Biomedical subjects
Robert Smith
Publications and source records attributed to Robert Smith.
Chronic daily headache.
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Quantifying headache symptoms and other headache features from chart notes.
OBJECTIVES: To describe a method for quantifying headache symptoms/features in family practice charts for patients diagnosed with headache NOS (not otherwise specified, ICD-9: 784) and to determine the share of NOS headache diagnoses with clinical data strongly suggestive of migraine or probable migraine headache. BACKGROUND: Headache is one of the most common pain symptoms that brings patients to a family physician. However, the majority of headache sufferers do not receive a specific headache diagnosis when they visit physicians. METHODS: We examined the chart notes of 454 patients exclusively diagnosed with one or more ICD-9 coded headache NOS diagnoses from July 1, 1995 through December 31, 1999 at a large suburban, university-affiliated practice. We developed a template containing 20 headache items combining International Headache Society diagnostic criteria and additional headache symptoms/features, and decision rules for coding symptoms/features and collected data from patient charts. We then developed decision rules and reclassified NOS headaches into categories strongly suggestive of migraine, probable migraine headache, or other diagnosis. Our main outcome measure is the consistency in the application of decision rules and diagnostic criteria. RESULTS: With this method we estimate 3 in 10 (29%) headache NOS patients may have had migraine (8%) or probable migraine headache (21%). Reclassified migraine visits averaged 6.5 migraine symptoms and reclassified probable migraine headache visits 4.7 migraine symptoms. Logistic regression analysis supports the consistency of diagnostic criteria for classifying headache based on coded symptoms/features--our model correctly predicted 96% of visits. Evidence of physical examination was recorded at 75% of visits suggesting that physician attention is focused on elimination of secondary headache. CONCLUSIONS: We think the use of our rigorous procedures reveals that a substantial amount of migraine and probable migraine headache may be missed in everyday practice. We hope our findings will provide a basis for the development of diagnostic methods more closely suited to the needs of nonspecialists, and contribute to a better standard of care for headache patients seen in primary care practice. Finally, we are hopeful that other researchers will consider using our template and guideline procedures in their efforts to identify diagnostic patterns and study headache and other health problems.
Q fever outbreak in industrial setting.
An outbreak of Q fever occurred in South Wales, United Kingdom, from July 15 through September 30, 2002. To investigate the outbreak a cohort and nested case-control study of persons who had worked at a cardboard manufacturing plant was conducted. The cohort included 282 employees and subcontractors, of whom 253 (90%) provided blood samples and 214 (76%) completed questionnaires. Ninety-five cases of acute Q fever were identified. The epidemic curve and other data suggested an outbreak source likely occurred August 5-9, 2002. Employees in the factory's offices were at greatest risk for infection (odds ratio 3.46; 95% confidence interval 1.38-9.06). The offices were undergoing renovation work around the time of likely exposure and contained straw board that had repeatedly been drilled. The outbreak may have been caused by aerosolization of Coxiella burnetii spore-like forms during drilling into contaminated straw board.
The ultrasound screen for penetrating truncal trauma.
A prospective blinded pilot study was performed at an urban level 1 trauma center to evaluate the efficacy of ultrasound in ruling out penetrating visceral truncal injury. For 8 months, 49 nonconsecutive patients who presented with truncal gunshot and stab wounds were evaluated by a 10-MHz ultrasound tranducer probe. The deepest muscle bundle and the fascia enveloping it was examined by ultrasound. These images were compared to the equivalent contralateral unaffected side of the patient. All the patients then underwent standard testing to evaluate for potential intracavitary injury. Forty-nine patients with a mean age of 28 years (SD, 8.8) were evaluated by ultrasound. A total of 58 injuries were evaluated of which 37 were stab wounds and 21 were gunshot wounds. Thoracoabdominal and back and flank injuries were the most commonly evaluated injuries. There were 20 true positives, 20 false positives, and 18 true negatives, each with approximately twice as many stab as gunshot wounds. There were no false negatives. The sensitivity and negative predictive value of ultrasound in determining clinically significant truncal visceral injury in penetrating truncal trauma is 100 per cent. The specificity and positive predictive value are both approximately 50 per cent. Ultrasonic examination of the injured abdominal wall layers in truncal penetrating trauma is an excellent screening tool. Simple comparative assessment with the unaffected contralateral side allows a highly sensitive method of decreasing the number of potentially morbid, time consuming, and expensive tests that are currently employed to rule out visceral injury.
Clinical benefits of neoral C2 monitoring in the long-term management of renal transplant recipients.
BACKGROUND: Cyclosporine monitoring using the 2-hr postdose sample, C2, has been shown to have advantages in monitoring de novo renal transplant recipients. The purpose of this study was to assess cyclosporine exposure, using C2, in stable renal transplant patients previously monitored by C0 to determine the effect of dose reduction on patients with C2 more than 10% above target and the course of those with C2 at and more than 10% below target, whose dose was not modified. METHODS: One hundred and seventy-five patients, three or more months after transplantation, had C2 assessed. The relationship of C2 to C0 and of both to renal function was analyzed by linear regression. Blood pressure, serum creatinine level, and lipids were followed for a mean of 15+/-2.6 months. RESULTS: Eighty-five patients had values more than 10% above target, 42 were within 10% of target, and 48 were more than 10% below target. Cyclosporine dose was reduced in all patients above target. In this group, serum creatinine level was stable overall, but fell significantly in 46 (54%) of 85 from 153+/-55 to 132+/-49 microM. Blood pressure also fell in that group from 135/82 to 131/77. Serum creatinine level was stable in the remaining two groups of patients. CONCLUSIONS: These data suggest that dose reduction in many overexposed patients leads to improvements in renal function and blood pressure. Further study is required to confirm the long-term benefits of this strategy.
Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group.
PURPOSE: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: This multicenter phase III trial randomly assigned 916 patients with hormone receptor-positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician's discretion. This report updates efficacy at a median follow-up of 32 months. RESULTS: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P <.0001), time to treatment failure (median, 9 v 5.7 months, respectively; P <.0001), overall objective response rate (32% v 21%, respectively; P =.0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not significant, survival was improved in the randomized letrozole arm over the first 2 years of the study. Approximately one half of the patients in each arm crossed over. Total duration of endocrine therapy ("time to chemotherapy") was significantly longer (P =.005) for patients initially on letrozole (median, 16 months) than for patients initially on tamoxifen (median, 9 months). Time to worsening of Karnofsky performance score was significantly delayed with letrozole compared with tamoxifen (P =.001). CONCLUSION: This study documents the superiority of letrozole over tamoxifen in first-line endocrine therapy in postmenopausal women with advanced breast cancer.
Pilot trial of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib plus carboplatin and paclitaxel in patients with stage IIIB or IV non-small-cell lung cancer.
PURPOSE: Gefitinib is an oral agent that inhibits the tyrosine kinase of the epidermal growth factor receptor. In phase I trials gefitinib was well tolerated and antitumor activity was seen in pretreated non-small-cell lung cancer (NSCLC) patients. Preclinical studies indicated enhanced effects when gefitnib was added to carboplatin or paclitaxel. This pilot trial combined gefitinib with carboplatin and paclitaxel to define the toxicities of the combination and assess drug-drug interactions in untreated advanced NSCLC patients. PATIENTS AND METHODS: Initially (part 1) patients were randomly assigned to receive intermittent gefitinib with cycle 1 or 2 of chemotherapy. Thereafter (part 2), the highest dose of gefitinib that was given without dose-limiting toxicity (DLT) from part 1 was administered continuously beginning with the first cycle of chemotherapy. Three sequentially enrolled cohorts received gefitinib 250 and 500 mg (intermittently) and 500 mg (continuously). RESULTS: We treated 24 patients; nine patients with 250 mg and 15 patients with 500 mg (nine patients continuous). Two occurrences of DLT were observed. One patient (500 mg, part 1) developed grade 3 rash and another patient (part 2) developed prolonged neutropenia. Steady-state gefitinib levels did not affect exposure to chemotherapy. In a limited sample, chemotherapy modestly increased the gefitinib area under concentration-time curve at steady-state and minimum steady-state trough concentration. Partial responses were observed in five of 24 patients. The median survival was 8 months. CONCLUSION: The gefitinib with carboplatin and paclitaxel regimen was generally well tolerated and no unanticipated toxicities or clinically relevant pharmacokinetic interactions were observed. Both doses of gefitinib were believed to be safe for further study with chemotherapy. This regimen was thus tested in a completed randomized phase III trial.
Combining biomarkers to detect disease with application to prostate cancer.
In early detection of disease, combinations of biomarkers promise improved discrimination over diagnostic tests based on single markers. An example of this is in prostate cancer screening, where additional markers have been sought to improve the specificity of the conventional Prostate-Specific Antigen (PSA) test. A marker of particular interest is the percent free PSA. Studies evaluating the benefits of percent free PSA reflect the need for a methodological approach that is statistically valid and useful in the clinical setting. This article presents methods that address this need. We focus on and-or combinations of biomarker results that we call logic rules and present novel definitions for the ROC curve and the area under the curve (AUC) that are applicable to this class of combination tests. Our estimates of the ROC and AUC are amenable to statistical inference including comparisons of tests and regression analysis. The methods are applied to data on free and total PSA levels among prostate cancer cases and matched controls enrolled in the Physicians' Health Study.
Mechanisms of glomerular immune injury: effects of antioxidant treatment.
Significant glomerular vasoconstriction and production of reactive oxygen species has been known to occur with exposure to anti-glomerular basement membrane antibody (AGBM-Ab) in the rat model. Previously published studies have demonstrated that such effects can be reduced by therapy with phentolamine, an alpha-adrenergic antagonist. It was hypothesized that antioxidant pretreatment with water-soluble probucol would improve glomerular hemodynamics 60 to 90 min after the administration of AGBM-Ab. These relationships were examined with both in vivo renal micropuncture and in vitro studies in rats. Single-nephron GFR (SNGFR) decreased markedly in untreated rats after AGBM-Ab as a result of afferent and efferent arteriolar vasoconstriction with consequent reductions in nephron plasma flow (SNPF) and decreases in the glomerular ultrafiltration coefficient (LpA). Basal SNGFR was increased, and SNGFR was significantly higher after AGBM-Ab in probucol-treated versus untreated rats. This finding was due solely to higher values for SNPF and prevention of afferent arteriolar constriction. A reduction in LpA after AGBM-Ab was not prevented by probucol treatment. In vitro analyses of glomeruli revealed reduced myeloperoxidase activity in antioxidant-treated rats. Lipoxygenase activity and leukotriene products, however, were not changed by antioxidant therapy, yet vasoconstriction was prevented. H(2)O(2) generation before and after formyl-methionyl-leucyl-phenylalanine stimulation was significantly reduced before and after AGBM-Ab in glomeruli harvested from rats that were treated with the antioxidant. Antioxidant therapy in this model of AGBM-Ab injury did not prevent reductions in LpA, an index of glomerular membrane damage, but did prevent afferent arteriolar vasoconstriction. Reactive oxygen species generation was reduced by probucol. The specific mechanisms whereby antioxidant therapy ameliorates glomerular hemodynamic effects will be defined in additional studies and is likely to involve either enhanced vasodilator or diminished vasoconstrictor activity.
A conceptual model of the influence of stress on female reproduction.
Intriguingly, similar neurotransmitters and nuclei within the hypothalamus control stress and reproduction. GnRH neurone recruitment and activity is regulated by a balance between stimulation, suppression and permissiveness controlled by noradrenaline, neuropeptide Y and serotonin from the brain stem, impact from glutamate in the medial preoptic area and neuropeptide Y in the arcuate nucleus, in opposition to the restraining influences of gamma-aminobenzoic acid within the medial preoptic area and opioids from the arcuate nucleus. Stress also activates neuropeptide Y perikarya in the arcuate nucleus and brain stem noradrenaline neurones. The latter project either indirectly, via the medial preoptic area, or directly to the paraventricular nucleus to release corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP). Within the medial preoptic area, GnRH neurones synapse with CRH and AVP axons. Stimulation of CRH neurones in the paraventricular nucleus also activates gamma-aminobenzoic acid and opioid neurones in the medial preoptic area and reduces GnRH cell recruitment, thereby decreasing GnRH pulse frequency. Oestradiol enhances stress-induced noradrenaline suppression of LH pulse frequency but when applied in the paraventricular nucleus or brain stem, and not in the medial preoptic area or arcuate nucleus. The importance of CRH and AVP in the medial preoptic area needs confirming in a species other than the rat, which uses adrenal activation to time the onset of the GnRH surge. Another stress-activated pathway involves the amygdala and bed of the nucleus stria terminalis, which contain CRH neurones and accumulate gamma-aminobenzoic acid during stress.
Cost comparison of auditory brainstem response versus magnetic resonance imaging screening of acoustic neuroma.
The cost-effectiveness of current diagnostic approaches employed in patients with suspected acoustic neuroma was evaluated. Currently, patients with signs and symptoms suggestive of acoustic neuroma, such as sudden unilateral hearing loss and/or tinnitus, undergo auditory brainstem response (ABR) screening tests to rule out this condition. If the ABR is normal, acoustic neuroma can be ruled out. However, if the ABR is abnormal, magnetic resonance imaging (MRI) or computed tomography is necessary to confirm the diagnosis. When one considers the total costs of this screening approach, one can ask whether straight MRI screening of all of these patients would be a more cost-effective approach to diagnosing this condition. A retrospective chart review of patient records obtained from the acoustic diagnostics laboratory at Hotel Dieu Hospital, Kingston, Ontario, was performed. A database of patients who have undergone ABR testing over the past 2 years was compiled and analyzed to assess how many of them went on to receive MRI. The total costs (based on Ontario Health Insurance Plan [OHIP] fee schedule rates) of this approach were compared with the estimated costs of straight MRI screening performed on the same patient population. By making such an analysis, decisions regarding the most cost-effective approach to screening for acoustic neuroma can be objectively assessed.
A phase I trial of ZD9331, a water-soluble, nonpolyglutamatable, thymidylate synthase inhibitor.
PURPOSE: ZD9331 is a novel, direct-acting antifolate cytotoxic that does not require polyglutamation for activity, and is a specific thymidylate synthase inhibitor. This Phase I trial aimed to determine the maximum tolerated dose of ZD9331, given as a 30-min i.v. infusion on days 1 and 8 of a 21-day cycle. Pharmacokinetic parameters and tumor response were also assessed. EXPERIMENTAL DESIGN: A total of 71 patients, with a range of solid malignancies and refractory to standard therapies (44% had received > or =3 prior chemotherapy regimens), were treated. The most common malignancies were colorectal cancer (35% of patients) and ovarian cancer (31%). ZD9331 was escalated from 4.8 mg/m(2)/day. RESULTS: Dose-limiting toxicity occurred at 162.5 mg/m(2) ZD9331, with grade 4 thrombocytopenia, grade 4 neutropenia lasting > or =7 days, and grade 3 nonhematologic toxicity. Plasma clearance of ZD9331 was slow and dose-dependent; however, ZD9331 pharmacokinetics were nonlinear. Pharmacodynamics of ZD9331 were determined by measurement of plasma deoxyuridine, which increased at all of the dose levels; dose-related increases in plasma deoxyuridine were significant (P = 0.003) on day 5. Stable disease was observed in 37% of patients; 23% of ovarian cancer patients had a > or =50% reduction in CA125 levels. CONCLUSIONS: The maximum tolerated dose of this schedule was 130 mg/m(2). The toxicity profile at this dose was acceptable, with 7 of 28 patients treated developing grade 3/4 neutropenia and thrombocytopenia, 2 grade 4 diarrhea, and 2 grade 3/4 rash. This schedule was convenient and demonstrated activity in extensively pretreated patients; therefore, this is the recommended dose for study in Phase II trials.
Breast cancer worry and mammography use by women with and without a family history in a population-based sample.
Worry about breast cancer risk has been found to be a barrier to mammography use by women with a family history of breast cancer in some studies, although worry is generally found to increase mammography use among average risk women. Our study sought to examine the association of worry with mammography use in a population-based sample of women stratified by family history associated risk for breast cancer. A population-based sample of 6512 women completed a telephone interview. Fourteen percent (n = 948) of these reported a family history suggestive of elevated risk, including at least one affected first-degree relative. To examine the effects of worry on mammography use in women, a logistic regression model, including family history associated risk, age, and worry, was tested. Although family history was a significant predictor of mammography use in bivariate examinations, in the multivariate model it was not significant after adjustment for age and worry, which remained statistically significant predictors of mammography (P < 0.05). The association between worry and mammography use was best described by a quadratic term. Interaction terms for family history-associated risk and worry were not statistically significant predictors of mammography use. Worry about breast cancer risk appears to be associated with mammography use in an inverted u-shaped pattern. Women reporting moderate levels of worry were more likely to use mammography annually than those who were either mildly or severely worried. Severe worry may be a barrier to mammography use for all women not only those with a family history.
Phase I trial of ZD9331, a nonpolyglutamatable thymidylate synthase inhibitor, given as a 5-day continuous infusion to patients with refractory solid malignancies.
PURPOSE: This dose-escalating study investigated the toxicity, pharmacokinetics, and efficacy of the novel direct-acting antifolate ZD9331, given as a 5-day i.v. infusion every 3 weeks. EXPERIMENTAL DESIGN: Forty-five patients with refractory solid malignancies received ZD9331, which was escalated from 0.125 mg/m(2)/day. RESULTS: Dose-limiting grade 4 thrombocytopenia occurred in 3 of 6 patients treated at 8 mg/m(2)/day; other drug-related toxicities, across dose levels, included skin and gastrointestinal toxicity, lethargy, and asymptomatic, reversible, elevated transaminases. The maximum plasma concentration and area under the curve increased with dose. Clearance was dose-dependent and predominantly renal. At doses >/=2.4 mg/m(2)/day, plasma 2'-deoxyuridine levels were elevated consistently indicating inhibition of thymidylate synthase. Two patients had a partial response (breast, 1 patient; ovarian, 1 patient), and 10 patients had stable disease. CONCLUSION: The maximum tolerated dose was defined as 6 mg/m(2)/day, and the toxicity profile for this regimen was considered acceptable and manageable. Administration of ZD9331 lead to elevation of 2'-deoxyuridine levels, signifying thymidylate synthase inhibition, and evidence of antitumor activity was observed.
Stem cell factor induces eosinophil activation and degranulation: mediator release and gene array analysis.
Eosinophils are effector cells that play an important role in the damage induced by the allergic process by releasing inflammatory mediators and proteolytic factors after activation. Stem cell factor (SCF) is a primary cytokine involved in hematopoiesis and mast cell differentiation, proliferation, and activation. Studies have also indicated that SCF is directly involved in pathogenesis of allergic airway inflammation. In the present study, we examined the ability of SCF to activate murine eosinophils for increased mediator release and up-regulation of chemokines. Initial data demonstrated that eosinophils have significant levels of surface c-kit protein, SCF receptor. SCF-activated eosinophils degranulate and release eosinophil peroxidase and leukotriene C(4) in a dose-dependent manner. In addition, SCF was further shown to induce the release of CC chemokines, RANTES, macrophage-derived chemokine (MDC), macrophage inflammatory protein-1beta (MIP-1beta), and C10 from eosinophils. To identify the extent of SCF-induced activation of eosinophils, we also performed gene array analysis using an array containing 1153 genes related to inflammation, including cytokines and their receptors, growth factors, structural and cytoskeletal genes, signal transduction genes as well as several other classes related to immune/inflammatory responses. The gene analysis indicated that more than 150 genes were significantly up-regulated in eosinophils after SCF stimulation. The gene array results were verified using a quantitative real-time polymerase chain reaction analysis to identify the expression of several chemokine and chemokine receptor genes. Altogether, these studies indicate that SCF is a potent eosinophil degranulator and activator that may play a number of roles during an inflammatory/immune response.
Electrical coupling between mammalian cones.
BACKGROUND: Cone photoreceptors are noisy because of random fluctuations of photon absorption, signaling molecules, and ion channels. However, each cone's noise is independent of the others, whereas their signals are partially shared. Therefore, electrically coupling the synaptic terminals prior to forward transmission and subsequent nonlinear processing can appreciably reduce noise relative to the signal. This signal-processing strategy has been demonstrated in lower vertebrates with rather coarse vision, but its occurrence in mammals with fine acuity has been doubted (even though gap junctions are present) because coupling would blur the neural image. RESULTS: In ground squirrel retina, whose triangular cone lattice resembles the human fovea, paired electrical recordings from adjacent cones demonstrated electrical coupling with an average conductance of approximately 320 pS. Blur caused by this degree of coupling had a space constant of approximately 0.5 cone diameters. Psychophysical measurements employing laser interferometry to bypass the eye's optics suggest that human foveal cones experience a similar degree of neural blur and that it is invariant with light intensity. This neural blur is narrower than the eye's optical blur, and we calculate that it should improve the signal-to-noise ratio at the cone terminal by about 77%. CONCLUSIONS: We conclude that the gap junctions observed between mammalian cones, including those in the human fovea, represent genuine electrical coupling. Because the space constant of the resulting neural blur is less than that of the optical blur, the signal-to-noise ratio can be markedly improved before the nonlinear stages with little compromise to visual acuity.
Preoperative staging of rectal cancer using magnetic resonance imaging with external phase-arrayed coils.
HYPOTHESIS: Rectal cancer can be accurately staged preoperatively by magnetic resonance imaging (MRI) with external phase-arrayed coils. DESIGN: Comparison of MRIs with pathologic staging. SETTING: University hospital. PATIENTS: Twenty-eight consecutive patients with biopsy-proven rectal cancer who did not undergo irradiation. INTERVENTION: Patients underwent imaging using a 1.5-T MRI scanner with external phase-arrayed surface coils. Streaking of the perirectal fat and disruption of the bowel wall margin were interpreted as transmural invasion. Lymph nodes were defined as metastatic when they had a diameter of at least 0.5 cm. Tumors were staged according to the TNM staging system (American Joint Committee on Cancer guidelines) as confined to the bowel wall (T1-T2) and invading through the bowel wall (T3-T4). Patients underwent anterior resection (n = 15), abdominoperineal resection (n = 11), or local excision (n = 2). MAIN OUTCOME MEASURES: Calculation of sensitivity, specificity, and accuracy for invasion through the bowel wall and lymph node status. RESULTS: Sensitivity of MRI in detecting invasion through the bowel wall was 89% (16/18), specificity was 80% (8/10), and accuracy was 86% (24/28). Sensitivity for malignant lymphadenopathy was 67% (8/12), specificity was 71% (10/14), and accuracy 69% (18/26). CONCLUSION: Although more costly and not as accurate as endoscopic ultrasound, MRI with phase-arrayed coils had excellent sensitivity at detecting transmural penetration of rectal cancer.