Which cyclosporin formulation?
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Biomedical subjects
Publications and source records attributed to J Dark.
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Hibernation patterns were monitored continuously for 2.5 years in female squirrels that were neurologically intact or in which the hypothalamic suprachiasmatic nucleus (SCN) was completely ablated (SCNx). The number of hibernation bouts in SCNx squirrels increased by 159%, total hibernation time increased by 58%, and periodic arousals from hibernation were 47% longer in SCNx than in control squirrels; the duration of individual torpor bouts was 2 days shorter and far more variable in SCNx than in control animals. Some SCNx squirrels cycled through bouts of torpor continuously for nearly 2 years. The SCN appears to be part of the mechanism that controls the duration of the hibernation season and the temporal structure of individual torpor bouts.
The role of HLA phenotype as a risk factor for drug-induced gingival overgrowth was investigated in a cohort of 172 transplant recipients. Clinically significant overgrowth warranting surgical correction was observed in 72 patients (42%). Using stepwise regression modelling, 6 clinical parameters were identified as significant risk factors for the severity of gingival overgrowth. These were; age, sex, creatinine plasma level, duration of therapy, papilla bleeding index and concomitant medication with a calcium channel blocking drug. 3 HLA alleles were also identified as risk factors when adjusted for other clinically significant risk factors (HLA -DR2, A24, B37). However, when the p-values for the HLA variables were corrected to compensate for the use of multiple significance testing, only HLA-B37 remained statistically significant at the 5% level. Organ transplant patients are at risk of developing gingival overgrowth, with approximately 25% medicated with cyclosporin alone requiring corrective gingival surgery. This figure more than doubles in patients concomitantly medicated with a calcium blocking drug. The data at present available would suggest that the severity of gingival overgrowth is also significantly associated with the HLA-B37 phenotype.
We tested whether 1) glucose availability is a signal for initiation of torpor in male hamsters and 2) glucoprivation can override the inhibitory effects of androgens on daily torpor. Male hamsters maintained at ambient temperatures of 8-16 degrees C were injected with 2-deoxy-D-glucose (2DG), a glucose analogue that interferes with cellular glucose oxidation. 2DG (2,000-2,500 mg/kg body mass) induced torpor within 1 h of treatment in normal adult males in reproductive condition and in those bearing testosterone (T)-filled capsules that produced supraphysiological blood T concentrations; body temperatures were reduced from 37 to 25 degrees C for several hours. Latency to torpor was increased and duration of torpor was decreased in the T-treated hamsters. Food intake decreased substantially both on the day of torpor and on the succeeding day. Glucoprivation appears to counteract the potent inhibitory effect of androgens on torpor and induces a hypometabolic state that results in overall energy savings.
We tested the hypothesis that continued secretion of gonadal steroids is necessary to suppress hibernation in male golden-mantled ground squirrels in the weeks after the terminal arousal in spring. Juvenile and adult males were gonadectomized or sham gonadectomized 1 wk after the terminal arousal; 64% of castrated and none of the shamcastrated animals resumed hibernation. Latency to resumption of torpor was 9 +/- 2 days from the time of castration, and squirrels underwent 4.3 +/- 0.9 bouts before permanently regaining euthermia. Among squirrels that resumed hibernation, bout duration was significantly shorter and torpor was shallower after castration. Castration as late as 3 wk after the terminal arousal reinstated hibernation. We suggest that the terminal arousal of male squirrels in the spring is provoked by a steroid-independent mechanism similar to that operating earlier in the hibernation season; abandonment of hibernation is contingent on concomitant sustained increases in androgen secretion during the first few weeks of euthermia.
We report a case of combined coronary artery by-pass grafting and orthotopic liver transplantation on cardiopulmonary bypass, in a 56-yr-old man with rapidly progressive ischaemic heart disease and end-stage liver disease. Three months after surgery he is asymptomatic with normal liver function.
Photoregressed Siberian hamsters exposed at 19 days of age to constant light for 24 h manifested increased testicular development 16 days later. Hamsters that sustained lesions of the suprachiasmatic nucleus (SCN) 3 days after the light pulse had significantly heavier gonads than did sham-operated animals or hamsters pinealectomized at 19 days of age. Enhanced reproductive development after SCN ablation is not due solely to lesion-induced elimination of melatonin secretion. SCN neural activity beginning 3 days after the light pulse is not necessary for light-induced gonadal growth.
It is well established that both cyclosporin and nifedipine are associated with gingival overgrowth. Although both drugs are widely used in the management of organ transplant patients, there is little information on the prevalence and severity of this unwanted effect in cardiac transplant patients. This study evaluated the gingival health of 94 dentate cardiac transplant patients, all of whom were medicated with cyclosporin as a component of their immunosuppressive therapy. Sixty-three (63) of the patients were also medicated with nifedipine. Significantly higher gingival overgrowth scores (P < 0.0001) and periodontal probing depths (P = 0.001) were observed in patients medicated with the combination of cyclosporin and nifedipine than those medicated with cyclosporin alone. Likewise, there was a significantly greater need to carry out gingival surgery on patients taking the combination (62%), than those medicated with cyclosporin alone (25.8%) (P = 0.001). Patient's age, sex, duration of therapy, gingival bleeding index, and nifedipine therapy were important determinants for both the expression of gingival overgrowth and the need for surgery. Significant sequestration of nifedipine in the gingival crevicular fluid (GCF) was observed. The concentration of nifedipine in GCF did not relate to either the gingival changes or plasma concentration of the drug. Cardiac transplant patients are at risk of developing gingival overgrowth and approximately 50% require surgical intervention. This risk increases significantly when patients are medicated concomitantly with nifedipine.
Meadow voles exhibit seasonal changes in litter size, ovulation rates, and prenatal mortality. To investigate the proximate bases of seasonal changes in reproductive effort, adult female voles, maintained in long photoperiods (14 h of light/day), were injected daily with 10 micrograms melatonin 2 h before light offset to extend the duration of the nighttime melatonin pulse. At parturition the number, sex, and weight of offspring were assessed. The number of ovarian corpora lutea (CL), an index of potential litter size, was used to calculate rates of prenatal survival (i.e., pups per CL). Prenatal survival rates were reduced in female but not male pups of dams that had been injected before blastocyst implantation (Days 1-6 of pregnancy) with melatonin as compared with saline. Melatonin injections initiated after blastocyst implantation (Days 7-21 of pregnancy) did not affect prenatal survival, nor were birth weights of pups affected by either pre- or postimplantation melatonin treatment. We conclude that sex-specific prenatal survival is a labile feature of vole reproduction that may be under proximate control of photoperiod and melatonin before blastocyst implantation.
Siberian hamsters kept in long photoperiods (16 h light/day) at 10 degrees C do not display torpor when provided with food ad libitum but do reduce their body temperatures (Tb) from 37 degrees C to as low as 15 degrees C for several hours each day in response to food restriction. Female hamsters maintained in a long photoperiod and fed ad libitum were injected with 2-deoxy-D-glucose (2-DG), a glucose analogue that reduces cellular glucose oxidation, or mercaptoacetate (MA), a drug that disrupts fatty acid oxidation. Dosages of 2-DG in excess of 1,500 mg/kg body mass reliably induced torpor with latencies of approximately 50 min from time of injection to a decrease in Tb below 30 degrees C; 79% of females displayed torpor at a dosage of 2,500 mg/kg. MA was uniformly ineffective in inducing torpor and did not increase incidence of torpor when combined with 2-DG treatment or food restriction. Decreased availability of glucose may be the major metabolic signal for inducing torpor in Siberian hamsters; availability of fatty acids appears to play little if any role in regulating this behavior.
Removal of the olfactory bulbs lengthened the period of circannual rhythms (CARs) of body mass and plasma testosterone (T) concentrations in male golden-mantled ground squirrels, but did not otherwise alter their expression. The period of the CAR was approximately 2 months longer in bulbectomized than in sham-operated animals. Peak values of body mass and T were unaffected by bulbectomy. All neurologically intact, but only 50% of bulbectomized, squirrels displayed normal hibernation patterns. We conclude that the olfactory bulbs are not the site of essential circannual oscillators. Circannual reproductive and hibernation cycles of ground squirrels are less subject to modulation by the olfactory bulbs than are the corresponding rhythms of several non-circannual hamster species.
Male golden-mantled ground squirrels held at 23 degrees C were fed high-fat (HF) or standard (chow) diets. In December, ambient temperature was reduced to 6 degrees C, food was removed, and frequency and duration of torpor bouts were monitored continuously by radiotelemetry. Reproductive condition and body composition were assessed upon terminal arousal in the spring. Juvenile males fed the HF diet weighed more than chow-fed controls before and throughout the hibernation season and had significantly greater lipid masses at terminal arousal. Testes masses and plasma testosterone concentrations were substantially higher in HF than in chow-fed juveniles. The accelerated reproductive development of fatter squirrels was not contingent upon increases in the total number of days spent in torpor, number of torpor bouts, or the average duration of each arousal from torpor. Access to the HF diet had no effect on body mass, adiposity, or reproductive status of adult male ground squirrels in spring. Threshold levels of white adipose tissue and associated differences in availability of metabolic fuels may be permissive for testicular growth during the hibernation season. Juveniles exceed this threshold only when fed the HF diet.
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Rates of brain growth differed in meadow voles maintained in long (LP) or short (SP) photoperiods postnatally. At 35 days of age, brain weight was greater by 6.6% in LP males and by 4.7% in LP females as compared to their SP counterparts. Whole brain galactolipid content, an index of brain myelin, was greater by 15.6% in LP as compared to SP males. At 70 days of age, brains of LP males were 4% heavier than those of SP males. Differences attributable to photoperiod were most pronounced in midbrain and hindbrain (8% and 14%, respectively). DNA and galactolipid contents were greater by 11% and 15%, respectively, in hindbrain of LP males. Photoperiod did not affect any of these measures in diencephalon, striatum, or cerebellum. Short day lengths reduce myelination in meadow voles, presumably by decreasing proliferation rates of oligodendroglia. This is one facet of a general delay in somatic development associated with being born at the end of the normal breeding season when day lengths are decreasing or below a critical threshold.
Male meadow voles kept in a long photoperiod (LP) from birth to 70 days of age have heavier brains than those kept in a short photoperiod (SP). Brain weights of male voles kept in the LP first exceeded those of SP animals at 20 days of age; differences were greatest at 35 days (5.8%) and persisted through 140 days of age (2%), although the magnitude of the difference declined progressively. Accelerated compensatory increases in brain weight were observed in voles transferred from the SP to the LP at 70 days of age. Total brain DNA content, an index of cell number, was not significantly affected by initial or final photoperiod, although it increased 7.8% within 70 days after voles were transferred from the SP to the LP. Brain weights (but not DNA content) of males exceeded those of females, but this sex difference was present only in the LP. We suggest that short day lengths retard brain development by reducing rates of myelination and possibly reducing cell size as well; this is part of a general retardation of somatic growth associated with a delayed onset of puberty that can be reversed by a stimulatory LP but, ordinarily, occurs spontaneously as voles become refractory to short day lengths.
In most adult mammals, brain weights of males exceed those of females. The role of androgens in the genesis of this sex difference was assessed in meadow voles by acute neonatal or chronic postweaning manipulation of testosterone titers. Female voles given a single injection of testosterone propionate (TP) on the second day of postnatal life had brain weights in adulthood that were indistinguishable from those of male voles and significantly heavier than those of control females. Whole brain DNA content, a measure of cell number, was not increased by neonatal TP treatment. Females treated with TP from day 19 to 70 had lower brain weights than control females and males gonadectomized at 19 days of age had greater brain weights than did intact male voles at day 70. The sex dimorphism in brain weight reflects organizational effects of testosterone during perinatal development. Beginning at weaning, and continuing through postpubertal development, testosterone decreases brain weight in both sexes. We suggest that testosterone affects brain weight by altering cell size or non-cellular components rather than cell number.
Hibernation and body mass rhythms were studied in 13 golden-mantled ground squirrels maintained in an LD 12:12 photoperiod at 5 degrees C. Complete or partial ablation of the suprachiasmatic nuclei (SCN) disrupted normal hibernation rhythms. Over the course of 2 years, several animals progressed through 4 hibernation cycles, one squirrel manifested two abnormally long hibernation seasons, and another failed to hibernate. Squirrels with intact SCN exhibited normal circannual hibernation rhythms at intervals of 11.5 +/- 0.3 months. Hibernation coincided with the weight loss phase of the body mass cycle in control squirrels, but these two rhythms were dissociated in animals with lesions of the SCN. The annual plasma testosterone rhythm was normal or slightly phase-delayed in squirrels with SCN lesions maintained at 23 degrees C. The SCN may be part of a neural circuit that mediates circannual organization of hibernation rhythms.