Search PubMed⌕ Search

Biomedical subjects

K J Smith

Publications and source records attributed to K J Smith.

At least 145 records · Page 8Linked to original sources
PubMed1997

Histopathologic features seen in cutaneous photoeruptions in HIV-positive patients. Military Medical Consortium for the Advancement of Retroviral Research (MMCARR).

BACKGROUND: There have been scattered reports of HIV+ patients with increased reactions to light as well as anecdotal reports of HIV+ patients with increased morbidity secondary to radiation therapy. METHODS: As a part of a military study of HIV+ patients, we followed 987 patients for cutaneous disease for 4 years. All patients were questioned on a periodic basis about increased sensitivity to light. These patients received a physical examination at each protocol visit, and they were given the opportunity to receive all their dermatologic care within the HIV clinic. Fourteen of the patients with photo-induced eruptions were evaluated clinically at the time of the eruption, and 11 of these were biopsied. RESULTS: Thirty-three of the patients reported photo-induced reactions unrelated to oral medications. Although sensitivity to light often began in the early stages of HIV disease, reactions became more severe and more chronic with disease progression. Histologic features varied from few to numerous apoptotic/necrotic keratinocytes within the mid to upper levels of the epidermis associated with a perivascular inflammatory infiltrate, to apoptotic/necrotic keratinocytes throughout an acanthotic epidermis with a lichenoid/interface infiltrate. CONCLUSIONS: Although the pathogenesis of these light reactions is not known, these reactions may be related to depletion of endogenous scavengers which results in increased oxidative stress and is modulated by the pattern of immune dysregulation and metabolic dysregulation induced by HIV disease.

Acantholysis↗
PubMed1997

A combined inhibitor of matrix metalloproteinase activity and tumour necrosis factor-alpha processing attenuates experimental autoimmune neuritis.

Matrix metalloproteinases (MMPs) and the cytokine tumour necrosis factor (TNF)-alpha are implicated in the pathology of inflammatory demyelinating diseases of the CNS, and may also be involved in peripheral demyelinating diseases such as acute inflammatory demyelinating polyradiculoneuropathy. We have tested an inhibitor of MMP activity and TNF-alpha processing, BB-1101, in experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome. Treatment with BB-1101 from the time of immunization prevented the development of EAN, and when given from the onset of symptoms, it significantly reduced disease severity. These results indicate that MMPs and/or TNF-alpha are involved in the pathogenesis of EAN, and that drugs of this type may have potential as novel therapeutic agents in the therapy of peripheral nervous system demyelinating diseases.

Animals↗
PubMed1997

Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible.

Diseases such as multiple sclerosis and Guillain-Barré syndrome are characterized not only by widespread loss of myelin from nerve fibres, but also by widespread inflammation in the central and peripheral nervous systems, respectively. While the demyelination alone is sufficient to block conduction and thereby cause symptoms, there is increasing evidence that the inflammation may also contribute significantly to the conduction block, although the mechanisms are not understood. Nitric oxide is an important inflammatory mediator which is elevated within the central nervous system in multiple sclerosis and which can be experimentally applied to tissues using nitric oxide donors. We report that such compounds cause reversible conduction block in both normal and demyelinated axons of the central and peripheral nervous systems. Notably, conduction in demyelinated and early remyelinated axons is particularly sensitive to block by nitric oxide, so that at lower concentrations, including those expected at sites of inflammation, demyelinated axons are selectively affected. We therefore propose that inflammation may directly cause symptoms via nitric oxide release, and that the inhibition of such release may open a new therapeutic avenue for demyelinating disease.

Animals↗
PubMed1997

Slow sodium-dependent potential oscillations contribute to ectopic firing in mammalian demyelinated axons.

Ectopic action potentials can arise at regions of axonal demyelination, and are believed to contribute to a range of symptoms in patients with demyelinating conditions such as multiple sclerosis. The mechanism(s) by which the ectopic impulses are generated are uncertain. We have previously shown that such ectopic activity can result from inward potassium currents. Paradoxically, the potassium channel blocking agent 4-aminopyridine (4AP) can sometimes cause ectopic activity in demyelinating lesions. To study this phenomenon we have made intra-axonal recordings of ectopic activity in demyelinated axons, both in the presence and absence of 5 mM 4AP. 4AP promoted a pattern of firing which was observed, albeit less frequently, in demyelinated axons in the absence of this drug, namely trains of single impulses, or trains of short, high-frequency bursts of impulses. When recorded close to the demyelinated lesion, the impulses were generated by an underlying, almost sinusoidal oscillation of the membrane potential. This oscillation was abolished by the sodium channel blocking agent tetrodotoxin (0.1-1 microM). We conclude that the ectopic spiking induced by 4AP is generated by membrane potential oscillations associated with the site of demyelination. The sodium-dependent current underlying these oscillations, together with the prolonged inward potassium currents which we have previously described, may contribute to the generation of ectopic discharges in a range of disorders of myelinated axons.

4-Aminopyridine↗
PubMed1997

Human immunoglobulin ameliorates rat experimental autoimmune neuritis.

Human immunoglobulin is an effective treatment for Guillain-Barré syndrome, although the mechanism of action is not understood. We have investigated the effect of human immunoglobulin in an animal model of Guillain-Barré syndrome, namely experimental autoimmune neuritis (EAN), induced in Lewis rats by immunization with bovine spinal root myelin. Human immunoglobulin administered intraperitoneally at the time of onset of disease accelerated the rate of recovery from EAN. This improvement was associated with a reduction in the titre of anti-rat myelin antibodies and may be due to earlier remyelination of demyelinated nerve fibres. This model may facilitate further investigation of the mechanism of therapeutic action of immunoglobulin in inflammatory neuropathy.

Animals↗
PubMed1997

HMB45 negative spindle cell malignant melanoma.

Desmoplastic malignant melanoma (DMM) and spindle cell malignant melanoma (SCMM) form a continuum without a discrete separation. One feature characteristic of DMM is a negative reaction for HMB45, a marker for premelanosomes. Fifty-six cases of SCMM were stained with HMB45. The clinical features, histologic features, and survival data for HMB45(+) and HMB45(-) SCMM were compared. Thirty cases were HMB45(-), and 26 were HMB45(+). In the HMB45(-) cases, there was a 1.4:1 ratio of males to females, and in the HMB45(+) cases the ratio was 1:1.5. Only 12.9% of the HMB45(-) cases occurred on the trunk compared with 40% of the HMB45(+) cases. The average ages for the HMB45(-) and the HMB45(+) cases were 65.6 and 61 years, respectively. Follow-up was obtained on 22 cases: 11 HMB45(-) and 11 HMB45(+). Of the 11 HMB45(-) cases, four had a 5-year disease-free survival. Of the 11 HMB45(+) cases, only one had a 5-year disease free survival. HMB45(-) SCMM appear to have a less aggressive biologic potential than HMB45(+) SCMM.

Adult↗
PubMed1997

Histologically distinctive papular neutrophilic xanthomas in HIV-1 + patients.

Xanthomas may be associated with benign or malignant lymphoproliferative diseases, often with associated hypergammaglobulinema. In human immunodeficiency virus type 1 (HIV-1) disease, there is a high lymphoproliferative rate despite the immunodeficiency and increased cell death. We report three HIV-1-positive patients with facial papular xanthomatosis eruptions associated with hypergammaglobulinema, and an immunoglobulin A (IgA) gammopathy. Histopathologic features include lipid-laden macrophages, extracellular nuclear dust with phagocytosized nuclear debris, and hyalinization with areas of hyaline necrosis of collagen fibers. These distinctive papular xanthomas may be a marker of HIV-1 disease and of a pattern of immunodysregulation, immunodeficiency, and lymphoid proliferation seen in HIV-1 disease.

Adult↗
PubMed1997

CO2 laser debridement of sulphur mustard (bis-2-chloroethyl sulphide) induced cutaneous lesions accelerates production of a normal epidermis with elimination of cytological atypia.

Sulphur mustard (bis-2-chloroethyl sulphide; HD) exposure acutely produces lesions that vary from mild erythema, to blister formation, to necrosis. When blisters occur, with or without necrosis, healing of the lesions is delayed. Weanling pigs exposed to a mild erythema-producing dose of HD and to a moderate erythema-producing dose that consistently gave microblister formation were treated with CO2 laser (Tru-Pulse) debridement at 6, 24 or 48 h after exposure. The histopathological features observed at 14 days after exposure in control skin and skin exposed to both HD doses were compared with the features observed in CO2 laser-debrided skin in non-exposed and HD-exposed skin sites. The overlying epidermis in the non-laser treated lesions was thin, with cytological atypia and squamoid changes within the basal cell layer, as well as scattered apoptotic/necrotic keratinocytes. An increased inflammatory infiltrate and necrobiotic changes in the dermis were seen at the higher HD dose. All laser-treated lesions appeared identical, with a thick, differentiated epidermis and a well-formed basal cell layer. There was minimal inflammatory infiltrate. In the papillary dermis there were increased stromal cells. Laser debridement of mild clinical lesions induced by HD produced a more functional epidermis by 14 days as well as clearing the epidermis of damaged keratinocytes.

Animals↗
PubMed1997

Increased smooth muscle actin, factor XIIIa, and vimentin-positive cells in the papillary dermis of carbon dioxide laser-debrided porcine skin.

BACKGROUND: Pulsed carbon dioxide (CO2) laser debridement is now being used as therapy for photodamaged skin. It has been proposed that the long duration of erythema and a tissue scaffold, which results from tightening of the collagen helix induced by the laser heat, may lead to tightening of sagging skin and skin creases of lesser magnitude. METHODS: Weanling pigs exposed to mild and moderate erythema producing doses of sulfur mustard (bis-2-chloroethyl sulfide; HD) were treated with the CO2 laser (Tru-Pulse) at 6, 24, and 48 hours after exposure. In addition to histologic examination of laser-debrided and nondebrided biopsy specimens obtained at 14 days after exposure, immunohistochemical staining with antibodies to smooth muscle actin, Factor XIIIa, vimentin, and CD3 was performed. RESULTS: CO2 laser debridement of the HD-exposed skin resulted in clearing of the cytologic atypia induced by this chemical carcinogen and reduced the inflammatory infiltrate. In addition laser debridement resulted in increased numbers of stromal cells within the papillary dermis, which showed immunohistochemical staining for smooth muscle actin, Factor XIIIa, and vimentin. CONCLUSIONS: CO2 laser debridement is effective in clearing the epidermis of cytologically damage cells in HD as well as solar-damaged skin. In addition CO2 laser debridement may result in tightening of sagging skin and produce a decrease in skin creases initially, by inducing increased stromal cells within the papillary dermis, with prominent contractile actin filaments. The collagen produced by these stromal cells may subsequently maintain these improvements in the photoaged skin.

Actins↗
PubMed1997

Serological diagnosis of hantavirus infections by an enzyme-linked immunosorbent assay based on detection of immunoglobulin G and M responses to recombinant nucleocapsid proteins of five viral serotypes.

Worldwide, hantaviruses cause more than 100,000 human infections annually. Rapid and accurate methods are important both in monitoring acute infections and for epidemiological studies. We and others have shown that the amino termini of hantavirus nucleocapsid proteins (Ns) are sensitive tools for the detection of specific antibodies in hantavirus disease. Accordingly, we expressed truncated Ns (amino acids 1 to 117) in Escherichia coli from the five hantaviruses known to be pathogenic to man; Hantaan (HTN), Seoul (SEO), Dobrava (DOB), Sin Nombre (SN), and Puumala (PUU) viruses. In order to obtain pure antigens for use in an enzyme-linked immunosorbent assay (ELISA), the recombinant proteins were purified by polyhistidine-metal chelate affinity chromatography. Polyclonal animal antisera and a panel of serum specimens from hantavirus-infected individuals from Scandinavia, Slovenia, Russia, Korea, China, and the United States were used to evaluate the usefulness of the method. With both human and animal sera, it was possible to designate the antibody response into two groups: those with HTN, SEO, and DOB virus reactivity on the one hand and those with SN and PUU virus reactivity on the other. In sera from Scandinavia, European Russia, and the United States, the antibody response was directed mainly to the PUU and SN virus group. The sera from Asia reacted almost exclusively with the HTN, SEO, and DOB types of viruses. This was true for both the immunoglobulin M (IgM) and IgG antibody responses, indicating that this type of discrimination can be done during the acute phase of hantavirus infections. Both the HTN, SEO, and DOB virus and the PUU and SN virus types of antibody response patterns were found in patients from the Balkan region (Solvenia).

Animals↗
PubMed1997

Preservation of allergic contact dermatitis to poison ivy (urushiol) in late HIV disease. The implications and relevance to immunotherapy with contact allergens.

BACKGROUND: Delayed hypersensitivity reactions (DTH) are lost with progression of HIV disease. This loss of DTH commonly occurs before the onset of opportunistic infections and is an independent predictor of disease progression. OBJECTIVE: We wanted to determine whether patients in late HIV disease with a history of allergic contact dermatitis (ACD) to poison ivy continue to react to poison ivy. METHODS: Twelve HIV+ patients with a past history of ACD to poison ivy were tested with an extract prepared from poison ivy leaves. All but 1 patient had CD4+ T cell counts < 200/microliters, and 5 patients had had an opportunistic infection. RESULTS: All 12 patients showed positive reactions ranging from mild erythema and infiltration to marked erythema with bulla formation. CONCLUSIONS: ACD is considered a variant of DTH, and as DTH results in a T helper 1 cytokine pattern. However, the antigen-specific effector cells in ACD may be more diverse than in DTH. This diversity could explain the continued reaction to some contact allergens in late disease and may be important in the use of contact allergens for immunotherapy.

Catechols↗
PubMed1997

Pruritus in HIV-1 disease: therapy with drugs which may modulate the pattern of immune dysregulation.

BACKGROUND: Pruritus in HIV-1+ patients is common and increases with disease progression. The causes of pruritus are numerous including xerosis, drug and photoeruptions, follicular and papular eruptions as well as infestations and infections by a wide range of organisms. One other possible factor contributing to pruritus is the pattern of immune dysregulation. With advancing HIV-1 disease there is Th1 to Th2 cytokine switching. METHODS: After some positive results with prostaglandin inhibitors, we undertook a study in which we randomly placed patients on four different forms of therapy for their pruritus. The therapies included hydroxyzine with or without doxepin at night, pentoxifylline, indomethacin and topical moisturization with medium-strength topical steroids. All patients were evaluated for both subjective relief as well as side effects. RESULTS: Patients placed on indomethacin obtained relief more consistently and more completely. Patients on pentoxifylline had the fewest side effects of all oral therapies. Patients on antihistamines with or without doxepin had the highest incidence of side effects, although more of these patients reported a greater degree of relief than patients on pentoxifylline. All patients on oral therapy overall had greater relief than patients using topical steroids. CONCLUSION: The systemic therapies which may modulate the pattern of immune dysregulation seen in HIV-1 disease may be beneficial in the pruritus seen in late-stage patients.

Administration, Cutaneous↗
PubMed1997

Treatment of inflammatory neuropathy.

Experimental autoimmune neuritis (EAN) provides an accurate model for understanding the mechanism of acute and chronic inflammatory demyelinating polyradiculoneuropathy (AIDP and CIDP). Treatments aimed at every stage of the immune process in EAN have been effective in inhibiting or treating the disease, including antibodies directed against cell adhesion molecules on the endothelium, inhibition of T cells, removal or blockade of antibodies, depletion of complement, and interference with the release or action of macrophage effector molecules. In human disease the only proven treatments are plasma exchange and intravenous immunoglobulin (IVIg) in AIDP, and either of these regimens and also corticosteroids in CIDP. However the outcome from AIDP and CIDP remains unsatisfactory with existing immunosuppressive regimens. This problem arises from the fact that while demyelination appears to be effectively and promptly repaired by remyelination, it may be accompanied by axonal degeneration which can cause severe persistent disability. In addition to limiting demyelination, it will also be important to develop strategies to protect axons from degeneration and to enhance regeneration.

Animals↗
PubMed1997

Cutaneous angiosarcomas with a starry-sky pattern.

OBJECTIVE: A subgroup of epithelioid angiosarcomas, which we have identified, has a prominent starry-sky histologic pattern. All these neoplasms were evaluated with routine histopathology and with immunohistochemical stains. Clinical follow-up was also obtained to determine whether these angiosarcomas' had any other distinctive properties. DESIGN: Histopathologic features and immunohistochemical stains, including cytokeratin, epithelial membrane antigen, CD34, LCA, factor VIII-related antigen, KP-1, vimentin, HMB-45, and S100 protein were performed on all four neoplasms. PATIENTS: These angiosarcomas occurred on the extremities of patients with chronic edema as well as on the scalp of elderly patients. MAIN OUTCOME: All patients were dead within 5 years of diagnosis. Of the three patients where angiosarcoma was listed as the cause of death, all were dead within 30 months. RESULTS: All tumors showed a similar immunohistochemical staining pattern. Vimentin, factor VIII-related antigen, and CD34 were positive in all tumors. The remaining immunohistochemical stains including cytokeratin, which may be positive in other epithelioid angiosarcomas, were negative. CONCLUSIONS: We present a distinctive starry-sky histologic pattern in epithelioid angiosarcomas. Knowledge of this pattern may be important in the early diagnosis of this rapidly fatal neoplasm.

Aged↗
PubMed1997

Cytokeratin 7 staining in mammary and extramammary Paget's disease.

There are a variety of routine and immunohistochemical stains used to diagnose mammary and extramammary Paget's disease (MPD and EMPD). Most of the stains commonly used, however, show a positive reaction in the Paget's cells in all cases. We wanted to assess which immunohistochemical stain is the best for the diagnosis of MPD and EMPD, as well as the best stain for identifying small foci of tumors in evaluating tumor margins. We evaluated nine cases of MPD and nine cases of EMPD, which were randomly chosen, with a battery of immunohistochemical stains. These stains included cytokeratin 7, cytokeratin 20, carcinoembryonic antigen, Ber-EP4, and CAM 5.2. Cytokeratin 7 was the only immunohistochemical stain that stained all of the cases diffusely, and, in all of the cases, the staining of the Paget's cell was intense and specific within the epidermis. We concluded that cytokeratin 7 is the immunohistochemical stain of choice in the diagnosis of Paget's disease. Because cytokeratin 7 seems to identify single cells, it might also be valuable in evaluating surgical margins for small foci in a tumor such as EMPD, which might have a multifocal origin.

Adult↗
PubMed1997

Increased drug reactions in HIV-1-positive patients: a possible explanation based on patterns of immune dysregulation seen in HIV-1 disease. The Military Medical Consortium for the Advancement of Retroviral Research (MMCARR).

Drug reactions are common in HIV-1 disease, with the incidence having been reported to increase with increasing stage and with CD4+ T-cell counts below 200/microliters. However, there have been numerous reports of patients in which rechallenge, dosing changes or continued therapy have resulted in no recurrence or else clearing of the eruption. We followed 974 HIV-1-positive patients for 46 months as a part of a military study of HIV-1 disease. Within this group there were a total of 283 drug eruptions, with cutaneous manifestations in 201 patients in which clinical characteristics were noted and 86 patients in which cutaneous biopsies were performed. Serological evidence of reactivation or acute Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infections were also noted, as well as peripheral eosinophilia. The incidence of drug eruptions significantly increased with increasing Walter Reed stage and decreasing CD4 counts and CD4/CD8 ratio, as well as with increasing age and in patients with increased numbers of other dermatological diagnoses. In addition, white patients had significantly more drug eruptions than did black. Serological or culture evidence of acute or reactivated EBV or CMV was significantly increased in patients with drug eruptions. The majority of the eruptions were maculopapular or morbilliform with a predominantly perivascular mononuclear cell infiltrate. HIV-1 positive patients have an increased incidence of drug reactions, the incidence having been reported to increase in patients with less than 200 CD4+ T cells/microliter. However, at very low T4 counts, especially those less than 25/microliter, and at a CD4/CD8 ratio of less than 0.10, the probability of reactions to trimethoprim-sulphamethoxazole (TMP-SMZ) is decreased in late-stage HIV-1 patients. Maculopapular or morbilliform eruptions are the most common clinical presentations, often accompanied by one or more of the following: fever, arthralgias, eosinophilia, and serum transaminase elevation. Histologically the majority of these eruptions show a perivascular mononuclear cell infiltrate, sometimes with focal interface changes and apoptotic, necrotic cells within the epidermis. Acute hypersensitivity reactions and toxic epidermal necrolysis (TEN) or Stevens-Johnson's syndrome (SJS) with diffuse epidermal apoptosis and necrosis have also been less commonly described. In a study of cutaneous manifestations in an HIV-1 positive military population, drug reactions were evaluated in terms of clinical features, histopathology, demographic features and laboratory findings.

Adolescent↗
PubMed1996

Antagonist HIV-1 Gag peptides induce structural changes in HLA B8.

In the cellular immune response, recognition by CTL-TCRs of viral antigens presented as peptides by HLA class I molecules, triggers destruction of the virally infected cell (Townsend, A.R.M., J. Rothbard, F.M. Gotch, G. Bahadur, D. Wraith, and A.J. McMichael. 1986. Cell. 44:959-968). Altered peptide ligands (APLs) which antagonise CTL recognition of infected cells have been reported (Jameson, S.C., F.R. Carbone, and M.J. Bevan. 1993. J. Exp. Med. 177:1541-1550). In one example, lysis of antigen presenting cells by CTLs in response to recognition of an HLA B8-restricted HIV-1 P17 (aa 24-31) epitope can be inhibited by naturally occurring variants of this peptide, which act as TCR antagonists (Klenerman, P., S. Rowland Jones, S. McAdam, J. Edwards, S. Daenke, D. Lalloo, B. Koppe, W. Rosenberg, D. Boyd, A. Edwards, P. Giangrande, R.E. Phillips, and A. McMichael. 1994. Nature (Lond.). 369:403-407). We have characterised two CTL clones and a CTL line whose interactions with these variants of P17 (aa 24-31) exhibit a variety of responses. We have examined the high resolution crystal structures of four of these APLs in complex with HLA B8 to determine alterations in the shape, chemistry, and local flexibility of the TCR binding surface. The variant peptides cause changes in the recognition surface by three mechanisms: changes contributed directly by the peptide, effects transmitted to the exposed peptide surface, and induced effects on the exposed framework of the peptide binding groove. While the first two mechanisms frequently lead to antagonism, the third has more profound effects on TCR recognition.

Amino Acid Sequence↗