Biomedical subjects
Publications and source records attributed to C Leslie.
An alternative versatile synthesis of 5-cyanophthalide, a key synthetic intermediate in the preparation of the antidepressant drug Citalopram, is presented. The synthesis reported here allows the preparation of this important intermediate in three steps, avoiding the manipulation of environmentally detrimental cyanides.
BACKGROUND: Despite technical advances in the diagnosis and repair of blunt thoracic aortic injury (TAI),1,2 patients continue to die after arrival at trauma centers. Most of these deaths occur consequent to free intrapleural aortic rupture before surgical repair. We sought to identify characteristics of the subpopulation of blunt TAI patients at particular risk for early in-hospital death. METHODS: The records of a Level I trauma center were reviewed for the period from 1/1/90 through 5/1/00. Fifty-one patients with aortic injury were identified. A subgroup was identified with isolated aortic injury. The resultant study group consisted of 26 patients and included 11 cases of free rupture (FR) and 15 cases of contained rupture (CR). Data from both groups were analyzed for mechanism, abnormal vital signs, initial chest radiographic findings, symptoms, physical findings, time course from injury to rupture or treatment, clinical outcome, and pathologic findings. RESULTS: All 11 of the FR group died. In the CR group, 14/15 survived. Mechanism in all cases was "high-speed" or "head-on" motor vehicle collision. All cases with FR had the mediastinal abnormalities of "grossly widened mediastinum" + hemothorax; 10/11 had an episode of transient hypotension that initially responded to fluid resuscitation before their terminal event. In the CR group, there were a variety of chest radiographic findings, but only one "grossly widened mediastinum," no hemothorax, and no incidences of hypotension. However, multivariate analysis revealed that the combination of grossly widened mediastinum + hemothorax + transient hypotension was strongly and uniquely associated with those patients who went on to have free rupture (FR group) (p < 0.00001, Fisher's exact test). CONCLUSION: For patients exposed to a high-speed decelerative mechanism, the constellation of "grossly widened mediastinum + hemothorax with transient hemodynamic instability" appears not only to be highly specific for aortic injury but also to be a marker of impending sudden death from free rupture. This association would seem to warrant immediate surgery in this high-risk group without the traditional diagnostic studies.
The role of chemical control instability in the pathogenesis of obstructive sleep apnea (OSA) is not clear. We studied 32 patients with OSA during sleep while their upper airway was stabilized with continuous positive airway pressure. Twelve patients had repetitive OSA whenever they were asleep, regardless of body position or sleep stage, and were classified as having severe OSA (apnea-hypopnea index [AHI] = 88 +/- 19). The remaining 20 patients had sporadic OSA or repetitive OSA for only part of the time (mild/moderate OSA; AHI = 27 +/- 16). Susceptibility to periodic breathing (PB) was assessed by gradually increasing controller gain, using proportional assist ventilation. The increase in loop gain (LG) at each assist level was quantified from the ratio of assisted tidal volume (VT) to the VT obtained during single-breath reloading tests (VT amplification factor [VTAF]). Nine of 12 patients with severe OSA developed PB, with recurrent central apneas, whereas only six of 20 patients in the mild/moderate group developed PB (p < 0.02). This difference was observed despite the subjection of the mild/moderate group to greater amplification of LG; the highest values of VTAF in the mild/moderate and severe groups were 2.7 +/- 1.0 and 1.9 +/- 0.7, respectively (p < 0.01). We conclude that the chemical control system is more unstable in patients with severe OSA than in patients with milder OSA. We speculate that this may contribute to the severity of OSA, at least in some patients.
The professionalization of anthropology was grounded in a naturalistic tradition of field research. The empirical particularism of fieldwork wedded aesthetic and humanistic concerns with those of science in a discipline that assumed a species-wide and long-time perspective while focusing on the description and comparisons of local variations. Scientific progress has occurred in anthropology over the past century despite the distortions of colonialism, the Cold War, and other historical circumstances. Controversies about good and bad scientific work and about the humanistic character of anthropology have been an ongoing aspect of our discipline. The historical development of medical anthropology and important recent publications in this specialty illustrate the nature of the encompassing discipline and provide the ground on which 21st-century scholars will carry the science forward.
OBJECTIVE: To show that resuscitation from hypothermic, hemorrhagic shock using 65 degrees C intravenous fluid results in a more rapid return to euthermia compared with 40 degrees C intravenous fluid, without significant endothelial or hemolytic injury. DESIGN: Fourteen anesthetized beagles (10-12 kg) were cooled to a core temperature of 30 degrees C and hemorrhaged to a mean arterial pressure of 40 to 45 mm Hg for 30 minutes. The animals were randomized to receive either 65 degrees C or 40 degrees C intravenous fluid through a specially designed catheter at a rate of 80% of their blood volume per hour until euthermic (37 degrees C) or for 2 hours. MATERIALS AND METHODS: Blood pressure, pulmonary artery pressure, heart rate, and core temperature were continuously monitored. Blood samples were collected at baseline, after hemorrhage, 2 hours of resuscitation, and at postmortem examination after 7 days of survival. Laboratory measurements included complete blood count, plasma-free hemoglobin, and osmotic fragility. Values were compared using the Student's paired or unpaired t test with p approximately 0.05 indicating significance. Postmortem examination included light microscopy of the proximal superior vena cava or right atrium. RESULTS: Animals receiving 65 degrees C intravenous fluid warmed 3.6 degrees C/hour, significantly faster than the 40 degrees C animals (1.9 degrees C/hour). There were no significant differences in plasma-free hemoglobin or osmotic fragility. Endothelial injuries were found in two animals in each group. These defects occurred along the path of catheter insertion and not at the infusion site. CONCLUSIONS: Central intravenous fluid at 65 degrees C is a more rapid means of treating hypothermia than standard 40 degrees C intravenous fluid. It is safe even in hypovolemic animals.
Surface structure analysis is an important area of research, and in recent years notable advances have been made in this field, both in improved techniques for studying surfaces and in methods of analyzing them. This review aims to summarize the techniques available, particularly those relating to electron microscopy, and also to outline one of the newest areas of development, the application of direct methods to surface structure analysis.
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The cholinergic agonist carbachol induced the release of arachidonic acid in the 1321N1 astrocytoma cell line, and this was blocked by atropine, suggesting the involvement of muscarinic receptors. To assess the mechanisms of signalling involved in the response to carbachol, a set of compounds characterized by eliciting responses through different mechanisms was tested. A combination of 4beta-phorbol 12beta-myristate 13alpha-acetate and thapsigargin, an inhibitor of endomembrane Ca2+-ATPase that induces a prolonged elevation of cytosolic Ca2+ concentration, induced an optimal response, suggesting at first glance that both protein kinase C (PKC) and Ca2+ mobilization were involved in the response. This was consistent with the observation that carbachol elicited Ca2+ mobilization and PKC-dependent phosphorylation of cytosolic phospholipase A2 (cPLA2; phosphatide sn-2-acylhydrolase, EC 3.1.1.4) as measured by a decrease in electrophoretic mobility. Nevertheless, the release of arachidonate induced by carbachol was unaltered in media containing decreased concentrations of Ca2+ or in the presence of neomycin, a potent inhibitor of phospholipase C which blocks phosphoinositide turnover and Ca2+ mobilization. Guanosine 5'-[gamma-thio]triphosphate added to the cell-free homogenate induced both [3H]arachidonate release and cPLA2 translocation to the cell membrane fraction in the absence of Ca2+, thus suggesting the existence of an alternative mechanism of cPLA2 translocation dependent on G-proteins and independent of Ca2+ mobilization. From the combination of experiments utilizing biochemical and immunological tools the involvement of cPLA2 was ascertained. In summary, these data indicate the existence in the astrocytoma cell line 1321N1 of a pathway involving the cPLA2 which couples the release of arachidonate to the occupancy of receptors for a neurotransmitter, requires PKC activity and G-proteins and might operate in the absence of Ca2+ mobilization.
Autoimmunity (AI) exemplifies the potent and destructive activity expressed by the immune system when normal constraints against self-reactivity are lost or compromised. We have previously described a dramatic and intrinsic defect in cytokine expression in macrophages (M phi) from young AI-prone mice [1-3]. There are two points in particular that we believe speak to the importance of this observation: (i) Cytokine dysregulation is distinguished from many of the aberrancies reported in AI-prone mouse strains in that, as an inherent trait, it cannot arise as a consequence of the disease process. (ii) This defect is a remarkably consistent characteristic of M phi from strains that develop manifestations of systemic AI, including MRL/+, NZB, NZB/W F1, BXSB, and NOD, and distinguishes these strains from mice whose disease is predicated on defects in apoptosis (e.g., the lpr and gld mutations). The multigenic basis for disease and renal pathology in the former strains more closely mirror human lupus than do the disease manifestations of lpr and gld mice. In light of clear evidence that cytokines are key mediators of lymphocyte growth and function, a defect in the cytokine network has the potential to disrupt the normal regulation of self-reactivity, leading to the initiation of systemic AI.
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People over the age of 64 constitute 15% of the population in the UK, yet they consume approximately 30% of all National Health Service drug prescriptions, and adverse drug reactions account for 10.4% of all admissions to geriatric medical assessment wards. Many published studies concerning the pharmacology of old age are seriously flawed. Problems include failure to measure the drug bio-availability and the selection of subjects with overt or sub-clinical disease. It is difficult to make general rules about the effect of ageing on drug kinetics and dynamics. Each drug has to be tested separately.
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The scholars who use Social Science & Medicine in their research and teaching, who publish their work in it, participate in its peer review of manuscripts, and attend its conferences belong to various nationalities, disciplines, and cultural traditions. Our common enterprise originated in and depends upon liberal democratic social institutions, and assumes their values. With all our differences and disagreements, we are committed to scientific research in a common effort to improve human health and welfare. Our professional careers are a large part of our personal lives, so that our science, our lives, and our values are a single fabric. The present lecture is a meditation on this situation based upon my own heritage, personal experience, and career in anthropology, and on the recent publication in Social Science & Medicine of an essay that attributed the epidemiology of AIDS to racial variation.
Ofurace, oxadixyl, and alachlor were studied for their effect on hepatic xenobiotic biotransformation in male rats by dosing i.p. with 1 or 100 mg/kg of chemical for 7 days. Ofurace decreased ethoxyresorufin-O-deethylase and aniline p-hydroxylase activities but induced ethoxycoumarin-O-deethylase activity. Glutathione S-transferase and aminopyrine N-demethylase activities responded in a non dose-dependent manner, while cytochrome P-450 content and aldrin epoxidase activities were unchanged. Oxadixyl induced P-450 content, and ethoxycoumarin-O-deethylase and aminopyrine N-demethylase activities. It left ethoxyresorufin-O-deethylase, aldrin epoxidase and epoxide hydrolase activities unchanged and decreased aniline p-hydroxylase activities. Alachlor induced all activities excepting aldrin epoxidase (no change) and aniline p-hydroxylase (decreased). The data indicate that each of these acylanilide pesticides interacts with the monooxygenase system but with differing patterns.
Propiconazole, a foliar fungicide used for agricultural purposes was studied for its effects on the hepatic xenobiotic biotransformation in the rat. Rats were given an intraperitoneal injection of 0.1, 1, 10 or 100 mg/kg in corn oil for seven consecutive days. Induction was seen for cytochrome P-450, ethoxyresorufin-O-deethylase, ethoxycoumarin-O-deethylase, aldrin epoxidase, aminopyrine N-demethylase and microsomal expoxide hydrolase activities. Aniline p-hydroxylase and cytosolic glutathione S-transferase activities were unchanged. All responses occurred at only 100 mg/kg, except for that of aminopyrine N-demethylase which also occurred at the 10 mg/kg dose. SDS polyacrylamide gel electrophoresis showed increased staining of a protein band of molecular weight 54,000 corresponding to cytochrome P-450b and/or P-450d. Collectively these results suggest that cytochromes P-450b and P-450d have been induced after exposure of rats to propiconazole.
Chlordimeform, 4-chloro-o-toluidine and o-toluidine have all been found to have carcinogenic properties. Due to an empirical link between such properties and alteration of some biotransformation enzymes, the abilities of these three chemicals to affect cytochrome P-450 mediated biotransformation, epoxide hydrolase and glutathione S-transferase have been examined. Chlordimeform had no effect on the cytochrome P-450 content, aniline p-hydroxylase or glutathione S-transferase activities, but induced ethoxyresorufin-O-deethylase, ethoxycoumarin-O-deethylase and epoxide hydrolase activities and decreased aldrin epoxidase and aminopyrine N-demethylase activities. The metabolite 4-chloro-o-toluidine increased cytochrome P-450, ethoxyresorufin-O-deethylase, ethoxycoumarin-O-deethylase, glutathione S-transferase and epoxide hydrolase activities. o-Toluidine induced cytochrome P-450, ethoxyresorufin-O-deethylase, ethoxycoumarin-O-deethylase, and aldrin epoxidase activities. Ethoxy-resorufin-O-deethylase activity was induced approximately eight times by chlordimeform and 18 times by 4-chloro-o-toluidine and o-toluidine. Induction was seen at 50 mg/kg with chlordimeform and at 10 mg/kg with the other treatments. Chlordimeform increased the 7 alpha and 16 alpha androstenedione hydroxylase pathways. 4-Chloro-o-toluidine increased the 7 alpha, 16 beta and 16 alpha hydroxylase pathways, while o-toluidine increased the 7 alpha, 6 beta, 16 beta and 16 alpha hydroxylase pathways. All three chemicals marginally decreased the testosterone pathways. SDS-PAGE of rat microsomes revealed an increase in a protein band of MW c54,000 for the chlordimeform and 4-chloro-o-toluidine treated groups. Taken together with the increase in ethoxyresorufin-O-deethylase activity these observations are consistent with the induction of hepatic isozyme P-450d. Thus each chemical has been shown to induce various pathways of biotransformation with increases in the P-450c and P-450d specific substrate ethoxyresorufin-O-deethylase being a consistent finding.
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A program to train Community Health Workers was initiated in India in 1977 using a rhetoric that referred to claims for the success of health policies in China. This paper considers conflicting interpretations of the program at the time when it was implemented, its failure to use the extensive institutional structure of indigenous medicine, and the failure of those who planned and evaluated the program to utilize the substantial body of ethnographic work on medical practices and traditions in South Asia.