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1.
Hand Surg ; 15(3): 173-6, 2010.
Article in English | MEDLINE | ID: mdl-21089191

ABSTRACT

The clinical assessment of patients with peripheral nerve injury is primarily dependent on subjective clinical examination. We aimed to assess whether a thermotropic liquid crystal ring (TLC-ring) could provide the basis for an objective assessment of peripheral nerve injury by detecting temperature changes in the digits innervated by the damaged nerve. A group of patients with known median, ulnar or both digital nerve injuries were compared against a control group. TLC-rings, marketed to the general public as "mood rings", were applied to the affected and unaffected digits and the colour change recorded. Areas with nerve damage showed a statistically significant difference in colour response to those without damage. This study establishes the ability of TLCs to detect cutaneous temperature changes associated with peripheral nerve injuries. Further studies and improvements are needed to refine TLC as an acute assessment tool for peripheral nerve injuries.


Subject(s)
Liquid Crystals , Median Nerve/injuries , Peripheral Nervous System Diseases/diagnosis , Trauma, Nervous System/diagnosis , Ulnar Nerve/injuries , Adolescent , Adult , Female , Humans , Jewelry , Male , Middle Aged , Peripheral Nervous System Diseases/etiology , Peripheral Nervous System Diseases/genetics , Young Adult
3.
J Bone Joint Surg Br ; 89(7): 933-9, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17673589

ABSTRACT

The diagnosis of nerve injury using thermotropic liquid crystal temperature strips was compared blindly and prospectively against operative findings in 36 patients requiring surgical exploration for unilateral upper limb lacerations with suspected nerve injury. Thermotropic liquid crystal strips were applied to affected and non-affected segments in both hands in all subjects. A pilot study showed that a simple unilateral laceration without nerve injury results in a cutaneous temperature difference between limbs, but not within each limb. Thus, for detection of a nerve injury, comparison was made against the unaffected nerve distribution in the same hand. Receiver operating characteristic curve analysis showed that an absolute temperature difference > or = 1.0 degrees C was diagnostic of a nerve injury (area under the curve = 0.985, sensitivity = 100%, specificity = 93.8%). Thermotropic liquid crystal strip assessment is a new, reliable and objective method for the diagnosis of traumatic peripheral nerve injuries. If implemented in the acute setting, it could improve the reliability of clinical assessment and reduce the number of negative surgical explorations.


Subject(s)
Hand Injuries/diagnosis , Hand/innervation , Peripheral Nerve Injuries , Thermography/methods , Trauma, Nervous System/diagnosis , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Pilot Projects , Predictive Value of Tests , Prospective Studies
4.
Emerg Med J ; 22(12): 885-6, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16299202

ABSTRACT

We demonstrate radiological evidence that an external pelvic splint is effective at reducing open book pelvic fractures. Its use in the pre-hospital and emergency department settings should be encouraged in the initial management and resuscitation of patients with pelvic fractures.


Subject(s)
Fracture Fixation/methods , Fractures, Bone/therapy , Pelvic Bones/injuries , Splints , Accidents, Traffic , Adult , Fractures, Bone/diagnostic imaging , Humans , Male , Pelvic Bones/diagnostic imaging , Tomography, X-Ray Computed
8.
Mol Cell ; 7(1): 55-63, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11172711

ABSTRACT

A paramount role of telomeres is to prevent chromosome fusions. The fission yeast Taz1 protein regulates diverse telomere functions but is not essential for growth under stress-free conditions. Strikingly, however, taz1(-) cells exhibit lethal telomere fusions when subjected to nitrogen starvation, a treatment that induces an uncommitted G1 state. These fusions are formed by Ku-dependent nonhomologous end joining. Fusions also occur during normal growth in taz1(-) cells that lack rad22(+), a gene involved in homologous recombination. Our data suggest a model whereby taz1(-) telomeres are exposed to the prevailing mode of DNA repair, which is dictated by the cell cycle. Thus, Taz1 caps chromosome ends and provides the telomerespecific interaction that prevents Ku from treating telomeres as double-strand breaks.


Subject(s)
Antigens, Nuclear , Bacterial Outer Membrane Proteins/genetics , Chromosomes, Fungal/genetics , DNA Helicases , DNA Repair/physiology , DNA-Binding Proteins/genetics , Escherichia coli Proteins , Nuclear Proteins/genetics , Phosphoprotein Phosphatases , Protein Kinases , Saccharomyces cerevisiae Proteins , Schizosaccharomyces pombe Proteins , Schizosaccharomyces/genetics , Bacterial Outer Membrane Proteins/metabolism , Chromosomes, Fungal/metabolism , DNA, Fungal/genetics , DNA-Binding Proteins/metabolism , Fungal Proteins/genetics , Fungal Proteins/metabolism , G1 Phase/genetics , Ku Autoantigen , Nitrogen , Nuclear Proteins/metabolism , Schizosaccharomyces/cytology , Schizosaccharomyces/metabolism , Starvation , Telomere/genetics , Telomere/metabolism , Telomere-Binding Proteins
9.
J Med Chem ; 43(11): 2135-48, 2000 Jun 01.
Article in English | MEDLINE | ID: mdl-10841792

ABSTRACT

Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.


Subject(s)
Antigen Presentation , Dipeptides/pharmacology , HLA-DR Antigens/chemistry , Molecular Mimicry , Binding, Competitive , Carbohydrates/chemistry , Cathepsin B/metabolism , Cell Division/drug effects , Crystallography, X-Ray , Dipeptides/chemical synthesis , Dipeptides/chemistry , Humans , Methylation , Models, Molecular , Peptide Biosynthesis , Protein Conformation , Structure-Activity Relationship , T-Lymphocytes/cytology , T-Lymphocytes/drug effects
10.
Curr Opin Genet Dev ; 10(2): 169-77, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10753788

ABSTRACT

Telomere functions vary as the cell cycle progresses. Recent results highlight fluctuating associations between telomeres and DNA polymerases, DNA-damage repair proteins, and centrosome components. These associations reflect diverse roles of telomeres in chromosome maintenance and in the orchestration of chromosome movements during meiosis.


Subject(s)
Chromosomes, Fungal/genetics , Saccharomyces cerevisiae/genetics , Schizosaccharomyces/genetics , Telomere/genetics , Animals , Cell Cycle/genetics , Chromosomes, Fungal/enzymology , Humans , Saccharomyces cerevisiae/cytology , Saccharomyces cerevisiae/enzymology , Schizosaccharomyces/cytology , Schizosaccharomyces/enzymology , Telomere/enzymology
12.
Proc Natl Acad Sci U S A ; 96(11): 6102-6, 1999 May 25.
Article in English | MEDLINE | ID: mdl-10339548

ABSTRACT

The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARgamma subtype plays a central role in the regulation of adipogenesis and is the molecular target for the 2, 4-thiazolidinedione class of antidiabetic drugs. Structural studies have revealed that agonist ligands activate the PPARs through direct interactions with the C-terminal region of the ligand-binding domain, which includes the activation function 2 helix. GW0072 was identified as a high-affinity PPARgamma ligand that was a weak partial agonist of PPARgamma transactivation. X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix. In cell culture, GW0072 was a potent antagonist of adipocyte differentiation. These results establish an approach to the design of PPAR ligands with modified biological activities.


Subject(s)
Adipocytes/cytology , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Receptors, Cytoplasmic and Nuclear/chemistry , Thiazoles/pharmacology , Thiazolidinediones , Transcription Factors/antagonists & inhibitors , Transcription Factors/chemistry , Animals , Binding Sites , Cell Differentiation/drug effects , Cell Line , Chlorocebus aethiops , Crystallography, X-Ray , Humans , Kinetics , Ligands , Mice , Models, Molecular , Molecular Conformation , Molecular Sequence Data , Nuclear Proteins/metabolism , Protein Structure, Secondary , Receptors, Cytoplasmic and Nuclear/genetics , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Rosiglitazone , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazolidines , Transcription Factors/genetics , Transfection
13.
J Med Chem ; 41(25): 5055-69, 1998 Dec 03.
Article in English | MEDLINE | ID: mdl-9836622

ABSTRACT

3-¿4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-¿4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl¿ ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.


Subject(s)
Benzoates/chemical synthesis , DNA-Binding Proteins/agonists , Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Oxazoles/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Tyrosine/analogs & derivatives , Tyrosine/chemical synthesis , Administration, Oral , Animals , Benzoates/chemistry , Benzoates/pharmacology , Blood Glucose/metabolism , Cell Line , Diabetes Mellitus, Experimental/blood , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , Ligands , Lipids/biosynthesis , Male , Mice , Oxazoles/chemistry , Oxazoles/pharmacology , Radioligand Assay , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Solubility , Structure-Activity Relationship , Transcription Factors/metabolism , Tyrosine/chemistry , Tyrosine/pharmacology , ortho-Aminobenzoates
14.
Science ; 282(5388): 493-6, 1998 Oct 16.
Article in English | MEDLINE | ID: mdl-9774280

ABSTRACT

Deletion of the telomerase catalytic subunit gene trt1+ in Schizosaccharomyces pombe results in death for the majority of cells, but a subpopulation survives. Here it is shown that most survivors have circularized all of their chromosomes, whereas a smaller number maintain their telomeres presumably through recombination. When the telomeric DNA-binding gene taz1+ is also deleted, trt1- taz1- survivors use the recombinational mode more frequently. Moreover, the massive elongation of telomeres in taz1- cells is absent in the double mutant. Thus, Taz1p appears to regulate telomeric recombination as well as telomerase activity in fission yeast.


Subject(s)
Chromosomes, Fungal/metabolism , Proteins/metabolism , RNA , Recombination, Genetic , Schizosaccharomyces pombe Proteins , Schizosaccharomyces/physiology , Telomere-Binding Proteins , Telomere/genetics , Telomere/metabolism , Chromosomes, Fungal/genetics , DNA Probes , DNA, Fungal/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Deletion , Genes, Fungal , Proteins/genetics , Schizosaccharomyces/enzymology , Schizosaccharomyces/genetics , Telomerase/genetics , Telomerase/metabolism
15.
Nature ; 392(6678): 828-31, 1998 Apr 23.
Article in English | MEDLINE | ID: mdl-9572143

ABSTRACT

The alignment of homologous chromosomes during meiosis is essential for their recombination and segregation. Telomeres form and protect the ends of eukaryotic linear chromosomes, and are composed of tandem repeats of a simple DNA sequence and the proteins that bind to these repeats. A role for telomeres in meiosis was suspected from observations of telomere clustering in meiotic cells, and has now been supported experimentally by the dramatic rearrangement of telomere locations during premeiotic stages in fission yeast. Here we show that the fission yeast telomere protein, Taz1, is required for stable association between telomeres and spindle pole bodies during meiotic prophase. In the absence of Taz1, telomere clustering at the spindle pole bodies is disrupted, meiotic recombination is reduced, and both spore viability and the ability of zygotes to re-enter mitosis are impaired to a level that would be expected if chromosome segregation were occurring randomly. Such telomeric association mediated by telomere-specific proteins may also be important for proper chromosome alignment and recombination during meiosis in humans.


Subject(s)
DNA-Binding Proteins/physiology , Meiosis/physiology , Schizosaccharomyces pombe Proteins , Schizosaccharomyces/genetics , Telomere-Binding Proteins , Telomere , Chromosomes, Fungal/physiology , Gene Deletion , Humans , Meiosis/genetics , Mitosis/physiology , Recombination, Genetic , Schizosaccharomyces/physiology , Spindle Apparatus/physiology , Telomere/physiology
16.
Drug Des Discov ; 15(3): 191-8, 1998 May.
Article in English | MEDLINE | ID: mdl-9689501

ABSTRACT

The interleukin-1 proteins (IL-1 alpha and IL-1 beta) are key mediators of inflammatory and immunological responses, and several in vitro and in vivo studies with protein-based antagonists have demonstrated the potential usefulness of IL-1 receptor antagonists to treat various inflammation related diseases. Based on the X-ray crystal structures of IL-1 ligands and site-directed mutagenesis data, a noncontiguous binding epitope encompassing Arg4, Phe46, Ile56, Lys93, Lys103, and Glu105 for IL-1 beta was proposed. In this paper we describe the synthesis and binding assay results of small molecule IL-1 receptor antagonists designed on the basis of the three-dimensional structure of the binding epitope. Among these, the compound 45 was found to inhibit IL-alpha binding to the Type I receptor with an IC50 value of 3 microM. A hypothesis generated using BioCad CATALYST program is also presented to rationalize these observations.


Subject(s)
Benzene Derivatives/chemical synthesis , Benzene Derivatives/pharmacology , Receptors, Interleukin-1/antagonists & inhibitors , Benzene Derivatives/metabolism , Catalysis , Drug Design , Enzyme-Linked Immunosorbent Assay , Models, Molecular , Molecular Conformation , Receptors, Interleukin-1/metabolism , Structure-Activity Relationship
17.
Heart ; 77(3): 273-5, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9093049

ABSTRACT

Head up tilt is an established test for assessing patients with vasovagal syncope. Prolonged asystole during the test has previously been reported in patients suffering from the malignant form of this syndrome. Little is known about the prognostic significance of this response and there is no consensus about the optimum treatment. Four such patients are reported who were treated pharmacologically. During follow up they remained free from major events and their symptoms were well controlled. Conservative management is the initial method of choice and only if this fails should implantation of a dual chamber permanent pacemaker be considered.


Subject(s)
Heart Arrest/etiology , Syncope, Vasovagal/physiopathology , Tilt-Table Test , Adolescent , Adrenergic beta-Antagonists/therapeutic use , Adult , Anti-Arrhythmia Agents/therapeutic use , Disopyramide/therapeutic use , Female , Heart Arrest/physiopathology , Humans , Male , Metoprolol/therapeutic use , Middle Aged , Prognosis , Syncope, Vasovagal/prevention & control
18.
Nature ; 385(6618): 744-7, 1997 Feb 20.
Article in English | MEDLINE | ID: mdl-9034194

ABSTRACT

Telomeres, the specialized nucleoprotein structures that comprise the ends of eukaryotic chromosomes, are essential for complete replication, and regulation of their length has been a focus of research on tumorigenesis. In the budding yeast Saccharomyces cerevisiae, the protein Rap1p binds to telomeric DNA and functions in the regulation of telomere length. A human telomere protein, hTRF (human TTAGGG repeat factor) binds the telomere sequence in vitro and localizes to telomeres cytologically, but its functions are not yet known. Here we use a genetic screen to identify a telomere protein in fission yeast, Taz1p (telomere-associated in Schizosaccharomyces pombe), that shares homology to the Myb proto-oncogene DNA-binding domain with hTRF. Disruption or deletion of the taz1+ gene causes a massive increase in telomere length. Taz1p is required for the repression of telomere-adjacent gene expression and for normal meiosis or sporulation. It may be a negative regulator of the telomere-replicating enzyme, telomerase, or may protect against activation of telomerase-independent pathways of telomere elongation.


Subject(s)
DNA-Binding Proteins/metabolism , Fungal Proteins/metabolism , Proto-Oncogene Proteins/chemistry , Schizosaccharomyces pombe Proteins , Schizosaccharomyces/metabolism , Telomere-Binding Proteins , Telomere/metabolism , Trans-Activators/chemistry , Amino Acid Sequence , Chromosomes, Fungal/metabolism , Cloning, Molecular , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Fungal Proteins/chemistry , Fungal Proteins/genetics , Humans , Molecular Sequence Data , Proto-Oncogene Mas , Proto-Oncogene Proteins c-myb , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Sequence Homology, Amino Acid , Spores, Fungal
19.
Heart ; 76(4): 370-1, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8983688

ABSTRACT

A subaortic membrane predisposes to bacterial endocarditis usually affecting the aortic valve and left ventricular outflow tract. Endocarditis involving the subaortic membrane itself has been described twice only; once at operation and once at postmortem. The case of a man with vegetations involving a subaortic membrane that were detected preoperatively and the echocardiographic appearances of these findings are reported.


Subject(s)
Aortic Stenosis, Subvalvular/microbiology , Endocarditis, Bacterial/complications , Mitral Valve/abnormalities , Adult , Aortic Stenosis, Subvalvular/diagnostic imaging , Echocardiography , Echocardiography, Transesophageal , Endocarditis, Bacterial/diagnostic imaging , Humans , Male
20.
Parasite Immunol ; 18(8): 377-86, 1996 Aug.
Article in English | MEDLINE | ID: mdl-9229391

ABSTRACT

Human isotype specific antibody responses to a recombinant pi-class glutathione S-transferase (Ov24) from Onchocerca volvulus were assessed by ELISA, using a large and well-characterized bank sera (n = 238) from an hyper-endemic area of moderate intensity from Sierra Leone. IgG1, IgG4 and IgA responses, but neither IgG2 nor IgE response, to Ov24 were detected in infected subjects. The relationships between Ov24 antibody levels and skin microfilarial density, number of nodules, age, sex, eosinophil counts and clinical sign of reactive and chronic pathology were analysed using Pearson's correlation coefficient. Significant correlations between both IgA and IgG3 antibody levels and age were found (P < 0.01). Although no firm conclusions could be drawn from this study sample regarding the relationships between antibody levels and parasite load or clinical status, a negative correlation (P = 0.06) between Ov24 IgG3 antibody levels and microfilarodermia was found.


Subject(s)
Antibodies, Helminth/blood , Glutathione Transferase/immunology , Immunoglobulin Isotypes/blood , Onchocerca volvulus/enzymology , Onchocerca volvulus/immunology , Onchocerciasis/immunology , Adolescent , Adult , Age Factors , Aged , Animals , Case-Control Studies , Child , Child, Preschool , Female , Glutathione Transferase/genetics , Helminth Proteins/genetics , Helminth Proteins/immunology , Humans , Infant , Infant, Newborn , Male , Microfilariae/isolation & purification , Middle Aged , Onchocerca volvulus/genetics , Onchocerciasis/epidemiology , Onchocerciasis/parasitology , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Seroepidemiologic Studies , Sierra Leone/epidemiology , Skin/parasitology
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