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Biomedical subjects

K J Smith

Publications and source records attributed to K J Smith.

At least 55 records · Page 3Linked to original sources
PubMed2001

Telomerase activity in Kaposi's sarcoma, squamous cell carcinoma, and basal cell carcinoma.

Patients with acquired immune deficiency syndrome (AIDS) often develop Kaposi's sarcoma (KS), an unusual skin tumor. The malignant nature of KS has long been disputed. Telomerase activity that maintains telomere length and ensures chromosomal stability, a frequently appearing marker in human malignancies, has been proposed to play a critical role in supporting continued cell growth, hence formation of tumors. We examined telomerase activity in tissue extracts from 22 KS, 10 squamous cell carcinoma (SCC), and 22 basal cell carcinoma (BCC) using the telomeric repeat amplification protocol (TRAP). All of the tumor tissues were previously cryopreserved at -80 degrees C. In this study, all tumor samples tested were positive for telomerase activity. Consistent with the presence of the enzyme activity, the skin tumors had relatively long telomeres. Inhibitors in the tissue extracts of some samples needed to be diluted or extracted by phenol before the enzyme activity was detected in the TRAP assay. All KS as well as two other skin carcinoma samples revealed positive telomerase activity. Our finding supports telomerase's role in tumor cell immortality and suggests the true neoplastic nature of KS.

Adult↗
PubMed2001

Spindle cell epithelioma of the vagina shows immunohistochemical staining supporting its origin from a primitive/progenitor cell population.

Spindle cell epitheliomas of the vagina (SCEVs) coexpresses epithelial and mesenchymal markers and were first described as a "mixed tumors of the vagina." However, unlike mixed tumors of other organs, which are believed to originate from myoepithelial cells, SCEVs neither immunohistochemically nor ultrastructurally show features of myoepithelial cells. The present expanded battery of immunohistochemical stains is presented on this rare tumor, including cytokeratin AE1/AE3, CK7, CK20, S100 protein, epithelial membrane antigen, alpha-smooth muscle actin, desmin, CD34, CD99, Bcl-2, vimentin, estrogen and progesterone receptors, and Ki-67. There was minimal expression of alpha-smooth muscle actin and negative staining with S100 protein, with coexpression of cytokeratins and vimentin and expression of estrogen and progesterone receptors, as previously reported in SCEVs. In addition, diffuse expression of CD34, CD99, and Bcl-2 immunohistochemical stains was found, which has not previously been reported. The coexpression of CD34, CD99, and Bcl-2 in SCEVs is consistent with its origin from a primitive/progenitor cell population.

Adult↗
PubMed2001

Delayed cutaneous hypersensitivity reactions to hirudin.

Hirudin is one of the new synthetic antithrombin agents, which is most commonly used in patients with type II heparin-induced thrombocytopenia and in patients with hypersensitivity reactions to unfractionated heparin as well as low-molecular-weight heparins. Hirudin is comparable to heparin as an antithrombotic agent and also has been studied as a primary treatment in patients who experienced acute myocardial infarctions. We describe a patient with a history of type II heparin-induced thrombocytopenia who was placed on intravenous hirudin therapy. After extravasation of the intravenous hirudin site, the patient developed a delayed hypersensitivity reaction that histologically showed an epithelioid granulomatous infiltrate. Although rare reports of hypersensitivity reactions to hirudin have been published, these reactions have not been well characterized and the histopathologic changes have not been described.

Biopsy↗
PubMed2001

Electrically active axons degenerate when exposed to nitric oxide.

Axonal degeneration is a major cause of permanent deficit in inflammatory neurological diseases such as multiple sclerosis. Axons undergo degeneration specifically at the site of the inflammatory lesions, suggesting that locally produced inflammatory factors mediate the phenomenon. One such factor is nitric oxide (NO), which we have previously reported can cause reversible conduction block in axons. Here we confirm these observations and extend them to show that axons exhibit the early stages of wallerian degeneration if they are conducting impulses at physiological frequencies while they are exposed to the low micromolar concentrations of NO that are likely to occur at sites of inflammation. Rat dorsal roots were concurrently exposed in vivo to both NO and sustained impulse activity at 1, 50, or 100 Hz. Although our in vivo observations necessarily focused on the more acute responses, morphological examination of exposed roots at the end of the recording period revealed nodal and paranodal changes consistent with acute wallerian degeneration in roots stimulated at 50 or 100 Hz. This interpretation was confirmed in a few experiments that were prolonged to permit more obvious indicators of degeneration to develop. In these experiments the formation of myelin ovoids and frank axonolysis occurred in more than 95% of fibers. Roots stimulated at only 1 Hz appeared normal. We propose that the combination of normal impulse traffic and NO at sites of inflammation may cause axonal degeneration and that electrical activity may therefore be an important factor in causing permanent disability in patients with neuroinflammatory disorders.

Action Potentials↗
PubMed2001

Pericarditis presenting and treated as an acute anteroseptal myocardial infarction.

Early recognition and treatment of acute myocardial infarctions have been accepted as improving patient mortality. With the popular use of thrombolytic therapy, it is necessary to rule out contraindications and to consider other causes for ST segment elevation. A unique patient experiencing chest pain with marked and localized ST segment elevation in the anteroseptal leads is presented. He was treated with thrombolytic therapy. Subsequent investigations ruled out the diagnosis of myocardial infarction and confirmed the diagnosis of pericarditis. Although the patient's outcome was uncomplicated, physicians are urged to consider the diagnosis of pericarditis before using thrombolytic therapy to avoid life-threatening complications.

Diagnosis, Differential↗
PubMed2000

Solution structure of the NADP(H)-binding component (dIII) of proton-translocating transhydrogenase from Rhodospirillum rubrum.

Transhydrogenase is a proton pump found in the membranes of bacteria and animal mitochondria. The solution structure of the expressed, 21.5 kDa, NADP(H)-binding component (dIII) of transhydrogenase from Rhodospirillum rubrum has been solved by NMR methods. This is the first description of the structure of dIII from a bacterial source. The protein adopts a Rossmann fold: an open, twisted, parallel beta-sheet, flanked by helices. However, the binding of NADP(+) to dIII is profoundly different to that seen in other Rossmann structures, in that its orientation is reversed: the adenosine moiety interacts with the first betaalphabetaalphabeta motif, and the nicotinamide with the second. Features in the structure that might be responsible for changes in nucleotide-binding affinity during catalysis, and for interaction with other components of the enzyme, are identified. The results are compared with the recently determined, high-resolution crystal structures of human and bovine dIII which also show the reversed nucleotide orientation.

Amino Acid Sequence↗
PubMed2000

Tumour necrosis factor-alpha has few morphological effects within the dorsal columns of the spinal cord, in contrast to its effects in the peripheral nervous system.

There is circumstantial evidence implicating the pro-inflammatory cytokine tumour necrosis factor (TNF) in the pathogenesis of multiple sclerosis (MS), but there is no direct evidence that TNF can produce demyelination in the central nervous system (CNS). We demonstrate here that single injections of TNF into the dorsal columns of adult rats produced a mild inflammatory response indistinguishable from that seen in control cords, but did not induce demyelination. A similar response was seen when TNF-alpha was injected into dorsal columns where central axons had been remyelinated by Schwann cells. In marked contrast, single intraneural injections of TNF into sciatic nerves produced acute changes in the endoneurial microvascular bed that were followed by demyelination and degeneration.

Animals↗
PubMed2000

The cost-effectiveness of sildenafil.

BACKGROUND: Coverage of sildenafil by health insurance plans is a contentious issue. OBJECTIVE: To evaluate the cost-effectiveness of sildenafil treatment for erectile dysfunction. DESIGN: A Markov decision model to estimate the incremental cost-effectiveness of sildenafil compared with no drug therapy. DATA SOURCES: Values for the efficacy and safety of sildenafil and quality-of-life utilities were obtained from the published medical literature. Base-case values were chosen to bias against sildenafil use. TARGET POPULATION: Men 60 years of age with erectile dysfunction. TIME HORIZON: Lifetime. PERSPECTIVE: Societal and third-party payer. INTERVENTION: Sildenafil or no treatment in identical hypothetical cohorts. OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) gained. RESULTS OF BASE-CASE ANALYSIS: The cost per QALY gained for sildenafil treatment compared with no therapy was $11,290 from the societal perspective and $11,230 from the third-party payer perspective. RESULTS OF SENSITIVITY ANALYSIS: From the societal perspective, the cost per QALY gained associated with sildenafil was less than $50,000 if treatment-related morbidity was less than 0.8% per year, mortality was less than 0.55% per year, treatment was successful in more than 40.2% of patients, or sildenafil cost less than $244 per month. The results were sensitive to variation of erectile dysfunction utilities, but cost per QALY gained was less than $50,000 if successful treatment increased utility values by 0.05 or more on a scale of 0 (death) to 1 (perfect health). CONCLUSIONS: In an analysis biased against use of sildenafil, the cost-effectiveness of sildenafil treatment compared favorably with that of accepted therapies for other medical conditions.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2000

Cost effectiveness of vaccination strategies in adults without a history of chickenpox.

PURPOSE: Some authorities recommend varicella antibody testing or vaccination for adults without a history of chickenpox, but the cost effectiveness of these interventions is uncertain. SUBJECTS AND METHODS: Using a Markov decision model, we estimated the cost effectiveness of three strategies for adults with no history of chickenpox: no vaccination, varicella antibody testing followed by vaccination for those without antibody, and vaccinating all. Societal and third-party payer perspectives were taken, with costs and benefits discounted at 3% per year. Assumptions for the baseline analysis were chosen to bias against no vaccination. RESULTS: In the baseline analysis for 20- to 29-year-old patients, testing followed by vaccination compared with no vaccination is cost saving from a societal perspective and costs $6,670 per quality-adjusted life-year (QALY) gained from a third-party payer perspective. When less favorable assumptions are used, results are sensitive to the rates of compliance with vaccination follow-up; testing followed by vaccination costs more than $50,000 per QALY if <75% comply. For patients 30 years of age and older, the incremental cost of testing followed by vaccination is at least $97,100 per QALY compared with no vaccination, with costs greater than $50,000 per QALY unless testing costs less than $7.73, the chickenpox case-fatality rate is >0.067% (baseline 0.025%), or immunity with no chickenpox history is <25% (baseline 71%). In either age group, vaccinating all has an incremental cost of $2 to $16 million per QALY gained compared with testing followed by vaccination. CONCLUSION: Testing followed by vaccination for varicella in US adults aged 20 to 29 years may be cost effective by conventional criteria but is sensitive to rates of compliance with vaccination protocols. Testing or vaccination of older adults is expensive but may be cost effective in patients with lower probabilities of immunity or in those who have a greater risk of complications from chickenpox.

Adult↗
PubMed2000

Perspectives in dermatopathology: telomeres and telomerase in ageing and cancer; with emphasis on cutaneous disease.

Shortening of telomeres occurs with cell proliferation and correlates well with ageing in humans. Telomerase is a ribonucleoprotein, and is the body's most widely studied mechanism for extension of telomeres to circumvent cellular ageing. Telomerase levels remain at low or unmeasurable levels in most somatic cell populations with only a few exceptions. However, in transformed cell populations, upregulation of telomerase or some other mechanism for telomere extension is required for immortality. The telomere-telomerase system has been proposed to be an adaptation of organisms with prolonged lifespan to avoid malignant tumors, at the cost of the cellular dysfunctions associated with the aged phenotype. Therapies to modulate telomere length and telomerase levels hold promise for therapy of cancer and ageing as well as for genetic conditions that predispose to an aged phenotype.

Aging↗
PubMed2000

The cutaneous cellular infiltrate to stingray envenomization contains increased TIA+ cells.

Stingrays result in approximately 2000 stings annually in the U.S.A., and thus are one of the most important venomous marine animals. After envenomization, there is immediate, intense pain with subsequent oedema, cyanosis followed by local erythema and petechiae. Progressive local necrosis and ulceration is variable, sometimes leading to gangrene. To characterize the inflammatory infiltrate at the site of a stingray injury, we examined tissue obtained approximately 4 days after stingray envenomization. Routine histology and immunohistochemical stains for lymphoid markers, including CD3, CD4, CD8, CD20, KP-1 and TIA were performed, and demonstrated a central area of haemorrhagic necrosis with a surrounding infiltrate of lymphoid cells and eosinophils. Approximately one-third of the mononuclear cells were TIA+, and these cells appeared mainly to correspond to the cells which were CD3+ and CD4+. The inflammatory cells, including the lymphoid populations, suggest that an immunological reaction may contribute to the delayed healing of stingray injuries.

Adult↗
PubMed2000

Cholesterol metabolsim defect associated with Conradi-Hunerman-Happle syndrome.

We present a 6-week-old black girl with Conradi-Hunerman-Happle syndrome (CHS). The mother had no past medical history of illness, and the pregnancy progressed normally to a spontaneous vaginal delivery at 36 weeks. There was no known significant family history. A diagnosis of chondrodysplasia punctata was made at birth from physical examination and X-ray findings. On physical examination at 6 weeks, a koala face, a saddle nose, and a right-sided cataract were noted (Fig. 1a,b). There was unilateral left-sided ichthyosis well demarcated at the midline, with whorled brown fine scale following Blashko's lines on the patient's right side. Orthopedic complications were bilateral but were more pronounced on the left side. There was bilateral shortening of the humerus, with polydactyly of the right hand, arachnodactyly of the left fingers, bilateral clubbing, and mild contractures of the feet. X-Rays showed multiple calcifications along the spine, proximal and distal femoral epiphysis, and proximal humeral epiphysis (Fig. 2). The patient was treated with emollients (aquaphor) twice daily with continuing improvement in ichthyosis. The clubbed feet were treated with splinting and the polydactyly was corrected by surgery. Ophthalmology was to follow the patient for her right-sided cataract. At the patient's 4-month follow-up, the ichthyosis showed a marked improvement with some residual hypo- pigmented atrophoderma noted. The distribution remained unchanged. Biopsies taken of ichthyotic lesions showed compact hyperkeratosis and follicular plugging. Vesicles within the stratum corneum contained amorphous material (Fig. 3a,b). The granular cell layer was thickened with retained oval nuclei. The epidermal and adnexal epithelium were disorganized. Increased apoptotic/dyskeratotic keratinocytes were seen within the epidermis, but were most evident within the follicular epithelium. Ultrastructural studies showed saccular dilations of the acellular space within the stratum corneum. These acellular spaces were filled with unprocessed lamellated pleated sheets and vesicle complexes and processed lamellae. Dyskeratotic cells were seen within the stratum spinosum. Red blood cell (RBC) plasmalogen levels and polyunsaturated fatty acids (PUFA), including decosahexaenoic acid (DHA), were within normal limits. Plasma very long chain fatty acids (VLCFA), including C26 : 0/C22 : 0 ratios, phytanic and pristanic acids, plasmalogen, and phytanic/pristanic ratios, trihydroxycholestanic acid (THCA) and dihydroxycholestanoic acid (DHCA) including their ratios, THCA/cholic acid and DHCA/chenodeoxycholic acid, and PUFAs including DHA were within normal limits. Urine organic acids and piecolic acid were within normal limits. Despite these normal values, there was an increase in cholest-8(9)-en-3beta-ol of 6.8 microg/mL (normal, 0.01-0.10 microg/mL) and an increase in 8-dehydrocholesterol (5.1 microg/mL) (normal, <0.10 microg/mL).

Abnormalities, Multiple↗
PubMed2000

Smoldering HTLV-1-induced T-cell lymphoma localized within the skin; a radiation-resistant tumor.

BACKGROUND: Human T-cell lymphotrophic virus type 1 (HTLV-1)-induced lymphoproliferative disease occurs in approximately 3-5% of people in endemic areas who have been HTLV-1 positive for decades. Lymphoproliferative disease may present as four subtypes, including an acute adult T-cell leukemia/lymphoma (ATLL), an aggressive HTLV-1 lymphoma, chronic ATLL, and smoldering ATLL. MATERIALS AND METHODS: A 72-year-old HTLV-1+ Haitian woman presented with a 2-year history of a cutaneous eruption localized to the right arm. The eruption had evolved into multinodular lesions over the past 6-7 months. Peripheral blood and cutaneous biopsy specimens were evaluated. Immunohistochemical studies for lymphoid markers were performed on the cutaneous biopsy material, and polymerase chain reaction (PCR) and Southern blot assay were evaluated for the presence and integration of HTLV-1 within the genome. RESULTS: The biopsy specimen showed a pleomorphic T-cell infiltrate with epidermotrophism, and an immunohistochemical phenotype showing CD3+, CD4+, CD8-, CD25, CD30-, HLDA-DR+ cells. PCR and Southern blot assay evaluation showed a single clonal integration of HTLV-1 provirus within a monoclonal tumor cell population. The patient had no abnormal lymphoid forms on peripheral smear at presentation, and no evidence of other organ involvement. CONCLUSIONS: Smoldering HTLV-1-induced lymphoma is uncommon even in endemic areas. In previously reported cases, the smoldering variant was accompanied by abnormal forms in the peripheral blood and/or by other signs of systemic disease. This case illustrates that smoldering disease may be localized to the skin with no detected morphologic abnormalities on peripheral smear.

Aged↗
PubMed2000

Histopathologic features seen in Gianotti-Crosti syndrome secondary to Epstein-Barr virus.

BACKGROUND: Gianotti-Crosti syndrome (GCS) or infantile papular acrodermatitis presents as a symmetric erythematous lichenoid papular and papulovesicular eruption of the face, extremities, and buttocks, usually occurring in young children. GCS has been associated with hepatitis B and enteroviruses, as well as Epstein-Barr virus (EBV) and, rarely, cytomegalovirus. OBJECTIVE: The purpose of this study was to use immunohistochemical studies to determine the pattern of the lymphoid infiltrate and evidence for viral antigens in cases of EBV-associated GCS. METHODS: Routine histologic and immunohistochemical stains were evaluated in 3 patients with typical GCS. All 3 patients showed serologic evidence of an acute EBV infection. The immunohistochemical studies included monoclonal antibodies for CD3, CD4, CD8, CD20, TIA, S-100 protein, KP-1, EBV latent membrane antigen-1, and EBV-encoded nuclear antigen-2. RESULTS: All biopsy specimens showed minimal epidermal spongiosis with marked papillary dermal edema. The associated inflammatory infiltrate showed a mixed mononuclear cell infiltrate with rare eosinophils. Immunohistochemical stains for latent membrane antigen-1 and EBV-encoded nuclear antigen-2 were negative for EBV. The majority of mononuclear cells showed membrane staining for CD3, 30% to 40% of the CD3 mononuclear cells showed positive staining for CD4, and 50% to 60% showed positive staining with CD8. TIA(+) cells appeared to correspond to the CD8(+) cells. CONCLUSION: Although papillary dermal edema has been reported within the spectrum of histologic findings in GCS, it was marked and a consistent finding in the 3 cases in which EBV was the most likely etiologic agent. The presence of large numbers of cytotoxic T cells in the inflammatory infiltrate may have accentuated this histologic finding and may be a relatively distinctive histologic finding with GCS associated with EBV.

Acrodermatitis↗
PubMed2000

Effects of 4-aminopyridine on demyelinated axons, synapses and muscle tension.

Several clinical trials have demonstrated that 4-amino-pyridine (4-AP), a potassium channel-blocking agent, improves symptoms in some patients with multiple sclerosis. The beneficial effects have typically been attributed to the restoration of conduction to demyelinated axons, since this effect was previously demonstrated experimentally. However, the clinical dose is approximately 250-1000 times lower than that used experimentally, potentially making extrapolation of the experimental findings unreliable. To examine the action(s) of 4-AP in demyelinating disorders, the drug was administered at clinical doses, both in vivo and in vitro, to rat dorsal column axons which had been experimentally demyelinated by the intraspinal injection of ethidium bromide. 4-AP had no consistent effect in restoring conduction to demyelinated axons, even to axons which were held just on the verge of conducting by adjusting the lesion temperature. However, 4-AP had prominent effects that did not involve demyelinated axons, including the potentiation of synaptic transmission and an increase in skeletal muscle twitch tension. We propose that these latter effects may be largely responsible for the beneficial action of 4-AP in multiple sclerosis patients. If so, the dominant effects of 4-AP in multiple sclerosis patients are independent of demyelination, and it follows that 4-AP may be beneficial in other neurological disorders in which function is diminished.

4-Aminopyridine↗
PubMed2000

Cutaneous microenvironment of human immunodeficiency virus (HIV)-seropositive and HIV-seronegative individuals, with special reference to Staphylococcus aureus colonization.

A cross-sectional quantitative study of cutaneous bacterial and yeast flora at seven body sites in 99 human immunodeficiency virus-seropositive and 50 seronegative military personnel was performed. Statistically significant differences in carriage rates were only observed for Staphylococcus aureus on the foreheads of seropositive individuals. Seronegative individuals demonstrated staphylococcal carriage rates 1.3 to 2 times as great as those of historical controls (defined as healthy individuals not receiving any medications) at five of six body sites. We conclude that seropositive military personnel do not exhibit statistically significant elevations in densities and carriage rates of the microorganisms examined (except Staphylococcus aureus), relative to seronegative individuals. Seropositive individuals may be predisposed to staphylococcal carriage. The elevated staphylococcal carriage rates of military personnel undergoing basic training warrants a formal evaluation of the impact of training exercises on cutaneous flora. The information gained may serve to limit the spread of infection during training exercises and battlefield conditions.

Adolescent↗