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Michael Williams

Publications and source records attributed to Michael Williams.

At least 19 recordsLinked to original sources
PubMed2025

Absolute quantification of the living skin microbiome overcomes relic-DNA bias and reveals specific patterns across volunteers.

BACKGROUND: As the first line of defense against external pathogens, the skin and its resident microbiota are responsible for protection and eubiosis. Innovations in DNA sequencing have significantly increased our knowledge of the skin microbiome. However, current characterizations do not discriminate between DNA from live cells and remnant DNA from dead organisms (relic DNA), resulting in a combined readout of all microorganisms that were and are currently present on the skin rather than the actual living population of the microbiome. Additionally, most methods lack the capability for absolute quantification of the microbial load on the skin, complicating the extrapolation of clinically relevant information. RESULTS: Here, we integrated relic-DNA depletion with shotgun metagenomics and bacterial load determination to quantify live bacterial cell abundances across different skin sites. Though we discovered up to 90% of microbial DNA from the skin to be relic DNA, we saw no significant effect of this on the relative abundances of taxa determined by shotgun sequencing. Relic-DNA depletion prior to sequencing strengthened underlying patterns between microbiomes across volunteers and reduced intraindividual similarity. We determined the absolute abundance and the fraction of population alive for several common skin taxa across body sites and found taxa-specific differential abundance of live bacteria across regions to be different from estimates generated by total DNA (live + dead) sequencing. CONCLUSIONS: Our results reveal the significant bias relic DNA has on the quantification of low biomass samples like the skin. The reduced intraindividual similarity across samples following relic-DNA depletion highlights the bias introduced by traditional (total DNA) sequencing in diversity comparisons across samples. The divergent levels of cell viability measured across different skin sites, along with the inconsistencies in taxa differential abundance determined by total vs live cell DNA sequencing, suggest an important hypothesis for certain sites being susceptible to pathogen infection. Overall, our study demonstrates a characterization of the skin microbiome that overcomes relic-DNA bias to provide a baseline for live microbiota that will further improve mechanistic studies of infection, disease progression, and the design of therapies for the skin. Video Abstract.

Humans↗
PubMed2004

Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist.

Histamine H3 receptors regulate the release of a variety of central neurotransmitters involved in cognitive processes. A-349821 ((4'-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone) is a novel, non-imidazole H3 receptor ligand, displaying high affinity for recombinant rat and human H3 receptors, with pKi values of 9.4 and 8.8, respectively, and high selectivity for the H3 receptor versus H1, H2, and H4 histamine receptors. A-349821 is a potent H3 receptor antagonist in a variety of models using recombinant human and rat receptors, reversing agonist induced changes in cyclic AMP formation (pKb= 8.2 and pKb= 8.1, respectively), [35S]-GTPgammaS binding (pKb= 9.3 and pKb= 8.6, respectively) and calcium levels (human pKb= 8.3). In native systems, A-349821 competitively reversed agonist induced inhibition of electric field stimulated guinea-pig ileum (pA2= 9.5) and histamine-mediated inhibition of [3H]-histamine release from rat brain cortical synaptosomes (pKb= 9.2). Additionally, A-349821 inhibited constitutive GTPgammaS binding at both rat and human H3 receptors with respective pEC50 values of 9.1 and 8.6, demonstrating potent inverse agonist properties. In behavioral studies, A-349821 (0.4 mg/kg-4 mg/kg) potently blocked (R)-alpha-methylhistamine-induced dipsogenia in mice. The compound also enhanced cognitive activity in a five-trial inhibitory avoidance model in spontaneously hypertensive rat (SHR) pups at doses of 1-10mg/kg, with the 1mg/kg dose showing comparable efficacy to a fully efficacious dose of ciproxifan (3mg/kg). These doses of A-349821 were without effect on spontaneous locomotor activity. Thus, A-349821 is a novel, selective non-imidazole H3 antagonist/inverse agonist with balanced high potency across species and favorable cognition enhancing effects in rats.

Animals↗
PubMed2004

Management of patients admitted with an Acute Coronary Syndrome in New Zealand: results of a comprehensive nationwide audit.

AIMS: To audit all patients presenting to a New Zealand hospital with a myocardial infarction or unstable angina (an acute coronary syndrome [ACS]) over a 14-day period, to assess their number, presentation type and patient management during the hospital admission. METHODS: We formed a group of clinicians to lead the local audit process with one representative for each hospital (n=36) that admitted ACS patients. A comprehensive data form was used to record individual patient information for patients admitted between 0000 hours on 13 May 2002 to 2400 hours on 26 May 2002. RESULTS: 930 patients were admitted with a suspected or definite ACS: 11% with a ST-segment-elevation myocardial infarction (STEMI), 31% with a non-STEMI, 36% with unstable angina pectoris (UAP), and 22% with another cardiac or medical diagnosis. Cardiac investigations were limited: echocardiogram (20%), exercise treadmill test (20%), cardiac angiogram (21%). In-hospital revascularisation rates were low for those patients with a definite presentation with an ACS (STEMI, non-STEMI, UAP, n=721). Percutaneous coronary intervention (PCI) rates were 13%, 8%, and 4%--with coronary artery bypass grafting (CABG) rates being 4%, 3%, and 4% respectively. The use of discharge medications of proven benefit was also generally low (n=695): aspirin (82%), clopidogrel (8%), beta-adrenergic blockers (63%), angiotensin converting enzyme (ACE) inhibitors (43%), and statins (55%). CONCLUSIONS: A collaborative group of clinicians has performed a nationwide audit of acute coronary syndrome patients, which has demonstrated low levels of investigations, evidence-based treatments, and revascularisation. There is a need for a comprehensive national strategy--particularly for continuing audit of the treatment of patients presenting with a suspected or definite acute coronary syndrome to a New Zealand hospital.

Adult↗
PubMed2004

Acute Coronary Syndrome patients in New Zealand receive less invasive management when admitted to hospitals without invasive facilities.

AIM: To compare differences in the presentation and management of acute coronary syndrome (ACS) patients presenting to interventional versus non-interventional New Zealand hospitals. METHODS: We assessed the data collected by the New Zealand Cardiac Society ACS Audit Group over 14 days from each hospital in New Zealand (n=36) that admits ACS patients. Patient management at intervention centres (5 public, 3 private) was compared with non-intervention centres (28 public). Investigations and revascularisation procedures performed on transferred patients were attributed to the referring centre. RESULTS: From 0000 hours on 13 May 2002 to 2400 hours on 26 May 2002, 930 patients were admitted to a New Zealand hospital with a suspected or definite ACS: ST-segment-elevation myocardial infarction [STEMI] (11%), non-STEMI (31%), unstable angina pectoris [UAP] (36%), or another cardiac or medical diagnosis (22%). Patients admitted to a non-intervention centre (n=612) were the same age (median 70 years) with similar risk factors, but were more likely to be Maori (8.2% vs 3.8%, p=0.0063) and were less likely to have a history of prior cardiac angiography (26% vs 28%, p=0.02) or percutaneous coronary intervention [PCI] (9.6% vs 14%, p=0.03) than patients admitted to an intervention centre (n=318). Patients admitted to a non-intervention centre were more likely to have a chest X-ray (88% vs 81%, p<0.0024), as likely to have an exercise treadmill test (20% vs 22%, p=0.39), but less likely to receive an echocardiogram (17% vs 26%, p<0.0005), a cardiac angiogram (17% vs 30%, p<0.0001), or neither a treadmill nor a cardiac angiogram (68% vs 53%, p<0.0001) for cardiac risk assessment. For patients with a definite ACS presentation (STEMI, Non-STEMI, UAP, n=721), PCI was performed less often for patients admitted to non-intervention centres: 3% vs 14% (p<0.0001), although the rate of coronary artery bypass grafting was similar: 3% vs 5% (p=0.16). CONCLUSION: Patients admitted to a hospital without cardiac interventional facilities receive fewer investigations and less revascularisation than patients admitted to Intervention Centres. Hence patients admitted with an acute coronary syndrome in New Zealand receive inequitable management. A comprehensive National strategy is needed to improve access to optimal cardiac care.

Adult↗
PubMed2004

[3H]A-317491, a novel high-affinity non-nucleotide antagonist that specifically labels human P2X2/3 and P2X3 receptors.

A-317491 is a potent and selective antagonist of P2X3 and P2X(2/3) receptors. In the present studies, the ability of [3H]A-317491 to label recombinant human P2X(2/3) and P2X(3) receptors was characterized. Using membranes prepared from 1321N1 cells expressing P2X(2/3) receptors, [3H]A-317491 specifically labeled high-affinity (Kd = 0.9 nM) recognition sites. High-affinity [3H]A-317491 binding was not detected in membrane preparations from native 1321N1 cells or cells expressing homomeric P2X1, P2X2, or P2X3 receptors. Specific [3H]A-317491 P2X3 receptors could only be reliably detected following treatment of intact P2X3 receptor-expressing cells with apyrase (1 U/ml) both before and during membrane preparation. Under these conditions, [3H]A-317491 also labeled high-affinity (Kd = 9 nM) binding sites. Lower affinity binding components (Kd values of 87-790 nM) were detected in both assays using higher ligand concentrations that likely represent nonfunctional recognition sites. [3H]A-317491 binding to both P2X(2/3) and P2X3 receptors was reversible, and ligand kinetic studies provided similar estimates of the high-affinity binding constants. Potent P2X3 receptor agonists 2-methylthio-ATP, 2,3-O-(4-benzoylbenzoyl)-ATP, and alpha,beta-methylene adenosine triphosphate also potently inhibited specific [3H]A-317491 binding to both P2X(2/3) and P2X3 receptors. The pharmacological profile for P2X receptor antagonists to inhibit [3H]A-317491 binding to P2X(2/3) and P2X3 receptors was highly correlated (r = 0.98, P < 0.05), and a similar rank order of potency was observed for blockade of P2X(2/3) receptor-mediated calcium influx. These data demonstrate that [3H]A-317491 is the first useful radioligand for the specific labeling of P2X3-containing channels.

Calcium↗
PubMed2003

Two novel and selective nonimidazole histamine H3 receptor antagonists A-304121 and A-317920: I. In vitro pharmacological effects.

Histamine H3 receptor (H3R) antagonists enhance neurotransmitter release and are being developed for the treatment of a variety of neurological and cognitive disorders. Many potent histamine H3R antagonists contain an imidazole moiety that limits receptor selectivity and the tolerability of this class of compounds. Here we present the in vitro pharmacological data for two novel piperazine amide ligands, A-304121 [4-(3-((2R)-2-aminopropanoyl-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone] and A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl-)-2-furamide], and compare them with the imidazole H3R antagonists ciproxifan, clobenpropit, and thioperamide. Both A-304121 and A-317920 bind potently to recombinant full-length rat H3R(pKi values = 8.6 and 9.2, respectively) but have lower potencies for binding the full-length human H3R (pKi values = 6.1 and 7.0, respectively). A-304121 and A-317920 are potent antagonists at rat H3R in reversing R-alpha-methylhistamine [(R)-alpha-MeHA] inhibition of forskolin-stimulated cAMP formation (pKb values = 8.0 and 9.1) but weak antagonists at human H3Rs in cyclase (pKb values = 6.0 and 6.3) and calcium mobilization (pKb values = 6.0 and 7.3) assays in cells co-expressing Galphaqi5-protein. Both compounds potently antagonize native H3Rs by blocking histamine inhibition of potassium-evoked [3H]histamine release from rat brain cortical synaptosomes (pKb values = 8.6 and 9.3) and (R)-alpha-MeHA reversal of electric field-stimulated guinea pig ileum contractions (pA2 values = 7.1 and 8.3). A-304121 and A-317920 are also more efficacious inverse agonists in reversing basal guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTP gamma S) binding at the human H3R (pEC50 values = 5.7 and 7.0) than are the imidazole antagonists. These novel and selective piperazine amides represent useful leads for the development of H3R antagonist therapeutic agents.

Animals↗
PubMed2003

Two novel and selective nonimidazole H3 receptor antagonists A-304121 and A-317920: II. In vivo behavioral and neurophysiological characterization.

Pharmacological blockade of central histamine H3 receptors (H3Rs) enhances cognition in rodents and offers promise for the clinical treatment of neurological disorders. However, many previously characterized H3R antagonists are either not selective for H3Rs or have potentially significant tolerability issues. Here, we present in vivo behavioral and neurophysiological data for two novel and selective H3R antagonists with improved safety indices. Functional blockade of central H3Rs was first demonstrated for A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone] (1 mg/kg) and A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl)-2-furamide] (0.45 mg/kg) by significantly attenuating an acute dipsogenia response to the selective H3R agonist (R)-alpha-methylhistamine [(R)-alpha-MeHA]. Cognitive performance was improved in a five-trial rat pup avoidance test following administration of A-304121 (10 mg/kg) or A-317920 (3 mg/kg), with efficacy comparable with previously published observations for reference H3R antagonists thioperamide (10 mg/kg), ciproxifan (3 mg/kg), and GT-2331 [(1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole] (1 mg/kg). Social memory was also significantly enhanced in the adult rat with A-304121 (3, 10 mg/kg) and A-317920 (1, 3 mg/kg) at doses that produced no significant change in electroencephalogram slow-wave amplitude activity. Relative therapeutic indices (TIs) of 30 and 42 were estimated for A-304121 and A-317920, respectively, by comparing doses producing adverse effects in general observation studies with potency in inhibitory avoidance, which were superior to TIs of 8, 10, and 18 observed for the reference antagonists thioperamide, ciproxifan, and GT-2331, respectively. A-304121 and A-317920 represent a series of novel, H3R-selective piperazine amides that enhance cognition in vivo, which could offer advantages over existing H3R antagonists or cognition-enhancing agents.

Analysis of Variance↗
PubMed2003

Target validation.

With the publication of draft maps of the human genome and an interim agreement that the human genome comprises approximately 21000 genes, there has been considerable anticipation that many novel disease-specific molecular targets will be rapidly identified and that these will form the basis of many new drug discovery programs. Genes associated with a given disease can thus be identified using genotyping and microarray approaches. However, transitioning from the identification to the subsequent validation and prioritization of their cognate proteins as bona fide drug targets using proteomic techniques--a process that could appropriately be termed targetomics--is still very much in its infancy, with expectations far exceeding present capabilities. The criteria for target validation have yet to be determined and the timing to success has been underestimated. Integrated pharmacological approaches that involve the use of the traditional null hypothesis approach and statistically validated replication have been largely overlooked in the enthusiasm to be the first to find new targets. Inevitably, the only useful measure of target validation occurs when a drug-like molecule, selective for the identified target, is advanced to the clinic where it can be shown to be efficacious in the appropriate human disease state.

Animals↗
PubMed2003

The family costs of attending hospital outpatient appointments via videoconference and in person.

We compared the costs incurred by families attending outpatient appointments at the Royal Children's Hospital (RCH) in Brisbane with those incurred by families who had a consultation via videoconference in their regional area. In each category 200 families were interviewed. The median time spent travelling for videoconferences was 30 min compared with 80 min for face-to-face appointments. Families interviewed in the outpatient department had travelled a median distance of 70 km, while those who had a videoconference at the local hospital had travelled only 20 km. It cost these families much more to attend an appointment at the RCH than to attend a videoconference. Ninety-six per cent of families (193) reported at least one of the following types of expense: 150 families had expenses related to parking (median A 10 dollars), 156 had fuel expenses (median A 10 dollars) and 122 reported costs related to meals purchased at the RCH (median A 10 dollars). Only 21 families who had their appointment via local videoconference reported any additional costs. Specialist appointments via videoconference were a more convenient and cheaper option for families living in regional areas of Queensland than the conventional method of attending outpatient appointments at the specialist hospital in Brisbane.

Ambulatory Care↗
PubMed2003

Small bowel obstruction and internal hernias after laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Small bowel obstruction (SBO) is a recognized complication of open bariatric surgery; however, the incidence after laparoscopic procedures is not clearly established. This paper reviews our experience with small bowel obstruction after laparoscopic Roux-en-Y gastric bypass. METHODS: Between 1995 and 2001, 711 (246 antecolic, 465 retrocolic) patients underwent a laparoscopic proximal divided Roux-en-Y gastric bypass via the linear endostapler technique. 13 patients (1.8%) developed SBO requiring surgical intervention. There were 11 females and 2 males, ages 29-60 (mean 38), with mean weight 126 kg (range 105-188), and mean BMI 50 (range 41-59). 7 obstructive patients (55%) had undergone previous open abdominal surgery. Median time to obstruction was 21 days (range 5-1095). Mean follow-up of all patients is 43 months (range 3-79). RESULTS: Etiology of obstruction was internal hernia - 6, adhesive bands - 5 (only 2 were related to prior open surgery), mesocolon window scarring - 1, and incarcerated ventral hernia - 1. The incidence of SBO was 4.5% (11/246) in the retrocolic group, and 0.43% (2/465) in the antecolic group, which was highly significant (P=.006). 1 adhesive patient required an open bowel resection for ischemia. There was 1 death. CONCLUSION: SBO occurred with an overall incidence of 1.8% in a large series of laparoscopic gastric bypass patients, and was associated with a high morbidity. A significant decrease in occurrence was found after adoption of antecolic placement of the Roux limb.

Adolescent↗
PubMed2003

Genome-based drug discovery: prioritizing disease-susceptibility/disease-associated genes as novel drug targets for schizophrenia.

The search for new classes of antipsychotics based on novel targets identified from linkage/linkage association in diseased cohorts and microarray approaches using tissue from affected individuals is a high priority in central nervous system research. Genes linked to schizophrenia, a disease affecting 1% of the population, have been identified on nearly every chromosome of the human genome leading to a diverse choice of targets for validation. Interestingly, while the majority of currently used antipsychotic medications act by blocking dopamine receptors, there have been few genetic studies implicating the dopamine receptor family in disease etiology. Recently, four genes have been identified that encode dysbindin, neuroregulin, D-amino acid oxidase and G72, respectively, that support previous studies suggesting that schizophrenia may result from a hypofunction of glutamatergic neurotransmission. Linkage and microarray studies have similarly supported studies implicating the alpha 7 neuronal nicotinic receptor in the etiology of schizophrenia. Microarray studies using brain tissue from schizophrenic patients have shown changes in gene expression that number in the thousands, involving a number of proteins related to synaptic structure and function (PSYN gene group) and cellular metabolism. The majority of these proteins are not traditional drug discovery targets, nor are their functional roles in schizophrenia obvious, providing a challenge to validate them from the drug target identification/drug discovery perspective. The current state-of-the-art in genome-based approaches to schizophrenia, target discovery highlights a need for a multidisciplinary, integrative, null hypothesis-based approach to sort through these novel genes as drug targets.

Antipsychotic Agents↗
PubMed2002

A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat.

P2X3 and P2X2/3 receptors are highly localized on peripheral and central processes of sensory afferent nerves, and activation of these channels contributes to the pronociceptive effects of ATP. A-317491 is a novel non-nucleotide antagonist of P2X3 and P2X2/3 receptor activation. A-317491 potently blocked recombinant human and rat P2X3 and P2X2/3 receptor-mediated calcium flux (Ki = 22-92 nM) and was highly selective (IC50 >10 microM) over other P2 receptors and other neurotransmitter receptors, ion channels, and enzymes. A-317491 also blocked native P2X3 and P2X2/3 receptors in rat dorsal root ganglion neurons. Blockade of P2X3 containing channels was stereospecific because the R-enantiomer (A-317344) of A-317491 was significantly less active at P2X3 and P2X2/3 receptors. A-317491 dose-dependently (ED50 = 30 micromolkg s.c.) reduced complete Freund's adjuvant-induced thermal hyperalgesia in the rat. A-317491 was most potent (ED50 = 10-15 micromolkg s.c.) in attenuating both thermal hyperalgesia and mechanical allodynia after chronic nerve constriction injury. The R-enantiomer, A-317344, was inactive in these chronic pain models. Although active in chronic pain models, A-317491 was ineffective (ED50 >100 micromolkg s.c.) in reducing nociception in animal models of acute pain, postoperative pain, and visceral pain. The present data indicate that a potent and selective antagonist of P2X3 and P2X2/3 receptors effectively reduces both nerve injury and chronic inflammatory nociception, but P2X3 and P2X2/3 receptor activation may not be a major mediator of acute, acute inflammatory, or visceral pain.

Analgesics, Non-Narcotic↗
PubMed2002

N-[3-(1H-imidazol-4-ylmethyl)phenyl]ethanesulfonamide (ABT-866, 1),(1) a novel alpha(1)-adrenoceptor ligand with an enhanced in vitro and in vivo profile relative to phenylpropanolamine and midodrine.

N-[3-(1H-Imidazol-4-ylmethyl)phenyl]ethanesulfonamide (ABT-866, 1) is a novel alpha(1) agent having the unique profile of alpha(1A) (rabbit urethra, EC(50) = 0.60 microM) agonism with alpha(1B) (rat spleen, pA(2) = 5.4) and alpha(1D) (rat aorta, pA(2) = 6.2) antagonism. An in vivo dog model showed 1 to be more selective for the urethra over the vasculature than A-61603 (2), ST-1059 (3, the active metabolite of midodrine), and phenylpropanolamine (4).

Adrenergic alpha-Agonists↗