Neurogenic plasma leakage in mouse airways

1. This study sought to determine whether neurogenic inflammation occurs in the airways by examining the effects of capsaicin or substance P on microvascular plasma leakage in the trachea and lungs of male pathogen-free C57BL/6 mice. 2. Single bolus intravenous injections of capsaicin (0.5 and 1 micromol kg(-1), i.v.) or substance P (1, 10 and 37 nmol kg(-10, i.v.) failed to induce significant leakage in the trachea, assessed as extravasation of Evans blue dye, but did induce leakage in the urinary bladder and skin. 3. Pretreatment with captopril (2.5 mg kg(-1), i.v.), a selective inhibitor of angiotensin converting enzyme (ACE), either alone or in combination with phosphoramidon (2.5 mg kg(-1), i.v.), a selective inhibitor of neutral endopeptidase (NEP), increased baseline leakage of Evans blue in the absence of any exogenous inflammatory mediator. The increase was reversed by the bradykinin B2 receptor antagonist Hoe 140 (0.1 mg kg(-1), i.v.). 4. After pretreatment with phosphoramidon and captopril, capsaicin increased the Evans blue leakage above the baseline in the trachea, but not in the lung. This increase was reversed by the tachykinin (NK1) receptor antagonist SR 140333 (0.7 mg kg(-1), i.v.), but not by the NK2 receptor antagonist SR 48968 (1 mg kg(-1), i.v.). 5. Experiments using Monastral blue pigment as a tracer localized the leakage to postcapillary venules in the trachea and intrapulmonary bronchi, although the labelled vessels were less numerous in mice than in comparably treated rats. Blood vessels of the pulmonary circulation were not labelled. 6. We conclude that neurogenic inflammation can occur in airways of pathogen-free mice, but only after the inhibition of enzymes that normally degrade inflammatory peptides. Neurogenic inflammation does not involve the pulmonary microvasculature.     

Effect of A-ring modifications on the DNA-binding behavior and cytotoxicity of pyrrolo[2,1-c][1,4]benzodiazepines.

Several A-ring-modified analogues of the DNA-binding antitumor agent DC-81 (5) have been synthesized in order to study structure-reactivity/cytotoxicity relationships. For two molecules (23 and 30) the modifications required the addition of a fourth ring to give the novel dioxolo[4,5-h]- and dioxano[5,6-h]pyrrolo[2,1-c][1, 4]benzodiazepin-11-one (PBD) ring systems, respectively. Another three analogues (34, 38, and 48) have the native benzenoid A-ring replaced with pyridine, diazine, or pyrimidine rings to give the novel pyrrolo[2,1-c][1,4]pyridodiazepine, pyrrolo[2,1-c][1, 4]diazinodiazepine, and pyrrolo[2,1-c][1,4]pyrimidinodiazepine systems, respectively. The other new analogues (16a,b) have extended chains at the C8-position of the DC-81 structure. During the synthesis of these compounds, a novel tin-mediated regiospecific cleavage reaction of the dioxole intermediate 18 was discovered, leading to the previously unknown iso-DC-81 (20). In addition, an unusual simultaneous nitration-oxidation reaction of 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (8) was found to produce 3-(4-carboxy-2-methoxy-5-nitrophenoxy)propanoic acid (9), a key intermediate, in high yield. In general, the results of cytotoxicity and DNA-binding studies indicated that none of the changes made to the A-ring of the PBD system significantly improved either binding affinity or cytotoxicity in comparison to DC-81. This result suggests that the superior potency of natural products such as anthramycin (1), tomaymycin (2), and sibiromycin (3) is due entirely to differences in C-ring structure, and in particular exo or endo unsaturation at the C2-position and C2-substituents containing unsaturation. This study also provided information regarding the influence of A-ring substitution pattern on the relative stability of the interconvertible N10-C11 carbinolamine, carbinolamine methyl ether, and imine forms of PBDs.     

Should accident and emergency nurses request radiographs? Results of a multicentre evaluation.

OBJECTIVE--To evaluate whether waiting time in accident and emergency (A&E) departments is shortened when experienced nurses request peripheral limb radiographs before a patient is assessed by a doctor. DESIGN--Simultaneous prospective trial in four A&E departments in the United Kingdom with doctors and nurses requesting radiographs; 2000 patients were randomly allocated to either a "Nurse First" or "Doctor First" category. SUBJECTS--Patients older than 5 years presenting with recent peripheral limb injuries. MAIN OUTCOME MEASURES--Timing of the various stages of a patient's passage through the A&E department comparing the orthodox route with a group of patients in whom an experienced A&E nurse had the option of requesting a radiograph before a medical assessment. RESULTS--There was a significant reduction in the time spent in A&E when no radiograph was requested (P << 0.001). The mean time saved in the "Doctor First" (DF) group was 51 min, and in the "Nurse First" (NF) group 36 min. For those who were sent for an x ray 14 min was saved by getting the patient to see the nurse first. However, because the overall referral rate for x rays was greater in the NF group, (78% of patients compared with 74% of the DF group, a significant 4% increase (P = 0.05) this potential benefit was largely lost. Overall the average waiting time in the DF group of 92.5 min (95% confidence interval: 89.2 to 96.1 min) was reduced to 88.5 min (95% CI:85.2 to 91.8 min) in the NF group, a non-significant saving of 4 min. There was no overall difference between the proportion of relevant abnormalities reported by the radiologists for the DF or NF groups (G2 = 0.739, 1df, P = 0.30); however, there was a significant association between the number of relevant abnormalities reported by the radiologists and the different hospitals (G2 = 9.7626, 3df, P = 0.02). Hospital C had the highest abnormality rate reported by the radiologists in both the DF (45%) and the NF (51%) groups. The most time saved in A&E was in the DF category when comparing those who did not have an x ray [58 (CI 54-63) min] with those who did [109 (CI 104-114) min], a saving of 51 min. The corresponding time saved in the NF category between those who did not have an x ray [59 (CI 53-65) min] and those who did [95 (CI 91-99) min] was 36 min. CONCLUSIONS--14 min can be saved by getting the patient to see the nurse first; however, because nurses in three out of four hospitals requested more radiological examinations than doctors, overall only 4 min waiting time was saved when peripheral limb radiographs were requested by nurses. The findings are somewhat against expectations but do identify that specific training and constant monitoring is essential if nurses are to request peripheral limb radiographs, as reflected in hospital C results.     

Studies on the stability of trimelamol, a carbinolamine-containing antitumor drug

The stability of trimelamol (N2,N4,N6-trimethylol-N2,N4,N6-trimethylmelamine) a synthetic carbinolamine-containing antitumor drug, has been studied. Two major degradation pathways have been characterized and a unified mechanism proposed to rationalize the chemistry involved. One degradation pathway involves the consecutive loss of hydroxymethylene units by elimination of formaldehyde until the parent trimethylmelamine (4) results. An HPLC method was used to obtain kinetic data for the loss of trimelamol and to monitor the order of appearance of three degradation products. This pathway was shown to follow first-order kinetics at all pH values studied at both 18 and 37 degrees C. The second pathway involves the coupling of two trimelamol molecules via a methylene bridge to form bis(trimelamol) (6) which had been previously referred to in the literature as a "polymer". This reaction is acid catalyzed and temperature dependent. Bis(trimelamol) is virtually water insoluble and adheres strongly to glass surfaces. Finally, t1/2 values have been determined for trimelamol in aqueous solution at different temperatures, and the kinetics of formation of degradation products has been studied over a period of 30 h under a variety of conditions of pH and temperature. The data reported here are relevant to both the formulation and clinical administration of trimelamol, and may contribute to an understanding of mechanism of action and future analogue development studies.     

Pulmonary embolism in surgical patients: 1959-79

The Edinburgh surgical statistics (audit) have been analysed for the years 1959, 1964, 1969, 1974, and 1979 to determine the trends in pulmonary embolism in surgical patients who died. There was a total of 61,038 operations, 1528 postoperative deaths, 804 necropsies, and 158 reported pulmonary emboli. The incidence of embolism diagnosed clinically and at necropsy fell throughout the period. This fall held good after corrections for necropsy rates, prognosis, and proportions of major operations. Although the overall necropsy rate fell from 58% to 40%, in patients expected to have a good prognosis the rate rose from 68% to 75%. Necropsy-proved embolism in "good prognosis" patients fell from 0.5% to 0.15% per 100 major operations. The main reduction has taken place since most surgeons in the area adopted methods of prophylaxis against venous thrombosis, but a direct relationship is not proved by this study.     

Early stage nasopharyngeal carcinoma: radiotherapy dose and time factors in tumor control

OBJECTIVE: To evaluate radiotherapy dose and length of treatment in the control of early stage nasopharyngeal carcinoma (NPC) treated with a combination of external radiotherapy and brachytherapy, MATERIALS & METHODS: We reviewed the records of 133 patients with early stage nasopharyngeal carcinoma (stage I or II, AJC/UICC staging system) who received definitive radiotherapy in Chang Gung Memorial Hospital from 1979 to 1991. The median follow-up time was 7.1 years with a minimum of 2 years. All patients were treated with megavoltage external radiotherapy to the nasopharynx area (63-72 Gy) followed by high dose rate intracavitary brachytherapy (5-16.5 Gy in one to three fractions, spaced 1-2 weeks apart). The median total dose and time of irradiation was 75 Gy (69.8-81.4 Gy) and 11.6 weeks (7.8-20 weeks) respectively. Survival analysis was used to examine the effect of several variables on prognosis. RESULTS: The 5-year rates were 86.4% for local control, 84.7% for disease free survival, 88.5% for actuarial survival and 84.2% for overall survival. The treatment group (combination of time and dose of irradiation) was the most important prognostic factor according to Cox's proportional hazard model. Patients receiving radiation at a total dose of < or = 75 Gy completed in < 12 weeks showed the best prognosis. CONCLUSION: Treatment time and total treatment dose are both important factors in treating early stage NPC. Decreasing the total radiation time to < 12 weeks and not exceeding a radiation dose of 75 Gy gave the best results.      

‘It’s not the government’s responsibility to get me out running 10 km four times a week’ - Norwegian men’s understandings of responsibility for health

The individualization of health has been extensively discussed in the last few decades. Empirical work, however, has mainly had its origins within neoliberal societies. Norway, as a social democratic welfare state based on universal social rights and egalitarianism is thus of interest in understanding how people’s talk reflects national policies. Through a series of 18 in-depth interviews with a heterogeneous group of middle-aged and elderly men in rural Norway, this paper explores lay men’s understandings of individuals’ responsibility for health vis-à-vis the state’s. The men in this study expressed complex but shared notions of the state’s and the individual’s responsibility for health. The individual’s main responsibility was to act in specific ways in order to maintain good health. However, little blame was placed on those who did not act in the expected way. The state’s main responsibilities were to facilitate the healthy lifestyle of individuals and act as a safety net for those in need. The state was also viewed as being responsible for providing universal health care free of charge, regardless of the reason for the need. We argue that the political and societal values of Norway are reflected in the men’s talk about responsibility for health, alongside neoliberal ideas found in other Western societies. Importantly, however, we conclude that a social democratic welfare state system supports and facilitates agency with regard to health, lifestyle and one’s life more broadly.