Biomedical subjects
Publications and source records attributed to M Hunt.
Preference tests were used to assess a range of enrichment options for rats kept under standard New Zealand (and similar) caging conditions. The rats did not show significant preferences for most of the options, over an empty cage. The exceptions were shredded paper, a nesting box and a semi-enriched condition incorporating a range of modifications. These cage modifications are recommended for the enrichment of laboratory rats.
PURPOSE: Conventional radiotherapeutic techniques are associated with lung toxicity that limits the treatment dose. Motion of the tumor during treatment requires the use of large safety margins that affect the feasibility of treatment. To address the control of tumor motion and decrease the volume of normal lung irradiated, we investigated the use of three-dimensional conformal radiation therapy (3D-CRT) in conjunction with the deep inspiration breath-hold (DIBH) technique. METHODS AND MATERIALS: In the DIBH technique, the patient is initially maintained at quiet tidal breathing, followed by a deep inspiration, a deep expiration, a second deep inspiration, and breath-hold. At this point the patient is at approximately 100% vital capacity, and simulation, verification, and treatment take place during this phase of breath-holding. RESULTS: Seven patients have received a total of 164 treatment sessions and have tolerated the technique well. The estimated normal tissue complication probabilities decreased in all patients at their prescribed dose when compared to free breathing. The dose to which patients could be treated with DIBH increased on average from 69.4 Gy to 87.9 Gy, without increasing the risk of toxicity. CONCLUSIONS: The DIBH technique provides an advantage to conventional free-breathing treatment by decreasing lung density, reducing normal safety margins, and enabling more accurate treatment. These improvements contribute to the effective exclusion of normal lung tissue from the high-dose region and permit the use of higher treatment doses without increased risks of toxicity.
Isoprostaglandin F(2alpha) type-III (formerly known as 8-iso-prostaglandin F(2alpha)) is produced in large quantities in vivo in clinical situations associated with oxidant stress such as atherosclerosis, hypercholesterolemia, and myocardial reperfusion. Isoprostaglandin F(2alpha) type-III may alter smooth muscle and platelet functions. The aim of this study was to evaluate the effects of isoprostaglandin F(2alpha) type-III on isolated human internal mammary arteries, and to characterise the signalling underlying mechanisms. In organ baths, concentration-dependent contractions of human internal mammary arteries were obtained in response to isoprostaglandin F(2alpha) type-III stimulation. The responses to isoprostaglandin F(2alpha) type-III were inhibited in a concentration-dependent manner by the thromboxane A(2) receptor antagonist, GR 32191 ([1R-[1 alpha(Z), 2beta,3beta,5 alpha(+)-7-[[1, 1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cyclo pentyl]-4-4heptanoic acid], hydrochloride), 3x10(-9) to 3x10(-7) M). However, this effect was associated with a decreased maximal contraction. AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid, 10(-6) to 3x10(-5) M), an EP(1)-DP receptor antagonist had no effect on isoprostaglandin F(2alpha) type-III-induced contractions. The maximal responses to isoprostaglandin F(2alpha) type-III were significantly reduced in the presence of the cyclooxygenase inhibitor indomethacin (10(-5) M) (E(max): 147+/-20% vs. 213+/-19% in control group, P<0.05). Isoprostaglandin F(2alpha) type-III stimulated thromboxane B(2) release (5.7-fold increase) from human internal mammary arteries. Baicaleine, a non-specific lipoxygenase inhibitor, (10(-4) M) and AA 861 (2,3,5-trimethyl-6-(12-hydroxy-5, 10-dodecadiynyl)-1,4 benzoquinone), a 5-lipoxygenase inhibitor (10(-5) M) did not affect isoprostaglandin F(2alpha) type-III response. In conclusion, this study shows that (1) isoprostaglandin F(2alpha) type-III is a vasoconstrictor in human internal mammary arteries, with a potency equivalent to prostaglandin F(2alpha), (2) the contractions induced by isoprostaglandin F(2alpha) type-III are mediated by TP receptor but not EP(1)-DP-receptor activation, (3) thromboxane A(2) but not cysteinyl leukotrienes production is involved in the vascular effects of isoprostaglandin F(2alpha) type-III. Isoprostaglandin F(2alpha) type-III, produced at sites of free radical generation, may play an important role in internal mammary artery spasm in situations of oxidant stress such as coronary bypass surgery.
PURPOSE: To compare acute and late toxicities of high-dose radiation for prostate cancer delivered by either conventional three-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT). MATERIALS AND METHODS: Between September 1992 and February 1998, 61 patients with clinical stage T1c- T3 prostate cancer were treated with 3D-CRT and 171 with IMRT to a prescribed dose of 81 Gy. To quantitatively evaluate the differences between conventional 3D-CRT and IMRT, 20 randomly selected patients were planned concomitantly by both techniques and the resulting treatment plans were compared. Acute and late radiation-induced morbidity was evaluated in all patients and graded according to the Radiation Therapy Oncology Group toxicity scale. RESULTS: Compared with conventional 3D-CRT, IMRT improved the coverage of the clinical target volume (CTV) by the prescription dose and reduced the volumes of the rectal and bladder walls carried to high dose levels (P<0.01), indicating improved conformality with IMRT. Acute and late urinary toxicities were not significantly different for the two methods. However, the combined rates of acute grade 1 and 2 rectal toxicities and the risk of late grade 2 rectal bleeding were significantly lower in the IMRT patients. The 2-year actuarial risk of grade 2 bleeding was 2% for IMRT and 10% for conventional 3D-CRT (P<0.001). CONCLUSIONS: The data demonstrate the feasibility and safety of high-dose IMRT for patients with localized prostate cancer and provide a proof-of-principle that this method improves dose conformality relative to tumor coverage and exposure to normal tissues.
Patient setup and geometrical factors can potentially lead to excessive spinal cord doses when treating lymphoma patients with matched mantle and para-aortic (PAN) fields. To ensure cord protection, partial transmission blocks are often used at the matchline. This study evaluates optimal placement of these blocks. Three patients were planned using a variety of mantle/PAN field geometries, including significantly different field lengths and isocenter vertical positions. Field matching in all cases was based on a standard gap calculation. Half-transmission blocks (HTB) were positioned on (a) both posterior fields, (b) both anterior fields, and (c) the posterior PAN field only. Doses were calculated with and without effects of setup uncertainty. HTB on both posterior fields yielded a lower maximum cord dose but slightly poorer target coverage than HTB on both anterior fields. HTB on the posterior PAN field alone resulted in a maximum cord dose similar to HTB on both anterior fields. Setup uncertainty decreased but did not eliminate the differences between block placement methods. HTB of sufficient size on both posterior fields ensures a maximum cord dose less than the prescription without significant compromise of target coverage.
In 3 experiments, kindergarten and second-grade children's retention was examined in the context of 2 distinctiveness manipulations, namely, the von Restorff and bizarre imagery paradigms. Specifically, children learned lists of pictures (Experiments 1a and 1b) or interactive images (Experiment 2) and were asked to recall them 3 weeks later. In Experiments 1a and 1b, distinctiveness was manipulated perceptually (changing colors) and conceptually (changing categories or switching to a numeral), whereas in Experiment 2, distinctiveness concerned the interaction (common or bizarre) between the referents. The results showed that (a) older children retained more information than younger children, (b) younger but not older children failed to benefit from numerically distinct information, and (c) distinctiveness in other domains facilitated children's retention. These results highlight the importance of distinctive information in children's retention.
Two experiments examined the cognitive processes underlying judgements of set size and judgements of frequency of occurrence in young (Experiments 1 and 2) and older (Experiment 2) adults. Previous research has implicated the availability heuristic in set-size judgements, whereas an automatic processing mechanism has been implicated in judgements of frequency of occurrence. In the current experiments, path analysis was employed to investigate the role of an availability bias in performance on the judgement tasks. In Experiments 1 and 2, both types of judgement were influenced by repetition frequency of words independent of the availability (recall) of specific exemplars. Experiment 2 extended the investigation to include age differences. Although older adults' recall performance was poorer overall, the availability bias was age invariant, and there were no age differences in either set-size or frequency-of-occurrence judgements. Our results indicate that both set-size and frequency-of-occurrence judgements are independent of the availability bias evident in recall, and they support the notion that an automatic processing mechanism underlies both types of judgement.
Free radical generation can initiate the peroxidation of arachidonic acid, resulting in a non-cyclooxygenase-dependent production of bioactive prostaglandin F2-like compounds. We have investigated the effects of iso-prostaglandin F2alpha type III, (iPF2alpha-III, formerly named 8-iso prostaglandin F2alpha) on human saphenous veins, and characterized the underlying mechanisms. In organ baths, the contractile effects of iPF2alpha-III were tested on saphenous vein rings coming from 22 patients. iPF2alpha-III induced concentration-dependent contractions of isolated human saphenous veins. The maximal contraction did not differ significantly from that of prostaglandin F2alpha (PGF2alpha). The pD2 values for iPF2alpha-III, PGF2alpha, endothelin-1 (ET-1), and U46619 (a stable thromboxane A2 mimetic) were 6.31+/-0.12, 5.66+/-0.13, 7.37+/-0.08, and 7.99+/-0.31, respectively (p < 0.001 for U46619 vs. iPF2alpha-III and PGF2alpha; and ET-1 vs. PGF2alpha). Emax values of iPF2alpha-III, PGF2alpha, ET-1, and U46619 were 137.7+/-24.3%, 145.9+/-7.5%, 92.9+/-16.8%, and 238.7+/-23.7%, respectively (p < 0.001 for U46619 vs. iPF2alpha-III, PGF2alpha and ET-1; and for PGF2alpha vs. ET-1). The responses to iPF2alpha-III were inhibited by GR 32191 10(-7) M, a TP-receptor antagonist, without affecting the maximal response (pD2 values were 5.98+/-0.06 in the absence, and 5.22+/-0.05 in the presence of GR32191; p < 0.001). Concentration-effect curves to iPF2alpha-III were not affected by phosphoramidon 10(-5) M (an endothelin converting enzyme inhibitor), BQ123 10(-6) M (a selective ET(A)-receptor antagonist), BQ788 10(-6) M (a selective ET(B)-receptor antagonist), and indomethacin 10(-5) M (a cyclooxygenase inhibitor). Finally, the contractile response of iPF2alpha-III did not involve the release of thromboxane B2 and ET-1, measured using enzyme immunoassays. This study demonstrates that iPF2alpha-III is a vasoconstrictor of human saphenous veins, with a potency fourfold greater than that of PGF2alpha, and 50 times less than that of the thromboxane A2 mimetic, U46619. These effects are mediated at least in part by TP-receptor stimulation, but do not involve thromboxane A2 or ET-1 release.
An unstable chromosomal element encoding multiple antibiotic resistance in Shigella flexneri serotype 2a was found to include sequences homologous to the csg genes encoding curli in Escherichia coli and Salmonella enterica serovar Typhimurium. As curli have been implicated in the virulence of serovar Typhimurium, we investigated the csg loci in all four species of Shigella. DNA sequencing and PCR analysis showed that the csg loci of a wide range of Shigella strains, of diverse serotypes and different geographical distributions, were almost universally disrupted by deletions or insertions, indicating the existence of a strong selective pressure against the expression of curli. Strains of enteroinvasive E. coli (EIEC), which share virulence traits with Shigella spp. and cause similar diseases in humans, also possessed insertions or deletions in the csg locus or were otherwise unable to produce curli. Since the production of curli is a widespread trait in environmental isolates of E. coli, our results suggest that genetic lesions that abolish curli production in the closely related genus Shigella and in EIEC are pathoadaptive mutations.
Pasteurella multocida is the causative agent of fowl cholera and other diseases of production animals. Isolates are classified into five groups based on capsular antigens and into 16 serotypes based on LPS antigens. Strains causing fowl cholera are most frequently designated A:1, A:3 or A:4. Whole cell bacterins can provide some degree of protection, but only against the homologous LPS serotype. There is good evidence that cross-protective antigens are expressed only under in vivo conditions. Empirically derived, live, attenuated vaccines can protect against heterologous serotypes, but because the basis for attenuation is undefined, reversion to virulence is not uncommon. Work in our laboratory is aimed at using a variety of approaches to identify potential protective antigens or virulence genes to be used as candidates for attenuating mutations or as the basis for vaccine antigen delivery systems. The gene encoding an outer membrane protein, Oma87, which is a homologue of the D15 protective antigen of Haemophilus influenzae, was cloned and sequenced. Rabbit antiserum prepared against recombinant Oma87 could passively protect mice against infection. Type 4 fimbriae form the basis of vaccines against ovine footrot and bovine keratoconjunctivitis. We have identified type 4 fimbriae on the surface of P. multocida, purified the fimbrial subunit protein, PtfA, and determined its N-terminal amino acid sequence. Subsequent cloning of the ptfA gene and its inactivation will now be used to assess the importance of type 4 fimbriae in virulence. There has long been anecdotal evidence for the importance of capsule in virulence, but unequivocal genetic evidence for such a role is lacking. We have cloned and characterised the capsule biosynthetic locus in P. multocida A:1 and identified four bex genes involved in capsule transport and genes encoding enzymes involved in the biosynthesis and transfer of the N-acetyl glucosamine and glucuronic acid components of the capsule. It has been suggested that the low concentration of available iron in vivo acts as an environmental cue for expression of cross-protective antigens. Accordingly, we have cloned and characterised the gene encoding transferrin binding protein, Tbpl, so that its role in immunity and virulence can be investigated. Although P. multocida is not normally considered haemolytic, we have observed haemolysis under anaerobic conditions. Standard library construction and screening resulted in the identification of the mesA gene which encodes an esterase enzyme resulting in a haemolytic phenotype under anaerobic conditions. Virulence studies with mesA- mutants were performed to assess its role in pathogenesis. Using a promoterless phoA gene vector system, the cloning of proteins homologous to known surface proteins of other species as well as proteins unique to P. multocida, allowing their potential as vaccine components to be assessed.
PURPOSE: To evaluate the potential benefits of intensity modulated tangential beams in the irradiation of the intact breast. METHODS AND MATERIALS: Three-dimensional treatment planning was performed on five left and five right breasts using standard wedged and intensity modulated (IM) tangential beams. Optimal beam parameters were chosen using beams-eye-view display. For the standard plans, the optimal wedge angles were chosen based on dose distributions in the central plane calculated without inhomogeneity corrections, according to our standard protocol. Intensity-modulated plans were generated using an inverse planning algorithm and a standard set of target and critical structure optimization criteria. Plans were compared using multiple dose distributions and dose volume histograms for the planning target volume (PTV), ipsilateral lung, coronary arteries, and contralateral breast. RESULTS: Significant improvements in the doses to critical structures were achieved using intensity modulation. Compared with a standard-wedged plan prescribed to 46 Gy, the dose from the IM plan encompassing 20% of the coronary artery region decreased by 25% (from 36 to 27 Gy) for patients treated to the left breast; the mean dose to the contralateral breast decreased by 42% (from 1.2 to 0.7 Gy); the ipsilateral lung volume receiving more than 46 Gy decreased by 30% (from 10% to 7%); the volume of surrounding soft tissue receiving more than 46 Gy decreased by 31% (from 48% to 33%). Dose homogeneity within the target volume improved greatest in the superior and inferior regions of the breast (approximately 8%), although some decrease in the medial and lateral high-dose regions (approximately 4%) was also observed. CONCLUSION: Intensity modulation with a standard tangential beam arrangement significantly reduces the dose to the coronary arteries, ipsilateral lung, contralateral breast, and surrounding soft tissues. Improvements in dose homogeneity throughout the target volume can also be achieved, particularly in the superior and inferior regions of the breast. It remains to be seen whether the dosimetric improvements achievable with IMRT will lead to significant clinical outcome improvements.
BACKGROUND: There are many reports of psychological morbidity in spousal carers of patients with dementia. The consequences of this increased stress on the immune system are unclear. We investigated whether antibody responses to influenza vaccination differed between carers and a control group, and the relation of the antibody response to the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: 50 spousal carers of dementia patients, median age 73 years (IQR 66-77), and 67 controls (68 years [66-71]) of similar socioeconomic status were enrolled. Anxiety and depression were measured by the Savage Aged Personality Screening Scale and stress by the Global Measure of Perceived Stress scale. Principal-component analysis was used to yield a summary score of emotional distress from these two scales. Salivary cortisol concentrations were measured over a single day at three times (0800-1000, 1100-1300, and 2000-2200). Participants received a trivalent influenza vaccine and IgG antibody titres to each strain were measured on days 0, 7, 14, and 28. FINDINGS: Mean scores of emotional distress were significantly higher in carers at each time point than in controls (all p<0.0003). Mean (SD) salivary cortisol concentrations, calculated as area under the curve (AUC), were higher in carers than controls at all three assessments (6 months 16.0 [8.0] vs 11.2 [4.4], p=0.0001; respectively). Eight (16%) of 50 carers and 26 (39%) of 67 controls had a four-fold increase in at least one of the IgG titres (p=0.007). There was an inverse relation between AUC cortisol and IgG antibody titre to the Nanchang strain that was significant on day 14 (r=-0.216, p=0.039). INTERPRETATION: Elderly carers of spouses with dementia have increased activation of the hypothalamic-pituitary-adrenal axis and a poor antibody response to influenza vaccine. Carers may be more vulnerable to infectious disease than the population of a similar age.
1.1. Acyl-CoA thioesterases hydrolyze acyl-CoAs to the corresponding free fatty acid plus CoASH. The activity is strongly induced in rat and mouse liver after feeding the animals peroxisome proliferators. To elucidate the role of these enzymes in lipid metabolism, we have cloned the cDNAs corresponding to the inducible cytosolic and mitochondrial type I enzymes (CTE-I and MTE-I) and studied tissue expression and nutritional regulation of expression of the mRNAs in mice. The constitutive expression of both mRNAs was low in liver, with CTE-I being expressed mainly in kidney and brown adipose tissue and MTE-I expressed in brown adipose tissue and heart. As expected, the expression in liver of both the CTE-I and MTE-I mRNAs was strongly induced (> 50-fold) by treatment with clofibrate. A similar level of induction was observed by fasting and a time-course study showed that both mRNAs were increased already at 6 hours after removal of the diet. Refeeding normal chow diet to mice fasted for 24 hours normalized the mRNA levels with a T1/2 of about 3-4 hours. Feeding mice a fat-free diet further decreased the expression, possibly indicating repression of expression. The strong expression of MTE-I and CTE-I in the heart was increased about 10-fold by fasting. To further characterize these highly regulated enzymes, we have cloned the corresponding genes and promoter regions. The structures of the two genes were found to be very similar, consisting of three exons and two introns. Exon-intron borders conform to general consensus sequences and especially the first exon appears to be highly conserved. The promoter regions of both the CTE-I and MTE-I genes contain putative peroxisome proliferator response elements (PPREs), suggesting an involvement of peroxisome proliferator-activated receptors in the regulation of these genes.
Each of six kangaroos, tested in a seminatural environment. learned to respond readily to water and to sniff at but not ingest an aqueous solution of 0.1% isoamyl acetate plus 0.5% quinine. Avoidance of the odor stimulus typically occurred after licking at the solution on two to three trials for most subjects. Kangaroos also learned to avoid lower concentrations of isoamyl acetate and to discriminate between isoamyl acetate and ethyl acetate. These results are among the first to document olfactory function in kangaroos. The odor-cued taste-avoidance procedure provides a relatively simple test of olfaction that can be used in the field with open-range animals.
The development of scanning CO2 laser systems has enabled rapid and uniform facial resurfacing in photoaged and acne scarred skin. A problem faced by the laser surgeon is making the scanner pattern produced by these lasers fit the cosmetic unit to be resurfaced. This may be achieved by the use of wet gauze to absorb the energy of the unwanted portion of the scanner pattern. The wet gauze is folded to lie along the cosmetic unit boundary and the scanner pattern rotated until it conforms to the required shape. On the eyelids, saline soaked cotton tipped applicators are used to lift the eyelashes away from the path of the laser beam. This allows treatment of the entire lower eyelid cosmetic unit without damage to the eyelashes.
The authors describe the historical evolution and present status of affirmative action in medical school admission policies. The demographic transformation of the medical student body between 1965 and 1998 from a homogeneous white and male group to one that includes a significant number of women and minority students is presented. Challenges to affirmative action are outlined. In addition, the authors note the increasing diversity of the general population and discuss the benefits of diversity to medical practice, research, and education. However, the upper ranks of professors and administrators remain white and male. The rationale for an innovative course on the history of bias in medicine and the benefits that diversity brings to the medical enterprise are presented.
In response to tensions created by a racial misunderstanding, the authors developed a course for first year medical students entitled Race and Gender in Medicine. The course, presented in a seminar format, enables the participants to discuss openly their concerns about diversity and its impact on their institution and the medical enterprise. Physician speakers describe their experiences with gender bias, racism, and other discriminatory practices and then present strategies they used to overcome these obstacles in their career path. Given the increasing heterogeneity of the population, the authors advocate integrating a course such as this one into the curriculum that will help prepare students to practice humane medicine in the multiracial, multiethnic, and multicultural society of the 21st century.
Patient records must be comprehensive, clear, accurate and updated on a regular basis. A pilot study which introduced multidisciplinary case notes to a mental health-care unit found they fulfilled these requirements. Staff who used the multidisciplinary case notes preferred them to traditional methods of record-keeping.