Medical Research Council Grant Research Articles

The Medical Research Council's approach to allegations of scientific misconduct.

The UK's Medical Research Council (MRC) introduced a specific policy and procedure for inquiring into allegations of scientific misconduct in December 1997; previously cases had been considered under normal disciplinary procedures. The policy formally covers staff employed in MRC units, but those in receipt of MRC grants in universities and elsewhere are expected to operate under similar policies. The MRC's approach is stepwise: preliminary action; assessment to establish prima facie evidence of misconduct; formal investigation; sanctions; and appeal. Strict time limits apply at all stages. The procedure will be evaluated after two years. The indications so far are that the procedure is robust, and its clarity and transparency have been an asset to all parties. The MRC is also convinced that it is equally important to achieve a working culture that fosters integrity. Thus education and training in good research practices are fundamental to the prevention of research misconduct.

A NON-NITRERGIC SMOOTH MUSCLE RELAXANT FACTOR RELEASED FROM RAT URINARY BLADDER BY MUSCARINIC RECEPTOR STIMULATION

To study the possible release of a relaxant factor from isolated rat bladder tissue. Thoracic aortae and urinary bladders were obtained from 55 female Sprague-Dawley rats. The bladder body was used in its original tubular shape as the donor tissue in a co-axial bioassay system, and the aorta served as acceptor tissue. In a co-axial bioassay system with endothelium-free, norepinephrine-contracted, rat aortic preparations mounted within urothelium-intact urinary bladder, carbachol caused a concentration-dependent relaxation, amounting to 64+/-7% (n = 10) of the induced contraction, suggesting release of a relaxing factor. The relaxant effect of carbachol was lost if the urinary bladder segment was removed. However, the relaxation was affected neither by removal of the urothelium, nor by bladder segment inversion. It was resistant to inhibition of the L-arginine/nitric oxide and cyclo-oxygenase pathways, and unaffected by beta-adrenoceptor blockade and K+ channel inhibition. The relaxation was not associated with any significant changes in the intracellular levels of cGMP or cAMP. A previously unrecognized non-adrenergic, non-nitrergic, non-prostanoid inhibitory mediator is released from the rat urinary bladder by muscarinic receptor stimulation. The physiological importance of such a factor remains to be established.

Can haemophilic arthropathy be prevented?

Can haemophilic arthropathy be prevented?

Infant emmetropization

Aim: The Cambridge vision screening programme allows the emmetropization process to be described in a large infant population (n = 278 infants). Cycloplegic retinoscopy refraction change between 9 and 20 months of age is described for various refractive components.Methods: Following videorefractive VPR‐1 screening at 75 cm, of over 5000 infants, groups of infants with large lags (>2.8 D) and normal lags (<2.8 D) of accommodation were longitudinally followed‐up. All were non‐strabismic. 1% cyclopentolate retinoscopy results (sphero‐cyl lens neutralized ± 0.5 D) were analysed.Results: For all components, the emmetropization rate significantly correlated with the initial powers (difference v mean correlation R).The relationship of hyperopia and astigmatism reduction will be discussed. Emmetropization in a subgroup of infants wearing spectacles will also be presented.Conclusion: Analysis of infant emmetropization shows the refractive components emmetropize with their rate of reduction related to initial power.Acknowledgement: Supported by Medical Research Council Grant G7908507.

A role for islet peptide YY in the regulation of insulin secretion.

The authors are grateful to Ms L. Bengtsson and Ms L. Kvist for technical assistance. The study was financially sup ported by The Swedish Medical Research Council (grants no. 14X‐6834 and 12X‐712); The Novo Nordic Founda tion; Swedish Diabetes Association; The Crafoord, Albert Pa~Olsson and Ernhold Lundstro~Dm Foundations and by the Faculty of Medicine, Lund University, Lund, Sweden.

Pharmacokinetic and biological activities of dermatan sulfate (Mediolanum MF701) in healthy human volunteers.

Annals of the New York Academy of SciencesVolume 556, Issue 1 p. 292-303 Pharmacokinetic and Biological Activities of Dermatan Sulfate (Mediolanum MF701) in Healthy Human Volunteersa J. DAWES, Corresponding Author J. DAWES MRC/SNBTS Blood Components Assay GroupPresent address: Heart Research Institure, 145–147 Missended Rd., Camperdown, Sydney, NSW 2050, Australia.Search for more papers by this authorB. A. HODSON, B. A. HODSON MRC/SNBTS Blood Components Assay GroupSearch for more papers by this authorI. R. MacGREGOR, I. R. MacGREGOR Scottish National Blood Transfusion Service Headquarters Laborntory, Edinburgh, United KingdomSearch for more papers by this authorD. S. PEPPER, D. S. PEPPER Scottish National Blood Transfusion Service Headquarters Laborntory, Edinburgh, United KingdomSearch for more papers by this authorC. V. PROWSE, C. V. PROWSE South-East Scotland Blood Transfirsion Service, Edinburgh, United KingdomSearch for more papers by this author J. DAWES, Corresponding Author J. DAWES MRC/SNBTS Blood Components Assay GroupPresent address: Heart Research Institure, 145–147 Missended Rd., Camperdown, Sydney, NSW 2050, Australia.Search for more papers by this authorB. A. HODSON, B. A. HODSON MRC/SNBTS Blood Components Assay GroupSearch for more papers by this authorI. R. MacGREGOR, I. R. MacGREGOR Scottish National Blood Transfusion Service Headquarters Laborntory, Edinburgh, United KingdomSearch for more papers by this authorD. S. PEPPER, D. S. PEPPER Scottish National Blood Transfusion Service Headquarters Laborntory, Edinburgh, United KingdomSearch for more papers by this authorC. V. PROWSE, C. V. PROWSE South-East Scotland Blood Transfirsion Service, Edinburgh, United KingdomSearch for more papers by this author First published: June 1989 https://doi.org/10.1111/j.1749-6632.1989.tb22511.xCitations: 4 a This work was supported by Medical Research Council grant nos. PG8218470 and G8607394SA. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume556, Issue1Heparin and Related Polysaccharides: Structure and ActivitiesJune 1989Pages 292-303 RelatedInformation

147 CONDITIONS AND LIMITATIONS FOR DIRECT mRNA SEQUENCING USING OLIGONUCLEOTIDE PRIMERS

The feasibility of direct mRNA sequencing for the purpose of characterizing mutations of relatively low abundance messages was examined. A 906 base pair PstI fragment corresponding to the coding region of hypoxanthine phosphoribosyltransferase (HPRT) cDNA was inserted into a pGEM plasmid and HPRT RNA was generated in quantity. Varied amounts of HPRT RNA were diluted with 12 ug of human lymphoblast poly A+ RNA. A 20-base oligonucleotide primer, complementary to HPRT mRNA, and RNA were heated to 80° C for 3 min, hybridized for 45 min at 54° C and subjected to Sanger dideoxy sequencing reactions. dNTP-labelled sequencing produced reliable results at a message abundance of greater than 0.1%, but was marred by anomalous banding and high background at lower abundances. Primer-labelled sequencing produced reliable sequence at a message abundance of 0.05%. The minimal message requirement for the primer-labelled sequencing method was determined by using between 3 and 50 ug of poly A+ RNA in the sequencing of HPRT mRNA (∼ 0.01% of poly A+ mRNA) and phosphoglycerate kinase (PGK) mRNA (∼ 0.05% of poly A+ mRNA). Reliable sequence was obtained from 0.01 pmole of either PGK or HPRT message. The region of interest in a PGK variant previously characterized as a single amino acid substitution was sequenced. Direct sequencing is indicated to be useful for messages whose abundance is equal or greater than 0.05%. Supported by the Medical Research Council grant MT-8665.

146 MOUSE MODELS OF PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY. CHARACTERIZATION OF PARTIALLY AND SEVERELY ENZYME DEFICIENT MUTANTS

Two mutations of purine nucleoside phosphorylase (PNP) were identified in the carrier state of the first generation progeny of male mice treated with ethylnitrosourea mated to untreated females. The variants are assigned the gene symbols Np-1e and Np-1f. Both carriers have approximately half normal PNP activity in erythrocytes and Np-1a/Np-1a was distinct from the inbred strain background, Np-1a/Np-1a on isoelectric focusing, whereas Np-1a/Np-1a was not distinguishable. In the homozygous state, Np-1a and Np-1a differ and determine a more basic pattern of PNP activity than the Np-1a allele. NP-1A is stable in the presence of phosphate at 55° C whereas the half lives for the mutants were 30 and 7.5 min for NP-1E and NP-1F respectively. The substrate Michaelis constants for the variants were unchanged from controls and the maximal velocities for erythrocytes were: 16.8 ± 1.1, NP-1A; 2.16 ± 0.12, NP-1E; and 0.50 ± 0.03, NP-1F (nmole/min/mg protein). Brain, heart, kidney, liver, spleen leukocytes and thymocytes also showed reductions in activity, 4-27% of normal for NP-1E and 0.1-3.9% for NP-1F. Purine nucleoside excretion correlated with the severity of the enzyme deficiency. The substrates of PNP are not found normally ingurine < 10 uM, but inosine and guanosine were present for Np-1e/Np-1e mice, total 150 ± 84 uM; as were inosine, guanosine, deoxyinosine, and deoxyguanosine for Np-1f/Np-1f mice, total 1490 ± 190 uM. Supported by the Medical Research Council grant MT-6376.

Comparison of chiropractic and hospital outpatient management of low back pain: a feasibility study. Report of a working group.

This is the report of a feasibility study of a randomised controlled trial of chiropractic and hospital outpatient management for low back pain of mechanical origin. Preparations for the study included an approach to the General Medical Council for guidance about the intended collaboration between medically qualified and heterodox practitioners, detailed communication with local general practitioners, and the provision of a Medical Research Council (MRC) grant to cover payments to the chiropractors for work carried out in the course of the study. A total of 238 patients were considered, 197 of whom had initially presented to Northwick Park Hospital and the remaining 41 to the chiropractic clinic in Harrow. Only 6% of the patients presenting to the hospital refused to enter. The single most frequent reason for ineligibility in the hospital patients was freedom from pain at the time of the first hospital visit (23%). A variety of medical contraindications accounted for the exclusion of a further 24% of hospital patients. Patients presenting to the chiropractic group tended to have had shorter current episodes of back pain but to have had more NHS treatment in the past than those presenting to hospital. The commonest reason for exclusion among those presenting to the chiropractic clinic was refusal to enter (34%). Only 5% of the chiropractic patients were ineligible for medical reasons. Overall, 16% of those presenting to hospital and 44% of those presenting to the chiropractors were eligible and willing to enter the randomised treatment phase of the study. Of the 50 patients who entered the treatment phase, all but seven completed treatment and the six weekly self-completed assessments of progress. Patients whose current episodes had lasted less than a month progressed significantly more rapidly than those with longer current episodes. It is likely that sufficient numbers of patients with low back pain are prepared to take part in a formal randomized controlled trial. The organization and working methods for such a trial appear to be feasible. A full scale multicentre trial should aim to include about 2000 patients.

313 THE α-ADRENERGIC RECEPTORS IN BROWN ADIPOCYTES OF DEVELOPING RATS

Specific binding of α-adrenergic ligands [3H] olonidine and [3H]RX 781097 was observed with plasma membrane fragments isolated from interscapular brown adipose tissue of 7-day-old rats. Scatchard and Woolf analyses of the data and results on specific displacement of [3H] norepinephrine by low concentrations of epinephrine and yohimhine were consistent with the existence in brown adipocytes of a homogeneous class of the binding sites. Competition experiments on both α-agonists and α-antagonists binding were consistent with pharmacological definition of the α2-adrenoreceptor subtype. Chemical denervation by 6-hydroxy-dopamine resulted in a more pronounced distinction of the two affinity states of the receptors. A two-slope Scatchard plot showed mean apparent KD of 29 and 250 nM for the α2H and α2L, respectively. The maximum number of sites was somewhat higher (0.58 pmol/mg protein) than in control animals. Pre-treatment of infant rats with yohimbine (7 days of 10 mg/kg b.w. daily) has resulted in increased specific binding of [3H] yohimbine. Comparison studies using the β-receptor ligand [3H] dihydroal-prenolol seem to indicate “hybrid” characteristics. Competition binding studies may be interpreted in terms that both the α-and β-adrenoreceptors in brown adipocytes of infant rats are “hybrid” species which may in fact reside within integrated protein molecules. (Supported by Canadian Medical Research Council Grant MA-7217).

THE α2-ADRENERGIC RECEPTORS IN BROWN ADIPOCYTES OF DEVELOPING RATS

We have previously described a link between cyclic GMP and α-adrenergic stimulation in vivo of brown fat of developing rats. Subsequent in vitro experiments showed that cyclic GMP content of brown adipocytes is influenced by pharmacologically - defined α2 - adrenergic receptors. Since these thermogenic cells are known to possess predominantly the β1 - adrenoreceptors, we have undertaken a series of in vitro binding studies. Partially purified cell membrane fragments from brown fat of 7-day-old rats exhibited a large proportion of non - specific binding for both yohimbine and rauwolscine. However, evidence was obtained for the presence of a relatively small number of high-affinity (α2H) binding sites for the α2-adrenergic antagonists, which seem to readily interconvert to a low affinity form (α2L). The age of the animals, the purity of the membrane fraction, and the ionic composition of the incubation media were found to influence the relative proportions of these two affinity forms of the α2-receptors. Preliminary results indicated that the existence of the two states of the α2-receptors may add another dimension to the regulation of both the functional and the proliferative responses of the brown adipocytes during perinatal development of the rat. The mechanism of the apparent link between the α2-adrenergic receptors and the guanylate cyclase activity in brown adipose tissue remains to be established. (Supported by Canadian Medical Research Council grant MA-7217).

Minimizing the impact of intestinal surgery.

Efforts are increasing to make life as normal as possible for patients who require surgical removal of diseased portions,of the alimentary tract. Studies on ileoanal anastomosis and ileostomy occluding devices are under way at the Mayo Clinic and elsewhere. At Mayo, a "resurrected technique" used in the 1940s in Europe and the United States is now being used for some patients. Colonic disease limited to the mucosa is treated by colectomy, mucosal proctectomy, and endorectal-ileal pull-through with preservation of the anal sphincter ( Surg Gynecol Obstet 1947;84:1095-1099). Surgical resident Jacques Heppell, MD, who under a Canadian Medical Research Council grant is working with Keith A. Kelly, MD, explains that continence is related not only to good sphincter function but also to the reservoir capacity of the rectum. The hypothesis is that, after such surgery, the terminal ileum can dilate secondary to chronic intermittent occlusion by sphincter contraction. The sphincter pressure that

Minimizing the impact of intestinal surgery

Efforts are increasing to make life as normal as possible for patients who require surgical removal of diseased portions,of the alimentary tract. Studies on ileoanal anastomosis and ileostomy occluding devices are under way at the Mayo Clinic and elsewhere. At Mayo, a resurrected technique used in the 1940s in Europe and the United States is now being used for some patients. Colonic disease limited to the mucosa is treated by colectomy, mucosal proctectomy, and endorectal-ileal pull-through with preservation of the anal sphincter ( Surg Gynecol Obstet 1947;84:1095-1099). Surgical resident Jacques Heppell, MD, who under a Canadian Medical Research Council grant is working with Keith A. Kelly, MD, explains that continence is related not only to good sphincter function but also to the reservoir capacity of the rectum. The hypothesis is that, after such surgery, the terminal ileum can dilate secondary to chronic intermittent occlusion by sphincter contraction. The sphincter pressure that

Scanning Electron Microscopic Study of the Human Fallopian Tube. Report II. Fetal Life, Reproductive Life, and Postmenopause

Scanning Electron Microscopic Study of the Human Fallopian Tube. Report II. Fetal Life, Reproductive Life, and Postmenopause

Scanning Electron Microscopic study of the Human Endometrium

Scanning Electron Microscopic study of the Human Endometrium

The effect of changes in the blood flow to the tongue on the chorda tympani response in rat.

AbstractThe summated chorda tympani response to taste stimuli was recorded in rats during repeated occlusion of the blood flow to the tongue. It was then observed that the response diminished and disappeared within a few minutes after bilateral or ipsilateral occlusion of the blood supply. Intravital staining through the lingual artery showed that each half of the tongue was chiefly supplied with blood from its ipsilateral lingual artery. A close relation between the simultaneous variation of the systemic blood pressure and the taste response was also observed and is discussed here.This study was supported by grants from Swedish Medical Research Council grant No B71–14X‐2467.04 and Svenska Maltdrycksforskningsinstitutet.

The antigens of Mycoplasma hominis.

SUMMARYA genital strain ofMycoplasma hominiswas fractionated by differential centrifugation after disruption of the cells by alternate cycles of freezing and thawing, by gas cavitation under nitrogen, or by ultrasonic treatment.Antigens of the cell membrane were distinct from those in the soluble cell contents, judging from metabolic inhibition (MI), indirect haemagglutination (IHA), gel-diffusion and immunoelectrophoresis tests, and by the antibody response in rabbits inoculated with these fractions. The antigens which gave rise to MI and IHA antibody were located in the cell membrane.Extraction of whole cells ofM. hominisby various chemical methods suggested that the active components were protein in nature and that there was no lipid hapten, as inM. pneumoniae, or polysaccharide, as inM. mycoidesvar.mycoides.This work was partly supported by a Medical Research Council grant, which provided the remuneration of MRH.We thank Professor R. A. Kekwick and Dr J. M. Creeth of the Biophysics Department of this Institute for their advice on the processing of plasma and density gradient centrifugation, and Mr F. C. Belton of the Microbiological Research Establishment, Porton, Wilts, for growing a 50 litre batch ofM. hominis.

A Method of Evaluating the Effectiveness of a Community Health Service*

Social Policy & AdministrationVolume 1, Issue 4 p. 29-48 A Method of Evaluating the Effectiveness of a Community Health Service* Albert Kushlick, Albert Kushlick Wessex Regional Hospital BoardSearch for more papers by this author Albert Kushlick, Albert Kushlick Wessex Regional Hospital BoardSearch for more papers by this author First published: October 1967 https://doi.org/10.1111/j.1467-9515.1967.tb00071.xCitations: 4 * This article is based on a paper read to a Conference on Pediatric Research “Problems of Assessing Effectiveness of Child Health Services”, Warrenton, Virgina, U.S.A., March 1967. For the past four years the author has been engaged in an epidemiological survey of mental subnormality in the south of England. The aim of this survey has been to enable the Wessex Regional Hospital Board, which serves a population of just under two million people, to plan and develop its services for the mentally subnormal. It was set up at the Board's initiative, on the advice of Professor Jack Tizard. It was financed up to May of this year by the Ministry of Health and the Nuffield Provincial Hospitals Trust Fund and now by a Medical Research Council Grant. Recently the data obtained from the survey have been used to plan and develop a new form of residential care for the subnormal and to evaluate the effectiveness of the new services. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume1, Issue4October 1967Pages 29-48 RelatedInformation

Speech at High Atmospheric Pressures

A spectrographic study of speech recorded at various atmospheric pressures in a decompression chamber has revealed certain systematic factors concerning formant-frequency shifts that support an acoustic theory of the origin of these effects. The typical “nasal” quality is due to the shunting effects of the vocal-cavity walls. The relative loading effect of this impedance increases as the impedance level of the air cavities increases with increasing density of the air. A supplementary x-ray study at high pressure showed a normal velar function. The complete theory has implications on normal speech production. [Study supported by the Swedish Medical Research Council grants T 312 and W 267; the Swedish Technical Research Council; the National Institutes of Health, U. S. Department of Health, Education, and Welfare, under research grant NB-04003-02; the U. S. Air Force under grant AF EOAR 64-28; and the U. S. Army under contract DA-91-591-EUC-3080.]

Physiological and Psychological Responses to Stress in Neurotic Patients

At the beginning of the war part of the Maudsley Hospital moved to Mill Hill School, and a neurosis centre of 550 beds was established. During the six years of war some 20,000 neurotic patients, both forces and civilian, were treated at this centre. Within the centre a special unit for the study of Forces patients with effort syndrome (E.S.) was set up. This unit was in existence from 1939 to 1945, and during this period 2,324 cases of E.S. were treated. The writer was associated with this unit throughout, working in association with a cardiologist (Paul Wood (1)), and with other psychiatrists (Lewis (2), Guttmann (3), Gillespie (4)). Much of the material brought together in this thesis has already been published (Jones (3, 5, 6, 7, 8, 9, 10, 11, 12, 38, 43)). During most of the war years the writer was in receipt of a Medical Research Council grant.