Morphine and propranolol co-administration impair consolidation of Y-maze spatial recognition memory

In the present study, the interaction between morphine and the beta-adrenergic receptor antagonist, propranolol (PROP), in memory consolidation was investigated in a two-trial recognition Y-maze task. Four sets of Y-maze experiments were carried out in mi

Irregular morphine administration affects the retention but not acquisition of conditioned place preference in rats

Drug addiction is increasingly viewed as the expression of abnormal associative learning following repeated exposures to the drugs of abuse Previous I studies have demonstrated that the patterns of repetition such as frequency and spacing are important to many kinds of learning and memory retention We hypothesized that drug repetition pattern might affect the reward-related learning although the total doses of the drug were the same. In the present study, we tested morphine-induced place preference following either regular or irregular pattern of morphine pairing in rats Regular morphine group received morphine administration daily at a regular time with the same dose Irregular morphine groups received morphine administration either at the same time but irregular doses, irregular time but same dose, or irregular time and irregular doses. We found that rats, who received irregular morphine pairing, exhibited similar acquisition of peace preference but different preference retentions compared with regular morphine-treated rats after the same total dose of morphine Rats, who received morphine administration at the same time but irregular doses and at irregular time and irregular doses, showed rapid disruption of place preference than the regular morphine group. Rats, who received morphine at irregular time but the same dose, showed similar retention of place preference to regular morphine group Our results suggest that the pattern of drug pairing plays an important role in the retention of reward-related memory This study may provide new evidence to broaden our understanding of the development and maintenance of drug craving (C) 2009 Elsevier B V. All rights reserved

Efficient and divergent synthesis of cyclophosphamide analogues from 2-arylamino-3-acetyl-5, 6-dihydro-4H-pyrans

A facile and efficient one-pot synthesis of substituted cyclophosphamidic chlorides and their analogues has been developed from readily available enaminones, 2-arylamino-3-acetyl-5,6-dihydro4H-pyrans.

Knocking-Down Cyclin A(2) by siRNA Suppresses Apoptosis and Switches Differentiation Pathways in K562 Cells upon Administration with Doxorubicin

Cyclin A(2) is critical for the initiation of DNA replication, transcription and cell cycle regulation. Cumulative evidences indicate that the deregulation of cyclin A(2) is tightly linked to the chromosomal instability, neoplastic transformation and tumor proliferation. Here we report that treatment of chronic myelogenous leukaemia K562 cells with doxorubicin results in an accumulation of cyclin A(2) and follows by induction of apoptotic cell death. To investigate the potential preclinical relevance, K562 cells were transiently transfected with the siRNA targeting cyclin A(2) by functionalized single wall carbon nanotubes. Knocking down the expression of cyclin A(2) in K562 cells suppressed doxorubicin-induced growth arrest and cell apoptosis. Upon administration with doxorubicin, K562 cells with reduced cyclin A(2) showed a significant decrease in erythroid differentiation, and a small fraction of cells were differentiated along megakaryocytic and monocyte-macrophage pathways. The results demonstrate the pro-apoptotic role of cyclin A(2) and suggest that cyclin A(2) is a key regulator of cell differentiation.

In Praise of Folly: International Administration and the Corruption of Humanity

Bain, William, 'In Praise of Folly: International Administration and the Corruption of Humanity', International Affairs, (2006) 82(3) pp.525-538 RAE2008

Catholic grievances in relation to the administration of Indian affairs : being a report presented to the Catholic Young Men's National Union, at its eighth annual convention, held in Boston, Massachusetts, May 10th and 11th, 1882

http://www.archive.org/details/catholicgrieva00mealrich

A new world a new American foreign policy: the Carter administration, Nicaragua, and the legacy of the Vietnam War, 1977-1981

The impact of the Vietnam War conditioned the Carter administration’s response to the Nicaraguan revolution in ways that reduced US engagement with both sides of the conflict. It made the countries of Latin America counter the US approach and find their own solution to the crisis, and allowed Cuba to play a greater role in guiding the overthrow of Nicaraguan dictator Anastasio Somoza Debayle. This thesis re-evaluates Carter’s policy through the legacy of the Vietnam War, because US executive anxieties about military intervention, Congress’s increasing influence, and US public concerns about the nation’s global responsibilities, shaped the Carter approach to Nicaragua. Following a background chapter, the Carter administration’s policy towards Nicaragua is evaluated, before and after the fall of Somoza in July 1979. The extent of the Vietnam influence on US-Nicaraguan relations is developed by researching government documents on the formation of US policy, including material from the Jimmy Carter Library, the Library of Congress, the National Security Archive, the National Archives and Records Administration, and other government and media sources from the United Nations Archives, New York University, the New York Public Library, the Hoover Institution Archives, Tulane University and the Organization of American States. The thesis establishes that the Vietnam legacy played a key role in the Carter administration’s approach to Nicaragua. Before the overthrow of Somoza, the Carter administration limited their influence in Nicaragua because they felt there was no immediate threat from communism. The US feared that an active role in Nicaragua, without an established threat from Cuba or the Soviet Union, could jeopardise congressional support for other foreign policy goals deemed more important. The Carter administration, as a result, pursued a policy of non-intervention towards the Central American country. After the fall of Somoza, and the establishment of a new government with a left wing element represented by the Sandinistas, the Carter administration emphasised non-intervention in a military sense, but actively engaged with the new Nicaraguan leadership to contain the potential communist influence that could spread across Central America in the wake of the Nicaraguan revolution.

The Ford administration, Angola and the perception of Post-Vietnam US credibility, 1974-1976

This thesis is a study of how the Gerald Ford administration struggled to address a perceived loss of US credibility after the collapse of Vietnam, with a focus on the role of Secretary of State Henry Kissinger in the formulation, implementation and subsequent defence of US Angolan policy. By examining the immediate post-Vietnam period, this thesis shows that Vietnam had a significant impact on Kissinger’s actions on Angola, which resulted in an ill conceived covert operation in another third world conflict. In 1974, Africa was a neglected region in Cold War US foreign policy, yet the effects of the Portuguese revolution led to a rapid decolonization of its African territories, of which Angola was to become the focus of superpower competition. After South Vietnam collapsed in April 1975, Kissinger became fixated on restoring the perceived loss of US prestige, Angola provided the first opportunity to address this. Despite objections from his advisors, Kissinger methodically engineered a covert program to assist two anti-Marxist guerrilla groups in Angola. As the crisis escalated, the media discovered the operation and the Congress decided to cease all funding. A period of heated tensions ensued, resulting in Kissinger creating a new African policy to outmanoeuvre his critics publicly, while privately castigating them to foreign leaders. This thesis argues that Kissinger’s dismissal of internal dissent and opposition from the Congress was influenced by what he perceived as bureaucrats being affected by the Vietnam syndrome, and his obsession with restoring US credibility. By looking at the private and public records – as expressed in government meetings and official reports, US newspaper and television coverage and diplomatic cables – this thesis addresses the question of how the lessons of Vietnam failed to influence Kissinger’s actions in Angola, but the lessons of Angola were heavily influential in the construction of a new US-African policy.

3-year results of docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer: a pilot study.

BACKGROUND: Docetaxel has proven efficacy in metastatic breast cancer. In this pilot study, we explored the efficacy/feasibility of docetaxel-based sequential and combination regimens as adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: From March 1996 till March 1998, four consecutive groups of patients with stages II and III breast cancer, aged < or = 70 years, received one of the following regimens: a) sequential Doxorubicin (A) --> Docetaxel (T) --> CMF (Cyclophosphamide+Methotrexate+5-Fluorouracil): A 75 mg/m q 3 wks x 3, followed by T100 mg/m2 q 3 wks x 3, followed by i.v. CMF Days 1+8 q 4 wks x 3; b) sequential accelerated A --> T --> CMF: A and T administered at the same doses q 2 wks with Lenograstin support; c) combination therapy: A 50 mg/m2 + T 75 mg/m2 q 3 wks x 4, followed by CMF x 4; d) sequential T --> A --> CMF: T and A, administered as in group a), with the reverse sequence. When indicated, radiotherapy was administered during or after CMF, and Tamoxifen after CMF. RESULTS: Ninety-three patients were treated. The median age was 48 years (29-66) and the median number of positive axillary nodes was 6 (1-25). Tumors were operable in 94% and locally advanced in 6% of cases. Pathological tumor size was >2 cm in 72% of cases. There were 21 relapses, (18 systemic, 3 locoregional) and 11 patients (12%) have died from disease progression. At median follow-up of 39 months (6-57), overall survival (OS) was 87% (95% CI, 79-94%) and disease-free survival (DFS) was 76% (95% CI, 67%-85%). CONCLUSION: The efficacy of these docetaxel-based regimens, in terms of OS and DFS, appears to be at least as good as standard anthracycline-based adjuvant chemotherapy (CT), in similar high-risk patient populations.

Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer.

PURPOSE: Taxanes (paclitaxel or docetaxel) have been sequenced or combined with anthracyclines (doxorubicin or epirubicin) for the first-line treatment of advanced breast cancer. This meta-analysis uses data from all relevant trials to detect any advantages of taxanes in terms of tumor response, progression-free survival (PFS), and survival. PATIENTS AND METHODS: Individual patient data were collected on eight randomized combination trials comparing anthracyclines + taxanes (+ cyclophosphamide in one trial) with anthracyclines + cyclophosphamide (+ fluorouracil in four trials), and on three single-agent trials comparing taxanes with anthracyclines. Combination trials included 3,034 patients; single-agent trials included 919 patients. RESULTS: Median follow-up of living patients was 43 months, median survival was 19.3 months, and median PFS was 7.1 months. In single-agent trials, response rates were similar in the taxanes (38%) and in the anthracyclines (33%) arms (P = .08). The hazard ratios for taxanes compared with anthracyclines were 1.19 (95% CI, 1.04 to 1.36; P = .011) for PFS and 1.01 (95% CI, 0.88 to 1.16; P = .90) for survival. In combination trials, response rates were 57% (10% complete) in taxane-based combinations and 46% (6% complete) in control arms (P < .001). The hazard ratios for taxane-based combinations compared with control arms were 0.92 (95% CI, 0.85 to 0.99; P = .031) for PFS and 0.95 (95% CI, 0.88 to 1.03; P = .24) for survival. CONCLUSION: Taxanes were significantly worse than single-agent anthracyclines in terms of PFS, but not in terms of response rates or survival. Taxane-based combinations were significantly better than anthracycline-based combinations in terms of response rates and PFS, but not in terms of survival.

Toward the development of national telehealth services: the role of Veterans Health Administration and future directions for research.

The Veterans Health Administration (VHA) in the Department of Veteran Affairs (VA) has emerged as a national and international leader in the delivery and research of telehealth-based treatment. Several unique characteristics of care in VA settings intersect to create an ideal environment for telehealth modalities and research. However, the value of telehealth experience and initiatives in VA settings is limited if telehealth strategies cannot be widely exported to other public or private systems. Whereas a hierarchical organization, such as VA, can innovate and fund change relatively quickly based on provider and patient preferences and a growing knowledge base, other health provider organizations and third-party payers may likely require replicable scientific findings over time before incremental investments will be made to create infrastructure, reform regulatory barriers, and amend laws to accommodate expansion of telehealth modalities. Accordingly, large-scale scientifically rigorous telehealth research in VHA settings is essential not only to investigate the efficacy of existing and future telehealth practices in VHA, but also to hasten the development of telehealth infrastructure in private and other public health settings. We propose an expanded partnership between the VA, NIH, and other funding agencies to investigate creative and pragmatic uses of telehealth technology. To this end, we identify six specific areas of research we believe to be particularly relevant to the efficient development of telehealth modalities in civilian and military contexts outside VHA.

An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer.

BACKGROUND: A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective. METHODS AND RESULTS: Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide) chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%). When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06). Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8%) of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04), representing a viable alternative therapy. CONCLUSIONS: Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding microRNA and mRNA expression profiles. Importantly, we also present evidence to support the concept that analysis of molecular variables can present a rational strategy to identifying alternative therapeutic opportunities.

Characteristics of primary care office visits to nurse practitioners, physician assistants and physicians in United States Veterans Health Administration facilities, 2005 to 2010: a retrospective cross-sectional analysis.

UNLABELLED: BACKGROUND: Primary care, an essential determinant of health system equity, efficiency, and effectiveness, is threatened by inadequate supply and distribution of the provider workforce. The Veterans Health Administration (VHA) has been a frontrunner in the use of nurse practitioners (NPs) and physician assistants (PAs). Evaluation of the roles and impact of NPs and PAs in the VHA is critical to ensuring optimal care for veterans and may inform best practices for use of PAs and NPs in other settings around the world. The purpose of this study was to characterize the use of NPs and PAs in VHA primary care and to examine whether their patients and patient care activities were, on average, less medically complex than those of physicians. METHODS: This is a retrospective cross-sectional analysis of administrative data from VHA primary care encounters between 2005 and 2010. Patient and patient encounter characteristics were compared across provider types (PA, NP, and physician). RESULTS: NPs and PAs attend about 30% of all VHA primary care encounters. NPs, PAs, and physicians fill similar roles in VHA primary care, but patients of PAs and NPs are slightly less complex than those of physicians, and PAs attend a higher proportion of visits for the purpose of determining eligibility for benefits. CONCLUSIONS: This study demonstrates that a highly successful nationwide primary care system relies on NPs and PAs to provide over one quarter of primary care visits, and that these visits are similar to those of physicians with regard to patient and encounter characteristics. These findings can inform health workforce solutions to physician shortages in the USA and around the world. Future research should compare the quality and costs associated with various combinations of providers and allocations of patient care work, and should elucidate the approaches that maximize quality and efficiency.

The accuracy and completeness for receipt of colorectal cancer care using Veterans Health Administration administrative data.

BACKGROUND: The National Comprehensive Cancer Network and the American Society of Clinical Oncology have established guidelines for the treatment and surveillance of colorectal cancer (CRC), respectively. Considering these guidelines, an accurate and efficient method is needed to measure receipt of care. METHODS: The accuracy and completeness of Veterans Health Administration (VA) administrative data were assessed by comparing them with data manually abstracted during the Colorectal Cancer Care Collaborative (C4) quality improvement initiative for 618 patients with stage I-III CRC. RESULTS: The VA administrative data contained gender, marital, and birth information for all patients but race information was missing for 62.1% of patients. The percent agreement for demographic variables ranged from 98.1-100%. The kappa statistic for receipt of treatments ranged from 0.21 to 0.60 and there was a 96.9% agreement for the date of surgical resection. The percentage of post-diagnosis surveillance events in C4 also in VA administrative data were 76.0% for colonoscopy, 84.6% for physician visit, and 26.3% for carcinoembryonic antigen (CEA) test. CONCLUSIONS: VA administrative data are accurate and complete for non-race demographic variables, receipt of CRC treatment, colonoscopy, and physician visits; but alternative data sources may be necessary to capture patient race and receipt of CEA tests.