Practice tip. A gamma radiation sterilised disposable theatre lamp handle.
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Equipment Design↗
Biomedical subjects
A Watson
Publications and source records attributed to A Watson.
Alpha adrenergic blockers and adrenaline. A mysterious collapse.
In 1995 I encountered a problem with the use of adrenaline in the resuscitation of a patient on prazosin who had an anaphylactic collapse resulting from a bee sting. I concluded that the problem was the result of the 'reversed adrenaline effect' and I predicted that other drugs with alpha adrenergic receptor blocking activity such as the phenothiazines could similarly obstruct the action of adrenaline. A literature review of the reversed adrenaline effect revealed a number of animals studies but no articles relating to humans. I present this case study as another example of drugs with alpha adrenergic receptor blocking activity (thioridazine and amitriptyline) obstructing the action of adrenaline in anaphylactic collapse.
Adrenergic Uptake Inhibitors↗
Early postinfection antiviral treatment reduces viral load and prevents CD4+ cell decline in HIV type 2-infected macaques.
Reports of significant reductions in plasma viral load by anti-HIV drugs have raised the possibility that antiviral therapy, if initiated sufficiently early, may result in sustained control of infection and prolonged clinical benefits. We evaluated the effects of intervention coincident with infection using an antiviral nucleoside, d4T, in Macaca nemestrina infected with a highly pathogenic isolate of HIV-2 (HIV-2[287]). Infection with this virus reproducibly results in high viremia and rapid CD4+ cell depletion, allowing a sensitive measurement of the treatment effect on viral load and clinical outcome. Compared to the control group, d4T-treated macaques showed significantly lower (2-3 log10) plasma- and cell-associated viral load. No CD4+ cell decline was observed in the treatment group while on therapy with d4T whereas CD4+ cells of control macaques declined from a preinfection mean of 32% of PBMCs to below 10%. Notably, when d4T treatment was withdrawn after 16 weeks, five of the six macaques continued to control viral load and have maintained normal CD4+ cell level for more than a year. These results demonstrate that early antiviral intervention, even of a limited duration, may constitute an important strategy against lentiviral-induced disease.
Animals↗
Why can't a computer be more like a brain?
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Algorithms↗
Characterization of the pathogenic KU-SHIV model of acquired immunodeficiency syndrome in macaques.
By animal-to-animal passage in macaques we derived a pathogenic chimeric simian-human immunodeficiency virus (SHIV) that caused CD4+ T cell loss and AIDS in pigtail macaques and used it to inoculate 20 rhesus and pigtail macaques by the intravaginal and intravenous routes. On the basis of the outcome of infection and patterns of CD4+ T cell loss and viral load, disease was classified into four patterns: acute, subacute, chronic, and nonprogressive infection. During the study period, 15 of the 20 animals developed fatal disease, including AIDS, encephalitis, pneumonia, and severe anemia. Opportunistic pathogens identified in these animals included Pneumocystis, cytomegalovirus, Cryptosporidium, Toxoplasma, and Candida. No single parameter by itself predicted outcome, although a combination of low CD4+ T cell counts in blood, high plasma virus levels, and presence of autoantibodies to red blood cells reliably predicted a fatal outcome. Five animals (25%) died within 3 months of inoculation and constituted the group with acute disease, whereas the nine animals (45%) with subacute disease died between 3 and 8 months postinoculation. This 70% mortality within 8 months is significantly shorter than in HIV-1-infected human beings, of whom 70% develop fatal disease a decade after infection. SHIV infection in macaques provides a useful model with which to evaluate antiviral strategies, combining all the advantages of the SIVmac system, yet using a virus bearing the envelope gene of HIV-1.
AIDS-Related Opportunistic Infections↗
Superior tarsal conjunctival bullae in cicatricial pemphigoid.
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Anti-Infective Agents↗
The bigger the burn, the greater the stress.
Data characterizing the endocrine stress response to burn injury in children are sparse. We have measured the levels of the stress hormones arginine vasopressin, catecholamines-adrenaline, noradrenaline and dopamine-atrial natriuretic peptide and hormones of the renin-angiotensin-aldosterone system in admission blood samples taken from 35 children admitted to the burns unit of the regional children's hospital. Hormone levels were compared with the size of burn injury. With the exception of adrenaline, there were significant positive correlations between vasopressin (r = 0.707, p < 0.0001), plasma renin activity (r = 0.721, P < 0.0001), angiotensin II (r = 0.512, P = 0.002), aldosterone (r = 0.620, P < 0.0001), noradrenaline (r = 0.430, P = 0.0189), dopamine (r = 0.627, P = 0.0024) and percentage burn surface area, and a negative correlation between atrial natriuretic peptide (r = 0.548, P = 0.0008) and burn surface area. It is concluded that the hormones which react to stress are very sensitive to burn injury in children, and that the magnitude of their response is closely related to the size of the burn surface area.
Arginine Vasopressin↗
Photochemotherapy for mycosis fungoides: current status.
Phototherapy for mycosis fungoides is reviewed with particular emphasis on PUVA (psoralen ultraviolet A-range) therapy and its combination with other topical and systemic treatments. PUVA therapy has the advantages of being available in all major centres, is simple to administer, relatively inexpensive and has relatively low toxicity. Medium-term results suggest that PUVA is as effective as any of the other topical therapies for stage I disease. Its combination with alpha-interferon produces significant benefit in stage II or more advanced disease. Long-term non-melanoma skin cancer is increased with PUVA and combination PUVA usage, but melanoma is not increased. Its long-term position in comparison to other therapies with regard to morbidity, mortality and quality of life needs further evaluation.
Evaluation Studies as Topic↗
Naltrexone: a case report of pruritus from an antipruritic.
Intense, generalized pruritus associated with mycosis fungoides was relieved using subcutaneous naloxone but intensified when changed to the new oral opioid antagonist, naltrexone. Rechallenge again led to worsening in pruritus. This unexpected adverse effect is surprising as naltrexone and naloxone are currently thought to work via similar opioid receptor binding. The worsening of the itch may have been due to adaptation in opioid receptor expression induced by prolonged naloxone therapy, possibly highlighting differential opioid receptor affinity between naltrexone and naloxone, or may have represented an idiosyncratic adverse reaction. Naltrexone and naloxone have been reported to reduce pruritus due to cholestasis, uraemia, morphine epidurals, and possibly atopic dermatitis and urticaria. Naltrexone has the convenience of oral administration and a longer half-life. The role of the opioid system and naltrexone in pruritus is reviewed.
Female↗
Plasma viremia in macaques infected with simian immunodeficiency virus: plasma viral load early in infection predicts survival.
A reliable method for the quantitation of plasma viremia in nonhuman primates infected with simian immunodeficiency virus (SIV) and related viruses is described. This method is based on an established quantitative-competitive PCR format and includes a truncated control for internal assay calibration. Optimization of assay conditions has significantly improved amplification specificity, and interassay variability is comparable to that of commercially available assays for human immunodeficiency virus (HIV) quantitation. This procedure was used to monitor viral loads in a group of Macaca mulatta animals that were infected with SIVsmE660 for over 2 years. Highly diverse profiles of plasma viremia were observed among animals, and high viral loads were associated with more rapid disease progression. Spearman rank correlation analyses were done for survival versus three parameters of viral load: plasma viremia, p27 core antigen, and frequency of infected peripheral blood mononuclear cells. Plasma viremia had the strongest overall correlation and was significantly (P < 0.05 to P < 0.01) associated with survival at 10 of the 13 time points examined. Plasma viremia did not correlate with survival during the primary viremia phase; however, the strength of this correlation increased with time postinfection and, remarkably, viremia levels as early as week 6 postinfection were highly predictive (P < 0.01) of relative survival. These findings are consistent with the available clinical data concerning viral load correlates early in HIV infection, and they provide further support for the view that disease outcome in lentiviral infection may be largely determined by events that occur shortly after infection.
Animals↗
Intravenous colistin sulphomethate in acute respiratory exacerbations in adult patients with cystic fibrosis.
BACKGROUND: Patients with cystic fibrosis have received more intravenous antibiotic courses as median survival has steadily increased. A number of centres have adopted a policy of regular (three monthly) rather than on demand intravenous antipseudomonal antibiotics. More widespread bacterial antibiotic resistance has resulted from this increased antibiotic use. Most Pseudomonas aeruginosa strains remain fully sensitive to colistin but its use has been resisted owing to concerns about neurotoxicity and nephrotoxicity. A study was carried out to assess the safety and efficacy of intravenous colistin in the treatment of acute respiratory exacerbations in adult patients with cystic fibrosis. METHODS: Patients with chronic Pseudomonas aeruginosa colonisation who presented with protocol defined respiratory tract exacerbations were randomised to receive treatment for 12 days with either colistin (2 MU tds intravenously) alone or with a second anti-pseudomonal antibiotic. Comparisons of the absolute values of respiratory function tests on days 1, 5, and 12 and of overnight oxygen saturation on days 1 and 12 were the primary outcome measures. Patient's weight, clinical and chest radiographic scores, and peripheral blood markers of inflammation were also documented. The effect of each treatment regimen individually was assessed by the change in clinical measurements from baseline values. Adverse renal effects were monitored by measurement of serum levels of urea and electrolytes, creatinine clearance, and ward urine testing. Neurotoxicity was monitored by direct questioning for symptoms. RESULTS: Fifty three patients, 18 of whom entered the study twice, were enrolled. The mean forced expiratory volume in one second (FEV1) increased significantly in both groups, mean forced vital capacity (FVC) only with dual therapy. Both groups showed a non-significant increase in overnight oxygen saturation. All patients showed clinical improvement. Thirty seven adverse neurological events (two severe) were reported in 33 patients in the monotherapy group and 37 (none severe) in 36 patients in the dual therapy group. One patient withdrew because of severe weakness and dizziness. All other adverse neurological events were well tolerated and resolved during or shortly after treatment. Significant changes were seen in mean serum urea levels in both groups, but in only four patients to a level above the normal range, and in creatinine clearance in the dual therapy group. At 24 month follow up no long term adverse consequences from intravenous colistin were found in patients who completed the study. CONCLUSIONS: Intravenous colistin is an effective treatment for Pseudomonas aeruginosa associated pulmonary exacerbations in patients with cystic fibrosis. Assessment of the individual effect of each treatment regimen suggests a greater efficacy when colistin is combined with a second antibiotic to which the pseudomonas shows in vitro sensitivity. Changes in renal function should be monitored.
Acute Disease↗
Nebulised bronchodilators, corticosteroids, and rhDNase in adult patients with cystic fibrosis.
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Adrenal Cortex Hormones↗
Diaphragm thickness and inspiratory strength in patients with Duchenne muscular dystrophy.
BACKGROUND: There is little information on the morphometric characteristics of the diaphragm in patients with Duchenne muscular dystrophy. METHODS: The thickness of the diaphragm was measured at the zone of apposition using B mode ultrasonography in 10 boys with Duchenne muscular dystrophy of mean (SD) age 10.3 (1.3) years and 12 normal controls of mean (SD) age 11.3 (2.0) years during relaxation (DiTrelax) and during maximum effort inspiratory manoeuvres (DiTPimax) at functional residual capacity. RESULTS: DiTrelax was greater in the patients with Duchenne muscular dystrophy (1.74 (0.21) mm) than in controls (1.48 (0.20) mm), mean difference (95% CI) 0.26 (0.08 to 0.44), despite considerable impairment of maximum effort inspiratory mouth pressure (Pimax) (patients with Duchenne muscular dystrophy -37 (8) cm H2O, controls -80 (33) cm H2O), mean difference (95% CI) 43 (65 to 20). During a Pimax manoeuvre, compared with measurements taken during relaxation, the diaphragm thickened 1.6 times in patients with Duchenne muscular dystrophy and 2.3 times in controls (DiTPimax 2.62 (0.7) mm and 3.5 (0.85) mm, respectively), mean difference (95% CI) -0.88 (-1.58 to -0.18). CONCLUSIONS: Resting diaphragm thickness is increased in young patients with Duchenne muscular dystrophy with impaired respiratory muscle force. This finding could be analogous to the pseudo-hypertrophy that is observed in some limb muscle groups.
Child↗
Size and strength of the respiratory and quadriceps muscles in patients with chronic asthma.
There have been few studies of respiratory and limb muscle size and function in middle-aged patients with asthma and persistent airways obstruction. We have compared the forces generated by the respiratory and thigh muscles with their dimensions assessed by ultrasound in nine middle-aged patients with chronic asthma (mean age 56 (SD 8) yrs; functional residual capacity/total lung capacity ratio (FRC/TLC) 60 (10)%), and in nine normal subjects (aged 53 (7) yrs; FRC/TLC 55 (5)%). Diaphragm thickness was measured at the zone of apposition by B-mode ultrasound during relaxation (DiTrelax) and during a maximum-effort inspiratory manoeuvre (DiTpI,max) at FRC. Cross-sectional area of the relaxed rectus femoris muscle (ARF) was determined by ultrasound at mid-thigh level. Isometric strength of the right quadriceps muscle group was measured during maximum voluntary contraction. Asthmatic patients had preserved quadriceps strength and ARF but moderately impaired maximum inspiratory pressure (PI,max) (-52 (18) cmH2O) and thicker DiTrelax (2.2 (0.4) mm), compared to normal subjects (-73 (21) cmH2O and 1.7 (0.3) mm, respectively). Middle-aged patients with chronic asthma and a small increase in functional residual capacity/total lung capacity ratio have preserved limb muscle force and dimensions, modestly impaired inspiratory muscle strength, and slightly increased thickness of the costal diaphragm. Future studies of respiratory muscle function in asthma should be aided by measurement of diaphragm thickness and of limb muscle strength and size. Such studies are required particularly in older patients with severe hyperinflation who are most likely to have impairment of muscle function.
Airway Obstruction↗
An evaluation of two aerosol delivery systems for rhDNase.
Increasingly, proteins are delivered to the respiratory tract as an aerosol, and clinical efficacy is dependent on optimal delivery of the protein in an intact form. The object of this study was to compare the in vivo and in vitro results of two aerosol delivery systems for the aerosolization of recombinant human deoxyribonuclease I (rhDNase) in patients with cystic fibrosis (CF). Patients with CF who were to be initiated on rhDNase were randomized either to the Hudson nebulizer and Pulmo-Aide compressor or to the Sidestream nebulizer driven by the CR50 air compressor. An in vitro study was performed in six sets of the two aerosol delivery systems. One hundred and seventy three patients were randomized in this open study, where rhDNase was administered for 7 days. Improvements in pulmonary function were observed in both groups following 1 week of therapy with rhDNase. Changes in the Sidestream/CR50 and Hudson/Pulmo-Aide groups, respectively, were: 16 and 11% for forced expiratory volume in one second (p=0.14); 12 and 10% for forced vital capacity (p=0.70); and 14 and 7% for forced expiratory flow at 25-75% of expiration (FEF(25-75)) (p=0.18). A greater proportion of patients in the Sidestream/CR50 group (58%) had a >10% response in FEF(25-75) compared to the Hudson/Pulmo-Aide group (42%; p=0.03). The Sidestream nebulizer had a faster nebulization rate (p<0.05), lower mass median diameter for the aerosol mass produced (p<0.001), higher percentage of particles in the respirable range (p<0.001) and greater respirable output (p<0.005), compared to the Hudson nebulizer. The Sidestream/CR50 combination is a quicker, more efficient system in vitro than the Hudson/Pulmo-Aide combination, whereas the in vivo study only suggested a difference. Clinically, the two systems have similar efficacy.
Adult↗
Bax promotes neuronal cell death and is downregulated during the development of the nervous system.
The Bcl-2 and Bcl-x proteins suppress programmed cell death, whereas Bax promotes apoptosis. We investigated the pattern of expression of Bcl-2, Bax and Bcl-x during neuronal differentiation and development. All three proteins were widely expressed in neonatal rats but, in the adult, Bax levels were 20- to 140-fold lower in the cerebral cortex, cerebellum and heart muscle, whereas Bcl-x was not downregulated in any of the tissues examined. In the cerebral cortex and cerebellum, the decrease in Bax levels occurred after the period of developmental cell death. Further, microinjection of a Bax expression vector into cultured sympathetic neurons, which depend on nerve growth factor for survival, induced apoptosis in the presence of survival factor and increased the rate of cell death after nerve growth factor withdrawal. This effect could be blocked by co-injection of an expression vector for Bcl-xL or for the baculovirus p35 protein, an inhibitor of caspases (ICE-like proteases). These results suggest that, during development, the sensitivity of neurons to signals that induce apoptosis may be regulated by modulating Bax levels and that Bax-induced death requires caspase activity.
Aging↗
Electrophysiological basis of human fallopian tubal fluid formation.
A preparation for the maintenance of human Fallopian tubal epithelial cells as a polarized layer in primary culture was used to study the electrophysiological basis of tubal fluid formation in terms of the movement of Na+, K+ and Cl- ions. Transepithelial potential difference (PD) and short-circuit current (Iscc) were recorded by mounting the epithelial cells in a modified Ussing chamber. Resistance (R) was calculated from the measurements of PD and Iscc. The epithelia, although confluent, formed a 'leaky' electrical system and resistances greater than 300 omega cm-2 were rarely achieved. The sodium channel blocker, amiloride (100 mumol l-1), produced only small effects on PD and Iscc. The potassium channel blocker, tetraethylammonium chloride (TEA) (25 mmol l-1), also produced small, but significant changes in PD, Iscc and R while the chloride channel blocker, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS) (1 mmol l-1), induced a marked increase in PD and Iscc, and a fall in R, when added to the basal surface of the cells. Bathing the apical surface of the cells with chloride-free medium also produced a marked increase in PD, Iscc and R: bathing the basal surface of the cells with chloride-free medium produced a marked decrease in PD and Iscc. Extracellular ATP (10 mumol l-1), added to either the apical or the basal surface of the cells, induced a transient increase in PD and Iscc and a decrease in R. Amiloride, TEA or furosemide had no effect on the response of the cells to ATP. SITS, applied to the apical surface, significantly reduced the response of the cells to ATP. We conclude that the major driving force for human tubal fluid formation is the transepithelial secretion of chloride ions into the oviduct lumen and that exogenous ATP is a potential modulator of secretion.
4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗