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Biomedical subjects

S Freeman

Publications and source records attributed to S Freeman.

At least 73 records · Page 4Linked to original sources
PubMed1999

Inhibitors of inositol monophosphatase.

Inositol monophosphatase (IMPase) catalyses the hydrolysis of myo-inositol monophosphates to myo-inositol, which is required in the phosphatidyl inositol cell signalling pathway. Here the enzyme structure, mechanism and inhibition of IMPase are reviewed. Lithium, an effective therapy for manic depression, is an uncompetitive inhibitor. In the search for alternative inhibitors to lithium, substrate-based inhibitors, bisphosphonates, terpenoid and tropolone analogues are described.

Inositol↗
PubMed1999

The effect of head orientation on the vestibular evoked potentials to linear acceleration impulses in rats.

OBJECTIVE: To investigate the influence of linear acceleration impulses delivered when the head is held in different static head orientations, on the first wave of the short latency vestibular evoked potential (VsEP). The first wave is the compound action potential of the primary vestibular neurons synchronously activated. BACKGROUND: It has been shown previously that the VsEP elicited in response to linear acceleration is initiated mainly in the otolith organs. These organs are responsive to both dynamic and static linear forces, including gravity. METHODS: VsEPs to linear acceleration stimuli (4g) were recorded when the rats head was oriented so that a) the plane of the utricular macula was aligned with the plane of the stimulus, b) in supine position and c) with the head pitched up and down in various angles with respect to gravity (stimulus-head spatial relation remained constant) as compared to a reference position. RESULTS: With the stimulus aligned with the plane of the utricular macula, the amplitude of the first wave of the L-VsEPs was significantly larger than in the reference position. In the supine position, the amplitude of the first wave was significantly larger and the latency was significantly shorter. The amplitude of the first VsEP wave tended to be larger in the "head up" orientations as compared to the "head down" orientations (not statistically significant). CONCLUSIONS: These results demonstrate the influence of head position and gravity on the VsEPs to linear acceleration impulses, which is in accordance with their otolithic origin.

Acceleration↗
PubMed1999

The rôle of thymidine phosphorylase/PD-ECGF in cancer chemotherapy: a chemical perspective.

The angiogenic growth factor thymidine phosphorylase/PD-ECGF has been identified as a potential target in the development of anti-cancer drugs. This review firstly discusses the biological rôle of TP/PD-ECGF and its importance in the activation of 5-fluorouracil and its prodrugs. The chemistry and chemotherapeutic potential of TP/PD-ECGF inhibitors are also discussed.

Animals↗
PubMed1999

A similarity model for the human angiogenic factor, thymidine phosphorylase/platelet derived-endothelial cell growth factor.

Thymidine phosphorylase (EC 2.4.2.4), identical to the angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), is up-regulated in several tumour types. A similarity model of human thymidine phosphorylase was built, based on the crystal structure of the Escherichia coli enzyme. The high residue conservation between the two enzyme sources (39% sequence identity and 53% sequence similarity) aided model building. The human model was very similar to the E. coli enzyme's crystal structure, with the main tertiary structure difference being the destruction of helix 15 in E. coli by the presence of a loop in the human model. The model was used to rationalize the nature of the binding of the substrates thymine and thymidine, and of known inhibitors using a quantitative docking algorithm. Ab initio calculations on the nM inhibitor 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride gave its conformation and distribution of charge. Subsequent quantitative docking studies have led to the suggestion, for the first time, that this inhibitor behaves as an oxycarbenium ion transition-state analogue, explaining its strong reported inhibition.

Amino Acid Sequence↗
PubMed1999

Constructing the pediatric nurse: eugenics and the gendering of infant hygiene in early twentieth century Berlin.

This article explores the connections between infant mortality, eugenic thinking, and the professional development of pediatricians and pediatric nurses in the early twentieth century. It argues that the goal of the physicians affiliated with Germany's National Hospital to Combat Infant Mortality was to create and disseminate a centrally-controlled message about infant hygiene, and to transform infant care into a medically-managed event. The deeply gendered ways in which both the hygienic program, and the medical division of labor were constructed, had the ambiguous result of expanding training opportunities for pediatric nurses, while at the same time, severely limiting their professional autonomy.

Eugenics↗
PubMed1999

Differential effect of the loop diuretic furosemide on short latency auditory and vestibular-evoked potentials.

OBJECTIVE: This study aimed to investigate the differential effect of the loop diuretic furosemide on the auditory and vestibular (otolith) end organs in the same animals simultaneously. DESIGN AND METHODS: Auditory nerve-brain stem-evoked responses (ABR-generated in the cochlea) and short latency vestibular-evoked responses to linear acceleration impulses (L-VsEP-generated in the otolith organs) were recorded from albino Sabra rats both before and at minute intervals after intravenous injections of the loop diuretic furosemide. In some animals, an equal volume of saline was injected to control for the effect of the injection itself. In most animals, more than one injection of saline or furosemide was possible (furosemide, N = 17 injections in 10 rats; saline, N = 18 injections in 9 rats). Peak-to-peak amplitude and peak latency changes in the first wave in each recording (representing end-organ activity) as a function of postinjection time were compared between the two evoked potentials using analysis of variance and repeated t-tests. RESULTS: Saline injections caused only minor changes in the amplitude of the ABR and the L-VsEP. After administration of furosemide, the amplitude of the L-VsEP hardly changed. However, there was a noticeable decrease in the amplitude of the ABR. CONCLUSIONS: Although furosemide has a major depressant effect on cochlear function, vestibular end-organ activity is hardly altered.

Analysis of Variance↗
PubMed1998

Characterization of siglec-5, a novel glycoprotein expressed on myeloid cells related to CD33.

We describe the characterization of siglec-5 (sialic acid-binding Ig-like lectin-5), a novel transmembrane member of the immunoglobulin superfamily, highly related to the myeloid antigen, CD33. A full-length cDNA encoding siglec-5 was isolated from a human activated monocyte cDNA library. Sequencing predicted that siglec-5 contains four extracellular immunoglobulin-like domains, the N-terminal two of which are 57% identical to the corresponding region of CD33. The cytoplasmic tail is also related to that of CD33, containing two tyrosine residues embodied in immunoreceptor tyrosine-based inhibitory motif-like motifs. The siglec-5 gene was shown to map to chromosome 19q13.41-43, closely linked to the CD33 gene. When siglec-5 was expressed on COS cells or as a recombinant protein fused to the Fc region of human IgG1, it was able to mediate sialic acid-dependent binding to human erythrocytes and soluble glycoconjugates, suggesting that it may be involved in cell-cell interactions. By using specific antibodies, siglec-5 was found to have an expression pattern distinct from that of CD33, being present at relatively high levels on neutrophils but absent from leukemic cell lines representing early stages of myelomonocytic differentiation. Western blot analysis of neutrophil lysates indicated that siglec-5 exists as a disulfide-linked dimer of approximately 140 kD.

Amino Acid Sequence↗
PubMed1998

Regulation of Ca2+-dependent Cl- conductance in a human colonic epithelial cell line (T84): cross-talk between Ins(3,4,5,6)P4 and protein phosphatases.

1. We have studied the regulation of whole-cell chloride current in T84 colonic epithelial cells by inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P4). New information was obtained using (a) microcystin and okadaic acid to inhibit serine/threonine protein phosphatases, and (b) a novel functional tetrakisphosphate analogue, 1, 2-bisdeoxy-1,2-bisfluoro-Ins(3,4,5,6)P4 (i.e. F2-Ins(3,4,5,6)P4). 2. Calmodulin-dependent protein kinase II (CaMKII) increased chloride current 20-fold. This current (ICl,CaMK) continued for 7 +/- 1.2 min before its deactivation, or running down, by approximately 60 %. This run-down was prevented by okadaic acid, whereupon ICl,CaMK remained near its maximum value for >= 14.3 +/- 0.6 min. 3. F2-Ins(3, 4,5,6)P4 inhibited ICl,CaMK (IC50 = 100 microM) stereo-specifically, since its enantiomer, F2-Ins(1,4,5,6)P4 had no effect at >= 500 microM. Dose-response data (Hill coefficient = 1.3) showed that F2-Ins(3,4,5,6)P4 imitated only the non-co-operative phase of inhibition by Ins(3,4,5,6)P4, and not the co-operative phase. 4. Ins(3,4,5,6)P4 was prevented from blocking ICl,CaMK by okadaic acid (IC50 = 1.5 nM) and microcystin (IC50 = 0.15 nM); these data lead to the novel conclusion that, in situ, protein phosphatase activity is essential for Ins(3,4,5,6)P4 to function. The IC50 values indicate that more than one species of phosphatase was required. One of these may be PP1, since F2-Ins(3,4,5,6)P4-dependent current blocking was inhibited by okadaic acid and microcystin with IC50 values of 70 nM and 0.15 nM, respectively.

Calcium↗
PubMed1998

Long-term persistence of activated cytotoxic T lymphocytes after viral infection of the central nervous system.

Mice intranasally inoculated with influenza A/X-31 are protected against a subsequent intracerebral challenge with the neurovirulent influenza A/WSN and this heterotypic protection is mediated by CD8(+) cytotoxic T lymphocytes. We have studied the kinetics of this secondary immune response and found that despite the elimination of replication-competent virus by day 10, we were able to recover activated influenza-specific cytotoxic T lymphocytes (CTLs) that killed freshly ex vivo from the brains of mice for at least 320 d after the intracerebral inoculation. The activated antiviral CTLs expressed high levels of the early activation marker CD69, suggesting continuing TCR signaling despite a lack of viral protein and major histocompatibility complex staining by immunohistochemistry in the brain parenchyma and barely detectable levels of viral nucleic acid by single and two-step reverse transcription PCR. Local persistence of activated lymphocytes may be important for efficient long-term responses to viruses prone to recrudesce in sites of relative immune privilege.

Animals↗
PubMed1998

Combination therapy with thymosin alpha1 and interferon for the treatment of chronic hepatitis C infection: a randomized, placebo-controlled double-blind trial.

Hepatitis C is a major cause of liver disease leading to cirrhosis. Although interferon (IFN) is the only approved therapy, treatment is characterized by low response rates and dose-limiting side effects. We evaluated the addition of thymosin alpha1 (TA1), an immunomodulatory peptide, to the standard treatment regimen for hepatitis C to determine if combination therapy shows biological activity using outcome measures including normalization of alanine aminotransferase levels, histological activity, and viral load during treatment. We performed a randomized, double-blind, placebo-controlled trial to compare the biological activity of a combination TA1 and IFN with that seen for IFN alone in patients with chronic hepatitis C infection. One hundred nine patients were randomized for intention to treat and received 1.6 mg of TA1 subcutaneously twice weekly and 3 MU of IFN three times weekly; 3 MU of IFN three times weekly and placebo TA1; or placebo for both agents. All patients had chronic HCV infection with confirmation of chronic hepatitis on liver biopsy. Biochemical responders were followed up until alanine aminotransferase (ALT) levels became abnormal or for 26 weeks, and relapsers were retreated for 26 weeks in the same treatment arm. One hundred three patients completed treatment for 26 weeks, and six patients dropped out. The groups were similar with regard to sex, gender distribution, baseline histological activity index (HAI) score, risk factors, and viral titers. End-of-treatment biochemical response was seen in 37.1% of patients treated with combination therapy, 16.2% of patients treated with IFN alone, and 2.7% of untreated controls by intent-to-treat analysis (IFN/TA1 vs. IFN, chi2 = 4.05, P = .04). HCV RNA clearance was seen in 37.1% of IFN/TA1-treated patients and 18.9% of IFN-treated subjects. Mean HCV RNA titers were significantly lower than baseline at weeks 8, 16, and 24 after drug initiation among patients treated with IFN/TA1 but not in the other treatment arms. Histological improvement, as evidenced by a decrease in HAI of more than two points, occurred in the combination therapy arm more frequently than in comparison groups. Cumulative sustained biochemical responses were 14.2% and 8.1% in the IFN/TA1 and IFN arms, respectively, based on an intention-to-treat model. The combination of TA1 and standard IFN treatment for chronic hepatitis C showed evidence of biological activity at the completion of treatment by biochemical, histological, and virological outcome measures. Further research involving longer duration and varied dosing is needed.

Adult↗
PubMed1998

Complexity and human health: the case for a transdisciplinary paradigm.

Transdisciplinary thinking is an emerging philosophy underpinning health social science. We advance a definition of transdisciplinary thinking and link it with complexity theory. Complexity theory's concern with non-linear relationships, interactive causality and emergent properties of systems compels researchers to adopt a transdisciplinary perspective. We construct a generic framework for analyzing health processes from diverse disciplines and apply it to coronary heart disease in the Australian Coalfields. Insights from this analysis support our argument that transdisciplinary thinking maximizes understanding of the complexity of human health.

Adult↗
PubMed1998

Allergic contact dermatitis to ethoxyquin in a farmer handling chicken feeds.

Farm workers handling animal feeds are exposed to a variety of chemicals, some of which may cause allergic contact dermatitis. A case of allergy to ethoxyquin (a preservative added to chicken feed to inhibit vitamin degradation) in a chicken farmer is presented. Although the offending allergen was identified in this patient, it proved difficult to find ethoxyquin-free chicken feed products and the patient's dermatitis persisted. When facing the clinical problem of dermatitis in animal workers, the possibility of allergic contact dermatitis to components in animal feeds must be considered.

Adult↗
PubMed1998

Tea tree oil allergy: what is the offending agent? Report of three cases of tea tree oil allergy and review of the literature.

Tea tree oil is currently enjoying popularity as a 'cure-all' for a variety of skin conditions, from infections to psoriasis, and many household and personal products containing Melaleuca oil are available. However, despite its chemical complexities and enthusiastic use, there have been only a few reports of allergic reactions to tea tree oil. At the Skin and Cancer Foundation (Sydney, NSW, Australia), three of 28 normal volunteers tested strongly positive to patch testing with tea tree oil. Following further patch testing with tea tree oil constituents, all three patients reacted strongly to two preparations containing sesquiterpenoid fractions of the oil. Because patients often neglect to mention that they have used 'natural' remedies, it is important that physicians are aware of the potential adverse effects of these products. Furthermore, identification of the allergenic ingredients in tea tree oil may assist the growing industry to produce safer products.

Adult↗
PubMed1998

Predictive sensitivity of human cancer cells in vivo using semipermeable polysulfone fibers.

An in vivo experimental model was developed to predict efficiently and accurately chemosensitivity of human tumors. Human cancer cells either from cultured cell lines or from patients' tumors were injected directly into semipermeable polysulfone fibers subsequently implanted into immunocompetent rats. Results suggest utility of this novel model system for predicting tumor sensitivity to a wide range of anticancer agents and for potentially guiding the treatment of cancer patients in the clinical setting.

Animals↗
PubMed1998

Gene therapy for malignant mesothelioma: a novel approach for an incurable cancer with increased incidence in Louisiana.

Malignant mesothelioma (MM) is a tumor of the pleura for which there is no satisfactory treatment. It is an almost universally fatal disease, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalities is superior to no treatment at all. Because of the dismal prognosis for patients with MM, new modes of treatment are desperately needed. A promising area of research into the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-TK). By virtue of their expression of HSV-TK, the transduced cells are rendered susceptible to the antiviral drug, ganciclovir (GCV). Nearby untransduced tumor cells are killed by a so-called bystander effect. We are describing a Phase I clinical gene therapy trial for MM, which we are presently conducting at the Louisiana State University Medical Center of New Orleans. The purpose is to study the safety and to determine the maximal tolerated dose of an HSV-TK-transduced ovarian cancer cell line (PA1-STK cells) that is infused into the pleural cavities of patients. This infusion is followed by systemic administration of GCV. The hope is that administration of GCV will result in killing of both the transduced ovarian cancer cells as well as the nearby malignant cells.

Ganciclovir↗
PubMed1997

Virus dissemination through the brain parenchyma without immunologic control.

After inoculation into the cerebrospinal fluid, the neurovirulent influenza virus A/WSN caused a rapidly progressive encephalitis that was uniformly fatal within 8 days. After inoculation into the brain parenchyma, the same virus replicated for 7 to 20 days without causing clinical illness, but when infection reached the cerebrospinal fluid, encephalitis was lethal within a further 6 days. As the virus spread through the brain parenchyma, there was intense intracerebral inflammation, with up-regulation of MHC class I and MHC class II expression and recruitment of CD44(high) CD49d(high) T cells. However, this was not associated with antiviral Ab production, and the infiltrating cells, unlike primed A/WSN-specific T cells, did not eliminate the virus in vivo or show evidence of virus recognition in vitro. Thus, a neurovirulent virus was able to disseminate widely through the brain parenchyma and induce considerable intracerebral inflammation without eliciting protective immunity.

Animals↗