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Biomedical subjects

J S Williamson

Publications and source records attributed to J S Williamson.

At least 19 recordsLinked to original sources
PubMed2005

Pseudo-peptides derived from isomannide as potential inhibitors of serine proteases.

Hepatitis C, Dengue and West Nile virus are among of the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes, and are a primary target in the drug development field. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N-t-Boc amino acid amides derived of isomannide as potential serine proteases inhibitors.

Animals↗
PubMed2004

N- t-Boc-amino acid esters of isomannide. Potential inhibitors of serine proteases.

Hepatitis C, Dengue and West Nile virus are some of the most important flaviviruses, that share one important serine protease enzyme. Serine proteases are the most studied class of proteolytic enzyme and, in these cases, a primary target for drug discovery. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N- t-Boc amino acid esters derived of isomannide as potential serine proteases inhibitors.

Amino Acids↗
PubMed2004

Transformation of artemisinin by Cunninghamella elegans.

Semi-synthetic derivatives of the anti-malarial drug artemisinin hold great promise in the search for an effective and economical treatment of chloroquine-resistant forms of malaria. Unfortunately, synthetic functionalization of the artemisinin skeleton is often tedious and/or impractical. We seek to utilize 7beta-hydroxyartemisinin, obtained from microbial transformation, as a semi-synthetic precursor for the synthesis of novel 7beta-substituted artemisinin anti-malarial agents. Here we employ liquid cultures of Cunninghamella elegans as a means for the rational and economical bioconversion of artemisinin to 7beta-hydroxyartemisinin in 78.6% yield. In addition, there were three other bioconversion products: 7beta-hydroxy-9alpha-artemisinin (6.0%), 4alpha-hydroxy-1-deoxoartemisinin (5.4%), and 6beta-hydroxyartemisinin (6.5%).

Antimalarials↗
PubMed2004

Anti-Helicobacter pylori agents. An update.

Helicobacter pylori infection is the major causative factor of a number of gastric pathologies. Several classes of compounds have been identified as anti-H. pylori agents. Here we provide a review of anti-H. pylori compounds that have recently appeared in the literature, including the guanidino, antibiotics, acetamide, pyrazole and benzimidazole compounds.

Anti-Bacterial Agents↗
PubMed2002

Hydroxamic acids as pharmacological agents.

A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A(4) hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.

Amidohydrolases↗
PubMed2001

Vascular resistance in human muscle flaps.

Important differences in free muscle flap survival have been reported in the setting of long arterial and venous vein grafts. The authors provide insight into the etiology of flap failure by addressing the following question: Do differences in flap type result in clinically significant different vascular resistances and consequently anastomotic patency? A total of 15 human flaps were studied intraoperatively: 9 gracilis, 3 rectus abdominis, and 3 latissimus dorsi. The muscle was isolated on a single pedicle and hemodynamic stability was ensured. The venous pedicle was then divided. A timed collection of effluent was used to determine flow. Vascular resistance was calculated by dividing the change in pressure by the flow, and standardizing this for temperature and hematocrit. Average vascular resistance and standard deviation for the gracilis, rectus, and latissimus flaps was 10.34 +/- 7.77 mmHg per milliliter per minute, 2.79 +/- 1.50 mmHg per milliliter per minute, and 3.17 +/- 1.05 mmHg per milliliter per minute respectively. An inverse relationship between muscle vascular resistance and flap mass was found (p < 0.001). This indicates that larger muscles have less vascular resistance. The decreased resistance gives rise to higher flow rates and, as a result, potentially improved vein graft patency. The clinical implication is that a larger flap should be used when high flow-through is critical. The role of flap vascular territory makeup continues to be pursued.

Abdominal Muscles↗
PubMed2001

A review of cancer chemopreventive agents.

In the late 20(th) century, the treatment of cancer began to include its prevention. Today, compounds exist that will lower the risk of developing certain types of cancer. This has been demonstrated in studies where chemically induced tumor growth has been slowed or reversed. Anti-inflammatory compounds having chemopreventive activity are piroxicam, sulindac, aspirin, celecoxib and curcumin. The selective estrogen receptor modulators, tamoxifen and raloxifene, are beneficial in the prevention of estrogen dependent tumors. Retinoids, vitamin A derivatives, such as targretin and fenretinide are useful in the prevention of tumors. Compounds containing sulfur, such as sulforaphane and oltipraz, are even useful as radioprotective agents. The steroid dehydroepiandosterone can inhibit experimental carcinogenesis. All of these chemical classes provide a start for the medicinal chemist to design more effective chemopreventive agents. The biomarkers used to determine the chemopreventive activity of new compounds are quite often activities of enzymes. The identification of those individuals at high risk is still in its infancy and presents a troubling dilemma.

Animals↗
PubMed2001

Helicobacter pylori: current chemotherapy and new targets for drug design.

Helicobacter pylori infection is a major cause of many diseases of the gastrointestinal tract, including gastritis, non-ulcer dyspepsia, peptic ulcer disease, and gastric cancers. It is estimated that more than half of the human race is affected by this organism. Although effective treatments are available which will eliminate the organism in about 90 percent; of cases in developed countries, the pandemic occurrence of Helicobacter pylori infection coupled with its ability to develop resistance to our current arsenal of antimicrobial regimens and subsequently reinfect patients makes the pathogenic potential of this microorganism a major global health concern. Provided is a review of the current and evolving therapeutic regimens used in the eradication of Helicobacter pylori, the difficulties associated with in vitro drug screening, as well as potentially new therapeutic targets. In addition, the discovery, the unique physiology, biochemistry, and pathogenicity of this remarkable microorganism is examined.

Bacterial Adhesion↗
PubMed2001

Toe-to-finger transfer for post-traumatic reconstruction of the fingerless hand.

OBJECTIVE: To assess the utility of toe-to-finger transfers (TFTs) for post-traumatic reconstruction of the fingerless hand. DESIGN: A case series. SETTING: A regional trauma centre. PATIENTS: Eight men, mean age was 36 years (range from 25-59 yr), who had lost all the fingers from a hand due to a crush-degloving injury (6 patients), frostbite (1 patient) or a burn injury (1 patient). INTERVENTION: TFT. Twelve TFTs were cone and the mean time from injury to reconstruction was 17.2 months. MAIN OUTCOME MEASURES: Objective (range of motion, moving 2-point discrimination, grip strength, key pinch, Jebsen-Taylor hand assessment, return to work) and subjective (activities of daily living and a questionnaire) measures. RESULTS: Eleven of the 12 transfers survived. Six of the 7 in whom the transfer was successful were available for follow-up (mean 45 mo). Range of motion was 10 degrees at the distal interphalangeal joint, 18 degrees at the proximal interphalangeal joint and 59 degrees at the metacarpophalangeal joint. Sensation was protective in all. Grip strength and key pinch were 26.1% and 70.2% of the contralateral hand respectively. Jebsen-Taylor assessment indicated that basic activities were possible but slowed. All 6 patients returned to work and could perform 92.6% of the activities of daily living unassisted. Hand and foot symptoms were mild. Two-thirds were appearance conscious, 5 of the 6 went on to altered vocations and all reported overall satisfaction as high. CONCLUSION: This study supports TFT for reconstruction of the fingerless hand in that, although transferred toe function may be poorer than a normal finger, the hand is restored to a useful, sensate and versatile functional unit, such that global hand and patient function, as well as patient satisfaction, are very good.

Adult↗
PubMed2000

Angiogenesis: new targets for the development of anticancer chemotherapies.

Angiogenesis is the process by which new blood vessels are formed from preexisting microvasculature. To ensure an adequate blood supply, tumor cells release angiogenic factors that are capable of promoting nearby blood vessels to extend vascular branches to the tumor. In addition, larger tumors have been shown to release angiogeneic inhibitory factors that prevent blood vessels from sending branches to smaller, more distant tumors that compete for oxygen and nutrients. Angiogenesis is a complex multistep biochemical process, and offers several potential molecular targets for non-cytotoxic anticancer therapies. Strategies for exploiting tumor angiogenesis for novel cancer drug discovery include: (i) inhibition of proteolytic enzymes that breakdown the extracellular matrix surrounding existing capillaries; (ii) inhibition of endothelial cell migration; (iii) inhibition of endothelial cell proliferation; (iv) enhancement of tumor endothelial cell apoptosis. There is also a host of miscellaneous agents that inhibit angiogenesis for which the specific mechanisms are not clear. Several methods have been developed for measuring antiangiogenic activity both in vitro and in vivo. Although there has been intensive research efforts focused at the phenomena of angiogenesis, as well as the search for antiangiogenic agents for more than two decades, many questions remain unanswered with regard to the overall biochemical mechanisms of the angiogenesis process and the potential therapeutic utility of angiogenic inhibitors. Nevertheless potent angiogenic inhibitors capable of blocking tumor growth have been discovered, and appear to have potential for development into novel anticancer therapeutics. However there are still hurdles to be overcome before these inhibitors become mainstream therapies.

Angiogenesis Inhibitors↗
PubMed1995

Cultured epithelial autograft: five years of clinical experience with twenty-eight patients.

Cultured epithelial autograft (CEA) has been used as an adjunct in burn wound coverage at the Vancouver Hospital and Health Sciences Centre since 1988, and has been available to all patients admitted with significant burn injuries. During the 5-year period from 1988 to 1992 inclusive, 28 patients treated with CEA survived long enough for assessment. The mean age was 35.3 years with a mean total body surface area burn of 52.2% and a mean total full thickness injury of 42.4%. CEA was applied to wounds covering between 2% and 35% body surface area (BSA; mean 10.4%) after excision to fat or fascia. Most wounds had interim homograft coverage. Preservation of homograft dermis was attempted in three patients at the time of removal without effect. The mean CEA "take" was 26.9% of the grafted area. Eight patients had 50% or greater take and were discharged with between 1 and 19% BSA covered with CEA. Thirteen patients had no take on wounds between 2 and 16% BSA. Overall mortality in burn patients treated at the Vancouver Hospital and Health Sciences Centre from 1988 to 1992 was not significantly different from 1983 to 1987 with the populations being similar in terms of total BSA burns, age, inhalation injury, and homograft availability. When compared to a matched control population from the preceding 5 years, when CEA was not available, there was no significant difference in duration of hospital stay or number of autograft harvests. However, approximately one more debridement without autograft harvest per CEA patient occurred. Timing and depth of wound excision, interim coverage, type of dressing, and wound microbiology were not found to influence good versus poor take. The anterior trunk and thighs were the best recipient sites. Subjective differences between CEA and meshed autograft were noted. The results show that after 5 years of use, CEA engraftment continues to be unpredictable and inconsistent, and hence, it should be used as only a biologic dressing and experimental adjunct to conventional burn wound coverage with split thickness autograft.

Adolescent↗
PubMed1991

Characterization of brain-infiltrating mononuclear cells during infection with mouse hepatitis virus strain JHM.

The eradication of infectious virus from the central nervous system (CNS) following infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) is thought to be immune-mediated. Furthermore, a significant decrease of infectious virus coincides with the appearance of prominent inflammatory infiltrates in the brain and spinal cord. In the present study, mononuclear cells infiltrating the brain during JHMV infection were isolated and characterized. While all subsets of immune cells were present, there appeared to be a temporal relationship between the peak incidence of CD8+ T cells (40% of total isolated cells) and reduction of virus at day 7 post-infection. Cells with the natural killer (NK) phenotype (at least 30%) were also present throughout infection. These data suggest that CD8+ T cells and NK cells are prominent among cells which infiltrate the brain during JHM virus infection and may have important roles in reduction of virus within the CNS.

Animals↗
PubMed1990

Ocular molecules and cells that regulate immune responses in situ.

Regulation of T cell-dependent immune responses is mediated in part by bone marrow-derived antigen presenting cells (APC) that (a) process and present antigens which engage the T cell receptor and (b) secrete cytokines that influence the threshold of T cell activation. The anterior chamber of the eye is lined by the corneal endothelium (which rests on a stroma and epithelium that is devoid of class II MHC + APC) and iris/ciliary body (which contain significant numbers of bone marrow-derived cells, one third of which are class II MHC +). When tested in vitro, these potential APCs fail to present antigens in a form that activates T cells. Moreover, iris/ciliary body cells actually suppress activation of T cells exposed to antigens on conventional APC. In addition, aqueous humor under normal circumstances contains factors (one of which is TGFB) that are potent inhibitors of antigen-driven T cell activation, but spare other aspects of T cell function. Evidence suggests that the bone marrow-derived cells in iris/ciliary body are the source of this factor. Thus, the anterior chamber contains powerful forces that can prevent induction and can suppress expression of T cell mediated immunity. It is proposed that these forces are responsible for immunologic privilege and anterior chamber associated immune deviation, and for suppressing pathologic proliferation and inflammation in the anterior segment of the eye.

Animals↗
PubMed1990

Effective clearance of mouse hepatitis virus from the central nervous system requires both CD4+ and CD8+ T cells.

Both CD4+ and CD8+ T cells are required for the clearance of virus from the central nervous system following infection with the JHM strain of mouse hepatitis virus. Development of antiviral antibodies requires the presence of CD4+ T cells but appears to play a minimal role in the reduction of virus. The data presented are consistent with the hypothesis that clearance of JHM virus is mediated by virus-specific CD8+ T cells, which appear to require the presence of CD4+ T cells.

Animals↗
PubMed1989

Induction of delayed hypersensitivity to alloantigens coinjected with Langerhans cells into the anterior chamber of the eye. Abrogation of anterior chamber-associated immune deviation.

Inoculation of P815 tumor cells (DBA/2 origin) into the anterior chamber of eyes of BALB/c mice normally produces anterior chamber-associated immune deviation (ACAID) whereby delayed hypersensitivity (DH) responses to the minor H alloantigens of the tumor cells are suppressed. Based on our previous work showing an association of Langerhans cell infiltration into central cornea with the abrogation of ACAID, we have hypothesized that the induction of ACAID may depend upon the avoidance of local antigen processing within the anterior chamber. In this study, we have examined whether various putative antigen-presenting cells coinjected with allogeneic P815 cells into the anterior chamber could alter the course of the subsequent systemic alloimmune response. BALB/c recipients of intracameral P815 cells admixed with BALB/c spleen cells, B cells, or A20 B lymphoma cells developed ACAID. However, recipients of tumor cells admixed with cutaneous epidermal cells containing LC, and those receiving intracameral P815 cells admixed with purified LC developed vigorous DBA/2-specific delayed hypersensitivity responses. We conclude that avoidance of antigen processing and presentation by specialized APC such as dendritic LC within the anterior chamber is a condition for the induction of ACAID. Since under normal circumstances the anterior chamber is lined by tissues that are devoid of LC and contain very few class II MHC-expressing cells, this immunologically privileged site appears to be designed physiologically to avoid the unique form of local antigen presentation offered by dendritic LC--a condition that favors induction of selective immunologic incompetence.

Animals↗
PubMed1989

O dealkylation and aliphatic and aromatic hydroxylation of 3-methoxy-17 beta-estradiol by Aspergillus alliaceus.

Aspergillus alliaceus UI 315 was examined for its ability to metabolize 3-methoxy-17 beta-estradiol. Preparative-scale incubations with this substrate afforded good yields of 6 beta-hydroxy-17 beta-estradiol, 4-hydroxy-17 beta-estradiol, and 4,6 beta-dihydroxy-17 beta-estradiol, which were identified by high-pressure liquid chromatography, 1H and 13C nuclear magnetic resonance, and high-resolution mass spectrometry.

Aspergillus↗
PubMed1989

Immunoregulatory properties of bone marrow-derived cells in the iris and ciliary body.

Iris and ciliary body of mouse eyes have been examined for the presence of bone marrow-derived cells possessing the capability of functioning as antigen-presenting cells (APC). We have determined that iris and ciliary body contain significant numbers of cells bearing T200, indicating their bone marrow origin. Most of these express the F4/80 marker typically found on mature macrophages. However, approximately one-third of the cells express Ia and a similar number express Mac-1 markers. Virtually none of the cells express Thy-1 or surface immunoglobulin. Whole preparations of excised iris/ciliary body, or single cell suspensions prepared from these tissues were then assayed for their capacity to induce proliferation among allogeneic lymphocytes. It was discovered that iris/ciliary body tissues or cells did not function as alloantigen-presenting cells, although tissue and cells derived from the corneal limbus were allostimulatory. In addition, iris/ciliary body tissues and cells displayed the ability to suppress mixed lymphocyte reactions to which they had been added as regulatory cells. We conclude that normal iris and ciliary body contain bone marrow-derived cells that fail to function as alloantigen-presenting cells. However, cells were present that have the capacity to inhibit alloimmune lymphocyte proliferation. The strategic location of inhibitory cells in the tissues that line the anterior chamber of the eye raises the possibility that these cells may play a role in the phenomenon of immunological privilege that is characteristic of this site.

Animals↗