Strategy and the NHS--do we need it?
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Biomedical subjects
Publications and source records attributed to C Cole.
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In a randomised, single-blinded, placebo-controlled study, 27 parturients in labour receiving epidural 0.125 per cent bupivacaine, were assessed to evaluate the efficacy of patient-controlled epidural analgesia (PCEA) compared with continuous infusion epidural analgesia (CIEA). Group A (n = 14) received a background infusion of 4 ml.hr-1 0.125 per cent bupivacaine, with further 4 ml aliquots, self-administered, as required (up to 16 ml.hr-1). Group B (n = 11) received a continuous infusion of 12 ml.hr-1 through the same PCA apparatus, but with the demand-button deactivated. Both groups were similar in respect to age, height, weight, duration and outcome of labour, birthweight and neonatal Apgar scores. Patients in Group A (PCEA) received significantly less local anaesthetic than those in Group B (11.2 vs 15.2 mg.hr-1). Pain relief was similar in both groups. Patients expressed overall satisfaction with PCEA, appreciating control over their own pain relief and less reliance on medical staff. PCEA is a safe, effective means of providing optimal analgesia during labour, with minimal local anaesthetic requirement.
The influence of specific contiguous stretches of amino acids predominantly in the carboxy terminal third of the SV40 large T antigen on the immortalization of cells in culture was investigated. Mutants that bear either small in-phase or frameshift deletions in the large T antigen coding sequence were transfected into primary mouse embryo fibroblasts of C57Bl/6 origin (B6/MEF). The frequency of immortalization was determined as the number of colonies that developed from cells escaping senescence. The results indicated that the terminal 81 amino acids of large T antigen are not needed for efficient immortalization or tumorigenicity. In contrast removal of as few as three amino acids encoded in the vicinity of the Dde-1 site at 0.234 map units (m.u.) severely restricted immortalization, suggesting that this region of the coding sequence either structurally or functionally is essential to at least one parameter of the transformed cell phenotype. The T antigen produced by dlA2433 which bears a deletion of nine nucleotides at 0.234 m.u. fails to associate stably with the cellular protein p53. The results showed that the addition of long stretches of amino acids (96 or 97 residues) from the open reading frame at the 3' end of the early region inactivated immortalizing functions, although the addition of as many as 18 amino acids from other reading frames was not detrimental. The evidence presented also confirmed that wild-type levels of ATPase activity are not necessary for immortalization or tumorigenicity of B6/MEF. Finally, we show that one of the mutants that immortalized primary cells did not produce dense foci on a cell monolayer. This last result indicated that independent functions are required for these two parameters of the transformed cell phenotype.
Rowena Keleher and Carol Cole set the scene for change with a brief description of the current rapidly developing internal and external environment of the NHS. They then identify a range of "supports" used to facilitate such change, explore how they are selected and examine their apparent advantages and disadvantages. Common themes leading to effective change are drawn out. Finally, a four-factor model for effective change is presented; deficiencies in current change efforts identified and recommendations for improvements suggested.
A total of 278 families of probands with Duchenne or Becker muscular dystrophy has been ascertained and offered genetic counselling. Linkage studies have been performed in these families using polymorphic DNA markers identifying loci linked to Duchenne and Becker muscular dystrophy. The clinical features of the probands are discussed: there was marked intrafamilial resemblance in the severity of the disease. We estimate that a complete study of potential carriers in these families would require analysis of samples from approximately 1400 subjects. The results of linkage studies tended to move women's carrier risk estimates (based on CK and pedigree data) towards the extremes of the risk categories, providing a more definitive risk estimate for 81% of the women who were previously in the middle range of carrier risk probabilities. About 70% of the families had only one affected member. Linkage analysis altered carrier risk estimates in 95% of sisters and aunts of index cases, but only affected estimates of the mother's carrier risks in about 11% of isolated cases. Even where linkage studies were not helpful in elucidating carrier risks, information could usually be obtained for use in prenatal diagnosis if required. We have assessed the attitudes to pregnancy and prenatal diagnosis of women at risk of being carriers of Duchenne or Becker muscular dystrophy and report 17 pregnancies in these women.
The mutant dlA2414 bears a frame-shift deletion of nucleotides 2936-2927 in the coding sequence for the simian virus 40 (SV40) large T antigen. Based on its nucleotide sequence, this mutant should produce a T antigen containing the first 627 authentic large T antigen amino acids followed by 97 amino acids encoded in the alternate open reading frame at the 3' end of the early region. This protein resembles the hypothetical T* protein that would be translated from an early SV40 mRNA if it were spliced to permit utilization of the open reading frame. We show that stable mouse cell lines can be generated that express the T antigen produced by dlA2414 and that this T antigen has an altered carboxy terminus. In addition, the expected tryptic peptides were missing from the large T antigen and replaced by more hydrophobic peptides. The T*-like protein produced by dlA2414 was apparently less stable than wild-type T antigen and did not stably complex with the cellular phosphoprotein p53. This protein retained the ability to immunize mice against a challenge of syngeneic SV40-tumor cells. The dlA2414 T antigen was expressed at the surface of cells as shown by in vitro lymphocyte-mediated cytotoxicity assay. The results presented here also showed that the expression of a T*-like protein at the cell surface is not likely to be essential for tumorigenesis of cells transformed by SV40.
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We have searched for linkage between polymorphic loci defined by DNA markers on the X chromosome and X-linked Emery-Dreifuss muscular dystrophy (EDMD). There are high recombination rates between EDMD and the Xp loci known to be linked to Becker and Duchenne muscular dystrophy. There is a suggestion of linkage between EDMD and the loci DXS52 and DXS15, defined by probes St14 and DX13 respectively, located at Xq28. Z for DXS15 = 1.14 at theta = 0.15. This is in agreement with the previously reported linkage between a disorder strongly resembling EDMD and colour-blindness (Thomas et al. 1972), suggesting that there is a second locus on the X chromosome concerned with muscle integrity.
We have probed the DNA of 156 Duchenne muscular dystrophy (DMD) patients, representing 140 kindreds, with cloned DNA sequences derived from Xp21 and known to show deletions in some DMD patients. Sixteen cases showed a deletion, as defined by lack of hybridisation to one or more of the four probes used. However, two of these cases were brothers, so 15 independent deletions (10.7%) are represented. The deletion map is compatible with the suggested order for the sites of the probes used in the study, that is, telomere----pERT87.15----pERT87.8----pERT87.1----pX J1.1----754----centromere. Further mapping of these deletions and characterisation of the deletion breakpoints should facilitate more accurate molecular localisation of the gene or genes which, when mutated, are responsible for causing DMD.
We have studied the inheritance of four cloned DNA sequences which recognise restriction fragment length polymorphisms on the short arm of the X chromosome in families with Becker and Duchenne muscular dystrophy. We have confirmed linkage of two probe loci to the disease loci and have combined our results with those previously published to give a maximum lod score of 11.642 at a recombination fraction of 0.15 for DXS41 (probe 99.6), and a maximum lod of 15.84 at a recombination fraction of 0.15 for DXS84 (probe 754). Linkage of these diseases to the loci defined by the pERT87 probes and probe pXJ1.1 has also been studied, giving maximum lod scores of 8.634 and 5.118 at recombination fractions of 0.02 and 0.00 respectively. The information obtained using these polymorphic DNA markers, combined with pedigree and CK data, can be used to give more accurate genetic counselling to women at risk in Becker and Duchenne families.
UV radiation (200-400 nm) is generally considered to be outside the range of visible illumination for mammals. The aim of this study was to determine if UV wavelengths can influence pineal physiology. Experiments on hamsters confirm that wavelengths as low as 305 nm are transmitted through the clear ocular media to the retina. Furthermore, low irradiances of broadband (340-405 nm) and monochromatic (360 nm) UV radiation are capable of suppressing high nocturnal levels of pineal melatonin in intact, but not blind, hamsters. These data indicate that the hamster eye and neuroendocrine system are able to detect and respond to near-UV wavelengths.
Aztreonam, a new monobactam antibiotic with specific gram-negative aerobic activity, was used in combination with clindamycin in the treatment of 40 women with pelvic infection, including post-partum endometritis, pelvic inflammatory disease, and post-hysterectomy pelvic cellulitis. Clinical cure was achieved in 87 percent of patients. Failure was related to the limited gram-positive aerobic spectrum of clindamycin. All aerobic gram-negative enteric organisms were sensitive in vitro to less than 0.125 microgram/ml of aztreonam.
A small but measurable component of some indoor lighting is ultraviolet radiation (UVR); whether it is sufficient to modify the indoor worker's risk for chronic skin changes is not directly answerable with available technology. A first approach to this question involves a) estimating a range of annual background solar exposure for indoor workers currently at risk; b) determining whether, and at what levels, UVR exposure is a part of specified indoor lighting; and c) calculating the increment in risk implied by a and b. This algorithm predicts that some lighting conditions that meet NIOSH recommended standards would still result in significant increases in the risk of cumulative UVR damage, including skin cancer. More information concerning actual exposure conditions, the relation of spectral effectiveness for luminosity and UVR production, and dose-time reciprocity are required to improve our predictions of long-term cutaneous effects of indoor lighting.
The authors previously predicted the failure of posterior cervical fusions utilizing methylmethacrylate cement as an instantaneous "fusion" mass, based on research using an in vitro canine experimental model. This report describes the results of in vivo canine studies on the same subject. Three groups of dogs had application of a posterior C4-C5 20-gauge cerclage wire and autologous iliac crest bone graft; application of a posterior C4-C5 20-gauge cerclage wire and methylmethacrylate cement; or application of a C4-C5 20-gauge cerclage wire only. This group represented the control group. The dogs were allowed to live for 3 months postoperatively, at which time they were killed and their spine fusions studied radiologically, mechanically, and histologically. Five of the bone fusions united solidly radiologically. Their flexion stability was statistically superior to the others. Histologic studies confirmed solid union of the fusion mass to the underlying bone. Four of the six methylmethacrylate fusions demonstrated cerclage wire fracture and methacrylate-bone separation by the second postoperative month. At the time the dogs were killed, their flexion stability was statistically inferior to the bone fusions and tended to be inferior to the controls as well. Histologically, fibrous tissue was noted to have grown between the methacrylate "fusion" mass and the underlying bone. This work provides a mechanical explanation for the well-known success of the traditional bony fusion. It further supports our original prediction regarding the failure of methylmethacrylate "fusions."
To study the association between mycobacterial disease and the acquired immunodeficiency syndrome, we reviewed the records of all cases of tuberculosis and all cases of the syndrome reported in Dade County, Florida, from January 1980 through June 1983. Tuberculosis was diagnosed in 27 of 45 Haitians with the syndrome, but in only 1 of 37 non-Haitians with the syndrome (p less than 0.001). Among the 27 Haitians with the syndrome and tuberculosis, 19 had extrapulmonary tuberculosis, whereas among 286 Haitian patients with tuberculosis without the syndrome, only 56 had extrapulmonary tuberculosis (p less than 0.001). Tuberculosis preceded the syndrome by 1 to 17 months (mean, 6) in 22 patients. In 10 patients with the syndrome and positive sputum cultures who were treated with conventional antituberculosis drugs, the cultures became negative within 1 to 4 months and tuberculosis did not recur. The frequency of disseminated atypical mycobacteriosis or positive sputum cultures for atypical mycobacteria was not significantly different between Haitian (11.3%) and non-Haitian (8.3%) patients with the syndrome.
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Ear swelling, as measured by an engineer's micrometer, shows a positive relationship to doses of ultraviolet radiation (over a range of 0 to 7.4 times the minimally damaging dose) during the first 4 d after irradiation. Subsequently, doses greater than 3 D (see text) caused significant thickening associated with scab formation. Doses of 3 D and lower continued to show a well-correlated dose-response to the end of the study. Changes in ear thickness afford a metric indication (non-invasively and repetitively) of the severity of a skin response to UV.