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Biomedical subjects

L Smith

Publications and source records attributed to L Smith.

At least 181 records · Page 10Linked to original sources

Data for diagnosis, monitoring and treatment in indigenous health: the case of cervical cancer.

Deficiencies in the availability and quality of data on the health status of indigenous Australians have long been recognised. For cervical cancer, data demonstrate a 2-5 fold greater incidence rate and an 8-10 fold greater mortality rate for Indigenous women compared to non-Indigenous Australians. However, incidence and mortality data are only available for some states and there is little or no information available on the geographic or social distribution of risk, or the reasons for risk differentials. There are also little or no data on the utilisation of, or preferences for, screening services. Thus, while there is clearly a need for a cervical cancer control program specifically to target Indigenous women, current data are inadequate to inform planning and implementation, and current systems are inadequate to monitor effectiveness. This situation is the result of insufficient research and inadequate attention to recording of Indigenous status in routine data systems and applies to a greater or lesser extent across the spectrum of health of Indigenous Australians. Health workers across the spectrum in mainstream and Indigenous medical services have a shared responsibility for improving the availability and quality of data and ensuring the appropriate use of information necessary to achieve and monitor improvements in service delivery and health status of Indigenous people.

Australia↗

Enhanced phenotypic expression of alpha-1-antitrypsin deficiency in an MZ heterozygote with chronic hepatitis C.

A middle-aged white man of Scotch-Irish ancestry, being treated for chronic hepatitis C, was found to be heterozygous for alpha1-antitrypsin deficiency (PiMZ phenotype) after diagnostic PAS-positive, diastase-resistant globules were detected in a liver biopsy. The globules had not been present in a biopsy obtained 4 yr previously. He was also found to be heterozygous for the cys282tyr mutation of the HFE gene, which is the chief cause of HLA-linked hereditary hemochromatosis (HHC). His liver disease progressed over 4 yr from mild hepatitis to moderate hepatitis with cirrhosis despite therapy with interferon-alpha, and phlebotomy plus interferon. These conditions appeared to have synergistic effects, with the chronic viral hepatitis unmasking the alpha1AT deficiency, and the alpha1AT deficiency (and possibly the heterozygosity for HHC), exacerbating the course of the hepatitis C.

Adult↗

Typing of dengue viruses in clinical specimens and mosquitoes by single-tube multiplex reverse transcriptase PCR.

In recent years, dengue viruses (serotypes 1 to 4) have spread throughout tropical regions worldwide. In many places, multiple dengue virus serotypes are circulating concurrently, which may increase the risk for the more severe form of the disease, dengue hemorrhagic fever. For the control and prevention of dengue fever, it is important to rapidly detect and type the virus in clinical samples and mosquitoes. Assays based on reverse transcriptase (RT) PCR (RT-PCR) amplification of dengue viral RNA can offer a rapid, sensitive, and specific approach to the typing of dengue viruses. We have reduced a two-step nested RT-PCR protocol to a single-tube reaction with sensitivity equivalent to that of the two-step protocol (1 to 50 PFU) in order to maximize simplicity and minimize the risk of sample cross-contamination. This assay was also optimized for use with a thermostable RT-polymerase. We designed a plasmid-based internal control that produces a uniquely sized product and can be used to control for both reverse transcription or amplification steps without the risk of generating false-positive results. This single-tube RT-PCR procedure was used to type dengue viruses during the 1995 and 1997-1998 outbreaks in Nicaragua. In addition, an extraction procedure that permits the sensitive detection of viral RNA in pools of up to 50 mosquitoes without PCR inhibition or RNA degradation was developed. This assay should serve as a practical tool for use in countries where dengue fever is endemic, in conjunction with classical methods for surveillance and epidemiology of dengue viruses.

Aedes↗

Work shift duration: a review comparing eight hour and 12 hour shift systems.

OBJECTIVES: Shiftwork is now a major feature of working life across a broad range of industries. The features of the shift systems operated can impact on the wellbeing, performance, and sleep of shiftworkers. This paper reviews the current state of knowledge on one major characteristic of shift rotas-namely, shift duration. Evidence comparing the relative effects of eight hour and 12 hour shifts on fatigue and job performance, safety, sleep, and physical and psychological health are considered. At the organisational level, factors such as the mode of system implementation, attitudes towards shift rotas, sickness absence and turnover, overtime, and moonlighting are discussed. METHODS: Manual and electronic searches of the shiftwork research literature were conducted to obtain information on comparisons between eight hour and 12 hour shifts. RESULTS: The research findings are largely equivocal. The bulk of the evidence suggests few differences between eight and 12 hour shifts in the way they affect people. There may even be advantages to 12 hour shifts in terms of lower stress levels, better physical and psychological wellbeing, improved durations and quality of off duty sleep as well as improvements in family relations. On the negative side, the main concerns are fatigue and safety. It is noted that a 12 hour shift does not equate with being active for only 12 hours. CONCLUSIONS: There can be considerable extension of the person's time awake either side of the shift. However, the effects of longer term exposure to extended work days have been relatively uncharted in any systematic way. Longitudinal comparative research into the chronic impact of the compressed working week is needed.

Absenteeism↗

Fluticasone propionate 750 micrograms/day versus beclomethasone dipropionate 1500 micrograms/day: comparison of efficacy and adrenal function in paediatric asthma.

BACKGROUND: Previous studies have suggested a 2:1 efficacy advantage of fluticasone propionate (FP) over beclomethasone dipropionate (BDP) in adults on high dose inhaled steroids and children on low dose inhaled steroids. The lower doses of FP required to provide equivalent efficacy to BDP also appear to have fewer systemic effects as measured by adrenal function. METHODS: The efficacy and safety of FP 750 micrograms/day and BDP 1500 micrograms/day were compared in 30 children with persistent asthma (requiring 1000-2000 micrograms/day of inhaled corticosteroids) in a 12 week randomised double blind crossover study. Medication was delivered by a spacer device in two divided doses. Primary efficacy variables were peak expiratory flows (PEF). Adrenal function was assessed by 24 hour urinary free cortisol levels at eight and 12 weeks and ACTH and low dose synacthen tests (LDST) at 12 weeks. The results were adjusted for sequence and period differences. RESULTS: There was no difference in the primary efficacy variables over the two 12 week treatment periods (difference in adjusted means for morning PEF 1.3 l/min (95% CI -6.1 to 8.8), p = 0.112) and symptom scores (cough, tachypnoea, wheeze, shortness of breath; difference in adjusted means of night time scores: -0.06 (95% CI -0.14 to 0.03); p = 0.136). Similar degrees of mild adrenal dysfunction were found during BDP and FP treatment phases. Identical height gain velocities were shown during the corresponding periods. CONCLUSIONS: FP 750 micrograms/day is as effective as BDP 1500 micrograms/day in children with persistent asthma. At these very high doses we were unable to demonstrate a safety advantage of FP over BDP as assessed by adrenal function. However, measures of adrenal function may have been influenced by concurrent and previous systemic steroid usage, and possibly by effects of disease activity.

Administration, Inhalation↗

Expression and function of recombinant endothelial nitric oxide synthase gene in canine basilar artery after experimental subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Gene transfer with recombinant viral vectors encoding vasodilator proteins may be useful in therapy of cerebral vasospasm after subarachnoid hemorrhage (SAH). Relaxations mediated by nitric oxide are impaired in cerebral arteries affected by SAH. The present study was designed to determine the effect of SAH on the efficiency of ex vivo adenovirus-mediated gene transfer to canine basilar arteries and to examine whether expression of recombinant endothelial nitric oxide synthase (eNOS) gene may have functional effects on vasomotor reactivity of spastic arteries affected by SAH. METHODS: Replication-deficient recombinant adenovirus vectors encoding bovine eNOS (AdCMVeNOS) and Escherichia coli beta-galactosidase (AdCMVbeta-Gal) genes were used for ex vivo gene transfer. Rings of basilar arteries obtained from control dogs and dogs exposed to SAH were incubated with the vectors in minimum essential medium. Twenty-four hours after gene transfer, expression and function of the recombinant genes were evaluated by (1) histochemical or immunohistochemical staining, (2) beta-galactosidase protein measurement, and (3) isometric tension recording. RESULTS: Transduction with AdCMVbeta-Gal and AdCMVeNOS resulted in the expression of recombinant beta-galactosidase and eNOS proteins mostly in the vascular adventitia. The expression of beta-galactosidase protein was approximately 2-fold higher in SAH arteries than in normal arteries. Endothelium-dependent relaxations caused by bradykinin and substance P were suppressed in SAH arteries. The relaxations to bradykinin were significantly augmented in both normal and SAH arteries after AdCMVeNOS transduction but not after AdCMVbeta-Gal transduction. The relaxations to substance P were augmented by AdCMVeNOS transduction only in normal arteries. Bradykinin and substance P caused relaxations even in endothelium-denuded arteries, when the vessels were transduced with AdCMVeNOS. These endothelium-independent (adventitia-dependent) relaxations to bradykinin observed after AdCMVeNOS transduction were similar between normal and SAH arteries, whereas those to substance P were significantly reduced in SAH arteries compared with normal arteries. CONCLUSIONS: These results suggest that expression of recombinant proteins after adenovirus-mediated gene transfer may be enhanced in cerebral arteries affected by SAH and that successful eNOS gene transfer to spastic arteries can at least partly restore the impaired nitric oxide-mediated relaxations through local (adventitial) production of nitric oxide.

Adenoviridae↗

An empirical study of the psychodynamics of suicide.

This paper presents results from an empirical study of four key psychodynamic concepts (self-directed aggression, object loss, ego functioning disturbance, pathological object relations) of suicidal behavior. The sample consists of hospitalized psychiatric patients following a suicide attempt (attempters: n = 52) and demographically similar hospitalized psychiatric patients with no history of suicidal behavior (controls: n = 47). The study was designed to ascertain whether attempters differed from matched psychiatric control patients on the four psychodynamic constructs hypothesized to be associated with suicide. It was predicted that attempters would manifest higher levels of depression and self-targeted anger, a more significant history of loss, less adaptive defenses, and more primitive object representations. Results strongly supported an object-relational view of suicidal behavior. In addition, support for the loss hypothesis was found in the identification of one specific constellation of losses. Namely, attempters were significantly more likely to report a history of childhood loss combined with a recent loss in adulthood than were their nonattempter counterparts. Limited support was provided for the other two hypotheses in differentiating suicidal from nonsuicidal severely ill psychiatric patients. This unexpected finding is examined and suggestions are made for the refinement and greater specification of psychodynamic theories regarding the etiology of suicidal behavior, with the aim of differentiating individuals prone to such action from those with similar psychopathology and dynamic issues who do not actually attempt suicide. Limitations of the study are discussed and implications of the findings for the theory and treatment of suicidal behavior are offered.

Adolescent↗

Phase I and pharmacokinetic study of paclitaxel in combination with biricodar, a novel agent that reverses multidrug resistance conferred by overexpression of both MDR1 and MRP.

PURPOSE: To evaluate the feasibility of administering biricodar (VX-710; Incel, Vertex Pharmaceuticals Inc, Cambridge, MA), an agent that modulates multidrug resistance (MDR) conferred by overexpression of both the multidrug resistance gene product (MDR1) P-glycoprotein and the MDR-associated protein (MRP) in vitro, in combination with paclitaxel. The study also sought to determine the maximum-tolerated dose (MTD) of paclitaxel that could be administered with biologically relevant concentrations of VX-710 and characterize the toxicologic and pharmacologic profiles of the VX-710/ paclitaxel regimen. PATIENTS AND METHODS: Patients with solid malignancies were initially treated with VX-710 as a 24-hour infusion at doses that ranged from 10 to 120 mg/m2 per hour. After a 2-day washout period, patients were re-treated with VX-710 on an identical dose schedule followed 8 hours later by paclitaxel as a 3-hour infusion at doses that ranged from 20 to 80 mg/m2. The pharmacokinetics of both VX-710 and paclitaxel were studied during treatment with VX-710 alone and VX-710 and paclitaxel. Thereafter, patients received VX-710 and paclitaxel every 3 weeks. RESULTS: VX-710 alone produced minimal toxicity. The toxicologic profile of the VX-710/paclitaxel regimen was similar to that reported with paclitaxel alone; neutropenia that was noncumulative was the principal dose-limiting toxicity (DLT). The MTD levels of VX-710/ paclitaxel were 120 mg/m2 per hour and 60 mg/m2, respectively, in heavily pretreated patients and 120/60 to 80 mg/m2 per hour in less heavily pretreated patients. At these dose levels, VX-710 steady-state plasma concentrations (Css) ranged from 2.68 to 4.89 microg/mL, which exceeded optimal VX-710 concentrations required for MDR reversal in vitro. The pharmacokinetics of VX-710 were dose independent and not influenced by paclitaxel. In contrast, VX-710 reduced paclitaxel clearance. At the two highest dose levels, which consisted of VX-710 120 mg/m2 per hour and paclitaxel 60 and 80 mg/m2, pertinent pharacokinetic determinants of paclitaxel effect were similar to those achieved with paclitaxel as a 3-hour infusion at doses of 135 and 175 mg/m2, respectively. CONCLUSION: VX-710 alone is associated with minimal toxicity. In combination with paclitaxel, biologically relevant VX-710 plasma concentrations are achieved and sustained for 24 hours, which simulates optimal pharmacologic conditions required for MDR reversal in vitro. The acceptable toxicity profile of the VX-710/ paclitaxel combination and the demonstration that optimal pharmacologic conditions for MDR reversal are achievable support a rationale for further trials of VX710/paclitaxel in patients with malignancies that are associated with de novo or acquired resistance to paclitaxel caused by overexpression of MDR1 and/or MRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Phase I and pharmacokinetic study of GI147211, a water-soluble camptothecin analogue, administered for five consecutive days every three weeks.

GI1147211 is a 7-substituted 10,11-ethylenedioxy-20(S)-camptothecin analogue that inhibits the nuclear enzyme topoisomerase I. In this Phase I and pharmacological study, 24 patients with advanced solid malignancies received a total of 72 courses of GI147211 as a 30-min infusion daily for 5 consecutive days, at doses ranging from 0.3 to 1.75 mg/m2/day. Severe neutropenia precluded dose escalation above 1.5 mg/m2/day in minimally pretreated patients, and both severe neutropenia and thrombocytopenia were dose limiting in heavily pretreated patients at doses above 1.0 mg/m2/day. These doses are, therefore, recommended for subsequent Phase II evaluations of GI147211 in patients with comparable prior therapy. Nonhematological toxicities, including nausea, vomiting, fatigue, and anorexia, were mild to moderate. The disposition of GI147211 in blood was described by a linear three-compartment model, with renal elimination accounting for only 11% of drug distribution. No relationship was observed between the pharmacological exposure to GI147211 and effects on neutrophils; however, patients who developed dose-limiting myelosuppression did experience greater exposure to both the lactone and total forms of the drug. The hydrolysis kinetics of GI147211 revealed not only a shift of the drug to the inactive carboxylate form in human serum albumin but also stabilization of the lactone in erythrocytes, perhaps accounting for the observed lactone:total area under the concentration-time curve ratio of 0.27. These results indicate that GI147211 exhibits predictable toxicities and that further studies are warranted to determine the distinct role of this compound among currently available camptothecin analogues.

Adult↗

Impact of the Libby Zion case on graduate medical education in internal medicine.

Residency training in New York State was substantially altered by the Libby Zion case. Work-hour limitations and augmented supervisory requirements changed the patterns of training--particularly in internal medicine--but with uncertain impacts on the quality of education and patient care. In this historical analysis, we review another major effect of the case: a substantial augmentation of the number of trainees. The need to maintain adequate inpatient staffing--within the ground rules of the Residency Review Committee, and in consideration of the reimbursement formulae and financial climate of New York State--conspired to promote substantial residency program expansion. Similar forces contributed to a national trend to increase the number of trainees. The history, cost and impact of these personnel changes are reviewed.

Evaluation Studies as Topic↗

Nursing assessment and intervention for adult hemodialysis patients: application of Roy's Adaptation Model.

A comprehensive assessment tool and intervention typology for adult hemodialysis patients, based on the Roy Adaptation Model, is presented. The Roy model is reviewed, and examples from the assessment tool and intervention typology are presented. A case study illustrates application of the tool and typology to nephrology nursing. Comparison of the tool and typology with the ANNA Standards of Clinical Practice revealed that the Roy Adaptation Model includes additional important aspects of nephrology nursing practice.

Adaptation, Physiological↗

Shift length as a determinant of retrospective on-shift alertness.

OBJECTIVES: This study examined the combined effects of shift length (8 versus 12 hours) and night-to-morning-shift changeover time (0600 versus 0700) on retrospective on-shift alertness ratings. METHODS: An abridged version of the Standard Shiftwork Index, which included retrospective alertness ratings, was completed by 4 groups of industrial shift workers. Two groups worked 8-hour shift systems and started their morning shifts at either 0600 or 0700; the other 2 groups worked 12-hour systems, starting their day shifts at either 0600 or 0700. RESULTS: The 8-hour workers reported considerably higher levels of alertness in the afternoon, while the 12-hour workers were more alert than the 8-hour workers in the morning and at 2200. Workers who started their shift around 0600 were less alert during the morning than those who started around 0700. The data suggested that the combined effects of working 8-hour shifts and starting the morning shift at around 0600 have particularly deleterious effects upon alertness. CONCLUSIONS: Effects on alertness can be explained in terms of differences in elapsed time on duty, sleep duration, sleep disruption, and chronic fatigue. The findings of this study appear to contradict previous research demonstrating that the major deleterious effects of extended shifts and delayed changeovers upon alertness occur at night. However, it is acknowledged that the absence of a difference in alertness at night may have been due to floor effects. Nevertheless, the implications of the alertness ratings for performance and safety, particularly during the afternoon, should not be ignored.

Adult↗

Can Oxford heal itself?

The fast-growing HMO was hammered on Wall Street after revealing its massive computer problems. Those foul-ups are being fixed, but now comes the hard part--reclaiming the trust of stunned shareholders and outraged doctors.

Computer Systems↗