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Biomedical subjects

M Williams

Publications and source records attributed to M Williams.

At least 73 records · Page 4Linked to original sources
PubMed2002

Partially matched related donor peripheral blood progenitor cell transplantation in paediatric patients adding fludarabine and anti-lymphocyte gamma-globulin.

Twenty-one paediatric patients (11 males and 10 females) received a CD34-selected partially matched related donor transplant for malignant (16 cases) and non-malignant conditions (five cases). The average cell dose was 11.13 x 10(6)/kg. Fifteen of 16 patients with malignant conditions and one with non-malignant disease received total body irradiation plus cyclophosphamide. Three of 5 patients with non-malignant conditions and one with leukaemia, received busulphan plus cyclophosphamide. One patient with Fanconi anaemia received 100 mg/kg of cyclophosphamide. Fludarabine (25 mg/m(2)/day for 5 days) was administered prior to all these regimens. Additionally, anti-lymphocyte gamma-globulin (12.5 mg/kg/day) was administered from day -2 to day +2. Three (15%) patients failed to achieve complete chimaerism (CC). These patients received a second cell infusion. Two of them achieved CC. In the third patient, the percentage of donor cells was increased. The likelihood for engraftment was not related to the cell dose received. Acute graft-versus-host disease (GVHD) occurred in nine patients but only one developed GVHD >grade II. Eight patients developed active viral infections, which resolved after treatment. Patients receiving cell doses higher than our average had a significantly faster CD3 and CD4 cell recovery and experienced a lower incidence of viral infections. After 480 +/- 255 days of median follow-up, 16/21 patients are alive and well and have CC. Three patients died of leukaemic relapse and a fourth from progression of his disease (adreno-leuko-dystrophy). We conclude that partially matched related donors are a feasible source of haemopoietic progenitor cells for transplantation for patients without matched familial or unrelated donors.

Adolescent↗
PubMed2002

A modified Kleihauer technique for the quantification of foetomaternal haemorrhage.

The Kleihauer technique, based on acid elution of maternal red cells, is the mostly widely used technique in the UK to screen for, and estimate the volume of, foetomaternal haemorrhage (FMH) and for determining the need for additional doses of anti-D immunoglobulin to prevent maternal alloimmunization. However, technicians often report difficulties in identifying and accurately counting maternal red cells in the blood film, leading to imprecision in the calculated FMH. In this report, we describe a simple modification of the standard Kleihauer technique, based on performing acid elution of only half of the film. Compared to the standard method, the modified technique showed improved accuracy and reduced interobserver variability across a range of simulated FMH volumes. There was a high degree of correlation between the new technique and FMH estimated by flow cytometry (r2 = 0.916, P < 0.001). Technicians found the new technique easy to incorporate into routine practice in a busy teaching hospital laboratory and were impressed by the relative ease of counting maternal ghost cells. The modified technique has been used routinely in our laboratory for 3 years, during which time our performance in the UK National External Quality Assurance Scheme for FMH has been uniformly satisfactory.

Clinical Laboratory Techniques↗
PubMed2002

Successful pregnancy after hysteroscopic metroplasty.

Congenital anomalies of the uterus have been estimated to affect 0.06-10% of women. Uterine septae account for approximately 80% to 90% of these anomalies and is also associated with the poorest reproductive outcome. Pregnancy loss in patients with a septate uterus has been reported to be as high as 90% after other causes for miscarriages have been excluded. We present here the first experience in Jamaica, of a successful pregnancy outcome after hysteroscopic metroplasty in a woman with a septate uterus and three previous miscarriages.

Adult↗
PubMed2001

Adolescent versus adult responses to vertical spinal loading.

This study compared the vertical spinal creep response between adolescent and adult males. Thirty healthy male subjects, 15 adolescents (aged 12 to 16 years) and 15 adults (aged 30 to 57 years) were measured. Spinal creep was measured continuously over 25 min under loaded and unloaded conditions using a seated stadiometer that controlled spinal posture. Both adolescent and adult subjects showed significant increase in vertical spinal creep with time but the magnitude of vertical spinal creep was significantly greater in adolescent than in the adult subjects.

Adolescent↗
PubMed2001

Pharmacological properties of A-204176, a novel and selective alpha1A adrenergic agonist, in in vitro and in vivo models of urethral function.

A-204176 (N-[5-(1H-imidazol-4-y1)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide) is a potent and selective alpha1A adrenoceptor agonist that binds with 17-fold and 9-fold greater affinity to the alpha1A (Ki=176 nM) than the alpha1b and alpha1d subtypes, respectively. In functional studies A-204176 is potent (pD2=6.4) and efficacious (83% of maximum control phenylephrine response) at rabbit urethra alpha1A receptors, with weaker potency and greatly reduced efficacy at rat spleen alpha1B (pD2=5.3, 11%) and rat aorta alpha1D (pD2=4.4, 10%) subtypes. In anesthetized female dogs, A-204176 is more potent than the non-selective alpha1 adrenoceptor agonist phenylpropanolamine (PPA) to increase measures of urethral tone and is more efficacious to increase pressure in the proximal region of the urethra. Significant increases on parameters of the urethral pressure profilometry were induced at 100 and 300 nmol/kg, i.v., by A-204176 and PPA, respectively. A-204176 was more potent than PPA to increase the abdominal pressure required to produce leakage. In the simultaneous measurement of intraurethral pressure and mean arterial blood pressure, A-204176 displays enhanced urethral selectivity relative to PPA. However, despite its selectivity for alpha1A versus alpha1B and alpha1D adrenoceptors in vitro, A-204176 did not display the degree of urethral selectivity in vivo that would have been expected. The observed effect of A-204176 on blood pressure may be due to the presence of extra-synaptic alpha1A adrenoceptors in the vasculature or to activation of spinal and supraspinal alpha1A adrenoceptors. These data indicate that A-204176 may represent a useful pharmacological tool to investigate the functional role of the alpha1A adrenoceptor in the urethra and to elucidate the lack of uroselectivity observed in vivo.

Adrenergic alpha-Antagonists↗
PubMed2001

Zinc regulates the function and expression of the iron transporters DMT1 and IREG1 in human intestinal Caco-2 cells.

Trace metals influence the absorption of each other from the diet and it has been suggested that the divalent metal transporter (DMT1) represents a common uptake pathway for these important micronutrients. However, compelling evidence from our laboratory suggests that DMT1 is predominantly an iron transporter, with lower affinity for other metals. Several studies have shown that increasing dietary iron downregulates DMT1. Interestingly, our current data indicate that zinc upregulates DMT1 protein and mRNA expression and also pH-dependent iron uptake. Transepithelial flux of iron was also increased and was associated with a rise in IREG1 mRNA expression.

Caco-2 Cells↗
PubMed2001

The organic content of the Tagish Lake meteorite.

The Tagish Lake meteorite fell last year on a frozen lake in Canada and may provide the most pristine material of its kind. Analyses have now shown this carbonaceous chondrite to contain a suite of soluble organic compounds (approximately 100 parts per million) that includes mono- and dicarboxylic acids, dicarboximides, pyridine carboxylic acids, a sulfonic acid, and both aliphatic and aromatic hydrocarbons. The insoluble carbon exhibits exclusive aromatic character, deuterium enrichment, and fullerenes containing "planetary" helium and argon. The findings provide insight into an outcome of early solar chemical evolution that differs from any seen so far in meteorites.

Amino Acids↗
PubMed2001

Macrophage accumulation associated with rat cardiac allograft rejection detected by magnetic resonance imaging with ultrasmall superparamagnetic iron oxide particles.

BACKGROUND: Acute cardiac allograft rejection continues to be the cause of graft loss and contributes to the morbidity and mortality after cardiac transplantation. In this study, we report a new method for detecting organ rejection in transplantation with an MR-based technique using dextran-coated ultrasmall superparamagnetic iron oxide (USPIO) particles. These particles ( approximately 27 nm in diameter) are known to shorten relaxation times in MRI experiments. METHODS AND RESULTS: A new rat model of heterotopic heart and lung transplantation has been developed for MRI experiments. Allotransplantations (DA-->BN) were performed (n=8), with syngeneic transplantations (BN-->BN) serving as controls (n=8). MR images were obtained with a gradient echo method. At postoperative day 7, allotransplants developed moderate rejection as determined histopathologically. A significant reduction in MR signal intensity was observed after USPIO injection into rats with allotransplanted hearts. Syngeneic transplants showed no differences in MR signal intensity before and after USPIO injections. After injection of USPIO particles at postoperative day 6, a group of allotransplanted rats was treated with cyclosporin A (3 mg/kg). Animals treated with cyclosporin A for 7 days showed no reduction in MR signal intensity after USPIO reinjection at day 14, whereas animals treated for 4 days showed a significant decrease in MR signal intensity in the transplanted hearts indicative of acute graft rejection. Pathological analysis of these animals revealed that dextran-coated USPIO particles were taken up by the infiltrating macrophages that accumulated within the rejecting cardiac graft. CONCLUSIONS: This MRI method offers promise as a noninvasive method for detecting transplant allograft rejection.

Animals↗
PubMed2001

Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase.

Elongation factor 2 kinase (eEF2k) phosphorylates and inactivates eEF2. Insulin induces dephosphorylation of eEF2 and inactivation of eEF2 kinase, and these effects are blocked by rapamycin, which inhibits the mammalian target of rapamycin, mTOR. However, the signalling mechanisms underlying these effects are unknown. Regulation of eEF2 phosphorylation and eEF2k activity is lost in cells in which phosphoinositide-dependent kinase 1 (PDK1) has been genetically knocked out. This is not due to loss of mTOR function since phosphorylation of another target of mTOR, initiation factor 4E-binding protein 1, is not defective. PDK1 is required for activation of members of the AGC kinase family; we show that two such kinases, p70 S6 kinase (regulated via mTOR) and p90(RSK1) (activated by Erk), phosphorylate eEF2k at a conserved serine and inhibit its activity. In response to insulin-like growth factor 1, which activates p70 S6 kinase but not Erk, regulation of eEF2 is blocked by rapamycin. In contrast, regulation of eEF2 by stimuli that activate Erk is insensitive to rapamycin, but blocked by inhibitors of MEK/Erk signalling, consistent with the involvement of p90(RSK1).

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2001

Prevalence of vaginal colonization by drug-resistant Candida species in college-age women with previous exposure to over-the-counter azole antifungals.

We enrolled 382 college-age women in a cross-sectional survey to investigate the relationship between use of over-the-counter (OTC) azole-based antifungal drugs and vaginal colonization by drug-resistant Candida. This study showed no correlation (P=.506) between previous OTC exposure and colonization of drug-resistant Candida in vaginal flora. However, a small number of resistant Candida species isolates were obtained from women with a history of multiple exposures to OTC antifungals; given the widespread use of these products, this may be an emerging concern.

Adult↗
PubMed2001

A phosphatocopid crustacean with appendages from the Lower Cambrian.

Here we describe a phosphatocopid arthropod with preserved soft anatomy from Lower Cambrian rocks of Shropshire, England, which provides evidence for the occurrence of Crustacea, including Eucrustacea, in the Early Cambrian. The find identifies an important, stratigraphically early source of well-preserved fossils (Konservat-Lagerstätte).

Animals↗
PubMed2001

Discovery of 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine, an orally active, non-nucleoside adenosine kinase inhibitor..

Adenosine (ADO) is an endogenous homeostatic inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic and antiinflammatory actions of ADO. Optimization of the high-throughput screening lead, 4-amino-7-aryl-substituted pteridine (5) (AK IC(50) = 440 nM), led to the identification of compound 21 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, ABT-702), a novel, potent (AK IC(50) = 1.7 nM) non-nucleoside AK inhibitor with oral activity in animal models of pain and inflammation.

Adenosine Kinase↗
PubMed2001

Three loci modify growth of a transgene-induced mammary tumor: suppression of proliferation associated with decreased microvessel density.

In earlier studies it was observed that the genetic background significantly affected the phenotype of a transgene-induced mammary tumor. Tumors arising in an (I/LnJ x PyMT) F1 hybrid background appeared earlier than in the FVB/N-TgN(MMTV-PyVT)(634Mul) parent, but accumulated less tumor mass, indicating a net decrease in tumor growth. Quantitative genetic mapping in a backcross identified three loci that were associated with the decreased proliferative capacity of the I/LnJ F1 tumors. Molecular analysis of the tumors suggests that these loci may act by restricting the tumor's ability to recruit microvessels. The three loci, designated Mmtg1-3, are unlinked to the angiogenic genes Fgf2, Flt1, Flk4, Flk1, Vegf, and Vegfc, as well as the precursors of the endogenous antiangiogenic molecules angiostatin and endostatin. The Mmtg loci may therefore provide novel targets for antiangiogenic therapeutic strategies.

Animals↗
PubMed2001

Contribution of soft tissue deformation below the sacrum to the measurement of total height loss in sitting.

This study investigated the contribution of soft tissue deformation below the sacrum (S) and vertical spinal creep to total height loss (THL) measured in sitting. Eight asymptomatic subjects (four males, four females) aged between 21 and 51 years were measured. Simultaneous measurement of THL and S were commenced after the subjects had been sitting for 5 min. THL was recorded while subjects were positioned in a seated stadiometer, which controlled their spinal posture. S was measured by placing an ultrasound transducer at the level of the top of the subject's sacrum. Over 25 min of sitting with loaded and unloaded interventions applied to their spine, different response characteristics between S and THL were noted. This study demonstrated that soft tissues below the sacrum could contribute up to 30% on average of total height loss. This suggests that researchers should take into account the soft tissue deformation outside the spine when studying vertical creep in sitting.

Adult↗
PubMed2001

HIV-1 Nef blocks transport of MHC class I molecules to the cell surface via a PI 3-kinase-dependent pathway.

HIV causes a chronic infection by evading immune eradication. A key element of HIV immune escape is the HIV-1 Nef protein. Nef causes a reduction in the level of cell surface major histocompatibility complex class I (MHC-I) protein expression, thus protecting HIV-infected cells from anti-HIV cytotoxic T lymphocyte (CTL) recognition and killing. Nef also reduces cell surface levels of the HIV receptor, CD4, by accelerating endocytosis. We show here that endocytosis is not required for Nef-mediated downmodulation of MHC-I molecules. The main effect of Nef is to block transport of MHC-I molecules to the cell surface, leading to accumulation in intracellular organelles. Furthermore, the effect of Nef on MHC-I molecules (but not on CD4) requires phosphoinositide 3-kinase (PI 3-kinase) activity. We propose that Nef diverts MHC-1 proteins into a PI 3-kinase-dependent transport pathway that prevents expression on the cell surface.

Blotting, Western↗