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Biomedical subjects

J C Austin

Publications and source records attributed to J C Austin.

At least 19 recordsLinked to original sources
PubMed2006

Applications and limitations of empiric data in provision of recurrence risks for schizophrenia: a practical review for healthcare professionals providing clinical psychiatric genetics consultations.

Schizophrenia is a common disorder that may frequently be encountered when taking family histories in the genetics clinic, whether or not the referral is for a psychiatric indication. Like in other common disorders, the provision of recurrence risks for schizophrenia is a complex clinical issue because empiric recurrence risks (while reasonably well established) can rarely be used without individual tailoring. This review seeks to identify and detail some pertinent issues surrounding the clinical utility of empiric recurrence risks for schizophrenia, and to provide an overview of important factors to consider when tailoring empiric risks for individual patients.

Empirical Research↗
PubMed2005

The potential impact of genetic counseling for mental illness.

Mental disorders are relatively highly heritable, yet complex with important interactions between genetic risk and environmental factors in determining illness expression. Due to the high prevalence of these complex disorders, steady increase in knowledge about genetic contributions, and increasing public awareness, this area may come to represent a significant proportion of all genetic counseling. The potential impact of genetic counseling in mental illness is broad. As well as the conventional expectations, genetic counseling may have the positive outcomes of reducing the guilt, shame, and stigma associated with mental illness, even within families. However, like many interventions in medicine, genetic counseling for mental disorders could potentially have unintended consequences resulting in increased stigma, guilt, and shame. The potential impacts of genetic education and providing recurrence risks on stigma are reviewed, as well as the role of education about the environment as a way of modifying family members' guilt. The review allows a preliminary formulation of a series of suggestions for genetic counseling in mental illness.

Attitude to Health↗
PubMed2003

Interleukin 10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumour activity.

Intravesical BCG therapy is effective in the treatment of superficial bladder cancer. Both clinical and experimental results suggest a role for cytokines and delayed-type hypersensitivity (DTH) in BCG-induced antitumour immunity. We characterized the modulatory effects of BCG on bladder cytokine expression and determined the relationship between DTH and BCG antitumour activity. The bladders of mice were instilled with BCG through a catheter. Bladder tissue RNA and urine were collected for evaluation of cytokine expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ELISA. IFN-gamma and TNF-alpha, the two major cytokines associated with DTH, were efficiently induced by BCG. IL10, an important down-regulator of DTH, was also induced by BCG. Constitutive levels of IL4 and IL5 were observed, but neither IL4 nor IL5 were modulated by BCG. Similar results were observed in the kinetic analysis of urinary cytokines in patients after intravesical BCG therapy. Production of Th1 (T helper type 1) cytokines (IFN-gamma, IL2 and IL12) preceded that of the Th2 (T helper type 2) cytokine IL10. A tendency toward higher ratios of IFN-gamma versus IL10 for BCG responders also was observed. In animal studies the absence of IL10 abrogated either by antibody inhibition or the use of genetically modified, IL10 deficient (IL10-/-) mice resulted in enhanced DTH responses. Under conditions of enhanced DTH, a significant enhancement in antitumour activity was observed. These data demonstrate that DTH and its associated mononuclear infiltration and cytokine production are important to the antitumour activity of intravesical BCG therapy, and suggest that effects to diminish IL10 production may have therapeutic value.

Animals↗
PubMed2001

Evaluation of gene transfer efficiency by viral vectors to murine bladder epithelium.

PURPOSE: In pre-clinical gene therapy studies of bladder cancer there is tremendous variation in the ability of viral vectors to deliver genetic material to bladder epithelium. Possible explanations for this variability may involve the physical parameters of delivering vectors in these experimental models. We examined the effects of intravesical volume and pressure during instillation as well as chemical modification of the bladder epithelium on subsequent gene expression in the bladder in mice. MATERIALS AND METHODS: Female C57B1/6 mice underwent intravesical instillation of the replication restricted canarypox virus (ALVAC) recombinant for the reporter genes luciferase or beta-galactosidase. Similar viral titers were instilled at different volumes and a pressure transducer measured intravesical pressure when the vector was instilled. Also, various agents, including 0.6 N hydrochloric acid, 0.4% oxychlorosene, poly-L-lysine and 0.25 M. ammonium chloride, were used to modify the bladder surface before vector instillation and then assayed for transgene expression. RESULTS: As expected, maximum intravesical pressure measured during instillation was significantly greater in mice instilled with a higher volume (33.1 versus 9.8 mm. Hg). Significantly more gene expression was detected in bladders instilled with a higher volume of viral vectors (p <0.05). Likewise, higher instillation pressures resulted in higher transgene expression in distant organs. Modification of the bladder epithelium with agents such as oxychlorosene and poly-L-lysine resulted in elevated gene expression with only minimal increases in systemic activity. CONCLUSIONS: Significant differences in gene expression are achieved by varying physical parameters during intravesical instillation. Increased gene expression associated with larger volume instillation may be responsible for some reported variability of gene transfer to the bladder. Alternate manipulations, such as modifying the bladder surface, may be done to enhance gene transfer to the urothelium without increasing systemic distribution.

Animals↗
PubMed2000

Viral vector delivery in solid-state vehicles: gene expression in a murine prostate cancer model.

BACKGROUND: Although there are increasingly more clinical trials involving gene therapy, efficient gene transfer remains a major hurdle to success. To enhance the efficiency of delivery of viral vectors in gene therapy protocols, we evaluated the effect of various matrices to act as a vehicle for recombinant virus during intratumoral injection. METHODS: The ability of several vehicles (catgut spacer, polyglycolic acid, chromic catgut, and gelatin sponge matrix) to deliver the canarypox virus ALVAC to the cells of the murine prostate cancer cell line RM-1 was studied in vitro and in vivo. ALVAC recombinants encoding the murine cytokines interleukin 2 (IL-2), interleukin 12 (IL-12), and tumor necrosis factor-alpha (TNF-alpha) were used to assess enhancement of antitumor activity after intratumoral inoculation. Confirmatory experiments were conducted by use of another mouse prostate cancer cell line, RM-11, and a mouse bladder cancer cell line, MB-49. All statistical tests were two-sided. RESULTS: The gelatin sponge matrix proved to be the most effective solid-state vehicle for delivering viral vectors to cells in culture. In addition, this matrix statistically significantly enhanced expression of ALVAC-delivered reporter genes in tumor models when compared with fluid-phase delivery of virus (P =.037 for the RM-1 model and P =.03 for the MB-49 model). Statistically significant growth inhibition of established tumors was observed when a combination of the three recombinant ALVAC viruses expressing IL-2, IL-12, and TNF-alpha was delivered with the matrix in comparison with 1) fluid-phase intratumoral injection of the ALVAC recombinants, 2) no treatment, or 3) treatment with parental ALVAC (all P<.05). CONCLUSIONS: Viral vector delivery in a solid-state vehicle resulted in improved recombinant gene expression in vivo and translated to greater inhibition of tumor growth in an immunotherapy protocol for heterotopic tumor nodules. The efficient delivery of reporter genes described herein may prove useful in many solid tumor gene therapy protocols.

Animals↗
PubMed2000

Biomarker distribution after injection into the canine prostate: implications for gene therapy.

OBJECTIVE: To evaluate the distribution of biomarkers after transrectal injection into the canine prostate and to report a method for enhancing the distribution of gene expression. MATERIALS AND METHODS: Carbon black was first used to evaluate the histopathological distribution in canine prostate of single or multiple injections via the transurethral, transperineal and transrectal routes. The distribution of canarypox virus (ALVAC) vector-delivered gene expression was then compared using both fluid-phase injection techniques and delivery in a solid carrier composed of a gelatine sponge matrix. RESULTS: After transurethral administration, carbon black was detected as scattered particles in ducts and acini, mostly in the periphery of the gland. Direct transrectal injection of carbon black resulted in a localized collection at the site of injection, with only a minimal peri-acinar distribution. Transrectal injection of the fluid-phase (virus suspended in diluent) ALVAC vector encoding the beta-galactosidase gene resulted in a similar distribution, with limited gene expression at the site of injection and in the needle track. Delivery of the same number of virus particles in the gelatine sponge matrix resulted in qualitatively greater gene expression. CONCLUSIONS: Direct injection of the canine prostate with biomarkers, including viral vectors, in the fluid-phase results in very localized gene expression, while the distribution was more widespread after delivery in a gelatine sponge matrix.

Animals↗
PubMed1999

A phase II study of [90Y] yttrium-capromab pendetide in the treatment of men with prostate cancer recurrence following radical prostatectomy.

There is currently no curative therapy for men who have disseminated prostate cancer following failed radical prostatectomy. The purpose of this trial was to investigate systemic radioimmunotherapy in these men. Eight patients with occult metastatic prostate cancer following radical prostatectomy as evidenced solely by a rising serum PSA and evidence of soft tissue lesions outside the prostatic fossa detected by an [111I]indiumcapromab pendetide scan received an infusion of 10 mg of capromab pendetide labeled with 9 mCi/m2 of [90Y]yttrium. Serum PSA was used to measure response rate. There were no complete or partial responses by PSA criteria. Significant unexpected bone marrow toxicity developed in the first 6 of 8 patients treated. The last two patients received co-infusion of edetate calcium disodium in an effort to decrease marrow suppression. In these two patients less marrow toxicity was seen. Repeat 111In-capromab pendetide scans were uninterpretable due to grossly altered whole-body biodistribution of the radioimmunoconjugate. Retrospective analysis of serial PSA values after closure of the study showed a decrease in the log slope PSA for seven of eight patients following radioimmunotherapy, with a statistically significant change in the mean log slope (p = 0.01). The clinical significance of this small but measurable change is uncertain. We conclude that radioimmunotherapy for occult metastatic prostate cancer using 90Y-capromab-pendetide at the dose described does not lower serum PSA, is associated with significant hematologic toxicity, and leads to complexation of the immunoconjugate following subsequent capromab pendetide infusion.

Adenocarcinoma↗
PubMed1998

IL-10 regulates thrombus-induced vein wall inflammation and thrombosis.

Vein wall inflammation associated with venous thrombosis is mediated by an imbalance in proinflammatory as compared with antiinflammatory molecules. We hypothesize that IL-10 is an important antiinflammatory cytokine that influences vein wall inflammation and thrombus propagation during venous thrombosis. To test this hypothesis a model of inferior vena caval thrombosis was used. Studies were performed at sacrifice 2 days after thrombus induction and included leukocyte morphometrics, myeloperoxidase activity, vein wall permeability, thrombus weight, and IL-10 ELISA analysis from the vein wall. IL-10 was elevated in the vein wall during venous thrombosis. Neutralization of IL-10 increased inflammation, while supplementation with rIL-10 demonstrated a dose- and time-dependent decrease in inflammation. Interestingly, a low 2.5-microg rIL-10 dose given at time of initiation of thrombosis most significantly decreased inflammation. Thrombus weight was importantly diminished by reconstitution of IL-10. These studies support an important role for IL-10 in the regulation of thrombus-associated inflammation and thrombosis and suggest that IL-10 could be used as a therapeutic agent in the treatment of venous thrombosis.

Animals↗
PubMed1996

Treatment of stress urinary incontinence in women with urethral hypermobility and intrinsic sphincter deficiency.

PURPOSE: We compared 2 treatment modalities (sling cystourethropexy and periurethral collagen injection) in patients with intrinsic sphincter deficiency alone or with urethral hypermobility (combined stress urinary incontinence). MATERIALS AND METHODS: We retrospectively reviewed a series of 50 consecutive patients treated surgically for intrinsic sphincter deficiency during a 2-year period. All patients were evaluated by history and physical examination to assess urethral hypermobility and urodynamic testing. Intrinsic sphincter deficiency was assessed by abdominal leak point pressure and video urodynamics. Of the 50 patients 28 underwent a pubovaginal sling operation and 22 received a periurethral injection of collagen. RESULTS: Of the patients studied 40% had combined stress urinary incontinence. A pubovaginal sling procedure resulted in a cure rate of 81% in this group, compared to 25% for periurethral injection of collagen. CONCLUSIONS: A subgroup of women exists with combined stress urinary incontinence due to urethral hypermobility and intrinsic sphincter deficiency. When treated with sling cystourethropexy women with combined stress urinary incontinence do as well or better than those with intrinsic sphincter deficiency alone and those treated with periurethral collagen injection do worse.

Adult↗
PubMed1995

Stereoelectronic activation of methylenetetrahydrofolate by thymidylate synthase: resonance Raman spectroscopic evidence.

Resonance Raman (RR) spectra are reported for the ternary complex of Escherichia coli thymidylate synthase with the cofactor 5,10-methylenetetrahydrofolate (CH2-H4-folate) and the inhibitor 5-fluoro-2'-deoxyuridylate, excited at 337 or 356 nm, in resonance with perturbed absorption bands of the p-aminobenzoylglutamate (PABA-Glu) portion of the cofactor. For comparison, RR spectra were obtained with 260 nm excitation for PABA-Glu in various solvents, and for CH2H4-folate and H4-folate in aqueous solution. These reference spectra are assigned to modes of PABA-Glu in its benzenoid form. The ternary complex RR spectra are very different, however, and are assigned, with the aid of isotopic data, to the PABA-Glu in a predominantly quinoid form. Similar spectra were obtained for the ternary complexes of the E58Q and K48Q mutants, indicating that neither Glu58 nor Lys48 are essential for maintaining the quinoid structure, even though their side chains complement the dipolar charge distribution of the quinoid form of PABA-Glu. Since these are the only charged residues in the PABA-Glu vicinity, electrostatic stabilization is not essential to maintenance of the quinoid structure. It is proposed that quinoid formation results from steric forces, probably resulting from the protein conformation change known to accompany cofactor binding, which enforce coplanarity of the PABA-Glu ring and substituents. This stereoelectronic change activates the cofactor by opening the methylene bridge. A second RR spectrum of the ternary complex, previously proposed to reflect an alternate structure, is shown to result instead from irreversible formation of a laser-induced photoproduct.

Escherichia coli↗
PubMed1995

Resonance Raman characterization of the binary and ternary complexes of thymidylate synthase with 5-nitrodeoxyuridylate.

Resonance Raman (RR) spectra are reported for the binary complex of Escherichia coli thymidylate synthase (TS) with the substrate analog inhibitor 5-nitrodeoxyuridylate (NDU). The TS/NDU binary complex RR spectrum shows many similarities to the RR spectra of thiol adducts of NDU or of 5-nitro-1-methyluracil formed in solution, providing strong evidence in support of the formation of a covalent link between Cys146 of TS and C6 of NDU. Spectral differences between the model compounds and the binary complex reflect the consequences of fixing the conformations of the uracil and ribose rings at the enzyme active site. The RR spectra of the ternary complexes of TS/NDU with either tetrahydrofolate (H4-folate) or the cofactor 5,10-methylenetetrahydrofolate (CH2H4-folate) show that a covalent link is not formed between C11 of CH2H4-folate and C5 of NDU. Neither does the methylene bridge of CH2H4-folate remain intact in the ternary complex; either CH2H4-folate is present as the N5 iminium cation species or the methylene group is lost as formaldehyde. A shift in the NO2 symmetric stretching frequency in the ternary complex indicates expulsion of water molecules from the region of the NO2 group by the cofactor.

Deoxyuracil Nucleotides↗
PubMed1995

Ultraviolet resonance Raman spectroscopy of delta 5-3-ketosteroid isomerase revisited: substrate polarization by active-site residues.

The delta 5-3-ketosteroid isomerase (EC 5.3.3.1) of Pseudomonas testosteroni promotes extremely rapid conversion of delta 5- to delta 4-3-ketosteroids by a conservative intramolecular proton transfer via an enolic intermediate. The competitive inhibitor 19-nortestosterone displays marked spectroscopic changes upon binding to the enzyme, but the mechanisms responsible for these changes have not been unequivocally established. Ultraviolet resonance Raman (UVRR) spectra are reported for 19-nortestosterone in acid solutions and for this ligand when bound to delta 5-3-ketosteroid isomerase, as well as to its D38N and Y14F/D38N mutants. The frequencies of UVRR bands associated with C = O and C = C stretching can be used to monitor the state of polarization of the enone fragment of the steroid and the effects of the catalytic side chains, Tyr-14 and Asp-38, on these polarizations. Strong polarization is indicated by marked frequency downshifts of the C = O and C = C bands in the native protein; the downshifts are diminished by the mutations of these catalytic residues. The lower polarizing effects of the Y14F and D38N single mutants and the Y14F/D38N double mutant indicate that most of the polarization of the conjugated ketone is attributable to hydrogen-bond donation by the hydroxyl group of Tyr-14. A smaller contribution of Asp-38 is detected which is, in part, cooperative with that of Tyr-14. Reference spectra of hydrogen-bonded and protonated forms of 19-nortestosterone are reassigned, on the basis of the species identification of D. C. Hawkinson and R. M. Pollack [(1993) Biochemistry 32, 694-698].(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1992

Substrate polarization by residues in delta 5-3-ketosteroid isomerase probed by site-directed mutagenesis and UV resonance Raman spectroscopy.

delta 5-3-Ketosteroid isomerase (KSI: EC 5.3.3.1) of Pseudomonas testosteroni catalyzes the isomerization of delta 5-3-ketosteroids to delta 4-3-ketosteroids by the stereospecific transfer of the steroid 4 beta-proton to the 6 beta-position, using Tyr-14 as a general acid and Asp-38 as a base. Ultraviolet resonance Raman (UVRR) spectra have been obtained for the catalytically active double mutant Y55F + Y88F, which retains Tyr-14 as the only tyrosine residue (referred to as the Y14(0) mutant), and the Y14F mutant, which has 50,000-fold lower activity. The UVRR results establish that binding of the product analog and competitive inhibitors 19-nortestosterone or 4-fluoro-19-nortestosterone to the Y14(0) mutant does not result in the formation of deprotonated Tyr-14. The UVRR spectra of the steroid inhibitors show large decreases in the vinyl and carbonyl stretching frequencies on binding to the Y14(0) enzyme but not on binding to the Y14F enzyme. These changes cannot be mimicked by protonation of the steroids. For 19-nortestosterone, the vinyl and carbonyl stretching frequencies shift down (with respect to the values in aqueous solution) by 18 and 27 cm-1, respectively, on binding to Y14(0) KSI. It is proposed that the changes in the steroid resonance Raman spectrum arise from polarization of the enone moiety via the close proximity of the charged Asp-38 side chain to the vinyl group and the directional hydrogen bond between Tyr-14 and the 3-carbonyl oxygen of the steroid enone. The 230-nm-excited UVRR spectra do not, however, show changes that are characteristic of strong hydrogen bonding from the tyrosine hydrogen. It is proposed that this hydrogen bonding is compensated by a second hydrogen bond to the Tyr-14 oxygen from another protein residue. UVRR spectra of the Y14(0) enzyme obtained using 200 nm excitation show enhancement of the amide II and S Raman bands. The secondary structure of KSI was estimated from the amide II and S intensities and was found to be low in alpha-helical structure. The alpha-helix content was estimated to be in the range of 0-25% (i.e., 10 +/- 15%).

Binding, Competitive↗
PubMed1989

An ultraviolet resonance Raman study of dehydrogenase enzymes and their interactions with coenzymes and substrates.

Ultraviolet resonance Raman (UVRR) spectra, with 260-nm excitation, are reported for oxidized and reduced nicotinamide adenine dinucleotides (NAD+ and NADH, respectively). Corresponding spectra are reported for these coenzymes when bound to the enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and liver and yeast alcohol dehydrogenases (LADH and YADH). The observed differences between the coenzyme spectra are interpreted in terms of conformation, hydrogen bonding, and general environment polarity differences between bound and free coenzymes and between coenzymes bound to different enzymes. The possibility of adenine protonation is discussed. UVRR spectra with 220-nm excitation also are reported for holo- and apo-GAPDH (GAPDH-NAD+ and GAPDH alone, respectively). In contrast with the 260-nm spectra, these show only bands due to vibrations of aromatic amino acid residues of the protein. The binding of coenzyme to GAPDH has no significant effect on the aromatic amino acid bands observed. This result is discussed in the light of the known structural change of GAPDH on binding coenzyme. Finally, UVRR spectra with 240-nm excitation are reported for GAPDH and an enzyme-substrate intermediate of GAPDH. Perturbations are reported for tyrosine and tryptophan bands on forming the acyl enzyme.

Alcohol Dehydrogenase↗
PubMed1989

Factors predicting failure of medical therapy for gastric ulcers.

We reviewed the charts of all patients admitted with a diagnosis of gastric ulcer from January 1970 to December 1980. Multiple risk factors were recorded in patients receiving medical treatment and compared in those patients successfully treated medically versus those requiring operation after a failed course of medical treatment. One hundred patients were treated medically without surgical intervention, and 34 patients underwent operation after medical therapy failed. Significant risk factors in patients requiring operative therapy included smoking (p = 0.03), multiple trauma and sepsis (p = 0.02), large ulcers (p = 0.03), and multiple ulcers (p = 0.02). We have identified a set of factors associated with a high risk of failure of medical therapy. Patients with any of these risk factors may be treated most effectively by a limited trial of medical therapy with close follow-up. If their ulcer disease does not respond readily to standard medical therapy, they should be considered for early elective surgery.

Emergencies↗