Combined spinal-epidural techniques and the awake/asleep debate.
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Anesthesia, Epidural↗
Biomedical subjects
J Jenkins
Publications and source records attributed to J Jenkins.
T-cell telomere length maintained in HIV-infected long-term survivors.
BACKGROUND AND METHODS: We have used the erosion of telomeric DNA as a measure of cellular division to study the replicative history of isolated T-lymphocyte subpopulations from a group of HIV-infected long-term survivors and age-matched healthy controls. RESULTS: In keeping with previous studies, we found that CD45RO+ (memory) T-cells showed greater telomere erosion than CD45RA+ (naive) T-cells. We did not, however, find any significant differences in the telomere lengths of isolated CD4+, CD8+, CD45RA+ or CD45RO+ T-cells between HIV-infected long-term survivors and age-matched controls. Further, we found no evidence of telomerase activation in T-cells from the HIV-infected groups to account for the lack of telomere erosion. CONCLUSIONS: Our data show no evidence, through telomere shortening, of clonal exhaustion or replicative senescence due to an increased rate of immune cell turnover in HIV-infected long-term survivors.
Adult↗
Crystallization and preliminary crystallographic analysis of the endo-polygalacturonase from Erwinia carotovora ssp. carotovora.
Crystals of endo-polygalacturonase from Erwinia carotovora ssp. carotovora have been grown from polyethylene glycol 6000 by the hanging-drop method. Polygalacturonase is important in the virulence of this plant pathogen. The protein crystallizes in space group C2 with unit-cell parameters a = 81.3, b = 53.0, c = 103.1 A, beta = 112.6 degrees and with a single molecule in the asymmetric unit. The crystals diffract to 1.9 A.
Bacillus subtilis↗
Sequential antimicrobial therapy: treatment of severe lower respiratory tract infections in children.
Although there have been a number of studies in adults, to date there has been little research into sequential antimicrobial therapy (SAT) in paediatric populations. The present study evaluates the impact of a SAT protocol for the treatment of severe lower respiratory tract infection in paediatric patients. The study involved 89 paediatric patients (44 control and 45 SAT). The SAT patients had a shorter length of hospital stay (4.0 versus 8.3 days), shorter duration of inpatient antimicrobial therapy (4.0 versus 7.9 days) with the period of iv therapy being reduced from a mean of 5.6 to 1.7 days. The total healthcare costs were reduced by 52%. The resolution of severe lower respiratory tract infection with a short course of iv antimicrobials, followed by conversion to oral therapy yielded clinical outcomes comparable to those achieved using longer term iv therapy. SAT proved to be an important cost-minimizing tool for realizing substantial healthcare costs savings.
Administration, Oral↗
Information Technology for postgraduate education: survey of facilities and skills in the South West Deanery.
OBJECTIVE: To determine the Information Technology (IT) infrastructure available to, and IT skills of, obstetric specialist registrars across the South West Deanery. DESIGN: Open prospective study. SETTING: NHS Hospitals in the South West Deanery. METHODS: Two separate surveys. Firstly, the computer equipment available to trainees was determined at each hospital in the deanery on site using a software programme. Secondly, IT skills of a sample of 22 specialist registrars were assessed using a checklist at a series of four workshops. MAIN OUTCOME MEASURES: Computers with sufficient specification to use CD-ROMs, to access the Internet, and to support data-, audio- and video-conferencing. The number of trainees with IT skills to use a computer-aided learning package and the Internet. RESULTS: Sixty-six percent of trainees have access to a computer with a CD-ROM drive. Sixty-six percent also have access to the Internet at their place of work. Thirteen percent have access to data-conferencing but there were no computers in the Deanery able to support audio- or video-conferencing. Twenty-five percent of trainees have no IT skills and require basic training in the use of computers. Thirty-six percent of our sample would require training to be able to use computer-based tutorials programs. Seventy-seven percent of trainees require training to be able to use the Internet without assistance. CONCLUSION: A significant minority of trainees do not have access to computers with sufficient specification to run basic tutorial programmes or access the Internet. Similarly, a large minority of trainees do not even have a basic knowledge of computer technology and IT training is required for the majority of trainees for them to reap the potential benefits which computer-based tutorials systems and the Internet can give.
Computers↗
Nursing in genitourinary medicine: 10 years on from the Monks Report. The membership of GUNA. Genito-Urinary Nurses Association.
Various reports and surveys since 1988 have highlighted differences in gradings and diversity of roles and responsibilities of nurses in genitourinary medicine (GUM). In addition there was no method of defining how many nurses work in the speciality. Therefore the Genito-Urinary Nurses Association (GUNA) undertook a survey last year to establish how many nurses, of what grade, undertaking what roles are working in GUM clinics. Over half the clinics in the UK responded, from full-time busy London clinics to small part-time rural clinics. The results suggest approximately 2000 nurses working in GUM nationally, with a wide diversity of grades, roles and responsibilities still apparent 10 years after the Monks Report. Further analysis of the data obtained by the survey is given in the report.
Female Urogenital Diseases↗
The patient's perception of chronic pain.
Chronic pain is common among hospital inpatients. Patients with chronic pain have low expectations of pain relief. The patient's need for information is frequently not met.
Acute Disease↗
Urine control theory derived from Roy's conceptual framework.
The urine control theory, a middle range theory substructed from Roy's adaptation model, is presented to explicate the phenomenon of urine control. Urine in the bladder is identified as the focal stimulus, and the impact of the cognator subsystem in relation to urine control is described. The role of contextual stimuli related to mobility and the environment is also described. Relationships between concepts are explained and supported with individual case studies. The case findings are used to exemplify the interrelationships in the model. The urine control theory can be used by practitioners to inform practice and by researchers to guide research designs.
Activities of Daily Living↗
Crystal structure of polygalacturonase from Erwinia carotovora ssp. carotovora.
The crystal structure of the 40-kDa endo-polygalacturonase from Erwinia carotovora ssp. carotovora was solved by multiple isomorphous replacement and refined at 1.9 A to a conventional crystallographic R-factor of 0.198 and Rfree of 0.239. This is the first structure of a polygalacturonase and comprises a 10 turn right-handed parallel beta-helix domain with two loop regions forming a "tunnel like" substrate-binding cleft. Sequence conservation indicates that the active site of polygalacturonase is between these two loop regions, and comparison of the structure of polygalacturonase with that of rhamnogalacturonase A from Aspergillus aculeatus enables two conserved aspartates, presumed to be catalytic residues, to be identified. An adjacent histidine, in accord with biochemical results, is also seen. A similarity in overall electrostatic properties of the substrate-binding clefts of polygalacturonase and pectate lyase, which bind and cleave the same substrate, polygalacturonic acid, is also revealed.
Amino Acid Sequence↗
IL-2 adenovector-transduced autologous tumor cells induce antitumor immune responses in patients with neuroblastoma.
In many different murine models, the immunogenicity of tumor cells can be increased by transduction with a range of immunostimulatory genes, inducing an immune response that causes regression of pre-existing unmodified tumor cells. To investigate the relevance of these animal models to pediatric malignancy, we used autologous unirradiated tumor cells transduced with an adenovirus-IL-2 to immunize 10 children with advanced neuroblastoma. In a dose-escalation study, we found that this tumor immunogen induced a moderate local inflammatory response consisting predominantly of CD4(+) T lymphocytes, and a systemic response, with a rise in circulating CD25(+) and DR+ CD3(+) T cells. Patients also made a specific antitumor response, manifest by an IgG antitumor antibody and increased cytotoxic T-cell killing of autologous tumor cells. Clinically, five patients had tumor responses after the tumor immunogen alone (one complete tumor response, one partial response, and three with stable disease). Four of these five patients were shown to have coexisting antitumor cytotoxic activity, as opposed to only one of the patients with nonresponsive disease. These results show a promising correlation between preclinical observations and clinical outcome in this disease, and support further exploration of the approach for malignant diseases of children.
Adenoviridae↗
Structural basis for specificity of papain-like cysteine protease proregions toward their cognate enzymes.
Synthetic peptides corresponding to the proregions of papain-like cysteine proteases have been shown to be good and selective inhibitors of their parental enzymes. The molecular basis for their selectivity, quite remarkable in some cases, is not fully understood. The recent determination of the crystal structures of three distinct papain-like cysteine protease zymogens allows detailed structural comparisons to be made. The reasons for the specificity shown by each proregion toward its cognate enzyme are explained in terms of the three-dimensional structure of the proregion and the interface between the mature enzyme and the proregion. These comparisons reveal that insertion and substitution of amino acids within the proregion cause major rearrangement of sidechains on the enzyme/proregion interface, allowing detailed surface and charge recognition.
Amino Acid Sequence↗
Interleukin-2 gene-modified allogeneic tumor cells for treatment of relapsed neuroblastoma.
Tumor cells that have been genetically modified to express immunostimulatory genes will induce effective antitumor responses in a range of syngeneic animal models. For human applications, transduced autologous tumor cell lines are often difficult or impossible to prepare, so that there are strong incentives for substituting a standardized allogeneic tumor cell line. However, such lines may be inferior immunogens if they differ from host tumors in the antigens they express. We have evaluated the safety, immunostimulatory, and antitumor activity of an interleukin-2-secreting allogeneic neuroblastoma cell line in 12 children with relapsed stage IV neuroblastoma. They received two to four subcutaneous injections of cells in a dose-escalating schedule, up to a maximum of 10(8) cells per injection. There was induration and pruritus at the injection site, and skin biopsies revealed mild panniculitis with CD3+ cells surrounding scanty residual tumor cells. There was a limited but significant peripheral monocytosis. No patient showed any increase in direct cytotoxic effector function against the immunizing cell line, but 3 patients had a rise in the frequency of neuroblastoma-reactive cytotoxic T lymphocyte precursor cells. One child had > 90% tumor response (PR), 7 had stable disease, and 4 had progressive disease in response to vaccine alone. Although these results offer some encouragement for the continued pursuit of allogeneic vaccine strategies in human cancer, the antitumor immune responses we observed are inferior to those obtained in an earlier immunization study using autologous neuroblastoma cells. Hence, we suggest that this earlier approach remains preferable, its difficulties notwithstanding.
Cancer Vaccines↗
Crystallization and preliminary X-ray analysis of a member of a new family of pectate lyases, PeIL from Erwinia chrysanthemi.
PeIL, a pectate lyase (E.C. 4.2.2.9) from E. chrysanthemi 3937 that is not homologous to the lyases with known structures, has been purified and crystallized by the hanging-drop method using a variety of organic solvents as precipitant. Elongated lathes grown from poly(ethylene glycol) plus isopropanol belong to the space group P212121 with cell dimensions a = 55.5, b = 58.2, c = 16.4 A with a single molecule in the asymmetric unit. Although complete data sets have been collected to 2.3 A resolution, these crystals diffract to at least 1.9 A resolution and are suitable for structure determination. Chunky plates grown using other organic solvents as the precipitant diffracted to 3 A resolution and were partially characterized as a second orthorhombic crystal form with space group P21212 and cell dimensions a = 119.1, b = 140.5 and c = 105.4 A, suggesting four molecules in the asymmetric unit.
Crystallization↗
Structure and evolution of parallel beta-helix proteins.
Three bacterial pectate lyases, a pectin lyase from Aspergillus niger, the structures of rhamnogalacturonase A from Aspergillus aculeatus, RGase A, and the P22-phage tailspike protein, TSP, display the right-handed parallel beta-helix architecture first seen in pectate lyase. The lyases have 7 complete coils while RGase A and TSP have 11 and 12, respectively. Each coil contains three beta-strands and three turn regions named PB1, T1, PB2, T2, PB3, and T3 in their order of occurrence. The lyases have homologous sequences but RGase A and TSP do not show obvious sequence homology either to the lyases or to each other. However, the structural similarities between all these molecules are so extensive that divergence from a common ancestor is much more probable than convergence to the same fold. The region PB2-T2-PB3 is the best conserved region in the lyases and shows the clearest structural similarity. Not only is the pleating and the direction of the hydrogen bonding in the sheets conserved, but so is the unusual alphaL-conformation turn between the two sheets. However, the overall shape, the position of long loops, a conserved alpha-helix that covers the amino-terminal end of the parallel beta-helix and stacks of residues in alphaR-conformation at the start of PB1 all suggest a common ancestor. The functional similarity, that the enzymes all bind alpha-galactose containing polymers at an equivalent site involving PB1 and its two flanking turn regions, further supports divergent evolution. We suggest that the stacking of the coils and the unusual near perpendicular junction of PB2 and PB3 make the parallel beta-helix fold especially likely to maintain similar main chain conformations during divergent evolution even after all vestige of similarity in primary structure has vanished.
Amino Acid Sequence↗
Fluticasone propionate results in improved glucocorticoid receptor binding affinity and reduced oral glucocorticoid requirements in severe asthma.
BACKGROUND: Inhaled glucocorticoids (iGC) have become important first line agents in the management of moderate-to-severe asthma. Severe asthma is associated with reduced glucocorticoid receptor (GCR) binding affinity. METHODS: To evaluate the potential impact of inhaled fluticasone propionate on markers of airway inflammation [GCR binding affinity (Kd) and eosinophil cationic protein (ECP)] and oral GC requirements in steroid-dependent asthmatics, we examined the effects of fluticasone propionate (FP) 500 microg or 1000 microg BID and placebo in a double-blind, randomized study of 13 steroid-dependent asthmatics at a single center. Glucocorticoid receptor binding affinity and ECP values were obtained at baseline, 4, 6, 26, and 52 weeks after patients were enrolled into the study. Oral GC dose and FEV1 values were also recorded at each visit. RESULTS: Inhaled FP resulted in large reductions in oral GC requirement by 6 weeks of therapy while no reduction was seen in the placebo group. All patients in the FP 2000 microg/d group who continued double-blind therapy at 52 weeks were able to eliminate oral prednisone use. In contrast, every patient in the placebo group had to be withdrawn from the study due to poor asthma control. Associated with the oral GC dose reduction on high dose FP therapy, were improvements in GCR binding affinity with the GCR Kd falling from 42.5 nM at baseline to 19.5 nM at 6 weeks (P=.08). The GCR KD values remained stable thereafter with values of 23.5 nM at 26 weeks (P=.02) and 19.5 nM at 52 weeks (P=.01). In addition, high dose FP therapy resulted in reductions in serum ECP values. CONCLUSION: This study suggests that high dose FP therapy results in significant oral GC sparing effects associated with improved GCR binding affinity and reductions in serum ECP levels in patients with steroid-dependent asthma.
Administration, Oral↗
Phase II study of CI-980 (NSC 635370) in patients with previously treated advanced soft-tissue sarcomas.
Doxorubicin and ifosfamide are the two most active agents in the treatment of soft-tissue sarcomas. Patients whose tumors have failed these two drugs have very limited systemic therapy options. It is, therefore, important to identify newer drugs with activity against this disease. CI-980 is a synthetic mitotic inhibitor that binds to tubulin at the colchicine binding site and inhibits the polymerization of tubulin and blocks cell cycle progression in mitosis. Given its broad spectrum activity against several solid tumor models in vivo, we decided to perform a phase 2 study of this drug in previously treated soft-tissue sarcomas. A total of 18 eligible and evaluable patients were entered in the first stage of the trial. The median age was 53 yrs (range, 17-72). No objective responses have been noted. Six patients had stable disease after a median of 3.5 cycles of chemotherapy while 12 others had progressive disease. A total of 48 cycles were administered, 42 of which were administered at dose level 0 (4.5 mg/m2/d x 3). The median AGC nadir was 1.2/microl(0.1 -4.7) on day 10 and the median platelet nadir was 150,000/microl (31,000-338,000). Twenty cycles were complicated with grade 3-4 neutropenia and two cycles were complicated with FUO. There were no CNS toxicities. One patient had a grade 1 thrombophlebitis in 2 cycles and one other patient had a grade 4 thrombophlebitis in one cycle. In conclusion, CI-980 was well tolerated at this dose and schedule but inactive in soft-tissue sarcomas.
Adolescent↗
Superfamilies: the 4/7 superfamily of beta alpha-barrel glycosidases and the right-handed parallel beta-helix superfamily.
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Glycoside Hydrolases↗
Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas.
The authors evaluate the efficacy and feasibility of dose-intensive doxorubicin and ifosfamide combination chemotherapy in patients with sarcomas. From January 1995 to April 1996, 33 evaluable patients with either metastatic sarcoma or primary sarcomas with a high-risk for metastases (all except one was previously untreated with chemotherapy) were treated on two consecutive protocols. The median age was 45 years (range, 15-68 years). The first protocol included doxorubicin at 75 mg/m2 given as a 72-hour infusion on days 1 to 3 along with ifosfamide at 2 g/m2/d over 2 hours x 5, days 1 to 5 (protocol AI 75/10). Granulocyte colony-stimulating factor (G-CSF) was used only if indicated according to American Society of Clinical Oncology guidelines. The second protocol included doxorubicin at 90 mg/m2 as a 72-hour continuous infusion and ifosfamide at 2.5 g/m2/d for 4 days (protocol AI 90/10) with prophylactic G-CSF. A median of four cycles were administered (range, 1-6). Three patients achieved a pathologic complete response (CR) and 18 patients achieved a partial response (PR) for a response rate (RR) of 64% (95% confidence interval (CI), 45-80%). Response rate for the subset of patients with soft-tissue sarcomas was 66% (95% CI, 46-82%). Only three patients progressed on therapy. Febrile neutropenia was noted in 31% of cycles at AI 75/10 and in 56% of cycles at AI 90/10. One patient developed reversible grade 3 central nervous system (CNS) toxicity. There was one treatment-related death on AI 90/10 secondary to doxorubicin cardiac toxicity at a cumulative dose of 435 mg/m2. Dose-intensive doxorubicin plus ifosfamide is feasible in appropriately selected patients and appears to be a very active regimen in patients with sarcomas. The authors are currently testing this regimen with G-CSF and thrombopoietin.
Adolescent↗