Regulation of gene expression by oxygen levels in mammalian cells.
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Animals↗
Biomedical subjects
M Wood
Publications and source records attributed to M Wood.
Effect of a pharmacist-education initiative on ketorolac use and costs in a Medicaid program.
The effects of a pharmacist-education initiative on the use and costs of ketorolac in a state Medicaid program are reviewed. An intervention letter describing changes in the manufacturer's prescribing guidelines for ketorolac and providing suggestions for interacting with physicians regarding the use of ketorolac was sent to 150 of the 301 pharmacies that participate in New Mexico's Medicaid program. The remaining 151 pharmacies served as a control group. Ketorolac claims records for three months before and after the intervention were reviewed. The mean quantity of ketorolac tablets, total days' supply, and number of prescriptions filled per pharmacy per month were calculated for both periods. The number of prescriptions not filled as a result of the intervention as well as the number that could have been avoided, the number of cases of peptic ulceration (ketorolac's major adverse effect) that would be avoided, and the associated cost savings if all the state's Medicaid pharmacies had been included in the intervention were estimated. A total of 167 pharmacies (90 intervention and 77 control) dispensed ketorolac for Medicaid patients during the study period. Ketorolac dispensing rates declined during the postintervention period in both the intervention group and the control group, but the reduction was greater in the intervention group. It was predicted that if all pharmacies were included in an intervention, 135.6 fewer prescriptions for ketorolac would be filled each year; as a result, 1.14 cases of peptic ulceration would be avoided and net Medicaid costs would be reduced by $1638. Sending educational letters to pharmacists was associated with a modest reduction in ketorolac use in a state Medicaid program; a net reduction in Medicaid costs if the intervention were extended to all pharmacies that participate in the state's Medicaid program was projected.
Analysis of Variance↗
Simultaneous determination of codeine and its seven metabolites in plasma and urine by high-performance liquid chromatography with ultraviolet and electrochemical detection.
A sensitive and selective high-performance liquid chromatography method has been developed for the measurement of codeine and its seven metabolites, norcodeine, morphine, normorphine, codeine-6-glucuronide, morphine-6-glucuronide, morphine-3-glucuronide and norcodeine glucuronide, in plasma and urine. The compounds were recovered from plasma and urine using solid-phase extraction with C18 cartridges and separated on a reversed-phase C8 column with a mobile phase consisting of 77% buffer (5 mM sodium phosphate monobasic and 0.70 mM sodium dodecyl sulfate, pH 2.35) and 23% acetonitrile. Codeine, norcodeine, codeine-6-glucuronide, norcodeine glucuronide and morphine-3-glucuronide were detected by ultraviolet detection at 214 nm, with a detection limit of 0.02 nmol/ml for each compound in plasma. Morphine-6-glucuronide, normorphine and morphine were monitored by electrochemical detection at 350 mV, with a detection limit of 0.003 nmol/ml for each compound in plasma. The assay showed good reproducibility and accuracy using external standardization. The recovery and inter-day variation for all compounds in plasma samples were 63.40-77.90% and 3.49-16.77% (R.S.D.) and while in urine were 64.98-90.13% and 2.93-9.96% (R.S.D.), respectively.
Chromatography, High Pressure Liquid↗
The impact of gastroesophageal reflux disease on health-related quality of life.
BACKGROUND: Gastroesophageal reflux disease (GERD) affects health-related quality of life. METHODS: We enrolled 533 adults with a history of heartburn symptoms for at least 6 months of moderate to severe heartburn in 4 of the 7 days before study entry. Patients were treated with ranitidine 150 mg twice a day for 6 weeks and Gelusil antacid tablets as needed. We measured physician-rated symptoms and the Medical Outcomes Study short-form 36 (SF-36) Health Survey at baseline and after 6 weeks of treatment. Baseline results were compared with normative data for the US population and for patients with selected chronic diseases. Treatment response was defined as no episode of moderate to severe heartburn for 7 days. Statistical significance was set at P <0.001. RESULTS: GERD patients reported significantly worse scores on all 8 SF-36 scales, physical function and well-being, and emotional well-being compared with the general population. Patients with GERD reported worse emotional well-being than patients with diabetes or hypertension. Treatment responders demonstrated significantly less pain and better physical function, social function, vitality, and emotional well-being compared with nonresponders. CONCLUSIONS: Patients with GERD experience decrements in health-related quality of life compared with the general population. The impact of GERD is most striking on measures of pain, mental health, and social function. Successful treatment for GERD results in improvements in health-related quality of life.
Adult↗
Primary intraocular lens implantation for penetrating lens trauma in Africa.
OBJECTIVE: This study aimed to audit the surgical strategy of primary posterior chamber intraocular lens implantation for cases of recent penetrating trauma involving the lens in an African population. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: Seventy-two cases are reported, including all patients who underwent primary intraocular lens implantation for traumatic cataract extraction performed within 1 month of injury between 1988 and 1996. MAIN OUTCOME MEASURES: Demographic characteristics and follow-up attendance rates are analyzed. Surgical technique and the occurrence of intraoperative and postoperative complications are reported. Visual outcomes are reported with detailed analysis for cases of poor visual outcome. RESULTS: Mean age was 14.3 years (standard deviation = 11.1), 57 (79%) were male and 15 (21%) were female (chi-square = 23.66, P < 0.01). Fifty-eight patients (80%) attended for follow-up with a mean follow-up duration of 14.3 months (standard deviation = 17.3). No demographic or surgical differences were identified between attendees and nonattendees. The posterior capsule had been breached by the trauma in 27 (38%) cases, and 15 of these required anterior vitrectomy. Capsular fixation of the implant was achieved in 49% of patients, the remainder having sulcus fixation. Intraoperative rupture of the posterior capsule occurred in four cases. The only common postoperative complication was acute fibrinous anterior uveitis, which occurred in 29 (40%) patients, and 32% of patients followed up for at least 6 months required secondary posterior capsulotomy. This was more common in younger patients (chi-square = 4.2, P < 0.05). Corrected postoperative visual acuities were available for 51 patients, of which 71% achieved 20/60 or better visual acuity. Patients 6 years of age or younger were less likely to achieve 20/60 (chi-square = 6.61, P = 0.01). CONCLUSIONS: This surgical strategy has proved successful, producing good visual results and causing no sight-threatening complications. Primary posterior capsulotomy may be appropriate for younger patients.
Adolescent↗
Patient-assigned health state utilities for depression-related outcomes: differences by depression severity and antidepressant medications.
BACKGROUND: Major depressive disorder is a prevalent psychiatric disorder in primary care associated with impaired patient functioning and well-being. We compared patient utilities for hypothetical depression-related and current health states and to examine differences in utilities by patient demographic and clinical characteristics. METHODS: Seventy patients with DSM-III-R major depressive disorder or dysthymia who completed at least 8 weeks of antidepressant treatment were recruited from primary care practices. Patients assessments included the Hamilton Depression Rating Scale (HDRS), SF-36 Health Survey, and standard gamble interviews to obtain utilities for 11 hypothetical depression-related states, varying depression severity and antidepressant treatment, and the patient's current health state. RESULTS: The mean utility for severe depression was 0.30 and 25% of patients rated this state as worse than or equivalent to death. Utilities varied from 0.55 to 0.63 for moderate depression, 0.64 to 0.73 for mild depression, and 0.72 to 0.83 for antidepressant maintenance therapy. Statistically significant differences were observed in mean utilities by level of disease severity and by tricyclic antidepressants compared with the newer antidepressants (i.e., fluoxetine, nefazodone). There were no significant differences in utilities for hypothetical states by demographic variables. Mean patient-assigned utilities for current health varied by depression severity and presence of medication side effects. CONCLUSIONS: Health state utility scores can be provided by patients with depression and the utility scores provided by patients for hypothetical states demonstrate differences by disease severity and antidepressant treatment. LIMITATIONS: The sample size was small which may limit generalizability and statistical power for detecting important differences. The study findings are limited to patients who have successfully completed 8 weeks of antidepressant treatment. CLINICAL RELEVANCE: Understanding patient preferences for depression outcomes is important for economic evaluations of new antidepressants and for understanding patient behavior and adherence to antidepressant treatment regimens.
Adolescent↗
Achieving clinical behaviour change: a case of becoming indeterminate.
This paper is based on an empirical study of attempts to achieve change in clinical behaviour across a United Kingdom National Health Service (NHS) Health Authority (HA). We suggest that the evidence based medicine (EBM) movement underpinning such attempts is premised upon a highly rationalistic conception of change. Here the generation and implementation of research findings into clinical practice is understood as movement between discrete entities. Drawing upon poststructural philosophy, social studies of science and technology, social anthropology, and gender studies, we challenge such linear perspectives through a more immanent alternative. We conceive of change as movement within indeterminate or ambiguous relationships. We then proceed to discuss the implications of this modality for the management of clinical behaviour change.
Delivery of Health Care↗
Reliability and validity of the Gastrointestinal Symptom Rating Scale in patients with gastroesophageal reflux disease.
The objective of this study was to evaluate the reliability and validity of the gastrointestinal Symptom Rating Scale (GSRS) in US patients with gastroesophageal reflux disease (GERD). Five hundred and sixteen adults with predominant heartburn symptoms of GERD were recruited from gastroenterologist and family physician practices and treated with 6 weeks of 150 mg ranitidine twice daily to identify poorly responsive symptomatic GERD. The GSRS, the Medical Outcomes Study Short Form-36 (SF-36) Health Survey and the Psychological General Well-being (PGWB) scale were administered at baseline and after 6 weeks of treatment. Reported ratings of GERD-related symptoms from physician and patient diaries were measured. The GSRS contains five scales: reflux syndrome, abdominal pain, constipation syndrome, diarrhoea syndrome and indigestion syndrome. The internal consistency reliabilities for the GSRS scales ranged from 0.61 to 0.83 and the intraclass correlation coefficients ranged from 0.42 to 0.60. The GSRS scale scores were correlated with the SF-36 and PGWB scales and with the number and severity of heartburn symptoms. Patients with two or three clinician-rated GERD-related symptoms reported worse GSRS scale scores compared with patients with fewer symptoms (p < 0.0001). Statistically significant differences in the mean GSRS scale scores were observed between treatment responders and non-responders (p < 0.0001) and patients showing a response to treatment had larger mean changes in their GSRS scales than patients not showing a response to treatment (p < 0.0001). The standardized response means ranged from 0.42 to 1.43 for the GSRS scale scores. It was concluded that the GSRS is a brief, fairly comprehensive assessment of common gastrointestinal symptoms. The GSRS has good reliability and construct validity and the GSRS scales discriminate by GERD symptom severity and are responsive to treatment. The GSRS is a useful patient-rated symptom scale for evaluating the outcomes of treatment for GERD.
Adult↗
Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells.
Oxidative stress is implicated in a number of neurological disorders including stroke, Parkinson's disease, and Alzheimer's disease. To study the effects of oxidative stress on neuronal cells, we have used an immortalized mouse hippocampal cell line (HT-22) that is particularly sensitive to glutamate. In these cells, glutamate competes for cystine uptake, leading to a reduction in glutathione and, ultimately, cell death. As it has been reported that protein kinase C activation inhibits glutamate toxicity in these cells and is also associated with the inhibition of apoptosis in other cell types, we asked if glutamate toxicity was via apoptosis. Morphologically, glutamate-treated cells underwent plasma membrane blebbing and cell shrinkage, but no DNA fragmentation was observed. At the ultrastructural level, there was damage to mitochondria and other organelles although the nuclei remained intact. Protein and RNA synthesis inhibitors as well as certain protease inhibitors protected the cells from glutamate toxicity. Both the macromolecular synthesis inhibitors and the protease inhibitors had to be added relatively soon after the addition of glutamate, suggesting that protein synthesis and protease activation are early and distinct steps in the cell death pathway. Thus, the oxidative stress brought about by treatment with glutamate initiates a series of events that lead to a form of cell death distinct from either necrosis or apoptosis.
Amino Acid Chloromethyl Ketones↗
Sperm retrieval and fertilization in repeated percutaneous epididymal sperm aspiration.
Percutaneous epididymal sperm aspiration (PESA) for retrieval of spermatozoa for intracytoplasmic sperm injection (ICSI) is a new simplified technique in the treatment of men with obstructive azoospermia. There has been a fear that the PESA procedure, being blind, could cause damage to the epididymal duct system and make it impossible to retrieve spermatozoa if a repeated procedure is required. We report here on repeated PESA procedures from the same unilateral epididymis. Twenty-seven men with obstructive azoospermia were investigated retrospectively regarding sufficiency of the number of motile spermatozoa for ICSI, fertilization rate (FR) and possibility of collecting spermatozoa for cryopreservation in repeated PESA procedures. Sufficient motile spermatozoa for ICSI were found in a similar proportion of men at the first two attempts: 91 and 89% respectively. Fertilization rate and the possibility of collecting spermatozoa for cryopreservation were also similar at the first two PESA procedures: 62 versus 67% and 33 versus 33% respectively. At the third procedure, motile spermatozoa for ICSI were retrieved in 86% (6/7), FR was 47% and spermatozoa were cryopreserved in one case. Two men underwent a fourth PESA. In both cases, a sufficient number of motile spermatozoa for ICSI was found and FR was 62%. This study shows that in men with obstructive azoospermia, PESA can be repeated on the same unilateral epididymis up to three times, with good opportunity of retrieving sufficient motile spermatozoa for ICSI.
Adult↗
The politicization of antimicrobial resistance.
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Editorial↗
Design, testing, and results of an outcomes-managed approach to patients requiring prolonged mechanical ventilation.
BACKGROUND: Outcomes management that uses critical pathways may decrease costs while improving outcomes for patients who require prolonged mechanical ventilation. OBJECTIVE: To study the efficacy of an outcomes-managed approach to weaning patients from prolonged (more than 3 days) mechanical ventilation. METHODS: A method of multidisciplinary care delivery was designed that included an outcomes manager, a care pathway for patients receiving mechanical ventilation, and weaning protocols. Data collection consisted of three parts: a retrospective review of 124 patients who required prolonged ventilation during a 1-year period before implementation of the care model, a 6-month prospective study in which 91 patients were alternately assigned by month to an outcomes-managed approach or a non-outcomes-managed approach, and a 6-month prospective study of 90 patients in which an outcomes-managed approach without alternate-month assignment was used. RESULTS: Outcomes management had no significant effect on total duration of mechanical ventilation or length of stay in the hospital, days of mechanical ventilation without tracheostomy, days of mechanical ventilation with tracheostomy, or outcome (weaned, withdrawal from mechanical ventilation, death, or transfer without weaning). However, duration of mechanical ventilation was 1.3 days shorter, length of stay in the hospital was 2.1 days shorter, and the cost per case was $ 3341 less for patients in the outcomes-managed group than for patients in the non-outcomes-managed group. CONCLUSION: Outcomes-managed care did not have a significant effect on duration of ventilation, length of stay in the hospital, or outcome in patients receiving long-term mechanical ventilation.
Adult↗
Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas.
AKT2, an oncogene encoding a protein serine-threonine kinase implicated in phosphatidylinositol-3-OH kinase signaling, is amplified in some human ovarian and pancreatic carcinomas. We previously demonstrated that the tumorigenicity and invasiveness of pancreatic ductal adenocarcinoma (PDAC) cell lines with amplified AKT2 could be markedly reduced by transfection with antisense AKT2 constructs. To evaluate further the extent of AKT2 alterations in PDAC, DNA and immunohistochemical analyses were performed to assess amplification or overexpression of AKT2, respectively, in 72 PDACs. Thirty-five PDACs were subjected to Southern analyses, and AKT2 amplification was detected in seven tumors (20%). Forty-one formalin-fixed PDAC specimens were examined immunohistochemically with an anti-AKT2 monoclonal antibody, and moderate to intense staining was observed in eight tumors (20%). AKT2 immunostaining paralleled AKT2 genomic status in each of four cases in which both Southern and immunohistochemical analyses were performed. No obvious relationship was observed between AKT2 status and tumor TNM stage or grade. These observations suggest the utility of immunohistochemical analysis in assessing alterations of AKT2 in human cancers. Furthermore, the role played by the AKT2 kinase in the signaling pathways of various mitogenic growth factors implicated in the development of pancreatic cancer suggests that alteration of AKT2 may be an important component in the pathogenesis of a substantial subset of PDACs.
Carcinoma, Ductal, Breast↗
Salmonella hindmarsh infection in sheep and ponies.
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Animals↗
Molecular pathology of primary and metastatic ductal pancreatic lesions: analyses of mutations and expression of the p53, mdm-2, and p21/WAF-1 genes in sporadic and familial lesions.
BACKGROUND: The molecular pathology underlying the development and progression of ductal pancreatic adenocarcinoma is poorly understood relative to that of other major cancers in industrialized societies. The frequency, nature, and distribution of p53 abnormalities, their temporal relationship to the metastatic and clinicopathologic phenotypes of sporadic and familial pancreatic cancer, and their consequent effects on the genetics and expression of critical wild-type p53-regulated genes (mdm-2 and p21/WAF-1) warrant examination in pancreatic adenocarcinoma. This molecular and immunochemical study of the p53, mdm-2, and p21/ WAF-1 genes and gene products examined the largest series of nonneoplastic, neoplastic, and metastatic ductal pancreatic lesions reported to date in relation to clinicopathologic profile. METHODS: Histologically confirmed specimens of primary (n = 136) and metastatic (n = 23) sporadic and familial ductal pancreatic adenocarcinoma lesions were subjected to immunochemical analyses of p53 expression in which a panel of 3 antibodies was utilized. A panel of nonneoplastic but histologically abnormal pancreatic lesions (n = 77) from individuals with varied histories of cigarette smoking were subjected to similar immunohistochemical examinations. In addition, 3 specimens from patients with chronic pancreatitis, 2 specimens of normal fetal pancreata, and 16 specimens of normal adult pancreata were examined as control tissues. Suitable frozen and archival microdissected tumor lesions were evaluated for mutations in exons 4-9 of the p53 gene by single strand conformation polymorphism (SSCP) and dideoxy sequencing analyses in which two distinct sets of outer and nested intron-based amplification primers were used for each exon. A subset of 25 tumor specimens and 18 tumor-derived cell lines for which the p53 mutation status was known were examined for amplification and/or overexpression of the mdm-2 gene; amplification was determined by Southern hybridization and overexpression by immunohistochemical and Western blot analyses. Similarly, mutations in the coding region of p21/WAF-1 gene were examined by SSCP and DNA sequence analyses, and steady-state expression of the p21/WAF-1 protein was assessed by Western blot analysis in these subsets of tumors and tumor-derived cell lines. RESULTS: Positive ductal nuclear p53 immunostaining was demonstrated in 56% of primary tumors and 54% of metastatic lesions. The frequency did not differ significantly between sporadic and familial lesions, and immunostaining was not observed in ductal, acinar, or islet cell elements of normal pancreata or histologically abnormal benign pancreatic lesions from cigarette smokers. A total of 70% of tumor samples revealed reproducible SSCP abnormalities for p53; 42% of these were found in exons 7 and 8. DNA sequence analysis of cases with greater than 35% epithelial cellularity (n = 25) revealed 17 missense mutations, 12 of which were transitions. Seventy-five percent of these transitions were of G:C-->A:T type. A total of 22% of the p53 mutations identified were microdeletions, along with one insertional mutation at exon 8. None of the normal pancreata from sporadic or familial lesions revealed germ-line p53 alterations. Moreover, the frequency and spectra of p53 alterations exhibited no clear, statistically significant association with tumor grade, TNM stage, or patients' cigarette-smoking histories. The mdm-2 gene was neither amplified nor overexpressed immunochemically in a subset of ductal adenocarcinomas, and there was no clear relationship between the p53 mutation status and the status of the mdm-2 gene or protein. Similarly, SSCP and DNA sequence analysis of the p21/WAF-1 gene revealed only 2 genetic abnormalities in a series of 25 primary tumors and 15 tumor-derived cell lines; 1 of the cell lines also revealed the absence of immunoreactive p21/WAF-1 protein...
Adult↗
Telementoring. A practical option in surgical training.
BACKGROUND: Telemedicine offers significant advantages in bringing consulting support to distant colleagues. There is a shortage of surgeons trained in performing advanced laparoscopic operations. AIM: Our aim was to evaluate the role of telementoring in the training of advanced laparoscopic surgical procedures. METHODS: Student surgeons received a uniform training format to enhance their laparoscopic skills and intracorporeal suturing techniques and specific procedural training in laparoscopic colonic resections and Nissen fundoplication. Subsequently, operating rooms were equipped with three cameras. Telestrator (teleguidance device), instant replay (to critique errors), and CD-ROM programs (to provide information of reference) were used as intraoperative educational assistance tools. In phase I, four colonic resections were performed with the mentor in the operating room (group A) and four colonic resections were performed with the mentor on the hospital grounds, but not in the operating room (group B). The voice and video signals were received at the mentor's location, using coaxial cable. In phase II, two Nissen fundoplications were performed with the mentors in the operating room (group C) and two Nissen fundoplications were performed with the mentors positioned five miles away from the operating room (group D), using currently existing land lines at the T-1 level. RESULTS: There were no differences in the performances of the surgeons and outcome of the operations between groups A & B and C & D. It was possible to tackle the intraoperative problems effectively. CONCLUSIONS: The telementoring concept is potentially a safe and cost-effective option for advanced training in laparoscopic operations. Further investigation is necessary before routine transcontinental patient applications are attempted.
Fundoplication↗
Plasma morphine and glucuronide (M3G and M6G) concentrations in hospice inpatients.
Plasma morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) concentrations were quantified by high performance liquid chromatography (HPLC) in 36 hospice inpatients receiving morphine orally or subcutaneously. The data were analyzed in relation to dose, serum creatinine, serum gamma glutamyl transferase, and presence or absence of opioid-induced adverse effects. There were significant associations (P < 0.05) between plasma morphine, M3G (subcutaneous route only), and M6G concentrations and dose for both routes of administration. The mean dose-corrected plasma morphine concentration for the subcutaneous group was three times that of the oral group, confirming present oral to subcutaneous dose conversion practices. Nineteen patients experienced symptoms attributed to morphine: nausea and vomiting in ten and acute delirium in nine. Serum creatinine was elevated in patients with adverse effects (P = 0.031), as were the dose-corrected plasma M3G (P = 0.029) and M6G (P = 0.043) concentrations. All seven patients with serum creatinine concentrations above the normal range had symptoms attributed to opioid-induced adverse effects. Plasma M3G, M6G, and dose-corrected plasma M3G and M6G concentrations were significantly (P < 0.001) higher in these patients than in those with normal serum creatinine concentrations. The data indicate that accumulation of M3G and M6G may be a causal or aggravating factor in the nausea and vomiting and cognitive function profile of palliative and terminal care patients with significant renal function impairment.
Adult↗
In situ hybridization studies of metalloproteinases 2 and 9 and TIMP-1 and TIMP-2 expression in human prostate cancer.
The expression of MMP-2, MMP-9, TIMP-1, TIMP-2, and the urokinase receptor were examined in fetal and normal prostate tissues, benign prostatic hyperplasia and prostate cancer (n = 117). In situ hybridization with digoxigenin-labeled oligonucleotide probes demonstrated that TIMP-1 and TIMP-2 were expressed at elevated levels in the stroma of Gleason sum 5 tissues, whereas MMP-2 and MMP-9 were expressed at relatively low levels. In higher Gleason sum tissues (GS 8-10), TIMP-1 and TIMP-2 were not expressed, whereas MMP-2 and MMP-9 were intensely expressed. Furthermore, TIMP-1 and TIMP-2 expression was high in organ-confined specimens (OC, n = 43), somewhat lower in specimens with capsular penetration (CP, n = 29), and low or negative in samples with surgical margin/seminal vesicle (M/SV, n = 17) and lymph node (LN, n = 13) involvement. In contrast, MMP-2 and MMP-9 expression was low in the OC tissues; and noticeably higher in CP, M/SV, and LN specimens. Finally, correlation of TIMP and MMP expression with GS and pathological stage versus cure rate further revealed that a high percentage of organ-confined, GS 5 specimens expressing TIMP and little MMP were cured. In comparison, few of the GS 7-10 patients with capsular penetration and expressing MMP and little TIMP were cured. The data suggest that TIMP-1 (and TIMP-2) and MMP-2 (and MMP-9) are independent predictors of outcome.
Collagenases↗