Are women worrying about heart disease?

Women at risk for coronary artery disease (CAD) may not be worried about the disease. In this study, demographic, CAD-risk, and CAD-worry data collected from Durham Veterans' Affairs Medical Center women veterans were examined using bivariate and multivariate analysis with worry as the outcome. Excluding CAD patients (N = 64) and incomplete data (N = 17) of 328 women, 42% worried about CAD. Younger age, single marital status, obesity, family history, and hyperlipidemia were associated with worry. Of women with up to three risk factors, fewer than half worried about CAD. Higher-risk women were unconcerned about CAD. This could undermine prevention efforts.     

Cutaneous photoprotection using a hydroxyl radical scavenger in photodynamic therapy

Photodynamic therapy (PDT) is emerging as an effective therapy for a variety of malignant diseases, including head and neck cancer. Prolonged cutaneous photosensitivity following therapy, however, remains the most significant side effect. The biochemical mechanism of this sensitivity, and indeed of the tumoricidal effect of PDT, is uncertain, but is believed to involve formation of singlet oxygen and possibly other oxygen-derived free radicals. This laboratory recently reported that a singlet oxygen scavenger, diphenylisobenzofuran (DPIBF), afforded cutaneous photoprotection to 67% of animals treated with PDT. Those results, the first from an in vivo study, supported the idea that singlet oxygen plays a significant role in PDT and its associated toxicity. They also, however, suggested that it is not the sole intermediate. The current study looks at the photoprotective effects of the hydroxyl radical scavenger dimethyl thiourea, alone and in conjunction with DPIBF. Our results strongly support a role for the hydroxyl radical in producing the cutaneous phototoxicity associated with PDT.     

国产阿克拉霉素A的体内外抗肿瘤作用

国产阿克拉霉素A(aclacinomycin;ACM-A)能明显抑制体外培养小鼠白血病P₃₈₈和人体胃癌SGC-7901细胞的生长。在0.01 μg/ml浓度时能抑制65.4%的克隆形成,ED₅₀为0.0085μg/ml。ACM-A对白血病小鼠有显著治疗作用,延长小鼠生命时间143%,并有半数小鼠获得治疗。对Ehrlich腹水癌和肉瘤-180也有较强的抑制作用,对肉瘤-180的作用与adriamycin相似。ACM-A主要抑制³H-TDR和。H-UR分别参人人体胃癌细胞的DNA和RNA;大剂量时对蛋白质合成也有影响。P₃₈₈细胞实验中证明ACM-A对DNA合成的抑制程度与adriamycin相似,低于daunomycin。     

Highly potent indanamine serotonin uptake blockers as radiotracers for imaging serotonin uptake sites

Two highly potent indanamine serotonin (5-HT) uptake blockers, trans-3′-(4′-bromophenyl)-1-indanamine (trans-[¹¹C]DBPI or [¹¹C]Lu 19-056) and its iodo analog, trans-3′(4′-[¹²⁵I]iodophenyl)-1-indanamine (trans-[¹²⁵I]DIPI) were evaluated as radiotracers for imaging 5-HT uptake sites in vivo. Trans-[¹¹C]DBPI was synthesized by N-methylation of the normethyl precursor with [¹¹C]iodomethane. Trans-[¹²⁵I]DIPI was synthesized by iododestannylation of the tributyltin precursor with [¹²⁵I]NaI. Radiochemical yields for the [¹¹C] and [¹²⁵I] radiotracers were 34 and 40%, with specific activities of 4000 and 1800 mCi/μmol, respectively. In vitro, the iodo analog, trans-DIPI, showed an IC₅₀ value of 0.26 nM in inhibition of [³H]paroxetine binding to 5-HT uptake sites in rat cortex. The potency was found to be equivalent to that of paroxetine or McN5652. In vivo, after i.v. injection into mice, both radiotracers showed high uptake in brain (3–4% dose/whole brain at 15 min) and high accumulation into target tissues such as hypothalamus and olfactory tubercles (7–8% dose/g at 60 min). The binding was blocked by pre-injection of 5 mg/kg of paroxetine. While the in vivo distribution agreed with previously reported 5-HT uptake site distribution, the radiotracers showed high uptake in non-target tissues such as cerebellum, resulting in low target-to-non-target ratios (1.5–1.6 at 60 min). Since washout from non-target regions was slower than from target regions, longer-time observation with ¹²⁵I up to 6 h did not improve the ratios. HPLC analyses of mouse brain homogenates and blocking studies indicated that the high uptake in non-target regions is not the result of metabolism or any interaction of the radiotracers with those tissues via specific binding sites. In spite of low target-to-non-target ratios, target regions with high density of 5-HT uptake sites, such as the raphe nuclei, superior colliculi and substantia nigra, were visualized with trans-[¹²⁵I]DIPI by ex vivo autoradiography, since the radiotracer showed high specific binding (total minus nonspecific binding).     

咯利普兰逆转豚鼠离体气管对沙丁胺醇的耐受性

本研究目的旨在观察PDEIV抑制剂咯利普兰对沙丁胺醇(SB)耐受性的影响。用豚鼠离体气管标本,预先接触SB1μmol·L^-1,1h可使SB对抗乙酰甲胆碱气管收缩作用的剂量反应曲线右移5倍,最大松弛率下降30%,形成SB气管松弛作用的耐受性。磷酸二酯酶(PDE)IV抑制剂咯利普兰能翻转SB气管松弛作用的耐受性,但PDEII抑制剂氰胍哒嗪则不能。虽然蛋白合成抑制剂环己酰亚胺对SB耐受性无预防作用,但上述结果仍提示SB气管松弛作用的耐受性可能与PDEIV活性的增高有关。     

The effects of ablation of visual cortex in neonatal rabbits on the organization of retinothalamic and retinopretectal projections

Primary visual cortex was ablated unilaterally in neonatal rabbits. Following a survival of 2-4 months, retrograde degeneration of the dorsal lateral geniculate nucleus (LGd) was assessed, and reorganization of retinofugal pathways was studied using methods of anretrograde transport of [3H]proline or of horseradish peroxidase. A complete lesion of primary visual cortex resulted in complete retrograde degeneration of the LGd with no sparing of any class of neurons. The terminations of retinofugal axons in the pretectum and thalamus were compared with those observed in normal animals. No major reorganization of ipsilateral retinofugal projections was observed in either the thalamus and pretectum ipsilateral to the ablated cortex, or in the thalamus and pretectum contralateral to the ablated cortex. However, contralateral retinofugal projections to the thalamus and to the pretectum ipsilateral to the ablated cortex were significantly different from normal. In the thalamus, the projections to the lateral posterior nucleus were expanded in area and increased in density. In the pretectum, the projections to the rostral pretectal areas were greatly increased in area, especially in the region of the olivary pretectal nucleus and posterior pretectal nucleus. However, the density of these projections was not increased relative to normal. Consideration of these results in relation to other published data on the anatomical consequences of neonatal visual cortex lesions, both in mammals which show behavioral sparing following neonatal visual cortex lesions and in mammals which, like the rabbit, show no behavioral sparing, suggests that: (1) behavioral sparing may correlate with patterns of survival or death of neurons in the thalamus and retina; and (2) reorganization of retinofugal pathways is not necessarily associated with behavioral sparing.     

Alpha interferon for hepatitis C virus infection in haemophilic patients

We have conducted a controlled trial in 20 haemophilic patients in which intravenous recombinant interferon alpha-2a, 3 mega units thrice weekly, was used to treat chronic hepatitis C infection. The study endpoints included complete and paritial normalization of serum ALT, and loss of serum HCV RNA as determined by polymerase chain reaction (PCR). Interferon treatment was effective, and resulted in improvement in ALT in nine (45%) and a loss of HCV RNA in five patients (26%), but a sustained normalization of ALT has been seen in only one case. Responses were poor in those with HIV coinfection or with HCV genotype 1 (Simmonds classification). Troublesome side-effects were reported in 80%. The occurrence of a factor VIIIc inhibitor during the study was possibly an autoimmune complication of interferon. In conclusion, we have shown lower response rates than those seen in post-transfusion hepatitis C infection and suspect that current interferon regimes are unlikely to influence the natural history of HCV infection in haemophilia. Consideration should be given to trials of higher dosage interferon, and of long-term maintenance therapy for those who relapse.     

CYCLOSPORINE A IMMUNOSUPPRESSION IN SHEEP WITH RESPONSE ENHANCEMENT BY CONCOMITANT KETOCONAZOLE

1. The pharmacokinetics of a single dose of Cyclosporine A (CsA) administered to sheep by intravenous (i.v.) route were examined. 2. Concomitant administration of ketoconazole was found to increase the area under the blood CsA concentration-time curve (AUC) and was effective when adminstered by the oral or intraperitoneal route. 3. The effects of CsA and ketoconazole on the immune system of sheep were also assessed. 4. A single dose of CsA 5mg/kg resulted in abrogation of in vitro lymphocyte function manifest at 24h after injection of CsA. Normal responsiveness recovered in 48-72h. Numbers of T lymphocytes in peripheral blood were elevated transiently at 48h although no other significant alteration in lymphocyte subsets was observed with this treatment. 5. Concomitant ketoconazole administration enhanced the CsA-induced suppression of in vitro lymphocyte responses. Blood levels of CsA (AUC values to 24h) were significantly elevated with concomitant ketoconazole administration and depression of lymphocyte responses to mitogens were also significantly enhanced. An increase in the proportion of T4 positive cells in the blood was observed at 48h and at 7 days after administration of CsA with ketoconazole. 6. These findings indicate that CsA effectively abrogates immunocompetence in the sheep and this immunosuppressive effect is enhanced by concomitant administration of ketoconazole.     

Regional mu-opioid receptor binding in insular cortex is decreased in bulimia nervosa and correlates inversely with fasting behavior.

The endogenous opioid system of the brain has been implicated in feeding behavior. Abnormal repeated activation of this system may constitute a neural substrate for the compulsive eating behavior observed in bulimia nervosa. This study examined the binding potential of the brain mu-opioid receptor (mu-OR) in bulimia nervosa. METHODS: Eight women with bulimia nervosa and 8 female controls underwent brain MRI followed by (11)C-carfentanil PET. Voxel-based methods were used to assess group differences in mu-OR binding between controls and bulimic subjects and to correlate mu-OR binding with the frequency of recent self-reported abnormal eating behaviors in bulimic subjects. RESULTS: mu-OR binding in the left insular cortex was less in bulimic subjects than in controls and correlated negatively with recent fasting behavior. CONCLUSION: Changes in mu-OR binding in the insula may be important in the pathogenesis or maintenance of the self-perpetuating behavioral cycle of bulimic subjects because the insula is the primary gustatory cortex and has repeatedly been implicated in the processing of the reward value of food.