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Biomedical subjects

Karen Brown

Publications and source records attributed to Karen Brown.

At least 19 recordsLinked to original sources
PubMed2024

Mosquitoes provide a transmission route between possums and humans for Buruli ulcer in southeastern Australia.

Buruli ulcer, a chronic subcutaneous infection caused by Mycobacterium ulcerans, is increasing in prevalence in southeastern Australia. Possums are a local wildlife reservoir for M. ulcerans and, although mosquitoes have been implicated in transmission, it remains unclear how humans acquire infection. We conducted extensive field survey analyses of M. ulcerans prevalence among mosquitoes in the Mornington Peninsula region of southeastern Australia. PCR screening of trapped mosquitoes revealed a significant association between M. ulcerans and Aedes notoscriptus. Spatial scanning statistics revealed overlap between clusters of M. ulcerans-positive Ae. notoscriptus, M. ulcerans-positive possum excreta and Buruli ulcer cases, and metabarcoding analyses showed individual mosquitoes had fed on humans and possums. Bacterial genomic analysis confirmed shared single-nucleotide-polymorphism profiles for M. ulcerans detected in mosquitoes, possum excreta and humans. These findings indicate Ae. notoscriptus probably transmit M. ulcerans in southeastern Australia and highlight mosquito control as a Buruli ulcer prevention measure.

Animals↗
PubMed2007

Demographic, medical, and psychosocial correlates to CAM use among survivors of colorectal cancer.

GOALS OF WORK: Complementary and alternative medicines (CAM) use among cancer patients is becoming more prevalent; however, our understanding of factors contributing to patients' decisions to participate in CAM is limited. This study examined correlates of CAM use among colorectal cancer (CRC) survivors, an understudied population that experiences many physical and psychological difficulties. MATERIALS AND METHODS: The sample was 191, predominantly white, CRC survivors (mean age = 59.9 +/- 12.6) who were members of a colon disease registry at a NYC metropolitan hospital. Participants completed assessments of sociodemographic characteristics, psychosocial factors [e.g., psychological functioning, cancer specific distress, social support (SS), quality of life (QOL)], and past CAM use (e.g., chiropractic care, acupuncture, relaxation, hypnosis, and homeopathy). MAIN RESULTS: Seventy-five percent of participants reported using at least one type of CAM; most frequently reported was home remedies (37%). Younger (p < 0.01) or female patients (p < 0.01) were more likely to participate in CAM than their older male counterparts. Among psychosocial factors, poorer perceived SS (p = 0.00), more intrusive thoughts (p < 0.05), and poorer overall perceived QOL (p < 0.05) were associated to CAM use. In a linear regression model (including age, gender, SS, intrusive thoughts, and perceived QOL), only age remained a significant predictor of CAM use. CONCLUSION: These findings demonstrate that CAM use is prevalent among CRC survivors and should be assessed routinely by providers. CAMs may serve as a relevant adjunct to treatment among CRC patients as well as an indication of need for additional SS, especially among younger patients.

Aged↗
PubMed2006

Development of a novel site-specific mutagenesis assay using MALDI-ToF MS (SSMA-MS).

We have developed and validated a novel site-specific mutagenesis assay, termed SSMA-MS, which incorporates MALDI-ToF mass spectrometry (MALDI-MS) analysis as a means of determining the mutations induced by a single DNA adduct. The assay involves ligating an adducted deoxyoligonucleotide into supF containing pSP189 plasmid. The plasmid is transfected into human Ad293 kidney cells allowing replication and therefore repair or a mutagenic event to occur. Escherichia coli indicator bacteria are transformed with recovered plasmid and plasmids containing the insert are identified colormetrically, as they behave as frameshift mutations. The plasmid is then amplified and digested using a restriction cocktail of Mbo11 and Mnl1 to yield 12 bp deoxyoligonucleotides, which are characterized by MALDI-MS. MALDI-MS takes advantage of the difference in molecular weight between bases to identify any induced mutations. This analysis method therefore provides qualitative and quantitative information regarding the type and frequency of mutations induced. This assay was developed and validated using an O(6)-methyl-2'-deoxyguanosine adduct, which induced the expected GC-->AT substitutions, when replicated in human or bacterial cells. This approach can be applied to the study of any DNA adduct in any biologically relevant gene sequence (e.g. p53) in human cells and would be particularly amenable to high-throughput analysis.

Cell Line↗
PubMed2006

Tolerance for uncertainty and perceived risk among women receiving uninformative BRCA1/2 test results.

Women who receive uninformative BRCA1/2 genetic test results face ongoing uncertainty about their future cancer risks. This article prospectively examined the influence of intolerance for uncertainty and perceived breast cancer risk on psychological distress following the receipt of uninformative BRCA1/2 test results. Sixty-four women who received uninformative BRCA1/2 mutation test results completed measures of Intolerance for Uncertainty, perceived breast cancer risk, and measures of cancer-related, genetic testing, and general distress. Cancer-related (DeltaR(2) = 0.18, P < or = 0.001), general (DeltaR(2) = 0.04, P < or = 0.05), and genetic testing distress (DeltaR(2) = 0.12, P < or = 0.01) were associated with intolerance for uncertainty at 1 month post-disclosure. The interaction of intolerance for uncertainty and breast cancer perceived risk predicted cancer-related (DeltaR(2) = 0.10, P < or = 0.001) and genetic testing distress (DeltaR(2) = 0.09, P < or = 0.01) at 6 months post-disclosure. Distress was highest among patients with highest perceived risk and intolerance for uncertainty, suggesting that those who have difficulty coping with their ambiguous risk are at risk for long-term distress. The clinical and research implications of these results are discussed.

Adult↗
PubMed2006

A phase II trial of isolated limb infusion with melphalan and dactinomycin for regional melanoma and soft tissue sarcoma of the extremity.

BACKGROUND: Isolated limb infusion (ILI) is a minimally invasive technique of delivering regional chemotherapy in patients with advanced melanoma or soft tissue sarcoma of the limb. Reports from Australia of efficacy similar to that of isolated limb perfusion prompted us to conduct a phase II trial to evaluate the efficacy and safety of ILI. METHODS: Eligible patients had American Joint Committee on Cancer stage IIIB or IIIC melanoma or unresectable soft tissue sarcoma of the limb. Angiographic catheters were positioned just above the knee or elbow of the extremity. General anesthesia was performed, a proximal tourniquet was inflated, and a normothermic, low-flow, hypoxic infusion of melphalan and dactinomycin was circulated through the involved limb for 20 minutes. The tumor response was assessed by using standard criteria at 3 months. Morbidity was determined in the hospital and at 2, 6, and 12 weeks. RESULTS: Twenty-five patients were accrued to the trial, and 32 ILIs were performed (8 patients had 2 ILIs); 1 patient was not treated. Of the 22 assessable patients, 11 (50%) had a significant response at 3 months: 23% of patients had a complete response, and 27% of patients had a partial response. The median duration of complete response was 1 year (range, 6-32 months). Morbidity was acceptable. Peak morbidity occurred at 2 weeks and was considered moderate in most patients. Limb edema and erythema were common. No patient developed compartment syndrome or required amputation. CONCLUSIONS: ILI is well tolerated. Half of the patients experienced a complete or partial response.

Adult↗
PubMed2006

A novel 14C-postlabeling assay using accelerator mass spectrometry for the detection of O6-methyldeoxy-guanosine adducts.

Accelerator mass spectrometry (AMS) is currently one of the most sensitive methods available for the trace detection of DNA adducts and is particularly valuable for measuring adducts in humans or animal models. However, the standard approach requires administration of a radiolabeled compound. As an alternative, we have developed a preliminary 14C-postlabeling assay for detection of the highly mutagenic O6-methyldeoxyguanosine (O6-MedG), by AMS. Procedures were developed for derivatising O6-MedG using unlabeled acetic anhydride. Using conventional liquid chromatography/mass spectrometry (LC/MS) analysis, the limit of detection (LOD) for the major product, triacetylated O6-MedG, was 10 fmol. On reaction of O6-MedG with 14C-acetic anhydride, using a specially designed enclosed system, the predominant product was 14C-di-acetyl O6-MedG. This change in reaction profile was due to a modification of the reaction procedure, introduced as a necessary safety precaution. The LOD for 14C-di-acetyl O6-MedG by AMS was determined as 79 amol, approximately 18,000-fold lower than that achievable by liquid scintillation counting (LSC). Although the assay has so far only been carried out with labeled standards, the degree of sensitivity obtained illustrates the potential of this assay for measuring O6-MedG levels in humans.

Acetic Anhydrides↗
PubMed2006

Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver.

Current regimens of systemic chemotherapy result in only modest lengthening of survival in patients with advanced stage, liver-dominant, metastatic colorectal cancer who have failed first-line chemotherapy. The objective of this study was to investigate the safety and tolerability of NV1020, a replication-competent, attenuated, genetically engineered herpes simplex virus type 1 (HSV-1), in patients with hepatic colorectal metastases refractory to first-line chemotherapy. A phase I, open-label, dose-escalating study of a single 10-min hepatic arterial infusion of NV1020 in four cohorts. Three patients in each cohort received doses of 3 x 10(6), 1 x 10(7), 3 x 10(7), and 1 x 10(8) plaque-forming units. Adverse events were either mild or moderate in severity, and self-limiting. Only three serious adverse events (one transient rise in serum y-glutamyltransferase, one diarrhea, and one leukocytosis) experienced by three patients were considered to be possibly or probably related to NV1020. There were no deaths during the study, and there was no evidence of disseminated herpes infection. Viral presence was detected in only one saliva sample and two serum samples from one asymptomatic patient in the highest dose cohort. In the first week after viral administration only rare and minor increases were noted for tumor necrosis factor-alpha (six samples; three patients; peak, 40 pg/ml), interleukin (IL)-1 (two samples; two patients; peak, 28 pg/ml), and interferon-y (four samples; two subjects; peak, 54 pg/ml). No IL-2 was detected. Mild liver enzyme elevations were self-limiting and not associated with clinical symptoms. We conclude that NV1020, a genetically engineered but replication-competent HSV-1 oncolytic virus, can be safely administered into the hepatic artery without significant effects on normal liver function.

Adult↗
PubMed2006

Use of standardized patients in, undergraduate medical genetics education.

BACKGROUND AND PURPOSE: To study the effectiveness of a standardized patient (SP) program in increasing the competence of medical students in assessing genetic risks and communicating genetic information to patients. METHODS: Third-year medical students at the Mount Sinai School of Medicine had two encounters from 2001 to 2003 with the same SP, who portrayed a woman at risk for hereditary breast cancer. Assessment instruments included student self-assessment of skills, SP assessment of student communication skills, an observer checklist, grading of the student-drawn pedigree, and a knowledge test. Students also completed an evaluation form after the debriefing session at the end of each of the SP sessions. RESULTS: The SP program was completed by 136 students. The student self-evaluation of skills instrument revealed that students who completed the SP program felt more competent in their ability to draw a pedigree, assess genetic risks based on family history and pedigree information, and communicate genetic risks compared to students at the same level of training who did not participate in the SP program. Of participating students, 90% agreed that the program allowed them to identify areas for improvement in their skills, and 95% agreed that the exercise increased their confidence for having a similar patient interaction in the future. CONCLUSIONS: The use of SPs in undergraduate medical genetics education may be one means for increasing the confidence of medical students in skills that are related to genetic encounters.

Clinical Competence↗
PubMed2005

Mutation spectra induced by alpha-acetoxytamoxifen-DNA adducts in human DNA repair proficient and deficient (xeroderma pigmentosum complementation group A) cells.

Tamoxifen, a breast cancer drug, has recently been approved for the chemoprevention of this disease. However, tamoxifen causes hepatic carcinomas in rats through a genotoxic mechanism and increases the risk of endometrial tumors in women. DNA adducts have been detected at low levels in human endometrium, and there is much interest in determining whether DNA damage plays a role in tamoxifen-induced endometrial carcinogenesis. This study investigates the mutagenicity of tamoxifen DNA adducts formed by alpha-acetoxytamoxifen, a reactive ester producing the major DNA adduct formed in livers of tamoxifen-treated rats. pSP189 plasmid DNA containing the supF gene was treated with alpha-acetoxytamoxifen and adduct levels (0.5-8.0 adducts per plasmid) determined by (32)P-postlabeling. Adducted plasmids were transfected into nucleotide excision repair proficient (GM00637) or deficient (GM04429, XPA) human fibroblasts. After replication, plasmids were recovered and screened in indicator bacteria. Relative mutation frequencies increased with the adduct level, with 1.3-3.6-fold higher numbers of mutations in the XP cells compared to the GM00637 cells, indicating that NER plays a significant role in the removal of these particular tamoxifen DNA adducts. The majority of sequence alterations (91-96%) occurred at GC base pairs, as did mutation hotspots, although the type and position of mutations was cell-specific. In both cell lines, as the adduct level increased, the proportion of GC --> AT transitions decreased and GC --> TA transversions, mutations known to arise from the major tamoxifen adducts, increased. Given the high mutagenicity of dG-N(2)-tamoxifen adducts, if not excised, they may potentially contribute to the initiation of endometrial cancer in women.

Base Sequence↗
PubMed2005

Hepatic DNA adduct dosimetry in rats fed tamoxifen: a comparison of methods.

Liver homogenates from rats fed tamoxifen (TAM) in the diet were shared among four different laboratories. TAM-DNA adducts were assayed by high pressure liquid chromatography-electrospray tandem mass spectrometry (HPLC-ES-MS/MS), TAM-DNA chemiluminescence immunoassay (TAM-DNA CIA), and (32)P-postlabeling with either thin layer ((32)P-P-TLC) or liquid chromatography ((32)P-P-HPLC) separation. In the first study, rats were fed a diet containing 500 p.p.m. TAM for 2 months, and the values for measurements of the (E)-alpha-(deoxyguanosin-N(2)-yl)-tamoxifen (dG-N(2)-TAM) adduct in replicate rat livers varied by 3.5-fold when quantified using 'in house' TAM-DNA standards, or other approaches where appropriate. In the second study, rats were fed 0, 50, 250 or 500 p.p.m. TAM for 2 months, and TAM-DNA values were quantified using both 'in house' approaches as well as a newly synthesized [N-methyl-(3)H]TAM-DNA standard that was shared among all the participating groups. In the second study, the total TAM-DNA adduct values varied by 2-fold, while values for the dG-N(2)-TAM varied by 2.5-fold. Ratios of dG-N(2)-TAM:(E)-alpha-(deoxyguanosin-N(2)-yl)-N-desmethyltamoxifen (dG-N(2)-N-desmethyl-TAM) in the second study were approximately 1:1 over the range of doses examined. The study demonstrated a remarkably good agreement for TAM-DNA adduct measurements among the diverse methods employed.

Animals↗
PubMed2005

Long-term use of oral beclomethasone dipropionate for the treatment of gastrointestinal graft-versus-host disease.

Treatment of severe acute and chronic gastrointestinal (GI) graft-versus-host disease (GVHD) with prolonged high-dose systemic corticosteroids has limited success and considerable toxicity. Beclomethasone dipropionate (BDP) is a potent topically active steroid. We treated 15 patients with acute (n = 2) or chronic (n = 13) GI GVHD refractory to systemic corticosteroids with 28-day courses of oral BDP (2 mg 4 times daily). Response was measured by the change in GI score (sum of 6 GI symptoms) as well as the ability to taper or discontinue systemic corticosteroids. Nine (60%) of 15 evaluable patients responded to BDP, including 3 complete responses (a GI score of 0 or 1 and discontinuation of systemic corticosteroids). Attempts to taper calcineurin inhibitor during BDP therapy were unsuccessful. The 2 patients with acute GVHD had no response to BDP. Responders received a median of 3 cycles (range, 1-20), compared with 1 cycle (range, 1-5) in nonresponders. Suppression of the hypothalamic-adrenal axis was seen in 2 of the 5 patients tested, but neither demonstrated clinically significant symptoms. We conclude that BDP is safe and effective for long-term treatment of chronic GI GVHD. Multiple courses may be necessary to achieve or maintain response in some patients, and prolonged BDP therapy is a feasible alternative to prolonged systemic corticosteroids.

Administration, Oral↗
PubMed2005

Development and validation of a Breast Cancer Genetic Counseling Knowledge Questionnaire.

Women who undergo genetic counseling concerning their increased risk of developing breast cancer confront large quantities of complex information in a short period of time. Clinical reports have suggested that many women may not retain what they learned during counseling. A validated questionnaire to measure their knowledge, however, is lacking. In this study, we describe the development and validation of a questionnaire to assess knowledge of information typically included in genetic counseling for breast cancer. Items were empirically derived from detailed content analyses of actual genetic counseling sessions. The instrument's content validity was high, as evidenced by high levels of independent interrater agreement (0.93) on items. Subsequent data reduction and confirmatory factor analytic techniques yielded a highly reliable (alpha = 0.92) 27-item Breast Cancer Genetic Counseling Knowledge Questionnaire (BGKQ). Direct comparison of this questionnaire to a scale previously developed in the literature (BCHK; [Breast Cancer Res. Treat. 53 (1999) 69]) supported the utility of the new questionnaire for evaluation of knowledge after counseling. Compared to non-counseled groups (n = 45), women who had undergone genetic counseling (n = 28) scored significantly higher (P < 0.0001) on the BGKQ, but not on the other questionnaire, establishing the BGKQ's criterion validity. The BGKQ may, thus, provide a useful clinical and research tool for assessing knowledge of information provided during genetic counseling and exploring the potential impact of distress on knowledge, as well as the impact of knowledge on screening behaviors.

Adult↗
PubMed2005

Randomized comparison of vaginal and rectal measurement of intra-abdominal pressure during subtracted dual-channel cystometry.

OBJECTIVES: To compare the rectal (Prec) and vaginal (Pvag) measurement of intra-abdominal pressure during cystometry in women by assessment of patient acceptability and cystometrogram quality control. METHODS: Of 136 consecutive women undergoing cystometrography, 100 were randomized to measurement of Prec or Pvag. The patients' experience was measured using visual analogue scales of anticipated and actual discomfort and embarrassment before and after the procedure. The setup time was recorded, and quality control was assessed by the number of catheter events (pressure lines falling out, requiring flushing, or repositioning), and quality of the cough signal. RESULTS: A total of 136 consecutive patients were approached. Of those eligible, 50 were randomized to Prec and 50 to Pvag; 23 women declined randomization because of preference for a vaginal line. Overall, 81 line events occurred in 29 women with a vaginal line and 117 occurred in 34 women with a rectal line. No difference was found in patient acceptability nor in trace quality for the two routes. Despite catheter repositioning and flushing, only 13% of traces showed optimum trace quality throughout the entire investigation; the cough signal quality was worse after provocation, during voiding, and in women with prolapse. CONCLUSIONS: A significant proportion of patients undergoing cystometry expressed a preference for the vaginal line. The quality of output from cystometry was limited by the conditions of the investigation rather than the method of intra-abdominal pressure measurement.

Abdomen↗
PubMed2005

Accelerator mass spectrometry for biomedical research.

Accelerator mass spectrometry (AMS) is the most sensitive method for detecting and quantifying rare long-lived isotopes with high precision. In this chapter, we review the principles underlying AMS-based biomedical studies, focusing on important practical considerations and experimental procedures needed for the detection and quantitation of (14)C- and (3)H-labeled compounds in various experiment types.

Animals↗
PubMed2005

Tropical Medicine and Animal Diseases: Onderstepoort and the Development of Veterinary Science in South Africa 1908-1950.

This article traces the development of agricultural science at the Onderstepoort Veterinary Institute, near Pretoria, from its founding in 1908 until the 1950s, by which time many enzootic and epizootic diseases had either been eradicated, or were largely controllable through various forms of prophylaxis. The Institute demonstrated the political and economic significance attributed to the pastoral industry in South Africa and the conviction that scientific discoveries could increase output. During this period, researchers explicated the aetiology and provenance of hitherto mysterious diseases such as lamsiekte, geeldikkop and African horsesickness. They developed vaccines, some of which were adopted internationally. The nature of their investigations showed that veterinary science increasingly entailed more than just progress in biomedical procedures. Ecological factors, in particular the nutritional state of the veld, became a priority from the 1920s onwards as veterinarians saw their function as promoting animal health as well as eliminating disease. Dealing with contagious infections also incorporated less welcome, and at times controversial, approaches to disease control. The imposition of pastoral regulations illustrated the expanding powers of the South African state, founded on presumptions of scientific legitimacy. The article also explores the contribution made by African communities and settler farmers to the institutionalisation of veterinary knowledge, as well as the role South African researchers played in the evolution of a colonial, as well as an increasingly international, scientific culture.

Journal Article↗
PubMed2005

Arterial thrombosis in four patients treated with thalidomide.

Thalidomide has been associated with venous thrombotic events, as reported in the post-marketing surveillance reports by Celgene Corporation; as well as case reports in the literature. Seven arterial thrombotic events have been reported in patients receiving thalidomide with 3 cases occurring in patients with other predisposing conditions. We report 4 additional cases of arterial thromboses in 1 lymphoma and 3 myeloma patients treated with thalidomide. The mechanism for these events is unclear; however, it is significant that 2 patients were receiving concomitant anticoagulation with aspirin and warfarin.

Aged↗
PubMed2004

Techniques: the application of accelerator mass spectrometry to pharmacology and toxicology.

The exquisite sensitivity of accelerator mass spectrometry (AMS) is being used in biomedical applications to quantitate many isotopes, including 14C, 3H, 41Ca and 27Al, at attomole (10(-18)) concentrations. This enables compounds and metabolites to be measured in human urine and plasma after administration of low pharmacologically or toxicologically relevant doses of labelled chemicals and drugs. The detection of modified proteins or DNA in target organs after dosing with potential carcinogens has also been achieved in many studies. Advances aimed at increasing sample throughput and expanding applications by coupling AMS instruments directly to chromatographic separation systems are currently underway.

Animals↗