea, a grade 3 neutropenia lasting ≥3 weeks, and febrile neutropenia. At 400 mg dose level (DL), one of the six patients had a DLT, so the MTD was not reached. Across DLs, the objective response rate (RR) for 29 patients with measurable disease was 34% [95% confidence interval (CI), 20%-53%]; at 400 mg DL, the RR was 60% (n = 3/5; 95% CI, 23%-88%). Median progression-free survival was 6.2 months (95% CI, 2.9-10.1), and overall survival was 14.5 months (95% CI, 8.2-19.4). FANCD2 foci was negative or heterogeneous in 31% of patients and present in 69%. Objective RR were not associated with FANCD2 foci (P = 0.53). Conclusions: Combining veliparib with paclitaxel and cisplatin as first-line treatment for persistent or recurrent cervical cancer patients is safe and feasible. Clinical trial information: NCT01281852.

Public health and clinical implications of high hemoglobin A1c levels and weight in younger adult Native American people with diabetes.

BACKGROUND: Type 2 diabetes mellitus is a major public health issue for Native American people. Because glycemic levels are predictive of diabetes outcome, understanding determinants of high hemoglobin A(1c) (HbA(1c)) levels may provide targets for prevention efforts. OBJECTIVES: To investigate determinants of high HbA(1c) levels in Native American people. METHODS: We conducted a population-based, cross-sectional study of 206 participants with diabetes from 8 Native American communities in New Mexico. We used linear regression to assess the relationship of HbA(1c) level with age, body mass index (BMI), treatment type, duration of diabetes, physical activity, and diet. RESULTS: Age, dietary pattern, and treatment type were determinants of HbA(1c) levels. Participants younger than 55 years had the highest adjusted HbA(1c) levels at 9.5% and those 65 years and older had the lowest levels at 7.8%. According to a participant's dietary intake, HbA(1c) levels were highest for those who consumed the most fat and sugar, and high consumption of fat and sugar affected HbA(1c) levels most among those younger than 55 years. Participants treated with insulin had the highest hemoglobin A(1c) levels. Physical activity was not associated with HbA(1c) level. CONCLUSIONS: We found an increasing severity of diabetes among younger people. To avoid increased morbidity and mortality in the future, young Native American adults with diabetes need vigorous therapy to maintain tight glucose control. Arch Intern Med. 2000;160:3471-3476.

Diabetes mortality among New Mexico's American Indian, Hispanic, and non-Hispanic white populations, 1958-1987.

OBJECTIVE: To determine the diabetes-related mortality rates among New Mexico's American Indians, Hispanics, and non-Hispanic whites over a 30-yr period. RESEARCH DESIGN AND METHODS: Death certificates were used to identify diabetes as an underlying cause of death by ethnic group in New Mexico during each 5-yr period from 1958 through 1987. The age-adjusted rates were calculated by ethnic group and sex, and temporal trends were examined. Comparison was made to U.S. white age-adjusted rates during the same time period. RESULTS: Age-adjusted diabetes mortality rates for American Indians and Hispanics increased throughout the 30-yr period, and far exceeded rates for New Mexico non-Hispanic whites and U.S. whites by the 1983-1987 time period. The rates increased most dramatically among the state's American Indians, increasing 550% among women and 249% among men. Hispanic women and men experienced increases of 112 and 140%, respectively. CONCLUSIONS: New Mexico's American Indian and Hispanic populations have higher diabetes mortality rates than non-Hispanic whites, and American Indian mortality rates have risen dramatically over the 30-yr period included in our study. Although the high prevalence of diabetes in American Indians and Hispanics is a major contributor to these rates, other factors may also influence the reported mortality rates.

Rapid HbA1c testing in a community setting.

OBJECTIVE: To determine whether the DCA 2000 analyzer provides valid and reliable HbA1c results when used under field conditions and operated by nonmedical personnel. This study was part of a community diabetes education program, the Native American Diabetes Project, in which HbA1c was measured as an indicator of average glycemic control. RESEARCH DESIGN AND METHODS: Two study samples were taken, the first in the spring of 1994 and the second in the spring of 1995. Seven community members in 1994 and six new community members in 1995 were trained over 2 days, using standard protocol, to operate the DCA 2000 HbA1c analyzer and to collect two capillary blood samples from participants in the Native American Diabetes Project. Duplicate DCA 2000 HbA1c measurements performed by the community workers were compared with measurements from a high-performance liquid chromatography (HPLC) system. Validity and reliability measures were calculated. RESULTS: Of the participants, 43 were studied in 1994 and 14 in 1995. Comparison of the mean DCA 2000 results with those of HPLC showed high validity, with the absolute relative difference between the mean DCA 2000 and the external reference of HPLC (magnitude of mean DCA 2000-HPLC magnitude of /HPLC) as 4.0 and 2.0% for 1994 and 1995, respectively. The Pearson correlation coefficients (r) between these two measures were 0.968 and 0.996 for 1994 and 1995, respectively. While the 1994 data appeared to have less validity for values > 10%, they included only one value with a 60-min warm-up of the DCA analyzer. The 1995 data, all collected after a 60-min warm-up, had good correlation throughout the range of values. The within-run reliability was excellent, with an intraclass correlation coefficient of reliability of 0.959 and 0.975 for paired samples, for 1994 and 1995 respectively. The mean coefficient of variation for these paired measures was 3.0% in 1994 and 2.8% in 1995. Both validity and reliability were improved by changing the warm-up period of the DCA 2000 analyzer from 5 to 60 min. All correlation coefficients were statistically significant (P < 0.0001). CONCLUSIONS: The DCA 2000 gave valid and reliable HbA1c results when operated in a community setting by nonmedical personnel. Extending the warm-up period of the device to 60 min slightly improved the validity and reliability of the test.

Adaptation of the Dartmouth COOP Charts for use among American Indian people with diabetes.

OBJECTIVE: To adapt the Dartmouth COOP Charts for use among American Indians with diabetes and to evaluate the operating characteristics of the adapted charts because measures of health status have not been evaluated for use among American Indians with diabetes. RESEARCH DESIGN AND METHODS: American Indian adults participated in focus group conferences to adapt and review the Dartmouth COOP Charts for use in American Indian communities. American Indian participants with diabetes were interviewed and administered the adapted charts. The operating characteristics of the charts were evaluated by measuring internal and external consistency, reliability, and acceptability. RESULTS: Some of the wording and pictures were considered to be offensive and culturally inappropriate in American Indian communities. The adapted charts showed internal consistency in a comparison of interchart variables. CONCLUSIONS: The adapted Dartmouth COOP Charts are more culturally acceptable than the original charts and appear to measure constructs adequately.

Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib).

A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.

Effect of phosphoramidon (endothelin converting enzyme inhibitor) and BQ-123 (endothelin receptor subtype A antagonist) on blood pressure in hypertensive rats.

We reported previously that the endothelin converting enzyme (ECE) inhibitor phosphoramidon lowers mean arterial pressure (MAP) when infused in conscious, spontaneously hypertensive rats (SHRs). In this study we determined the dose-response relationship for this action in SHRs and in a high-renin hypertensive model, the renal artery-ligated rat. We also determined whether the ETA receptor antagonist BQ-123 (cyclo [D-Trp-D-Asp-Pro-D-Val-Leu]) might lower MAP in hypertensive rats. Phosphoramidon lowered MAP by 9 +/- 4, 31 +/- 4, and 40 +/- 4 mm Hg after 5 h when infused in SHRs at 10, 20, and 40 mg/kg/h. This lowering of MAP was associated with dose-related inhibition of the pressor response to a bolus intravenous injection of big ET (1-39) at 1 nmol/kg. BQ-123 also lowered MAP in SHRs (by 25 +/- 3 mm Hg), but only at a very high dose (50 mg/kg/h for 5 h). At this dose, BQ-123 blocked the pressor response to a bolus intravenous injection of ET-1 (1 nmol/kg), but the blockade was incomplete. Phosphoramidon infused in conscious, renal hypertensive rats lowered MAP by 31 +/- 9, 46 +/- 8, and 54 +/- 1 mm Hg after 5 h at 10, 20, and 40 mg/kg/h, respectively. This lowering of MAP was associated with blockade of the pressor response to big ET (1-39). BQ-123 did not lower MAP in renal hypertensive rats when infused at 30 mg/kg/h for 5 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of DDAVP on movement planning and execution processes in healthy young adults.

This study investigated the effects of an acute dose of DDAVP on speed and consistency of planning and execution of simple and complex movements in healthy young adults. A simple reaction time task (SRT), a simple movement task (SMT), and a complex movement task (CMT) were performed with and without a 0.6 ml intranasal dose (60 micrograms) of DDAVP. Results indicated DDAVP-treated individuals planned and executed CMT and SRT tasks faster and more consistently than did placebo-treated subjects. There were nonsignificant DDAVP effects on speed and variability of both RT and MT processes involved in the SMT.

Effects of DDAVP on movement planning and execution processes in the healthy elderly.

Effects of DDAVP on speed and consistency of planning and executing simple and complex movements in healthy older adults were studied. A simple reaction time (SRT) task, a single-plane movement task, and two tasks involving multiplane movements of distal upper extremities were performed with and/or without a 0.6 ml intranasal dose (60 micrograms) of DDAVP or placebo. Results indicated that DDAVP had no significant effect on speed or consistency of SRT processes, or the speed with which simple or complex movements were planned or executed. There was also no effect on retention of motor responses.

Communicating through stories: experience of the Native American Diabetes Project.

Stories appear to provide an indirect way of confronting the inherent conflict between the concepts of disease and wellness and assisting in the transition to a new concept of living well with the disease. This new concept may engender feelings of acceptance and hope that can facilitate application of knowledge and behavior change. In addition, culturally appropriate stories allow people to draw from their own personal beliefs and values to interpret and apply new information to their own lives. A good story takes listeners on a collective journey with many paths; each path is uniquely suited to the needs of the individual, with wisdom gained that is uniquely suited to their own life.

Challenges to participating in a lifestyle intervention program: the Native American Diabetes Project.

PURPOSE: This paper describes the factors that American Indian teachers in the Native American Diabetes Project (NADP) reported affected participation in the NADP lifestyle education sessions. METHODS: A postsession exit interview was conducted with each of the 7 mentors (teachers) of the NADP sessions. Interview questions addressed general perceptions of the sessions, factors that kept participants from coming to the sessions, and attitudes toward diabetes and persons with diabetes. Interviews were transcribed and responses reflecting factors related to participation were marked and organized into topic areas. RESULTS: Mentors reported a range of factors that affected participation in the sessions, such as conflicts with community activities and beliefs/attitudes about diabetes. The latter factor includes program knowledge, recruitment methods, attitudes toward the program, and beliefs about diabetes. CONCLUSIONS: Asking community members what factors they believe affect participation is an important component of increasing participation in community-based programs. Community members can provide a valuable personal perspective of actual and potential conflicts in the community.

Participant satisfaction with a culturally appropriate diabetes education program: the Native American Diabetes Project.

PURPOSE: The purpose of this paper is to report on participant satisfaction with the Native American Diabetes Project diabetes education program. METHODS: A questionnaire was designed to measure satisfaction among participants in the diabetes education program, which consisted of five sessions designed according to the Transtheoretical Model of Change and Social Action Theory with input from community members. Eight pueblo communities participated in the program. Sessions were taught by community mentors in three sites in New Mexico. One site taught sessions in a one-on-one format, and two sites taught sessions in a group format. RESULTS: The results showed that participant satisfaction did not vary based on session delivery type or by session site. Overall, participants responded positively to sessions designed according to Social Action Theory and with cultural competency. Retention rates for the sessions were 81% for group sessions and 91% for one-one-one sessions. CONCLUSIONS: Using a strong theoretical framework and community input to design diabetes education sessions may be important factors in participant satisfaction and retention in diabetes lifestyle education sessions.

Knowledge, attitudes and behaviors related to physical activity among Native Americans with diabetes.

OBJECTIVE: Native Americans (NA) have higher diabetes morbidity and mortality compared to other ethnic groups. Although exercise plays an important role in diabetes management, little is known about exercise among Native Americans with diabetes. Our goal was to describe knowledge, attitudes and behaviors related to exercise in Native American participants in New Mexico. DESIGN: Bilingual community members administered a questionnaire to assess knowledge, stage of change (a measure of exercise readiness), and physical activity behavior. Hemoglobin A1c (HbA1c) was measured by DCA 2000 analyzer. Height and weight were measured to calculate body mass index (BMI). Average random blood glucose (RBS) levels and diabetes duration were assessed through chart audit. SETTING: Questionnaires were completed in offices in or near the communities. PARTICIPANTS: 514 Native Americans with diabetes were identified as potential participants, 40% (142 women, 64 men) participated. RESULTS: 37% of participants knew exercise lowers blood sugar. 82% reported they were in the preparation, action, or maintenance stage of change for exercise behavior. Seventy seven percent of this population did not meet the Surgeon General's recommendation for accumulating 30 minutes of leisure time endurance exercise on most days of the week. However, 67% of participants fell within the "high activity" category for all moderate and vigorous activities. Average age, BMI and HbA1c were 58.5 yrs., 30.5 kg/m2, 8.6%, respectively. CONCLUSIONS: Interventions to increase physical activity awareness and participation could improve diabetes management and overall health for Native Americans. When evaluating physical activity, researchers need to consider usual activities of daily living and leisure time activities specific to that population. Failure to do so would be ethnocentric and could lead to inappropriate conclusions.

Diabetic amputations in the VA: are there opportunities for interventions?

Lower limb amputation (LLA) is a devastating complication experienced by some veterans with diabetes. The Veterans Affairs (VA) Healthcare system has identified the prevention of LLA as a priority goal. This study was designed to describe the sources of outpatient care received by veterans with diabetes who have undergone LLA, to determine whether these persons would have been impacted by a VA amputation prevention program. This study was also designed to describe prior amputation history, footwear history, and the pivotal events that led to these amputations. We found that the vast majority of these subjects identified the VA as their primary source of care, and thus would have been available for enrollment in a prevention program. Since over one-half of them had had a prior amputation, diabetics with a prior amputation should be particularly targeted for foot care interventions. Lastly, prescription of protective footwear has the potential to reduce the incidence of shoe-related ulcers and amputations.

Anthropometric, psychomotor, and hemodynamic changes during twenty-one continuous days of eating only meals, ready-to-eat (MREs).

This study investigated anthropometric, psychomotor, and hemodynamic changes in young adult men during 21 continuous days of eating only meals, ready-to-eat (MREs). The MRE diet group lost more weight and bodyfat (significant at abdominal site, total skinfolds, and total bodyfat percent), and had significantly greater gains in hand grip strength than did controls. Results support the contention that, when eaten as designed, MREs are nutritionally adequate for maintaining body weight and muscle strength without adverse effects.

A colorimetric detection system for Calymmatobacterium granulomatis.

OBJECTIVE: To incorporate the first polymerase chain reaction (PCR) assay for Calymmatobacterium granulomatis into a colorimetric detection system for use in routine diagnostic laboratories. METHODS: A capture oligonucleotide specific for the Klebsiella phoE gene was covalently linked to tosyl activated magnetic beads. Biotinylated phoE PCR products obtained from 14 positive specimens from patients with donovanosis and isolates of Klebsiella pneumoniae, K rhinoscleromatis, and K ozaenae were cleaved with HaeIII for the purpose of differentiation, captured by the prepared beads, and subjected to standard EIA detection methodology. Eight samples from unrelated genital conditions underwent the same procedure. It was anticipated from the sequence data that the biotinylated fragment would be cleaved from the capture oligonucleotide target region in the three Klebsiella phoE products (that is, a negative colorimetric result) while the entire fragment of interest would remain intact in the positive C granulomatis phoE products (that is, a positive colorimetric result). RESULTS: All 14 positive specimens from patients with donovanosis gave strong colorimetric readings with this detection system. Isolates of K pneumoniae, K rhinoscleromatis, K ozaenae, and the eight specimens from unrelated genital conditions were negative. CONCLUSION: The successful development of a colorimetric detection system for C granulomatis incorporating two levels of specificity enables the molecular diagnosis of this condition to be undertaken by routine diagnostic laboratories. This should have an important role in the Australian government's campaign to eradicate donovanosis by 2003 though the test still needs to undergo trials and be validated using a larger number of samples from geographically diverse parts of the world in order to ascertain the generalisability of the methodology.