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Biomedical subjects

A Jordan

Publications and source records attributed to A Jordan.

At least 19 recordsLinked to original sources
PubMed1996

Allosteric regulation of the third ribonucleotide reductase (NrdEF enzyme) from enterobacteriaceae.

Enterobacteriaceae contain genes for three separate ribonucleotide reductases: nrdAB code for a class Ia enzyme, active during aerobiosis, nrdDG for a class III enzyme, active during anaerobiosis, and nrdEF for a cryptic class Ib enzyme. The NrdEF enzyme provides the active reductase in other, widely different bacteria. Here, we describe the allosteric regulation of the Salmonella typhimurium NrdEF enzyme. It consists of two tightly bound homodimeric proteins, R1E and R2F. Nucleoside triphosphates (ATP, dATP, dGTP, and dTTP) regulate the substrate specificity by binding to a single site of the R1E protein (one nucleotide per polypeptide). Regulation is similar to that of the NrdAB enzyme, with one major exception: dATP stimulates reduction of CDP (and UDP) under conditions when dATP strongly inhibits all activity of the NrdAB enzyme. The nrdA-coded R1 protein contains a second binding site for dATP (and ATP) that controls general enzyme activity. All known R1E proteins lack the 50 N-terminal amino acids of R1, and we propose that the activity site is located in this area of the protein. The more sophisticated regulation of NrdAB enzymes of eukaryotes provides protection against the possibly harmful overproduction of dNTPs.

Allosteric Regulation↗
PubMed1996

The ribonucleotide reductase system of Lactococcus lactis. Characterization of an NrdEF enzyme and a new electron transport protein.

Escherichia coli contains the genetic information for three separate ribonucleotide reductases. Two of them (class I enzymes), coded by the nrdAB and nrdEF genes, respectively, contain a tyrosyl radical, whose generation requires oxygen. The NrdAB enzyme is physiologically active. The function of the nrdEF gene is not known. The third enzyme (class III), coded by nrdDG, operates during anaerobiosis. The DNA of Lactococcus lactis contains sequences homologous to the nrdDG genes. Surprisingly, an nrdD- mutant of L. lactis grew well under standard anaerobic growth conditions. The ribonucleotide reductase system of this mutant was shown to consist of an enzyme of the NrdEF-type and a small electron transport protein. The coding operon contains the nrdEF genes and two open reading frames, one of which (nrdH) codes for the small protein. The same gene organization is present in E. coli. We propose that the aerobic class I ribonucleotide reductases contain two subclasses, one coded by nrdAB, active in E. coli and eukaryotes (class Ia), the other coded by nrdEF, present in various microorganisms (class Ib). The NrdEF enzymes use NrdH proteins as electron transporter in place of thioredoxin or glutaredoxin used by NrdAB enzymes. The two classes also differ in their allosteric regulation by dATP.

Amino Acid Sequence↗
PubMed1996

Promoter identification and expression analysis of Salmonella typhimurium and Escherichia coli nrdEF operons encoding one of two class I ribonucleotide reductases present in both bacteria.

Salmonella typhimurium and Escherichia coli cells have two different class I ribonucleotide reductases encoded by the nrdEF and nrdAB operons. Despite the presence of one additional ribonucleotide reductase, the nrdAB-encoded enzyme is essential to the aerobic growth of the cell because nrdAB-defective mutants of both species are not viable in the presence of oxygen. Several factors controlling nrdAB gene transcription have been analysed intensively. Nothing is known about the expression of the nrdEF genes. To study this subject, and after cloning of E. coli nrdEF genes and sequencing of their 5' ends, the promoter of this operon has been identified by primer extension in both bacterial species. The +1 position was 691 bp and 692 bp upstream of the translational start points of the nrdE genes of S. typhimurium and E. coli, respectively. Downstream of the +1 position, and before the nrdE gene, two open reading frames (ORFs) of 81 and 136 amino acid residues are present in both bacteria. The synthesis of a polypeptide with a molecular mass of 9 kDa, corresponding to the first of these two ORFs, was observed by using the T7 RNA polymerase expression system. Comparison of the amino acid predicted sequence of this ORF reveals a significant similarity with glutaredoxin proteins. Competitive, reverse-transcription polymerase chain reaction experiments indicate that transcription from the nrdEF promoter normally takes place in wild-type cells. nrdEF transcription is increased by hydroxyurea, which inhibits class I ribonucleotide reductase activity, in both RecA+ and RecA- cells. nrdA(ts) mutants show a higher level of nrdEF transcription than wild-type cells at either the permissive or the restrictive temperature. nrdEF expression was unaffected by changes in DNA supercoiling whether caused by the introduction of either topA::Tn10 and hns::Tn10 mutations or by the inhibition of DNA gyrase with the antibiotic novobiocin. In contrast to the nrdAB genes, the nrdEF operon is not essential to the cells because nrdEF-defective mutants are viable under both aerobic and anaerobic conditions.

Amino Acid Sequence↗
PubMed1996

Developing a new method to record care at home for children with cancer: an example of research and practice collaboration in a regional paediatric oncology unit.

Academics need to address the facilitation of nurses in practice to research and develop the care given to patients if nursing is to move closer towards a research-based profession. This paper describes a project involving collaboration between an academic department of nursing and nurses working in clinical practice providing care at home for children with cancer. The project involved an audit of the nursing care records for the service, and the development of a new style of record-keeping which described and quantified complex nursing care. The authors discuss the method and results of the project, describing the benefits of research and practice collaboration.

Child↗
PubMed1996

Functional restoration in chronic low back pain.

Conventional treatments have not slowed down the ever expanding low back pain (LBP) problem. Traditional treatment has most probably contributed to the growth of the problem. Therefore, in a search for new solutions, 'functional restoration' has been devised. In connection with chronic LBP the term has been associated with a full-day program lasting from 3 to 5 weeks. It includes multidisciplinary treatment of patients in groups with intensive physical and ergonomic training, psychological pain management, back school, as well as teaching in social/work related issues. The key concepts are 'acceptance of the pain', 'activity', 'self-responsibility', 'multidisciplinary' and 'quantitative functional evaluation (QFE)'. The latter is aimed so that the participants can feel the physical improvement, encouraging them to be able to go back to work, or at least to lead a more active life style. Several controlled studies suggest a lasting effect in terms of regaining their ability to work and improving pain behavior for a good part of disabled chronic LBP patients. However, it is noteworthy that randomized studies seemingly show poorer results than studies not employing randomized controls.

Ergonomics↗
PubMed1996

Rehabilitation of neck/shoulder patients in primary health care clinics.

OBJECTIVE: To review the literature pertaining to neck/shoulder pain and its treatment primarily through rehabilitation. A discussion regarding the theoretical basis for clinical rehabilitation is presented. DATA SOURCE: A Medline literature search was performed. English and Scandinavian language articles were reviewed. Key words included neck/shoulder pain, neck pain, rehabilitation and exercise. STUDY SELECTION: The studies included used rehabilitation of the cervical musculature as the main treatment therapy on patients suffering from neck/shoulder pain as defined by the Standardized Nordic Questionnaires. DATA SYNTHESIS: The relatively new concept of neck/shoulder rehabilitation seems to result in pain reduction, restoration of functional values and psychological benefit for patients suffering from chronic, recurrent, post-traumatic or postoperative neck/shoulder pain. Successful protocols seem to be dependent upon sufficient dosage, duration and a relative disregard of pain. Side effects seem to be rare. CONCLUSIONS: Rehabilitation of patients with neck/shoulder pain offers great promise; sufficient documentation exists to warrant serious consideration from all practitioners in the primary health sector. Future studies will be necessary to further clarify which rehabilitative procedures are most suitable for different patient types.

Arthralgia↗
PubMed1996

Implementation of neck/shoulder rehabilitation in primary health care clinics.

OBJECTIVE: To provide primary health care practitioners with the practical information necessary to implement rehabilitation of patients with neck/shoulder pain in clinical facilities. Equipment and program design are discussed in detail. DATA SOURCE: A Medline literature search was performed. English and Scandinavian language references were included in the review. Key words included neck/shoulder pain, neck pain, rehabilitation, equipment, exercise. STUDY SELECTION: The studies selected included clinical trials in which rehabilitation was the main intervention in the treatment of patients with neck/shoulder pain. DATA SYNTHESIS: Reestablishing functional capacities of the musculature of the cervical spine can be accomplished with modest equipment and can be easily incorporated into the clinical setting. The extensors of the cervical spine are the most important muscle group that require rehabilitation and exhibit the highest values in all strength parameters. High-intensity rehabilitative protocols accompanied by the encouragement of fellow patients and support from personnel are essential for treatment success. CONCLUSIONS: Complete primary health care treatment of patients with chronic, recurrent and post-traumatic neck/shoulder pain will necessitate longer rehabilitation programs. Future studies will provide additional information regarding specific program design.

Arthralgia↗
PubMed1995

Two different operons for the same function: comparison of the Salmonella typhimurium nrdAB and nrdEF genes.

By using a P22 phage-mediated cloning system, the nrdAB genes of Salmonella typhimurium (St), encoding a ribonucleotide reductase (RR) of class I, have been isolated. The coding regions of the St nrdAB operon show a very high identity with those of the homologous operon of Escherichia coli (Ec). Nevertheless, there are significant differences in their promoter regions since, although the promoters of both operons present two DnaA boxes, these boxes are located downstream from the transcription start point in St, being upstream in Ec. Moreover, the deduced amino-acid sequences of the St nrdAB showed a very limited overall identity (28%) with the products of St nrdEF, which encode a second class-I RR. Expression of St nrdAB and nrdEF is inducible by hydroxyurea, an inhibitor of RR activity. Alignment of the promoter regions of the nrdAB and nrdEF operons of both St and Ec reveals the presence of a consensus sequence. St is the first organism from which two different RR belonging to the same biochemical class are known.

Base Sequence↗
PubMed1994

A second class I ribonucleotide reductase in Enterobacteriaceae: characterization of the Salmonella typhimurium enzyme.

The nrdA and nrdB genes of Escherichia coli and Salmonella typhimurium encode the R1 and R2 proteins that together form an active class I ribonucleotide reductase. Both organisms contain two additional chromosomal genes, nrdE and nrdF, whose corresponding protein sequences show some homology to the products of the genes nrdA and nrdB. When present on a plasmid, nrdE and nrdF together complement mutations in nrdA or nrdB. We have now obtained in nearly homogeneous form the two proteins encoded by the S. typhimurium nrdE and nrdF genes (R1E and R2F). They correspond to the R1 and R2 proteins. Each protein is a homodimer. Together they catalyze the reduction of CDP to dCDP, using dithiothreitol or reduced glutaredoxin, but not thioredoxin, as an electron donor. CDP reduction is strongly stimulated by low concentrations of dATP, presumably acting as an allosteric effector. Protein R2F contains an antiferromagnetically coupled dinuclear iron center and a tyrosyl free radical. The E. coli and S. typhimurium chromosome thus have maintained the information for a potentially active additional class I ribonucleotide reductase, whose role in vivo is as yet unknown. The allosteric regulation of this enzyme differs from that of the normally expressed reductase.

Allosteric Regulation↗
PubMed1994

FDA recommendations for preclinical testing of gonadotropin releasing hormone (GnRH) analogues.

Gonadotropin-releasing hormone (GnRH) agonists and antagonists are synthetic analogues synthesized by modifications of the naturally occurring hypothalamic decapeptide GnRH. These modifications significantly increase the biological potency and duration of action of GnRH agonists as well as the solubility, potency, and duration of action of GnRH antagonists while decreasing GnRH antagonists toxicity. The field of GnRH analogues has expanded significantly during the past few years in terms of the number of analogues, therapeutic indications, formulations, and mode of administration. This paper provides recommendations for nonclinical testing of GnRH analogues and reflects the type and degree of toxicity testing expected by the Division. However, these recommendations are not formal guidelines in that alternative testing methods will be considered. Furthermore, these recommendations should not be used as guidance for testing of other new drugs.

Amino Acid Sequence↗
PubMed1994

Toxicology of depot medroxyprogesterone acetate.

Depo-Provera (depot-medroxyprogesterone acetate or DMPA), administered either subcutaneously or intramuscularly, has undergone a thorough toxicological evaluation in a number of animal species. DMPA has been tested in short- and long-term toxicity studies in rodents, rabbits, and monkeys. It has been examined for its effects on reproduction in mice, rats, and rabbits, and for carcinogenic potential in rats, mice, beagle dogs, and rhesus monkeys. Genotoxicity tests have been performed in vitro and in vivo. This paper describes the toxicology data submitted to the US FDA in support of the New Drug Application (NDA) for Depo-Provera as well as data published in the literature. When interpreted in the light of the available pharmacokinetic information, these data demonstrate that DMPA is not significantly different from other contraceptive progestogens in its toxic and tumorigenic potential.

Animals↗
PubMed1994

Regulatory considerations for oligonucleotide drugs: updated recommendations for pharmacology and toxicology studies.

This article describes pharmacology and toxicity studies for oligonucleotide drugs that are recommended for inclusion in the initial Investigational New Drug Application (IND), a first request to use an investigational drug in clinical trials. Recent observations of non-sequence-dependent cardiovascular toxicity and deaths in monkeys following intravenous infusions of phosphorothioates have raised a potential safety concern for oligonucleotide drugs. This concern should be considered by drug sponsors in designing pre-IND nonclinical development programs and Phase I clinical protocols. Pre-IND conduct of pharmacodynamic cardiovascular screening is highly recommended for defining safe clinical dosing regimens for phosphorothioate (and, possibly, other charged-backbone) oligomers. Additionally, drug sponsors are encouraged to (1) conduct research into-the mechanisms responsible for this dose-limiting toxicity, (2) institute liberal publication policies for research conducted under industrial sponsorship, and (3) communicate with reviewing divisions at FDA for updated guidance in this field when planning pre-IND safety studies. Recommendations for nonclinical studies during development of oligonucleotides will be modified as new information regarding the biological properties of oligonucleotides becomes available.

Animals↗
PubMed1994

Risk of hepatitis C in patients who received blood from donors subsequently shown to be carriers of hepatitis C virus.

A retrospective study was undertaken to identify recipients of blood from donors subsequently shown to be positive for hepatitis C virus using second-generation tests and polymerase chain reaction. The main aims were to determine the numbers of such recipients who were still alive and traceable, and to determine the risk of infection in this group. The feasibility and workload of this procedure, which is currently not practised in the U.K. or U.S.A., was also assessed. In the first six months of routine testing 42,697 donors were tested. Of 20 confirmed to be HCV-positive, 15 were regular donors. Eighty-three components were prepared from 63 anti-HCV positive previous donations from these donors. In all, nine recipients were found to be alive. All were positive for anti-HCV. We conclude that although this retrospective procedure is time-consuming and difficult, substantial numbers of infected recipients can be identified. The availability of treatment for chronic hepatitis C for such patients should encourage transfusion services to reassess current policies on the hepatitis C retrospective.

Blood Donors↗
PubMed1994

Cloning and sequencing of the genes from Salmonella typhimurium encoding a new bacterial ribonucleotide reductase.

A plasmid library of Salmonella typhimurium was used to complement a temperature-sensitive nrdA mutant of Escherichia coli. Complementation was obtained with two different classes of plasmids, one carrying the E. coli nrdAB-like genes and the second containing an operon encoding a new bacterial ribonucleotide reductase. Plasmids harboring these new reductase genes also enable obligately anaerobic nrdB::Mud1 E. coli mutants to grow in the presence of oxygen. This operon consists of two open reading frames, which have been designated nrdE (2,145 bp) and nrdF (969 bp). The deduced amino acid sequences of the nrdE and nrdF products include the catalytically important residues conserved in ribonucleotide reductase enzymes of class I and show 25 and 28% overall identity with the R1 and R2 protein, respectively, of the aerobic ribonucleoside diphosphate reductase of E. coli. The 3' end of the sequenced 4.9-kb fragment corresponds to the upstream region of the previously published proU operon of both S. typhimurium and E. coli, indicating that the nrdEF genes are at 57 min on the chromosomal maps of these two bacterial species. Analysis of the nrdEF and proU sequences demonstrates that transcription of the nrdEF genes is in the clockwise direction on the S. typhimurium and E. coli maps.

Amino Acid Sequence↗
PubMed1994

Evaluation of the atypical cytologic smear. Validity of the 1991 Bethesda System.

The 1991 Bethesda System states that atypical squamous or glandular cells of undetermined significance should be further classified as reactive or premalignant/malignant. The validity of this qualification for identification of patients with cervical intraepithelial neoplasia (CIN) was tested. One hundred twenty-four cytologic smears with squamous atypia were reviewed retrospectively by two cytopathologists blind to the colposcopy results. The smears were classified as favoring either reactive or premalignant/malignant processes. Subjective criteria used in the classification were based on the pathologists' experience. All patients underwent colposcopy and selected biopsy under the direction of a gynecologic oncologist. Of the 124 atypical smears, 69 were classified as favoring reactive processes and 55 as favoring premalignant/malignant processes by cytopathologist 1. Cytopathologist 2 classified 68 as reactive and 56 as premalignant/malignant. Colposcopy and selected biopsy revealed the following lesions: 34 cases of human papillomavirus (27.4%), 17 of CIN 1 (13.7%), 4 of CIN 2 (3.2%), 2 of CIN 3 (1.6%) and 67 without pathology (54.0%). All six patients with squamous atypia and underlying CIN 2 and 3 lesions had their cytology classified as premalignant/malignant by the cytopathologists. In these patients this qualification had high sensitivity (100%) and negative predictive value (100%). The 1991 Bethesda System classification above, when applied to patients with squamous atypia, was effective in identifying patients with serious pathologic cervical lesions. If used as a triage method, colposcopy should be reserved for atypical lesions classified as premalignant/malignant, potentially decreasing the cost of health care without decreasing the quality of that care.

Adult↗
PubMed1994

Back pain, sciatica and disability following first-time conventional haemilaminectomy for lumbar disc herniation. Use of "Low Back Pain Rating Scale" as a postal questionnaire.

To determine the value of "Low Back Pain Rating Scale" as a postal questionnaire, a retrospective study was undertaken of patients who had undergone first-time lumbar disc surgery 14-72 months previously. Rate of response was 86% (261/304). From the results, it was concluded that 87% of the patients felt that a satisfactory surgical outcome was obtained; 67% had minor or major functional restrictions of their daily activities; 65% experienced significant low-back symptoms in the period prior to follow-up examination; and 57% experienced sciatica. Thirty-seven patients were receiving pensions in the postoperative period due to continued back pain. "Low Back Pain Rating Scale" used as a postal questionnaire was found to be useful in determining general overall assessment status in patients who had undergone lumbar surgery. This evaluation method could be used as a quality control in future studies regarding this patient group.

Adult↗