Gene transfer and bone marrow transplantation.
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Bone Marrow Purging↗
Biomedical subjects
M Roberts
Publications and source records attributed to M Roberts.
Androgen suppressive effect of GnRH agonist in ovarian hyperthecosis and virilizing tumours.
OBJECTIVE: Recent studies have suggested that androgen secretion by ovarian virilizing tumours may be gonadotrophin dependent. The aim of this study was to investigate the suppressive effect of GnRH agonist administration on androgen secretion in women with such tumours. DESIGN AND PATIENTS: A single i.m. injection of D-Trp-6-GnRH (GnRHa), 3.75 mg, was given to five unrelated patients referred for clinical symptoms of virilization with plasma testosterone (T) levels greater than 7 nmol/l but with normal dehydroepiandrosterone sulphate (DHEAS) levels. Diagnoses of adrenal tumour or a non-classical 21-hydroxylase deficiency were screened for by the dexamethasone suppression test, ACTH stimulation test and adrenal CT scanning, and were ruled out in all patients. The one premenopausal patient received cyproterone acetate in a dose of 50 mg twice daily for 3 weeks, starting 1 week before GnRHa administration. MEASUREMENT: Testosterone, androstenedione (A), DHEAS, 17-hydroxyprogesterone (OHP), LH and FSH plasma concentrations were measured by radioimmunoassay of blood samples taken before and 3 weeks after GnRHa. RESULTS: In each patient, GnRHa suppressed gonadotrophin levels and reduced T and A to the range for normal control women. With these results, and because accurate localization of an ovarian androgen secreting tumour could not be achieved by pelvic ultrasonography and CT scanning, exploratory laparotomy was undertaken. A Sertoli-Leydig cell tumour was found in the premenopausal patient, and granulosa cell tumour, hilus cell tumour and two hyperthecoses in the four post-menopausal patients. After bilateral ovariectomy and hysterectomy in the post-menopausal woman and after unilateral ovariectomy in the premenopausal women, androgen levels were normalized. CONCLUSIONS: In virilized women, the findings of increased serum testosterone with normal gonadotrophin levels and GnRHa suppression of gonadotrophins leading to normalization of testosterone levels, suggest that various ovarian androgen-secreting tumours, as well as hyperthecosis, are not autonomous but apparently depend upon continuous gonadotrophin stimulation.
17-alpha-Hydroxyprogesterone↗
Endometrial cytology: evaluation of samples obtained by outpatient aspiration.
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Aged↗
Silent exertional myocardial ischemia in the elderly: a quantitative analysis of anginal perceptual threshold and the influence of autonomic function.
OBJECTIVE: To assess the perception of angina in the elderly and its relationship to autonomic function. DESIGN: Prospective cohort study of patients with exertional ischemia. SETTING: Medical, geriatric and cardiac outpatient clinics in two centers. PARTICIPANTS: All subjects had ischemic heart disease as evidenced by positive treadmill stress tests and, in some, diagnostic angiography and/or documented Q wave infarction. In the first study (I), 37 older patients (range 70-82 years) and 39 younger patients (range 42-59 years) were studied. In a subsequent study (II), a further 49 patients were divided into 2 groups: those with good perception of angina (Anginal Perception Threshold < 15 seconds, group A, 26 patients) and those with no angina despite ischemia (group B, 23 patients). MEASUREMENTS: Anginal perceptual threshold (APT), age, cardiovascular autonomic function, and blood pressure were measured. APT was defined as the time between onset of 1 mm ST depression to the onset of angina during treadmill stress testing. Autonomic function was studied using heart rate ratios before and after the valsalva maneuver, heart rate responses to deep breathing, and heart rate and blood pressure responses to standing. RESULTS: In study I, APT in the older patients was delayed by a median value of 49 seconds [79 (range 15-188) versus 30 (-99 to 97) seconds in the younger patients, P < 0.001]. There was no significant correlation between prolonged APT and autonomic dysfunction when younger and older groups were analyzed independently or together. When, however, the high APT subgroup (APT > 30 seconds) was analyzed separately, there was a significant correlation between APT prolongation and impaired valsalva response (r = -0.4; P < 0.005). In study II, 21 of 23 patients (91.3%) with positive exercise test but with no angina (group B) had at least one abnormal autonomic function test compared with 5 of 26 (19%) patients with good anginal perception (group A). Of note, group A was significantly younger than group B [60 (53-63) years vs 66 (62-70 years, P < 0.001]. CONCLUSION: Elevation of APT in the elderly suggests that warning of critical myocardial ischemia is delayed. Autonomic dysfunction may be one of the underlying mechanisms.
Adult↗
Characterization of defined ompR mutants of Salmonella typhi: ompR is involved in the regulation of Vi polysaccharide expression.
The ompB operon, comprising the ompR and envZ genes, was cloned from a Salmonella typhi Ty2 cosmid bank and characterized by DNA sequence analysis. The S. typhi ompR and envZ genes contained open reading frames encoding proteins of 240 and 451 amino acids, respectively. Comparison with the Salmonella typhimurium OmpB protein sequences revealed 99.5% homology. The DNA sequence data were used to identify appropriate restriction sites for generating a defined deletion of 517 bp within the open reading frame of the ompR gene. This deletion was introduced by homologous recombination into the chromosomes of two S. typhi strains which already harbored defined deletions in both the aroC and aroD genes. The presence of the deletions within ompR was confirmed by Southern hybridization and sequencing of the DNA fragments surrounding the deleted regions by PCR. The S. typhi ompR mutants displayed a marked decrease in OmpC and OmpF porin expression as demonstrated by examination of outer membrane preparations. It was also found that S. typhi strains harboring the defined ompR deletions no longer agglutinated with Vi antiserum. However, when a functional ompB operon was introduced back into the S. typhi ompR mutants, either on a multicopy plasmid or as a single-copy chromosomal replacement, the Vi+ phenotype was restored. The levels of Vi synthesis were also found to be sensitive to different concentrations of sodium chloride present in the growth medium, although the levels of sensitivity varied between different isolates of S. typhi. It is therefore concluded that the ompR-envZ two component regulatory system plays an important role in the regulation of Vi polysaccharide synthesis in S. typhi and that one of the environmental signals for this regulation may be osmolarity.
Agglutination↗
Nurse in profile. Flight nurse, Air Ambulance Service of New South Wales.
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Air Ambulances↗
Clinical and biochemical characteristics of collapsed ultra-marathon runners.
To evaluate the characteristics of runners with exercise-associated collapse (EAC), we studied the time of onset of collapse, rectal temperatures, cardiovascular status, and incidence of readily identifiable medical conditions in 46 male athletes who collapsed during or after a 56-km ultramarathon footrace run on a cool day. Data were compared with 65 control runners who did not collapse in the same race. Weight changes during recovery were studied in a subsample of both groups. The majority (85%) of runners with EAC collapsed after they had completed the race; rectal temperatures (38.5 +/- 1.3 degrees C, mean +/- SD; range 35.5-42.0 degrees C) and supine heart rates (87.5 +/- 17.2 min-1; range 60-138) were only modestly elevated. Postrace serum sodium concentrations, changes in plasma volume, and mass during recovery were not significantly different from values in control runners. We conclude that: (i) most cases of EAC (85%) occur after the finish line; (ii) runners collapsing during the race are more likely to have a readily identifiable medical condition than runners collapsing after the finish line; (iii) runners collapse most frequently near cutoff times for medals and race closure times; and (iv) 16% of EAC casualties and 19% of control runners have identifable biochemical abnormalities.
Adult↗
[Depressive states and chronic asthenic syndromes in general practice].
It has been shown in Great Britain that general practitioners fail to recognize as many as 50% of the cases of depressive illness that present to them. The diagnosis is missed particularly when it is the physical type of symptom, such as asthenia, that is prominent. The Royal College of Psychiatrists, in association with the Royal College of General Practitioners, has launched the "Defeat Depression" campaign which includes amongst its aims the intention to provide up-to-date educational materials to family doctors on the recognition and treatment of depression. We have held two consensus meetings jointly with psychiatrists and primary care physicians and the results have been published in the British Medical Journal (2). One of our key recommendations is that, when medication is used to treat depressive illness in general practice, the antidepressants should be continued for six months after full remission has taken place. At present patients in general practice take their drugs for a total of three or four weeks. One of the reasons for patients abandoning their medication prematurely has been revealed by surveys that we have carried out on the general public. The lay person has little confidence in the efficacy of antidepressants and, perhaps more importantly, believes that they are addictive. It is therefore no surprise, then, that patients are keen to stop their antidepressants before they become dependent on them.(ABSTRACT TRUNCATED AT 250 WORDS)
Antidepressive Agents↗
Arthroscopic lateral ankle stabilization.
The indications for arthroscopic stabilization include those patients with isolated ruptures or strains of the ATF. The procedure is particularly convenient for patients with ankle joint pathology that is already most commonly treated arthroscopically, such as chronic instability, in which inflamed synovium or meniscoid bodies are to be excised. Although significant stability can be gained with this technique, injuries that result in damage to the calcaneofibular ligament may require additional open surgery, since this ligament cannot be visualized arthroscopically. However, the anchoring techniques described in this article can still be used when performing open surgery.
Ankle Injuries↗
The use of live attenuated Salmonella for oral vaccination.
Studies of the pathogenesis of Salmonella at the molecular level have led to the identification of several classes of genes that are involved in survival in the host. This has led to the availability of a panel of attenuating lesions which are now being used to develop several rationally attenuated strains which are being evaluated as oral vaccines against human and animal salmonellosis. Much effort has been directed towards the development of a more efficacious single dose oral typhoid vaccine and there are now several candidates in Phase 1 studies. The successful development of a genetically defined oral typhoid vaccine will not only be a major step forward in the control of typhoid but will pave the way for development of practical human vaccines based on using the strain to deliver heterologous antigens to the human immune system. We have concentrated on developing a single dose oral tetanus vaccine based on constructing strains expressing fragment C (a non-toxic immunogenic protein derived from tetanus toxin). Several different promotors have been used for controlling the expression of fragment C and these have been introduced into double aro mutants of S. typhimurium and compared for their ability to elicit protective immune responses in mice. This work has demonstrated that it is possible to protect mice against tetanus toxin challenge after a single oral dose of one of these recombinant Salmonella strains. Analogous hybrid S. typhi double aro mutants have now been constructed for potential use in humans.
Administration, Oral↗
Alterations in the activity of adenylate cyclase and high affinity GTPase in Alzheimer's disease.
The aim of this study was to assess the effect of Alzheimer's disease has on the functional integrity of several signal transduction proteins. The relative levels of the G-protein alpha subunits Gs alpha-L, Gs alpha-S, Gi alpha-2 and G(o) alpha were measured by western blotting and found to be unchanged in membranes prepared from Alzheimer-diseased frontal cortex or hippocampus compared to control brains. However the activity of the G-protein associated enzyme, high affinity GTPase, was found to be reduced in the frontal cortex (reduced by 25%) and by a similar magnitude in the hippocampus (reduced by 27%) of Alzheimer subjects. The same membrane preparations were also assayed for the activity of adenylate cyclase. Basal enzyme activity was not significantly altered in Alzheimer diseased hippocampus, but was markedly reduced (by 45%) in the frontal cortex. The ability of fluoride and aluminium ions to stimulate adenylate cyclase was not significantly changed in either brain region. This suggests that G-proteins, especially Gs, are still able to interact with this enzyme. These results indicate that although the presence of Alzheimer's disease does not significantly alter G-protein levels, changes have taken place in the overall activity of these proteins. However this alteration does not affect their ability to stimulate adenylate cyclase activity.
Adenylyl Cyclases↗
The acquired immunodeficiency syndrome in Australia: incidence 1982-1991.
OBJECTIVE: To describe the incidence of the acquired immunodeficiency syndrome (AIDS) in Australia between 1982 and 1991. DESIGN: State and Territory Health Departments notified new diagnoses of AIDS to the National AIDS Registry. Information reported for each case included sex, date of birth, date of AIDS diagnosis, presumed mode of exposure to the human immunodeficiency virus (HIV), and illness(es) on which the diagnosis of AIDS was based. RESULTS: To the end of March 1992, 3,160 cases of AIDS were reported as having been diagnosed between 1982 and the end of 1991. The cumulative incidence per head of population was about twice as high in New South Wales as in Australia as a whole. Over 97% of cases were in men, of whom 91% were adults or adolescents reporting homosexual contact. In women, 40% of cases were acquired through receipt of blood, blood products or tissue. The annual incidence of AIDS rose sharply until about 1988, but the annual rates of increase slowed in subsequent years. This trend was also apparent in cases acquired through sexual contact between men. In other exposure groups, numbers of cases were much smaller and trends less apparent. However, there was no indication of a similar levelling in AIDS incidence, except among blood transfusion recipients, in whom incidence may be declining. CONCLUSION: Transmission of HIV among people with AIDS in Australia has been overwhelmingly attributed to sexual contact between men. The annual incidence of cases attributed to sexual contact between men appears to be stabilising.
Acquired Immunodeficiency Syndrome↗
HLA-DR4 subtypes in New Zealand Polynesians. Predominance of Dw13 in the healthy population and association of Dw15 with rheumatoid arthritis.
OBJECTIVE: To analyze HLA-DR4 alleles in New Zealand Polynesians with rheumatoid arthritis (RA). METHODS: Thirty Polynesians and 30 Caucasians with RA, as well as 65 Polynesian and 60 Caucasian healthy blood donors, were DR4 subtyped using the polymerase chain reaction and sequence-specific oligonucleotide probes. RESULTS: The frequency of DR4 (DRB1*04) was increased in both Polynesian (P < 0.001) and Caucasian (P < 0.005) RA patients compared with race-matched controls. Dw4 (DRB1*0401) was detected in 15 of 30 Caucasian patients but only 2 of 30 Polynesian patients (P < 0.001). In Polynesians, RA was associated with Dw15 (DRB1*0405), which was present in 11 of 30 patients and 3 of 65 controls (P < 0.001). Dw13 (DRB1*0403) was the most frequent DR4 allele in healthy Polynesians, but was not significantly associated with RA. CONCLUSION: The predominance of the Dw13 subtype in Polynesians may explain in part the low prevalence of RA in this population. The association of Dw15 with RA in Polynesians supports the hypothesis that the third hypervariable region of DR beta determines susceptibility to RA.
Arthritis, Rheumatoid↗
Protection of mice against respiratory Bordetella pertussis infection by intranasal immunization with P.69 and FHA.
Intranasal immunization of adult female Balb/c mice with the Bordetella pertussis antigens FHA or P.69, greatly enhanced their ability to clear B. pertussis from their lungs following aerosol challenge compared with ovalbumin-immunized controls. Low numbers of lymphocytes secreting antibodies (IgG, IgA and IgM) against the immunizing antigens could be isolated from the lungs of immunized mice. Following aerosol challenge with B. pertussis there was a large increase in the numbers of FHA or P.69-specific antibody-secreting cells in the lungs of mice immunized with these antigens. Intranasal immunization, particularly with FHA, also primed mice to develop a systemic serum anti-pertussis antibody response subsequent to challenge. However, pulmonary clearance of B. pertussis correlated most closely with the local antibody response. A strong anti-FHA response was demonstrated in the lungs of mice that received a booster dose of FHA 9 months after their previous exposure to FHA, demonstrating that long immunological memory can develop in the murine respiratory tract following direct application of pertussis antigens to the respiratory tract mucosa.
Adhesins, Bacterial↗
Bluff your way in epidemic models.
The literature on the mathematical modelling of infectious diseases has grown enormously in recent years, both in quantity and quality. Here, we briefly point to the purposes of these modelling exercises and introduce the main ideas behind compartmental models, to act as a guide to the (bio)mathematical literature that is less directly accessible.
Humans↗
A prospective evaluation of the hepatotoxicity of lofepramine in the elderly.
Lofepramine has been acclaimed as an effective and safe antidepressant, particularly for the elderly. Recent case reports of hepatic toxicity following treatment with lofepramine, however, caused clinicians to question its use in a patient population who frequently have concomitant physical illness. From published data the incidence of serious side effects as well as the implications for its use remain unclear. In this study, 52 patients over the age of 65 years treated with lofepramine were monitored over a 12-week period. The results suggest that for the overwhelming majority of patients, any rise in liver enzyme activity is transient. It is recommended, however, that LFTs be monitored for the first 12 weeks of treatment.
Aged↗
The development of oral vaccines based on live attenuated Salmonella strains.
Safe, live attenuated Salmonella strains can be produced by introducing defined non-reverting mutations into the chromosome. Such rationally attenuated strains have proved to be excellent oral vaccines in several animal species and can therefore be considered as candidate vaccines against invasive salmonellosis in both animals and man. A panel of attenuating lesions is now available from which it is possible to tailor the level of attenuation and hence produce strains with different immunogenic properties. Because of the spectrum of immune responses produced by such Salmonella vaccine strains they have been utilised extensively as vectors for delivering heterologous antigens to the mammalian immune system. We have focussed on the development of a single dose oral tetanus vaccine based on attenuated Salmonella strains expressing a non-toxic, immunogenic protein derived from tetanus toxin (fragment C). Several different expression systems have been used for fragment C and candidate vaccine strains have been constructed that are capable of protecting orally immunised mice against a lethal challenge with tetanus toxin. An oral tetanus vaccine may help to reduce the mortality rate from tetanus in the developing world by overcoming the problems associated with the implementation of vaccine programmes using the current parenteral vaccine.
Administration, Oral↗
Mapping of genes controlling Leishmania major infection in CXS recombinant inbred mice.
Previous studies demonstrated that growth of the primary lesion following Leishmania major infection in inbred mice comes under the control of a single major gene designated Scl-1. Preliminary mapping studies had suggested a chromosome 8 location for the gene. In this paper a more detailed study of different disease phenotypes (lesion growth, splenomegaly, liver parasite load) in 14 CXS recombinant inbred (RI) mouse strains was undertaken in order to obtain a more definitive map location for the gene. Using the Kruskal-Wallis generalization of the Wilcoxon Rank-Sum Test to assign RI strains to parental phenotypes, high concordances with genes at the mid (Il-3) to distal end (Dlb-1, Hox-2, Sigje, Mtv-3 and Es-3) of chromosome 11 were demonstrated with two strains (LV39 and NIH173) of L. major given as promastigotes subcutaneously into the shaven rump. The results suggest that the most likely location for the previously described single major gene (Scl-1) regulating early lesion expansion is at the distal end of mouse chromosome 11, with the possibility that a gene located more proximally influences later phases of the infection.
Animals↗