阴茎勃起神经再生模型和机制的研究

探明神经性勃起功能障碍(NED)的分子生物学机制以期对该类疾病进行神经调控干预,是男科学研究的当务之急。本文回顾了急性神经损伤、前列腺癌、糖尿病和帕金森病所致的NED的研究进展。通过利用大鼠阴茎勃起神经的盆腔大神经节(MPG),在体外构建一个三维培养体系来研究各种生长因子和细胞信号通路对神经再生的影响。体外结果表明脑源性神经生长因子(BDNF)通过JAK/STAT信号通路可显著促进NED的恢复,并在体内证实了该效应。因此,通过调控JAK/STAT信号通路来达到神经调控干预措施预防治疗神经性勃起功能障碍成为可能。     

Curcumin Reduces Burn Progression in Rats

Objectives Cutaneous burns are dynamic injuries with a central zone of necrosis surrounded by a zone of ischemia. Conversion of this ischemic zone to full necrosis over the days following injury is due in part to highly reactive oxygen radicals. Curcumin is a component of the Oriental spice turmeric that has been shown to have antioxidant and antiapoptotic properties. The authors hypothesized that treatment of burns with curcumin would reduce the conversion of the ischemic zone to full necrosis. Methods This was a randomized controlled experiment. Twenty Sprague‐Dawley rats were used. Two burns were created on each animal's dorsum using a brass comb with four rectangular prongs preheated in boiling water and applied for 30 seconds, resulting in four rectangular 10 × 20–mm full‐thickness burns separated by three 5 × 20–mm unburned interspaces (zone of ischemia). Animals were randomized to curcumin or vehicle by oral gavage 30 minutes before injury and at 24, 48, and 72 hours after injury. Wounds were observed at one, two, and three days after injury for visual evidence of necrosis in the unburned interspaces. Full‐thickness biopsy specimens from the interspaces were evaluated with hematoxylin and eosin staining seven days after injury for evidence of necrosis. The percentage of interspaces that progressed to necrosis was compared with chi‐square tests. Results Forty comb burns with 120 unburned interspaces were created, evenly distributed between curcumin and vehicle alone. The percentage of interspaces that progressed to full‐thickness necrosis at one, two, three, and seven days after injury in the curcumin and vehicle groups were 30% versus 63% (p = 0.003), 30% versus 70% (p < 0.001), 63% versus 95% (p = 0.02), and 63% versus 95% (p = 0.02), respectively. Conclusions Pretreatment of rats with oral curcumin followed by once‐daily oral treatment for three days reduced the percentage of unburned skin interspaces that progressed to full necrosis.     

Doctors as managers: investors and reluctants in a dual role.

Government reform of the NHS in the UK has sought to increase the involvement of doctors (clinicians) in hospital management. Using frameworks from the psychological contract and organisational misbehaviour literatures, this paper examines the processes involved when clinicians assume management roles. This literature seeks to explain breaches to expectations regarding prior agreements with management and subsequent actions of 'getting even' as a result of breaches to the employment relationship. A qualitative methodology using interviews was undertaken, which identified two distinct groups of clinician-manager. Investors actively pursued a management opportunity as an alternative to clinical medicine, whilst reluctants tended to assume a management role to protect particular specialities from outside influence or from those they thought would be inappropriate clinician-managers. Investors and reluctants often had very little prior experience of management and managers and had problems reconciling their dual clinician-management role. Poor relationships with hospital managers who often had no understanding of their dual responsibilities led to tensions and conflict, which questions continued developments in this important area of UK health policy. Suggestions for improving this process are outlined.     

Critical trust: understanding lay perceptions of health and safety risk regulation

The binary opposition of trusting or not trusting is inadequate to understand the often ambiguous and contradictory ideas people possess about risk regulators, particularly when knowledge and experience of such institutions is limited. The paper reports qualitative and quantitative data from a major study of public perceptions (n?=?30 focus groups) of UK risk regulators. We compare the complex and widely different ‘trust profiles’ of two regulatory organisations which are institutionally related (the Health and Safety Executive and the Railways Inspectorate) but very separate in the minds of our participants. The paper develops the notion of critical trust to interrogate the various ways in which people make sense of such organisations, as well as discussing the modes of reasoning that people deploy. The paper argues that views of participants are the outcome of a reconciliation of diverse perceptions concerning the role of the organisation, structural factors and the nature of the regulated risk.     

Oral administration of methylergometrine shows a late and unpredictable effect on the non-pregnant human menstruating uterus

Objective: To study the pharmacodynamic and pharmacokinetic properties of oral and intravenous methylergometrine upon uterine motility during menstruation. Study-design: Intra-uterine pressure was measured in six volunteers with a fluid-filled sponge-tipped catheter during menstruation. Methylergometrine was given orally (0.5 mg) or intravenously (0.2 mg) in a cross-over design. Results: After intravenous administration, a fast increase of the frequency of uterine contractions and basal tone occurred with a decrease of amplitude, lasting at least 30 min. Oral administration had a late and less marked effect on uterine motility. An intravenous dose administered 24 h after an oral dose had no effect on uterine motility. Pharmacokinetic data, such as the maximum plasma concentration (C_max), the time at which C_max is reached (t_max) and the half-life of absorption (t_1/2abs) also demonstrated large individual variations after oral administration. Conclusion: Oral administration of methylergometrine had an unpredictable and late effect on uterine motility on the menstruating uterus, probably due to an unpredictable bioavailability, in contrast with the fast and predictable effect after intravenous administration.     

Influences on Food Selection of Women on High- and Low-Fat Diets

There is evidence that long-term maintenance of a low-fat diet reduces preference for high-fat foods. Sensory evaluation of the taste of fat, and preference for high and low-fat foods were studied in a group of former participants in a randomized dietary intervention trial aimed at lowering fat consumption. Intervention subjects consuming less than 25% of daily calories as fat and control subjects consuming more than 35% of daily calories as fat agreed to be in a "taste perception" study. In Study 1, subjects tasted 20 dairy solutions containing different levels of fat and sugar. Subjects rated the perceived intensity of fat taste, and of liking, for each of the solutions. In Study 2, subjects were asked to taste and rate 4 high-fat and 4 low-fat snack foods, and were then allowed to freely consume these foods in a preference test. Intervention and control subjects were similar in their sensory evaluation of the taste of fat in Study 1. In Study 2, intervention subjects reported a reduced hedonic rating of the taste of high-fat snack foods compared to control subjects, yet intervention subjects consumed the same amount of high-fat snack foods as control subjects. We conclude that a successful outcome in a dietary intervention may be due to social and cognitive factors, in addition to potential changes in hedonic response to fat.     

Synthesis and Evaluation of Azole-Substituted Tetrahydronaphthalenes as Inhibitors of P450 arom,P450 17, and P450 TxA2

In search of potential drugs for the treatment of estrogen- and androgen-dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH₃ substituent at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-triazol-1-yl substituent in 2-position were synthesized with and without C₁-spacer between the rings (compounds 2 – 26 ). The compounds were tested in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA₂ (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition of P450 18 (bovine adrenal mitochondria), P450 see (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vivo, selected compounds were examined in Sprague Dawley rats regarding P450 TxA₂ inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin-primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre- and postmenopausal model). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found: 7-OCH₃-2-(imidazol-4-ylmethylene)-1-tetralone ( 4 ) and 7-OCH₃-2-(imidazol-4-ylmethyl)-tetralin ( 12 ) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12 , the 6-OCH₃ derivative (compound 11 ) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA₂: 2-(imidazol-1-ylmethyl)-1-tetralone ( 13 ) is a selective inhibitor of P450 TxA₂, whereas 7-OCH₃-2-(imidazol-1-ylmethyl)-tetralin ( 17 ) as well as 2-(imidazol-1-ylmethyl)-tetralin ( 16 ) and 7-OCH₃-2-imidazol-1-yl-3,4-dihydronaphthalene ( 25 ) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests.