Biomedical subjects
Publications and source records attributed to M Wilkinson.
Microsystems are devices that incorporate a combination of microfluidic, micromechanical, micro-optical and microelectronic components. This users' guide provides information on how to access the technology and find the resources needed for design, prototyping and manufacture in Europe.
Microsystems incorporate a combination of microfluidic, micromechanical, micro-optical and microelectronic components. This article, the fourth in a series exploring the impact the technology is likely to have on medical products during the next decade, looks at cochlear implants, retinal implants and devices to stimulate the optical cortex.
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The identification of estrogen-responsive genes in the heart, is necessary to understand estrogen-induced changes in cardiac function. Using Delta RNA fingerprinting, we demonstrate that a single injection of estradiol benzoate (50 microg, s.c.) revealed mRNA species that were elevated, down-regulated, or were unaffected in the heart tissue of ovariectomized female rats. One of the upregulated genes was identified, by cloning and sequencing, to have 95.8% (230/240) identity with the 3' end of the rat ant1 gene encoding the mitochondrial adenine nucleotide translocator, ANT1. Using the isolated ANT1 cDNA (280 bp) as a probe in Northern analysis, estrogen was shown to upregulate the expression of cardiac ANT1, by at least 3-fold in female rats, from as early as 1 h to as long as 24 h. In contrast, estrogen treatment had no effect on ANT1 expression in heart tissue from male rats. RNA yields were low in rat atria and no transcript was detectable by Northern analysis. Using primers specific to the known rat ANT1 gene, the estrogen upregulation of the cardiac ANT1 transcript in female rat was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR); a predicted product of 249 bp was obtained and this was stimulated by at least 3-fold upon estrogen treatment for 24 h.
High-functioning children with autistic-spectrum disorder show the typical pattern of lower Comprehension relative to their own scores on Block Design. This profile is shared, almost exactly, by age- and IQ-matched children with poorer control PKU. Quite distinct profiles are shown by children with better control PKU, who show no difference between Block Design and Comprehension, and by children with head injury involving frontal lobe contusion, who show slightly better Comprehension that Block Design. The data bear on several questions: the relation between Comprehension deficits and language functions measured by Vocabulary; the limits of the advantages conveyed by higher IQ to autistic individuals; whether impaired Comprehension in autism indexes persisting symptoms and/or impairments on theory of mind tasks; the possibility that dopamine deficiency is common to autism and poorer control PKU; and the need for future research aimed at understanding the relations among neurodevelopmental disorders.
This is a presentation of a doctoral thesis of 1870. The author was English but the thesis and the examinations were in French. Elizabeth Garrett Anderson, usually referred to as E.G.A., was the first woman in Britain to obtain the title of M.D., but not the first in Europe. Nadeshda Prokofevna Suslova, a Russian, received her M.D. in 1867 in Zurich, the most liberal university at that time, soon to be flooded by female students from Russia. E.G.A. had been applying to the few possible European universities but she settled for Paris after the Empress Eugenie had decided that she should be accepted there. This meant that she could succeed without having to be a Paris resident, just by writing a thesis and passing a series of examinations presided over by Paul Broca. This was important as she was already conducting private and dispensary practice, and could not find a locum (she insisted on a woman). E.G.A. had suffered many setbacks, for being a woman, as such being unacceptable in dissection rooms and operating theatres, and generally in a professional career where women were unheard of. She was finally permitted to receive her medical diploma from the Worshipful Society of Apothecaries of London. She wrote about her thesis: "I have chosen Headache as its subject. I had to find a subject which could be well studied without post-mortem observations, of which I can have but very few in either private or dispensary practice; and I wished also to take a large subject, one that demanded some insight into the harmony that exists between the main physiological functions." Marcia Wilkinson (M.W.), who worked in the Elizabeth Garrett Anderson Hospital in London for 35 years, heard there of E.G.A.'s thesis on migraine and sent for it from Paris. In 1966 she translated it into English from the original French, being interested both in the subject and in the person of this resolute and lucid woman. When H. Isler found the French thesis in the British Library he intended to translate it but, after discussion, we decided on a joint effort (95% of the translation is by M.W.; very few details were changed, and some footnotes added for better understanding). We think that E.G.A.'s text is a classic, showing profound understanding, sound practical advice, and also, in its theoretical part, the limits of neurophysiological knowledge in Paris when Brown-Sequard was "charge des cours" there. We may add that in her various examinations she had to answer questions, in French, on the use of footprints by the police, the general nature of fishes, toxic fishes, electric fishes, cod liver oil, and the secretion of tears. She earned much applause from the public, which consisted of male French students, and the overt appreciation of Paul Broca, head examiner, and Dr Wurtz, the Dean of the Faculte de Médecine. The impact of her thesis in the 19th century was modest. It appears to be rather marginal in the German literature of the early 20th century, but it has imprinted the management of migraine at the City of London Migraine Clinic in the last thirty years. The importance of nutrition, regular meals, regular habits, the need to supplement analgesics with antiemetics, and the treatment of the attack with rest, and great quantities of hot tea, were certainly related to E.G.A.'s doctrine. The internationally prevailing recommendation to give antiemetics, and then only analgesics, as well as the combination of both in one tablet, may thus be traced back to E.G.A. via the teachings of M.W. and Nat Blau.
The adipocyte-derived hormone, leptin, and its receptor, are now known to be integral components of a physiological signalling system that regulates fuel stores and energy balance. Constitutive leptin expression has been demonstrated only in adipose tissue, placenta and stomach. We have used RT-PCR to show that leptin mRNA is selectively transcribed in specific areas of rat brain and pituitary, and in a rat glioblastoma cell line. Using immunocytochemistry we have also shown leptin protein immunoreactivity in the corresponding tissues and cells, and confirmed this by Western blot using two epitope-specific antisera. Leptin mRNA expression in the hypothalamus is suppressed by fasting (48hr), suggesting a role for brain leptin in the central regulation of appetite. These data support the hypothesis that central nervous system derived leptin is a likely ligand for central leptin receptors.
We examined home care as an alternative to hospital admission in exacerbations of chronic obstructive pulmonary disease (COPD). We performed a pilot study to investigate the feasibility of using telecommunications technology to assist in the support of acutely ill patients with exacerbations of COPD at home. Realtime, interactive video, via an analogue video-phone, was used to allow patients in their own homes to obtain nursing support from a nurse located at a distant base station. Six individuals, four male and two female, had video-phones installed in their homes by members of the nursing intervention team. The age range was 52-72 years, mean 61.5. These patients used the system on 18 occasions. Experience in home telecare, via interactive video, has been limited to provision of ongoing support for relatively stable individuals with chronic illness. This pilot project represents the first attempt at providing home telecare in the UK to those experiencing an acute exacerbation of their chronic illness, who would otherwise have merited acute hospital admission.
OBJECTIVE: To determine whether cardiac oxytocin receptors are detectable by radioligand binding assay. Results from in vitro and in vivo animal studies suggest a possible direct effect of oxytocin on the cardiovascular system. DESIGN: A radioligand binding assay was used to characterize and quantify specific binding of [3H] oxytocin to standardized micropunches (thickness 400 microm; diameter 2 mm) obtained from rat left ventricle and human right atrium. Tissues from fetal and newborn rat heart were also studied. MAIN RESULTS: Saturable, high affinity binding of [3H] oxytocin to rat left ventricle was observed, consisting of a high affinity site (affinity [KD] approximately 1 nM; receptor density [Bmax] approximately 1480 fmol/mg protein) and a higher capacity, lower affinity site (KD approximately 75 nM; Bmax 3730 fmol/mg protein). Binding was displaceable by oxytocin, vasopressin and the agonist [Thr4, Gly7] oxytocin but not by the antagonist atosiban. Cardiac binding was reduced in ovariectomized (ie, estrogen-free) rats and increased in late gestation rats, when blood levels of ovarian steroids are maximal. Cardiac oxytocin receptors were undetectable in fetal and newborn rat heart. High concentrations of specific [3H] oxytocin binding were also found in samples of human right atrial appendage. CONCLUSIONS: These data confirm the presence of a specific oxytocin binding site in rat left ventricle and in human atrium. Binding density is regulated by ovarian steroids and is especially marked in the late stage of pregnancy. These observations provide an explanation for the putative direct effect of oxytocin on cardiac function.
OBJECTIVE: To determine whether cardiac output can be augmented by preferentially activating cardiac adrenergic efferent neurons. DESIGN: Elicited cardiac output responses were compared when cardiac myocytes were directly stimulated by a beta1-adrenoceptor agonist versus when they were indirectly influenced by beta2- adrenergic-sensitive cardiac efferent neurons. ANIMALS AND METHODS: The beta1-adrenoceptor agonist dobutamine or the selective beta2-adrenoceptor agonist terbutaline was continuously infused individually into the systemic circulation of 15 anesthetized pigs for 20 mins in 5 and 15 microgram/kg/min doses. Heart rate, left atrial chamber pressure, regional left ventricular intramyocardial systolic pressure, left ventricular chamber pressure and aortic pressure were monitored. Cardiac output was determined via the thermodilution technique before and at 10 min intervals during drug infusions. Ventricular tissues were removed thereafter and immediately frozen in liquid nitrogen for subsequent cardiac myocyte cell surface beta-adrenoceptor analysis. MAIN RESULTS: Both doses of terbutaline increased heart rate (approximately +18%) and cardiac output (approximately +20%). Heart rate (+12%) and cardiac output (+16%) increased when the high dose of dobutamine was tested. Left ventricular intramyocardial systolic pressure was increased by dobutamine (+15%) but not by terbutaline. Porcine ventricular cardiac myocytes primarily possess cell surface beta1-, rather than beta2-, adrenoceptors, making it unlikely that cardiac myocytes were directly affected by the doses of terbutaline tested. CONCLUSIONS: Beta2-adrenoceptor agonists enhance cardiac output primarily as a result of neuronally induced increases in heart rate in the porcine model. Adrenergic efferent neuronal enhancement of heart rate may be an effective way to increase cardiac output independently of directly augmented ventricular dynamics. Further study is required to determine whether the diseased myocardium can be supported by such neurocardiological means.
The odours of adult males, which accelerate the timing of puberty of female mice, activate c-fos in the accessory olfactory bulb (AOB). To test the hypothesis that NMDA receptors are involved in the male odour-induced increase in c-fos expression, we studied the effects of the non-competitive NMDA receptor agonist MK-801 on male odour-induced c-fos expression in the AOB of juvenile female mice. Surprisingly, MK-801 increased FOS-like immunoreactivity (FLI) within the AOB in the absence of male odour and had no effect on male odour-induced c-fos expression. We suggest that MK-801 increases AOB mitral cell activity by disinhibiting GABAergic granule cells, resulting in increased c-fos expression throughout the AOB.
Intraventricular administration of carbachol can induce phase shifts in wheel-running activity in rodents, which depend on circadian phase and are mediated via muscarinic cholinergic receptors in Syrian hamsters. We studied the circadian variation in binding of [3H]-N-methylscopolamine ([3H]NMS), a hydrophilic muscarinic receptor antagonist, in micropunches obtained from the anterior hypothalamus and occipital cortex of Syrian hamsters housed in a 14:10 light:dark cycle. Binding sites were characterized on cells contained within 1 mm punches (obtained from slices 300 microm thick), using a method to selectively detect cell surface (functional) receptors. Atropine sulphate was used to determine nonspecific binding. Cortex showed a significant daily rhythm in [3H]NMS binding with a peak occurring late in the light phase and a trough at lights on, while the hypothalamus showed no detectable rhythm. Following suprachiasmatic nucleus (SCN) ablation or maintenance in constant darkness, the rhythm in the cortex was abolished. These findings suggest that photic information conveyed via the SCN is responsible for the receptor binding rhythm in the cortex. Autoradiographic studies ([3H]NMS; 2 nM, 3 weeks exposure) clearly revealed both M1 and M2 subtypes of muscarinic receptors in the region of the SCN and the visual cortex.
MK801 induces Fos-like immunoreactivity (FLI) in the paraventricular nucleus (PVN) in a sex, age, hormone and dosage dependent manner. MK801 (1.0 mg/kg) elicited greater behavioural disruption, but less FLI in the PVN of cycling and lactating female rats, compared to like-treated males. Results from gonadectomized rats with or without acute steroid replacement resembled those seen in intact rats but sex differences were extinguished. At a lower dose (0.1 mg/kg), behavioural effects were diminished but females exhibited more behavioural disruption. At this dose however, more FLI was seen in the PVN of females compared to males, but only male-lactating female differences were significant. Taken together, the data suggest that the action of MK801 on the PVN is influenced by gonadal steroids.
Narratives are not only about events, but also about the emotions those events elicit. Understanding a narrative involves not just the affective valence of implied emotional states, but the formation of an explicit mental representation of those states. In turn, this representation provides a mechanism that particularizes emotion and modulates its display, which then allows emotional expression to be modified according to particular contexts. This includes understanding that a character may feel an emotion but inhibit its display or even express a deceptive emotion. We studied how 59 school-aged children with head injury and 87 normally-developing age-matched controls understand real and deceptive emotions in brief narratives. Children with head injury showed less sensitivity than controls to how emotions are expressed in narratives. While they understood the real emotions in the text, and could recall what provoked the emotion and the reason for concealing it, they were less able than controls to identify deceptive emotions. Within the head injury group, factors such as an earlier age at head injury and frontal lobe contusions were associated with poor understanding of deceptive emotions. The results are discussed in terms of the distinction between emotions as felt and emotions as a cognitive framework for understanding other people's actions and mental states. We conclude that children with head injury understand emotional communication, the spontaneous externalization of real affect, but not emotive communication, the conscious, strategic modification of affective signals to influence others through deceptive facial expressions.
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Zolmitriptan is a selective 5-HT1B/1D receptor agonist for acute oral migraine therapy. This randomized, placebo-controlled, parallel-group study investigated the efficacy and tolerability of oral zolmitriptan (5, 10, 15 and 20 mg) in the treatment of single acute migraine attacks. Of 1181 patients randomized, 840 were evaluable for the primary efficacy analysis. Headache response rates (a reduction in headache intensity from severe or moderate at baseline to mild or no pain at 2 hours post-treatment) were similar across the zolmitriptan dose groups (66%, 71%, 69% and 77% for 5 mg, 10 mg, 15 mg and 20 mg, respectively) and were significantly higher than that for placebo (19%; all groups P < 0.001). A headache response was reported at 1 hour by 40-50% of zolmitriptan recipients (16% placebo). At 2 hours post dose, 39-47% of zolmitriptan-treated patients were pain-free, compared with 1% of placebo recipients. Headache recurrence occurred in 21-29% (upper 95% CI 37.1) of zolmitriptan-treated patients and in 65% (95% CI 38.3, 85.8) of placebo recipients. Zolmitriptan was well tolerated at each dose. The most commonly reported adverse events were asthenia, dizziness, paraesthesia and feelings of heaviness. Most adverse events were of mild or moderate intensity and were transient. The frequency of adverse events was dose-related. Although, zolmitriptan 5 mg exhibited the most favourable efficacy and tolerability profile, the dose response data suggest that lower doses would also offer significant efficacy. Copyright 1998 Lippincott Williams & Wilkins
S-fluoxetine is the long-acting enantiomer of the racemic antidepressant serotonin reuptake inhibitor. Sixty-five patients needing migraine prophylaxis were recruited into a phase II, double-blind, placebo-controlled trial. After a 1-month placebo run-in, 53 patients met entry criteria with regard to attack frequency and were randomized, 27 to S-fluoxetine and 26 to matching placebo. Three failed to start treatment and there were 17 early discontinuations, 9 from S-fluoxetine, 8 from placebo, at similar times and for similar reasons. The primary efficacy variable was attack frequency and analysis compared decline-from-baseline in the two groups. This was earlier and greater (1.7 attacks/28 days, or 52%) on active therapy than on placebo (1.1 attacks/28 days, or 27%), and statistically significant in month 2 (F = 4.93; p = 0.033) and month 4 (F = 4.55; p = 0.041). As secondary measures of efficacy, migraine-days per month and Patient's Global Impression of Disease Severity coherently reflected the changes in attack frequency. Mean attack severity and acute medication use (doses per attack) were unaltered by either treatment. There were no serious adverse events. Withdrawals for adverse events were four from each group but none was considered causally related. The finding of greater efficacy of S-fluoxetine than of placebo should be interpreted conservatively, since the analysis in the final month was made on only half of the entered patients. It supports progression to phase III evaluation, which was the purpose of the study.