Antenatal differentiation of the human intervertebral disc

Summary To study the antenatal differentiation of the human intervertebral disc, the columns of forty eight embryos and fetuses were examined histologically. The primitive disc is composed of two structures: the notochord which shows a progressive expansion into the disc, and the fibrocartilaginous perinotochordal disc. No histological sign of interaction between notochordal and perinotochordal cells, which may explain the notochordal expansion into the discs, was seen. On the other hand, the notochordal intervention in the cartilaginous differentiation of the inner zone is probable.

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Différenciation anténatale du disque intervertébral humain

Résumé Cette étude de la différenciation anténatale du disque intervertébral humain repose sur l'examen de coupes histologiques de quarante huit colonnes vertébrales d'embryons et de foetus. Le disque primitif est composé de deux structures : la notochorde, qui présente une expansion progressive de son diamètre au sein du disque, et le disque périnotochordal, d'abord mésenchymateux puis fibrocartilagineux. Il n'a pas été mis en évidence de signe histologique témoignant d'une interaction entre les cellules notochordales et les cellules périnotochordales qui puisse expliquer l'expansion de la notochorde au sein des disques. Le rôle de la notochorde dans la différenciation cartilagineuse de la zone centrale est par contre probable.

     

Economic evaluation of pharmaceuticals: a European perspective

In recent years there has been a large increase in the number of economic evaluations of pharmaceuticals. Many of these studies have been commissioned by individual pharmaceutical companies, in support of new or existing products. In 2 countries, Australia and Canada (in the province of Ontario), draft guidelines issued by the government have outlined the requirements for economic evaluations to be submitted in support of requests for reimbursement (government subsidy) of particular products. One consequence of the guidelines is that they clarify what is required, and in specifying the procedure for submission of dossiers, identify a clear audience for the economic evaluation. In contrast, the situation in Europe is diverse. A wide range of healthcare systems exist, including national health services and more liberal systems, involving a wide range of insurers and providers. European countries also differ widely in their approach to the pricing and reimbursement of pharmaceuticals. Because of this diversity, the nature, conduct and impact of economic evaluation in Europe is not clear. It is therefore difficult for pharmaceutical companies to develop appropriate strategies for economic evaluation and for analysts to decide on appropriate study methodology. This article reviews the nature of any official guidance or requirements for economic evaluation, the potential for use of economic evaluation, the range of studies carried out and the identifiable impacts. There is currently no official guidance in any country, although some countries are considering issuing guidelines. In some countries there is official encouragement to pharmaceutical companies to undertake studies, and where economic data have been presented they have been considered by the relevant committees. The potential uses of economic evaluation vary widely from country to country. These can be classified in terms of a potential role in undertaking national price negotiations, deciding on reimbursement status or copayment level, deciding on inclusion in local formularies or in treatment guidelines, or in improving prescribing decisions. Approximately 80 economic evaluations of pharmaceutical products have been conducted to date in Europe, covering a wide range of clinical areas. There are relatively few examples of identifiable effects of such studies. In part this is because it is often difficult to assess the part played by various items of data. Nevertheless, the overriding conclusion is that economic evaluation of medicines is likely to be more relevant in Europe in the future. The problem for the pharmaceutical industry is in determining when and how.     

Indirect costs in economic studies: confronting the confusion

Indirect costs of disease often constitute a substantial part of estimated costs or savings in economic evaluations of healthcare programmes. The human capital approach is almost unanimously used for estimating indirect costs, defined as production loss due to disease, although a growing number of authors question its validity. This article discusses the relevance of indirect cost estimates for health policy and reviews the current empirical and methodological literature on this issue. It describes several important issues and controversies regarding indirect costs, such as the consequences of short term absence from work for productivity, reduced productivity without absence from work, the influence of unemployment on production loss, the relation between health effects and indirect costs, and the possible medium term macroeconomic consequences of absence from work and disability. It concludes that indirect costs are relevant for health policy, provided that the estimates of indirect costs reflect the real changes in production due to disease, including the production of unpaid labour. Future research should focus on attaining these estimates. Indirect costs in economic evaluations should preferably be presented separately from direct costs, health effects and other study outcomes.     

温血心停跳液与冷晶体心停跳液对狗心率变异性的影响

为探讨体外循环（ＣＰＢ）导致心脏植物神经系统（ＣＡＳ）损伤的机理,了解温血心停跳液能否防止ＣＰＢ后心率变异性（ＨＲＶ）的降低,采用对照方法观察了温血心停跳液与冷晶体心停跳液对狗ＨＲＶ的影响。结果显示：ＣＰＢ后温血心停跳液组（ＷＢ组）和冷晶体心停跳液组（ＣＣ组）的全频谱（ＴＰ）、低频（ＬＦ）和高频（ＨＦ）均较术前明显降低（Ｐ＜０．０５）,而且ＣＣ组比ＷＢ组降低更明显（Ｐ＜０．０５）,但ＬＦ／ＨＦ在组内及组间均无明显变化（Ｐ＞０．０５）。ＣＰＢ后２４小时平均心率（ＭＨＲ）明显增加（Ｐ＜０．０５）,且ＣＣ组高于ＷＢ组（Ｐ＜０．０５）。本研究表明：采用温血心停跳液或冷晶体心停跳液的ＣＰＢ不会干扰ＣＡＳ平衡,但均能使ＨＲＶ降低,温血心停跳液不能防止ＨＲＶ损害。     

The cost effectiveness of diclofenac plus misoprostol compared with diclofenac monotherapy in patients with rheumatoid arthritis

The objective of our study was to estimate the cost effectiveness of treatment with a fixed-dose combination of diclofenac and misoprostol compared with diclofenac monotherapy in the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers in rheumatoid arthritis (RA) patients. A model was used to incorporate estimates of costs, incidence of ulcers and their complications, death rates and the efficacy of misoprostol. The costs per ulcer-free period gained and costs per additional survivor were calculated. Cost effectiveness was calculated for the treatment of all RA patients, and of risk groups only. All costs were measured in 1995 Netherlands guilders (NLG; exchange rate at the time of the study: NLG1 = $US0.60). The analysis showed that if 100 RA patients receive 3 months of treatment with diclofenac plus misoprostol, instead of diclofenac alone, this will lead to overall additional costs of NLG773, while 0.82 symptomatic ulcers and 0.019 deaths will be prevented. If misoprostol is given only to patients at high risk for NSAID-induced ulcer, cost savings will occur instead of additional costs. Univariate sensitivity analysis showed that the outcomes are sensitive to changes in: (i) the percentage of ulcers treated in the ambulatory setting; (ii) the price difference between diclofenac and the fixed-dose diclofenac-misoprostol combination; (iii) the percentage of ulcers with complications; and (iv) the efficacy of misoprostol. In conclusion, it can be stated that treatment with diclofenac-misoprostol is cost saving in RA patients at high risk for NSAID-induced ulcers. For RA patients in general, the cost-effectiveness of this intervention compares favourably with that of other prophylactic treatments.     

Pharmacokinetic aspects of rectal formulations of Temazepam

An in vitro/in vivo study was carried out with different rectal formulations of temazepam. Pharmacokinetic data were determined in a cross-over study in 10 volunteers after rectal administration of 10 mg temazepam as a polyethylene glycol based suppository (selected from in vitro data), a liquid-filled capsule and a micro-enema respectively, using oral administration of a liquid-filled capsule as a reference. Serum levels of temazepam indicate an instantaneous and complete release from the micro-enema (F_rel=0.94±0.21, C_max 205±36.9 g/l, t_max 0.49±0.31 hour) and a slower but complete release of temazepam from the suppository (F_rel=1.01±0.25, C_max 202±41.3 g/l, t_max 1.48±0.41 hour). A high interindividual variation in absorption profiles was observed after rectal administration of the liquid-filled capsule (F_rel 0.72±0.36, C_max 182±122 g/l, t_max 4.08±4.28 hour), which makes it less suitable for rectal use. The micro-enema and suppository appear to be useful as rectal formulations for temazepam.     

Headache and family history

In two headache questionnaire surveys we inquired about the occurrence of headache in the mothers, fathers, siblings and children of the respondents. In total, 633 people completed valid questionnaires, 260 in the first survey and 373 in the second. The hypothesis was that familial headache occurrence would be positively associated with headache frequency. In each survey, the regression of headache frequency on the number of parents having headache was highly significant. Neither sex nor the sibling and children variables were significant predictors. In the cross-tabulations of the parental occurrence of headache with headache frequency we saw a clear "break-point" between the "no headache" and the headache frequency categories studied. For the final analyses the dichotomy "headache/no headache" was related in fourfold tables to headache occurrence in the father and the mother separately, and to the number of headache parents. The positive associations were not simply due to the large number of migraine cases since they remained after removing the migraineurs.     

Relative risk factors for osteoporotic fracture: A pilot study of the MEDOS questionnaire

Summary This study tested selected elements of a questionnaire devised to detect risk factors for osteoporosis in a large case-control study of hip fracture. The questions were applied to two separate studies. The first utilised a hospital sample of postmenopausal women with established vertebral osteoporosis, and responses were compared to woman with primary osteoarthritis. In a second study, the questionnaire was applied to apparently healthy women participating in a study of bone density. Significant differences between patients with osteoporosis and osteoarthritis were observed in body mass index, the prevalence of appendicular fractures, the degree of immobilisation, the age of menarche, exposure to sunlight and indices of physical activity. Significant differences were found in bone mass in healthy women divided according to the age of menarche, parity and duration of lactation. These data identify previously established risk factors for osteoporosis and suggest that the MEDOS questionnaire will provide a powerful tool for the future assessment of risk factors in osteoporosis. Collaborating centers: Dilen G., Istanbul; Gennari C., Siena; Lopez Vaz A.A., Porto; Lyritis G., Athens; Mazzuoli G.D., Rome; Miravet L., Paris; Passeri M., Parma; Perez Cano R., Sevilla; Rapado A., Madrid; Ribot C., Toulouse. Project group: Allander E., WHO Collaborating Centre for the Epidemiology of Rheumatic Conditions, Huddinge; Dequeker J., WHO Consultant, Leuven; Gonzalez A., Sandoz, Basle; Kanis J.A., European Osteoporosis Foundation, Sheffield; Keen D., Sandoz, Basle; Khaltaev N., WHO Non-communicable Diseases, Geneva; Plüss M., Sandoz, Basle.     

Involvement of deprivation and environmental lead in neural tube defects: a matched case-control study

OBJECTIVE: To analyse the prevalence of neural tube defects in small geographical areas and seek to explain any spatial variations with reference to environmental lead and deprivation. SETTING: The Fylde of Lancashire in the north west of England. DESIGN: Cases were ascertained as part of a prospective survey of major congenital malformations in babies born in the Fylde to residents there between 1957 and 1981. A matched case-control analysis used infants with cardiovascular system, alimentary tract, and urinary system malformations as controls. Conditional logistic regression was used to assess the effects of more than 10 micrograms/l lead in drinking water and the Townsend deprivation score. RESULTS: The prevalence of neural tube defects in 1957-73 was higher in Blackpool, Fleetwood, and North Fylde, whereas the three control groups showed no significant spatial variation. In 1957-81 mothers living in electoral wards with either a higher proportion of houses with more than 10 micrograms/l lead in the water or a higher deprivation score had a greater risk of having a baby with a neural tube defect. For spina bifida and cranium bifidum alone, this was also true. For anencephaly, deprivation was less important although the effect of lead was still seen. In some neural tube defects, lead may act independently of other possible factors associated with deprivation. It seemed unlikely that lead levels changed significantly during the survey. The percentage of houses with 10 micrograms/l or more of lead in the water in 1984-5 was similar to that found in Great Britain 10 years previously. CONCLUSION: There is evidence to suggest that lead is one cause of neural tube defects, especially anencephaly. This could link the known preventive actions of hard water and folic acid. Calcium is a toxicological antagonist of lead. One cause of a deficiency of folic acid is impaired absorption secondary to zinc deficiency, which may be produced or exacerbated by lead.