Brown University School of Medicine.
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Curriculum↗
Biomedical subjects
S R Smith
Publications and source records attributed to S R Smith.
A clinicopathological study of sinonasal neuroendocrine carcinoma and sinonasal undifferentiated carcinoma.
OBJECTIVE: Sinonasal undifferentiated carcinoma (SNUC) and sinonasal neuroendocrine carcinoma (SNEC) are relatively newly recognized, rare entities requiring further clinicopathological analysis to advance our understanding and determine prognostic distinctions between them. STUDY DESIGN: Retrospective chart review. METHODS: Cases were retrieved from the Copath system. One patient was seen in consultation from an outside institution. Histological and immunohistochemical findings, patient demographics, treatment regimens, and outcomes were analyzed and compared. RESULTS: Ten patients (7 men, 3 women) ranging in age from 17 to 58 years (mean age, 44.7 y) were included. Four patients were classified with SNEC, six as having SNUC. The predominant site was the superior nasal cavity or ethmoids (seven cases), followed by the maxilla (four cases). Disease in four patients was clinically staged as N1 (three with SNUC, one with SNEC), and in six patients as NO (three with SNEC, three with SNUC). Of the nine patients who were treated initially with surgical resection, seven received postoperative radiation therapy alone, one received postoperative radiation and chemotherapy, and one had only limited postoperative chemotherapy. One patient was treated with radiation therapy and chemotherapy alone, without surgical resection. Follow-up was obtained ranging from 6 to 108 months (mean period, 26.4 mo). Three patients died of disease 10, 14, and 41 months, respectively, after diagnosis. Three patients had persistent disease at 6, 9, and 21 months, respectively, two of them with distant metastases. Four patients were disease free after 6, 18, 31, and 108 months, respectively. CONCLUSIONS: SNUC and SNEC are both aggressive tumors, usually presenting in middle age as a nasal mass. Both tumors have the capacity to metastasize locally and distantly, and both can result in poor outcomes. This small series precludes a demographic or prognostic distinction between the two groups.
Adolescent↗
Access and use of specific dental services in HIV disease.
OBJECTIVES: This study examined factors associated with the use of specific dental services by persons with HIV disease. METHODS: The data were derived from 1,588 adults who participated in a series of up to six interviews as part of the AIDS Cost and Service Utilization Surveys. Use of dental services such as examinations, x-rays, cleaning, fillings, extractions, root canals, crown and bridge or dentures, and periodontal procedures were evaluated using logistic regression and generalized estimating equations were applied. RESULTS: Multivariate analyses showed that medical insurance, an education beyond high school, income higher than $1,300 per month, high ambulatory visits, and receipt of psychological counseling were generally associated with higher service use. Blacks, those with an inpatient admission, and CD4+ cell counts less than 500 cells/microL were significantly less likely to use most types of dental services. CONCLUSIONS: The study concludes that disparities exist in the use of several dental services similar to those seen in the general population.
Acquired Immunodeficiency Syndrome↗
Reliability and validity of DSM-IV axis V.
OBJECTIVE: The authors investigated the reliability and convergent and discriminant validity of the DSM-IV Global Assessment of Functioning Scale and two experimental DSM-IV axis V global rating scales, the Global Assessment of Relational Functioning Scale and the Social and Occupational Functioning Assessment Scale. METHOD: Forty-four patients admitted to a university-based outpatient community clinic were rated by trained clinicians on the three DSM-IV axis V scales. Patients also completed self-report measures of DSM-IV symptoms as well as measures of relational, social, and occupational functioning. RESULTS: The Global Assessment of Functioning Scale, Global Assessment of Relational Functioning Scale, and Social and Occupational Functioning Assessment Scale all exhibited very high levels of interrater reliability. Factor analysis revealed that the Global Assessment of Relational Functioning Scale and the Social and Occupational Functioning Assessment Scale are each more related to the Global Assessment of Functioning Scale individually than they are to each other. The Global Assessment of Functioning Scale was significantly related to concurrent patient responses on the SCL-90-R global severity index. The Social and Occupational Functioning Assessment Scale was significantly related to concurrent patient responses on the SCL-90-R global severity index and to a greater degree with both the Social Adjustment Scale global score and the Inventory of Interpersonal Problems total score. Although the Global Assessment of Relational Functioning Scale was not significantly related to any of the three self-report measures, it was related to the presence of clinician-rated axis II pathology. CONCLUSIONS: The three axis V scales can be scored reliably. The Global Assessment of Relational Functioning Scale and the Social and Occupational Functioning Assessment Scale evaluate different constructs. These findings support the validity of the Global Assessment of Functioning Scale as a scale of global psychopathology; the Social and Occupational Functioning Assessment Scale as a measure of problems in social, occupational, and interpersonal functioning; and the Global Assessment of Relational Functioning Scale as an index of personality pathology. The authors discuss further refinement and use of the three axis V measures in treatment research.
Adult↗
Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin-10 in endotoxemic mice.
Previous studies have shown that mice primed with Corynebacterium parvum produce higher levels of inflammatory cytokines than unprimed mice upon challenge with lipopolysaccharide (LPS). Herein, we describe experiments in which two cannabinoid (CB) agonists, WIN 55212-2 [(R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]1, 4-benzoxazin-6-yl](1-naphthyl)methanone) and HU-210 [(-)-11-hydroxy-delta(8) tetrahydrocannabinol-dimethylheptyl], were examined for their effects on LPS-induced cytokines in C. parvum-primed and unprimed mice. These agonists have been reported to bind selectively to the CB2 and CB1 receptor subtypes, respectively. WIN 55212-2 (3.1-50 mg/kg i.p.) and HU-210 (0.05-0.4 mg/kg i.p.) decreased serum tumor necrosis factor-alpha and interleukin-12 (IL-12) and increased IL-10 when administered to mice before LPS. The drugs also protected C. parvum mice (but not unprimed mice) against the lethal effects of LPS. The protection afforded to C. parvum mice could not be attributed to the higher levels of IL-10 present in these mice after agonist treatment. The WIN 55212-2- and HU-210-mediated changes in the responsiveness of mice to LPS were antagonized by SR141716A [N-(piperdin-1-yl)-5-(4-chloropheny)-1-(2, 4-dichloropheny)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride], a selective CB1 receptor antagonist, but not by SR144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2. 1]heptan-2-yl]5-(4-choro-3-methylphenyl)-1-(4-methylbenzyl)p yrazole-3 -carboxamide], a selective antagonist at the CB2 receptor. Therefore, both CB agonists modulated LPS responses through the CB1 receptor. Surprisingly, SR141716A itself modulated cytokine responses in a manner identical with that of WIN 55212-2 and HU-210 when administered alone to mice. The agonist-like effects of SR141716A, which were more striking in unprimed than in primed mice, suggested that the antagonist also could function as a partial agonist at the CB1 receptor. Our findings indicate a role for the CB1 receptor subtype in cytokine modulation by CB ligands.
Animals↗
Brown University School of Medicine: class of 2000.
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Adult↗
The pathophysiology of poor teaching.
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Clinical Competence↗
Economic effects on medical education.
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Capital Financing↗
Diagnosis and management of BK polyomavirus interstitial nephritis in renal transplant recipients.
BACKGROUND: Interstitial nephritis caused by BK polyomavirus is a recognized complication of renal transplantation. A study of renal transplant recipients at Duke University Medical Center was undertaken to evaluate diagnostic modalities and assess clinical outcomes in transplant polyomavirus infections. METHODS: Polyomavirus nephritis was identified in 6 of 240 patients who received renal transplants between January 1996 and June 1998 and an additional patient who underwent transplantation in 1995. The clinical records of these seven patients were reviewed, as were all renal biopsy and nephrectomy specimens. Electron microscopy (EM) was performed on negatively stained urine samples from 6 patients with polyomavirus infection and 23 patients with other diagnoses. RESULTS: Patients with polyomavirus infection shared several clinical features, including ureteral obstruction (5/7 patients), lymphocele (3/7), bacterial urinary tract infection (3/7), hematuria (3/7), cytomegalovirus infection (3/7), and immunosuppression with mycophenolate mofetil (6/7). All patients experienced elevations in serum creatinine, which stabilized or decreased in four patients with altered or decreased immunosuppression. The diagnosis of polyomavirus infection was established by renal biopsy and EM of urine in five patients, by biopsy alone in one, and by EM alone in one. Sequential examinations of urine by EM were used to monitor the course of infection in six patients. CONCLUSIONS: Interstitial nephritis due to BK polyomavirus occurred in 2.5% of patients receiving renal transplants at our center since 1996. Polyomavirus infection can cause transplant dysfunction and graft loss, but progression of the infection can frequently be abrogated with alterations in immunosuppressive therapy. Both renal biopsy and EM of urine samples are useful in the diagnosis and monitoring of polyomavirus infections.
Adult↗
Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact.
Embryological data suggest that endothelial cells (ECs) direct the recruitment and differentiation of mural cell precursors. We have developed in vitro coculture systems to model some of these events and have shown that ECs direct the migration of undifferentiated mesenchymal cells (10T1/2 cells) and induce their differentiation toward a smooth muscle cell/pericyte lineage. The present study was undertaken to investigate cell proliferation in these cocultures. ECs and 10T1/2 cells were cocultured in an underagarose assay in the absence of contact. There was a 2-fold increase in bromodeoxyuridine labeling of 10T1/2 cells in response to ECs, which was completely inhibited by the inclusion of neutralizing antiserum against platelet-derived growth factor (PDGF)-B. Antisera against PDGF-A, basic fibroblast growth factor, or transforming growth factor (TGF)-beta had no effect on EC-stimulated 10T1/2 cell proliferation. EC proliferation was not influenced by coculture with 10T1/2 cells in the absence of contact. The cells were then cocultured so that contact was permitted. Double labeling and fluorescence-activated cell sorter analysis revealed that ECs and 10T1/2 cells were growth-inhibited by 43% and 47%, respectively. Conditioned media from contacting EC-10T1/2 cell cocultures inhibited the growth of both cell types by 61% and 48%, respectively. Although we have previously shown a role for TGF-beta in coculture-induced mural cell differentiation, growth inhibition resulting from contacting cocultures or conditioned media was not suppressed by the presence of neutralizing antiserum against TGF-beta. Furthermore, the decreased proliferation of 10T1/2 cells in the direct cocultures could not be attributed to downregulation of the PDGF-B in ECs or the PDGF receptor-beta in the 10T1/2 cells. Our data suggest that modulation of proliferation occurs during EC recruitment of mesenchymal cells and that heterotypic cell-cell contact and soluble factors play a role in growth control during vessel assembly.
Animals↗
Pharmaceutical cost savings of treating obesity with weight loss medications.
OBJECTIVE: To evaluate, in compliant patients, the pharmaceutical costs of treating obesity with fenfluramine/mazindol, fenfluramine/phentermine, caffeine/ephedrine, or mazindol relative to the pharmaceutical costs of treating obesity-related comorbid conditions and reducing cardiovascular risk. METHODS AND PROCEDURES: Subjects were between 18 and 60 years of age with a BMI of >30 kg/m2. Pharmaceutical costs were evaluated in 73 of 220 subjects taking medications for diabetes, hyperlipidemia, or hypertension before and after treatment using fenfluramine with mazindol or phentermine. The pharmaceutical cost of weight loss, cardiac risk reduction, and low-density lipoprotein (LDL) cholesterol reduction was calculated for fenfluramine with mazindol or phentermine, caffeine with ephedrine, or mazindol alone, and compared to approved lipid-lowering medications. RESULTS: Losses of 6% to 10% of initial body weight reduced pharmacy costs $122.64/month for insulin treated diabetes, $42.92/month for sulfonylurea-treated diabetes, $61.07/month for hyperlipidemia treated with medication, and $0.20/month for hypertension treated with medication. Blood pressure and laboratory evidence of insulin resistance improved in all medication groups. Caffeine/ephedrine was most cost-effective of the three treatments in reducing weight, cardiac risk, and LDL cholesterol. DISCUSSION: Obesity medications produced a substantial weight loss in compliant patients and resulted in a net pharmaceutical cost savings compared to treating obesity related comorbid conditions.
Adolescent↗
The inhibition of glycogen synthesis by fatty acids is not mediated by inhibition of extracellular signal-regulated kinase 1/2.
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Animals↗
Optical testing of condoms.
Condoms provide one of the most important means of preventing pregnancy and the spread of human immunodeficiency virus (HIV) and other sexually transmitted diseases. Pinhole defects may lead to the passage of sperm or viruses through the condom wall. Embedded particles, which may become dislodged in handling or use, may represent latent pinhole defects. Thin regions in the condom wall may lead to breakage in use. Testing for such defects in regulatory laboratories, or in the factories as part of production screening or quality assurance efforts, is a major tool for ensuring condom reliability. A new optical method for testing condoms is presented, sensitive to pinholes, thin regions, and embedded particles. The method could supplement or replace the existing, less powerful, electrical test techniques in either regulatory testing laboratories or in the factory. The optical techniques presented provide quantitative data on the condoms tested, rather than just accept/reject decisions. They thus support detailed monitoring of production or lot characteristics that is generally not possible with existing electrical techniques. The ability of the optical techniques to separately test for and identify not only pinholes, but also thin regions and embedded particles, which are not separately tested for with the electrical technologies, is an especially important new capability. Further, the new optical techniques allow the locations of defects found to be precisely marked, making possible a microscopic examination of defects useful in studying their structure and possible causes. The optical technique is also totally nondestructive, in that it does not alter the defects whose structures are of interest. Initial results are reported on the testing of latex condoms purchased in retail stores. Condoms identified optically as being potentially defective were subjected to industry standard leak and burst testing. Results of the various tests are summarized. The data suggest that use of the new optical test techniques could have prevented an unexpectedly large number of condoms with significant pinhole and thin region defects from reaching the public. Optical test systems could be used to support either regulatory, quality assurance, or clinical field testing of latex or nonlatex condoms. Due to their high rate capability and level of automation, they could also be applied to 100% screening testing in the factory. The new test techniques could also be used to detect defects in a wide range of other thin sheets and membranes.
Condoms↗
Acute asthma in the pediatric emergency department.
The management of children with acute asthma remains a difficult and challenging process. Although newer asthma medications are being developed, they are unlikely to have a large impact on the management of children with acute asthma. The leukotriene inhibitors are new anti-inflammatory agents for asthma and are beneficial for the treatment of patients with chronic asthma but have no therapeutic effect during the acute phase of an exacerbation. Older treatments, including the use of magnesium and heliox, have been revisited. Although some children with severe asthma may respond, these do not provide relief for most children with acute exacerbation. The new challenge for asthma care is finding ways to link children with their primary care providers so that regular asthma care can be established. The NHLBI recommends that children with asthma have regular visits with their primary care providers (e.g., four times a year). Regular care results in better adherence to medical and preventive management plans and improves the relationship between patients and physicians. Instituting an asthma action plan, which instructs families on when and how to begin therapy for an acute exacerbation, may prevent progression to a more severe condition.
Acute Disease↗
Endogenous mouse interleukin-10 is up-regulated by exogenously administered recombinant human interleukin-10, but does not contribute to the efficacy of the human protein in mouse models of endotoxemia.
In murine models of experimental endotoxemia, inflammatory cytokines as well as antiinflammatory interleukin-10 (IL-10) appear in the circulation after the injection of lipopolysaccharide (LPS). There is considerable experimental evidence to suggest that the major function of endogenously produced IL-10 is to down-regulate inflammatory cytokine production. Indeed, the protective effects of exogenously administered IL-10 against murine endotoxin lethality have been shown to correlate with its ability to inhibit the LPS-induced production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). While mouse IL-10 (mIL-10) has been used in the majority of studies in murine endotoxemia, we have found the human homolog to be equally effective in suppressing inflammatory cytokine production and in protecting mice from endotoxin lethality. However, we have recently observed that the LPS-induced endogenous IL-10 response is enhanced when mice are treated with recombinant human IL-10 (rhuIL-10). The upregulation of endogenous IL-10 by exogenously administered rhuIL-10 is particularly evident in mice that are primed with Corynebacterium partum (Proprionibacterium acnes). In the present study, we have examined the potential contributions of the increased circulating levels of mouse IL-10 to the inhibitory effects seen with rhuIL-10 on inflammatory cytokine production and endotoxin lethality. We show that pretreatment with a neutralizing anti-mouse IL-10 monoclonal antibody (mAb) has no effect on the ability of rhuIL-10 to suppress an LPS-induced inflammatory cytokine response in these mice. In contrast, the suppressive effects of the human protein on inflammatory cytokine responses are blocked completely by pretreating the animals with an anti-huIL-10 mAb. These data show that despite the up-regulated endogenous IL-10 response, it is the exogenously administered rhuIL-10 that is directly responsible for the suppressed inflammatory cytokine responses that are observed when the human protein is given to endotoxemic mice.
Animals↗
Depth of vaporization and the effect of pulse stacking with a high-energy, pulsed carbon dioxide laser.
BACKGROUND: Laser resurfacing of photodamaged skin has become popular, but questions regarding its safety with regard to the risks of scarring have arisen. OBJECTIVE: This study was designed to investigate the depth of vaporization and residual thermal necrosis of single-pulse vaporization and multiple passes versus pulse-stacking and multiple passes. The potential significance of operator technique and laser parameters is considered. METHODS: Skin samples from surgical excisions were treated by means of a Coherent Ultrapulse carbon dioxide laser at 250 mJ per pulse and 500 mJ per pulse with a 3 mm collimated beam and a repetition rate of 10 Hz. A total of 70 treatment areas were performed. Blinded analysis of the histologic effects of single-pulse, double-pulse, and triple-pulse vaporization after 1 through 10 passes was undertaken. RESULTS: A plateau of vaporization was observed after 3 passes at both 250 and 500 mJ whether single-, double-, or triple-pulse vaporization was used. This plateau occurs at approximately 100 to 250 microm from the skin surface. Thermal necrosis is well controlled only with single-pulse vaporization. There is a direct linear increase in the depth of thermal necrosis both with the number of pulses stacked and the number of passes. CONCLUSION: Pulsed carbon dioxide laser resurfacing is a safe and self-limited procedure if a pulse width of less than 1 msec is used with single-pulse vaporization and fluences of 3.5 J/cm2 and 7.0 J/cm2. There appears to be little justification for performing more than 3 or 4 passes. Pulse stacking may significantly increase residual thermal necrosis, thereby increasing the risk of scarring. Operator technique may be significant in avoidance of this occurrence.
Cicatrix↗
Factors associated with utilization of care for oral lesions in HIV disease.
OBJECTIVES: The purpose of this study was to examine factors associated with utilization of care for oral lesions in people with HIV disease. STUDY DESIGN: The data were derived from 1424 adults who participated in a series of up to 4 interviews as part of the AIDS Cost and Service Utilization Survey. Treatment for thrush, oral sores, and other conditions was evaluated through use of logistic regression, with generalized estimating equations being applied. RESULTS: In all, 9.1% of those in the study sample reported being treated. After adjusting for CD4 cell count and other variables, regression analyses indicated that blacks (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.32-0.91) and Hispanics (OR, 0.59; 95% CI, 0.36-0.98) had significantly lower odds of reporting being treated. Respondents with more than a high school education (OR, 1.64; 95% CI, 1.08-2.51), clinical trial participants (OR, 1.92; 95% CI, 1.27-2.90), and those receiving counseling (OR, 2.22; 95% CI, 1.60-3.09) were more likely to report being treated. CONCLUSIONS: Utilization of care for oral lesions is very low. Educational and racial differences exist among those respondents who received care for HIV-associated oral lesions.
Adolescent↗
Visceral adipose tissue: a critical review of intervention strategies.
OBJECTIVE: To review the published literature regarding the effect of caloric restriction, pharmacologic intervention, and exercise to promote the loss of visceral adipose tissue (VAT) DESIGN: A review was conducted of published studies which measured VAT using computed tomography or magnetic resonance imaging before and after caloric restriction, pharmacologic therapy, or exercise. STUDIES REVIEWED: 23 separate studies were reviewed. Men represented 38% and women 63% of the 599 volunteers. There were 17 black volunteers and 30 patients with NIDDM included in these studies. MEASUREMENTS: Data regarding the baseline and change in VAT, body fat, and body weight were collected. RESULTS: Most interventions demonstrated a preferential loss of VAT regardless of the intervention applied. When expressed as percent change in VAT/percent change in body fat, a ratio can be calculated which we call the Selectivity Index (SI). When this index is applied to the literature reviewed, two observations can be made. First, the Selectivity Index is higher when baseline body fat is higher. Second, there is a direct relationship between the Selectivity Index and the baseline visceral fat ratio. These two observations suggest that individuals with greater visceral fat mass, either through an increase in the body weight or the propensity to store fat in the visceral depot, lose more visceral fat when adjusted to the loss of body fat. CONCLUSION: In conclusion, the Selectivity Index is useful to compare the ability of an intervention to specifically target the loss of AT. This simple index can serve as a benchmark for comparing intervention studies to each other.
Adipose Tissue↗