A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Effects of triamcinolone on quality of life in patients with persistent allergic rhinitis.

OBJECTIVE: To study the effects of triamcinolone acetonide on health-related quality of life (HRQL) in adult patients with allergic rhinitis. METHODS: This study was conducted in South Africa as a placebo-controlled, multicenter, randomized, double-blind study. Following a 7-day baseline run-in, patients were treated for 28 days with either triamcinolone or placebo. Interviewer-assisted quality-of-life assessments were conducted using the Juniper Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). Total symptom scores, including nasal congestion, were measured using daily diary cards. RESULTS: A total of 337 patients were recruited and 253 patients completed the study per protocol, of which 55 had seasonal allergic rhinitis (SAR) and 198 had persistent allergic rhinitis (PAR). Improvements in the mean scores per area of the RQLQ were significantly better with triamcinolone compared with placebo for the entire study group for activities (P = .04 at visit 4) and sleep, nasal symptoms, emotional problems, and overall score (P = .002, P = .04, P = .03, and P = .04, respectively, at visit 3). When the patients with SAR were separated from the patients with PAR in the analysis, improvement with triamcinolone was better than placebo only in the PAR patients. The overall investigator and patient assessments of relief favored triamcinolone. CONCLUSIONS: Triamcinolone given for 4 weeks improves symptom scores and HRQL in patients with allergic rhinitis. The ability of triamcinolone to relieve nasal congestion symptoms in PAR patients was correlated with improvements in HRQL.

The effect of dietary protein on reproduction in the mare. V. Endocrine changes and conception during the early post partum period.

Pregnant Anglo-Arab and Thoroughbred mares (n = 24) were divided randomly according to age and breed into 4 groups of 6 mares each from approximately 6 weeks before their expected foaling date. Diets received by the 4 groups varied in essential amino-acid and total protein contents. Serum progestagen, FSH and LH concentrations were determined from the day of parturition until foal heat and during the 1st oestrous cycle following foal heat. Serum progestagen, FSH and LH concentrations did not differ between the treatment groups. Progestagen concentrations were high (mean = 7.0: 5.2-16.4 ng/ml) at parturition but decreased rapidly within 48 h. As progestagen concentrations decreased LH concentrations increased from Days 3-6 post partum to reach maximum values at, or the day after ovulation. FSH concentrations declined 3-4 d after parturition and increased 2-3 d before ovulation at foal heat. The duration of elevated progestagen concentrations during the luteal phase of the subsequent oestrous cycle affected the interovulatory period. A 12-14 d FSH cyclical releasing pattern occurred. Season/photoperiod affected the resumption of normal oestrous cyclicity during the post partum period. The duration of the 1st oestrous cycle after foal heat in mares fed a low-quality protein diet showed a greater range (13-30 d) compared to mares fed a high-quality protein diet (18-26 d).

The effect of dietary protein on reproduction in the mare. VI. Serum progestagen concentrations during pregnancy.

Sixty-four Thoroughbred and Anglo-Arab mares aged 6-12 years were used, of which 40 were non-lactating and 24 lactating. Foals from these 24 mares were weaned at the age of 6 months. Non-lactating and lactating mares were divided into 4 dietary groups each. The total daily protein intake and the protein quality (essential amino-acid content) differed in the 4 groups of non-lactating and 4 groups of lactating mares. The mares were covered and the effect of the quantity and quality of dietary protein on serum progestagen concentrations during pregnancy was studied. A sharp decline in serum progestagen concentrations was recorded in all dietary groups from Days 18 to 40 of pregnancy, with some individual mares reaching values of less than 4 ng/ml. Serum progestagen concentrations recorded in some of the non-lactating mares on the low-quality protein diet increased to higher values (p < 0.05) than those of mares in the other 3 dietary groups at 35-140 days of pregnancy. A similar trend was observed for the lactating mares on a low-quality protein diet at 30-84 days of pregnancy. No such trends were observed in any of the other dietary groups. High-quality protein supplementation increased serum progestagen concentrations during the 1st 30 days of pregnancy. Lactation depressed serum progestagen concentrations until after the foals were weaned.

The effect of dietary protein on reproduction in the mare. VII. Embryonic development, early embryonic death, foetal losses and their relationship with serum progestagen.

Sixty-four Thoroughbred and Anglo-Arab mares aged 6-12 years were randomly allocated to 4 dietary groups and fed diets that differed in the total protein content and quality (essential amino-acids). Forty mares were non-lactating and 24 lactating. Eight mares were withdrawn from the investigation owing to injuries or gynaecological pathology. An overall conception rate of 94.6% and a foaling rate of 80% was achieved. Five of 14 (35.7%) mares (Group 1) fed a low-quality protein diet suffered from early embryonic loss before 90 days of pregnancy compared to 3 of 41 (7.3%) mares in the remaining groups that received the higher-quality protein in their diets. Serum progestagen concentrations of mares in Group 1 that suffered foetal loss were indicative of luteal function insufficiency during the 1st 40 days post-ovulation. Non-lactating mares in all 4 groups gained on average approximately 30 kg in mass during the 90 days before the breeding period. Lactating mares in Group 1 (low-quality protein) lost on average 25 kg in mass during lactation, with no weight loss observed among the lactating mares in the other 3 groups. No difference in the diameter of the embryonic vesicle was found between dietary groups until Day 35 of pregnancy.

The effect of dietary protein on reproduction in the mare. I. The composition and evaluation of the digestibility of dietary protein from different sources.

Four rations that differed in their crude protein and essential amino-acid content were compiled. Digestibility of the crude protein and essential amino-acid contents were determined biologically in a feeding trial using 4 Anglo-Arab stallions. Their respective daily diets were: Diet 1:2 kg cubes, 5 kg tef hay (Eragrostis tef); Diet 2:2 kg cubes, 5 kg lucerne hay (Medicago sativa); Diet 3:2 kg cubes, 5 kg tef hay, 200 g fishmeal; Diet 4:2 kg cubes, 5 kg lucerne hay, 200 g fishmeal. The concentrations of the amino-acids threonine, iso-leucine, leucine and arginine were increased in the total ration when lucerne hay replaced the tef hay while fishmeal supplementation increased the methionine and lysine contents, which provided a wide-range of concentrations of digestible amino-acids in each of the 4 rations.

The effect of dietary protein on reproduction in the mare. II. Growth of foals, body mass of mares and serum protein concentration of mares during the anovulatory, transitional and pregnant periods.

The effect of 4 different diets, in terms of protein quantity and quality, on total serum protein (TSP), albumin and globulin was investigated. Non-pregnant mares that were not lactating (n = 36), pregnant mares that had foaled (n = 24) and their foals (n = 24) were used in this study. Daily total protein intake had no effect on blood protein concentrations in the mares. Total protein intake and quality (available essential amino-acids) did affect the body mass of mares during lactation. When mares were fed the minimum recommended (National Research Council 1989) total daily protein, foal mass decreased by approximately 25% at weaning compared to the foals whose dams were on a higher level of protein intake. The TSP concentrations of foals at birth were on average 10 g/l lower than those of the mares. Albumin concentrations of foals during the first 60 days of life were on average 2-3 g/l lower than those of the mares. Globulin concentrations of foals were approximately 5 g/l lower than those of mares at weaning.

The effect of dietary protein on reproduction in the mare. III. Ovarian and uterine changes during the anovulatory, transitional and ovulatory periods in the non-pregnant mare.

In the main experiment the total daily protein intake and quality (essential amino-acids) was varied in 4 groups of mares. The incidence of oestrus in mares during the transitional period was unaffected by protein nutrition. Ovarian activity, as evaluated by follicular development and size of the ovaries, was affected. Mares that received low-quality protein (Groups 1 and 2) had a higher number of smaller follicles (< 10 mm) that developed during the transitional period compared to mares on a high-quality protein intake (Groups 3 and 4). The mares that received the high quality protein ovulated 2-3 weeks earlier in the breeding season in a synchronised period of 4-5 weeks compared to a period of 6-8 weeks in Groups 1 and 2. The duration of the subsequent oestrous cycles was not affected. There was no difference in the diameter of the largest follicle of mares between groups on the day before ovulation. In a separate experiment, 5 maiden Anglo-Arab mares, 4-5 years of age, were slaughtered at different stages during the anovulatory, transitional and ovulatory periods of the breeding cycle. The morphology of the ovaries and uteri of these mares was described and photographed for use as guidelines when comparing ovarian changes and follicular activity of mares.

The effect of dietary protein on reproduction in the mare. IV. Serum progestagen, FSH, LH and melatonin concentrations during the anovulatory, transitional and ovulatory periods in the non-pregnant mare.

The effect of total protein intake and protein quality on the serum concentrations of certain reproductive hormones during the anovulatory, transitional and ovulatory periods were studied in 36 Anglo-Arab mares. High-quality protein stimulated FSH and LH production during the late transitional period. Serum progestagen and melatonin concentrations were unaffected by the quality of protein nutrition during the anovulatory period. Mares receiving high-quality protein exhibited a 10-14-day cyclical pattern of FSH release approximately 4-6 weeks earlier than the mares fed the lower-quality protein diet, and also ovulated 3-4 weeks earlier than the mares on the lower-quality protein diet. Progesterone concentrations during the 1st oestrous cycle after the anovulatory period were unaffected by protein quality in the diet.

Involution of the post partum uterus of the Boer goat.

The microscopic uterine involutionary changes were studied in Boer goats (n = 16) from 2 h to 34 d post partum. The endometrial epithelium showed a linear decrease in thickness with time post partum. A highly significant negative correlation (r = -0.94; P less than 0.01) was found between the endometrial epithelium layer thickness and time post partum. The lamina propria layer showed a rapid decrease during the first 20 d post partum and then tended to level out. According to the statistical model (y = AeBt + Ct2) fitted by 25.2 d post partum, the thickness of the lamina propria layer was static. The myometrium decreased significantly (P less than 0.01) in thickness from Day 24 to Day 34 post partum. The thickness of the serosa followed a linear-type decrease during the observation period, while in the glandular epithelium the decrease was rapid during the first 12 d following parturition. The uterine glands reached normal size 22.1 d after parturition. The involution process of the uterus was microscopically complete by Day 28 post partum, the main indicator being the degree of recovery of the endometrial epithelium over the caruncular areas.

Clinical characteristics of childhood asthma.

A prospective study was undertaken of 298 asthmatic children attending a paediatric allergy clinic in Bloemfontein. A detailed history was obtained, and skin tests were performed. Male predominance and an early age of onset were confirmed. Symptomatic allergic rhinitis was an extremely common finding. A family history of allergy was obtained in over 90% of cases. Respiratory tract infections, changes in the weather and exercise were found to be the most common asthma-inducing factors. Common allergens were grass pollen (63%) and animal danders. House-dust mite (25%) and dietary allergens (less than 20%) were relatively uncommon. The failure to recognise the symptoms of asthma in children, particularly young children, was identified as an ongoing problem.

The bent-leg syndrome in sheep. II. Association with genetic markers.

Comprehensive blood typing (17 factors) and electrophoretic protein markers (haemoglobins, transferrins and albumins) were determined on S.A. Mutton Merino sheep (n = 275). The frequencies of these genetic markers were compared between ram lambs with normal and ram lambs with bent-legs and in a second trial between non-affected ewes and their lambs and ewes and lambs which were considered to be carriers of genetic factors resulting in the bent-leg syndrome. The presence of blood factors 2, 3 and 13 and the absence of factors 8, 10 and 17 is possibly linked to the bent-leg syndrome. Although the frequencies of TFA and TFD alleles were higher in the suspected carrier animals than non-affected animals, no definite linkage to the bent-leg syndrome was found. Haemoglobin and albumin type showed no correlation with the bent-let syndrome.

The bent-leg syndrome in sheep. I. The effect of pregnancy and age of the ewe on concentrations of plasma minerals.

The effect of age of the ewe and pregnancy on concentrations of plasma calcium, phosphorus and magnesium and its relationship to the bent-leg syndrome in lambs, were investigated. This study included Merino ewes (n = 74), Dohne Merino ewes (n = 127), S A Mutton Merino ewes (n = 123) and S A Mutton Merino lambs (n = 145). Over a period of 8 years, 52 S A Mutton Merino ram lambs out of a total of 602 ram lambs weaned (8,6%), developed the bent-leg syndrome compared to the 2 ewe lambs out of 591 ewe lambs (0,3%) weaned. It was found that both the age of the ewe and pregnancy had no contributing effect in the development of this syndrome. The ewes of which the offspring developed the bent-leg syndrome, had an inverse plasma Ca:P ratio. Approximately 15% of the S A Mutton Merino ewes which gave birth to offspring which developed the bent-leg syndrome, had more than one lamb which developed this condition over the past 8 years. It is suggested that these ewes are carriers of certain genetic factors which can cause excessive phosphorus absorption. No differences in the concentration of plasma calcium, phosphorus and magnesium were found between ewe and ram lambs.

The influence of experimentally induced copper deficiency on the fertility of rams. I. Semen parameters and peripheral plasma androgen concentration.

The influence of molybdenum and molybdenum plus sulphate-induced copper deficiencies on semen quality and peripheral plasma testosterone concentrations in South African Mutton Merino rams was investigated. All animals received an identical ration, supplemented with molybdenum in one group (M) and molybdenum plus sulphate in another (MS) while the control group (C) received additional copper supplementation. After almost a year on these rations, rams in Group MS produced ejaculates of lower volume, lower sperm concentration, poorer sperm motility and morphology than rams of the other 2 groups. The fructose concentration in the ejaculates of group MS rams was also lower than that of rams in the other groups. Peripheral plasma testosterone concentrations in Group MS were lower than in Groups C or M. Liver copper concentrations and clinical signs were consistent with a severe copper deficiency in Group MS and a mild deficiency in Group M. After the copper deficiency was reversed, the above parameters reverted to normal. It was concluded that an experimentally induced copper deficiency produced reversible impairment of testicular function in rams.

The influence of experimentally induced copper deficiency on the fertility of rams. II. Macro- and microscopic changes in the testes.

The macro- and microscopic changes of the testes caused by molybdenum as well as a molybdenum plus sulphate induced copper deficiency were investigated in S.A. Mutton Merino rams. Judged on testes measurements, the testes development of rams suffering from a severe copper deficiency was slower (P less than or equal to 0.05) when compared with rams in the control group. Histological examinations of the testes of the rams which suffered from a severe copper deficiency revealed that the seminiferous tubules were less developed and less active than those of the control group. This was mainly due to the inactivity of the Sertoli cells. Where rams suffered from a copper deficiency, the Sertoli cells contained only a small volume of cytoplasm. The typical fingerlike cytoplasmic evaginations of the Sertoli cells into the lumen of the seminiferous tubules were absent while the nuclei of these cells were darkly stained, in some cases even pycnotic. Spermatocytogenesis was normal because primary spermatocytes with dark stained thread-like chromatin were observed in most of the seminiferous tubules. The process of spermiogenesis (metamorphic phase) did not take place. This can be accounted for by the inactivity of the Sertoli cells.

Breed differences in plasma calcium, phosphorus and magnesium concentrations of Merino, Dohne Merino and S.A. Mutton Merino sheep with relation to the bent-leg syndrome.

Plasma calcium, phosphorus and magnesium concentrations were determined in ewes and their single and twin lambs from birth for 120 days in Merino, Dohne Merino and South African Mutton Merino sheep. Mineral concentrations as well as the plasma calcium: phosphorus ratio were compared between breeds. Throughout the experimental period, plasma calcium and phosphorus concentrations were higher in both single and twin lambs than in the ewes of all 3 breeds. No breed differences in plasma calcium concentrations were found. Animals of the S.A. Mutton Merino breed had significantly higher (P less than 0.05) plasma phosphorus concentrations than the other 2 breeds. The plasma Ca:P ratio in the Merino and Dohne Merino ram lambs was approximately 1.1:1 and in the S.A. Mutton Merino 0.9:1. This converse plasma Ca:P ratio found in both the S.A. Mutton Merino ewes and lambs is believed to result in an induced plasma ionised calcium deficiency which leads to improper calcification of bone. This is believed to be a contributing factor in the bent-leg syndrome. No difference was recorded in body mass between ram lambs suffering from the bent-leg syndrome and unaffected ram lambs. Plasma magnesium concentrations were not affected by breed or age of the animals.

Efficacy of grass-maize pollen oral immunotherapy in patients with seasonal hay-fever: a double-blind study.

Forty patients with a well-documented history of seasonal hay fever and a positive skin-prick test specific to grass pollen, including Bermuda grass and maize pollen (Zea maize), were allocated randomly on a double-blind basis to receive either an oral mixed grass-maize pollen extract or a matched placebo during the 1981/1982 grass pollen season. After 12 months the code was broken and patients on placebo were transferred to active therapy while patients on active therapy continued with maintenance therapy for another 12 months during the 1982/1983 grass pollen season. The assessment of the effect of the orally administered grass-maize pollen extract was on the clinical symptoms. During the first year the patients on active therapy had significantly fewer hay fever symptoms during the summer months compared with the placebo group. During the second study year, with all patients on active therapy, both groups had markedly milder symptoms compared with the placebo group. Side-effects were negligible. This study concludes that oral immunotherapy with grass-maize pollen extract in grass pollen-sensitive seasonal hay fever patients is safe and effective.