Coma in thrombotic thrombocytopenic purpura.
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Coma↗
Biomedical subjects
F M Williams
Publications and source records attributed to F M Williams.
Prevalence of the diffuse infiltrative lymphocytosis syndrome among human immunodeficiency virus type 1-positive outpatients.
OBJECTIVE: To ascertain the prevalence of the diffuse infiltrative lymphocytosis syndrome (DILS) in human immunodeficiency virus type 1 (HIV-1)-positive outpatients. METHODS: The presence of sicca symptoms and visible salivary gland enlargement was determined by interview and physical examination, and the clinical stage was determined by chart review, in 523 HIV-positive patients. The diagnosis of DILS was established in those with parotid gland enlargement by minor salivary gland biopsy or radionuclide scintigraphy. RESULTS: Definite DILS was found in 15 (3%) of the 523 patients, and possible DILS in 18 (3.4%). The prevalence of definite DILS was significantly higher in African Americans (4.5%). Self-reported facial swelling and xerophthalmia that was not explained by the effects of medication were found more frequently in those with DILS than in the non-DILS patients. Patients with DILS had higher CD8 counts (mean +/- SD 1,456 +/- 813/mm3) compared with those without DILS (934 +/- 624/mm3; P < 1 x 10(-6)), and were less advanced in their HIV clinical stage (Centers for Disease Control and Prevention stages A or B in 76% compared with 60% of the non-DILS group; P = 0.01). CONCLUSION: DILS is an important problem in HIV-infected outpatients and tends to occur in patients whose clinical disease is at a less advanced stage. Patients with parotid gland enlargement accompanied by sicca symptoms should be screened for HIV infection.
Diagnosis, Differential↗
A comparison of the electrophysiological effects of two organophosphates, mipafox and ecothiopate, on mouse limb muscles.
Adult male albino mice were given single subcutaneous injections of either mipafox (110 mumol/kg) or ecothiopate (0.5 mumol/kg), two organophosphorus compounds (OPs). Acetylcholinesterase activity was measured in the soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch) muscles. At 7 and 28 days after dosing, in vitro electrophysiological measurements were carried out in the soleus and EDL. Action potentials and end-plate potentials were evoked at 30 Hz and recorded intracellularly from single muscle fibers. The amplitudes, time course, and latencies of these potentials were measured and the variability (jitter) of latencies was calculated. Recordings after mipafox were also made with 3-Hz stimulation. Acetylcholinesterase activity was inhibited by mipafox (65% in the soleus; 76% in the EDL) and ecothiopate (59% in the soleus; 42% in the EDL). Mipafox and ecothiopate both increased postjunctional (muscle action potential) jitter in the soleus and EDL at 7 days after dosing. Organophosphates caused an increase in end-plate potential amplitudes in the soleus. Mipafox caused an increase in prejunctional (end-plate potential) jitter at 28 days after dosing in both muscles. A single dose of ecothiopate also caused an increase in prejunctional jitter at 28 days in the soleus. The OP-induced increase in jitter was different at different frequencies of stimulation. The results show that there are electrophysiological changes in both muscles after administration of organophosphorus compounds. The slow-twitch soleus appears more sensitive to prejunctional changes caused by OPs than the fast-twitch EDL.
Acetylcholinesterase↗
Accelerated cutaneous nodulosis during methotrexate therapy in a patient with rheumatoid arthritis.
Rheumatoid nodulosis is characterized by multiple small subcutaneous granulomatous nodules typically located on the elbows in approximately 20% of patients with rheumatoid arthritis. Accelerated rheumatoid nodulosis, especially involving the hands and feet, has recently been reported in patients receiving methotrexate therapy for rheumatoid arthritis. We describe a woman with seropositive, erosive rheumatoid arthritis who, on two occasions, developed nonperiarticular subcutaneous nodules and new heart murmurs during methotrexate therapy, while her arthritis remained under good control. The nodules resolved after methotrexate was discontinued and recurred after methotrexate was reintroduced. They again resolved after methotrexate was stopped and colchicine was added. Her DNA oligotyping was positive for HLA-DRB1*0401, a genetic risk factor associated with accelerated rheumatoid nodulosis. Cutaneous biopsy specimens revealed palisading granulomas and giant cells consistent with rheumatoid nodulosis.
Antirheumatic Agents↗
The antiphospholipid syndrome and vascular surgery.
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Antiphospholipid Syndrome↗
Structural organization of the human reduced folate carrier gene: evidence for 5' heterogeneity in lymphoblast mRNA.
The reduced folate carrier (rfc1) gene encodes a protein that is involved in the intracellular accumulation of folates. Point mutations in this gene and alterations resulting in the down regulation of its message are major factors involved in the resistance to antifolate chemotherapeutic compounds. As a framework for understanding the significance of such changes in relation to gene expression and function, in this report we describe the organization of the rfc gene from human lymphoblasts. The gene contains 5 exons (2 to 6) coding for protein. At least four 5' exons, used in a mutually exclusive manner in the production of the rfc message from lymphoblast cells, are spliced to exon 2, which contains the translational start site. "Semi-quantitative" PCR indicates that exon 1 is preferentially used. The major transcriptional start site has been mapped by RACE and RNase protection to a region 109 to 135 base pairs 5' to the start of exon 1. The 5' region of the gene has no TATA box-like sequence but contains several consensus binding sites for transcriptional factors such as SP-1, MZF1, CREB, AP-1, ETS, GATA-1 and GATA-2. The overall organization of the human gene is similar to that of the hamster and mouse genes.
Alternative Splicing↗
Reactivation of coccidioidomycosis in a fit American visitor.
The case history is presented of an American visitor, known to have had primary coccidioidomycosis previously, who became very unwell during a visit to the UK. Despite consideration of reactivation of coccidioidomycosis from the outset, other pathogens were identified while Coccidioides immitis was not initially, leading to a delay in treatment.
Bronchoalveolar Lavage Fluid↗
Effect of Tri-O-cresyl phosphate (TOCP) on proteolytic enzyme activities in mouse liver in vivo.
To develop a clearer understanding of the biochemical mechanisms of toxicity in higher animals, we determined the effect of four sublethal dosages (0.25 to 1.0 g/Kg) of organophosphate (OP), and of tri-ortho-cresyl phosphate (TOCP) on the activities of a representative range of cytoplasmic and lysosomal proteolytic enzymes in mouse liver in vivo. Administration of the lowest sublethal dosage of TOCP (0.25g/1Kg, 24 hours) resulted in significant inhibition (10 to 30% of control activity) of the cytoplasmic proteases tripeptidyl aminopeptidase and proline endopeptidase only. An increasing dosage of TOCP (1g/Kg for 7 days) resulted in significant inhibition (10 to 50% of control activity) of the cytoplasmic proteases alanyl aminopeptidase, leucyl aminopeptidase, tripeptidyl aminopeptidase, and proline endopeptidase, as well as the lysosomal proteases dipeptidyl aminopeptidase I and cathepsins B, D, and L. The activities of the cytoplasmic proteases arginyl aminopeptidase and dipeptidyl aminopeptidase IV, and of lysosomal proteases dipeptidyl aminopeptidase II and cathepsin H were not significantly altered following TOCP administration at this higher dosage. All of the above proteases are involved in the general process of intracellular protein turnover (common to all tissues), and may also have more specialized functions such as the processing of physiologically active hormonal peptides, and the processing of antigenic proteins in the immune response. Data obtained in the present study suggest that inhibition of the above enzymes by OP such as TOCP may represent a previously unrecognized toxicity hazard induced by the latter compound in higher animals.
Aminopeptidases↗
Thromboprophylaxis in antiphospholipid syndrome pregnancies with previous cerebral arterial thrombotic events: is warfarin preferable?
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Adult↗
Antiphospholipid syndrome patients' monocytes are "primed" to express tissue factor.
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Antiphospholipid Syndrome↗
Effect of pirimiphos-methyl on proteolytic enzyme activities in rat heart, kidney, brain and liver tissues in vivo.
To elucidate whether pesticide toxicity in higher animals involves pesticide-induced dysfunction of the intracellular protein catabolic process, we have determined the effect in vivo of the organophosphate insecticide pirimiphos-methyl on the activities of representative protein catabolising cytoplasmic and lysosomal proteases (responsible for the various stages of the protein degradation cascade and essential for normal cell functioning) in heart, kidney, brain and liver target tissues in the rat. In liver tissue (the major site of pesticide metabolism), the activities of all of the cytoplasmic proteases investigated (alanyl-, arginyl-, leucyl aminopeptidases, dipeptidyl aminopeptidase IV, tripeptidyl aminopeptidase, proline endopeptidase) were significantly inhibited (by 20-40% of control activity) following administration of 10 mg pirimiphos-methyl/kg bodyweight, whereas of the lysosomal proteases investigated, only the activities of dipeptidyl aminopeptidase I and cathepsin D were significantly reduced (by 15-20% of control activity). In contrast, there was no insecticide-induced inhibition of protease activities in heart, kidney or brain tissues; some lysosomal enzymes (dipeptidyl aminopeptidase I, cathepsins L and D) showed significantly increased activities in these tissues (the reason for which remains to be determined). We conclude that the effect of pirimiphos-methyl on proteolytic enzyme activities differs in different target tissues, and that pirimiphos-methyl induced inhibition of proteases in liver tissue may represent a previously unrecognised toxicity hazard in higher animals.
Animals↗
Role of nitric oxide in the dilator actions of capsaicin-sensitive nerves in the rabbit coronary circulation.
Perivascular sensory nerves release calcitonin gene-related peptide (CGRP) and substance P, the dilator actions of which can be regulated by nitric oxide (NO). This study investigated the role of NO in the vasodilation caused by sensory nerve stimulation, by capsaicin, or exogenous CGRP and substance P in the isolated perfused coronary circulation of the rabbit. Coronary perfusion pressure (CPP) was raised in order to observe vasodilator responses, using the thromboxane mimetic, U46619. Capsaicin (3 x 10(-6) moles), alpha CGRP (3 x 10(-11) moles) and substance P (3 x 10(-12) moles) caused comparable reductions in CCP. At these concentrations, responses to capsaicin and CGRP were inhibited by the antagonist CGRP(8-37) but unaffected by the neurokinin-1 receptor antagonist, CP 96,345. The nitric oxide synthase inhibitor, NG nitro L-arginine methyl ester inhibited the effects of substance P and capsaicin but not CGRP. These results suggest that CGRP release following capsaicin-induced sensory nerve activation is modulated by NO.
Animals↗
The effects of multiple low doses of organophosphates on target enzymes in brain and diaphragm in the mouse.
1. Multiple low doses of the direct acting organophosphates, ecothiopate, paraoxon and mipafox produced persistent and additive inhibition of diaphragm acetylcholinesterase. Paraoxon and mipafox had similar effects on brain acetylcholinesterase. There was greater recovery from inhibition between doses for paraoxon and ecothiopate than for mipafox. 2. Ecothiopate did not inhibit brain acetylcholinesterase but there was a small increase in activity. 3. Mipafox also had a cumulative inhibitory effect on brain neuropathy target esterase. 4. These results have particular implication for the use of multiple low doses of organophosphates occupationally by man.
Animals↗
Effects of multiple doses of organophosphates on evoked potentials in mouse diaphragm.
1. Male albino mice were injected s.c. with an organophosphate (mipafox, ecothiopate or paraoxon). Treatments were either a single injection or multiple daily injections with lower doses for 5 or 8 days. At 3 h after injection the activity of brain and diaphragm acetylcholinesterase and of brain neuropathy target esterase (NTE) was measured. Also measured in the diaphragm at 3 h post dose was the duration of spontaneous miniature endplate potentials (eMEPPs), recorded extracellularly. 2. At 7 and 28 days after dosing action potentials and evoked endplate potentials, produced by stimulating the phrenic nerve at 30 Hz, were recorded in diaphragm muscle. The amplitudes, time-course and latencies of these potentials were measured and the variability of latencies (jitter) was calculated. 3. Single doses of mipafox (20 mg/kg), ecothiopate (0.192 mg/kg) or paraoxon (0.415 mg/kg) in the mouse produced ca. 70% inhibition of diaphragm acetylcholinesterase at 3 h after dosing. All three OPs produced a prolongation of the half-decay times of eMEPPs. 4. All three OPs in the above single doses produced increased muscle action potential (postjunctional) jitter but only mipafox produced an increase in endplate potential (prejunctional) jitter. Mipafox in a slightly reduced single dose (17.5 mg/kg) had no effect on prejunctional or postjunctional jitter. 5. Multiple dosing with mipafox (8 mg/kg daily for 5 days) increased both postjunctional and prejunctional jitter at both 7 and 28 days after the end of dosing. After multiple dosing with mipafox (5 mg/kg daily for 5 days) postjunctional (but not prejunctional) jitter was increased. Multiple doses of paraoxon (0.166 mg/kg daily for 5 days) or ecothiopate (0.76 mg/kg daily for 5 days) increased prejunctional and postjunctional jitter. 6. Depending on the dosing regime, all three OPs tested were capable of increasing both prejunctional and postjunctional jitter. Neither ecothiopate nor paraoxon inhibited NTE, so this prejunctional effect is not likely to be related to 'classical' OP-induced delayed neuropathy. The prejunctional effects may be related to long-term inhibition of acetylcholinesterase and the triggering mechanism for increase in prejunctional jitter may involve a relationship between the inhibition of acetylcholinesterase and the time for which it is inhibited. The differences between the time-courses of increases in prejunctional and postjunctional jitter and the differential effects of the different multiple dosing regimes indicate that it is likely that the triggering relationship between enzyme inhibition and time is different for prejunctional and postjunctional effects.
Action Potentials↗
Metabolism of n-hexane by rat liver and extrahepatic tissues and the effect of cytochrome P-450 inducers.
1. The in vitro metabolism of n-hexane was studied in rat liver, lung, brain and skeletal muscle microsomes and in microsomes prepared from cell lines expressing human cytochrome P-450 2E1 or 2B6. The hydroxylated metabolites of n-hexane were quantified by gas chromatography-mass spectometry. 2. Rat liver and extensor digitorum longus (EDL, fast-twitch skeletal muscle) microsomes and the CYP 2B6 microsomes produced the pre-neurotoxic metabolite of n-hexane, 2-hexanol as a major metabolite in contrast to the other rat tissues examined. 3. Inhibition of 2- and 3-hexanol production from n-hexane by rat lung microsomes using metyrapone, an inhibitor of cytochrome P-450 2B1 activity, resulted in almost complete inhibition of lung microsomal activity. 4. Production of all three hexanols was significantly increased with phenobarbital-induced rat liver microsomes, with a 10-fold increase in 2- and 3-hexanol production. A slight increase in 2-hexanol production with phenobarbital-induced rat EDL and brain microsomes was observed. No increase in n-hexane metabolism was noted following induction with beta-naphthoflavone or with ethanol.
Animals↗
An investigation into the role of rat skeletal muscle as a site for xenobiotic metabolism using microsomes and isolated cells.
1. The role of skeletal muscle microsomes as a site of extrahepatic xenobiotic metabolism using n-hexane as a model substrate was investigated. The observed cytochrome P450-dependent metabolism was compared with that found with liver, and brain microsomal fractions. 2. Rat skeletal muscle microsomes metabolised n-hexane to 1-, 2- and 3-hexanol at rates 40-300 times lower than observed with rat liver microsomes. 3. Fast-twitch extensor digitorum longus muscle (EDL) microsomes had twice as much n-hexane hydroxylase activity as the slow-twitch soleus and furthermore the EDL microsomes produced 2-hexanol, a bioactivation product of n-hexane, as a major metabolite. 4. Metabolism of hexane to 1-, 2- and 3-hexanol and 2-hexanon was demonstrated in cultured rat myoblasts. 5. Ethoxyresorufin and pentoxyresorufin O-dealkylation were not detected in either muscle microsomes or myoblasts although immunocytochemical localisation studies were suggestive of the presence of cytochrome P-450. 6. In conclusion, rat skeletal muscle has a low level of xenobiotic metabolism activity. The relevance to neuromuscular toxicity of n-hexane is discussed.
Animals↗
The percutaneous absorption and skin distribution of lindane in man. I. In vivo studies.
1. The absorption and distribution of lindane through skin was examined using human volunteers. Two different preparations were employed, one with acetone as the vehicle and the other, a commercial product, consisting primarily of white spirit as the solvent base. 2. The mean peak plasma concentrations of lindane following exposure to the acetone and white-spirit based applications were 0.91 and 0.47 ng/ml, respectively. The similarity between these levels did not reflect the 40-fold higher dose of lindane in the acetone vehicle. White spirit enhanced the penetration of lindane with respect to the acetone vehicle, highlighting the influence of vehicle upon percutaneous absorption. Low levels of trichlorophenol glucuronide metabolites, but no lindane, were detected in the urine. 3. The exposure site was washed at 6 h to mimic a decontamination procedure at the end of a working day. The proportion of the applied dose unabsorbed by 6 h was 80% and 10% for the acetone and the white spirit-based formulation, respectively. Small areas of the exposed site were tape stripped at 6 and 24 h to assess any lindane that may be associated with the stratum corneum. High levels were observed in the stratum corneum at 6 h exposure (up to 30% of the applied dose for the white spirit based formulation). However, this level had decreased by 24 h (by at least 90% of the amount found at 6 h). A gauze or gauze/shirt combination covering the application site between 6 and 24 h did account for some of this loss of lindane from the stratum corneum attributed to friction and removal of exfoliated cells. The unaccounted proportion was presumed to have been absorbed through the skin into the systemic circulation. This demonstrates the absorption of chemicals can occur from a depot in the stratum corneum even following a wash procedure.
Acetone↗
The percutaneous absorption and skin distribution of lindane in man. II. In vitro studies.
1. The absorption of lindane through human skin was assessed in vitro using static diffusion cells with 50% aqueous ethanol as the receptor fluid. Four formulations of lindane were applied, three of which were commercial preparations. The dermal distribution of lindane within the skin was also examined, focusing particularly on any association of lindane to the stratum corneum. The results were then compared with a parellel in vivo study. 2. Two of the formulations contained white spirit as the predominant solvent, and lindane absorption was greatest from these preparations in terms of the percentage of the applied dose (15-25% by 24 h). Absorption was less from an aqueous spray dilution (3% by 24 h), with absorption from acetone being the least (< 1% by 24 h). Similar amounts of lindane penetrated by 24 h for the acetone and white spirit-based applications (approx. 8 micrograms). This supported the in vivo observation that similar plasma lindane levels were recorded following exposure to the acetone solution and the white spirit-based formulation A, although the lindane concentration in acetone was 40-fold higher. 3. For the acetone and water-based preparations, a soap/water swab of the skin surface at 6 h contained the majority of the applied dose (around 75%). Substantial amounts of lindane were recovered in tape-strippings taken at 6 h (representative of stratum corneum content) which were significantly greater than lindane in the remainder of the skin, for the acetone solution and formulation A. This provided a strong indication that lindane had accumulated in the stratum corneum, a property that has been linked with other lipophilic chemicals.
Acetone↗