Correlation of cytochrome P450 (CYP) 1A2 activity using caffeine phenotyping and olanzapine disposition in healthy volunteers.

Olanzapine has previously been shown to have predominant metabolism by cytochrome (CYP) P450 1A2. Caffeine has been shown to provide an accurate phenotypic probe for measuring CYP1A2 activity. The purpose of this study is to determine if a significant correlation exists between olanzapine disposition and caffeine metabolic ratios. Subjects were phenotyped for CYP1A2 activity with caffeine probe methodology. After 200-mg caffeine administration, blood (4 h), saliva (6 and 10 h), and urine (8 h total) were collected for high-performance liquid chromatography (HPLC) analysis of caffeine and its metabolites.CYP1A2 activity was measured as plasma (PMR(4 h)), saliva (SMR(6 h) and SMR(10 h)), and three urinary metabolic (UMR1(8 h), UMR2(8 h), and UMR3(8 h)) ratios. Each of the 14 healthy nonsmokers (13 male) received a single 10 mg olanzapine dose after which blood was collected for HPLC determination of olanzapine concentrations at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 h postdose. Olanzapine pharmacokinetic parameters in this study were similar to those previously published. All caffeine metabolic ratios (PMR(4 h), SMR(6 h), SMR(10 h), UMR1(8 h), and UMR2(8 h)) significantly correlated with each other (p <0.001) except for UMR3(8 h), which did not correlate. A significant correlation (p <0.05) was also found between olanzapine clearance and PMR(4 h) (r=0.701), SMR(6 h) (r=0.644), SMR(10 h) (r=0.701), UMR1(8 h) (r=0.745), and UMR2(8 h) (r=0.710). A negative correlation was observed between olanzapine clearance and UMR3(8 h) (r=-0.029, p=NS). A significant correlation was found between olanzapine clearance and various caffeine metabolic ratios. Interpatient variability in CYP1A2 activity may explain the wide interpatient variability in olanzapine disposition. Compounds that modulate CYP1A2 activity may be expected to alter olanzapine pharmacokinetics accordingly.     

(18)F-FDG PET database of longitudinally confirmed healthy elderly individuals improves detection of mild cognitive impairment and Alzheimer's disease.

The normative reference sample is crucial for the diagnosis of Alzheimer's disease (AD) with automated (18)F-FDG PET analysis. We tested whether an (18)F-FDG PET database of longitudinally confirmed healthy elderly individuals ("normals," or NLs) would improve diagnosis of AD and mild cognitive impairment (MCI). METHODS: Two (18)F-FDG PET databases of 55 NLs with 4-y clinical follow-up examinations were created: one of NLs who remained NL, and the other including a fraction of NLs who declined to MCI at follow-up. Each (18)F-FDG PET scan of 19 NLs, 37 MCI patients, and 33 AD patients was z scored using automated voxel-based comparison to both databases and examined for AD-related abnormalities. RESULTS: Our database of longitudinally confirmed NLs yielded 1.4- to 2-fold higher z scores than did the mixed database in detecting (18)F-FDG PET abnormalities in both the MCI and the AD groups. (18)F-FDG PET diagnosis using the longitudinal NL database identified 100% NLs, 100% MCI patients, and 100% AD patients, which was significantly more accurate for MCI patients than with the mixed database (100% NLs, 68% MCI patients, and 94% AD patients identified). CONCLUSION: Our longitudinally confirmed NL database constitutes reliable (18)F-FDG PET normative values for MCI and AD.     

Role of Atypical Pathogens in Nursing Home–Acquired Pneumonia

ObjectivesNo international consensus has been reached on the empirical use of antibiotics with atypical coverage in nursing home–acquired pneumonia (NHAP). Aspiration is an important cause of NHAP, but it may not require antimicrobial treatment. This study aimed to investigate the prevalence and clinical characteristics of AP infections and review the need for empirical antibiotics with atypical coverage in NHAP.DesignA prospective cohort study.SettingFour nursing homes with a total number of 772 residents.ParticipantsPatients were aged ≥ 65 years, hospitalized for NHAP, which was defined as the presence of respiratory symptoms and abnormal chest radiographs, from April 2006 to March 2007.MeasurementsDemographics, clinical parameters, and investigation results were recorded. Microbial investigations comprised sputum routine and mycobacterial cultures, blood and urine cultures, serology, and nasopharyngeal aspirate viral culture and polymerase chain reaction tests. Suspected aspiration pneumonitis was arbitrarily defined as NHAP without pathogens identified.ResultsAfter excluding lone bacteriuria, 108 episodes of NHAP in 94 patients were included. Twelve APs were detected in 11 patients. There was no clinical feature to distinguish between infections caused by APs and other pathogens. The commonest APs were Mycoplasma pneumoniae (6) and Chlamydophila pneumoniae (3). No Legionella pneumophila was detected by urinary antigen test. None of the patients with AP infection received antibiotics indicated for AP infections. However, AP infections did not result in mortality. No pathogen was isolated in 31.5% of cases. Patients without pathogens isolated were less likely to have purulent sputum and crepitations on chest auscultation, compared with those with pneumonia caused by identified pathogens.ConclusionsAtypical pathogens (APs) were not associated with mortality even in cases where the prescribed antibiotics did not cover APs. NHAP may not necessarily be treated with empirical antibiotics covering APs.     

从免疫炎性损伤角度探讨5种清热解毒药物抗流感的机制及其临床意义

目的探讨黄芩、板蓝根、白头翁、虎杖、白花蛇舌草5种清热解毒代表药物抗流感病毒感染所致免疫炎性损伤的作用机制。方法在流感病毒亚洲甲型鼠肺适应株FM1感染小鼠后的不同时相(初期、极期、后期),采用ELISA法,动态观察清热解毒代表药物对小鼠血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1(IL-1)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)、γ干扰素(IFN-γ)5种炎性细胞因子含量的影响。结果黄芩在感染后第3日可显著降低血清TNF-α、IL-1、IL-6含量,并于感染后各时相均可增加IFN-γ含量,感染后第1~5日增加IL-10含量。板蓝根在感染后第3日能显著降低血清TNF-α含量,第3~5日降低IL-6含量,并在感染后第1天升高IL-10含量,在感染后第3~5日能升高IFN-γ含量。白头翁在感染后第3日能明显降低血清TNF-α、IL-1、IL-6含量,同时显著升高IL-10含量。虎杖在感染后第1日可显著升高血清IL-10含量,在感染后第5日升高IFN-γ含量。白花蛇舌草在感染后第3日降低血清IL-6含量,在感染后第5日升高IFN-γ含量。结论黄芩的抗流感作用主要表现在流感病毒感染引起的急性外感热病的极期;板蓝根在流感病毒感染的各个时相均有一定的治疗作用;白头翁在流感病毒感染的极期可抑制炎性损伤;虎杖在感染流感病毒的初期与后期均可减少促炎性细胞因子的分泌;白花蛇舌草在流感病毒感染的极期及后期均可起到一定的抗免疫炎性损伤。各药物均具有抑制炎性损伤、防止多脏器功能衰竭、防止休克、退热和抑制促炎性细胞因子的分泌,调节机体免疫,从而减轻炎症反应的作用。     

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA–HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10–480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA^−/low vs. HA^high) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA–binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HA^high subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA^−/low subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations.Breast tumors display substantial heterogeneity driven by genetic and epigenetic mechanisms (1–3). These processes select and support tumor cell subpopulations with distinct phenotypes in proliferation, metastatic/invasive proclivity, and treatment susceptibility that contribute to clinical outcomes. Currently, there is a paucity of biomarkers to identify these subpopulations (3–12). Although detection of genetic heterogeneity may itself be a breast cancer (BCa) prognostic marker (3, 13–15), the phenotypes manifested from this diversity are context-dependent. Therefore, phenotypic markers provide additional powerful tools for biological information required to design diagnostics and therapeutics. Glycomic approaches have enormous potential for revealing tumor cell phenotypic heterogeneity because glycans are themselves highly heterogeneous and their complexity reflects the nutritional, microenvironmental, and genetic dynamics of the tumors (16–18).We used hyaluronan (HA) as a model carbohydrate ligand for probing heterogeneity in glycosaminoglycan–BCa cell receptor interactions. We reasoned this approach would reveal previously undetected cellular and functional heterogeneity linked to malignant progression because the diversity of cell glycosylation patterns, which can occur as covalent and noncovalent modifications of proteins and lipids as well as different sizes of such polysaccharides as HA, is unrivaled (16, 17, 19). In particular, tumor and wound microenvironments contain different sizes of HA polymers that bind differentially to cell receptors to activate signaling pathways regulating cell migration, invasion, survival, and proliferation (19–22).More than other related glycosaminoglycans, HA accumulation within BCa tumor cells and peritumor stroma is a predictor of poor outcome (23) and of the conversion of the preinvasive form of BCa, ductal carcinoma in situ, to an early invasive form of BCa (24). HA is a nonantigenic and large, relatively simple, unbranched polymer, but the manner in which it is metabolized is highly complex (19, 25). There are literally thousands of different HA sizes in remodeling microenvironments, including tumors. HA polymers bind to cells via at least six known receptors (16, 19, 20, 26–32). Two of these, cluster designation 44 (CD44) and receptor for HA-mediated motility/HA-mediated motility receptor (RHAMM/HMMR), form multivalent complexes with different ranges of HA sizes (19, 29, 33), and both receptors are implicated in BCa progression (19–21, 23, 29, 30, 33–36). Elevated CD44 expression in the peritumor stroma is associated with increased relapse (37), and in primary BCa cell subsets may contribute to tumor initiation and progression (38–40). Elevated RHAMM expression in BCa tumor subsets is a prognostic indicator of poor outcome and increased metastasis (22, 33, 41). RHAMM polymorphisms may also be a factor in BCa susceptibility (42, 43).We postulated that multivalent interactions resulting from mixture of a polydisperse population of fluorescent HA (F-HA) sizes, typical of those found in remodeling microenvironments of wounds and tumors (19, 20, 29), with cellular HA receptors would uncover a heterogeneous binding pattern useful for sorting tumor cells into distinct subsets. We interrogated the binding of F-HA to BCa lines of different molecular subtypes, and related binding/uptake patterns to CD44 and RHAMM display, and to tumor cell growth, invasion, and metastasis.     

Off-pump coronary artery bypass surgery in selected patients is superior to the conventional approach for patients with severely depressed left ventricular function

OBJECTIVES:

Patients with coronary artery disease and left ventricular dysfunction have high mortality when kept in clinical treatment. Coronary artery bypass grafting can improve survival and the quality of life. Recently, revascularization without cardiopulmonary bypass has been presented as a viable alternative. The aim of this study is to compare patients with left ventricular ejection fractions of less than 20% who underwent coronary artery bypass graft with or without cardiopulmonary bypass.

METHODS:

From January 2001 to December 2005, 217 nonrandomized, consecutive, and nonselected patients with an ejection fraction less than or equal to 20% underwent coronary artery bypass graft surgery with (112) or without (off-pump) (105) the use of cardiopulmonary bypass. We studied demographic, operative, and postoperative data.

RESULTS:

There were no demographic differences between groups. The outcome variables showed similar graft numbers in both groups. Mortality was 12.5% in the cardiopulmonary bypass group and 3.8% in the off-pump group. Postoperative complications were statistically different (cardiopulmonary bypass versus off-pump): total length of hospital stay (days)—11.3 vs. 7.2, length of ICU stay (days)—3.7 vs. 2.1, pulmonary complications—10.7% vs. 2.8%, intubation time (hours)—22 vs. 10, postoperative bleeding (mL)—654 vs. 440, acute renal failure—8.9% vs. 1.9% and left-ventricle ejection fraction before discharge—22% vs. 29%.

CONCLUSION:

Coronary artery bypass grafting without cardiopulmonary bypass in selected patients with severe left ventricular dysfunction is valid and safe and promotes less mortality and morbidity compared with conventional operations.     

Reaching a Balance Between Privacy,Privilege and Planning: A Look at Barriers to Obtaining Information for Patients with Criminal Involvement

Persons with serious and persistent mental disorders present unique problems for the criminal justice system. The challenges are tremendous as courts venture into problem solving models, attempting to integrate mental health services with the criminal justice system. Gathering and accessing confidential information is often difficult. This article will identify and explore the legal issues related to obtaining such information.