A phase I study of sequential versus concurrent interleukin-3 and granulocyte-macrophage colony-stimulating factor in advanced breast cancer patients treated with FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy

Cumulative thrombocytopenia is a dose-limiting toxicity of dose- intensive chemotherapy for advanced breast cancer. In this phase I study, we have studied the hematologic toxicity associated with sequential interleukin-3 (IL-3) and granulocyte-macrophage colony- stimulating factor (GM-CSF; molgramostim) administration after multiple cycles of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy compared with that after concurrent cytokine administration or to each cytokine administered alone. Ninety- three patients with advanced breast cancer were treated with five cycles of FLAC chemotherapy and either IL-3 alone, GM-CSF alone, sequential IL-3 and GM-CSF administered by schedule A (5 days of IL-3 followed by 10 days of GM-CSF) or schedule B (9 days of IL-3 followed by 6 days of GM-CSF), or concurrent administration of IL-3 and GM-CSF for 15 days. Cohorts of patients were treated with one of four dose levels of IL-3 (1,2.5, 5, and 10 micrograms/kg) administered subcutaneously for each schedule of cytokine administration. The GM-CSF dose in all schedules was 5 micrograms/kg/day. Sequential IL-3 and GM- CSF (schedule B) was associated with higher platelet nadirs, shorter durations of platelet counts less than 50,000/microL, and the need for fewer platelet transfusions over five cycles of FLAC chemotherapy compared with concurrent cytokines, sequential IL-3 and GM-CSF schedule A, and GM-CSF alone. Concurrent IL-3 and GM-CSF was associated with unexpected platelet toxicity. The duration of granulocytopenia after FLAC chemotherapy was significantly worse with IL-3 alone compared with each of the GM-CSF-containing cytokine regimens. Although no cycle 1 maximum tolerated dose for IL-3 was defined in this study, 5 micrograms/kg was well tolerated over multiple cycles of therapy and is recommended for future studies. The data from this phase I study suggest that sequential IL-3 and GM-CSF with IL-3 administered for 9 days before beginning GM-CSF may be superior to shorter durations of IL- 3 administered sequentially with GM-CSF, to concurrent IL-3 and GM-CSF, and to either colony-stimulating factor alone in ameliorating the cumulative hematologic toxicity associated with multiple cycles of FLAC chemotherapy. Additional studies of sequential IL-3 and GM-CSF are warranted.     

Exploring Binge Drinking and Drug Use among American Indians: Data from Adolescent Focus Groups

Background: Risk factors for binge substance use and non-suicidal self-injury (NSSI) are similar, suggesting the importance of exploring how binge substance use and self-injury interrelate. Objectives: To gain insight from a sample of American Indian (AI) adolescents regarding how binge drinking and drug use function in their lives, including as overlapping forms of self-injury, and to identify community-based ideas for dual prevention strategies. Methods: A total of N?=?58 White Mountain Apache (Apache) adolescents participated in ten mixed gender (n?=?33 males, 55.9%) focus group discussions. Results were interpreted and categorized by Apache researchers and compared to Nock's behavioral model of NSSI. Results: Participants reported substance use most commonly with "family" and "friends," "at a house," or "around the community." Substance use was not confined to a particular time of day, and often occurred "at school." Commonly endorsed reasons fell into two main categories: "to avoid problems" or "to reduce negative feelings," versus "to be cool" or "to feel part of a group." All adolescents but one thought that some youths use substances excessively as a way to harm/injure themselves (n?=?25 responses). Prevention approaches included encouraging healthy relationships, teaching about consequences of use, providing alternative recreation, and changing/enforcing laws on the reservation. Conclusion: Tribal-specific data support the idea that binge substance use sometimes functions as a form of self-injury. Home/school environments are critical prevention settings, in addition to improved law enforcement and increased recreation. Scientific Significance: Understanding possible shared root causes and functions of binge substance use and self-injury may advance integrated prevention approaches.     

Dynamic holographic imaging of the beating human heart

Background--Currently, the reporting and archiving of echocardiographic data suffer from the difficulty of representing heart motion on printable 2-dimensional (2D) media. Methods and Results--We studied the capability of holography to integrate motion into 2D echocardiographic prints. Images of normal human hearts and of a variety of mitral valve function abnormalities (mitral valve prolapse, systolic anterior motion of the mitral leaflets, and obstruction of the mitral valve by a myxoma) were acquired digitally on standard echocardiographic machines. Images were processed into a data format suitable for holographic printing. Angularly multiplexed holograms were then printed on a prototype holographic "laser" printer, with integration of time in vertical parallax, so that heart motion became visible when the hologram was tilted up and down. The resulting holograms displayed the anatomy with the same resolution as the original acquisition and allowed detailed study of valve motion with side-by-side comparison of normal and abnormal findings. Comparison of standard echocardiographic measurements in original echo frames and corresponding hologram views showed an excellent correlation of both methods (P<0.0001, r2=0.979, mean bias=2.76 mm). In this feasibility study, both 2D and 3D holographic images were produced. The equipment needed to view these holograms consists of only a simple point-light source. Conclusions--Holographic representation of myocardial and valve motion from echocardiographic data is feasible and allows the printing on a 2D medium of the complete heart cycle. Combined with the recent development of online holographic printing, this novel technique has the potential to improve reporting, visualization, and archiving of echocardiographic imaging.     

Tumor necrosis factor-α and interleukin-6 in cirrhotic patients with spontaneous bacterial peritonitis

AIM: To evaluate the role of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cirrhotic patients who have hepatic and renal impairment with spontaneous bacterial peritonitis (SBP).METHODS: We prospectively studied 120 cirrhotic patients with SBP and 80 cirrhotic patients with sterile ascitic fluid. They included 144 males and 56 females with ages ranging between 34 and 62 years. The diagnosis of cirrhosis was established by clinical and laboratory criteria that did not require histological confirmation. The severity of underlying liver disease was evaluated using Pugh’s modification of Child’s criteria (Child-Pugh scores). Ascitic fluid was sent to the laboratory for cell count, culture, sensitivity testing, and measurement of chemical elements (i.e., albumin, glucose). Specimens were inoculated into aerobic and anaerobic blood culture bottles. Serum and ascitic fluid were also collected in sterile tubes at study entry (before the initiation of antibiotic treatment) and 48 h later. Assays for TNF-α and IL-6 in the serum and ascitic fluid were performed with an immunoenzymometric assay using manufacture’s instructions.RESULTS: Cytokine levels in serum and ascitic fluid were significantly higher in the patients with SBP. (plasma TNF-α: 135.35 ng/mL ± 11.21 ng/mL vs 92.86 ng/mL ± 17.56 ng/mL, P < 0.001; plasma IL-6: 32.30 pg/mL ± 7.07 pg/mL vs 12.11 pg/mL ± 6.53 pg/mL, P < 0.001; ascitic fluid TNF-α: 647.54 ± 107.11 ng/mL vs 238.43 ng/mL ± 65.42 ng/mL, P < 0.001); ascitic fluid IL-6: 132.84 ng/mL ± 34.13 vs 40.41 ± 12.85 pg/mL, P < 0.001). About 48 (40%) cirrhotic patients with SBP developed renal and hepatic impairment and showed significantly higher plasma and ascitic fluid cytokine levels at diagnosis of infection. [(plasma TNF-α: 176.58 ± 17.84 vs 135.35 ± 11.21 ng/mL) (P < 0.001) and (IL-6: 57.83 ± 7.85 vs 32.30 ± 7.07 pg/mL) (P < 0.001); ascitic fluid TNF-α: 958.39 ± 135.72 vs 647.54 ± 107.11 ng/mL, (P < 0.001), ascitic fluid IL-6: 654.74 ± 97.43 vs 132.84 ± 34.13 pg/mL, (P < 0.001)]. Twenty nine patients (60.4%) with SBP and renal impairment died whereas, only four patients (5.55%) with SBP but without renal impairment died from gastrointestinal hemorrhage (P < 0.0005).CONCLUSION: It appears that TNF-α production may enhance liver cell injury and lead to renal impairment. This correlated well with the poor prognosis and significantly increased mortality associated with SBP in cirrhotic patients.     

Cloning and sequencing of a complementary DNA encoding a Mr 70,000 human breast epithelial mucin-associated antigen

The human milk fat globule (HMFG) membrane contains several glycoproteins that have been referred to as breast differentiation antigens and that are expressed in normal breast, breast tumors, breast tumor-derived cell lines, and are found in breast cancer patient serum. These antigens include a high molecular weight mucin and several smaller components including Mr 150,000; 70,000; and 46,000 glycoproteins. We have used 2 monoclonal antibodies (McR2 and Mc13) that bind the Mr 70,000 component of HMFG to immunoscreen a lambda gt11 expression library prepared from human lactating breast tissue. We report here the sequence of a complementary DNA clone (BA70-1) that codes for a peptide that binds both McR2 and Mc13 but not monoclonal antibodies to the breast mucin or other components of HMFG.A 1.8-kilobase RNA was detected in 9 of 9 breast tumor cell lines using 32P-labeled BA70-1 as probe. The BA70-1 RNA was highly expressed in 6 of 9 cells lines of breast and several other carcinomas lines compared with a lymphoblastoid cell line (Raji). The BA70-1 complementary DNA sequence has no extensive homology with previously reported sequences including the high-molecular weight mucin complementary DNA. Since the Mr 70,000 molecule appears to be associated with the breast mucin by disulfide bonds, its study could help elucidate the structure of this latter complex and how it is organized in the cell membrane, and prove useful in diagnosis and therapy of breast cancer.     

Racial and Ethnic Disparities in Depression Care in Community-Dwelling Elderly in the United States

Objectives. We investigated racial/ethnic disparities in the diagnosis and treatment of depression among community-dwelling elderly.Methods. We performed a secondary analysis of Medicare Current Beneficiary Survey data (n = 33 708) for 2001 through 2005. We estimated logistic regression models to assess the association of race/ethnicity with the probability of being diagnosed and treated for depression with either antidepressant medication or psychotherapy.Results. Depression diagnosis rates were 6.4% for non-Hispanic Whites, 4.2% for African Americans, 7.2% for Hispanics, and 3.8% for others. After we adjusted for a range of covariates including a 2-item depression screener, we found that African Americans were significantly less likely to receive a depression diagnosis from a health care provider (adjusted odds ratio [AOR] = 0.53; 95% confidence interval [CI] = 0.41, 0.69) than were non-Hispanic Whites; those diagnosed were less likely to be treated for depression (AOR = 0.45; 95% CI = 0.30, 0.66).Conclusions. Among elderly Medicare beneficiaries, significant racial/ethnic differences exist in the diagnosis and treatment of depression. Vigorous clinical and public health initiatives are needed to address this persisting disparity in care.Depression is a significant public health concern for older Americans.1 It has been estimated that 6.6% of older Americans experience an episode of major depression during 1 year.2 If untreated or undertreated, depression can significantly diminish quality of life3 and increase mortality.4 Depression can complicate several comorbid general medical conditions that are common in older populations, including congestive heart failure,5,6 diabetes,7 and arthritis.8 Antidepressant treatment and psychotherapy have been shown to be effective in increasing rates of remission for depression in older adults.9Several studies during the 1990s identified racial/ethnic differences in the diagnosis and treatment of depression, both in the general adult population and among the elderly.10–14 Although there was a general increase in rates of depression diagnosis and antidepressant use during this period, some studies suggest that these increases are not consistent across racial/ethnic subgroups15 and that disparities in the treatment of diagnosed depression are persistent.10,16,17More recent studies (often combining the nonelderly and elderly adult population rather than considering these groups separately) have provided mixed findings. Some evidence indicates that minority group members with depression continue to receive less mental health care than do non-Hispanic Whites, and some studies suggest that mental health treatment differences by race/ethnicity may have worsened in the early 2000s.18–21 By contrast, 1 recent national study reported that although overall increases in treatment rates were modest in the 2000s, there were significant increases in treatment rates among African Americans, possibly narrowing the racial/ethnic gap among adults in general.22 However, this study did not examine disparities in treatment separately among older adults and was founded on household reported conditions that are only modestly related to provider diagnoses.23 The pattern of diffusion of depression treatment may differ between elderly and nonelderly adults. Consequently, racial/ethnic differences in diagnosis and treatment among the elderly remain a potentially important public health concern.We investigated whether there are racial/ethnic differences (1) in the rate of diagnosis of depression among the elderly, controlling for sociodemographic characteristics and depression symptoms (depressed mood and anhedonia) reported on a 2-item screener; and (2) in the treatment provided to those diagnosed with depression by a health care provider, adjusting for these covariates. In a large, nationally representative sample, we examined whether relationships between race/ethnicity and depression diagnosis or depression treatment are mediated by insurance coverage and perceived access to medical care, depression symptoms, and severity, or by other global measures of health such as self-reported health status and impairment in daily activities.