Search PubMed⌕ Search

Biomedical subjects

T J Brown

Publications and source records attributed to T J Brown.

At least 55 records · Page 3Linked to original sources
PubMed1999

Regulation of inflammatory responses by oncostatin M.

Oncostatin M (OM) is a pleiotropic cytokine produced late in the activation cycle of T cells and macrophages. In vitro it shares properties with related proteins of the IL-6 family of cytokines; however, its in vivo properties and physiological function are as yet ill defined. We show that administration of OM inhibited bacterial LPS-induced production of TNF-alpha and lethality in a dose-dependent manner. Consistent with these findings, OM potently suppressed inflammation and tissue destruction in murine models of rheumatoid arthritis and multiple sclerosis. T cell function and Ab production were not impaired by OM treatment. Taken together these data indicate the activities of this cytokine in vivo are antiinflammatory without concordant immunosuppression.

Animals↗
PubMed1999

Activation of SPARC expression in reactive stroma associated with human epithelial ovarian cancer.

OBJECTIVE: SPARC (secreted protein, acidic, rich in cysteine) is a calcium-binding counteradhesive glycoprotein that has the potential to play an important role in promoting tumor progression and invasiveness. SPARC has been reported to be markedly down-regulated in ovarian carcinomas relative to the normal surface epithelium and has been suggested to act as a tumor suppressor in ovarian cancer. To more precisely define potential changes in SPARC expression associated with malignant transformation of the ovary, we compared the distribution of SPARC mRNA and protein expression in patient specimens of malignant and nonmalignant ovaries. METHOD: SPARC mRNA and protein expression was examined in 24 human invasive ovarian cancers, 5 tumors of low malignant potential (LMP), and 8 nonmalignant ovaries by in situ hybridization and immunohistochemistry. RESULTS: In nonmalignant ovaries, SPARC mRNA expression was restricted to thecal and granulosa cells of vessiculated follicles. Cytoplasmic SPARC immunoreactivity was observed in these compartments, whereas variable SPARC immunostaining was observed in normal surface epithelial cells. In contrast, high-level expression of SPARC mRNA and protein was detected in stroma of ovaries containing malignant tumor cells, particularly at the tumor-stromal interface of the invading tumors. Lower levels and a more diffuse pattern of SPARC mRNA expression were associated with LMP specimens. SPARC mRNA was not expressed by ovarian adenocarcinoma or by surface epithelial cells. Consistent with the in situ hybridization data, SPARC immunoreactivity was found throughout the reactive stroma of specimens containing ovarian carcinoma. However, despite the lack of detectable SPARC mRNA, SPARC immunoreactivity was consistently observed within the cytoplasm of cancer cells. CONCLUSION: The pattern of SPARC expression shown in this study indicates that SPARC is up-regulated in reactive stroma associated with invasive ovarian cancer. Moreover, these results raise the possibility that SPARC secreted from the stroma is internalized by ovarian cancer cells and may exert important intracellular effects upon these cells.

Adenocarcinoma↗
PubMed1999

An overview of sexually transmitted diseases. Part II.

UNLABELLED: Sexually transmitted diseases are a persistent problem in the United States and throughout the world. Many of these infections involve the skin and may be encountered in the field of dermatology. This 3-part review highlights the cutaneous features, diagnosis, and treatment of 11 of the most common sexually transmitted diseases, other than AIDS. The second part of this series focuses on anogenital warts, chronic viral hepatitis, molluscum contagiosum, scabies, and pediculosis pubis. Additional features, such as epidemiology and transmission of the organism, are discussed when applicable. (J Am Acad Dermatol 1999;41:661-77.) LEARNING OBJECTIVE: At the conclusion of this learning activity, participants should be familiar with the clinical features, diagnosis, and treatment of sexually transmitted diseases (excluding AIDS) which have cutaneous presentations or involvement.

Anus Diseases↗
PubMed1999

Absorption of hyaluronan applied to the surface of intact skin.

Hyaluronan has recently been introduced as a vehicle for topical application of drugs to the skin. We sought to determine whether hyaluronan acts solely as a hydrophilic reservoir on the surface of intact skin or might partly penetrate it. Drug-free hyaluronan gels were applied to the intact skin of hairless mice and human forearm in situ, with and without [3H] hyaluronan. [3H]hyaluronan was shown by autoradiography to disseminate through all layers of intact skin in mouse and human, reaching the dermis within 30 min of application in mice. Cellular uptake of [3H]hyaluronan was observed in the deeper layers of epidermis, dermis, and in lymphatic endothelium. Absorption through skin was confirmed in mice by chromatographic analysis of blood, urine, and extracts from skin and liver, which identified 3H as intact hyaluronan and its metabolites, free acetate and water. Hyaluronan absorption was similarly demonstrated without polyethylene glycol, which is usually included in the topical formulation. [3H]hyaluronan absorption was not restricted to its smaller polymers as demonstrated by the recovery of polymers of (360-400 kDa) from both blood and skin. This finding suggests that its passage through epidermis does not rely on passive diffusion but may be facilitated by active transport. This study establishes that hyaluronan is absorbed from the surface of the skin and passes rapidly through epidermis, which may allow associated drugs to be carried in relatively high concentration at least as far as the deeper layers of the dermis.

Administration, Topical↗
PubMed1999

Merkel cell carcinoma: spontaneous resolution and management of metastatic disease.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous neoplasm. The primary form of initial treatment is wide surgical excision. The use of Mohs micrographic surgery as the primary form of treatment in MCC has been controversial. The course of MCC is often aggressive, with early metastasis, widespread disease, and death. Despite the poor prognosis, spontaneous regression has occasionally been reported. OBJECTIVE: We describe the clinical course of two patients with Merkel cell carcinoma who underwent treatment with Mohs micrographic surgery for the primary MCC. Metastases were excised in the first case and spontaneously regressed in the second. Both patients are without clinical disease at the time of this report. METHODS: Histopathology, clinical records, and the current literature are reviewed. RESULTS: One patients was without recurrence of MCC for 13 years of follow-up. The other patient experienced clinical spontaneous remission after nodal spread of the disease, with no recurrence for 18 months after clinical remission and 24 months after surgery. CONCLUSION: The treatment of Merkel cell carcinoma with Mohs micrographic surgery (MMS) has been successful for the control of primary skin disease, and is at least comparable to wide excision. Spontaneous regression may occur in the course of this usually relentless and aggressive disease. The explanation for spontaneous regression of MCC is unknown.

Aged↗
PubMed1999

Primary carcinosarcoma of the skin: report of a case and review of the literature.

BACKGROUND: Carcinosarcoma is a biphasic tumor composed of intimately admixed epithelial and mesenchymal elements, both of which are malignant. Primary cutaneous involvement is extremely rare. Therefore it has been difficult to characterize the clinical course of carcinosarcoma of the skin. OBJECTIVE: To describe a further case of carcinosarcoma of the skin and to provide a review of the literature. METHODS: The clinical records of the patient and histopathology of the neoplasm are reviewed. In addition, the results of all previously reported cases of carcinosarcoma of the skin are compiled for reexamination. RESULTS: After complete excision of the carcinosarcoma, the patient shows no evidence of disease for 9 months. Long-term follow-up is needed because of the risk of recurrence or metastasis that may occur with this neoplasm. CONCLUSION: Carcinosarcoma of the skin appears to be associated with a good prognosis when compared with similar tumors located elsewhere. Metastasis (with or without documented mortality) has been reported in 3 of 16 patients (16.7%). Death from local disease has been reported in one additional patient (6.3%). However, further cases with long-term follow-up are needed in order to better understand the nature of this cutaneous neoplasm.

Aged↗
PubMed1999

Characterisation of constrictor endothelin receptors in the human internal thoracic artery and saphenous vein.

We studied the endothelin receptors mediating contraction in the human saphenous vein (SV) and internal thoracic artery (ITA). In the SV, the ET(A)-receptor antagonist BQ123 (1 microM) did not significantly shift the ET-1 concentration-response curve but did cause a parallel shift in the ITA. In the SV, the ET(A)-receptor agonist sarafotoxin 6b (S6b) produced a monophasic concentration-response curve that was antagonised biphasically by BQ123 (0.1-1 microM). In the ITA, S6b was an ineffective agonist with contractions seen only at 3 x 10(-9) M upward. The ET(B)-receptor agonist sarafotoxin 6c (S6c) caused constrictions in only 74% of SV rings and 42% of ITA rings. In the tissues that did respond, S6c caused a monophasic concentration-response curve with a lower maximal response than ET-1. The ET(B) antagonist BQ788 did not antagonise the responses to ET-1 in either the SV or the ITA but did antagonise the responses to S6c in the SV. The results from this study suggest that mainly ET(A) receptors mediate the contractile responses in the human SV and ITA. There is also evidence for an ET(B)-mediated response, although the contractions were much smaller than those elicited by ET-1. We also conclude that the ET(A) receptors mediating responses in these human vessels are atypical because of the different effects of BQ123 on the two vessels.

Adult↗
PubMed1999

Evaluation of three commercial detection systems for Mycobacterium tuberculosis where clinical diagnosis is difficult.

AIMS: To assess the performance of three commercially available Mycobacterium tuberculosis detection systems employing nucleic acid amplification, when applied directly to respiratory and non-respiratory specimens from patients where the diagnosis of tuberculosis is difficult using clinical and traditional bacteriological methods. METHODS: 42 respiratory and 21 non-respiratory specimens were concentrated, examined with auramine staining, and cultured on Lowenstein-Jensen slopes. These specimens were also assayed using the Amplicor Mycobacterium tuberculosis test (AM) (Roche Diagnostic Systems), the Amplified Mycobacterium tuberculosis direct test (AMD) (Gen-Probe), and the LCx Mycobacterium tuberculosis assay (LMA) (Abbott Laboratories). RESULTS: All three amplification systems used in this study gave specificities of 100% when used on respiratory specimens. When used on non-respiratory specimens, AM and LMA gave specificities of 100% and AMD 75%. With respiratory specimens the AM, AMD, and LMA systems gave sensitivities of 75%, 65.2%, and 79.2%, respectively. With non-respiratory specimens the sensitivities were 50%, 66.7%, and 60%, while with smear negative, culture positive specimens they were 33.3%, 66.7%, and 55.6%. Positive predictive values of 100% were seen with all specimens except non-respiratory specimens assayed using AMD where the value was 66.7%. CONCLUSIONS: The manufacturers of these systems recommend that they should only be used for the direct analysis of respiratory specimens, and the US Food and Drug Administration has approved them for use only with smear positive specimens. This study confirms that sensitivities are lower for non-respiratory and smear negative specimens, but positive predictive values are high. Provided they are interpreted with caution, positive results with these tests in respiratory and non-respiratory specimens are useful in tuberculous patients who are otherwise difficult to diagnose. Each amplification has advantages and disadvantages compared with the others.

DNA, Bacterial↗
PubMed1999

Malignant melanoma: a clinical review.

The incidence of cutaneous malignant melanoma is increasing at an alarming rate. It is projected that Americans born in the year 2000 will have a 1 in 75 lifetime risk of developing melanoma. Long-term survival for patients with metastatic disease is only 5% and approximately 15% of patients diagnosed with melanoma eventually die from their disease. Conversely, the prognosis for early disease is excellent and often simple surgical excision is curative. It is therefore crucial that the practicing physician becomes familiar with all of the clinical and histologic presentations in order to ensure an accurate and prompt diagnosis. This, in turn, should lead to earlier detection and a more favorable prognosis.

Humans↗
PubMed1999

An overview of sexually transmitted diseases. Part I.

Sexually transmitted diseases are a persistent problem in the United States and throughout the world. Many of these infections involve the skin and may be encountered in the field of dermatology. This 3-part review highlights the cutaneous features, diagnosis, and treatment of 11 of the most commonly encountered sexually transmitted diseases, other than AIDS. However, this review does not cover sexually transmitted diseases such as chlamydia, which do not regularly have cutaneous manifestations. Part 1 focuses on syphilis, disseminated gonococcal infection, chancroid, lymphogranuloma venereum, granuloma inguinale, and genital herpes. Additional features, such as epidemiology and transmission of the organism, are discussed when applicable.

Chancroid↗
PubMed1998

Selective endothelin A receptor antagonists. 3. Discovery and structure-activity relationships of a series of 4-phenoxybutanoic acid derivatives.

The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)b utanoi c acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.

Administration, Oral↗
PubMed1998

Selective endothelin A receptor antagonists. 4. Discovery and structure-activity relationships of stilbene acid and alcohol derivatives.

This publication describes the synthesis and optimization of a novel series of stilbene endothelin antagonists. Analysis of the SAR established for previous papers in this series prompted the design and synthesis of (Z)-4-phenyl-5-(3-benzyloxyphenyl)pent-4-enoic acid 3 which was found to be a moderately active inhibitor of the binding of [125I]ET-1 to ETA receptors with an IC50 of 6 microM. More interestingly, the intermediate compound (E)-2-phenyl-3-(3-benzyloxyphenyl)propenoic acid 5 was equiactive with 3. Optimization of 5 resulted in the preparation of (E)-2-phenyl-3-(2-cyano-5-(thien-3-ylmethoxy))phenylprope noic acid 18 (RPR111723) which had an IC50 in the binding assay of 80 nM on the ETA receptor and a pKB of 6.5 in the functional assay, measured on rat aortic strips. Reduction of the acid group of 5 gave the first nonacidic ETA antagonist in our series, (E)-2-phenyl-3-(3-benzyloxyphenoxy)prop2-enol 6 with an IC50 of 20 microM. Optimization of 6 resulted in the preparation of 2-(2-methylphenyl)-3-(2-cyano-5-(thien-3-ylmethyl)phenyl)pro p-2-enol 33 with an IC50 of 300 nM on the ETA receptor.

Animals↗
PubMed1998

Identification of a non peptidic RANTES antagonist.

A series of phenothiazines demonstrating inhibition of RANTES binding to THP-1 cell membranes has been identified. The lead compound RP23618 (IC50 = 3 microM) was found to inhibit specific binding of 125I-RANTES, but not 125I-MCP-1 to THP-1 cell membranes and furthermore to antagonize RANTES, but not MCP-1-induced chemotaxis of THP-1 cells.

Cell Membrane↗
PubMed1998

Cutaneous manifestations of sexually transmitted diseases.

Sexually transmitted diseases remain a prevalent problem in the United States and throughout the world, despite efforts in prevention and education. This review highlights the cutaneous manifestations of the following sexually transmitted diseases: syphilis, chancroid, lymphogranuloma venereum, granuloma inguinale, genital herpes, genital warts, scabies, and pediculosis pubis. Emphasis is placed on the clinical findings, diagnostic methodology, and recommended treatment for each disease.

Humans↗
PubMed1998

Genital ulcers. Evaluation and treatment.

Ulcerations may appear on the genitalia in a variety of both infectious and noninfectious conditions. The vast diversity of etiologies, coupled with the often overlapping morphological features, make the diagnosis of genital ulcerations a challenging endeavor. This article highlights the most important clinical manifestations and laboratory findings which aid in the proper diagnosis of genital ulcerations.

Behcet Syndrome↗
PubMed1998

Atypical antagonism observed with BQ-123 in human saphenous vein.

At present, endothelin (ET) receptor classification remains controversial. We investigated the presence of atypical ETA receptors in human saphenous veins (SV). Human SV was obtained from 24 patients undergoing coronary artery bypass grafting. Vessels were set up in organ baths, stretched to a tension of 6 g, and left to relax before being challenged with 90 mM KCl. After KCl challenge, tissues were incubated with 2.8 microM indomethacin and 100 microM L-NMMA for 30 min followed by 30 min in the presence of antagonist before a concentration-response curve to ET-1 or sarafotoxin 6b (S6b) (10(-10)-10(-7) M) was constructed. In endothelium-intact vessels, incubated with indomethacin and L-NMMA, BQ-123 (1 microM) caused nonparallel shifts, with lower concentrations of ET-1 being antagonized more than higher concentrations. This antagonism with BQ-123 was unaffected by BQ-788 (0.1 microM; n = 6) or by desensitization of ETB receptors with S6c (0.1 microM; n = 8). Blocking the Ca2+ channels with nifedipine (1 microM; n = 5) did not affect the antagonism, nor did denuding the endothelium or leaving the endothelium intact (n = 5). When S6b was used as an agonist, BQ-123 (0.3-3 microM) caused concentration-dependent biphasic shifts, with low concentrations of S6b not being antagonized. In conclusion, the antagonism observed with BQ-123 is not due to the action of ET-1 at ETB receptors, changes in Ca2+ handling, or endothelium. This unusual action of BQ-123 suggests subtypes of the ETA receptor.

Adult↗