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Aim: Little is known about pyridoxine nutriture of children treated with isoniazid (INH) regimens. This study documents plasma pyridoxal 5′-phosphate (PLP) concentrations in children, HIV-infected and HIV-uninfected, receiving INH regimens. Methods: Children from the Western Cape of South Africa hospitalized for tuberculosis (TB) management were studied. Plasma PLP concentrations were determined on enrolment, 1-month after commencing TB treatment, and again after 4-month’s treatment. The children received a supplement meeting pyridoxine requirements. Results: Nineteen HIV-infected and 33 HIV-uninfected children received INH (dosage range 4–20 mg/kg) daily. Mean PLP plasma concentrations on enrolment were 8.32 (SD 6.75) ng/mL and 11.28 (SD 3.02) ng/mL in HIV-infected and HIV-uninfected children, respectively (p = 0.11) and after 4-month’s treatment 6.75 (SD 2.71) ng/mL and 14.76 (SD 7.96) ng/mL (p

Umbilical artery Doppler flow velocity waveform studies were performed over a period of 4 y on 242 women with severe pre-eclampsia before 34 wk gestation. Sixty-eight (28%) had absent end-diastolic umbilical artery Doppler flow velocities. One hundred and ninety-three infants survived to hospital discharge and were followed at 6-monthly intervals until 48 mo of age. The mean corrected developmental quotient was 94 +/- 8 at 24 mo of age and 87 +/- 9 at 48 mo. Ninety-two percent of the infants had a developmental quotient of >80 at 24 mo and 72% at 48 mo of age. This decline is thought to be due to the impact of social circumstances. There were no differences between the developmental quotients of the infants with normal and those with absent end-diastolic umbilical artery Doppler flow velocities at either 24 or 48 mo of age. At 24 mo of age, infants with absent end-diastolic umbilical artery Doppler flow velocities scored lower in the Performance subscale test (p = 0.03). The developmental quotients of infants from poorer socioeconomic backgrounds were significantly lower than those living in more privileged circumstances. At 48 mo, 153 (97%) of the children presented with normal gross motor development. Four infants had cerebral palsy. No differences were noted in the motor outcomes between the infants of women with normal umbilical artery waveforms and those with absent end-diastolic umbilical artery Doppler flow velocities.

This investigation retrospectively assessed inexpensive non-invasive qualitative methods to monitor the ingestion of anti-tuberculosis drugs isoniazid, rifampicin and rifapentine. Results showed that commercial test strips detected the isoniazid metabolites isonicotinic acid and isonicotinylglycine as efficiently as the isonicotinic acid method in 150 urine samples. The presence of rifamycins in urine samples (n=1085) was detected by microbiological assay techniques and the sensitivity compared to the n-butanol extraction colour test in 91 of these specimens. The proportions detected by the two methods were significantly different and the sensitivity of the n-butanol procedure was only 63.8% (95% CL 51.2-76.4%) as compared to that of the superior microbiological method. Final validation (n=691) showed that qualitative assays measure isoniazid and rifamycin ingestion with an efficiency similar to high-performance liquid chromatography. The qualitative procedures may therefore be valuable in clinical trials and in tuberculosis clinics to confirm drug ingestion.

Aims: To define the pharmacokinetics of isoniazid (INH) in children with tuberculosis in relation to the N-acetyltransferase 2 (NAT2) genotype. Methods: The first order elimination rate constant (k) and area under the concentration curve (AUC) were calculated in 64 children

The elimination of isoniazid is subject to the influence of the N-acetyltransferase 2 (NAT2) genotype, and individuals may be homozygotic slow, heterozygotic fast, or homozygotic fast acetylators of isoniazid. The early bactericidal activity (EBA) of an antituberculosis agent can be determined by quantitative culture of Mycobacterium tuberculosis in sputum samples obtained from patients with pulmonary tuberculosis during the first days of treatment. In these studies, the EBA of isoniazid during the first 2 days of treatment was determined for 97 patients with sputum smear-positive pulmonary tuberculosis following isoniazid doses of < or =37.5 mg, 75 mg, 150 mg, 300 mg, and 600 mg. The NAT2 genotype was determined in 70 patients, and the association between EBA and genotype was examined in this subgroup. Similarly, the relationship between EBA and isoniazid serum concentration was evaluated in 87 patients. The mean EBA of isoniazid increased with dose, but it levelled off between doses of 150 mg (mean EBA, 0.572) and 300 mg (mean EBA, 0.553). Significant differences were found in the mean EBA of isoniazid between the homozygous slow acetylator group and the heterozygous fast acetylator group and between the homozygous slow acetylator group and the homozygous fast acetylator group, but not between the heterozygous fast acetylator group and the homozygous fast acetylator group. The EBA appeared to reach a maximum at a 2-h isoniazid concentration of 2-3 microg/mL. These data confirm a significant effect of NAT2 genotype on the EBA of isoniazid over a range of doses.

Die vroee bakterisidiese aktiwiteit (VBA) van ’n antituberkulosemiddel is die daaglikse afname van M tuberculosis in log10 kolonievormende eenhede per ml sputum, tydens die eerste twee dae van behandeling met die middel. Dit weerspieel die vermoe van ’n middel om aktief metaboliserende organismes in tuberkulose-longholtes te dood. Dit is ’n relatief goedkoop metode om in ’n klein groep pasiente die antituberkulose-aktiwiteit van ’n middel, binne maande, in vivo te evalueer. Hierdie artikel som ons ondervinding op tydens sewe gepubliseerde VBA-studies, en die bronne van variasie in die prosedure word identifiseer. Die pasiente in hierdie studies was gemiddeld 33 jaar oud, met ’n gemiddelde gewig van 50 kg en 55% het ekstensiewe of massiewe longaantasting gehad. Die hoogste VBA-waardes (0,50-0,66) is gevind in pasiente wat isoniasied ontvang het, en die laagste waardes (0,05 en 0,09 respektiewelik) was gevind in pasiente wat die aminoglikosiede amikasien en paromomisien, albei in doserings van 15 mg/kg liggaamsgewig, ontvang het. Die algehele variasie in die VBA van 248 pasiente was 0,0312, en die variasie toegeskryf aan die proses van sputumproduksie en -versameling was 0,0223. Dit blyk dat die verskillende aspekte van sputumproduksie en -versameling, betrokke by die lewering van ’n verteenwoordigende sputummonster, ’n groter bydrae maak tot variasie tydens die prosedure as die laboratoriumaspekte van die tegniek. Die keuring van pasiente vir insluiting in VBA-studies, en hulle vermoe om saam te werk om ’n verteenwoordigende sputummonster te produseer, is van deurslaggewende belang in die suksesvolle voltooiing van VBA-studies.

Die vroeë bakterisidiese aktiwiteit (VBA) van ’n antituberkulosemiddel is die daaglikse afname van M tuberculosis in log10 kolonievormende eenhede per ml sputum, tydens die eerste twee dae van behandeling met die middel. Dit weerspieël die vermoë van ’n middel om aktief metaboliserende organismes in tuberkulose-longholtes te dood. Dit is ’n relatief goedkoop metode om in ’n klein groep pasiënte die antituberkulose-aktiwiteit van ’n middel, binne maande, in vivo te evalueer. Hierdie artikel som ons ondervinding op tydens sewe gepubliseerde VBA-studies, en die bronne van variasie in die prosedure word identifiseer. Die pasiënte in hierdie studies was gemiddeld 33 jaar oud, met ’n gemiddelde gewig van 50 kg en 55% het ekstensiewe of massiewe longaantasting gehad. Die hoogste VBA-waardes (0,50-0,66) is gevind in pasiënte wat isoniasied ontvang het, en die laagste waardes (0,05 en 0,09 respektiewelik) was gevind in pasiënte wat die aminoglikosiede amikasien en paromomisien, albei in doserings van 15 mg/kg liggaamsgewig, ontvang het. Die algehele variasie in die VBA van 248 pasiënte was 0,0312, en die variasie toegeskryf aan die proses van sputumproduksie en -versameling was 0,0223. Dit blyk dat die verskillende aspekte van sputumproduksie en -versameling, betrokke by die lewering van ’n verteenwoordigende sputummonster, ’n groter bydrae maak tot variasie tydens die prosedure as die laboratoriumaspekte van die tegniek. Die keuring van pasiënte vir insluiting in VBA-studies, en hulle vermoë om saam te werk om ’n verteenwoordigende sputummonster te produseer, is van deurslaggewende belang in die suksesvolle voltooiing van VBA-studies.Abstract A review of the determination of the early bactericidal activity of various antituberculosis agents The early bactericidal activity (EBA) of an antituberculosis agent is the daily decline in log10 colony forming units of M tuberculosis per ml of sputum during the first two days of treatment with the agent. It reflects the capacity of an agent to kill the actively metabolising organisms in tuberculosis lung cavities. It offers a relatively cheap means to evaluate the antituberculosis activity of an agent in a small group of patients within a matter of months. This article summarizes the authors’ experience in seven published EBA studies and identifies sources of variation in the procedure. The patients who participated in these studies had a mean age of 33 years, a mean weight of 50 kg and there was extensive or massive involvement of the lungs in 55% of patients. The highest EBA values (0,50-0,66) were found in groups of patients receiving isoniazid and the lowest values (0,05 and 0,09 respectively), in patients receiving the aminoglycosides amikacin and paromomycin in a dose of 15 mg/kg body weight. The variation in EBA in 248 patients was 0,0312 and the variation ascribable to the process of sputum production and collection was 0,0233. This implies that the different aspects of sputum production and collection involved in obtaining a representative sputum sample are responsible for most of the variation in EBA results. The selection of patients for inclusion in EBA studies and their ability to co-operate in producing a representative sputum specimen are of critical importance in the successful completion of EBA studies.

The use of cell cultures to test the biocompatibility of dental materials is gaining in importance. Any cytotoxic effects that restorative materials may have will be on the dental pulp and for that reason cultured pulp cells should be the model of choice for biocompatibility testing. The aim of this investigation was to study the growth and morphologic characteristics and toxic response of human pulp lines and to compare these parameters to those of human buccal mucosa fibroblasts. Twenty-one specimens of pulp tissue and six from buccal mucosa were cultured using standard techniques. Six pulp cell lines were cultured successfully as were all six from the buccal mucosa specimens. From these specimens, 12 growth curves were computed. To study the morphology of the cultured cells, they were observed microscopically and classified into three morphological types: slender elongated cells (type I), epithelioid shaped cells (type II) and large stellate cells (type III). Their numbers and proportions were determined for each cell line and compared statistically. To gauge sensitivity to toxic materials, cells were exposed to concentrations of arecoline. An analysis of the growth curves showed no statistical difference between pulp cells and buccal mucosa cells; the slopes of the curves, however, differed significantly between individual cell lines, and these individual differences were greater among pulp cell lines. The morphology of the pulp and mucosa fibroblasts was similar microscopically. There was no significant difference between the number and proportion of the cell types in the two groups, but there were significant differences between the individual cell lines. Pulp cells showed a greater inhibition of growth when exposed to arecoline. Because pulp fibroblasts are difficult to culture, their reported survival rate is poor; due to the differences that exist between individual cell lines, we conclude that pulp cells when used as single cell lines or even pooled may not be ideal for testing biocompatibility, especially if reproducibility is a prerequisite. Any evaluation will require tests on not one, but several cell lines in order to minimize the effect of inter-cell-line differences. Their greater sensitivity to toxic substances, on the other hand, may show that pulp cells could be more sensitive indicators of cytotoxicity.

The early bactericidal activity (EBA) of an antituberculosis agent is the rate of decrease in viable colony-forming units (CFU) per milliliter of sputum during the first 2 d of treatment of patients with previously untreated smear-positive pulmonary tuberculosis. The objective of this open randomized study was to evaluate the EBA of the combination of amoxicillin 3 g and clavulanic acid 750 mg. Ten patients with a mean age of 34 y and a mean weight of 56 kg received amoxicillin/clavulanic acid and 5 patients with a mean age of 34 y and a mean weight of 57 kg received no drug. In the patients receiving 1 dose of amoxicillin/clavulanic acid daily for 2 d the mean log10CFU/ml of sputum before treatment was 6.7402 (SD 0.539) and after 2 d of treatment 6.7046 (SD 0.609); the corresponding values in patients receiving no drug were 6.7823 (SD 0.563) and 6.7502 (SD 0.673), respectively. The EBA of 0.018 (SD 0.130) in patients receiving amoxicillin/clavulanic acid did not differ significantly from that of 0.016 (SD 0.069) in patients receiving no drug. It is unlikely that the combination of amoxicillin/clavulanic acid has an important place in the treatment of tuberculosis with the exception of those patients with multidrug-resistant tuberculosis who are otherwise therapeutically destitute.

SUMMARY Longitudinal data on an experimental subject arise when observations of a dependent variable are made at several successive values of an indexing variable x; often the indexing variable is time. When such data are recorded for a number of subjects, typically animal or human, the x-configuration may vary from subject to subject, producing irregular longitudinal data. Exact permutation methods are considered for comparing two or more groups of subjects. This approach entails choosing appropriate descriptive and test statistics and generating their exact distributions. The method is applied to two data sets, one relating to pigs and one to baboons. The second of these data sets involves a co-variate and the results are compared with those yielded by fitting a parametric mixed effects model. In the first example differences between groups were clearly established, and the graphical representations proposed were useful for describing the differences. In the second example the agreement between the results of the two methods of analysis was found to be very close.

This paper is concerned with the estimation of standard errors of location estimates associated with distribution-free test statistics. There are two popular approaches to this problem. The first of these is based on resampling methods like the bootstrap and jackknife. The second is based on properties of the relevant estimating equations and generally involve the estimation of gradients and the choice of a smoothing parameter. We propose a new completely general standard error estimation method, known as the translation method, which does not involbe resampling nor the user to specify the value of smoothing parameter. We show that the resulting variance estimator is asymptotically equivalent to a kernel quantile estimator with a specific bandwidth. The translation method is simple requiring just the null distribution of the test statistic and the values at which the test statistic changes. As such, it is envisaged that unlike other methods, the translation method could be used in statistical software pac...

Collections of sputum from 105 patients with newly diagnosed pulmonary tuberculosis were made before and at 1 and 2 d after the start of chemotherapy with isoniazid (INH) alone given to groups of patients in doses of 600 mg, 300 mg, 150 mg, 75 mg, 37.5 mg, 18.75 mg, and 9 mg daily, as well as from an untreated group. Counts of colony forming units (cfu) of Mycobacterium tuberculosis in the collections were set up on plates of selective 7H10 medium. The early bactericidal activity (EBA) of INH was defined as the decrease in log10 cfu/ml sputum/day during the first 2 d of treatment. A smooth curve relating EBA to log dose was obtained, with 600 mg INH yielding the highest mean EBA of 0.539, and 18.75 mg INH yielding the lowest EBA (0.111) that could be distinguished from the bactericidal activity of the untreated group. The ratio of the usual dose of 300 mg INH to the lowest dose, of 18.75 mg, that produced a detectable EBA, termed the therapeutic margin, was therefore 16, in contrast to the lower therapeutic margin of 4 for rifampin. The EBA was related to the INH acetylator genotype of patients treated with 600 mg or 9 mg INH.

Growth results of 43 ostrich males and females were used to compile growth parameters of a flock that is representative of Oudtshoorn birds, using the Gompertz model. Growth results comprised 19 recordings of body weight for each individual commencing from 1-day-old to day 520. Individual fits of data to the growth model were exceptionally good, resulting in low CV values of 0·02 and 0·03 for the mean values of all estimates of mature live weight for male and females respectively. The estimated mean mature body weights for the flock were 119·2 kg for males and 122·3 kg for females. Rates of maturing were 9100 and 8500 for males and females respectively which corresponded to ages of 180·83 and 199·2 days at which maximum gain in weight were achieved. None of these parameter estimates differed significantly between sexes. Results in the present study suggested substantial adjustments to growth parameters for Oudtshoorn ostriches published by du Preez, Jarvis, Capatos and de Kock, 1992.

In an experiment involving 30 roosters and 15 mature male ostriches the apparent metabolizable energy (ME) values, corrected for zero nitrogen retention (AMEn), were determined by balance method for maize and lucerne meal. A group of 10 roosters received maize as the sole dietary component. For the second group of 10 roosters a blend of 750 g/kg maize and 250 g/kg lucerne was prepared. The diet of the third group consisted of 500 g/kg maize and 500 g/kg lucerne meal. The ostrich basal diet consisted of 1000 g/kg lucerne, and was blended in the ratios 50 lucerne: 50 maize and 25 lucerne: 75 maize. Each dietary treatment was given to five ostriches, individually housed in metabolism crates. Food intake and excreta collection was carried out over a period of 5 days after the ostriches had been accustomed to the diets for 7 days. For roosters food intake and excreta collection lasted for 72 h after an adaptation period of 24 h.The AMEn value for maize was 14·49 (s.e. 0·046) MJ/kg in roosters while in ostriches AME,, values of 14·3 (s.e. 1·81) and 14·5 (s.e. 0·845) MJ/kg for the 500 g/kg inclusion and 250 g/kg inclusion respectively were found.In roosters lucerne meal yielded AME,, values of 4·49 (s.e. 0·506) and 4·05 (s.e. 0·321) at 250 g/kg and 500 g/kg inclusion levels respectively. For the ostriches a value of 8·9 (s.e. 0·755) Mj/kg was found for lucerne.True ME, corrected for zero nitrogen retention, (TMEJ was computed by regressing gross energy output on gross energy input over all feeding levels. Maize yielded values of 14·65 (s.e. 0·0455) and 14·9 (s.e. 0·351) for roosters and ostriches respectively while corresponding values for lucerne were 4·03 (s.e. 0·118) and 8·6 (s.e. 0·296) MJ/kg.It was concluded that the ostriches were capable of digesting a high starch diet such as maize to the same extent as adult roosters but ostriches were capable of digesting a high fibre ingredient such as lucerne meal much more efficiently.

A model is proposed for the fitting of species-area curves to data from the Stellenbosch region, South Africa. Basic assumptions of the model are finiteness of the number of species in a finite area, and random distribution of plant species over the region. The model involves a distribution of densities of different species, and the parameters of this distri- bution are useful for describing and classifying communities. The data of the Stellenbosch region suggest that the assump- tions of the model break down in areas greater than 500 m2.

On initial diagnosis or when metabolic control is poor, subjects with type 1 (insulin-dependent) diabetes mellitus often exhibit decreased high density lipoprotein (HDL) cholesterol levels, which have been associated in numerous studies in non-diabetic subjects with atherosclerosis and coronary artery disease. We measured the activities of plasma lecithin:cholesterol acyltransferase (LCAT), post-heparin lipoprotein lipase, and the composition of the HDL subfractions HDL2 and HDL3, in ten poorly controlled type 1 diabetic patients admitted to a metabolic ward (six women and four men, aged 18-37 years). The measurements were repeated after metabolic control had been optimised and again a week after discharge. The results were compared with those of ten healthy normolipidaemic subjects matched for age, sex and body mass. LCAT activity increased significantly (P0.05) with improved metabolic control in the diabetic patients, and showed positive within-person correlation with HDL2 cholesterol ester (r = 0.67; P0.01), HDL2 free cholesterol (r = 0.67; P0.01), phosphatidylcholine (r = 0.49; P0.05), total phospholipids (r = 0.50; P0.01) and apolipoprotein A-I (apo A-I: r = 0.72; P0.01). With improving metabolic control HDL2 lipid levels increased more than twofold and the compositional changes in HDL2 were reflected by an increased apo A-I:apo A-II ratio (P0.05) and a decreased triglyceride:apo A-I ratio (P0.05). Changes in HDL3 levels and composition were minor. The results of this study indicate that an increase in LCAT activity increases the concentration and changes the composition of HDL2 in type 1 diabetic patients with improved metabolic control.

Little is known about pyridoxine nutriture of children treated with isoniazid (INH) regimens. This study documents plasma pyridoxal 5'-phosphate (PLP) concentrations in children, HIV-infected and HIV-uninfected, receiving INH regimens.Children from the Western Cape of South Africa hospitalized for tuberculosis (TB) management were studied. Plasma PLP concentrations were determined on enrolment, 1-month after commencing TB treatment, and again after 4-month's treatment. The children received a supplement meeting pyridoxine requirements.Nineteen HIV-infected and 33 HIV-uninfected children received INH (dosage range 4-20 mg/kg) daily. Mean PLP plasma concentrations on enrolment were 8.32 (SD 6.75) ng/mL and 11.28 (SD 3.02) ng/mL in HIV-infected and HIV-uninfected children, respectively (p = 0.11) and after 4-month's treatment 6.75 (SD 2.71) ng/mL and 14.76 (SD 7.96) ng/mL (p0.001). On enrolment 9 (50%) HIV-infected and 5 (15%) HIV-uninfected children (p = 0.016) had suboptimal PLP concentrations (6 ng/mL); after 4-month's treatment 8 (42%) and 2 (6%) (p = 0.004).Plasma PLP concentrations in children treated for TB were low on enrolment in HIV-infected and HIV-uninfected children; after 4-month's treatment low values were still common in HIV-infected children. Additional pyridoxine supplementation of malnourished children treated for tuberculosis is advisable, particularly those HIV-infected.

Methods for deriving empirical Bayes estimators are generally available. Corresponding general techniques for assessing the performance of these estimators are not widely developed yet, however. In this paper we provide a general procedure for assessing and comparing the performance of the empirical Bayes estimators and other estimators in a given data set.

The early bactericidal activity of the aminoglycoside paromomycin (aminosidine) in doses of 7.5 and 15 mg/kg of body weight was measured in 22 patients with previously untreated smear-positive pulmonary tuberculosis. The fall in log 10 CFU per milliliter of sputum per day during the first 2 days of treatment for 7 patients receiving a paromomycin dosage of 7.5 mg/kg/day was 0.066, with a standard deviation (SD) of 0.216 and confidence limits from −0.134 to 0.266, and that for 15 patients receiving 15 mg/kg/day was 0.0924, with an SD of 0.140 and confidence limits from 0.015 to 0.170. The difference between the mean and zero was not significant for the 7.5-mg/kg dose group but was significant for the 15-mg/kg dose group ( t = 2.55, P = 0.023). Since paromomycin has no cross-resistance with streptomycin and has no greater toxicity than other aminoglycosides, these results suggest that it has the potential to substitute for streptomycin in antituberculosis regimens and may be a particularly valuable addition to the drug armamentarium for the management of multidrug-resistant tuberculosis.

No abstract

In today’s subscription-based industries of which telecommunication businesses, Internet services, medical aid, and the insurance industry are examples, management activities should be customer-centred and performance should be measured based on the firm’s customer value. In this study we investigate customer survival time in the Internet service providers industry. From the database of an Internet service provider, a random sample of 30 000 customers was selected. Factors potentially associated with churn in the ISP industry are investigated in this study. There are mainly two groups: demographic variables (gender, age, language and number of children) and usage related variables (the IT background of the customer and customer segment). Factors are examined individually. Nonparametric survival analysis techniques are used to analyse the data. Demographics and usage related factors have shown potential in determining the survival time of the customer and the event of churn. In particular, age and number of children and the customer usage segment appeared to be extremely important. The customers with age less than 26 years have higher risk of churn, while customers who use Internet for business purposes appeared to be more loyal. A special retention strategy should be formulated for these groups.

We studied the early bactericidal activity of twice the standard dose of rifampin in subjects with pulmonary tuberculosis evidenced by positive smears. The observed mean 2-day activity was almost double that reported at the standard dose. Further studies are warranted to establish whether higher rifampin doses might assist in shortening tuberculosis treatment.

This study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA90) and the influence of N-acetyltransferase-2 (NAT2) subtype on the ability of pulmonary tuberculosis (PTB) patients to reach the identified pharmacokinetic values after INH doses ranging from 0.2 to 10–12 mg/kg body weight. INH serum concentrations and NAT2 subtype were determined during four studies of PTB patients in three of whom the EBA of INH was determined. The relationship of EBA to area under the curve (AUC) $${\left( {{\text{AUC}}_{{0 - \infty }} } \right)}$$ and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the $${\text{AUC}}_{{0 - \infty }} $$ and 2-h serum concentrations at which EBA90 was reached. EBA90 was reached at an $${\text{AUC}}_{{0 - \infty }} $$ of 10.52 μg/ml per hour and 2-h serum concentrations of 2.19 μg/ml. An $${\text{AUC}}_{{0 - \infty }} $$ of 10.52 μg/ml per hour was reached by all 66 patients receiving a 10–12 mg/kg INH dose and all 21 receiving 6 mg/kg, except 1 of 10 (10%) homozygous fast (FF) acetylators; however, at 5 mg/kg, 4 of 12 (33%) FF and 26 of 27 (96%) heterozygous fast (FS), but all 21 homozygous slow (SS) acetylators did so; and 1 of 3 (33%) FF, 2 of 6 (33%) FS, but all 4 SS acetylators at dose 3 mg/kg. An INH 2-h serum concentration of 2.19 μg/ml was reached by all 66 patients receiving 10–12 mg/kg and all 21 receiving 6 mg/kg, except for 2 (20%) FF acetylators at a dose of 5 mg/kg; however, only 3 (25%) of 12 FF acetylators, but 26 (96%) of 27 FS acetylators, and all 21 SS acetylators reached this concentration; and at a dose of 3 mg/kg, 1 (33%) of 3 FF acetylators, 2 (33%) of 6 FF, but all 4 SS acetylators. At a 6 mg/kg dose, all except a minority of FF NAT2 acetylators, achieve an INH $${\text{AUC}}_{{0 - \infty }} $$ and 2-h INH serum concentrations associated with EBA90, as did all 4 SS acetylators receiving 3 mg/kg. Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH.

The Visual Treatment Objective (VTO) is an extremely valuable tool in the process of working out the treatment plan for the individual. This is especially true for the inexperienced operator. Often it becomes clear that extractions are indicated, but there remains uncertainty as to which teeth should be chosen for extractions to give the best results. As it is necessary to express the expected change in profile due to growth of the nose and also of the chin, VTO construction is helpful in determining the extraction decision. Clinical experience and research projects have indicated that the use of mean values has definite limitations when constructing a VTO for an individual. The primary objective of this investigation was to provide formulae by means of which anteroposterior changes in the facial profile of growing individuals for whom four premolar extraction treatment is proposed can be predicted with a greater measure of certainty. The records of 248 growing Caucasian orthodontic patients (120 males and 128 females) were selected and divided into Group 44 (four first premolar extractions), Group 45 (upper first premolar and lower second premolar extractions) and Group 55 (four second premolar extractions). Formulae are presented for the prediction of the amount of incisor retraction, anteroposterior nose growth and for chin growth. The formulae were derived by regression of incisor retraction, anteroposterior nose growth and chin growth on various predictors, and could be used in the construction of VTO's for selected cases.

The use of cell cultures to test the biocompatibility of dental materials is gaining in importance. Any cytotoxic effects that restorative materials may have will be on the dental pulp and for that reason cultured pulp cells should be the model of choice for biocompatibility testing. The aim of this investigation was to study the growth and morphologic characteristics and toxic response of human pulp lines and to compare these parameters to those of human buccal mucosa fibroblasts. Twenty-one specimens of pulp tissue and six from buccal mucosa were cultured using standard techniques. Six pulp cell lines were cultured successfully as were all six from the buccal mucosa specimens. From these specimens, 12 growth curves were computed. To study the morphology of the cultured cells, they were observed microscopically and classified into three morphological types: slender elongated cells (type I), epithelioid shaped cells (type II) and large stellate cells (type III). Their numbers and proportions were determined for each cell line and compared statistically. To gauge sensitivity to toxic materials, cells were exposed to concentrations of arecoline. An analysis of the growth curves showed no statistical difference between pulp cells and buccal mucosa cells; the slopes of the curves, however, differed significantly between individual cell lines, and these individual differences were greater among pulp cell lines. The morphology of the pulp and mucosa fibroblasts was similar microscopically. There was no significant difference between the number and proportion of the cell types in the two groups, but there were significant differences between the individual cell lines. Pulp cells showed a greater inhibition of growth when exposed to arecoline. Because pulp fibroblasts are difficult to culture, their reported survival rate is poor; due to the differences that exist between individual cell lines, we conclude that pulp cells when used as single cell lines or even pooled may not be ideal for testing biocompatibility, especially if reproducibility is a prerequisite. Any evaluation will require tests on not one, but several cell lines in order to minimize the effect of inter-cell-line differences. Their greater sensitivity to toxic substances, on the other hand, may show that pulp cells could be more sensitive indicators of cytotoxicity.

Umbilical artery Doppler flow velocity waveform studies were performed over a period of 4 y on 242 women with severe pre-eclampsia before 34 wk gestation. Sixty-eight (28%) had absent end-diastolic umbilical artery Doppler flow velocities. One hundred and ninety-three infants survived to hospital discharge and were followed at 6-monthly intervals until 48 mo of age. The mean corrected developmental quotient was 94 +/- 8 at 24 mo of age and 87 +/- 9 at 48 mo. Ninety-two percent of the infants had a developmental quotient of80 at 24 mo and 72% at 48 mo of age. This decline is thought to be due to the impact of social circumstances. There were no differences between the developmental quotients of the infants with normal and those with absent end-diastolic umbilical artery Doppler flow velocities at either 24 or 48 mo of age. At 24 mo of age, infants with absent end-diastolic umbilical artery Doppler flow velocities scored lower in the Performance subscale test (p = 0.03). The developmental quotients of infants from poorer socioeconomic backgrounds were significantly lower than those living in more privileged circumstances. At 48 mo, 153 (97%) of the children presented with normal gross motor development. Four infants had cerebral palsy. No differences were noted in the motor outcomes between the infants of women with normal umbilical artery waveforms and those with absent end-diastolic umbilical artery Doppler flow velocities.

The purpose of the investigation was to compare the morphology of fibroblasts cultured from healthy oral mucosa and mucosa of patients with oral submucous fibrosis (OSF) and to collate the occurrence of cell types of similar morphology. Cells cultured from biopsy specimens from the buccal mucosa of six subjects who did not chew the areca nut and six patients with OSF who chewed areca nut were grown according to standard techniques. Ninety cells per cell line were recorded daily for 8 days, classified into types F1, F2 and F3 according to their morphology, and the results statistically analyzed. We found that there was a relative increase of F3 cells in relation to F1 cells in OSF, resulting in the ratio of F3 to F1 cells being significantly larger in OSF than the ratio in the controls. As it has been reported that F3 cells in rat connective tissues produce significantly more collagen types I and III than F1 cells, we concluded that a change of fibroblast population has occurred in OSF and that this relative increase of F3 cells in humans, which could be committed to the production of large quantities of collagen, can be an explanation for the excessive collagen formation in OSF.

We have studied 51 patients who were anaesthetized with propofol and suxamethonium followed by 0.7% isoflurane and 66% nitrous oxide in oxygen to see if tramadol caused lightening of anaesthesia. A two-channel EEG was recorded and music was played via headphones. Two groups received tramadol 200 and 100 mg i.v. and the third group received saline. Tramadol caused significant, dose-dependent activation of the EEG, evidenced by increased frequencies and decreased amplitudes, but these changes were small and probably unimportant. Derived EEG variables did not approach values known to be associated with near-awakening during isoflurane anaesthesia. No patient moved on skin incision and there were no incidences of free recall.

A comparison of the effects of two low-dose oral contraceptives on lipid metabolism was undertaken in an open-group comparative design study at the Family Planning Clinic, Groote Schuur Hospital, Cape Town. Sixty healthy women aged 18-35 years requesting oral contraception were allocated alternately to use a monophasic oral contraceptive containing 30 micrograms ethinyloestradiol and 150 micrograms desogestrel (Marvelon, group A), or a triphasic oral contraceptive containing 30-40 micrograms ethinyloestradiol and 50-125 micrograms levonorgestrel (Triphasil, group B). The changes in the lipoprotein profile elicited by the two preparations differed significantly. Group A subjects had a much greater triglyceridaemic response (42.4%) than group B (14.6%) and had a significant increase in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 (Apo-A1). In group B, HDL-C decreased and Apo-A1 showed little change. Non-HDL-C (NHDL-C) and Apo-B levels hardly changed in either group. The atherogenic ratios, NHDL-C/HDL-C and Apo-B/Apo-A1 were higher in group B. This study confirmed a significant difference in the response of plasma lipoproteins to the two oral contraceptive preparations. The evidence suggests that the desogestrel-containing oral contraceptive elicits a less atherogenic lipoprotein profile than does the levonorgestrel-containing preparation. Although unsupported by direct clinical evidence that changes in the lipoprotein pattern induced by oral contraceptives cause atherosclerosis, these effects should be considered when prescribing oral contraceptives for women who have risk factors for cardiovascular disease.

In an age-matched sample of male and female inpatient alcoholics (n = 518) of the same ethnic background, subjects under 35 years of age described significantly more problem areas than older age groups. Elderly subjects over 55 were the least articulate group. The first-ever addiction treatment subjects reported the lowest mean number of years of problem drinking, the lowest mean Michigan Alcoholic Screening Test scores and the lowest mean daily alcohol intakes. They also displayed greater current social stability than the 2 readmission treatment categories. The general determinants of admission to this addiction unit centered around the experience of crises, social instability and psychological complaints. The most important specific determinants for the individual subject were the propensity to fight when drunk, followed by a positive parental history of excess alcohol intake. Criminal and occupational factors were infrequently encountered in female subjects, but widowhood was common in the older ones.

The preparation of several short courses on distribution-free statisti- cal methods for students at third and fourth year level in Australian universities led to the writing ofthis book. My criteria for the courses were, firstly, that the subject should have a clearly recognizable underlying common thread rather than appear to be a collection of isolated techniques. Secondly, some discussion of efficiency seemed essential, at a level where the students could appreciate the reasons for the types of calculations that are performed, and be able actually to do some of them. Thirdly, it seemed desirable to emphasize point and interval estimation rather more strongly than is the case in many of the fairly elementary books in this field. Randomization, or permutation, is the fundamental idea that connects almost all of the methods discussed in this book. Application of randomization techniques to original observations, or simple transformations of the observations, leads generally to conditionally distribution-free inference. Certain transformations, notably 'sign' and 'rank' transformations may lead to unconditionally distribution-free inference. An attendant advantage is that useful tabulations of null distributions of test statistics can be produced. In my experience students find the notion of asymptotic relative efficiency of testing difficult. Therefore it seemed worthwhile to give a rather informal introduction to the relevant ideas and to concentrate on the Pitman 'efficacy' as a measure of efficiency.

Empirical Bayes Methods. By J. Maritz and T. Lwin. ISBN 0 412 27760 3. Chapman and Hall, London, 1989. xii + 284 pp. £27.50.

SUMMARY The use of a simple permutation argument to set exact confidence limits for the location parameter of a symmetric distribution is described. The argument is applied to estimates based on original observations and on ranks and to M-estimates. Some key word8: Exact confidence limit; Location estimate; M-estimate; Ranks; Robustness.

The competing classical and inverse point estimators in statistical calibration can be obtained by direct or inverse regression and are to some extent supported by the maximum likelihood and Bayesian approaches, respectively. Both of these approaches depend on specific distributional assumptions, but these assumptions confuse the main issue because both estimators can be justified without reference to them. By using a compound estimation approach, it is shown that the classical estimator can be derived as a linear compound estimator satisfying the criterion of asymptotic unbiasedness, while the inverse estimator is a linear compound estimator without the unbiasedness constraint. This formulation requires neither specific distributional assumptions nor reference to direct or inverse regression. Assessments of the two estimators are made in terms of their performance in estimating the current x value. It is shown that superiority of the inverse estimator can only be guaranteed if the current x value is samp...

Summary Theil's (1950) method for inference about the slope of a straight line can be regarded as based on the median of all estimates of the slope derived from pairs of observations. The possibility of employing similar procedures for distribution-free inference about the intercept is investigated, and it is shown that, in certain circumstances, efficiencies close to 1 can be achieved with an exactly distribution-free procedure.

Rank tests are often used to analyse medical and biological data. The lack of invariance of the paired sample Wilcoxon signed rank test with respect to transformation of observations, and the choice of an appropriate rank test in the case of the two way analysis of variance random effects model, are discussed in the context of two medical examples.

Summary A method for estimating the asymptotic standard error of the sample median based on generalized least squares is outlined. The practical problems of implementing this new estimate along with those associated with two existing estimates are discussed. Finally a simulation study is presented to compare the three estimates.

We consider a sequence of contingency tables whose cell probabilities may vary randomly. The distribution of cell probabilities is modelled by a Dirichlet distribution. Bayes and empirical Bayes estimates of the log odds ratio are obtained. Emphasis is placed on estimating the risks associated with the Bayes, empirical Bayes and maximum lilkelihood estimates of the log odds ratio.

Summary The data that are used in constructing empirical Bayes estimates can properly be regarded as arising in a two-stage sampling scheme. In this setting it is possible to modify the conventional parameter estimates so that a reduction in expected squared error is effected. In the empirical Bayes approach this is done through the use of Bayes's theorem. The alternative approach proposed in this paper specifies a class of modified estimates and then seeks to identify that member of the class which yields the minimum squared error. One advantage of this approach relative to the empirical Bayes approach is that certain problems involving multiple parameters are easily overcome. Further, it permits the use of relatively efficient methods of non-parametric estimation, such as those based on quantiles or ranks; this has not been achieved by empirical Bayes methods.

Summary A modification to the least-squares estimating equations in simple linear regression, leading to exact distribution-free inference about slope, is outlined. The modification involves a general residual-transformation iψ and the cases of ψ— sign, rank, and the identity are discussed in some detail. It is also shown how exact inference about individual parameters in regressions with more than one design variable can be carried out by a restricted permutation argument coupled with a suitable design.

The estimation of the parameters of two or more geometric distribuionsis considered by usinq an empirical Bayesian approach. Robbins (1983) gave empirical Bayes estimates if the number of distributions N is large, buthere we consider the cascwhore N is small. The parameters of the prior distribution areest imated by looking at maximum like lihood and momentest imation methods.

Summary An empirical Bayes approach to interval estimation of an unknown parameter λ of a univariate data distribution is formulated, with special reference to some specific parametric forms of the data distributions and prior distributions. The connection with the notion of tolerance limits is traced.

Empirical Bayes approach to estimation of many parameters is considered. Special features of the techniques discussed are: (i) the handling of unequal sample sizes at various stages of an Empirical Bayes sampling scheme and (ii) a general iterative procedure for estimating the parameters of a parametric prior distribution based on the likelihood approach. Linear empirical Bayes estimation is also considered. Applica- tion of the general techniques is demonstrated with special reference to a multinomial data distribution. p where, for every i, 0 < Xi ~ m, 0 < 0i < 1 and i=1 ~ Xi : m, i=~=l 0i : 1. The above probability model is fundamental in the analysis of categorical data and contingency table analyses. In the above the quantity m often represents the sample size of a sample of objects classified into p classes. Suppose that in a current experiment, m observations are made on a p-category Bernoulli r.v. Y with probability 0i of belonging to category i. Let Xg be the number of Y's in i-th

A study was carried out to determine whether physical working capacity and mechanical efficiency at the task are important determinants of the level at which an individual performs a moderately heavy physical task under normal working conditions underground. The method allowed a number of important preliminary points about the underground task to be established. These were (a) There were significant differences between men's performances at the task. (b) In general, men maintained their rank order of performance at the task over a period of 5 months. (c) Local variations in the physical features of the underground work situation had a negligible effect upon the differences in men's performances at the task. The results of the study showed that neither of the two physiological factors examined was of any importance in determining a man's level of performance at the task, with the proviso that all men performing the task should have sufficiently high physical working capacities to enable them to pe...

The premises upon which simple methods for estimating an individual's maximum oxygen intake are based have boon tested. These premises are : (a) that heart rate and oxygen intake are linear functions of each other throughout the entire range of work up to the individual's maximum ; (b) that oxygen intake of the individual deviates very little from the mean straight line relating oxygon intake and rate of work for the population, so that the oxygon intake for a task performed against gravity can be estimated with reasonable precision from the rate of work ; and (c) that the individual variability of maximum heart rate round the mean for the population is sufficiently small to use the moan in a routine test procedure without the introduction of largo errors. Premises (b) and (c) are fully substantiated by the results reported here, Premise (a) is not strictly valid, as there is a bias of the order of 03 1. oxygon/min in the straight line relating heart rate and oxygen intake at high levels of work in most i...

SUMMARY The smooth empirical Bayes approach is based on using past observations to estimate a specified type of approximation to the prior distribution. This approach is applied to problems of empirical Bayes hypothesis testing and to the compound decision problem. Problems involving composite hypotheses are considered which have, hitherto, received much less attention than the case of two simple hypotheses. The methods are shown to be asymptotically optimal and results of studies involving finite sample numbers are reported, giving some indication of the rate of approach to optimality in specific cases.