Biomedical subjects
Publications and source records attributed to J M Brown.
The pain from insertion of two small cannulae was compared in 26 volunteers. Each subject was blindfolded and had both a 22 G and a 20 G cannula inserted in random order. One subject was rejected as cannulation was unsuccessful. Of the remaining 25 subjects, 12 found the 22 G more painful and 13 the 20 G. This difference was not significant (chi squared p > 0.1).
Although Nocardia farcinica surgical site infection outbreaks have been reported (though rarely), no source for these has been identified. From May 1992 through June 1993, 5 patients contracted N. farcinica sternotomy site infections following open heart surgery at hospital A. A case-control study comparing case-patients (n=5) with open heart surgery patients without subsequent sternotomy site infections (n=50) identified as risk factors diabetes (4/5 vs. 11/50, P<.02) and exposure to a particular anesthesiologist (anesthesiologist A; 4/5 vs. 9/50, P<.01). Four case-patients' isolates and a hand isolate of anesthesiologist A had an identical ribotype pattern (strain 1); the remaining case-patient's isolate and multiple isolates from anesthesiologist A's hands and home had a different ribotype pattern (strain 2). An intensified hand-washing regimen, barriers (gloves, gowns), and cleaning of anesthesiologist A's house were associated with termination of the outbreak. This is the first reported nosocomial N. farcinica outbreak to document the source and person-to-person transmission epidemiologically and molecularly.
OBJECTIVE: Considerable evidence exists to suggest that tumor hypoxia results in radioresistance. Historically, it has been difficult to assess tumor oxygen tension levels reliably. These levels can now be assessed in head and neck malignancies using the Eppendorf pO2 histograph, which uses a fine-needle electrode and a computerized micromanipulator. This technology was used to compare the pretreatment tumor oxygen tension level in lymph node metastases of patients with head and neck cancer to measurements taken during nonsurgical treatment after a partial response had been achieved. STUDY DESIGN: Prospective study. METHODS: Oxygen tension levels were measured in the cervical lymph nodes of 10 patients with biopsy-proven head and neck squamous cell carcinoma and cervical metastases who were being treated with nonsurgical management. These levels were obtained using the Eppendorf pO2 histograph system. Measurements were taken before the start of treatment and were repeated when the size of the cervical metastatic node had decreased by 50%. Normal subcutaneous tissue was measured during the same session. The mean and median pO2 levels, as well as the percentage of measurements with pO2 less than 5 mm Hg were determined. RESULTS: A mean of 72.6 measurements per session was taken from each lymph node. The median tumor pO2 measurement fell from a mean (+/-SD) of 13.9+/-8.0 mm Hg to 7.3+/-9.9 mm Hg. Even more dramatic, however, was the substantial increase in the percentage of values less than 5 mm Hg, a rise from 29% to 52%. CONCLUSIONS: While there is variability both in the pretreatment oxygenation of head and neck cervical metastases and in the change in tumor oxygen tension during treatment, there appears to be a decrease in the overall oxygenation of the tumors. The dramatic increase in very low oxygen measurements may reflect selective survival of radioresistant or chemoresistant hypoxic tumor cells. Cells at the very low level would be expected to be radiobiologically hypoxic (resistant to radiation-induced cell kill).
Lipopolysaccharide (LPS) preconditioning induces cardiac resistance to subsequent LPS or ischemia. This study tested the hypothesis that resistance to LPS and resistance to ischemia are two manifestations of cardiac cross-resistance which may involve reprogramming of cardiac gene expression. Rats were preconditioned with a single dose of LPS (0.5 mg/kg ip). Cardiac resistance to LPS was examined with a subsequent LPS challenge. Cardiac resistance to ischemia was determined by subjecting hearts to ischemia-reperfusion. Total RNA was extracted from myocardium for Northern analysis of mRNAs encoding protooncoproteins, antioxidant enzymes, and contractile protein isoforms. Rats preconditioned with LPS 1-7 days earlier acquired cardiac resistance to endotoxemic depression. This resistance temporally correlated with resistance to ischemia. Pretreatment with cycloheximide (0.5 mg/kg ip) abolished resistance to both LPS and ischemia. LPS preconditioning induced the expression of c-jun and c-fos mRNAs. LPS also transiently increased mRNAs encoding catalase and Mn-containing superoxide dismutase. The expression of both alpha- and beta-myosin heavy chain mRNAs was upregulated, whereas the expression of cardiac alpha-actin mRNA was suppressed. We conclude that 1) LPS induces sustained cardiac resistance to both LPS and ischemia, 2) resistance to ischemia and resistance to LPS seem to be two mechanistically indistinct components of cardiac cross-resistance, and 3) the cardiac cross-resistance is associated with reprogramming of myocardial gene expression.
OBJECTIVE: The study examined the characteristics of frequent users of inpatient treatment under public-sector managed care in Massachusetts between 1992 and 1995 and explored whether their pattern of inpatient utilization affected their overall use of hospital days. METHODS: Individuals with five or more admissions in any of four fiscal years (1992 to 1995) were identified using the Massachusetts Department of Mental Health client tracking system. The demographic and clinical characteristics of these patients and the types of hospitals they used were compared with those of all patients in case management programs who had a hospital admission but who did not meet study criteria for multiple admissions. RESULTS: Compared with other patients, patients with multiple admissions were more likely to be young Caucasian females with personality disorder and a history of substance abuse but not a current substance use disorder. They tended to be lower functioning as measured by the Georgia Role Functioning Scale (GRFS) and to have higher levels of distress, as measured by the global personal distress portion of the GRFS. They made up 6 to 8 percent of all clients with a psychiatric admission who were enrolled in a case management program, but they accounted for 21 to 27 percent of all admissions in the four fiscal years. Patients with multiple admissions had significantly longer lengths of stay when admitted to a hospital where they had not been previously admitted in the past 12 months. CONCLUSIONS: States setting up public-sector managed care or revising existing public-sector managed care contracts should ensure that subpopulations of persons at high risk for multiple admissions receive special attention. They should also create networks of inpatient providers to enable frequent users of acute care facilities to return to the same facility that previously discharged them.
OBJECTIVE: A national survey was conducted to determine the extent of consumer empowerment in the public mental health system. METHODS: A questionnaire was sent to mental health authorities in all U.S. states and territories asking whether consumer empowerment or responsibility was defined in statutes, regulations, or policies and whether consumers or family members were employed in central or field offices of the authority. A rating scale measured the extent of consumer empowerment, and correlations were examined between this rating and other variables. RESULTS: The survey achieved a 100 percent response rate. Twenty-two states (39 percent) addressed consumer empowerment and 16 (28 percent) consumer responsibility in a statute, regulation, or policy. Twenty-seven states (48 percent) had paid positions for consumers in central offices, and three (5 percent) had such positions for family members. Half the states had paid positions for consumers in field offices, and 12 states (24 percent) had such positions for family members. The extent of a state's consumer empowerment had no relationship to region of the country or the state's mental health budget. A significant positive relationship was found between extent of empowerment and the size of the state's population and the quality of its mental health services. CONCLUSIONS: State mental health authorities vary widely in their direct involvement with consumer empowerment. Results indicate that mental health authorities need to make a greater commitment to the achievement of such empowerment if it is to become a meaningful part of government involvement with mental health services.
The purpose of this study was to investigate 24-h estradiol and leptin levels in obese and nonobese children to further understand the roles of estradiol and leptin in obesity and puberty. We measured serum estradiol, leptin, insulin, glucose, and GH levels every hour for 24 h in 18 obese (12 females and 6 males) and 30 nonobese (11 females and 19 males) prepubertal and early pubertal (stages 1-2) children. Bone age and dual energy x-ray absortiometry (DEXA) were obtained upon completion of the 24-h study. Obese children were significantly younger than nonobese children, with no difference in pubertal stage, height, or bone age between the 2 groups. Obese children had greater bone age to chronological age ratios than nonobese children, indicating a more advanced rate of bone maturation. Mean 24-h estradiol levels correlated significantly with chronological age and bone age as well as with insulin-like growth factor I, insulin-like growth factor-binding protein-3, dehydroepiandrosterone sulfate, mean 24-h GH, and lean body mass. Mean 24-h estradiol levels did not differ between obese and nonobese children [1.65+/-1.47 us. 2.75+/-3.30 pmol/L (0.45+/-0.40 vs. 0.75+/-0.90 pg/mL), respectively]. Similar mean 24-h estradiol levels in obese and nonobese children are consistent with the increased bone maturation of the obese children. Estradiol did not correlate significantly with DEXA fat mass, body mass index, or arm fat measures of adiposity. Obese children had higher 24-h mean leptin concentrations than nonobese children (28.6+/-17.4 vs. 6.8+/-7.1 ng/mL; P < 0.001). Leptin concentrations positively correlated with DEXA fat mass, body mass index, and arm fat measurement of adiposity. Girls had higher 24-h mean leptin levels than boys when controlling for adiposity. Estradiol and leptin concentrations fluctuated over a 24-h period in both groups, with all children having higher leptin concentrations at night and higher estradiol concentrations in the morning. This diurnal rhythm was of a similar pattern, but at higher levels for leptin and lower levels for estradiol in the obese children compared to nonobese children. There was no significant correlation between estradiol and leptin levels. Bone mineral density, as measured by DEXA, did not differ between obese and nonobese children. Similar bone mineral density values in obese and nonobese children are consistent with the increased bone maturation of the obese children. Bone mineral density was not correlated with estradiol or leptin level in these children. In conclusion, obese children had similar estradiol levels and equivalent bone ages at a younger chronological age than nonobese children. Leptin was higher in these obese children, but did not correlate with estradiol level or bone age. These findings suggest that the role of leptin in both obesity and pubertal development is not directly correlated with the estradiol level.
The mouse mutant Doublefoot (Dbf) shows preaxial polydactyly of all four limbs. We have analysed limb development in this mutant with respect to morphogenesis, gene expression patterns and ectopic polarising activity. The results reveal a gain-of-function mutation at a locus that mediates pattern formation in the developing limb. Shh expression is identical with that of wild-type embryos, i.e. there is no ectopic expression. However, mesenchyme from the anterior aspects of Dbf/+ mutant limb buds, when transplanted to the anterior side of chick wing buds, induces duplication of the distal skeletal elements. Mid-distal mesenchymal transplants from early, but not later, Dbf/+ limb buds are also able to induce duplication. This demonstration of polarising activity in the absence of Shh expression identifies the gene at the Dbf locus as a new genetic component of the Shh signalling pathway, which (at least in its mutated form) is able to activate signal transduction independently of Shh. The mutant gene product is sufficient to fulfil the signalling properties of Shh including upregulation of the direct Shh target genes Ptc and Gli, and induction of the downstream target genes Bmp2, Fgf4 and Hoxd13. The expression domains of all these genes extend from their normal posterior domains into the anterior part of the limb bud without being focused on a discrete ectopic site. These observations dissociate polarising activity from Shh gene expression in the Dbf/+ limb bud. We suggest that the product of the normal Dbf gene is a key active constituent of the polarising region, possibly acting in the extracellular compartment.
Signals that induce neural cell fate in amniote embryos emanate from a unique cell population found at the anterior end of the primitive streak. Cells in this region express a number of fibroblast growth factors (FGFs), a group of secreted proteins implicated in the induction and patterning of neural tissue in the amphibian embryo. Here we exploit the large size and accessibility of the early chick embryo to analyse the function of FGF signalling specifically during neural induction. Our results demonstrate that extraembryonic epiblast cells previously shown to be responsive to endogenous neural-inducing signals express early posterior neural genes in response to local, physiological levels of FGF signal. This neural tissue does not express anterior neural markers or undergo neuronal differentiation and forms in the absence of axial mesoderm. Prospective mesodermal tissue is, however, induced and we present evidence for both the direct and indirect action of FGFs on prospective posterior neural tissue. These findings suggest that FGF signalling underlies a specific aspect of neural induction, the initiation of the programme that leads to the generation of the posterior central nervous system.
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Tirapazamine (TPZ, SR 4233, WIN 59075, 3-amino-1,2,4-benzotriazine 1,4-dioxide, Tirazone) is the lead compound in the benzotriazine di-N-oxide class of bioreductive anticancer agents. Extensive preclinical testing has established that the mechanism for the selective toxicity towards hypoxic cells is the result of a one-electron reduction of the parent molecule to a free radical species that interacts with DNA to produce single- and double-strand breaks and lethal chromosome aberrations. It has also shown activity when combined with fractionated irradiation and when combined with some chemotherapy agents, particularly cisplatin and carboplatin. In this review we address those questions about the drug that are most relevance to the clinical use of the compound. In particular we review the evidence for the mechanism of action of the drug, and also show that a large portion of the synergy seen in experimental tumors when TPZ is combined with cisplatin is the result of a cellular interaction between TPZ and cisplatin that depends on hypoxia. Also of relevance to clinical use is whether the toxicity of TPZ is cumulative such as occurs with nitroimidazoles, another class of hypoxia-activated agents. Such cumulative toxicity is not evident. Finally, we present an analysis based on the area under the curve for mice and humans that demonstrates that the doses being used in current Phase II radiotherapy protocols and Phase III chemotherapy protocols should be sufficient to produce clinical activity. We conclude that the preclinical data suggest that it is likely that TPZ will be active in the clinic, particularly when combined with cisplatin.
Tirapazamine (1,2,4-benzotriazin-3-amine 1,4-dioxide, SR 4233, WIN 59075) is the lead compound representing this class of anticancer drugs. It is also the first compound to be introduced in the clinic as a pure bioreductive cytotoxic agent. Tirapazamine represents a completely novel approach to the treatment of solid tumors and has generated considerable interest, with research being carried out on all aspects of the its anticancer activity. Phase III trials of tirapazamine in combination with cisplatin (cDDP) have recently been concluded, and phase II trials of triapazamine in combination with irradiation are presently being performed. We developed a drug discovery program into this class of compounds designed to produce derivatives with improved in vivo activity against solid tumors. Based on the hypothesis that these compounds require bioreductive activation for antitumor activity, the research was primarily directed at producing analogues with greater electron affinity and improved aqueous solubility. The in vitro and in vivo data for a variety of structural analogues clearly show that 1,2,4-benzotriazine 1,4-dioxides have considerable potential as anticancer agents. When their activity is compared directly with the activity observed for triapazamine, the most promising series of analogues appears to be the 3-alkyl-substituted derivatives, especially the 3-ethyl- and 3-(2'-methoxyethyl)-derivatives, SR 4895 and SR 4941 respectively.
Advanced practice nurses and staff nurse skin-care team members provided the necessary expertise and information to integrate AHCPR recommendations in a protocol for patients at risk for skin impairment. Regular practice monitoring and education regarding skin management have proven to be successful strategies. A skin-impairment management protocol is provided.
A polymorphism in the UL42-UL43 region of the human cytomegalovirus genome has been characterized by nucleotide sequence analysis, revealing a 929-bp insertion following nt 54,612 relative to the published strain AD169-UK genome sequence (M.S. Chee et al., 1990, Curr. Top. Microbiol Immunol. 154, 125-170). Although AD169-UK exhibited polymorphism in this genomic region, other CMV strains (Towne, Toledo, and AD169-ATCC) carried only the newly characterized longer form. The additional sequence altered the assignment of UL42 and UL43 open reading frames. UL42 decreased in size from 157 to 125 codons, retaining 76 of the previously reported carboxyl terminal codons, and UL43 increased in size from 187 to 423 codons, retaining 185 of the previously reported amino terminal codons. This additional sequence makes UL43 a more conserved betaherpesvirus US22 family member. Only AD169-UK exhibited restriction fragment length polymorphism in this region, suggesting that a deletion occurred during the propagation of this strain in cell culture. The additional sequence should be considered a bona fide part of the cytomegalovirus genome and the AD169 genome size should be corrected to 230,283 bp.