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K J Smith

Publications and source records attributed to K J Smith.

At least 109 records · Page 6Linked to original sources
PubMed1998

The spectrum of neurocristic cutaneous hamartoma: clinicopathologic and immunohistochemical study of three cases.

Neurocristic cutaneous hamartomas result from aberrant development of the neuromesenchyme. Thus, the elements within these tumors reflect the spectrum of differentiation that results from migration of neural crest-derived cells. We present three cases, in addition to routine hematoxylin-eosin staining, a battery of immunohistochemical staining, including S-100 protein, HMB-45, EMA, CD34, and neurofilament-protein stains, was performed on each specimen. A dermal melanocytic component was the dominant feature of two of these lesions, while neurosusenticular and neuromesenchymal components dominated in one tumor. Both tumors that developed on the scalp showed effects on the overlying epidermis and/or on adnexal development. The melanocytic component was positive for S-100 protein and HMB-45. The surrounding stroma showed tactoid bodies and increased CD34 staining. Neurocristic cutaneous hamartomas represent dysplastic development of neural crest-derived cells. Although melanocytic cells have been previously reported to be the dominant cell population, neurosusentacular and neuromesenchymal cells also may be the principal component. In cephalic areas, the neuromesenchyme may not only be an important component of the tumor, but may also effect the development of the overlying epithelium and adnexal structures. Although none of these cases presents evidence of malignant transformation, identification of these tumors could be important if malignant transformation results in the development of tumors with a distinctive biologic behavior.

Adult↗
PubMed1998

Is CD30 (Ki-1) immunostaining in cutaneous eruptions useful as a marker of Th1 to Th2 cytokine switching and/or as a marker of advanced HIV-1 disease?

CD30 is a member of the tumour necrosis factor/nerve growth factor receptor superfamily, which is expressed on CD4+ and CD8+ T-cell clones which produce T helper (Th) 2-type cytokines. It has been proposed that disease progression in HIV-1 is associated with Th1 to Th2 cytokine switching. In 70 cutaneous biopsies from HIV-1 positive patients in different stages of disease, we performed a battery of immunohistochemical stains. These included antibodies to CD3, UCHL-1, OPD-4, L-26, KP-1 and CD30 (Ki-1). In addition, we used a similar battery of stains on cutaneous biopsies of HIV-1 negative patients with inflammatory dermatoses which are established as Th1 or Th2 dominant, e.g. polar leprosy. CD30+ cells were rarely present in early stages of HIV-1 disease, but commonly present in later stages of disease. However, there were cases of late HIV-1 disease which did not contain CD30+ cells. Increased numbers of CD30+ cells were more commonly seen in later stages of HIV-1 disease. However, the expression of CD30 appeared to be better in predicting other established Th2 cutaneous infiltrates in HIV-1 negative patients than in predicting a Th2 cutaneous cytokine pattern in advanced HIV-1 disease.

Biomarkers↗
PubMed1998

Cutaneous reactions at the site of post-infection gp160 vaccination therapy in HIV-1+ patients. Military Medical Consortium for the Advancement of Military Medicine.

BACKGROUND: Post-infection vaccination with human immunodeficiency virus type 1 (HIV-1) specific antigens has been hypothesized as a mechanism for generating a more effective immune response to the HIV-1 virus. Cutaneous reactions at the site of immunization may provide information on the pattern of immune activation induced by the vaccine. OBJECTIVE: To evaluate exaggerated local cutaneous reactions in eight HIV-1+ patients enrolled in a phase I and II gp160 vaccine study. METHODS: Cutaneous biopsy specimens were obtained and evaluated using routine histologic, immunofluorescence, and immunohistochemical techniques. RESULTS: A mononuclear cell infiltrate with tissue eosinophilia, in some cases forming flame figures, was present on histologic sections. There was no evidence of immune complex deposition. Activated T-helper cells formed a major portion of the mononuclear cell infiltrate. CONCLUSIONS: A delayed-type hypersensitivity reaction, mediated by T cells with a T-helper 2 cytokine pattern, was favored by clinical and histologic features. The most likely antigen stimulating this reaction is residual lepidopteran used in the preparation of the vaccine; however, baculovirus antigens may also play a role. In addition, the adjuvant, aluminum phosphate, as well as the underlying patterns of immune dysregulation present in HIV-1+ patients, may potentiate these reactions.

AIDS Vaccines↗
PubMed1998

Cost effectiveness of newer antiviral agents for herpes zoster: is the evidence spotty?

Famciclovir and valaciclovir were approved for use in the treatment of herpes zoster despite controversy over antiviral therapy in zoster due to high costs and uncertain benefits. To explore these issues, a Markov decision model was developed, and the incremental cost effectiveness of antiviral treatment for herpes zoster was estimated using these agents compared with no antiviral therapy. A third-party payer perspective was taken. Sensitivity analyses were performed, modeling differences in antiviral efficacy, postherpetic neuralgia (PHN) risk, and other illness parameters. Treatment of severely symptomatic acute zoster was found reasonable from a cost-effectiveness standpoint in base-case and worst-case scenarios. Treatment of mildly symptomatic acute zoster was more expensive but would likely be considered cost effective in scenarios where PHN risk was higher, PHN duration longer, or antiviral shortening of PHN greater. Further research comparing antiviral efficacy in herpes zoster is needed.

2-Aminopurine↗
PubMed1998

Influence of flow rate on aerosol particle size distributions from pressurized and breath-actuated inhalers.

Particle size distribution of delivered aerosols and the total mass of drug delivered from the inhaler are important determinants of pulmonary deposition and response to inhalation therapy. Inhalation flow rate may vary between patients and from dose to dose. The Andersen Sampler (AS) cascade impactor operated at flow rates of 30 and 55 L/min and the Marple-Miller Impactor (MMI) operated at flow rates of 30, 55, and 80 L/min were used in this study to investigate the influence of airflow rate on the particle size distributions of inhalation products. Total mass of drug delivered from the inhaler, fine particle mass, fine particle fraction, percentage of nonrespirable particles, and amount of formulation retained within the inhaler were determined by ultraviolet spectrophotometry for several commercial bronchodilator products purchased in the marketplace, including a pressurized metered-dose inhaler (pMDI), breath-actuated pressurized inhaler (BAMDI), and three dry powder inhalers (DPIs), two containing salbutamol sulphate and the other containing terbutaline sulphate. Varying the flow rate through the cascade impactor produced no significant change in performance of the pressurized inhalers. Increasing the flow rate produced a greater mass of drug delivered and an increase in respirable particle mass and fraction from all DPIs tested.

Aerosols↗
PubMed1998

Induction of experimental autoimmune neuritis with peripheral myelin protein-22.

Two myelin proteins, P2 basic protein and P0 glycoprotein, can induce experimental autoimmune neuritis (EAN), a model of human inflammatory neuropathy. We investigated whether peripheral nerve myelin protein-22 (PMP22), the gene for which is duplicated in hereditary motor sensory neuropathy type la, can also induce EAN. PMP22 cDNA produced by the reverse transcriptase-polymerase chain reaction from rat sciatic nerve was expressed in Escherichia coli as a fusion protein with glutathione-S-transferase (GST). Ten Lewis rats were immunized with purified PMP22 fusion protein (50-100 microg) and eight controls with the same amount of GST. Two additional animals were immunized with each of two peptides (250 microg) of the human PMP22 extracellular sequences. Animals were examined daily until 20 days following immunization, when they underwent neurophysiological examination. A serum sample was then taken, prior to perfusion with glutaraldehyde and removal of the sciatic nerves and cauda equina. PMP22-immunized animals developed antibodies to the fusion protein and five out of 10 developed limp tails. No changes were observed in controls immunized with GST or in animals immunized with peptide. The mean compound motor action potentials elicited in the foot muscles by stimulation of the sciatic nerve at the sciatic notch and of the tibial nerve at the ankle were significantly reduced in the PMP22-immunized group (P < 0.05). Spinal roots from the group of animals immunized with PMP22 showed sparse infiltration of mononuclear cells, oedema and demyelination. PMP22 now deserves consideration as an autoantigen in human acute inflammatory demyelinating polyradiculoneuropathy.

Action Potentials↗
PubMed1998

Matrix metalloproteinase expression during experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome. We have shown recently that BB-1101, a broad-spectrum matrix metalloproteinase (MMP) inhibitor, prevents development of EAN when given from the day of immunization and, more important clinically, reduces disease severity when given from symptom onset. This suggests the involvement of MMP activity in the pathogenesis of EAN. However, the exact function and expression patterns of MMPs in acute inflammation of the PNS have not been investigated. MMP-like enzymes are also involved in the processing of tumour necrosis factor-alpha (TNF-alpha), which has been implicated previously in the pathology associated with EAN. In the present study we investigated the profile of MMP and TNF-alpha expression and their localization in sciatic nerve tissue during EAN, using a semiquantitative competitive reverse transcriptase-coupled polymerase chain reaction and immunohistochemistry. In the normal rat PNS, four of the 10 MMPs studied were constitutively expressed and four MMPs were differentially regulated during EAN. Expression of TNF-alpha was elevated at peak disease severity and localized to Schwann cells, macrophages and endoneurial blood vessels. Expression levels of 92 kDa gelatinase and stromelysin-1 were significantly increased early in the development of EAN and continued to rise, peaking at day 15 coincident with maximum disease severity. Schwann cells and endothelial cells were the main cellular source of these enzymes. Prominent infiltration of inflammatory cells into the sciatic nerve was concordant with a significant increase in the expression levels of matrilysin and macrophage metalloelastase. Both matrilysin and macrophage metalloelastase were detected in invading macrophages, T lymphocytes and resident Schwann cells. The selective upregulation of specific MMPs during EAN and their varied cellular localization suggests that MMPs play a multifactorial role in the aetiology of EAN. Activity of MMPs could participate in the disruption of the blood-nerve barrier, breakdown of the myelin sheath, the release of TNF-alpha, and facilitate leukocyte invasion into the PNS. These observations highlight MMPs as potential targets for therapeutic intervention in acute peripheral neuropathies, such as Guillain-Barré syndrome.

Animals↗
PubMed1998

Histopathologic and immunohistochemical features in human skin after exposure to nitrogen and sulfur mustard.

N-methyl-2,2'-dichlorodiethylamine (HN2)is a topical chemotherapeutic agent used as therapy for cutaneous T-cell lymphomas (CTCL). Di(2-chloroethyl)sulfide (SM), and less often HN2, have been used as chemical weapons, with the skin being a principle target. The mechanisms by which these chemicals produce their therapeutic and toxic effects in skin, however, are not clearly defined. We exposed human skin explants to two doses of HN2 and SM. At 18 hours after exposure, histopathologic features were compared. In addition, immunohistochemical markers to basement membrane proteins were used to evaluate the effects of both chemicals on the basement membrane zone. Gross vesication was not seen. Pyknotic nuclei with or without dyskeratotic changes within epidermal keratinocytes were present at both doses. These changes varied more between skin specimens than they did between doses. Ballooning degeneration was more marked after SM exposures. Diffuse dermal-epidermal separation was present only at high-dose exposures and did not appear to correlate with the degree of changes locally in the overlying epidermis. Antibodies to laminin-5 showed decreased immunoreactivity after exposure to HN2 and SM. Immunoreactivity for laminin- was decreased to a lesser extent, and immunoreactivity for collagen IV and VII was unchanged. HN2 and SM produce similar histopathologic and immunohistochemical features after cutaneous exposure. These features suggest that part of mechanism of action of HN2 and SM is a direct effect on the basement membrane zone. Understanding the effects of HN2 and SM separate from their effect on DNA may be important in designing therapies and in advancing our understanding of the pathophysiologic changes induced by these chemicals when delivered topically.

Autoantigens↗
PubMed1998

Nodular melanosis due to epithelial neoplasms: a finding not restricted to regressed melanomas.

Nodular or tumoral melanosis consists of nodular or sheetlike deposits of melanophages in the dermis. When nodular melanosis is present, a completely regressed malignant melanoma is a major diagnostic consideration. We present a case of nodular melanosis due to regression of a pigmented basal cell carcinoma with pilar differentiation. In addition to this case, we present five additional cases of epithelial neoplasms with melanin deposition in the stroma. In each case, the source of the melanin was non-neoplastic dendritic melanocytes intermingled among the tumor cells. Therefore, if nodular melanosis is found, pigmented epithelial neoplasms should also be considered in the differential diagnosis.

Aged↗
PubMed1998

A review of tumor suppressor genes in cutaneous neoplasms with emphasis on cell cycle regulators.

Cells normally have five options. These include renewal or proliferation, terminal differentiation, quiescence, senescence, and apoptosis. Many factors interact with cell cycle regulators to direct the cells toward these different options. Tumor suppressor genes play a pivotal role in this process. Alterations in these genes may limit the options that cells have and thus play a significant role in the multistep process of carcinogenesis. We will focus on tumor suppressor genes and especially tumor suppressor genes that interact directly with the cell cycle proteins.

Cell Cycle Proteins↗
PubMed1998

Eosinophilic globules in spindle cell and epithelioid cell nevi: composition and possible origin.

The presence of eosinophilic globules has been described as a helpful sign for the histologic differentiation of Spitz's nevus from malignant melanoma. The origin of these bodies is not clear, and they have been likened to Civatte or colloid bodies of lichen planus. This would suggest that they might originate from degenerating keratinocytes or melanocytes or both. These eosinophilic globules and the colloid bodies of lichen planus have been reported to be similar in that they both stain positively for type IV collagen and laminin. These previous reports have failed to include, or have not emphasized, the staining for keratin that separates these two bodies. We stained 10 spindle cell and epithelial cell (S&E) nevi for S-100 protein, keratin, vimentin, type IV collagen, and laminin. In all 10 cases of S&E nevi, the eosinophilic globules showed a positive reaction for type IV collagen and laminin and a negative reaction for keratin, S100 protein, and vimentin, unlike the colloid bodies of lichen planus, which showed a negative reaction for type IV collagen and laminin and also a strong positive reaction for keratin. These results suggest that the eosinophilic globules of Spitz's nevi are basement membrane material, perhaps synthesized by either basal cells, melanocytes or both, and are not degenerated basal cells or melanocytes.

Adolescent↗
PubMed1998

Lymphoid markers, activation markers, and adhesion molecules in cutaneous biopsy specimens from HIV+ patients with disease progression. The Military Medical Consortium for the Advancement of Retroviral Research.

BACKGROUND: One important factor in understanding the pathogenesis of human immune deficiency virus (HIV) disease is documenting the patterns of immune dysregulation present in HIV-positive patients. The cells which home to skin are mainly certain subsets of T cells and, as opposed to the peripheral blood, where circulating factors may inhibit terminal phenotypic differentiation, the cutaneous environment potentiates differentiation during cutaneous eruptions. OBJECTIVE: The authors' aim was to characterize the inflammatory dermatoses in biopsy specimens from HIV-positive patients with immunohistochemical stains for lymphoid markers, activation markers, and adhesion molecules and to determine if there was any correlation with the type of dermatosis and the HIV-disease stage. METHODS: Lymphoid and activation markers as well as adhesion molecules were studied on cutaneous biopsy specimens from 96 inflammatory dermatoses in HIV-positive patients. The dermatoses included psoriasiform dermatoses with and without a lichenoid component, perivascular lymphoid dermatoses, perivascular and periadnexal inflammatory dermatoses, spongiotic dermatoses, granulomatous dermatoses, and neutrophilic dermatoses with and without vasculitis. RESULTS: Although there was a decrease in CD4/CD8 ratios in the cutaneous inflammatory dermatoses with progression of the disease, the ratios of CD4/CD8 cells were far higher than those in the peripheral blood. There were also increasing numbers of CD23+ cells and increased E-Selectin expression on endothelial cells from the early stages of disease, with no consistent pattern of ICAM-1 expression on epithelial cells with disease progression. CONCLUSIONS: The expression of lymphoid markers, activation markers, and adhesion molecules in the skin with progression of HIV disease, is consistent with a T helper (Th)1 to Th0/Th2 cytokine pattern of immune dysregulation. This cytokine pattern may be modified by the cytopathic effects of HIV on lymphoid and dendritic populations and by effects of other concurrent infections. Significant numbers of CD4+ T cells in skin infiltrates, with low peripheral CD4 T-cell counts, suggest that the cutaneous T-cell populations may be distinctive.

Antigens, CD↗
PubMed1998

Lichenoid/Interface cutaneous eruptions to IVIg with the primary infusion may be related to the re-regulation of anti-idiotype network.

BACKGROUND: Intravenous immunoglobulin (IVIg) has been used in recent years to treat an increasing number of autoimmune diseases to decrease cytokine secretion and to neutralize toxins, in addition to the therapy of immunodeficiency disorders. In addition to angioedema-like hypersensitivity eruptions, there have been reports of eczematous, purpuric, petechial/purpuric, and vasculitic reactions to IVIg; however, there has been only one previous report of a case in which the patient developed a lichenoid dermatitis after infusion of IVIg. OBSERVATIONS: We present two patients with chronic inflammatory, demyelinating polyneuropathy, who after the first course of IVIg developed a folliculocentric interface/lichenoid eruption that cleared without therapy or with topical steroids. The eruption did not recur with subsequent IVIg infusions in either patient. CONCLUSIONS: The multiple diverse effects of IVIg on the immune system, and the re-regulation of the anti-idiotype network with repeat IVIg infusions, may explain why this eruption occurred with the initial infusion of IVIg and not with repeated infusions.

Aged↗
PubMed1998

Cost effectiveness of early treatment with oral aciclovir in adult chickenpox.

Treatment of adult chickenpox with aciclovir is controversial because of the relatively high cost of medication and small proven benefits of therapy. A decision-tree model was used to estimate the cost effectiveness of aciclovir, from third-party payer and societal perspectives: the incremental cost per quality-adjusted life-year (QALY) gained was calculated for aciclovir treatment of chickenpox compared with no antiviral therapy in immunocompetent adults who presented within 24 hours of the onset of chickenpox rash. Incremental costs for aciclovir compared with no antiviral treatment were 42,900 US dollars per QALY gained, when viewed from a third-party payer perspective; however, results are sensitive to variation of clinical parameters. From a societal perspective, aciclovir therapy was cost saving compared with no antiviral treatment; aciclovir remained cost saving or cost effective (less than 50,000 US dollars per QALY gained) when probabilities, quality-of-life utility values and costs were varied within clinically plausible ranges, and when other scenarios for chickenpox severity and aciclovir effectiveness were examined. From a societal perspective, oral aciclovir is cost effective, and perhaps cost saving, when given within 24 hours of rash onset in adult chickenpox. The argument for antiviral use may be less strong when viewed from the perspective of a third-party payer.

Acyclovir↗
PubMed1998

Extranodal multicentric Castleman's disease with cutaneous involvement.

Castleman's disease (CAD) is an unusual lymphoid hyperplasia that might be induced by an immunologic reaction to a virus or another infectious organism or drug. CAD commonly occurs in the mediastinal lymph nodes and less frequently in the neck lymph nodes, but other lymph nodes might be involved. Extranodal CAD is rare. We present a 72-year-old woman with diffuse 2- to 5-cm cutaneous nodules that had appeared a few months earlier. The patient underwent a biopsy, and the lesions resolved within 4 months. The patient was asymptomatic except for mild joint pains. Histopathologic findings showed a circumscribed nodule composed of lymphoid follicles with contracted germinal centers and expanded mantle zones. The lymphoid follicles were separated by perivascular bands of sclerotic collagen. Aggregates of epithelioid and dendritic histiocytes were present between follicles, with a prominent lymphoplasmacytic infiltrate and vascular proliferation. Although extranodal CAD has been reported in the skin, we think that this is the first reported case of multicentric cutaneous CAD without evidence of lymph node involvement.

Aged↗
PubMed1997

Conduction in segmentally demyelinated mammalian central axons.

The prominent symptoms associated with central demyelinating diseases such as multiple sclerosis (MS) are primarily caused by conduction deficits in affected axons. The symptoms may go into remission, but the mechanisms underlying remissions are uncertain. One factor that could be important is the restoration of conduction to affected axons, but it is not known whether demyelinated central axons resemble their peripheral counterparts in being able to conduct in the absence of repair by remyelination. In the present study we have made intra-axonal recordings from central axons affected by a demyelinating lesion, and then the axons have been labeled ionophoretically to permit their subsequent identification. Ultrastructural examination of 23 labeled preparations has established that some segmentally demyelinated central axons can conduct, and that they can do so over continuous lengths of demyelination exceeding several internodes (2500 micron). Such segmentally demyelinated central axons were found to conduct with the anticipated reduction in velocity and a refractory period of transmission (RPT) as much as 34 times the value obtained from the nondemyelinated portion of the same axon; the RPT was typically prolonged to 2-5 times the normal value. We conclude that some segmentally demyelinated central axons can conduct, and we propose that the restoration of conduction to such axons is likely to contribute to the remissions commonly observed in diseases such as MS.

Action Potentials↗
PubMed1997

Interaction of factor IXa with factor VIIIa. Effects of protease domain Ca2+ binding site, proteolysis in the autolysis loop, phospholipid, and factor X.

We previously identified a high affinity Ca2+ binding site in the protease domain of factor IXa involving Glu235 (Glu70 in chymotrypsinogen numbering; hereafter, the numbers in brackets refer to the chymotrypsin equivalents) and Glu245[80] as putative ligands. To delineate the function of this Ca2+ binding site, we expressed IXwild type (IXWT), IXE235K, and IXE245V in 293 kidney cells and compared their properties with those of factor IX isolated from normal plasma (IXNP); each protein had the same Mr and gamma-carboxyglutamic acid content. Activation of each factor IX protein by factor VIIa.Ca2+.tissue factor was normal as analyzed by sodium dodecyl sulfate-gel electrophoresis. The coagulant activity of IXaWT was approximately 93%, of IXaE235K was approximately 27%, and of IXaE245V was approximately 4% compared with that of IXaNP. In contrast, activation by factor XIa.Ca2+ led to proteolysis at Arg318-Ser319[150-151] in the protease domain autolysis loop of IXaE245V with a concomitant loss of coagulant activity; this proteolysis was moderate in IXaE235K and minimal in IXaWT or IXaNP. Interaction of each activated mutant with an active site probe, p-aminobenzamidine, was also examined; the Kd of interaction in the absence and presence (in parentheses) of Ca2+ was: IXaNP or IXaWT 230 microM (78 microM), IXaE235K 150 microM (145 microM), IXaE245V 225 microM (240 microM), and autolysis loop cleaved IXaE245V 330 microM (350 microM). Next, we evaluated the apparent Kd (Kd,app) of interaction of each activated mutant with factor VIIIa. We first investigated the EC50 of interaction of IXaNP as well as of IXaWT with factor VIIIa in the presence and absence of phospholipid (PL) and varying concentrations of factor X. At each factor X concentration and constant factor VIIIa, EC50 was the free IXaNP or IXaWT concentration that yielded a half-maximal rate of factor Xa generation. EC50 values for IXaNP and IXaWT were similar and are as follows: PL-minus/X-minus (extrapolated), 2.8 microM; PL-minus/X-saturating, 0.25 microM; PLplus/X-minus, 1.6 nM; and PL-plus/X-saturating, 0.09 nM. Further, Kd,app of binding of active site-blocked factor IXa to factor VIIIa was calculated from its ability to inhibit IXaWT in the Tenase assay. Kd,app values in the absence and presence (in parentheses) of PL were: IXaNP or IXaWT, 0. 19 microM (0.07 nM); IXaE235K, 0.68 microM (0.26 nM); IXaE245V, 2.5 microM (1.35 nM); and autolysis loop-cleaved IXaE245V, 15.6 microM (14.3 nM). We conclude that (a) PL increases the apparent affinity of factor IXa for factor VIIIa approximately 2,000-fold, and the substrate, factor X, increases this affinity approximately 10-15-fold; (b) the protease domain Ca2+ binding site increases this affinity approximately 15-fold, and lysine at position 235 only partly substitutes for Ca2+; (c) Ca2+ binding to the protease domain increases the S1 reactivity approximately 3-fold and prevents proteolysis in the autolysis loop; and (d) proteolysis in the autolysis loop leads to a loss of catalytic efficiency with retention of S1 binding site and a further approximately 8-fold reduction in affinity of factor IXa for factor VIIIa.

1-Carboxyglutamic Acid↗