PET imaging of cardiac hypoxia: opportunities and challenges.

Myocardial hypoxia is a major factor in the pathology of cardiac ischemia and myocardial infarction. Hypoxia also occurs in microvascular disease and cardiac hypertrophy, and is thought to be a prime determinant of the progression to heart failure, as well as the driving force for compensatory angiogenesis. The non-invasive delineation and quantification of hypoxia in cardiac tissue therefore has the potential to be an invaluable experimental, diagnostic and prognostic biomarker for applications in cardiology. However, at this time there are no validated methodologies sufficiently sensitive or reliable for clinical use. PET imaging provides real-time spatial information on the biodistribution of injected radiolabeled tracer molecules. Its inherent high sensitivity allows quantitative imaging of these tracers, even when injected at sub-pharmacological (≥pM) concentrations, allowing the non-invasive investigation of biological systems without perturbing them. PET is therefore an attractive approach for the delineation and quantification of cardiac hypoxia and ischemia. In this review we discuss the key concepts which must be considered when imaging hypoxia in the heart. We summarize the PET tracers which are currently available, and we look forward to the next generation of hypoxia-specific PET imaging agents currently being developed. We describe their potential advantages and shortcomings compared to existing imaging approaches, and what is needed in terms of validation and characterization before these agents can be exploited clinically.

Exposure to HIV-protease inhibitors selects for increased expression of P-glycoprotein (ABCB1) in Kaposi's sarcoma cells.

BACKGROUND: Given that HIV-protease inhibitors (HIV-PIs) are substrates/inhibitors of the multidrug transporter ABCB1, can induce ABCB1 expression, and are used in combination with doxorubicin for AIDS-Kaposi's Sarcoma (KS) treatment, the role that ABCB1 plays in mediating multidrug resistance (MDR) in a fully transformed KS cell line (SLK) was explored. METHODS: The KS cells were exposed to both acute and chronic treatments of physiological concentrations of different HIV-PIs (indinavir, nelfinavir, atazanavir, ritonavir, or lopinavir), alone or together with doxorubicin. The ABCB1 mRNA and protein expression levels were then assessed by qRT-PCR and western blotting, flow cytometry, and immunofluorescence. RESULTS: Chronic treatment of SLK cells with one of the five HIV-PIs alone or together resulted in increased resistance to doxorubicin. Co-treatment with one of the HIV-PIs in combination with doxorubicin resulted in a synergistic increase in resistance to doxorubicin, and the degree of resistance was found to correlate with the expression of ABCB1. The SLK cells were also revealed to be cross-resistant to the structurally unrelated drug paclitaxel. CONCLUSION: These studies suggest that ABCB1 is primarily responsible for mediating MDR in SLK cells selected with either HIV-PIs alone or in combination with doxorubicin. Therefore, the roles that ABCB1 and drug cocktails play in mediating MDR in KS in vivo should be evaluated.

The FIREBIRD-II CubeSat mission: Focused investigations of relativistic electron burst intensity, range, and dynamics.

FIREBIRD-II is a National Science Foundation funded CubeSat mission designed to study the scale size and energy spectrum of relativistic electron microbursts. The mission consists of two identical 1.5 U CubeSats in a low earth polar orbit, each with two solid state detectors that differ only in the size of their geometric factors and fields of view. Having two spacecraft in close orbit allows the scale size of microbursts to be investigated through the intra-spacecraft separation when microbursts are observed simultaneously on each unit. Each detector returns high cadence (10 s of ms) measurements of the electron population from 200 keV to >1 MeV across six energy channels. The energy channels were selected to fill a gap in the observations of the Heavy Ion Large Telescope instrument on the Solar, Anomalous, and Magnetospheric Particle Explorer. FIREBIRD-II has been in orbit for 5 years and continues to return high quality data. After the first month in orbit, the spacecraft had separated beyond the expected scale size of microbursts, so the focus has shifted toward conjunctions with other magnetospheric missions. FIREBIRD-II has addressed all of its primary science objectives, and its long lifetime and focus on conjunctions has enabled additional science beyond the scope of the original mission. This paper presents a brief history of the FIREBIRD mission's science goals, followed by a description of the instrument and spacecraft. The data products are then discussed along with some caveats necessary for proper use of the data.

Lead (II) detection and contamination routes in environmental sources, cookware and home-prepared foods from Zimatlán, Oaxaca, Mexico.

An interdisciplinary investigation, involving environmental geochemists, epidemiologists, nurses, and anthropologists, was undertaken to determine the contamination source and pathway of an on-going outbreak of lead poisoning among migrants originating from Zimatlán, Oaxaca, Mexico and living in Seaside, California, and among their US-born children. An initial investigation in Seaside identified grasshopper foodstuff ("chapulines") imported from Mexico and consumed as snacks, as containing alarmingly high lead concentrations (up to 2300 mg/kg). The focus in the present work concentrates on the Oaxacan area of origin of the problem in Mexico, and two potential sources of contamination were investigated: wind-borne dusts from existing mine residues as potential contaminants of soil, plant, and fauna; and food preparation practices using lead-glazed ceramic cookware. Over a three year period, sampling was conducted in Oaxaca using community-level sampling and also targeted sampling with families of cases with lead poisoning in California. In addition to fresh field chapulines, we analyzed for total lead: soil, water, mine residues, and plant materials, both from areas adjacent to or at an abandoned waste site containing mine tailings, and from fields where chapulines are collected; foodstuffs gathered in community markets or in a food transport business; and foodstuffs and cookware gathered from relatives of case families in California. Also, selected new and used lead-glazed clay cookware was extracted for lead, using 0.02 M citric acid and with 4% acetic acid. The results indicated significant presence of lead in mine wastes, in specific foodstuffs, and in glazed cookware, but no extensive soil contamination was identified. In-situ experiments demonstrated that lead incorporation in food is made very efficient through grinding of spices in glazed cookware, with the combination of a harsh mechanical action and the frequent presence of acidic lime juice, but without heating, resulting in high but variable levels of contamination.

Disclosure of complementary health approaches among low income and racially diverse safety net patients with diabetes.

OBJECTIVE: Patient-provider communication about complementary health approaches can support diabetes self-management by minimizing risk and optimizing care. We sought to identify sociodemographic and communication factors associated with disclosure of complementary health approaches to providers by low-income patients with diabetes. METHODS: We used data from San Francisco Health Plan's SMARTSteps Program, a trial of diabetes self-management support for low-income patients (n=278) through multilingual automated telephone support. Interviews collected use and disclosure of complementary health approaches in the prior month, patient-physician language concordance, and quality of communication. RESULTS: Among racially, linguistically diverse participants, half (47.8%) reported using complementary health practices (n=133), of whom 55.3% disclosed use to providers. Age, sex, race/ethnicity, nativity, education, income, and health literacy were not associated with disclosure. In adjusted analyses, disclosure was associated with language concordance (AOR=2.21, 95% CI: 1.05, 4.67), physicians' interpersonal communication scores (AOR=1.50, 95% CI: 1.03, 2.19), shared decision making (AOR=1.74, 95% CI: 1.33, 2.29), and explanatory-type communication (AOR=1.46, 95% CI: 1.03, 2.09). CONCLUSION: Safety net patients with diabetes commonly use complementary health approaches and disclose to providers with higher patient-rated quality of communication. PRACTICE IMPLICATIONS: Patient-provider language concordance and patient-centered communication can facilitate disclosure of complementary health approaches.

HIV disease and AIDS in women: current knowledge and a research agenda.

The study of the clinical manifestations, progression, and outcome of human immunodeficiency virus (HIV) infection in women has begun in earnest. AIDS-defining diseases that are more common in women than in men include wasting syndrome, esophageal candidiasis, and herpes simplex virus disease, whereas Kaposi's sarcoma is rare. Non-AIDS-defining gynecological conditions such as vaginal candida infections and cervical pathology are prevalent among women at all stages of HIV infection. Associations have been documented between the presence of human papillomavirus, lower genital tract neoplasia, and HIV-related immunosuppression. Pregnancy has not been confirmed to have an effect on the clinical progression of HIV disease in women incremental to the effect of time. Differential access and utilization of therapeutic interventions appear to account for much of the reported gender discrepancy in survival. Well designed epidemiological and clinical studies will help further scientific knowledge leading to early diagnosis, appropriate treatment, and timely prevention of the manifestations of HIV disease in women.

Design, synthesis, and structure-activity relationships of acetylene-based histamine H3 receptor antagonists.

New, potent, and selective histamine H3 receptor antagonists have been synthesized by employing the use of (1) an appropriately positioned nonpolar acetylene spacer group, (2) either a two-carbon straight chain linker or a conformationally restricting trans-cyclopropane ring between the C-4 position of an imidazole headgroup and the acetylene spacer, and (3) a Topliss operational scheme for side-chain substitution for optimizing the hydrophobic domain. Compounds 9-18 are examples synthesized with the two-carbon straight chain linker, whereas 26-31 are analogues prepared by incorporation of the trans-(+/-)-cyclopropane at the C-4 position of an imidazole headgroup. Synthesis of both the (1R,2R)- and (1S, 2S)-cyclopropyl enantiomers of the most potent racemic compound 31 (Ki = 0.33 +/- 0.13 nM) demonstrated a stereopreference in H3 receptor binding affinity for the (1R,2R) enantiomer 32 (Ki = 0.18 +/- 0.04 nM) versus the (1S,2S) enantiomer 33 (Ki = 5.3 +/- 0.5 nM). (1R,2R)-4-(2-(5,5-Dimethylhex-1-ynyl)cyclopropyl)imidazole (32) is one of the most potent histamine H3 receptor antagonists reported to date.

Effects of selected histamine H3 receptor antagonists on tele-methylhistamine levels in rat cerebral cortex.

The H3 antagonist thioperamide is thought to act on brain H3 autoreceptors to increase both the release and metabolism of neuronal histamine (HA). Our studies investigated the effects of several new brain-penetrating H3 antagonists on rat cerebral cortical levels of the HA metabolite tele-methylhistamine (t-MH). Animals were pretreated with H3 antagonists (0.3 to 30 mg/kg; 1-4 hr; i.p.) in the presence or absence of the monoamine oxidase inhibitor pargyline to prevent metabolism of t-MH. Cortical t-MH levels were measured by both radioimmunoassay (RIA) and gas chromatography-mass spectrometry (GC-MS). Pargyline (60 mg/kg; 1 hr; i.p.) produced an approximately 2-fold increase in t-MH levels as measured by either GC-MS or RIA. Thioperamide (+/- pargyline) increased t-MH levels as measured by both GC-MS and RIA. In contrast, neither 5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one (GT-2016) (+/- pargyline), 4-(6-cyclohexylhex-cis-3-enyl)imidazole (GT-2227) (+/- pargyline), nor clobenpropit (minus pargyline) increased t-MH levels as measured by GC-MS. A good agreement was found between t-MH levels as determined by either RIA or GC-MS except after treatment with GT-2016, which increased apparent t-MH brain levels according to the former but not the latter method. Subsequent studies suggest the in vivo formation of a GT-2016 metabolite, which can cross-react in the t-MH RIA. Although all H3 receptor antagonists studied to date seem capable of enhancing brain HA release, only thioperamide presently was found to enhance cortical t-MH levels. Thus, H3 receptor antagonists may differentially affect HA release and turnover, and brain t-MH levels may not be reliable predictors of H3 agonist, partial agonist, or antagonist in vivo activity.

Identifying multidrug resistance in previously treated tuberculosis patients: a mixed-methods study in Cambodia.

SETTING: Previously treated tuberculosis (TB) patients are a priority for drug susceptibility testing (DST) to identify cases with multidrug-resistant TB (MDR-TB). A Cambodia study found that one third of smear-positive previously treated patients had DST results. OBJECTIVE: To quantify the gaps in the detection of MDR-TB in previously treated TB patients in Cambodia, and describe health workers' perspectives on barriers, facilitators and potential interventions. DESIGN: Analysis of Cambodia's 2004-2012 case notifications and semi-structured interviews with stakeholders. RESULTS: The proportion of previously treated notifications varied significantly across provinces in 2010-2012. If there had been no attrition along the path to detecting MDR-TB among smear-positive notified cases in 2012, an estimated 75 additional MDR-TB cases could have been identified, which would double the number actually detected. Most were lost due to misclassification of previously treated patients as 'new'. Barriers include patients' reluctance to disclose and staff difficulty in eliciting treatment history, partly attributed to the availability of streptomycin (SM) only in hospitals. Facilitators include collection of sputum for DST even if previously treated patients are not receiving SM, streamlining sputum transportation and prompt reporting of results. CONCLUSION: Improved monitoring, supportive staff supervision and training, patient education, and correct classification of previously treated cases are essential for improving the detection of MDR-TB.

What happens between visits? Adverse and potential adverse events among a low-income, urban, ambulatory population with diabetes.

BACKGROUND: Little is known about adverse events (AEs) that occur between physician visits for ambulatory chronic disease patients. An automated telephone self-management support programme for a diverse population of diabetes patients was implemented to capture AEs, describe the self-management domains from which they emanate and explore contributing causes. METHODS: AEs and potential AEs (PotAEs) were identified among 111 ethnically diverse diabetes patients. An AE is an injury that results from either medical management or patient self-management; a PotAE is an unsafe state likely to lead to an event if it persists without intervention. Medical record reviews were conducted to ascertain which self-management domain was involved with the event and to explore contributing causes. RESULTS: Among the 111 patients, 86% had at least one event detected over the 9-month observation period. 111 AEs and 153 PotAEs were identified. For all events, medication management was the most common domain (166 events, 63%). Only 20% of events reflected a single contributing cause; in the remaining 80%, a combination of system, clinician and patient factors contributed to their occurrence. Patient actions were implicated in 205 (77%) events, systems issues in 183 (69%) events and inadequate physician-patient communication in 155 (59%) events. Aside from communication, primary care clinician actions contributed to the occurrence of the event in only 16 cases (6%). CONCLUSIONS: Our findings reveal a complex safety ecology, with multiple contributing causes for AEs and PotAEs among ambulatory diabetes patients. Moreover, patients themselves seem to be key drivers of safety and of AEs, suggesting that patient-level self-management support and patient-centred communication are critical to AE prevention.

Autocrine type I interferon amplifies dendritic cell responses to lipopolysaccharide via the nuclear factor-kappaB/p38 pathways.

The central role of dendritic cells (DC) in the initiation of immune responses requires these cells to be able to determine the degree of danger in their microenvironment. Abrogating the activity of type I interferon (IFN) secreted after lipopolysaccharide (LPS) stimulation of DC inhibits CD86 and human leucocyte antigen-DR (HLA-DR) upregulation at a low LPS concentration. At a higher concentration of LPS, while changes in surface phenotype are not dependent on type I IFN, this cytokine is required for maximal secretion of interleukin-12 (IL-12) and tumour necrosis factor-alpha (TNFalpha) by DC. Thus, the secretion and autocrine activity of type I IFN after Toll-like receptor stimulation enables DC to orchestrate a hierarchical maturation response with regard to changes in surface phenotype and secretion of cytokines. In addition, the activation of nuclear factor-kappaB and p38 pathways in DC can occur either in an additive fashion when DC are exposed to dual stimulation or can be activated in discrete phases over time when DC are exposed to LPS alone. The differential activation of these pathways provides a mechanism for DC to integrate the activation by multiple stimuli and thus amplify responses to pathogen infection.

The use of prostate specific antigen for prostate cancer screening: a managed care perspective.

A large nonprofit staff model Health Maintenance Organization experienced increased use of prostate specific antigen (PSA) as a screening test for prostate cancer beginning in May 1991. A critical evaluation of the evidence in support of PSA screening was done and concluded that the use of PSA to screen for prostate cancer did not meet the criteria for an effective screening program. A guideline stating that PSA was not recommended as a screening test was implemented focusing on a model of shared decision making. PSA test ordering decreased significantly when patients were fully informed about the evidence for PSA screening. If PSA screening had continued at the peak rate, the cascade of intervention initiated by screening would have resulted in significant complications and approximately $4,800,000 in increased costs.

Workplace health hazards: analysis of hotline calls over a six-year period.

Between 1981-1986 a state-based occupational health telephone hotline received more than 8,000 inquiries on over 3,000 hazardous agents. Major caller groups were employees (37%), employers (20%), health care providers, primarily physicians (19%), government agencies (12%), and labor unions (6%). Employees were the fastest growing caller group. Callers inquired about general health hazards of chemicals (65%), the relation of symptoms to work (22%), and risks to pregnancy (13%).

An evidence-based approach to evaluating and improving clinical practice: guideline development.

Group Health Cooperative of Puget Sound has developed a model for evaluating and improving clinical practice based on an explicit, evidence-based approach. It is designed to identify gaps between current and optimal practices, and to bring about changes in physician behavior so that health care outcomes (health status, patient satisfaction, provider satisfaction, cost/utilization) are maximized. This model stresses the importance of a rigorous process in looking objectively at evidence in working to improve outcomes. Discrete tools have been developed which help teams move successfully from problem identification to the ongoing evaluation and improvement of a new clinical practice.

A role for urokinase-type plasminogen activator in human immunodeficiency virus type 1 infection of macrophages.

Urokinase-type plasminogen activator (uPA), a proteinase which activates plasminogen by cleaving at -CPGR(arrow downward)V-, was shown to cleave the V3 loop in recombinant gp120 of human immunodeficiency virus type 1 (HIV-1) IIIB and MN strains, as well as a synthetic, cyclized peptide representing the clade B consensus sequence of V3. Proteolysis occurred at the homologous -GPGR(arrow downward)A-, an important neutralizing determinant of HIV-1. It required soluble CD4 and was prevented by inhibitors of uPA but not by inhibitors of likely contaminating plasma proteinases. It was accelerated by heparin, a known cofactor for plasminogen activation. In immune capture experiments, tight binding of uPA to viral particles, which did not depend on CD4, was also demonstrated. Active site-directed inhibitors or uPA diminished this binding, as did a neutralizing antibody to V3. Addition of exogenous uPA to the laboratory-adapted IIIB strain of HIV-1, the macrophage-tropic field strains JR-CSF and SF-162, or a fresh patient isolate of indeterminate tropism, followed by infection of macrophages with the various treated viruses, resulted in severalfold increases in subsequent viral replication, as judged by yields of reverse transcriptase activity and p24 antigen, as well as incorporation, as judged by PCR in situ. These responses were reversible by inhibitors or antibodies targeting the proteinase active site or the V3 loop. We propose that uPA, a transcriptionally regulated proteinase which is upregulated when macrophages are HIV infected, can be bound and utilized by the virus to aid in fusion and may be an endogenous component that is critical to the infection of macrophages by HIV-1.

Epidemiological evidence indicates asbestos causes laryngeal cancer.

A variety of opinions have been expressed in the literature concerning asbestos and laryngeal cancer. This paper presents an analysis of epidemiological studies based on criteria that prioritized the most heavily exposed cohorts. Emphasis was given to the six cohorts or subcohorts with lung cancer relative risk estimates of 2 or more. The two groups of workers with the highest lung cancer relative risk estimates (4.06 and 3.28) both gave strong support for a causal association of asbestos and laryngeal cancer, with relative risk estimates of 1.91 (90% confidence limits 1.00 to 3.34) and 3.75 (90% confidence limits 1.01 to 9.68), respectively. Confounding with cigarette smoking or alcohol consumption does not explain the findings. Case-control studies gave mixed results, but generally supported the hypothesis. It was concluded that asbestos is a probable cause of laryngeal cancer in view of the reasonable consistency of the studies, the strength of the association in key studies, the evidence for dose-response relationships, and the biological plausibility for asbestos being a cause of laryngeal cancer.

Cervicovaginal screening in women with HIV infection: a need for increased vigilance?

OBJECTIVE: To review the current literature on cervical disease (dysplasia, cervical intraepithelial neoplasia [CIN] or carcinoma) in women with HIV infection and to assess recommendations for cervicovaginal screening in these patients. DATA SOURCES: MEDLINE and AIDSLINE were searched for relevant articles published in English or French between January 1987 and February 1993, abstracts presented at international AIDS conferences from 1989 to 1993 were evaluated, and pertinent agencies and organizations were consulted. STUDY SELECTION: A total of 92 reports of gynecologic disease in women with HIV infection were examined; 32 studies were retained that reported pertinent findings on cervical dysplasia, CIN or cervical carcinoma. DATA EXTRACTION: The following criteria were used to extract data: study design (descriptive v. comparative), sample size, heterogeneity of the study population, presence of immunodeficiency indicators (i.e., absolute CD4+ lymphocyte count) and presence of concomitant vaginal infections. Recommendations were assessed for their specific application to women with HIV infection. DATA SYNTHESIS: Data on the associations between stage of cervical disease and response to treatment at varying levels of CD4+ lymphocyte depletion were incomplete. Recommendations by official bodies for cervicovaginal screening in women with HIV infection differed little from recommendations for standard care of all women of reproductive age. CONCLUSIONS: The consequences of a missed or delayed diagnosis of cervical disease for women with HIV infection can be severe. Pending further research, more frequent cervicovaginal screening through Papanicolaou testing and colposcopy in women with HIV infection is warranted.

An evidence-based approach to evaluating and improving clinical practice: implementing practice guidelines.

Clinical practice guidelines can improve health care outcomes, but they are only as effective as their implementation. We present a framework for implementing practice guidelines that begins by identifying the forces driving and restraining the adoption of the guideline. Strategies for changing physician behavior that strengthen the driving forces and weaken the restraining forces can then be incorporated into a comprehensive implementation program. Nine strategies for changing physician behavior are presented, based on a review of the literature and organizational experience at Group Health Cooperative of Puget Sound. In designing an implementation strategy, it is essential that the resources allocated to implementation are commensurate with the improvement in outcomes expected from the successful implementation of the guideline. All implementation programs should include plans for measuring outcomes to allow for continuing improvement. Guideline implementation, evaluation and improvement efforts are most likely to be successful when they are part of an explicit, evidence-based process for evaluating and improving clinical practice.