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Biomedical subjects

M Leach

Publications and source records attributed to M Leach.

At least 37 records · Page 2Linked to original sources
PubMed1998

Effects of inhibitors of the activity of cyclo-oxygenase-2 on the hypotension and multiple organ dysfunction caused by endotoxin: a comparison with dexamethasone.

1. Endotoxaemia is associated with the expression of the inducible isoform of cyclo-oxygenase, cyclo-oxygenase-2 (COX-2), and an overproduction of arachidonic acid (AA) metabolites. The role of the AA metabolites generated by COX-2 in the circulatory failure and multiple organ dysfunction caused by endotoxin is unclear. Dexamethasone prevents the expression of COX-2 and exerts beneficial effects in animal models of shock. 2. Here we compare the effects of two inhibitors of COX-2 activity, namely NS-398 (5 mg kg(-1), i.p., n=7) and SC-58635 (3 mg kg(-1), i.p., n=9) with those of dexamethasone (3 mg kg(-1), i.p., n=9) on the circulatory failure and organ dysfunction caused by lipopolysaccharide (LPS, E. coli, 6 mg kg(-1), i.v., n=11) in the rat. 3. Endotoxaemia for 6 h caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of 6-keto-PGF1alpha (indicator of the induction of COX-2) and nitrite/nitrate (indicator of the induction of iNOS). 4. Pretreatment of rats with dexamethasone attenuated the hypotension, the renal dysfunction, the hepatocellular and pancreatic injury and the induction of COX-2 and iNOS caused by LPS. In contrast, inhibition of COX-2 activity with SC-58635 or NS-398 neither attenuated the circulatory failure nor the multiple organ failure caused by endotoxin. 5. Thus, the prevention of the circulatory failure and the multiple organ injury/dysfunction caused by dexamethasone in the rat is not due to inhibition of the activity of COX-2. Our results suggest that an enhanced formation of eicosanoids by COX-2 does not contribute to the development of organ injury and/or dysfunction in rats with endotoxaemia.

6-Ketoprostaglandin F1 alpha↗
PubMed1998

Decline in the expression of copper/zinc superoxide dismutase in the kidney of rats with endotoxic shock: effects of the superoxide anion radical scavenger, tempol, on organ injury.

1. Endotoxaemia causes an enhanced formation of reactive oxygen species (ROS) which contribute to the multiple organ dysfunction syndrome (MODS) in septic shock. Here we investigate (i) the effects of endotoxin on the expression of two isoforms of superoxide dismutase (SOD), namely Cu/Zn-SOD (cytosol) and Mn-SOD (mitochondria) in the rat kidney, and (ii) the effects of the radical scavenger tempol on the MODS caused by lipopolysaccharide (LPS, E. coli, 6 mg kg(-1) i.v.) in the rat. 2. Endotoxaemia resulted in a rapid, but transient, decline in the expression of both mRNA and protein of Cu/Zn-SOD as well as an increase in the expression of the mRNA of Mn-SOD in the kidney. Endotoxaemia for 6 h also caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of nitrite/nitrate. 3. Pretreatment of rats with tempol (100 mg kg(-1) i.v. bolus injection, 15 min prior to LPS followed by an infusion of 30 mg kg(-1) i.v., n=9) did not affect the circulatory failure, but attenuated the renal dysfunction and the hepatocellular injury/dysfunction caused by LPS. Tempol did not affect the rise in nitrite/nitrate caused by endotoxin. 4. These results imply that an enhanced formation of ROS (including superoxide anions) in conjunction with inadequate defences against such ROS contributes to the injury and dysfunction of the kidney and the liver in endotoxic shock.

Animals↗
PubMed1998

Norethisterone therapy for bleeding due to gastrointestinal telangiectases in Glanzmann's thrombasthenia.

We report a case of a patient with Glanzmann's thrombasthenia and anti-GPIIb/IIIa alloantibodies who developed life-threatening and intractable bleeding from gastrointestinal telangiectatic lesions. After a period of transfusion-dependent gastrointestinal bleeding despite tranexamic acid, oral iron, omeprazole and platelet transfusions, the use of oral norethisterone produced a significant improvement with a marked reduction in her transfusion requirements.

Adult↗
PubMed1998

Acute liver failure induced by alcohol and paracetamol in an HCV-infected haemophiliac.

Paracetamol (acetaminophen) is frequently used by haemophiliacs in the management of acute or chronic pain, primarily due to its lack of adverse effects when taken at therapeutic doses. We describe acute hepatic and renal toxicity of paracetamol in a 36-year-old patient with haemophilia B, chronic hepatitis C and chronic alcohol abuse. Moderate doses of paracetamol (6 g/d for 4 d), taken with therapeutic intent, resulted in life-threatening organ dysfunction which gradually recovered with full supportive care.

Acetaminophen↗
PubMed1998

Efficacy of urate oxidase (uricozyme) in tumour lysis induced urate nephropathy.

Urate oxidase (uricozyme) is an enzyme of non-human origin capable of oxidizing human uric acid to allantoin, a highly soluble product at renal tubule pH. We report its efficacy in three patients with acute urate nephropathy due to tumour lysis in chronic lymphatic leukaemia and high grade lymphoma. Two patients had an additional obstructive nephropathy due to ureteric urate crystals. An intravenous infusion (100 units/kg in 50 ml saline over 30 min) was given for between two and five consecutive days. All patients showed a rapid fall in serum urate levels with associated diuresis, correction of metabolic disturbance and full resolution of uraemia within a week. The treatment was well tolerated and caused a rapid resolution of clinical symptoms in all cases. We review the literature relating to the use of this agent both in the treatment of hyperuricaemic acute renal failure and gouty arthritis.

Aged↗
PubMed1998

Transfusion-related acute lung injury (TRALI) following autologous stem cell transplant for relapsed acute myeloid leukaemia: a case report and review of the literature.

A fatal case of transfusion-related acute lung injury (TRALI) in a child post-autologous stem cell transplant for relapsed acute myeloid leukaemia is described. The implicated product was a single unit platelet concentrate containing anti-HLA A2 and granulocyte-specific anti-NA1 antibodies. The recipient typed as HLA A2/A2, NA1/NA1. This is the first reported case of TRALI following a transplant procedure for a haematological condition. It is also unusual in that the patient failed to make a full recovery and that two relevant leucocyte antibodies of clear specificity were identified in the donor plasma. The literature relating to the pathophysiology, clinical sequelae and management of TRALI is reviewed.

Acute Disease↗
PubMed1997

Peptidomimetic inhibitors of the human cytomegalovirus protease.

The development of peptidomimetic inhibitors of the human cytomegalovirus (HCMV) protease showing sub-micromolar potency in an enzymatic assay is described. Selective substitution of the amino acid residues of these inhibitors led to the identification of tripeptide inhibitors showing improvements in inhibitor potency of 27-fold relative to inhibitor 39 based upon the natural tetrapeptide sequence. Small side chains at P1 were well tolerated by this enzyme, a fact consistent with previous observations. The S2 binding pocket of HCMV protease was very permissive, tolerating lipophilic and basic residues. The substitutions tried at P3 indicated that a small increase in inhibitor potency could be realized by the substitution of a tert-leucine residue for valine. Substitutions of the N-terminal capping group did not significantly affect inhibitor potency. Pentafluoroethyl ketones, alpha,alpha-difluoro-beta-keto amides, phosphonates and alpha-keto amides were all effective substitutions for the activated carbonyl component and gave inhibitors which were selective for HCMV protease. A slight increase in potency was observed by lengthening the P1' residue of the alpha-keto amide series of inhibitors. This position also tolerated a variety of groups making this a potential site for future modifications which could modulate the physicochemical properties of these molecules.

Antiviral Agents↗
PubMed1997

Potentially prothrombotic abnormalities of coagulation in benign intracranial hypertension.

OBJECTIVE: Benign intracranial hypertension (BIH) may be caused by intracranial venous sinus thrombosis. Cerebral angiograms may, however, be normal in patients with BIH that are associated with conditions with an increased risk of venous thrombosis. This raises the possibility that unrecognised non-occlusive venous thrombus might impede CSF drainage. This study therefore examined the strength of the association between risk factors for thrombosis and BIH. METHODS: The incidence of prothrombotic abnormalities among a mixed prospectively and retrospectively investigated cohort of 38 patients with BIH, was compared with healthy obese subjects, and patients with other neurological diseases. Prothrombotic abnormalities investigated included anticardiolipin antibodies, lupus anticoagulant, antithrombin III, proteins C and S, plasma fibrinogen, kaolin cephalin clotting time, prothrombin time, and full blood counts. RESULTS: Evidence for the presence of an antiphospholipid antibody was found in 32% of cases. Cases of familial deficiency of antithrombin III, thrombocytosis, and polycythaemia were also noted. Additionally, an increased concentration of plasma fibrinogen was found in 26%. A coagulation abnormality was more often detectable in those subjects with normal or low body mass index and in those tested within six months of onset. CONCLUSION: There is a thrombotic pathogenesis in some cases of BIH.

Adolescent↗
PubMed1996

Haemoglobin Hallamshire (beta146 HIS --> TYR): a new high oxygen affinity haemoglobin responsible for familial erythrocytosis.

A new high oxygen affinity haemoglobin with the beta chain mutation beta146 HIS --> TYR is described. This variant was detected in a fit 34-year-old man with true erythrocytosis. The abnormal haemoglobin was identified as an extra band on cellulose acetate electrophoresis at pH 6.3 and was later confirmed by beta globin gene sequencing and oxygen dissociation studies. Whole blood containing Haemoglobin Hallamshire has a P50 of 18 mmHg. This newly described haemoglobin variant was also responsible for erythrocytosis in the mother and maternal half cousin of the index case. The identification of Haemoglobin Hallamshire provides confirmatory evidence of the important role of the C-terminal end of the chain in haemoglobin function.

Adult↗
PubMed1995

The sodium channel blocker and glutamate release inhibitor BW1003C87 and magnesium attenuate regional cerebral edema following experimental brain injury in the rat.

Excitatory amino acid (EAA) neurotransmitters may play a role in the pathophysiology of traumatic injury to the CNS. Although NMDA receptor antagonists have been reported to have therapeutic efficacy in animal models of brain injury, these compounds may have unacceptable toxicity for clinical use. One alternative approach is to inhibit the release of EAAs following traumatic injury. The present study examined the effects of administration of a novel sodium channel blocker and EAA release inhibitor, BW1003C87, or the NMDA receptor-associated ion channel blocker magnesium chloride on cerebral edema formation following experimental brain injury in the rat. Animals (n = 33) were subjected to fluid percussion brain injury of moderate severity (2.3 atm) over the left parietal cortex. Fifteen minutes after injury, the animals received a constant infusion of BW1003C87 (10 mg/kg, i.v.), magnesium chloride (300 mumol/kg, i.v.), or saline over 15 min (2.75 ml/kg/15 min). In all animals, regional tissue water content in brain was assessed at 48 h after injury, using the wet weight/dry weight technique. In saline-treated control animals, fluid percussion brain injury produced significant regional brain edema in injured left parietal cortex (p < 0.001), the cortical area adjacent to the site of maximal injury (p < 0.001), left hippocampus (p < 0.001), and left thalamus (p = 0.02) at 48 h after brain injury. Administration of BW1003C87 15 min postinjury significantly reduced focal brain edema in the cortical area adjacent to the site of maximal injury (p < 0.02) and left hippocampus (p < 0.01), whereas magnesium chloride attenuated edema in left hippocampus (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

A dementing illness associated with a novel insertion in the prion protein gene.

Following our previous report of an 144-bp insertion in the open reading frame of the prion protein (PrP) gene, we have now identified a larger, 216-bp, insertion in the gene. The insertion which is in frame encodes 9 extra octapeptide repeat sequences in addition to the 5 repeats normally present and represents the largest insertion so far detected in the PrP gene.

Alleles↗
PubMed1992

Inherited prion disease with 144 base pair gene insertion. 1. Genealogical and molecular studies.

Genealogical and molecular studies were carried out in four families in which early onset dementia is inherited as an autosomal dominant. These studies indicated that the four families derive from four siblings whose parents were born in the late 18th century in South-East England. The disease was found to be closely linked to a 144 bp insertion within the open reading frame of the prion protein (PrP) gene with a maximum LOD score of 11.02 at zero recombination. Within the general population the PrP gene is polymorphic at codon 129 (allele frequency approximately 30% valine, 70% methionine). The insertion in this family is always within a methionine-129 allele. The age at death of affected individuals whose normal allele encoded methionine at codon 129 was significantly lower than those whose normal allele encoded valine. The clinical features which were very variable and the neuropathological findings, which sometimes included spongiform encephalopathy, but which often did not, are described fully in the accompanying article (Collinge et al., 1992).

Base Sequence↗
PubMed1991

Insertions in the prion protein gene in atypical dementias.

A number of mutations have been demonstrated in the open reading frame (ORF) of the prion protein (PrP) gene in patients with familial Creutzfeldt-Jakob disease or Gerstmann-Sträussler syndrome. On the basis of detecting an insertion in the ORF of the PrP gene in a patient originally suspected to be suffering from familial Alzheimer-type dementia, we screened 101 individuals with atypical dementias for the known PrP gene mutations. Insertions were found in five individuals, whereas none of the other reported mutations in the PrP gene was detected in the present study. One of the five insertions was larger than that described previously, suggesting that the individuals with these mutations are unlikely to be all lineally related and that insertions in the PrP gene may not be uncommon in prion diseases.

Alzheimer Disease↗
PubMed1991

Evidence for a pseudo-autosomal locus for schizophrenia using the method of affected sibling pairs.

A susceptibility locus for schizophrenia in the 'pseudo-autosomal' region has been proposed on the basis of the reported excess of sex-chromosome aneuploidies (e.g. XXY and XXX) among patients with schizophrenia and the finding that schizophrenic sib-pairs are more often of the same than of the opposite sex. This hypothesis has been tested in 83 sibships with two or more siblings fulfilling Research Diagnostic Criteria for schizophrenia or schizoaffective disorder. Alleles at the pseudo-autosomal telomeric locus DXYS14, which is unlinked with sex, were analysed using the method of affected sib-pairs. Affected sibs shared alleles at DXYS14 more frequently than expected by random Mendelian assortment, supporting genetic linkage between DXYS14 and schizophrenia.

Alleles↗
PubMed1990

Prion dementia without characteristic pathology.

Gerstmann-Sträussler syndrome (GSS) was diagnosed in a family with presenile dementia by prion protein gene analysis. Extensive histological examination of the brain of an affected individual from this family showed no characteristic features of GSS or Creutzfeldt-Jakob disease (CJD). Thus "spongiform encephalopathy" (GSS or CJD) cannot always be excluded on neuropathological grounds in an individual dying of a dementing condition, and the true prevalence of these diseases is likely to be underestimated. Screening by prion protein gene analysis will help to determine the full clinical and neuropathological phenotype in familial cases. This observation may be relevant to the assessment of possible transmission of bovine spongiform encephalopathy to man.

Alleles↗