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Biomedical subjects

J English

Publications and source records attributed to J English.

At least 91 records · Page 5Linked to original sources
PubMed1988

Chronic tubulointerstitial nephritis and renal insufficiency associated with long-term "subtherapeutic" gentamicin.

To determine whether long-term "subtherapeutic" concentrations of aminoglycoside produce chronic tubulointerstitial nephropathy, Fisher rats were given gentamicin, 20 mg/kg/day, for up to 6 months via indwelling osmotic infusion pumps. Studies included renal histology, autoradiographic quantitation of renal cell tritiated thymidine uptake, renal function and renal cortical gentamicin assay. Acute proximal tubular injury, without tubular necrosis, followed by recovery, occurred during the first month. Subsequently only mild, nonprogressive tubulointerstitial changes and a twofold increase in tubular cell turnover were observed. Inulin clearance fell more than 50% during the 6 months of treatment compared with 10% in age-matched controls. Serum creatinine and creatinine clearance overestimated glomerular filtration rate during treatment and did not distinguish treated animals from controls. During the month after 6 months of gentamicin, tubular microcystic changes and active tubulointerstitial nephritis developed, with a continued fall in inulin clearance. In summary, gentamicin, in "subtherapeutic" doses, produces mild chronic tubulointerstitial nephritis with progressive renal failure. Cessation of treatment is associated with microcystic and inflammatory changes, suggesting that the renal response to tubular injury can be dissociated from the amount of toxin in the renal cortex. Keeping serum aminoglycoside levels below accepted therapeutic range for 6 months did not preclude nephrotoxicity.

Animals↗
PubMed1987

The effect of abolition of the endogenous corticosteroid rhythm on the circadian variation in methotrexate toxicity in the rat.

Monitoring of indices of haematological, renal and hepatic toxicity in rats after a single i.v. bolus of methotrexate has shown that they vary with the time of day at which the drug is administered. Maximum toxicity occurs after administration at 0600 h. Further experimentation has shown that the amount of corticosteroid present in the blood has a profound effect on the toxicity of methotrexate in the rat. If the endogenous production of corticosterone is suppressed by treatment with dexamethasone the toxicity of methotrexate is markedly increased at whatever clock time it is administered. However, if constantly high plasma levels are achieved by giving supplementary corticosterone methotrexate toxicity is diminished regardless of what time it is given. Since the timing of maximum methotrexate toxicity corresponds to the circadian nadir of endogenous plasma corticosterone concentration in the rat the possibility that it might be related to corticosterone production must be considered. Whether this phenomenon occurs in man and has any clinical relevance has yet to be investigated.

Adrenal Cortex Hormones↗
PubMed1987

Suppression of nocturnal plasma melatonin and 6-sulphatoxymelatonin by bright and dim light in man.

Previous studies have shown that bright light (2500 lux) suppresses nocturnal secretion of melatonin, while dim light (500 lux) has little or no effect. We have studied the effect of varying intensities of light on 5 normal male volunteers (age 18-28). The experiment was divided into 3 parts which took place at weekly intervals. Subjects remained under artificial light (fluorescent strip 150-250 lux) between 2000 h-2300 h, they then retired to bed in darkness. On each occasion, between 0030 h and 0100 h, the subjects were required to get up and were treated with light of different intensities; (a) less than 1 lux, (b) 300 lux and (c) 2500 lux respectively. Subjects returned to bed in darkness until 0700 h. Blood was sampled hourly from 2000 h-1000 h with additional samples at 2330 h, 0015 h, 0030 h, 0045 h, 0115 h and 0130 h. Plasma melatonin and 6-sulphatoxymelatonin (aMT6s), the major melatonin metabolite, were measured by radioimmunoassay. Dim (300 lux) and bright (2500 lux) light, both significantly suppressed melatonin levels compared to less than 1 lux (P less than 0.05 and P less than 0.01 respectively) at the following time points 0100 h, 0115 h and 0130 h. One subject did not show suppression with 300 lux. There was also a significant suppression of aMT6s levels, compared to less than 1 lux, after both 300 lux and 2500 lux at 0115 h (P less than 0.05, P less than 0.01), 0130 h (P less than 0.01, P less than 0.01) and 0200 h (P less than 0.01, P less than 0.001) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

Cyclosporine-induced acute renal dysfunction in the rat. Evidence of arteriolar vasoconstriction with preservation of tubular function.

Dose-related cyclosporine-induced renal dysfunction is the most frequent adverse effect noted with this exciting immunosuppressive drug. To investigate pathogenetic factors involved, we studied renal tubular function and afferent arteriolar morphology during severe experimental cyclosporine-induced reduction in glomerular filtration rate. Pair-fed male rats were given cyclosporine 50 mg/kg or olive oil vehicle alone by gavage for periods of 3-14 days. Glomerular filtration rate declined progressively, reaching a nadir of 0.18 +/- .05 ml/min/100 g vs. .86 +/- .03 ml/min/100 g in controls at 14 days (P less than 0.001). Despite the severe reduction in glomerular filtration rate there was no difference in fractional sodium excretion, fractional lithium excretion, enzymuria, or in vitro renal cortical slice uptake of tetraethylammonium in cyclosporine and vehicle-treated animals. Light microscopy showed vacuolar changes without evidence of tubular necrosis at 7 and 14 days in cyclosporine-treated rats. Progressive decline in the diameter of the afferent arteriole was noted by scanning electron microscopy. By day 14 the lumenal diameter of afferent arterioles from cyclosporine-treated animals was 8.9 +/- 0.4 micron vs. 13.5 +/- 0.4 micron in controls (P less than 0.05). We conclude that afferent arteriolar vasoconstriction rather than direct tubular injury is a major pathogenetic factor in experimental cyclosporine nephrotoxicity.

Acute Kidney Injury↗
PubMed1987

Metabolism and pharmacokinetics of melatonin in the ewe.

The pineal hormone melatonin has been used to advance the onset of the breeding season in sheep and thus produce lambs earlier in the year. If this reproductive manipulation is to be used commercially, some knowledge of the route of metabolism and identity of possible metabolites is necessary. A major metabolite of melatonin in rodents and man is 6-hydroxymelatonin sulphate (acetyl-methoxytryptamine-6-sulphate [aMT6S]). No significant amounts of this metabolite could be found in the plasma of untreated ewes. After subcutaneous implantation of melatonin for 5 months, plasma levels of aMT6S were also insignificant. On the other hand, both a single oral dose of melatonin (3 mg) and daily oral dosing gave rise to circulating levels of aMT6S in the range of 150 to 1,500 pg/ml for at least 18 h. The profiles seen after 180 days treatment were similar to those seen after a single dose, indicating that this route of melatonin metabolism is not induced by chronic administration. Intravenous injection of melatonin (200 or 20 micrograms) gave rise to detectable levels of aMT6S in the plasma. These results indicate that the quantitative aspects of melatonin metabolism differ according to the route of administration.

Administration, Oral↗
PubMed1987

Short-term variations of circulating melatonin in the ewe.

Melatonin levels have been studied in venous blood sampled at different frequencies (0.5-, 2-, and 60-min intervals) form intact ewes. All samples were taken during the dark phase of either natural or artificial photoperiods. In one experiment samples were taken simultaneously from both jugular veins to investigate the possible effects of "streaming" on the levels measured. Plasma cortisol was measured to ascertain whether or not the frequent removal of blood activated the ACTH stress axis. Plasma melatonin levels showed considerable variation with peaks of up to 365 pg/ml on a baseline of between 30 and 60 pg/ml. There was consistent evidence of intermittent peaks, the frequency of which increased with an increase in sampling frequency. Plasma cortisol showed no correlation with either the frequency or the amplitude of the melatonin peaks. When plasma samples were taken from both jugular veins a similar melatonin pattern was seen in the samples from both sides, but samples taken from the left jugular vein invariably showed higher levels than those taken from the right vein. This may be due to differential vascular drainage of the pineal to the two sides.

Animals↗
PubMed1987

Changes in plasma concentrations of LH, FSH and prolactin in ewes receiving melatonin and short-photoperiod treatments to induce early onset of breeding activity.

Breeding activity was similarly advanced in ewes given continuous (s.c. implant) or timed (oral dose at 15.30 h) melatonin treatments or subjected to a short (8 h light: 16 h darkness) artificial photoperiod. Treatments commenced in mid-June and were terminated in mid-November. Weekly and serial blood samples were collected before and after treatments commenced, to ascertain the effects on plasma prolactin, LH and FSH concentrations. In addition, serial blood samples were collected for 24 h plasma prolactin and melatonin estimations before and after cessation of the treatments. Plasma prolactin levels were significantly reduced immediately following the start of the melatonin (implant and oral) and short-photoperiod treatments but 'rebounded' to levels greater than control values. The normal seasonal (spring) rise in plasma prolactin was noted in the following year. Before the onset of breeding activity, mean plasma LH and FSH concentrations and LH pulse frequency did not change following any of the treatments. The 24-h plasma melatonin profile accurately reflected the various applied treatments but had re-entrained to the prevailing (natural) photoperiod 1 week after termination of the treatments. There were no significant group differences in 24-h plasma prolactin levels 1 week before or 1 and 11 weeks after the treatments had ceased. Such treatments, although successfully advancing the onset of breeding activity and modifying the seasonal plasma prolactin rhythm, were not manifested through any apparent change in peripheral LH or FSH.

Animals↗
PubMed1987

Induction of early seasonal sensitivity to melatonin in Suffolk-Cross ewes.

Anoestrous Suffolk-Cross ewes can be induced into early seasonal ovarian activity by administration of melatonin at the appropriate time of day or by melatonin implants. This treatment is successful if commenced in June, but not earlier in April or May and suggests that a critical period of long days may be necessary before artificial short-day melatonin profiles act as winter time-cues. We have investigated whether the lack of sensitivity to melatonin in April could be overcome in ewes in which breeding activity had been artificially moved forward the previous season. The results indicate that this was indeed the case and that the breeding season in untreated ewes which also previously experienced an early induced breeding season reverted to the normal timing for the Suffolk-Cross breed.

Animals↗
PubMed1987

Acute effects of iron therapy on zinc status during pregnancy.

The acute effects of iron therapy on zinc status during pregnancy were investigated. The 20 subjects studied were healthy and had unremarkable obstetric histories. The mean stage of gestation was 27 weeks (range 21-33 weeks). Initial hematologic indices (mean +/- SEM) were: hematocrit 36.5 +/- 0.4%, serum ferritin 32.6 +/- 6.1 ng/mL, and serum iron 117 +/- 13 micrograms/dL. Iron therapy, prescribed by the obstetric caregivers, provided a total average daily elemental iron intake of 261 mg (range 164-395 mg) from therapy and routine supplements. Laboratory studies of zinc status were obtained immediately before iron therapy and at one and four weeks thereafter. Initial plasma zinc was 62.9 +/- 2.1 micrograms/dL. A mean decline in plasma zinc of 4.0 +/- 1.8 micrograms/dL (P less than .05) was observed from baseline to one week. The decline remained statistically significant after adjustment for the expected physiologic decline over the same interval of gestation. No further decline occurred from one to four weeks. No significant treatment-related effects were observed for neutrophil zinc, mononuclear leukocyte zinc, or serum alkaline phosphatase activity. These results indicate that iron therapy in doses typically prescribed by obstetric caregivers in this country has an acute, measurable effect on maternal zinc status.

Adult↗
PubMed1986

Benign melanocytic naevi as a risk factor for malignant melanoma.

Examination of 180 patients with cutaneous malignant melanoma and 197 control patients in a case-control study showed that the risk of melanoma is strongly related to numbers of benign melanocytic naevi (moles). Some unusual features of naevi--a diameter exceeding 7 mm, colour variation, and irregular lateral outline--also showed a strong association with the risk of melanoma, but the relation of numbers of naevi to risk was present even in the group of patients whose naevi had none of these unusual features. Biopsy of clinically atypical naevi from several of the patients at highest risk generally did not show dysplastic histology. Thus a group of people at high risk of melanoma may be identified by using simple clinical assessment of naevi.

Adolescent↗
PubMed1986

Persistent 24-h variations of urinary 6-hydroxy melatonin sulphate and cortisol in Antarctica.

Bright light (2000-3000 lux) of sufficient intensity to suppress human melatonin secretion, acts as a strong zeitgeber in the entrainment of circadian rhythms in man. In polar conditions, light of this intensity is not experienced for several weeks during the winter. The entrainment of human circadian rhythms, in particular that of melatonin, is clearly of interest in these circumstances. Urinary 6-hydroxy melatonin sulphate (aMT6s) is a good index of melatonin secretion in man. In a limited study of seven male volunteers living on an Antarctic base the overall 24-h rhythm of aMT6s excretion was maintained at four different times of year (spring, summer, autumn and winter) and no significant seasonal effects were noted. Cortisol excretion, appeared to be markedly affected by the season although other factors such as social and environmental stress cannot be discounted. These observations suggest that in the absence of a strong light-dark cycle melatonin production may be entrained by other factors.

Antarctic Regions↗
PubMed1986

The effects of exogenous melatonin on endocrine function in man.

At two different times of year (spring and autumn) an oral preparation of the pineal neurohormone melatonin, or placebo, was administered to 12 healthy volunteers (10 men and two women in spring: the same group minus one man in autumn) daily at 1700 h for 1 month (spring), or 3 weeks (autumn) using a double-blind cross-over protocol. The daily dose was 2 mg melatonin in 5 ml corn-oil, and placebo consisted of the vehicle only. In spring the anterior pituitary hormones LH, PRL, GH together with T4, cortisol, testosterone and melatonin were measured at 1- to 6-h intervals for 24 h in plasma on the day following the last dose. In autumn PRL, cortisol and melatonin levels were measured on the last day of treatment. Subjective fatigue, mood and sleep records were kept throughout the studies. Melatonin increased early evening fatigue and actual sleep, but had no effect on mood: these results are reported in full elsewhere. Melatonin administration had no effect on the levels or 24-h rhythm of LH, GH, T4, testosterone or cortisol. An earlier fall in the nocturnal PRL was observed on both occasions. Overall PRL levels were higher in spring than in autumn. In five of the subjects, the secretion of endogenous melatonin was advanced by 1-3 h in the presence of exogenous melatonin. These observations suggest that the potential therapeutic use of melatonin as a hypnotic or in the treatment of jet lag is unlikely to be complicated by undesirable endocrine effects.

Adult↗
PubMed1986

A comparison of the efficiency of melatonin treatments in advancing oestrus in ewes.

Early oestrous cycles were induced in adult, maiden, 18-month-old Suffolk-cross ewes, maintained from birth in natural photoperiod by the following treatments applied from mid-June: subcutaneous implantation of melatonin (1 g) in Silastic packets, daily, oral, melatonin administration (3 mg/ewe) at 15:30 h, an artificial photoperiod of 8L:16D (lights on 07:30 h). Ovarian cycles began 5-10 weeks before those of control ewes maintained in a natural photoperiod. In contrast, the onset of ovarian cycles in ewes given s.c. implants of melatonin (1 g) in April, and a further group in May, was highly variable, and not significantly different from that of the control ewes. Plasma melatonin profiles in sheep with implants showed a night-time rise super-imposed on a constant level, which was itself within the physiological night-time range. Implant-derived melatonin declined with time but remained at or above physiological night-time levels for at least 3 1/2 months. These results indicate that melatonin implants in June, but not in April or May, advance onset of oestrus in the non-lactating, adult ewe. The effects of melatonin implants in June on onset of ovarian cycles were indistinguishable from those of melatonin feeding or artificial short photoperiod initiated at this time of year.

Administration, Oral↗
PubMed1986

Effects of various melatonin treatments on plasma prolactin concentrations in the ewe.

Ewes were treated with s.c. implants of melatonin in mid-April, mid-May and mid-June. From mid-June, other animals were given oral doses of melatonin daily at 16.30 h and another group was maintained under a short (8 h light:16 h darkness) artificial photoperiod (lights out 16.30 h). Serial blood samples were taken from all animals in June and July. Plasma prolactin concentrations were significantly reduced in ewes treated in May and June (implant, oral and photoperiod treatments) but not in those treated in April. After treatment in June, prolactin levels were significantly suppressed after 7 days of oral and implant melatonin therapy, and after 28 days of a short artificial photoperiod. Melatonin treatment appeared more efficient than an artificial photoperiod in reducing plasma prolactin concentrations.

Animals↗