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Biomedical subjects

John S Walsh

Publications and source records attributed to John S Walsh.

14 recordsLinked to original sources
PubMed2005

Eruptive epidermoid cysts resulting from treatment with imiquimod.

BACKGROUND: Because of its unique mechanism of action and safety profile, imiquimod, a topical immune response modifier, is used for many benign and malignant dermatologic conditions. Adverse effects are typically limited to treatment site erythema and erosion. OBJECTIVE: To describe a newly recognized adverse effect of imiquimod. METHODS: A 79-year-old woman being treated with imiquimod 5 days per week for a nodular basal cell developed a verrucous plaque over the treatment area after 7 weeks of therapy. RESULTS: Scouting biopsies demonstrated multiple comedones and ruptured epidermoid cysts. There was no evidence of residual basal cell carcinoma. CONCLUSIONS: Imiquimod is a new and novel treatment option for cutaneous malignancies. We report its successful use in the treatment of a nodular basal cell carcinoma. The multiple comedones and ruptured epidermoid cysts are newly reported adverse effects of imiquimod therapy.

Administration, Topical↗
PubMed2005

Muir-Torre syndrome: a case report and review of the literature.

The presence of sebaceous skin tumors with visceral neoplasms is known as Muir-Torre syndrome (MTS). It is a phenotypic subset of hereditary nonpolyposis colorectal cancer and is caused by mutations in genes encoding for mismatch repair (MMR) proteins. The presence of a sebaceous gland neoplasm should raise concern for a potential diagnosis of MTS. Immunohistochemical analysis of the sebaceous skin tumors can be helpful in screening for an MMR defect and preselecting patients who are at increased risk of a visceral malignancy. We report a case of MTS and show immunohistochemical analysis of the sebaceous neoplasm. We also review the literature on MTS and the effectiveness of immunohistochemical analysis in screening patients at risk for MTS.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2004

Enzymology of a carbonyl reduction clearance pathway for the HIV integrase inhibitor, S-1360: role of human liver cytosolic aldo-keto reductases.

S-1360, a 1,3-diketone derivative, was the first HIV integrase inhibitor to enter human trials. Clinical data suggested involvement of non-cytochrome P450 clearance pathways, including reduction and glucuronidation. Reduction of S-1360 generates a key metabolite in humans, designated HP1, and constitutes a major clearance pathway. For characterization of subcellular location and cofactor dependence of HP1 formation, [(14)C]-S-1360 was incubated with commercially available pooled human liver fractions, including microsomes, cytosol, and mitochondria, followed by HPLC analysis with radiochemical detection. Incubations were performed in the presence and absence of the cofactors NADH or NADPH. Results showed that the enzyme system responsible for generation of HP1 in vitro is cytosolic and NADPH-dependent, implicating aldo-keto reductases (AKRs) and/or short-chain dehydrogenases/reductases (SDRs). A validated LC/MS/MS method was developed for investigating the reduction of S-1360 in detail. The reduction reaction exhibited sigmoidal kinetics with a K(m,app) of 2 microM and a Hill coefficient of 2. The ratio of V(max)/K(m) was approximately 1 ml/(min mg cytosolic protein). The S-1360 kinetic data were consistent with positive cooperativity and a single enzyme system. The relative contributions of AKRs and SDRs were examined through the use of chemical inhibitors. For these experiments, non-radiolabeled S-1360 was incubated with pooled human liver cytosol and NADPH in the presence of inhibitors, followed by quantitation of HP1 by LC/MS/MS. Quercetin and menadione produced approximately 30% inhibition at a concentration of 100 microM. Enzymes sensitive to these inhibitors include the carbonyl reductases (CRs), a subset of the SDR enzyme family predominantly located in the cytosol. Flufenamic acid and phenolphthalein were the most potent inhibitors, with > 67% inhibition at a concentration of 20 microM, implicating the AKR enzyme family. The cofactor dependence, subcellular location, and chemical inhibitor results implicated the aldo-keto reductase family of enzymes as the most likely pathway for generation of the major metabolite HP1 from S-1360.

Alcohol Oxidoreductases↗
PubMed2004

Human carbonyl reduction pathways and a strategy for their study in vitro.

Carbonyl reduction plays a significant role in physiological processes throughout the body. Although much is known about endogenous carbonyl metabolism, much less is known about the roles of carbonyl-reducing enzymes in xenobiotic metabolism. Multiple pathways exist in humans for metabolizing carbonyl moieties of xenobiotics to their corresponding alcohols, readying these molecules for subsequent conjugation and/or excretion. When exploring carbonyl reduction clearance pathways for a drug development candidate, it is possible to assess the relative contributions of these enzymes due to their differences in subcellular locations, cofactor dependence, and inhibitor profiles. In addition, the contributions of these enzymes may be explored by varying incubation conditions, such as pH. Presently, individual isoforms of carbonyl-reducing enzymes are not widely available, either in recombinant or purified form. However, it is possible to study carbonyl reduction clearance pathways from simple experiments with commercially available reagents. This article provides an overview of carbonyl-reducing enzymes, including some kinetic data for substrates and inhibitors. In addition, an experimental strategy for the study of these enzymes in vitro is presented.

Animals↗
PubMed2004

Erythema multiforme associated with candesartan cilexetil.

Candesartan cilexetil is an angiotensin II receptor antagonist that is widely used in the treatment of hypertension. It is generally well tolerated and rarely has adverse effects. We report the case of a 50-year-old man with a 3-year history of hypertension that was difficult to manage because of intolerance to multiple medications. Treatment with candesartan cilexetil was initiated, and blood pressure control improved markedly. Five weeks later, the patient presented with a 2 x 3-cm ulcerative plaque covered with a fibrinous exudate on the right upper lip. Findings from a biopsy of the upper lip were diagnostic for erythema multiforme. Treatment with candesartan cilexetil was discontinued, and the lesions resolved completely within a few weeks. To our knowledge, this is the first report of erythema multiforme induced by the antihypertensive medication candesartan cilexetil.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

Cutaneous hyalohyphomycosis caused by Paecilomyces lilacinus: report of three cases and review of the literature.

Cutaneous infection with Paecilomyces lilacinus is encountered worldwide, with most infections occurring either iatrogenically or in immunocompromised hosts. We report three cases of cutaneous hyalohyphomycosis caused by P. lilacinus, one of which occurred in an immunocompetent individual. In addition, we review the 17 cases previously reported in the literature. Although this infection can be difficult to treat, most cases are not fatal. Most cases responded well to systemic azole antifungal agents, either alone or in association with surgical excision of the lesion. Paecilomyces species are saprophytic fungi found in soil and decaying organic matter. Infection in humans is rare, but when it occurs treatment is often difficult. We report three cases of cutaneous hyalohyphomycosis caused by P. lilacinus and review the 17 previously reported cases in which the clinical history and response to therapy were described.

Aged↗
PubMed2003

Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys.

Structure-activity relationships in rhesus monkeys for a novel mixed-onium class of ultra-short-acting nondepolarizing tetrahydroisoquinolinium neuromuscular blockers (NMBs) are described. Bis-onium chlorofumarate 20a with (1R,2S)-benzyltetrahydroisoquinolinium groups was a potent lead compound (ED(95) = 0.079 mg/kg) with an ultra-short duration of NMB effect (7.1 min) and a selectivity index (SI: defined as a ratio of the cardiovascular threshold dose to the ED(95)) similar to that of mivacurium (3). The mean threshold dose for cardiovascular effects with 20a was ca. 20 times its ED(95) value (SI = 20). A novel mixed-onium analogue of 20a was prepared by replacing the benzyltetrahydroisoquinolinium group distal to the fumarate chlorine atom with a (1S,2R)-phenyltetrahydroisoquinolinium moiety. The resulting mixed-onium chlorofumarate 24a displayed good NMB potency (ED(95) = 0.063 mg/kg), ultra-short duration of action (5.6 min) and an improved selectivity index (SI = 57). Several other mixed-onium derivatives containing octanedioate (25a; ED(95) = 0.103 mg/kg), difluorosuccinate (27c; ED(95) = 0.056 mg/kg), and fluorofumarate (28a; ED(95) = 0.137 mg/kg) linkers were also potent, ultra-short-acting NMBs with good to excellent selectivity index values (SI = 37-96). Octanedioate 25a was longer acting at higher doses compared to difluorosuccinate 27c and chlorofumarate 24a. Durations of NMB effect following a 0.4 mg/kg bolus dose (100% block) of 25a, 27c, and 24a were 16.9, 13.0, and 10.0 min, respectively. Recovery time for mixed-onium chlorofumarate 24a following a 1 h continuous infusion at 10-20 microg/kg/min (95-100% block) was ca. 5 min which is similar to that observed following a 0.2 mg/kg bolus dose of this compound and indicates a lack of cummulative effects. Preliminary studies with chlorofumarate 24a in whole human blood revealed that mixed-onium thiazolidine 29 was the major metabolite and that plasma cholinesterases do not play the primary role in duration of NMB effect. The NMB properties of 24a in rhesus monkeys led to its clinical evaluation as a possible alternative to succinylcholine.

Animals↗
PubMed2003

Nodular amyloidosis: review and long-term follow-up of 16 cases.

OBJECTIVES: To review the clinical presentations of nodular amyloidosis, examine these cases for evidence of plasma cell monoclonality, and obtain long-term follow-up data on progression to systemic amyloidosis. DESIGN: Retrospective case series with long-term follow-up data obtained by phone survey. SETTING: Mayo Clinic, Rochester, Minn, and Mayo Clinic, Jacksonville, Fla. PATIENTS: All patients diagnosed with nodular amyloidosis between 1971 and 2001. MAIN OUTCOME MEASURES: Clinical records and histopathologic characteristics were reviewed. Polymerase chain reaction to assess immunoglobulin gene rearrangement and immunohistochemical analysis to detect kappa and lambda light chain restriction were performed on paraffin-embedded specimens. Patients were contacted by phone to determine if progression to systemic disease had occurred. RESULTS: We identified 16 patients with nodular amyloidosis. Mean age at diagnosis was 60.8 years (range, 41-87 years). Eight (50%) of 16 patients had acral involvement. Immunohistochemical analysis demonstrated light chain restriction in 6 of 10 patients. At the time of diagnosis, no patient was known to have systemic amyloidosis. One patient, however, had a serum monoclonal lambda protein and died 4 years later secondary to systemic amyloidosis. Follow-up data were obtained in 14 of the remaining 15 patients, with a mean follow-up time of 10 years (range, 8 months to 24 years). None of the 14 patients had signs or symptoms suggesting progression to systemic amyloidosis. CONCLUSIONS: Nodular amyloidosis affects both sexes during middle age, with a tendency to affect acral sites. The relatively high rate of light chain restriction in our series provides further evidence for the presence of a local plasma cell clone. Progression to systemic amyloidosis is uncommon.

Adult↗
PubMed2003

Cutaneous nodular amyloidosis masquerading as a foot callus.

We report a unique case of a 69-year-old man who presented with a 1-year history of pink nodules and plaques limited to the anterior plantar surface of the right foot and a 30-year history of a callus on the right heel. Histologic examination findings of both areas showed deposits of amorphous, eosinophilic material and an infiltrate of plasma cells in the dermis. Congo red-stained deposits exhibited apple-green birefringence with polarized light. Results of an extensive clinical and laboratory evaluation showed no evidence of systemic amyloidosis. The diagnosis of nodular primary localized cutaneous amyloidosis (PLCA) was made. Nodular PLCA isolated to pedal or strictly plantar surfaces is an unusual presentation of PLCA. The origin and the clinical and histopathologic features of nodular PLCA are reviewed.

Aged↗
PubMed2002

The metabolic activation of abacavir by human liver cytosol and expressed human alcohol dehydrogenase isozymes.

Abacavir (ZIAGEN) is a reverse transcriptase inhibitor marketed for the treatment of HIV-1 infection. A small percentage of patients experience a hypersensitivity reaction indicating immune system involvement and bioactivation. A major route of metabolism for abacavir is oxidation of a primary betagamma unsaturated alcohol to a carboxylic acid via an aldehyde intermediate. This process was shown to be mediated in vitro by human cytosol and NAD, and subsequently the alphaalpha and gamma2gamma2 human isoforms of alcohol dehydrogenase (ADH). The alphaalpha isoform effected two sequential oxidation steps to form the acid metabolite and two isomers, qualitatively reflective of in vitro cytosolic profiles. The gamma2gamma2 isozyme generated primarily an isomer of abacavir, which was minor in the alphaalpha profiles. The aldehyde intermediate could be trapped in incubations with both isozymes as an oxime derivative. These metabolites can be rationalized as arising via the aldehyde which undergoes isomerization and further oxidation by the alphaalpha enzyme or reduction by the gamma2gamma2 isozyme. Non-extractable abacavir protein residues were generated in cytosol, and with alphaalpha and gamma2gamma2 incubations in the presence of human serum albumin (HSA). Metabolism and residue formation were blocked by the ADH inhibitor 4-methyl pyrazole (4-MP). The residues generated by the alphaalpha and gamma2gamma2 incubations were analyzed by SDS-PAGE with immunochemical detection. The binding of rabbit anti-abacavir antibody to abacavir-HSA was shown to be dependent on metabolism (i.e. NAD-dependent and 4-MP sensitive). The mechanism of covalent binding remains to be established, but significantly less abacavir-protein residue was detected with an analog of abacavir in which the double bond was removed, suggestive of a double bond migration and 1,4 addition process.

Alcohol Dehydrogenase↗