The effects of age and biological sex on the association between I-wave recruitment and the response to cTBS: An exploratory study.

The neuroplastic response to continuous theta burst stimulation (cTBS) is inherently variable. The measurement of I-wave latencies has been shown to strongly predict the magnitude and direction of the response to cTBS, whereby longer latencies are associated with stronger long-term depression-like responses. However, potential differences in this association relating to age and sex have not been explored. We performed cTBS and measured I-wave recruitment (via MEP latencies) in 66 participants (31 female) ranging in age from 11 to 78 years. The influence of age and sex on the association between I-wave recruitment and the response to cTBS was tested using linear regression models. In contrast to previous studies, there was not a significant association between I-wave latencies and cTBS response at the group level (p = 0.142, R2 = 0.033). However, there were interactions between I-waves and both age and sex when predicting cTBS response. Subgroup analysis revealed that preferential late I-wave recruitment predicted cTBS response in adolescent females, but not in adolescent or adult males or adult females. These data suggest that the generalisability of I-wave measurement in predicting the response to cTBS may be lower than initially believed. Prediction models should include age and sex, rather than I-wave latencies alone, as our findings suggest that, while each factor alone is not a strong predictor, these factors interact to influence the response to cTBS.

Cortical Plasticity and Interneuron Recruitment in Adolescents Born to Women with Gestational Diabetes Mellitus.

Exposure to gestational diabetes mellitus (GDM) in utero is associated with a range of adverse cognitive and neurological outcomes. Previously, we reported altered neuroplastic responses to continuous theta burst stimulation (cTBS) in GDM-exposed adolescents. Recent research suggests that the relative excitability of complex oligosynaptic circuits (late I-wave circuits) can predict these responses. We aimed to determine if altered I-wave recruitment was associated with neuroplastic responses in adolescents born to women with GDM. A total of 20 GDM-exposed adolescents and 10 controls (aged 13.1 ± 1.0 years) participated. cTBS was used to induce neuroplasticity. I-wave recruitment was assessed by comparing motor-evoked potential latencies using different TMS coil directions. Recruitment of late I-waves was associated with stronger LTD-like neuroplastic responses to cTBS (p = < 0.001, R2 = 0.36). There were no differences between groups in mean neuroplasticity (p = 0.37), I-wave recruitment (p = 0.87), or the association between these variables (p = 0.41). The relationship between I-wave recruitment and the response to cTBS previously observed in adults is also present in adolescents and does not appear to be altered significantly by in utero GDM exposure. Exposure to GDM does not appear to significantly impair LTD-like synaptic plasticity or interneuron recruitment.

Age-related decline of neuroplasticity to intermittent theta burst stimulation of the lateral prefrontal cortex and its relationship with late-life memory performance.

OBJECTIVE: Advanced age is accompanied by a deterioration in memory performance that can profoundly influence activities of daily living. However, the neural processes responsible for age-related memory decline are not fully understood. Here, we used transcranial magnetic stimulation (TMS) in combination with electroencephalography (EEG) to assess age-related changes in neuroplasticity in the human prefrontal cortex. METHODS: TMS-evoked cortical potentials (TEPs) were recorded before and following the neuroplasticity-inducing intermittent theta burst stimulation (iTBS), applied to the left lateral prefrontal cortex in healthy young (n = 33, mean age 22 ± 3 years) and older adults (n = 33, mean age 68 ± 7 years). RESULTS: iTBS increased the amplitude of the positive TEP component at 60 ms after the TMS pulse (P60) in young, but not older adults. This age-related decline in P60 plasticity response was associated with poorer visuospatial associative (but not working) memory performance in older adults. CONCLUSIONS: These findings suggest that neuroplasticity in the human lateral prefrontal cortex is reduced in older relative to young adults, and this may be an important factor in age-related memory decline. SIGNIFICANCE: This may have important implications for the early detection of cognitive decline and dementia.

Variability of the cortisol awakening response and morning salivary oxytocin in late adolescence.

Exogenously administered oxytocin interacts with the hypothalamic-pituitary-adrenal (HPA) axis to modulate endogenous cortisol levels, suggesting a synergistic role for these two hormones in the response to stress, cognitive performance and the development of psycho-behavioural disorders. The cortisol awakening response (CAR) is considered a reliable measure of HPA axis function in humans. However, the CAR appears to vary considerably from day to day and may be strongly influenced by the anticipated demands of the day ahead. The level of variation intrinsic to the CAR is unclear because few studies have examined the CAR in the absence of daily environmental variation. It is not known whether oxytocin has a similar or complementary awakening response. Therefore, over three consecutive days, we examined 12 adolescents (aged 15-17 years) in a highly-controlled sleep laboratory. Saliva was collected on days 4-6 of a 9-day laboratory visit. Cortisol and oxytocin levels were determined by an enzyme-linked immunosorbent assay from saliva sampled at 0, 15, 30 and 45 minutes, and 8 and 12 hours post-awakening. CAR magnitude varied between days and was associated with sleep duration and pre-awakening sleep stage. Conversely, oxytocin levels dropped dramatically in the first 15 minutes post-awakening and were highly consistent across participants and days. Older participants had higher awakening oxytocin concentrations. Although cortisol increases and oxytocin rapidly declines upon awakening, their diurnal variation does not appear to be related at basal, peripheral levels, consistent with a previous finding that exogenously administered oxytocin only modulates cortisol under conditions of stress.

Reduced Cortical Excitability, Neuroplasticity, and Salivary Cortisol in 11-13-Year-Old Children Born to Women with Gestational Diabetes Mellitus.

BACKGROUND: Children exposed to gestational diabetes mellitus (GDM) in utero are at increased risk of neurodevelopmental difficulties, including autism and impaired motor control. However, the underlying neurophysiology is unknown. METHODS: Using transcranial magnetic stimulation, we assessed cortical excitability, long-term depression (LTD)-like neuroplasticity in 45 GDM-exposed and 12 control children aged 11-13 years. Data were analysed against salivary cortisol and maternal diabetes severity and treatment (insulin [N = 22] or metformin [N = 23]) during pregnancy. FINDINGS: GDM-exposed children had reduced cortical excitability (p = .003), LTD-like neuroplasticity (p = .005), and salivary cortisol (p < .001) when compared with control children. Higher maternal insulin resistance (IR) before and during GDM treatment was associated with a blunted neuroplastic response in children (p = .014) and this was not accounted for by maternal BMI. Additional maternal and neonatal measures, including fasting plasma glucose and inflammatory markers, predicted neurophysiological outcomes. The metformin and insulin treatment groups had similar outcomes. INTERPRETATION: These results suggest that GDM can contribute to subtle differences in child neurophysiology, and possibly cortisol secretion, persisting into early adolescence. Importantly, these effects appear to occur during second trimester, before pharmacologic treatment typically commences, and can be predicted by maternal insulin resistance. Therefore, earlier detection and treatment of GDM may be warranted. Metformin appears to be safe for these aspects of neurodevelopment.

Acid-base balance and ventilation during sternal and lateral recumbency in field immobilized black rhinoceros (Diceros bicornis) receiving oxygen insufflation: a preliminary report.

Posture, ventilation, and acid-base balance using auricular venous blood values (pH, lactate, base excess [BE], HCO(3)(-), PO(2), SO(2), and PCO(2)), oxygen saturation of hemoglobin (SpO(2)), and end-tidal carbon dioxide (P(ET)CO(2)) were compared between sternal (STE) and lateral (LAT) recumbency in free-ranging black rhinoceros (Diceros bicornis bicornis) receiving oxygen insufflation. Data are reported as median, minimum, and maximum (median [minimum, maximum]). Thirty-six desert-adapted black rhinoceros (20 male, 16 female; age 8 [1.5, 33] yr) were immobilized in Namibia in March and April of 2008, from a helicopter, by remote intramuscular injection with etorphine HCl, azaperone, and hyaluronidase. Time from darting to recumbency was 6.0 (3, 15.5) min. Data were organized into two sampling periods: sample period 1 (P1, collected within 0-20 min postdarting; 13 [6.5, 19] min) and sample period 2 (P2, collected between 20-40 min postdarting; 32 [22.3, 39] min). All animals were acidemic (pH 7.24 [7.07, 7.32]) and hypoxemic (PO(2) 51 [38, 95.2]; SO(2) 78 [64, 96] mmHg) after capture. Lactate at P1 was 7.2 (3.2, 16.8) mmol/l and decreased (P=0.01) to 4.6 (1.2, 10.9) mmol/l at P2. At P2, lactate was less (P=0.06) in LAT 3.5 (1.2, 8.6) mmol/l than in STE posture 7.4 (3.1, 10.9) mmol/l. In P2, PO(2), SO(2), and SpO(2) were higher (P=0.02, 0.10, and 0.01, respectively) in STE than in LAT. End-tidal carbon dioxide in LAT was 38 (26, 47) mmHg and increased (P<0.001) rapidly to 48 (37, 55) mmHg when animals were moved into STE; no corresponding change in PCO(2) was observed. These preliminary findings suggest that STE posture in recumbent black rhinoceros reduces dead-space ventilation and improves oxygenation. Lateral posture was associated with lower blood lactate, quicker lactate recovery, or both. It is possible that the posture of recumbent rhinoceros after capture affects lactate accumulation and clearance, or both, and procedures should consider positioning in order to enhance perfusion.

Repeated use of the GnRH analogue deslorelin to down-regulate reproduction in male cheetahs (Acinonyx jubatus).

The GnRH analogue deslorelin, as a subcutaneous implant, was initially developed in Australia as an ovulation-inducing agent in mares. Its uses, for the suppression of reproduction in the domestic dog and cat and in other species, including humans, have been developed subsequently. Such implants have been used as a contraceptive modality in a variety of wild carnivores, both males and females. This paper describes the use of deslorelin implants as a contraceptive agent for cheetah males maintained in a semi-captive environment and housed in various camps together with females. Annually, male cheetahs were treated for 1 (n = 2), 2 (n = 7), 3 (n = 9), 4 (n = 3) or 5 (n = 1) consecutive years with an implant containing 4.7, 5.0 or 6.0 mg of deslorelin. On the first day of treatment and then on an annual basis, blood testosterone concentrations were analysed, testicular measurements were taken, appearance of penile spikes was determined, and semen was collected and evaluated. Pregnancy rates of mated or inseminated females were determined. A dose of 6 mg of deslorelin suppressed reproduction for at least 1 year, whereas with 4.7 and 5 mg of deslorelin, 3 of 17 males had a few non-motile spermatozoa in their ejaculates. All testosterone concentrations were basal at 1 year post-implant and no side effects were observed. We concluded that deslorelin implantation, at a dose of 6 mg, was a safe and reliable method of annual contraception in male cheetahs.

Cardiopulmonary effects of medetomidine or midazolam in combination with ketamine or tiletamine/zolazepam for the immobilisation of captive cheetahs (Acinonyx jubatus).

Captive cheetah (Acinonyx jubatus) scheduled for either general health examination or dental surgery were immobilised with combinations of medetomidine-ketamine (K/DET, n = 19), midazolam-ketamine (K/MID, n = 4) or medetomidine-tiletamine-zolazepam (Z/DET, n = 5). Induction time and arterial blood pressure was not statistically significantly (P > 0.05) different between treatment groups. Transient seizures were observed in the K/DET treated animals during induction. Hypertension was present in all groups during anaesthesia with mean (+/- SD) systolic pressure of 30.7 +/- 5.0 kPa for the K/DET group, 27.7 +/- 2.7 kPa for the K/MID group, and 33.1 +/- 4.6 kPa for the Z/DET group. Heart rate was statistically significantly (P < 0.05) lower in the K/DET group (69 +/- 13.2 beats/min) compared to the K/MID group (97 +/- 22.6 beats/min), and ventilation rate was statistically significantly (P < 0.05) lower in the K/MID group (15 +/- 0.0 breaths/min) compared with the K/DET group (21 +/- 4.6). A metabolic acidosis and hypoxia were observed during anaesthesia when breathing air. Oxygen (O2) administration resulted in a statistically significant (P < 0.05) increase in the arterial partial pressure of carbon dioxide (hypercapnoea), arterial partial pressure of O2, and % oxyhaemoglobin saturation.

Permanent testicular damage induced in rats by a single dose of tunicamycin.

Tunicamycin administered as a single subcutaneous dose of 200 micrograms/kg caused permanent destruction of seminiferous tubules in adult male rats. The fertility of females was unimpaired by doses of up to 450 micrograms/kg. Degenerative changes in seminiferous tubule epithelium commenced 3 to 5 days after injection and by day 19 affected 95% of tubule profiles in sections. In 95% of tubules only Sertoli cells survived to day 56. Tubules without any surviving cells were present from day 19 and slowly increased in number, a variable proportion becoming mineralised. No regeneration occurred within one year. Leydig cells became more prominent because of the atrophy of seminiferous tubules, but their total mass did not differ significantly from that of control rats, nor did the plasma concentration of testosterone. Changes in tissues other than the tests were transient. The testicular damage seems to have resulted from localised ischaemia caused by tunicamycin-induced vasoconstriction.

Antibodies to some pathogenic agents in free-living wild species in Tanzania.

A total of 535 sera from eight species of wildlife were collected from different game areas in Tanzania between 1987 and 1989. These sera were tested for antibodies against foot-and-mouth disease, bovine herpes virus types 1 and 2, lumpy skin disease, bovine viral diarrhoea, Akabane, bovine ephemeral fever, bluetongue, enzootic bovine leucosis, African horse sickness and African swine fever viruses and Brucella abortus based on the expected species susceptibility. Sera from buffalo Syncerus caffer, wildebeest Connochaetes taurinus and topi Damaliscus korrigum contained antibodies against the majority of the pathogens tested. Antibodies to fewer pathogens were detected in sera from the other species. No antibodies to lumpy skin disease virus were detected in any of the sera examined. African horse sickness antibodies were detected in sera from Zebra and African swine fever antibodies were detected in wart hog. The occurrence of antibodies to these agents suggests that wild species act as reservoirs of infection for some of these pathogens. However, until the susceptibility of individual species is proven by isolation of the aetiological agents their role must remain speculative.

A serological survey of rinderpest antibody in wildlife and sheep and goats in northern Tanzania.

An extensive serological survey for rinderpest antibody in wildlife, principally buffalo (Syncerus caffer), and sheep and goats has been undertaken in the previously endemic region of Northern Tanzania to determine whether or not the virus has continued to cycle in susceptible species since the last occurrence of overt disease in 1982. The results show that infection but not disease has occurred at least until 1987 in buffalo in parts of the Serengeti National Park but not in the other game areas of Tanzania where samples were taken. Sero-positive sheep and goats were widely distributed and have been found in 10 of the 14 districts sampled but there have been no reports of disease. These findings bring into question the possibility of eradicating the disease from Africa and continuous annual monitoring of this and other similar ecological zones will be required.

Does competition regulate ungulate populations? Further evidence from Serengeti, Tanzania.

Changes in populations of several ungulate species in the Serengeti-Mara region of East Africa over the past 30 years suggest several hypotheses for their regulation and coexistence. Recent censuses in the 1980s have allowed us to test the hypotheses that: (1) there was competition between wildebeest (Connochaetes taurinus) and Thomson's gazelle (Gazella thomsoni). This predicted that gazelle numbers should have declined in the 1980s when wildebeest were food limited. Census figures show no change in gazelle numbers between 1978 and 1986, a result contrary to the interspecific competition hypothesis; (2) wildebeest and African buffalo (Syncerus caffer) populations were regulated by intraspecific competition for food. Since both populations reached food limitation in the 1970s, the hypothesis predicted that the populations should have been stable in the 1980s. The results confirm these predictions for wildebeest and the buffalo population in the Mara reserve. In the Serengeti the buffalo population declined 41% over the period 1976-1984. The decline was not evenly distributed over the park, some areas showing an 80-90% decline, others no change or an increase in numbers. The decline was associated with proximity to human habitation; (3) an outbreak of the viral disease, rinderpest, in 1982 may have been the cause of the drop in buffalo population. Blood serum samples to measure the prevalence of antibodies were collected from areas of decreasing, stable and increasing populations. If rinderpest was the cause of decrease there should be a negative relationship between the prevalence of rinderpest and the instantaneous rate of increase (r). The results showed no relationship. We conclude that rinderpest was not the major cause of the drop in buffalo numbers. Elephant (Loxodonta africana) numbers dropped 81% in Serengeti in the period 1977-1986. In the Mara there was little change. The evidence suggests that extensive poaching in northern and western Serengeti during 1979-1984 accounted for the drop in both elephant and buffalo numbers.

The toxicity of phomopsin for sheep.

Pure phomopsin was administered to young Merino x Border Leicester wethers by single subcutaneous (SC) and by single and multiple intraruminal (IR) injection. The toxicity after IR injection was influenced by the size of individual doses and the time over which the total dose was given. At high levels of ingestion the toxicity of phomopsin may be limited by absorption rates; with low daily doses the capacity to repair liver damage may be sufficient to prevent cumulative effects. By SC injection a single dose of 10 micrograms/kg approximated the LD50. By IR injection the overall clinical, biochemical and histological responses closest to these of this SC dose resulted from a single dose of 1,000 micrograms/kg. The same total dose administered at daily rates of 50 or 200 micrograms/kg was more toxic and killed all sheep. A single dose of 500 micrograms/kg caused significant liver damage, but no deaths. Single doses of 125 and 250 micrograms/kg and repeated daily doses of 12.5 micrograms/kg over 16 weeks caused no detectable tissue damage. Inappetence was the most sensitive indicator of phomopsin toxicity. About 10% of the sheep differed substantially from the rest of the flock in their susceptibility to phomopsin poisoning.

Tunicamycin and corynetoxin poisoning in sheep.

Quantitative toxicity studies were carried out in sheep using corynetoxin, tunicamycin and toxic annual ryegrass (Lolium rigidum). Sheep were very sensitive to these toxins. The lethal dose was about 35 micrograms/kg bodyweight for pure tunicamycin given by subcutaneous injection and 3 to 5 mg/kg for corynetoxin administered orally as slurries of bacterial galls of known corynetoxin content. The total lethal dose was of the same order, whether given as a single dose or as repeated smaller doses, the maximum interval tested being 9 weeks between doses. This finding indicates that a second exposure of animals to toxic rye grass in the one season would present a greater risk than would a first exposure to the same field. It also demonstrates the advisability of the monitoring of pasture levels of gall contamination, as levels below those that produce clinical signs of the disease may still contribute to an accumulating burden of toxicity.

Correlation of the onset of experimental autoimmune encephalomyelitis-like clinical signs with oedema of the spinal cord in tunicamycin-poisoned rats.

The neurological signs induced by injection of tunicamycin are, in young adult rats, virtually identical to those typical of acute experimental autoimmune encephalomyelitis (EAE). Vasogenic exudation, of which the occurrence in the spinal cord of EAE rats has been shown to coincide with the onset of clinical signs, was investigated by quantitative electroimmunoblotting of central nervous system (CNS) tissue at various times following tunicamycin injection of young adult rats. Highly elevated levels of extravasated plasma proteins were observed in the spinal cord from 48 h after injection and, as in EAE rats, these increases coincided with the onset of neurological impairment. At 72 h post-injection, significant increases were also found in the brain of affected animals, albeit at much reduced levels. This is in contrast to previously reported findings in nursling rats where oedema was shown to be predominantly located in the brain. Quantitative electroimmunoblotting for myelin basic protein (MBP) in the CNS of tunicamycin-treated young adult rats indicated that, as in acute EAE, no extensive demyelination had occurred. These data provided further evidence that in both neurological diseases, vasogenic oedema of the spinal cord may be causally related to the appearance of neurological signs and suggested that its differential localization in the CNS may lead to differential neurological impairment.

Influences of various xenobiotic inducers on cytocidal toxicity of lasiocarpine and senecionine in primary cultures of rat hepatocytes.

The influences of in vivo pretreatment with phenobarbitone (PB), 3-methylcholanthrene (3-MC), 2,2',4,4',5,5'-hexachlorobiphenyl (HCBP), and 3,3',4,4'-tetrachlorobiphenyl (TCBP) on cytocidal hepatotoxicity of two pyrrolizidine alkaloids, lasiocarpine (LC) and senecionine (SC), were compared in short-term primary cultures of rat hepatocytes. Toxicity was measured by release of lactate dehydrogenase (LDH) into culture medium at 24 h. LC was slightly more toxic to control hepatocytes than SC in the graded response range of 10-160 microM. PB and HCBP (a PB-type polychlorobiphenyl inducer) similarly potentiated toxicity of SC, and each diminished the degree to which cell killing by LC and SC was inhibited by SKF-525-A. By comparison, 3-MC and TCBP (a 3-MC-type PCB inducer) each diminished toxicity of SC but had little effect on toxicity of LC. Alpha-naphthoflavone (ANF) potentiated toxicity of both LC and SC in hepatocytes induced by 3-MC or TCBP but had little effect on responses of hepatocytes induced by either PB or HDBP. These results indicate that xenobiotics that induce similar patterns of cytochrome P-450 isozymes have qualitatively similar modulating influences on cytocidal hepatotoxicity of pyrrolizidine alkaloids in primary cultures. However, the observed modulating effects could not be explained solely on the basis of altered activation rates by the cytochrome P-450 species known to be induced by the various xenobiotics.

Inhibition of glycosylation by corynetoxin, the causative agent of annual ryegrass toxicity: a comparison with tunicamycin.

The biological activities of corynetoxins, the causative agents of annual ryegrass toxicity, were compared with those of the closely related tunicamycins and found to be essentially identical. Both showed similar antibiotic activity against Newcastle disease virus and a range of gram-positive bacteria. In preparations of rat liver rough microsomes they also strongly inhibited the uridine diphospho-N-acetylglucosamine (UDP-GlcNAc):dolichol-P N-acetylglucosamine-1-phosphate (GlcNAc-1-P) transferase, an enzyme essential for N-glycosylation of glycoproteins. Pretreatment of rats with corynetoxins resulted in dose- and time-related reduction in the level of activity of this transferase in liver microsomal preparations. The implications of this reduction are discussed with reference to annual ryegrass toxicity, the only field disease known to be caused by tunicamycin-related compounds. Both corynetoxin and tunicamycin produced similar neurological effects and increased vascular permeability in nursling rats and they showed similar LD50-values of 137 and 132 micrograms/kg, respectively, in the nursling rats.