Biomedical subjects
G Robertson
Publications and source records attributed to G Robertson.
Pathophysiology and treatment of enuresis in adults.
Monosymptomatic nocturnal enuresis (MNE) in children is partly the result of inadequate reduction in the rate of urine output at night. This nocturnal polyuria is due to the lack of a rise in the anti-diuretic hormone, arginine vasopressin (AVP), and can be reduced or eliminated by treatment with desmopressin at bedtime. Since there is a 1% incidence of MNE among adults, this study investigated the circadian pattern of solute and water balance in nine young adult enuretics before and during desmopressin therapy and compared the results with nine-age- and sex-matched, healthy controls. Before treatment, enuretics and controls had similar total fluid intake, urine output, urine osmolality, plasma osmolality, plasma total protein, mean arterial pressure and plasma AVP. The circadian pattern of fluid intake was also normal in enuretics. This abnormality could not be attributed to a deficiency of plasma AVP or an increase in solute excretion, since both variables were similar to controls. Rather, their nocturnal polyuria appeared to be due to a marked nocturnal reduction in renal sensitivity to the antidiuretic effect of vasopressin. In seven enuretics, restudied during treatment with desmopressin (10-30 micrograms o.d.), circadian urine output was normal and enuresis was absent. These results indicate that: (i) The circadian pattern of urine output in healthy adults is largely due to a nocturnal decrease in solute excretion rather than a rise in plasma AVP; (ii) The subset of adults with persistent MNE also have nocturnal polyuria as a result of insensitivity to the antidiuretic action of AVP; (iii) These defects can be corrected by treatment with desmopressin.
Effects of bile duct ligation on hepatic expression of female-specific CYP2C12 in male and female rats.
Gender differences in hepatic sex steroid and drug metabolism result from hormonal regulation of specific cytochrome P450 genes (CYP). In male rats, bile duct ligation (BDL) is associated with down-regulation of the male-specific genes, CYP2C11 and CYP3A2, together with a decrease in serum testosterone levels and a two- to three-fold increase in serum estradiol concentrations. We anticipated that if estrogen is responsible for down-regulation of male-specific CYPs in BDL male rats, the female-specific CYP2C12, which is not normally present in adult male rat liver, should be up-regulated. We examined this proposal by determining the profile of hepatic cytochrome P450 enzymes in female rats subjected to BDL, and by seeking evidence for expression of CYP2C12 in male rats that do not normally express this gene. In female rats killed 5 days after BDL, total cytochrome P450 content and NADPH-cytochrome P450-reductase (P450-reductase) were decreased to 74% and 58% of control, respectively. Microsomal enzyme activities attributable to CYP2A1, CYP2C6, and CYP2E1 were 50% to 60% of control, but ethylmorphine N-demethylase, which in female liver is catalyzed by CYP2C12 and to a lesser extent CYP2C6, was significantly less affected (81% of control). Likewise, levels of CYP2C6 and P450-reductase proteins were decreased in proportion to the corresponding enzyme activities (50% to 60%), while CYP2C12 protein (and mRNA levels) were not altered in BDL female rat liver. In sham-operated male rats, transcripts for CYP2C12 were rarely detected, but mRNA levels rose to appreciable levels within 24 hours of BDL, and CYP2C12 protein was expressed in hepatic microsomes of BDL male rats. Administration of estradiol to male rats produced a similar elevation of CYP2C12 mRNA, to values approximately 40% of female rats. It is concluded that CYP2C12 is up-regulated in male rats with cholestasis caused by BDL, while CYP2C12 protein is preserved in female rats when other microsomal proteins are decreased. These changes may be related to the increase in serum estradiol levels that result from altered hepatic steroid metabolism. The results demonstrate that activities of individual drug-metabolizing enzymes in liver disease can be determined by dysregulation of the constitutive expression of hepatic CYP genes.
Knowing how to care for the dying.
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Trinitrophenyl-substituted nucleotides are potent antagonists selective for P2X1, P2X3, and heteromeric P2X2/3 receptors.
There are currently seven P2X receptor subunits (P2X1-7) defined by molecular cloning. The functional identification of these receptors has relied primarily on the potency of alpha,beta-methylene-ATP relative to that of ATP and on the kinetics of receptor desensitization. In the present experiments we found that the 2', 3'-O-(2,4,6-trinitrophenyl)-substituted analogs of ATP are selective and potent antagonists at some but not all P2X receptors. The trinitrophenyl analogs of ATP, ADP, AMP, and GTP produced a reversible inhibition of ATP-evoked currents in human embryonic kidney 293 cells expressing P2X1 receptors, P2X3 receptors, or both P2X2 and P2X3 (heteromeric) receptors; IC50 values were close to 1 nM. These compounds were at least 1000-fold less effective in blocking currents in cells expressing P2X2, P2X4, or P2X7 receptors (P2X5 and P2X6 not tested). GTP, 2,4,6-trinitrophenol, and the 2',3'-trinitrophenyl analog of adenosine (0.1-10 microM) had no effect. Thus, we have identified a structural motif that confers antagonist action at P2X receptors that contain P2X1 or P2X3 subunits (the alpha,beta-methylene-ATP-sensitive subclass).
Notifying patients exposed to blood products associated with Creutzfeldt-Jakob disease: integrating science, legal duties and ethical mandates.
The issue of notifying people who have been exposed to blood products that have been associated with Creutzfeldt-Jakob disease (CJD) has arisen at a time when the Canadian blood system is under intense scrutiny. As a result, the Canadian Red Cross Society issued a recommendation to health care institutions that recipients of CJD-associated blood products be identified, notified and counselled. Although Canadian jurisprudence in the realm of informed consent may support a policy of individual notification, a review of the scientific evidence and the applicable ethical principles arguably favours a policy of a more general public notification. Indeed, situations such as this require a unique approach to the formation of legal and ethical duties, one that effectively integrates all relevant factors. As such, the authors argue that individual notification is currently not justified. Nevertheless, if a system of general notification is implemented (e.g., through a series of public health announcements), it should provide, for people who wish to know, the opportunity to find out whether they were given CJD-associated products.
Meta-analyses of randomised controlled trials.
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Coping with the inexorable rise in medical admissions: evaluating a radical reorganisation of acute medical care in a Scottish district general hospital.
OBJECTIVE: To describe radical changes in acute medical care in a district general hospital and assess their impact on staff and patients. DESIGN: A before and after comparison of structure, process and outcome indicators in the year preceding and following reorganisation. SETTING: The Adult Medicine Clinical Directorate of the Royal Alexandra Hospital in Paisley, Scotland. SUBJECTS: Staff in the Medical Directorate and a random sample of 400 patients. INTERVENTIONS: The main stimulus for reorganisation was the pressure caused by a relatively steep rise in admissions. In response, the six existing general medical wards were converted into a 38-bed Medical Admissions Unit and five more specialised wards. A new acute receiving rota allowed each consultant to concentrate almost exclusively on acute receiving for one week at a time. RESULTS: The boarding of patients in non-medical wards was eliminated through improved bed management. The needs of patients became better matched to the specialism of their consultant. The cardiologist's share of in-patients with cardiological problems rose from 34% of 2,877 cases to 58% of 3,085 cases (p < 0.001) and the respiratory physicians' share of respiratory in-patients grew from 53% of 1,281 cases to 67% of 1,287 cases (p < 0.001). After the reorganisation, medical staff had significantly fewer concerns about losing track of patients (p < 0.01) or about boarding (p < 0.01), however, concern about 'blocked beds' became greater (p < 0.05). Nurses reported more time for health promotion (p < 0.01) but also a rise in stress (p < 0.05). More patients reported that staff had time to explain their treatment (85/109 (79%) before, 93/105 (89%) after, p < 0.05) and a higher proportion felt ready for discharge (91/108 (84%) before, 99/106 (93%) after, p < 0.05). CONCLUSIONS: Radical reorganisation of medical care in response to rising acute medical admissions is achievable and may lead to improvements in care.
Variegated expression of a globin transgene correlates with chromatin accessibility but not methylation status.
There are now many mammalian examples in which single cell assays of transgene activity have revealed variegated patterns of expression. We have previously reported that transgenes in which globin regulatory elements drive the lacZ reporter gene exhibit variegated expression patterns in mouse erythrocytes, with transgene activity detectable in only a sub-population of circulating erythroid cells. In order to elucidate the molecular mechanism responsible for variegated expression in this system, we have compared the chromatin structure and methylation status of the transgene locus in expressing and non-expressing populations of erythrocytes. We find that there is a difference in the chromatin conformation of the transgene locus between the two states. Relative to active transgenes, transgene loci which have been silenced exhibit a reduced sensitivity to general digestion by DNase I, as well as a failure to establish a transgene-specific DNase I hypersensitive site, suggesting that silenced transgenes are situated within less accessible chromatin structures. Surprisingly, the restrictive chromatin structure observed at silenced transgene loci did not correlate with increased methylation, with transgenes from both active and inactive loci appearing largely unmethylated following analysis with methylation-sensitive restriction enzymes and by sequencing PCR products derived from bisulphite-converted genomic DNA.
Bioethics for clinicians: 6. Advance care planning.
Advance rate planning is a process whereby a patient, in consultation with health care providers, family members and important others, makes decisions about his or her future health care. Grounded in the ethical principle of autonomy and the legal doctrine of consent, advance care planning helps to ensure that the norm of consent is respected should the patient become incapable of participating in treatment decisions. Physicians can play an important role by informing patients about advance care planning directing them to appropriate resources, counselling them as they engage in advance care planning and helping them to tailor advance directives to their prognosis.
Bioethics for clinicians: 5. Substitute decision-making.
Substitute decision-making is a means of making health care decisions on behalf of people who are incapable of making these decisions for themselves. It is based on the ethical principle of respect for autonomy. Substitute decision-making poses two main questions: Who-should make the decision for the incapable person, and, How should the decision be made? Because the applicable statutory and common law varies across Canada, clinicians should become familiar with the legal requirements of their own province or territory.
A malignant melanoma tumor suppressor on human chromosome 11.
Considerable molecular genetic and cytogenetic evidence indicates that chromosome 11 is a target for chromosome breakage, rearrangement, and loss during the development of human malignant melanomas. Abnormalities of the long arm of chromosome 11 are also evident in a wide variety of other human solid tumors, including carcinomas of the breast, ovary, cervix, and lung. In melanomas, these abnormalities tend to cluster in the lower half of the long arm of chromosome 11, indicating the possible presence of a melanoma tumor suppressor gene in this region. We tested this possibility by using microcell-mediated chromosome transfer to introduce normal copies of human chromosome 11 into two human malignant melanoma cell lines. In one cell line, MelJuSo, the presence of an additional copy of chromosome 11 severely reduced the ability of the cells to grow in culture. In a second cell line, UACC 903, there was a moderate reduction in cell growth in vitro, and the ability of the hybrid cells to form tumors in animals was suppressed. Suppression of tumorigenicity was even more strongly pronounced in a microcell hybrid that received an isochromosome 11q derived from the donor copy of chromosome 11. The formation of tumors was accompanied by a reduction in the copy number of chromosome 11. This provides functional evidence that a melanoma tumor suppressor resides on the long arm of chromosome 11. Thus, a third distinct locus, in addition to those previously defined on chromosomes 6 and 9, appears to play a role in the development of human malignant melanoma.
Age-dependent silencing of globin transgenes in the mouse.
Variegation of transgene expression, a heterocellular or mosaic pattern of expression seen in all mice in a given transgenic line, is a frequently observed but unexplained phenomenon. We have encountered variegation with globin transgenes; when lacZ expression is driven by globin control elements a proportion of erythrocytes express beta-galactosidase (beta-gal), while the remaining erythrocytes express none. The percentage of expressing cells is constant within each line (at any particular developmental stage), but varies between lines. Such variation may account for much of the line-to-line variability which has been reported in the expression of a transgene construct. We have now extended these observations by studying expression of several globin/lacZ transgenes with increasing age. Expression of beta-gal is variegated in all lines in adult mice, including those made with a beta-globin promoter and locus control region driving lacZ. The extent of variegation differs widely between lines, but in all lines there is a marked decline in the number of erythrocytes expressing beta-gal with increasing age. Progression of silencing continues long past the point at which globin switching is complete, suggesting that it is not related to this process. We observe that age-dependent silencing is most severe in high copy number animals. Increasing variegation of transgene expression with ageing of mice is likely to complicate interpretation of the developmental regulation of transgenes. We speculate that it reflects a general mechanism of epigenetic regulation.
Metastasis suppressed, but tumorigenicity and local invasiveness unaffected, in the human melanoma cell line MelJuSo after introduction of human chromosomes 1 or 6.
Progression of human melanoma toward increasing malignant behavior is associated with several nonrandom chromosomal aberrations, most commonly involving chromosomes 1, 6, 7, 9, and 10. We previously showed that introduction of human chromosome 6 into the highly metastatic human malignant melanoma cell line C8161 completely suppressed metastasis without altering tumorigenicity (Welch DR, Chen P, Miele ME, et al., Oncogene 9:255-262, 1994). Alterations of chromosome 1 are the most frequent chromosome abnormality observed in melanomas, and they frequently arise late in tumor progression. The purpose of the study presented here was to compare the effects of chromosomes 1 and 6 on malignant melanoma metastasis. By using microcell-mediated chromosome transfer, single copies of neo-tagged human chromosomes 1 or 6 were introduced into the human melanoma cell line MelJuSo. The presence of the added chromosome was verified by G banding of karyotypes, fluorescence in situ hybridization, and screening for polymorphic markers on each chromosome. The incidence and number of metastases per lung after intravenous or intradermal injection of parental MelJuSo cells was significantly (P<0.01) greater than those of hybrids containing either chromosome 1 or chromosome 6, although chromosome 1 was a less potent inhibitor of metastasis than chromosome 6. Cultures established from primary tumors and metastases remained neomycin resistant, suggesting that portions of the added chromosomes were retained. These results strengthen the evidence for the presence of a melanoma metastasis suppressor gene on chromosome 6. neo6/MelJuSo hybrids expressed 2.4- to 3.4-fold more of the melanoma differentiation-associated gene mda-6 (previously shown to be identical to WAF1/CIP1/Sdi1/CAP20) than parental metastatic cells. mda-6/WAF1 is among the candidate genes on chromosome 6. These results also demonstrate, for the first time, the existence of metastasis suppressor genes on human chromosome 1, although these genes appear to be less potent than the one encoded on chromosome 6.
The entry of mentally disordered people to the criminal justice system.
BACKGROUND: The police are the gatekeepers to the criminal justice system (CJS). It is agreed that where possible mentally ill people should be diverted to psychiatric care. The purpose of this investigation was to determine what factors were associated with the entry of obviously mentally ill people into the CJS. METHOD: The population of all detainees arrested in seven London police stations was observed to determine the presence of obvious mental illness. All detainees regarded as ill or known to have significant psychiatric histories were followed through the CJS to court disposal. Defendants diagnosed as psychotic by court liaison psychiatrists were identified and the circumstances of their arrest and detention examined. RESULTS: Of all police detainees observed, 1.4% were found to be acutely ill. Diversion of obviously ill detainees was common practice. The factor most strongly associated with entry to the CJS was the presence of violence at time of arrest. Other factors were the persistence of (petty) offending and the operation of court warrants issued as a result of the person's failure to appear at court when required to do so. CONCLUSIONS: Both police and courts are well aware of the inappropriateness of custody for acutely ill people and efforts are made to divert such people out of the CJS. Persistent petty offenders are often being recycled from the street to police station to court and back to the street without the benefit of care. A dedicated facility is recommended in central London to meet this need.
Position-dependent variegation of globin transgene expression in mice.
Expression of genes in eukaryotes has commonly been analyzed in a whole tissue, and levels of expression have been interpreted as the result of equivalent rates of transcription in every cell. We have produced transgenic mouse lines that express beta-galactosidase under the control of globin promoters linked to the major tissue-specific regulatory element of the alpha-globin locus, which permits the analysis of transgene expression in individual red blood cells. We find that expression of the transgene within all mouse lines is heterocellular. Individual cells either do not express the transgene at all or express it at a level characteristic of that line. The number of beta-galactosidase-expressing cells varies greatly between different lines of transgenic mice at any defined stage of development, but within a transgenic line, individual mice have strikingly similar numbers of expressing cells. This suggests that the degree of heterocellular expression is determined by the site of integration, as is seen in position-effect variegation.
Drunkenness among police detainees.
All detainees at seven police stations within the Metropolitan Police Area were observed by the authors. Continuous 24-hour cover was provided at each station for periods of 3 weeks. The number of people arrested for offences of drunkenness was noted, as was the apparent degree of drunkenness of all detainees, irrespective of arrest offence. Arrest for drunkenness in London was strongly associated with being white and with having been born in Scotland or Ireland. Within the confines of the station, being drunk was associated with aggressiveness, with the need for medical examination and with delays in implementing interview procedures. The physical condition of many chronically drunk people was very poor and evidence of long-term self neglect was common. Formal cautioning of drunkenness offenders has effectively removed such people from the courts; in the present study only 5% of those arrested for drunkenness alone were subsequently charged. Despite this the police in London must continue to arrest and detain the drunk and incapable for want of suitable alternatives.
Changing standards for thrombolysis in accident and emergency departments.
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