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K J Smith

Publications and source records attributed to K J Smith.

At least 19 recordsLinked to original sources
PubMed2002

Selective detection of the proton NMR spectra of molecules containing rare spins at natural abundance in liquid crystalline samples.

It is shown that the proton NMR spectra of molecules containing rare spins at natural abundance dissolved in a liquid crystalline solvent can be obtained free from the strong lines from the spectrum of the abundant isotopomer by the 2D HSQC NMR experiment. The technique can also give the individual chemical shifts of the rare spins, and, for a molecule containing another abundant nucleus, such as fluorine, the rare spin--(19)F total anisotropic couplings are also obtained. The usefulness of the technique is demonstrated for molecules containing (13)C as the rare spins.

Journal Article↗
PubMed2002

Cholesterol embolization syndrome: cutaneous histopathological features and the variable onset of symptoms in patients with different risk factors.

Cholesterol embolization syndrome (CES) may not only be due to direct dislodgement of cholesterol crystals from atherosclerotic plaques on the walls of arteries by surgery, angiogram or trauma, but may occur after anticoagulant and thrombolytic therapy. The latter two therapies both weaken the fibrin clot that stabilizes the atheromas in place; however, these two therapies commonly have different onsets of CES after their institution. We present three patients with different risk factors for CES who all presented with the pathognomonic triad of leg and/or foot pain, livedo reticularis and good peripheral pulses. In all three patients cholesterol emboli were demonstrated in cutaneous biopsy sections. In two patients there was associated renal involvement, which was fatal in one case. These cases illustrate that cutaneous biopsy may be diagnostic in patients with livedo reticularis, which progresses to necrosis and gangrene. In addition, they illustrate the problems and contradictions involved in treating patients with CES.

Aged↗
PubMed2001

The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer.

The type I receptor tyrosine kinases constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. The best characterized of these proteins are the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2/neu). We have developed potent quinazoline and pyrido-[3,4-d]-pyrimidine small molecules that are dual inhibitors of ErbB-2 and EGFR. The compounds demonstrate potent in vitro inhibition of the ErbB-2 and EGFR kinase domains with IC(50)s <80 nM. Growth of ErbB-2- and EGFR-expressing tumor cell lines is inhibited at concentrations <0.5 microM. Selectivity for tumor cell growth inhibition versus normal human fibroblast growth inhibition ranges from 10- to >75-fold. Tumor growth in mouse s.c. xenograft models of the BT474 and HN5 cell lines is inhibited in a dose-responsive manner using oral doses of 10 and 30 mg/kg twice per day. In addition, the tested compounds caused a reduction of ErbB-2 and EGFR autophosphorylation in tumor fragments from these xenograft models. These data indicate that these compounds have potential use as therapy in the broad population of cancer patients overexpressing ErbB-2 and/or EGFR.

Animals↗
PubMed2001

Prophylactic platelet transfusions from healthy apheresis platelet donors undergoing treatment with thrombopoietin.

Many patients receiving dose-intensive chemotherapy acquire thrombocytopenia and need platelet transfusions. A study was conducted to determine whether platelets harvested from healthy donors treated with thrombopoietin could provide larger increases in platelet counts and thereby delay time to next platelet transfusion compared to routinely available platelets given to thrombocytopenic patients. Community platelet donors received either 1 or 3 microg/kg pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) or placebo and then donated platelets 10 to 15 days later. One hundred sixty-six of these platelet concentrates were then transfused to 120 patients with platelets counts 25 x 10(9)/L or lower. Pretransfusion platelet counts (11 x 10(9)/L) were similar for recipients of placebo-derived and PEG-rHuMGDF-derived platelets. Early after transfusion, the median platelet count increment was higher in patients receiving PEG-rHuMGDF-derived platelets: 19 (range, -12-66) x 10(9)/L, 41 (range, 5-133) x 10(9)/L, and 82 (range, -4-188) x 10(9)/L for placebo-, 1-microg/kg-, and 3-micro/kg-derived platelets, respectively. This difference was maintained 18 to 24 hours after transfusion. Transfusion-free intervals were 1.72, 2.64, and 3.80 days for the recipients of the placebo-, 1-microg/kg-, and 3-micro/kg-derived platelets, respectively. The rate of transfusion-related adverse events was not different in recipients of placebo-derived and PEG-rHuMGDF-derived platelets. Therefore, when transfused into patients with thrombocytopenia, platelets collected from healthy donors undergoing thrombopoietin therapy were safe and resulted in significantly greater platelet count increments and longer transfusion-free intervals than platelets obtained from donors treated with placebo.

Adolescent↗
PubMed2001

Peroxisomes in dermatology. Part II.

BACKGROUND: Peroxisomes are small cellular organelles that were almost ignored for years because they were believed to play only a minor role in cellular functions. However, it is now known that peroxisomes play an important role in regulating cellular proliferation and differentiation as well as in the modulation of inflammatory mediators. In addition, peroxisomes have broad effects on the metabolism of lipids, hormones, and xenobiotics. Through their effects on lipid metabolism, peroxisomes also affect cellular membranes and adipocyte formation, as well as insulin sensitivity, and peroxisomes play a role in aging and tumorigenesis through their effects on oxidative stress. OBJECTIVE: To review genetically determined peroxisomal disorders, especially those that particularly affect the skin, and some recent information on the specific genetic defects that lead to some of these disorders. In addition, we present some of the emerging knowledge of peroxisomal proliferator activator receptors (PPARs) and how ligands for these receptors modulate different peroxisomal functions. We also present information on how the discovery of PPARs, and the broad and diverse group of ligands that activate these members of the superfamily of nuclear binding transcription factors, has led to development of new drugs that modulate the function of peroxisomes. CONCLUSION: PPAR expression and ligand modulation within the skin have shown potential uses for these ligands in a number of inflammatory cutaneous disorders, including acne vulgaris, cutaneous disorders with barrier dysfunction, cutaneous effects of aging, and poor wound healing associated with altered signal transduction, as well as for side effects induced by the metabolic dysregulation of other drugs.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Naturally processed HLA class II peptides reveal highly conserved immunogenic flanking region sequence preferences that reflect antigen processing rather than peptide-MHC interactions.

MHC class II heterodimers bind peptides 12-20 aa in length. The peptide flanking residues (PFRs) of these ligands extend from a central binding core consisting of nine amino acids. Increasing evidence suggests that the PFRs can alter the immunogenicity of T cell epitopes. We have previously noted that eluted peptide pool sequence data derived from an MHC class II Ag reflect patterns of enrichment not only in the core binding region but also in the PFRS: We sought to distinguish whether these enrichments reflect cellular processes or direct MHC-peptide interactions. Using the multiple sclerosis-associated allele HLA-DR2, pool sequence data from naturally processed ligands were compared with the patterns of enrichment obtained by binding semicombinatorial peptide libraries to empty HLA-DR2 molecules. Naturally processed ligands revealed patterns of enrichment reflecting both the binding motif of HLA-DR2 (position (P)1, aliphatic; P4, bulky hydrophobic; and P6, polar) as well as the nonbound flanking regions, including acidic residues at the N terminus and basic residues at the C terminus. These PFR enrichments were independent of MHC-peptide interactions. Further studies revealed similar patterns in nine other HLA alleles, with the C-terminal basic residues being as highly conserved as the previously described N-terminal prolines of MHC class II ligands. There is evidence that addition of C-terminal basic PFRs to known peptide epitopes is able to enhance both processing as well as T cell activation. Recognition of these allele-transcending patterns in the PFRs may prove useful in epitope identification and vaccine design.

Amino Acid Motifs↗
PubMed2001

Peroxisomes in dermatology. Part I.

BACKGROUND: Peroxisomes are small cellular organelles that were almost ignored for years because they were believed to play only a minor role in cellular functions. However, it is now known that peroxisomes play an important role in regulating cellular proliferation and differentiation as well as in the modulation of inflammatory mediators. In addition, peroxisomes have broad effects on the metabolism of lipids, hormones, and xenobiotics. Through their effects on lipid metabolism, peroxisomes also affect cellular membranes and adipocyte formation, as well as insulin sensitivity, and peroxisomes play a role in aging and tumorigenesis through their effects on oxidative stress. OBJECTIVE: To review genetically determined peroxisomal disorders, especially those that particularly affect the skin, and some recent information on the specific genetic defects that lead to some of these disorders. In addition, we present some of the emerging knowledge of peroxisomal proliferator activator receptors (PPARs) and how ligands for these receptors modulate different peroxisomal functions. We also present information on how the discovery of PPARs, and the broad and diverse group of ligands that activate these members of the superfamily of nuclear binding transcription factors, has led to development of new drugs that modulate the function of peroxisomes. CONCLUSION: PPAR expression and ligand modulation within the skin have shown potential uses for these ligands in a number of inflammatory cutaneous disorders, including acne vulgaris, cutaneous disorders with barrier dysfunction, cutaneous effects of aging, and poor wound healing associated with altered signal transduction, as well as for side effects induced by the metabolic dysregulation of other drugs.

Aging↗
PubMed2001

Chemical synthesis and biological activity of rat INSL3.

The recently identified protein, insulin 3 (INSL3), has structural features that make it a bona fide member of the insulin superfamily. Its predicted amino acid sequence contains the classic two-peptide chain (A- and B-) structure with conserved cysteine residues that results in a disulphide bond disposition identical to that of insulin. Recently, the generation of insl3 knockout mice has demonstrated that testicular descent is blocked due to the failure of a specific ligament, the gubernaculum, to develop. The mechanism by which INSL3 exerts its action on the gubernaculum is currently unknown. The purpose of this study was to, for the first time, synthesize rat INSL3 and test its action on organ cultures of foetal rat gubernaculum. INSL3 also contains a cassette of residues Arg-X-X-X-Arg within the B-chain, a motif that is essential for characteristic activity of another related member of the superfamily, relaxin. Hence, the relaxin activity of rat INSL3 was also tested in two different relaxin bioassays. The primary structure of rat INSL3 was determined by deduction from its cDNA sequence and successfully prepared by solid phase peptide synthesis of the two constituent chains followed by their combination in solution. Following confirmation of its chemical integrity by a variety of analytical techniques, circular dichroism spectroscopy confirmed the presence of high beta-turn and alpha-helical content, with a remarkable spectral similarity to the synthetic ovine INSL3 peptide and to synthetic rat relaxin. The synthetic rat INSL3 bound with very low affinity to rat relaxin receptors and had no activity in a relaxin bioassay. Furthermore, it did not augment or antagonize relaxin activity. The rat INSL3 did however induce growth of foetal rat gubernaculum in whole organ cultures demonstrating that INSL3 has a direct action on this structure.

Amino Acid Sequence↗
PubMed2001

Metastatic adenocarcinoma of the esophagus to the skin: new patterns of tumor recurrence and alternate treatments for palliation.

BACKGROUND: Esophageal cancer, particularly adenocarcinoma of the esophagus (ACE), has been steadily increasing in incidence in the United States. In the past, patients usually died rapidly with locoregional disease that leads to inanition and aspiration. However, today when patients with ACE are treated successfully with induction chemotherapy and radiation therapy, followed by surgical excision, ACE usually does not recur locally, but presents with metatastic disease. We present a 62-year-old white male with ACE, which was treated with induction chemotherapy and radiation therapy followed by surgical excision. After approximately 1 year with no evidence of locoregional recurrence, the patient presented with diffuse cutaneous metastatic disease. METHODS: In addition to routine staining immunohistochemical stains for CK(AE1/AE3), CK7, CK 20, EMA, alpha-smooth muscle (SM) actin, S-100 protein, CD34, P53, Bcl-2, c-erbB-2 were performed. RESULTS: The immunohistochemical profile was consistent with an esophageal origin showing positive staining with CK20 and CK7 as well as AE1/AE3 and EMA. In addition, there was marked nuclear expression of p53, as well as membrane expression of c-erb-B2; consistent with progression of the disease and poor response to further cytotoxic therapeutic regimes. CONCLUSIONS: With new therapeutic protocols, we can expect to see more metastatic disease with recurrences of ACE. The histopathologic features and the immunohistochemical profile of the recurrent tumors may be helpful in determining alternate forms of therapy that either alone or in combination could be useful in palliation and delaying progression.

Adenocarcinoma↗
PubMed2001

Common variable immunodeficiency treated with a recombinant human IgG, tumour necrosis factor-alpha receptor fusion protein.

Common variable immunodeficiency (CVI) is characterized by a failure in B-cell differentiation and impaired immunoglobulin secretion, but with a variable clinical presentation, including the development of sarcoidal granulomas and autoimmune diseases, as well as an increased incidence of malignancies. We present a 21-year-old white man who carried a diagnosis of juvenile rheumatoid arthritis and presented 6 years later with scarring alopecia showing sarcoidal granulomas. Further work confirmed the diagnosis of CVI, and with increasing systemic symptoms, it was elected to treat the patient with a tumour necrosis factor (TNF)-alpha antagonist, a TNF-alpha receptor IgG1 fusion protein. The patient showed improvement in his systemic symptoms and some hair regrowth after 3 months of therapy, and continued improvement in his systemic disease with only mild scalp hair thinning in the areas of prior involvement after almost 1 year of therapy. CVI and sarcoid may have overlapping clinical and immunological findings. Previous therapies for CVI, including intravenous immunoglobulin, have not altered the mortality of the disease. TNF-alpha is a primary cytokine and is elevated in CVI, and specific inhibition of TNF-alpha in this patient was effective in moderating his disease, including his skin disease.

Adult↗
PubMed2001

Trichophyton rubrum showing deep dermal invasion directly from the epidermis in immunosuppressed patients.

Trichophyton rubrum is the most widely encountered dermatophyte infection, and is usually regarded as exclusively keratinophilic often leading to chronic cutaneous and nail infections, even in healthy individuals. We present three patients with acute leukaemias, with ill-defined pre-existent cutaneous eruptions that were treated with a potent topical corticosteroid. All three patients received aggressive marrow toxic chemotherapy. These patients had progression of their cutaneous disease, which showed deep dermal invasion of T. rubrum, invading directly from the epidermis with no evidence of systemic spread. We conclude that systemic pancytopenia, in association with prolonged local immunosuppression, may increase the risk of direct dermal invasion of dermatophyte infections. However, even in these patients, the risk of systemic spread still appears very low. Amphotericin B did not appear effective in treating these dermatophyte infections.

Adolescent↗
PubMed2001

Peroxisomal proliferator-activated ligand therapy for HIV lipodystrophy.

Lipodystrophies associated with HIV disease have been reported in recent years and have included a general redistribution of fat with more central fat and increased dorsocervical fat. These lipodystrophies are commonly associated with hyperlipidemia and in some cases with insulin resistant diabetes. Although a similar redistribution of fat is seen in hypercortisolism, in general, serum and urinary cortisol levels are normal in these HIV-positive patients. However cortisol/dehydroepaindrosterone (DHEA) ratios are increased in HIV disease and may result in a relative hypercortisolism. Seven HIV-positive male patients on multidrug antiviral therapy including HIV protease inhibitors had developed increased central and dorsocervical fat over 1 year. All patients had increased serum lipids and three had insulin resistant diabetes. Four patients were treated initially with DHEA 100-200 mg/day, with addition of a cyclo-oxygenase (COX) inhibitor (indomethacin 100 mg/day) and three others were treated from the onset with a combination of DHEA 200 mg/day and a COX inhibitor (indomethacin 100 mg/day or naprosyn 1000 mg/day). All patients reported moderation or normalization of their serum lipids and some moderation of blood sugars while on DHEA alone. More marked improvement in blood sugar and noticeable decreases in the dorsocervical fat; however, occurred only with addition a COX inhibitor. Both DHEA and COX inhibitors have a number of mechanisms of action; among these is their role as a peroxisome proliferator-activator receptor ligand. Dysregulation of peroxisome function is associated with the spectrum of biochemical changes seen within these HIV associated lipodystrophies. Use of HIV protease inhibitors is reported in the majority of patients with these lipodystrophies, and protease inhibitors may accentuate the underlying peroxisome dysregulation. Supplementation with DHEA and a COX inhibitor may improve peroxisomal function.

Anti-HIV Agents↗
PubMed2001

Neonatal lupus erythematosus: factors which may lead to clinical disease in the foetus even in the absence of disease in the mother.

Neonatal lupus erythematosus (NLE) occurs in neonates of mothers who, in almost all cases, have auto-antibodies to the SSA/Ro associated proteins, but who may have no clinical disease. However, only a small percentage of mothers with SSA/Ro antibodies have affected babies, predisposing factors specific to the foetus or neonate (i.e. HLA pattern) and/or fetal maternal interactions have been proposed to be important. We present a mother with a family history of autoimmune disease, but without clinical disease, whose baby developed cutaneous NLE. Autoantibody determinations as well as the HLA-DR/DQ were performed in the mother and baby. Factors other than the HLA-DR/DQ status of the mother appear to be important in determining whether or not the neonate will develop NLE. Auto-antibodies to endogenous antigens common to the mother, transiently expressed developmental antigens, and the isotype specificity of transferred antibodies may be important in determining disease in the baby.

Adult↗
PubMed2001

Squamous cell carcinoma in situ (Bowen's disease) in renal transplant patients treated with 5% imiquimod and 5% 5-fluorouracil therapy.

BACKGROUND: Depending upon the patient's age at transplant, skin type, sun exposure, and the need for immunosuppressive therapy to prevent rejection, there is escalation in the development of cutaneous malignancies in organ transplant patients a number of years after transplantation. Thus, with the expansion in these procedures over the past decades, and the ever-lengthening survival of these patients, we are seeing an increase in cutaneous malignancies in this patient population. OBJECTIVE: To determine if combined therapy with 5% 5-fluorouracil and 5% imiquimod may be useful in the treatment of squamous cell carcinoma in situ. METHODS: We present five renal transplant patients, all more than 10 years posttransplantation, three with insulin-dependent diabetes, who developed multiple areas of squamous cell carcinoma (SCC) in situ. All these patients were on chronic immunosuppressive chemotherapy to prevent rejection, but were otherwise doing well. All the patients had biopsy-proven SCC in situ on their lower extremities that even in normal patients may be a challenge to treat. RESULTS: We treated these five patients with a combination of a local immune therapy, imiquimod cream, and a topical chemotherapeutic agent, 5% 5-fluorouracil (5-FU), with clearing of the areas of SCC in situ. CONCLUSION: Although immunotherapy must be used with caution in organ transplant patients to avoid graft rejection, topical imiquimod is a local immune modulator that potentiates local innate and possible adaptive immunity without measurable effects on systemic immunity. In addition, there is evidence that cytokines induced by imiquimod may improve the therapeutic efficacy of topical 5% 5-FU in the treatment of SCC in situ.

Administration, Cutaneous↗
PubMed2001

Bowen's disease (squamous cell carcinoma in situ) in immunosuppressed patients treated with imiquimod 5% cream and a cox inhibitor, sulindac: potential applications for this combination of immunotherapy.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) often have a protracted course. However, all these patients are immunosuppressed and may have a high incidence of cutaneous malignancies. OBJECTIVE: To determine if combination therapy using topical imiquimod cream 5% and the oral cyclooxygenase (COX) inhibitor are useful in the therapy of squamous cell carcinoma in situ (SCC in situ)/Bowen's disease in patients with long-standing CLL. METHODS: Five CLL patients with head and neck cutaneous SCC in situ, which met criteria for Bowen's disease, were treated with topical 5% topical imiquimod cream and an oral COX inhibitor, sulindac 200 mg twice a day. RESULTS: All patients showed clinical resolution and histologic clearing of the tumors after 16 weeks of therapy. CONCLUSION: The local immune modulator, 5% imiquimod, in combination with a COX inhibitor, with its many potential antitumor effects may stimulate the innate and possibly the adaptive immune responses to clear these malignancies.

Adjuvants, Immunologic↗