Mechanical cardiac support 2000: current applications and future trial design. June 15-16, 2000 Bethesda, Maryland.
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Equipment Design↗
Biomedical subjects
S Hunt
Publications and source records attributed to S Hunt.
A SNP resource for human chromosome 22: extracting dense clusters of SNPs from the genomic sequence.
The recent publication of the complete sequence of human chromosome 22 provides a platform from which to investigate genomic sequence variation. We report the identification and characterization of 12,267 potential variants (SNPs and other small insertions/deletions) of human chromosome 22, discovered in the overlaps of 460 clones used for the chromosome sequencing. We found, on average, 1 potential variant every 1.07 kb and approximately 18% of the potential variants involve insertions/deletions. The SNPs have been positioned both relative to each other, and to genes, predicted genes, repeat sequences, other genetic markers, and the 2730 SNPs previously identified on the chromosome. A subset of the SNPs were verified experimentally using either PCR-RFLP or genomic Invader assays. These experiments confirmed 92% of the potential variants in a panel of 92 individuals. [Details of the SNPs and RFLP assays can be found at http://www.sanger.ac.uk and in dbSNP.]
Base Composition↗
Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease.
BACKGROUND AND AIM: The immunosuppressive properties of 6-mercaptopurine and its parent compound azathioprine are mediated by their intracellular metabolism into active 6-thioguanine (6-TG) metabolites. Measurement of erythrocyte 6-TG metabolite levels has been proposed as a useful clinical tool for assessing treatment efficacy in patients with inflammatory bowel disease (IBD). AIM: The purpose of the study was to establish a therapeutic index of treatment efficacy based on measurement of erythrocyte 6-TG metabolite levels, and apply it clinically to guide therapy. METHODS: Heparinised blood was obtained from 82 adult patients with IBD on long term (more than three months) antimetabolite therapy (63 Crohn's disease; 19 ulcerative colitis). Erythrocyte 6-TG metabolite levels were measured using reverse phase high performance chromatography, and correlated with treatment efficacy. In 22 patients with refractory Crohn's disease despite long term azathioprine therapy, their dosage was increased by 25 mg/day at eight week intervals as needed. Serial erythrocyte 6-TG metabolite levels were measured at each clinic visit and correlated with treatment efficacy. RESULTS: Clinical remission, as defined by a low disease index score in patients weaned off or on a low alternate day dose (<20 mg on alternate days) of corticosteroid, was achieved in 68% of patients on long term antimetabolite therapy. Treatment efficacy correlated with erythrocyte 6-TG levels greater than 250 pmol/8x10(8) red blood cells in patients with colonic and fistulising Crohn's disease (p<0.01) but not in patients with ileocolonic disease. Eighteen of 22 patients with incompletely responsive Crohn's disease achieved disease remission by optimising their dose of azathioprine therapy. Median (range) erythrocyte 6-TG metabolite levels increased from 194 (67-688) to 303 (67-737) pmol/8x10(8) red blood cells (p<0.05). Clinical response associated well with a reduction in corticosteroid requirements. Mean (SEM) white blood cell count decreased from 8.6 (0.9) to 6.9 (0.6) x10(3)/microl with adjustment in azathioprine dosage. No patient incurred azathioprine induced leucopenia. CONCLUSION: Measurement of erythrocyte 6-TG metabolite levels is helpful in determining the adequacy of azathioprine dosage and can be used to optimise the dose of antimetabolite therapy to achieve an improved clinical response without inducing leucopenia. Patients who are clinically refractory to azathioprine therapy despite achieving high erythrocyte 6-TG levels (>250) should be considered for adjunct or alternative forms of immunosuppressive therapy or surgery.
Adolescent↗
Is the ultraviolet waveband a special communication channel in avian mate choice?
There is growing evidence that ultraviolet (UV) wavelengths play an important role in avian mate choice. One of the first experiments to support this idea showed that female zebra finches (Taeniopygia guttata) prefer UV-reflecting males to males whose ultraviolet reflection has been removed. The effect was very strong despite little or no UV reflection from several plumage areas. However, it is not clear how the importance of the UV waveband compares to other regions of the bird-visible spectrum. We tested whether the response of female zebra finches to the removal of male UV reflection is greater than to the removal of other wavebands. We presented females with a choice of males whose appearance was manipulated using coloured filters. The filters removed single blocks of the avian visible spectrum corresponding closely to the spectral sensitivities of each of the zebra finch's single cone classes. This resulted in males that effectively had no UV (UV-), no short-wave (SW-), no medium-wave (MW-) or no long-wave (LW-) plumage reflection. Females preferred UV- and SW- males. LW- and MW- males were least preferred, suggesting that female zebra finches show the greatest response to the removal of longer wavelengths. Quantal catches of the single cone types viewing body areas of the male zebra finch are presented for each treatment. Our study suggests it is important to consider the role of the UV waveband in avian mate choice in conjunction with the rest of the avian visible spectrum.
Animal Communication↗
Counseling female athletes: application of the stages of change model to avoid disordered eating, amenorrhea, and osteoporosis.
Research indicates that female athletes from all sports are at risk for developing disordered eating. amenorrhea, and resulting complications. These disorders, termed the female athlete triad by the American College of Sports Medicine, may lead to significant morbidity and mortality as well as medical and psychological problems. When female athletes feel pressured to fit a specific physical image, they may develop distorted body images and show disordered eating patterns. Menstrual dysfunction and premature osteoporosis may result from inadequate nutrition combined with excessive athletic training. Health professionals play important roles in prevention and treatment of these problematic behaviors. This paper examined the stages of the change behavior model and its use in addictive behaviors and provides theoretical applications of this model to reducing harmful behaviors in female athletes.
Adult↗
Technology evaluation: HspE7, StressGen Biotechnologies Corp.
StressGen is developing HspE7 (SGN-00101) as a potential therapy for human papillomavirus (HPV)-associated conditions. It is a recombinant fusion protein comprising the HPV E7 antigen and the heat shock protein, hsp65, from Mycobacterium bovis. By November 2000, it was in phase III trials for HPV-related anal dysplasia [405228]. Under an aggrement formed in November 1999, the US National Cancer Institute (NCI) is carrying out clinical trials with StressGen in diseases caused by HPV [347155].
Bacterial Proteins↗
Technology evaluation: IMC-1C11, ImClone Systems.
ImClone is developing IMC-IC11, an anti-angiogenesis chimeric monoclonal antibody specific vascular endothelial growth factor receptor 2 (VEGFR-2, also known Flk-1 in mice), for the potential treatment of cancer [156625]; it in phase I trials for the treatment of colorectal carcinoma [379143]. The related antibody DC-101 provided proof-of-principle that an anti-VEGF receptor antibody could strongly inhibit tumor growth and even cause tumor regression with the glioblastoma tumor cell line, GBM18 [388236]. In May 1998, the company was granted US-05747651 by the USPTO, covering antibodies against the extracellular portion of the FLK-1/KDR receptor [284054].
Angiogenesis Inhibitors↗
Technology evaluation: anticancer gene therapy, MediGene.
MediGene is developing recombinant adeno-associated virus (rAAV) vectors for the potential treatment of cancer, and in particular, melanoma and ovarian cancer [304021]. In June 2001, MediGene and its collaborator Aventis Pharma announced the start of a phase I/II trial for a vaccine against malignant melanoma [413513]. The therapy works by boosting the patient's immune response. Autologous or allogeneic tumor cells are transduced with recombinant adeno-associated virus (rAAV) vectors, which express immunomodulators, such as cytokines, and are then expanded in vitro. Following irradiation, these gene-modified cells are reintroduced to the host, leading to a specific antitumor response against the patient's own tumor cells [221820].
Animals↗
Technology evaluation: MetXia-P450, Oxford Biomedica.
Oxford BioMedica is developing gene therapies for treating various forms of cancer. The therapies comprise the transfer of several anticancer genes at a time using a recombinant retrovirus approach based on the company's proprietary LTR Deleted Vector and Accelerated Vector Evolution technologies [238147]. MetXia-P450 is a gene therapy construct containing the cytochrome P450 gene CYP2B6, and is designed to be injected directly into tumors to convert them into 'drug factories'. This is achieved because CYP2B6 converts the inactive produg form cyclophosphamide into the active cytotoxic drug. MetXia-P450 is in phase I/II trials for breast cancer [339582].
Aryl Hydrocarbon Hydroxylases↗
A fair way of donating hearts for transplantation.
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Germany↗
Salary equity among male and female internists in Pennsylvania.
BACKGROUND: Women constitute an increasing proportion of physicians in the United States. Historically, inequities have existed between male and female physicians in professional advancement, but evidence has suggested that disparities in salary are resolving. OBJECTIVE: To examine the current state of salary equity among male and female internists. DESIGN: Population-based survey mailed to all Board-certified female internists and a matched group of male internists who had graduated from medical school 10 to 30 years ago and were currently practicing. SETTING: Pennsylvania. PARTICIPANTS: 232 male and 213 female internists for whom data were complete. MEASUREMENTS: Respondents answered questions about demographic characteristics, training, practice type and setting, status within the practice, family life, and salary. RESULTS: Women were more likely to be involved in the least lucrative practice arrangements. They were more likely to be in low-paying specialties, to not be a partner in the practice, and to be salaried employees; they also spent fewer hours per week seeing patients. Even after adjustment for these differences, hourly earnings were significantly higher (14%) among men than among their female colleagues. Men's earnings significantly exceeded women's earnings among physicians with no academic affiliation, those in high-earning specialties, and those in general internal medicine. CONCLUSIONS: Significant salary differentials exist between male and female internists overall and in various medical practice settings.
Adult↗
Pharmacological blockade or genetic deletion of substance P (NK(1)) receptors attenuates neonatal vocalisation in guinea-pigs and mice.
The regulation of stress-induced vocalisations by central NK(1) receptors was investigated using pharmacological antagonists in guinea-pigs, a species with human-like NK(1) receptors, and transgenic NK1R-/- mice. In guinea-pigs, i.c.v. infusion of the selective substance P agonist GR73632 (0.1 nmol) elicited a pronounced vocalisation response that was blocked enantioselectively by the NK(1) receptor antagonists CP-99,994 and L-733,060 (0.1-10 mg/kg). GR73632-induced vocalisations were also markedly attenuated by the antidepressant drugs imipramine and fluoxetine (30 mg/kg), but not by the benzodiazepine anxiolytic diazepam (3 mg/kg) or the 5-HT(1A) agonist buspirone (10 mg/kg). Similarly, vocalisations in guinea-pig pups separated from their mothers were blocked enantioselectively by the highly brain-penetrant NK(1) receptor antagonists L-733,060 and GR205171 (ID(50) 3 mg/kg), but not by the poorly brain-penetrant compounds LY303870 and CGP49823 (30 mg/kg). Separation-induced vocalisations were also blocked by the anxiolytic drugs diazepam, chlordiazepoxide and buspirone (ID(50) 0.5-1 mg/kg), and by the antidepressant drugs phenelzine, imipramine, fluoxetine and venlafaxine (ID(50) 3-8 mg/kg). In normal mouse pups, GR205171 attenuated neonatal vocalisations when administered at a high dose (30 mg/kg) only, consistent with its lower affinity for the rat than the guinea-pig NK(1) receptor. Ultrasound calls in NK1R-/- mouse pups were markedly reduced compared with those in WT pups, confirming the specific involvement of NK(1) receptors in the regulation of vocalisation. These observations suggest that centrally-acting NK(1) receptor antagonists may have clinical utility in the treatment of a range of anxiety and mood disorders.
Animals↗
Determinants of coronary remodeling in transplant coronary disease: a simultaneous intravascular ultrasound and Doppler flow study.
BACKGROUND: Coronary remodeling plays a significant role in lumen loss in transplant allograft vasculopathy (TxCAD), but the determinants of remodeling are unknown. We assessed the relationship between remodeling and plaque topography, coronary compliance, and blood flow in TxCAD. METHODS AND RESULTS: One artery in each of 27 transplant patients was investigated with simultaneous intravascular ultrasound and coronary flow measurements (basal and hyperemic by Doppler flow wire). At 4 to 8 different cross sections (mean 5.1+/-1. 2), plaque topography (concentric or eccentric) was determined, and total vessel area, lumen area, and intimal/medial area (IMA) were measured. Mean remodeling ratio (vessel area/IMA) in eccentric lesions (E, n=28) was significantly larger than that in concentric lesions (C, n=70) (E 5.87+/-0.93 versus C 3.58+/-0.62; P<0.001), despite similar IMA (E 3.89+/-0.68 versus C 3.90+/-0.41; P=NS) and distribution of imaged segments. Remodeling ratio was consistently larger in eccentric lesions in all 3 vessel segments when analyzed separately, and mean remodeling ratio for each artery was larger in vessels with predominantly eccentric lesions. Coronary compliance ([Delta lumen area/diastolic lumen area]/Delta mean arterial pressure x 10(3)) was also significantly greater in eccentric lesions versus concentric lesions (proximal 1.00+/-0.39 versus 0.22+/-0.04; mid 0.71+/-0.17 versus 0.21+/-0.10; distal 0.43+/-0.13 versus 0. 01+/-0.08; all P<0.01). Coronary flow reserve was also significantly higher in coronary arteries with primarily eccentric lesions (E 2. 49+/-0.64 versus C 1.87+/-0.28; P<0.01). CONCLUSIONS: Vessel remodeling in transplant vasculopathy is significantly greater in eccentric lesions than in concentric lesions, possibly due to greater coronary compliance and resistive vessel function.
Compliance↗
A painful cutaneous nodule as the presentation of metastatic transitional cell carcinoma of the renal pelvis.
We report a 43-year-old man with HIV who presented with a painful, vascular-appearing nodule as the initial manifestation of metastasis of a prior transitional cell carcinoma of the renal pelvis. The transitional cell carcinoma had been treated by nephroureterectomy 4 years before the appearance of the nodule. Histopathologic comparison of the nodule with the prior transitional cell carcinoma and immunoperoxidase staining with monoclonal antibodies confirmed that the nodule was a metastasis of the original transitional cell carcinoma. In general, metastasis of transitional cell carcinoma to the skin is quite uncommon. This case is the first reported episode of transitional cell carcinoma of the renal pelvis metastasizing to the skin in the form of a vascular-appearing nodule. The significance of this unusual metastasis occurring in a person with HIV is unknown.
Adult↗
Enhanced bioavailability of azathioprine compared to 6-mercaptopurine therapy in inflammatory bowel disease: correlation with treatment efficacy.
BACKGROUND: Azathioprine and 6-mercaptopurine have proven efficacy in the treatment of Crohn's disease. Immunosuppression is mediated by their intracellular metabolism into active 6-thioguanine metabolites, and clinical responsiveness to therapy in patients with inflammatory bowel disease has been correlated with the measure of erythrocyte 6-thioguanine levels. AIMS AND METHODS: To perform a dosing equivalency analysis and comparison of clinical efficacy in 82 patients with inflammatory bowel disease on long-term (> 2 months) therapy with either branded azathioprine (Imuran) (n=26), generic azathioprine (n=38), or 6-mercaptopurine (n=18), based on the measurement of erythrocyte 6-thioguanine metabolite levels. RESULTS: Disease remission was achieved in 51% (42 out of 82) of patients treated with either azathioprine or 6-mercaptopurine therapy, and correlated well with high erythrocyte 6-thioguanine levels (> 250 pmoles/8 x 108 RBCs). Patients treated with either branded azathioprine or 6-mercaptopurine achieved significantly higher erythrocyte 6-thioguanine levels than patients treated with generic azathioprine, thereby suggesting that branded azathioprine has improved oral bioavailability compared to generic azathioprine. These data are consistent with the putative immunosuppressive role of 6-thioguanine metabolites in the treatment of inflammatory bowel disease, and provides a basis for developing a therapeutic index of clinical efficacy based on the measurement of erythrocyte 6-thioguanine metabolite levels. CONCLUSIONS: Our results suggest that differences in bioavailability may have clinical relevance when considering the need to optimize erythrocyte 6-thioguanine metabolite levels in patients deemed unresponsive to treatment on conventional drug dosages.
Administration, Oral↗
Sjögren's syndrome, cavitating lung disease and high sustained levels of antibodies to serine proteinase 3.
A case is described involving Sjögren's syndrome, high sustained levels of antibodies to serine proteinase 3, and cavitating lung disease. Possible diagnoses accounting for this unusual combination include a novel association of Sjögren's syndrome and Wegener's granulomatosis (suggested by the high and sustained levels of antibodies to serine proteinase 3) or a rare presentation of bronchiolitis obliterans organising pneumonia. Identification of the true nature of the patients illness facilitated more active management and a swift resolution of the clinical problem.
Aged↗
Primary bronchogenic carcinoma after heart or lung transplantation: radiologic and clinical findings.
Chronic immunosuppression in organ transplant recipients predisposes to the development of malignant disease. The authors describe their 29-year institutional experience of bronchogenic carcinoma developing after heart and lung transplantation. Seven cases of bronchogenic carcinoma were diagnosed in 1,119 heart and lung transplant recipients. Computed tomography scans and radiographs at time of diagnosis, as well as prior radiographs available in six patients were retrospectively analyzed by two radiologists in consensus. The seven cases involved six heart and one lung transplant recipients. Six patients were smokers with a mean smoking history of 66 pack-years. Mean time interval from transplantation to cancer detection was 25 months. Radiologic findings consisted of a solitary pulmonary nodule (n = 3), mass with satellite nodules (n = 1), and obstructive pneumonitis (n = 1). In the sixth patient, the cancer was not radiographically visible because of obscuration by adjacent fibrosis. On review, radiographic abnormalities were present a mean of 12 months prior to diagnosis in 66% of patients. In the heart or lung transplant population, bronchogenic carcinoma develops in recipients with extensive smoking histories. It presents radiographically as a nodule, mass, or obstructive pneumonitis, and is usually visible on radiographs before the time of diagnosis.
Adult↗
Oxygen regulation of a nodule-located carbonic anhydrase in alfalfa.
Control of the permeability to oxygen is critical for the function of symbiotic nitrogen fixation in legume nodules. The inner cortex (IC) seems to be a primary site for this regulation. In alfalfa (Medicago sativa) nodules, expression of the Msca1 gene encoding a carbonic anhydrase (CA) was previously found to be restricted to the IC. We have now raised antibodies against recombinant Msca1 protein and used them, together with antibodies raised against potato leaf CA, to demonstrate the presence of two forms of CA in mature nodules. Each antibody recognizes a different CA isoform in nodule tissues. Immunolocalization revealed that leaf-related CAs were localized primarily in the nitrogen-fixing zone, whereas the Msca1 protein was restricted exclusively to the IC region, in indeterminate and determinate nodules. In alfalfa nodules grown at various O(2) concentrations, an inverse correlation was observed between the external oxygen pressure and Msca1 protein content in the IC, the site of the putative diffusion barrier. Thus Msca1 is a molecular target of physiological processes occurring in the IC cells involved in gas exchange in the nodule.
Blotting, Western↗