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1.  Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain 
BJA: British Journal of Anaesthesia  2010;105(2):201-207.
Background
Choline is a dietary supplement that activates α7 nicotinic receptors. α7 nicotinic activation reduces cytokine production by macrophages and has antinociceptive activity in inflammatory pain models. We hypothesized that systemic administration of choline would reduce the inflammatory response from macrophages and have antinociceptive efficacy in a murine model of postoperative pain.
Methods
We studied the response of wild-type and α7 nicotinic knockout mice to heat and punctate pressure after a model surgical procedure. We investigated the effect of genotype and choline treatment on α-bungarotoxin binding to, and their production of tumour necrosis factor (TNF) from, macrophages.
Results
Choline provided moderate antinociception. The ED50 for choline inhibition of heat-induced allodynia was 1.7 mg kg−1 h−1. The ED50 for punctate pressure threshold was 4.7 mg kg−1 h−1 choline. α7 nicotinic knockout mice had no change in hypersensitivity to heat or pressure and were significantly different from littermate controls when treated with choline 5 mg kg−1 h−1 (P<0.05, 0.01). Choline 100 mM reduced binding of α-bungarotoxin to macrophages by 72% and decreased their release of TNF by up to 51 (sd 11)%. There was no difference by genotype in the inhibition of TNF release by choline.
Conclusions
Systemic choline is a moderately effective analgesic via activation of α7 nicotinic acetylcholine receptors. The antinocicepive effect may not be mediated by a reduction of TNF pathway cytokine release from macrophages. Although choline at millimolar concentrations clearly inhibits the release of TNF, this effect is not α7 subunit-dependent and occurs at concentrations likely higher than reached systemically in vivo.
doi:10.1093/bja/aeq113
PMCID: PMC2903311  PMID: 20511332
acetylcholine; acute pain, novel techniques; pharmacodynamics; pharmacology, dose–response; pharmacology, general
2.  Myeloid leukemia after hematotoxins. 
Environmental Health Perspectives  1996;104(Suppl 6):1303-1307.
One of the most serious consequences of cancer therapy is the development of a second cancer, especially leukemia. Several distinct subsets of therapy-related leukemia can now be distinguished. Classic therapy-related myeloid leukemia typically occurs 5 to 7 years after exposure to alkylating agents and/or irradiation, has a myelodysplastic phase with trilineage involvement, and is characterized by abnormalities of the long arms of chromosomes 5 and/or 7. Response to treatment is poor, and allogenic bone marrow transplantation is recommended. Leukemia following treatment with agents that inhibit topoisomerase II, however, has a shorter latency, no preleukemic phase, a monoblastic, myelomonocytic, or myeloblastic phenotype, and balanced translocations, most commonly involving chromosome bands 11q23 or 21q22. The MLL gene at 11q23 or the AML1 gene at 21q22 are almost uniformly rearranged. MLL is involved with many fusion gene partners. Therapy-related acute lymphoblastic leukemia also occurs with 11q23 rearrangements. Therapy-related leukemias with 11q23 or 21q22 rearrangements, inv(16) or t(15;17), have a more favorable response to treatment and a clinical course similar to their de novo counterparts.
PMCID: PMC1469761  PMID: 9118910
3.  Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. 
Molecular and Cellular Biology  1996;16(8):4107-4116.
TEL is a member of the Ets family of transcription factors which are frequently rearranged in human leukemia. The mechanism of TEL-mediated transformation, however, is unknown. We report the cloning and characterization of a chromosomal translocation associated with acute myeloid leukemia which fuses TEL to the ABL tyrosine kinase. The TEL-ABL fusion confers growth factor-independent growth to the marine hematopoietic cell line Ba/F3 and transforms Rat-1 fibroblasts and primary murine bone marrow cells. TEL-ABL is constitutively tyrosine phosphorylated and localizes to the cytoskeleton. A TEL-ABL mutant containing an ABL kinase-inactivating mutation is not constitutively phosphorylated and is nontransforming but retains cytoskeletal localization. However, constitutive phosphorylation, cytoskeletal localization, and transformation are all dependent upon a highly conserved region of TEL termed the helix-loop-helix (HLH) domain. TEL-ABL formed HLH-dependent homo-oligomers in vitro, a process critical for tyrosine kinase activation. These experiments suggest that oligomerization of TEL-ABL mediated by the TEL HLH domain is required for tyrosine kinase activation, cytoskeletal localization, and transformation. These data also suggest that oligomerization of Ets proteins through the highly conserved HLH domain may represent a previously unrecognized phenomenon.
PMCID: PMC231407  PMID: 8754809
4.  Management of myocardial infarction: implications for current policy derived from the Nottingham Heart Attack Register. 
British Heart Journal  1992;67(3):255-262.
OBJECTIVE--A register of patients with heart attacks in the Nottingham Health District has been maintained since 1973. Data from 1982 to 1984 inclusive, a period before trials of thrombolytic therapy started in Nottingham, were analysed to provide background information for the introduction of a policy of routine thrombolysis for appropriate patients. DESIGN--Data were collected prospectively on all patients transported to hospital in the Nottingham Health District with suspected myocardial infarction in the years 1982-84 and on patients treated at home during that time. SETTING--Two district general hospitals responsible for all emergency admissions in the health district. PATIENTS--6712 patients admitted to hospital with suspected myocardial infarction and 1887 patients found dead on arrival at hospital. Approximately 1500 patients in whom a myocardial infarction was suspected were treated at home, but only 125 were identified who had a definite or probable infarction. RESULTS--Among the patients admitted within 24 hours of the onset of symptoms, the median delay from onset to hospital admission was 174 minutes; 25% of patients were admitted within 91 minutes. The only factor that seemed to affect the time taken was the patient's decision to call a general practitioner or an emergency ambulance. If a general practitioner referred the patient to hospital the median delay was 247 minutes, compared with 100 minutes when the patient summoned an ambulance. Ninety three per cent of all patients were transported by ambulance. The median time from the call for the ambulance to hospital arrival was 29 minutes. Once a patient was admitted to hospital, the time to admission and general practitioner involvement seemed relatively unimportant as predictors of outcome. Patients admitted more than nine hours after onset of symptoms with a diagnosis of definite or probable infarction had a poorer outcome than those admitted earlier (in-hospital mortality 22.4% v 13.1%). The fatality rates of those admitted to a coronary care unit or to an ordinary medical ward are similar. CONCLUSION--Although the introduction of thrombolytic therapy has brought with it an increased awareness of the need to minimise any delay in time to admission, it seems that in a predominantly urban area like Nottingham, patients with a suspected heart attack will continue to be admitted to hospital most quickly if an ambulance crew rather than a general practitioner is called. Because the ambulance crew was in contact with such patients for only a short time it seems unlikely that administration of a thrombolytic drug in the ambulance would be helpful.
PMCID: PMC1024802  PMID: 1554544
5.  The limited potential of special ambulance services in the management of cardiac arrest. 
British Heart Journal  1990;64(5):309-312.
For six months a survey was made of all the patients in the Nottingham District Health Authority who died or who were brought to hospital after a cardiac arrest outside hospital. During this period just under half of the emergency ambulance shifts were covered by specially trained crews with defibrillators. During the study period the ICD coding of death certificates indicated that 894 (25%) of the 3575 deaths were due to ischaemic heart disease. During this period the ambulance service received 17,749 emergency calls, which included 445 patients who had cardiac arrests outside hospital. One hundred and forty seven of these patients were carried by ambulances equipped with defibrillators and resuscitation was attempted in 83. Seven patients survived to leave hospital. The special ambulance service was cost effective--a simple calculation suggests that the cost per life saved was approximately 2600 pounds, but it seems unlikely that special ambulance services will materially affect community fatality rates from ischaemic heart disease.
PMCID: PMC1216808  PMID: 2101595
6.  Flosequinan in heart failure: acute haemodynamic and longer term symptomatic effects. 
BMJ : British Medical Journal  1988;297(6642):169-173.
There is no single, simple test with which to evaluate new treatments for heart failure. Various methods need to be used, and a study of both the acute haemodynamic and longer term symptomatic effects of flosequinan, a new direct acting arteriolar and venous vasodilator, was therefore carried out in patients with heart failure. In one group of patients flosequinan increased cardiac output and caused a fall in pulmonary capillary wedge pressure, both effects lasting for 24 hours. In a double blind, placebo controlled study in another group flosequinan improved mean exercise tolerance from 9.9 to 12.7 minutes after four weeks of treatment. The drug also reduced perceived exertion during submaximal exercise and increased calf and therefore skeletal muscle blood flow. It reduced plasma renin activity and noradrenaline concentrations. Flosequinan possesses all the important properties of a drug likely to be of value in the treatment of heart failure.
PMCID: PMC1834251  PMID: 3044507
7.  Advanced training for ambulance crews: implications from 403 consecutive patients with cardiac arrest managed by crews with simple training. 
Sixty seven ambulance staff in Nottinghamshire completed a simple extended training programme in managing cardiac arrest and using a defibrillator. This enabled around one third of the ambulance emergency shifts to be manned by such a crew, with a defibrillator as part of their standard equipment. Forty four of 403 consecutive patients who suffered cardiac arrest in the community were managed by these crews and survived to leave hospital. The training programme does not include endotracheal intubation, intravenous infusion, or drug administration. The new official advanced training course for ambulance crews, which includes these skills, is inappropriate in its methods and may delay widespread introduction of emergency ambulances equipped with defibrillators.
PMCID: PMC1248546  PMID: 3121027
8.  Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells. 
Molecular and Cellular Biology  1987;7(6):2267-2275.
We have isolated cDNAs representing a previously unrecognized human gene that apparently encodes a protein-tyrosine kinase. We have designated the gene as HCK (hemopoietic cell kinase) because its expression is prominent in the lymphoid and myeloid lineages of hemopoiesis. Expression in granulocytic and monocytic leukemia cells increases after the cells have been induced to differentiate. The 57-kilodalton protein encoded by HCK resembles the product of the proto-oncogene c-src and is therefore likely to be a peripheral membrane protein. HCK is located on human chromosome 20 at bands q11-12, a region that is affected by interstitial deletions in some acute myeloid leukemias and myeloproliferative disorders. Our findings add to the diversity of protein-tyrosine kinases that may serve specialized functions in hemopoietic cells, and they raise the possibility that damage to HCK may contribute to the pathogenesis of some human leukemias.
Images
PMCID: PMC365351  PMID: 3496523
9.  Abnormalities of the peripheral circulation and respiratory function in patients with severe heart failure. 
British Heart Journal  1986;55(1):75-80.
To investigate the peripheral circulatory and respiratory abnormalities which occur in patients with heart failure, forearm and calf blood flow were measured before and after upright exercise, and respiratory gas exchange was measured during exercise in 26 patients with severe heart failure. Compared with a group of normal subjects the patients had reduced limb blood flow at rest and the response of limb blood flow to upright exercise was also abnormal. The increase in calf blood flow after exercise and the reduction in blood flow in the non-exercising forearm were both smaller in patients than in controls. There was a significant correlation between the maximum exercise duration of the patients and calf blood flow both after exercise and at rest. Compared with another group of control subjects the patients had a higher minute ventilation during exercise and a reduced oxygen consumption. The respiratory exchange ratio during exercise was also higher in patients than in controls. This suggests that there is early onset of anaerobic metabolism during exercise in patients with severe heart failure.
PMCID: PMC1232071  PMID: 3947485
10.  Simple training programme for ambulance personnel in the management of cardiac arrest in the community. 
The extended training for ambulance personnel in Nottinghamshire includes a period of training in cardiac resuscitation by defibrillation, and defibrillators are now part of the standard equipment of vehicles used on the accident and emergency service. Comparison of recent results with previous attempts in the City of Nottingham to provide a service for out of hospital cardiac arrest has shown that an elementary training course and the provision of defibrillators on emergency vehicles enables the ambulance service to save the lives of a reasonable proportion of those who suffer sudden death in the community. The extended training programme as a whole has proved acceptable to ambulance personnel and we believe that this programme could be the basis for a more widespread introduction of post basic training.
PMCID: PMC1416968  PMID: 3931812
11.  Home care for patients with suspected myocardial infarction: use made by general practitioners of a hospital team for initial management. 
Two hundred and sixty three general practitioners were offered the use of a hospital based service consisting of a medical senior house officer, a nurse attached to a coronary care unit, and a specially equipped ambulance estate car to help with the initial management of patients with suspected myocardial infarction who might be suitable for home care. One hundred and sixty nine general practitioners registered as potential users of this service; during 22 months they called the hospital team to see 271 patients, 235 of whom the team suspected had indeed suffered a myocardial infarction. During the same period, however, these general practitioners also admitted 317 patients with suspected myocardial infarction directly to hospital. Other general practitioners admitted 323 patients and deputising doctors 258. A further 529 patients with suspected infarction were admitted without the intervention of a general practitioner. Of the patients seen by the team, 54 required immediate admission to hospital; 17 of the remaining patients who initially appeared suitable for home care later required admission to hospital. In a large city such as Nottingham the provision of hospital based facilities to help general practitioners with home management is unlikely to make an appreciable impact on the overall pattern of care of patients with suspected myocardial infarction.
PMCID: PMC1442427  PMID: 6432118
12.  Early reporting of myocardial infarction: impact of an experiment in patient education. 
Many deaths from myocardial infarction occur before medical help is sought. A campaign was mounted in Nottingham ("Nottingham Heartwatch") to encourage early reporting. A total of 13 828 men and women aged 40 and over registered with three general practices were asked to telephone a hospital-based number if they developed chest pain lasting for more than 10 minutes. Patients from study practices reported chest pain earlier after our invitation than they had before and also earlier than patients from control practices. While accepting the advice to call early some patients from the study practices ignored our special number and telephoned their general practitioner. The calls received on the Heartwatch line yielded a lower percentage of definite and probable infarcts than the calls received by the patients' own doctors. The way in which the characteristics of the study practices might have influenced this difference is discussed since it has considerable implications for larger-scale attempts to bring patients with suspected myocardial infarction under medical care at the earliest opportunity.
PMCID: PMC1498672  PMID: 6805692

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