大环骨架结构的倍半萜化合物——Ⅵ.马兜铃新内酯的化学结构测定

自绵毛马兜铃(Aristolochia mollissima Hance)根茎中分得九个化合物,其中已报道的七个化合物是尿囊素、马兜铃内酯、绵毛马兜铃内酯、β-谷甾醇、马兜铃酸A、9-乙氧基马兜铃内酯和9-乙氧基马兜铃内酰胺,本文报道结晶K_3的化学结构,经光谱分析(IR,~1H-NMR,~(13)C-NMR,2D-NMR和MS),化学反应及X-衍射晶体分析,确证K_3为一个新骨架结构的倍半萜化合物,命名为马兜铃新内酯。     

Breast Cancer Worry among Women Awaiting Mammography: Is It Unfounded? Does Prior Counseling Help?

The purpose of this study was to explore the prevalence of breast cancer anxiety and risk counseling in women undergoing mammography, and the association with known risk factors for cancer. Women awaiting mammography were surveyed regarding anxiety, prior breast cancer risk counseling, demographic and risk factors. Anxiety was assessed via 7-point Likert-type scale (LS). Risk was defined by Gail model or prior breast cancer. Data were analyzed by nonparametric methods; significance determined at alpha = 0.05. Of 227 women surveyed, 54 were classified “higher risk”. Counseling prevalence was similar (52%) for all ethnic groups, but higher (72%, P<0.001) for “higher risk” women. On average, women awaiting screening/diagnostic mammography were somewhat worried (median LS = 4). Worry was significantly higher (P<0.05) in “higher risk” women (LS = 5), and in women living outside Honolulu (LS = 6). Counseling by primary care physicians (PCP) did not correlate with lower worry scores. It was concluded that most women awaiting mammography are not unduly anxious. Additionally, the findings showed a correlation between a woman''s concern about developing cancer with known risk factors and rural residence.     

Diagnosis of left ventricular systolic dysfunction (LVSD): development and validation of a clinical prediction rule in primary care

BACKGROUND: Diagnosing suspected left ventricular systolic dysfunction (LVSD) in the community is a challenge for GPs. We developed and validated a clinical prediction rule (CPR) for LVSD based on history, examination and electrocardiogram (ECG). METHODS: Prospective cohort studies of 458 symptomatic patients (derivation cohort) and 535 patients (validation cohort) in 26 general practices in Tayside and Fife, Scotland. All patients underwent a structured clinical examination and ECG and the 'reference standard' investigation of echocardiography to establish the presence of LVSD. RESULTS: Four elements from the clinical history and examination were all independently associated with LVSD--male sex [adjusted odds ratio (OR) 2.5; 95% CI 1.1, 5.0], presence of orthopnoea (OR 5.4; 1.9, 13.8) history of myocardial infarction (OR 5.6; 2.3, 13.6) and elevated jugular venous pulsations (OR 15.1; 4.6, 49.3). Addition of ECG (OR 20.6; 2.7, 158.6) provides important diagnostic information in terms of probability of LVSD. A CPR based on the presence or absence of these five elements will generate probabilities ranging from 1% to 97% for LVSD when applied to an individual patient. In the validation cohort, the model under-predicted the probability of LVSD, particularly at lower levels of expected risk, reflecting differences in the risk-factor profiles of the derivation and validation cohorts. CONCLUSIONS: The derived CPR provides quantitative estimates of post-test probability for LVSD. This rule requires further validation in other populations and settings because of the difficulties encountered in the validation cohort.     

WAY-318068: a novel, potent and selective noradrenaline re-uptake inhibitor with activity in rodent models of pain and depression

Background and purpose:

Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity.

Experimental approach:

In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (1-[(1S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one).

Key results:

WAY-318068 is a potent and effective inhibitor of the NET with a K_i of 8.7 nM in a binding assay, and an IC₅₀ of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits.

Conclusions and implications:

Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.     

Critical evaluation of lymphocyte functions in urological cancer patients.

One hundred three patients with varying stages of urological cancer (bladder, prostate, kidney) were investigated with regard to the following lymphocyte functions. T-cells were assessed numerically (E rosettes), their blastogenic response to phytohemagglutinin (pHA) was determined, and their cytotoxic potential against heterologous target cells in short-term presence of PHA (e.i., PHA-dependent cellular cytotoxocity) was evaluated. Similarly, B cells were numerically assessed (EA rosettes), and their function was evaluated by antibody-dependent cellular cytotoxicity against antibody-coated deterologous target cells. The data on cancer patients, divided on the basis of extent of disease and prior radiation therapy, were compared to those of normal young and age-matched controls. Our investigations emphasize the importance of the following factors: (a) comparison of data with age-matched controls, since several lymphocyte functions appear to change with age; (b) use of multiple controls to compensate for the inherent variability found in certain tests; (c) minimized contamination by nonlymphoid cells in the purified cell preparation; and (d) the influence of certain treatment regimens (radiation, chemotherapy, etc.) on the results. Radiotherapy significantly depressed T-cell number with a depression of PHA blastogenic responses as well as PHA-dependent cellular cytotoxicity. When all of these conditions were taken into account, the urological cancer patients as a group were found to have a lower proportional value of E rosettes (T-cells) and a reduced PHA blastogenic responsiveness. Certain cancer patients displayed an elevated PHA-dependent cellular cytotoxicity as compared to age-matched controls, which may indicate the presence of activated cells in the presence of tumors. With this identification of a group of cancer patients with markedly depressed E rosette values and PHA responsiveness, it will now be possible to follow them clinically in comparison with a group of cancer patients with normal T-cell functions.     

Fermentability of various fiber sources by human fecal bacteria in vitro.

Certain beneficial effects of fiber in the human diet may be mediated by short-chain fatty acids (SCFAs) produced during anaerobic fermentation in the colon. Two studies, both involving in vitro incubations with human fecal bacteria as inoculum, were conducted to assess fermentation of various fiber sources and to quantitate the SCFAs produced. In experiment 1, substrate fermentability based on total SCFA production ranked as follows: citrus pectin greater than soy fiber greater than sugarbeet fiber greater than pea fiber greater than oat fiber. Fermentation of soy fiber led to higher proportions of propionate and butyrate than did fermentation of other substrates. In experiment 2, fermentation of gum arabic, a mixture of arabic and guar, and apple pectin resulted in greater SCFA production than did fermentation of either oat fiber or corn bran. Fermentation of gums led to more propionate and butyrate production than did that of apple pectin. It may be possible to select fiber sources capable of supporting stipulated amounts of both total and individual SCFA production in the human colon.     

Physicochemical and immunological characterization of recombinant host-protective antigen (VP2) of infectious bursal disease virus.

Small fusions to the N-terminal end of the host-protective antigen (VP2) of infectious bursal disease virus lead to stable expression of VP2 in Escherichia coli and yeast, and reduce the levels of inclusion body formation in E. coli in comparison to VP2 constructs with larger N-terminal fusions. VP2 produced with small N-terminal fusions, like native viral VP2, can be fractionated into a high molecular weight 'multimeric' form and a monomeric form. A virus-neutralizing monoclonal antibody that only recognizes undenatured VP2 preferentially reacts with multimeric forms of recombinant VP2. Both native and recombinant monomeric forms of VP2 are non-immunogenic. The multimeric forms of viral and yeast-derived VP2 are highly immunogenic, while those produced in E. coli are not.     

Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats

Weanling male F344 rats were fed either a semi-purified diet low in methionine and lacking in choline and folic acid (folate/methyl deficient) or a supplemented control diet for periods of 2, 5, 7 days, 3 weeks, and 9 weeks. Two days after initiating the folate/methyl deficient diet in weanling F344 rats, the incidence of apoptotic bodies, identified by in situ end-labeling of 3'-OH DNA strand breaks, was significantly increased in liver sections from the deficient rats. Apoptotic cell death was confirmed biochemically by an increase in nuclear Ca2+/Mg2+-dependent endonuclease activity that paralleled the increase in apoptotic bodies over the 9-week feeding period. There was no morphologic evidence of necrotic foci or necrosis-associated inflammatory response over the 9-week period. Confirming that cell turnover is chronically elevated in this model, the increase in apoptotic rate was accompanied by a sustained increase in the mitotic index (MI). The DNA repair-associated enzyme, poly(ADPribose) polymerase (PARP), was similarly elevated and was associated with significant decreases in the substrate for ADPribose polymer synthesis, nicotinamide adenine dinucleotide (NAD). Because folate metabolites are essential for de novo purine and thymidine biosynthesis, prolonged deficiency in folic acid can induce an imbalance in the deoxynucleotide precursors for DNA replication/repair and negatively affect the fidelity of DNA synthesis. Using an HPLC method, hepatic deoxyuridine triphosphate (dUTP) levels were increased at 3 and 9 weeks after initiation of the deficient diet and levels of thymidine triphosphate (dTTP) were reduced. An increase in dUTP/ dTTP ratio is consistent with a block in folate-dependent de novo thymidylate biosynthesis and may predispose to uracil misincorporation and DNA repair-related DNA strand breaks.      

Depression in caregivers of demented patients is associated with altered immunity: impaired proliferative capacity, increased CD8+, and a decline in lymphocytes with surface signal transduction molecules (CD38+) and a cytotoxicity marker (CD56+ CD8+).

Changes in relevant immune parameters, including function, were found to be associated with depression in elderly caregiver wives of demented patients. We studied the relationship between immune cell phenotype and T cell proliferative capacity of such caregivers to levels of stress and depression over the course of a support group intervention. The data indicate the strongest association between depression (of all stress parameters) and impaired T cell proliferative capacity. Depression was also most strongly (of stress parameters) associated with a shift in T cell populations with an increase in CD8+ T cells, and a reduced percentage of CD38+ cells in both CD8+ and CD4+ T cell populations. Since CD38 is a signal transduction factor, it was interesting that a decreased percentage of CD38+ cells correlated with impaired T cell function (proliferation). Another significant difference was the reduction in natural killer (NK) cells as well as the percentage of the CD56+ component of the CD8+ population. This latter subset is important in MHC-unrestricted cytotoxicity, and has been found expanded in healthy centenarians. This study shows that both chronic stress, and depression in particular, and age have deleterious effects on T cells, and together could significantly contribute to the higher risk of disease and mortality associated with being a caregiver of a demented individual.