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Biomedical subjects

R E Smith

Publications and source records attributed to R E Smith.

At least 127 records · Page 7Linked to original sources
PubMed1995

The human 11 beta-hydroxysteroid dehydrogenase type II enzyme: comparisons with other species and localization to the distal nephron.

Effective glucocorticoid inactivation is currently thought to be an indispensable feature of mineralocorticoid target cells. The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) inactivates glucocorticoids and prevents them from binding to the non-selective mineralocorticoid receptor. In the kidney it is the NAD dependent high affinity isoform (11 beta-HSD2) which is thought to endow specificity on the receptor. The recent cloning of the human, sheep and rabbit 11 beta-HSD2 enzymes permits a comparison of the enzyme from the three species. Human and rabbit enzymes are 87% identical and of similar length, while the human and sheep enzymes have only 75% identity. The last 12 residues in all three species were found to be highly divergent, but most of the ovine dishomology can be accounted for by the deletion of a single nucleotide toward the C-terminus of the protein resulting in a shift in reading frame generating a protein 27 residues longer than the human isoform. Numerous other deletions were also observed in this region of the sheep cDNA sequence. Furthermore, the rabbit cDNA also displayed a large degree of dishomology with the human sequence a short distance downstream from the termination codon. Conserved overlapping cytoplasmic translocation signals were observed in all three species, suggesting a topology whereby the enzyme is anchored into the endoplasmic reticulum by multiple hydrophobic regions in the N-terminus and the bulk of the 11 beta-HSD2 peptide is sited in the cytoplasm. A polyclonal antibody generated against the C-terminus of human 11 beta-HSD2 was used to localize the enzyme within the kidney. A high level of immunoreactive was observed in distal tubules and collecting ducts, localizing the enzyme to the same part of the nephron as the mineralocorticoid receptor. Moderate levels of staining were also seen in vascular smooth muscle cells. These results support the notion that 11 beta-HSD2 is an autocrine protector of the mineralocorticoid receptor and that it plays an important role in cardiovascular homeostatic mechanisms.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Clinicopathologic study of retinal and choroidal biopsies in intraocular inflammation.

PURPOSE: We reviewed the clinical and histopathologic features of 33 intraocular tissue biopsy specimens from 32 patients and assessed the value of retinal and chorioretinal biopsies performed in patients with intraocular inflammation. METHODS: Twenty-four endoretinal biopsies and nine chorioretinal or choroidal biopsies were performed. On the basis of clinical indications, the specimens were processed for light microscopy, electron microscopy, immunohistochemical staining, in situ DNA hybridization, and polymerase chain reaction. RESULTS: Of the 24 endoretinal biopsy specimens, 19 were from patients with clinical signs suggestive of viral retinitis. Overall, the diagnosis of viral retinitis was suggested by electron microscopy, immunohistochemical staining, in situ DNA hybridization, or polymerase chain reaction in 53% (ten of 19) biopsies. The preoperative diagnosis was confirmed in seven of ten biopsies in cases of suspected cytomegalovirus retinitis, in one of seven biopsies in cases of suspected acute retinal necrosis, and in two of two biopsies in cases of progressive outer retinal necrosis. The remaining five endoretinal biopsies disclosed Candida in one specimen, subretinal fibrosis in one, and chronic inflammation in three. Histologic examination of the nine chorioretinal or choroidal biopsies disclosed lymphoma in two specimens, a subretinal neovascular membrane in one, uveal melanocytic proliferation in one, toxoplasmic retinochoroiditis in one, viral retinitis in one, and long-standing inflammation in three. CONCLUSION: In select cases of intraocular inflammation, intraocular tissue biopsies may provide clinically useful information.

Adolescent↗
PubMed1995

Microorganisms cultured from the anterior chamber of ruptured globes at the time of repair.

PURPOSE: We studied events leading to the development of posttraumatic endophthalmitis by examining the significance of 15 factors on microbial contamination of injured eyes. METHODS: A prospective study was done of 30 ruptured globes in patients admitted to an urban medical center. Cultures were taken from the conjunctiva before and after preoperative disinfection and from the anterior chamber at the beginning and end of wound repair. Twenty-five of 30 patients received a three-day regimen of intravenous antibiotics that were begun before surgery. RESULTS: Anterior chamber samples grew microorganisms in ten (33%) of 30 eyes, with positive cultures recovered from specimens taken at the beginning of wound repair in eight eyes and at the end of wound repair in six eyes. Contamination with indigenous flora may have occurred at the time of injury in one eye and during repair in another eye. Microbes recovered included Staphylococcus, Corynebacterium, and Aspergillus species. No patient developed endophthalmitis. Of the 15 factors studied, only intravenous antibiotics significantly decreased the incidence of positive anterior chamber cultures in eyes treated before wound repair compared with eyes not receiving such therapy (P = .002). CONCLUSIONS: Despite the frequency of anterior chamber microbial contamination during injury or repair of the wound, with our treatment protocol and the presence of physiologic mechanisms to reduce intraocular microbes, no eyes developed clinical endophthalmitis. With our limited sample size only intravenous antibiotic therapy was found significantly to reduce anterior chamber microorganisms at the time of surgical repair, supporting their prophylactic use against the development of posttraumatic endophthalmitis.

Adult↗
PubMed1995

Stevens-Johnson syndrome associated with methazolamide treatment reported in two Japanese-American women.

BACKGROUND: Systemic acetazolamide treatment has been reported in association with Stevens-Johnson syndrome (SJS). This is the first report of this syndrome associated with methazolamide treatment. The association is reported in two Japanese-American women. METHOD AND RESULTS: Two patients with SJS, which developed during treatment with methazolamide, are described. Other potential associations are discussed. CONCLUSIONS: Systemically administered carbonic anhydrase inhibitors, including both acetazolamide and methazolamide can be associated with SJS.

Adult↗
PubMed1995

Ocular manifestations of AIDS.

AIDS causes severe depression of the immune system through selective infection of CD4+ T lymphocytes. As such, certain infections and neoplasms occur in these patients often with ocular involvement. Among these, cytomegalovirus retinitis is by far the most common and remains a leading cause of visual loss. Intravenous ganciclovir and foscarnet, the two Food and Drug Administration-approved treatments for cytomegalovirus retinitis, are effective in most cases, but recurrences are the rule. In addition, these virustatic drugs require lifelong administration and dose-limiting toxicity affects many of these patients. Ongoing investigation into current and alternative therapies has produced some promising developments which are discussed here. Also reviewed are recent findings associated with other opportunistic pathogens and neoplasms that affect the eye in AIDS, including varicella-zoster virus, Toxoplasma gondii, and lymphoma.

AIDS-Related Opportunistic Infections↗
PubMed1995

Analysis of responses to kallidin, DABK, and DAK in feline hindlimb vascular bed.

Responses to kallidin, des-Arg9-bradykinin (DABK), and des-Arg10-kallidin (DAK) were investigated in the hindlimb vascular bed of the cat under constant-flow conditions. Injections of kallidin, DABK, and DAK into the hindlimb perfusion circuit produced dose-dependent vasodilator responses in the hindlimb vascular bed. Vasodilator responses to kallidin and bradykinin (BK) were similar in magnitude and time course, and both peptides were approximately 100-fold more potent than DABK or DAK. Responses to kallidin were decreased by the kinin B2 antagonist, HOE 140, whereas responses to DABK and DAK were reduced by des-Arg9[Leu8]BK, a kinin B1-receptor antagonist. N omega-nitro-L-arginine methyl ester (L-NAME) reduced vasodilator responses to kallidin, DABK, and DAK, whereas meclofenamate, atropine, and U-37883A, a vascular selective ATP-sensitive K+ (K+ATP) channel-blocking agent, did not alter responses to the three peptides. These data suggest that both kinin B1 and B2 receptors are normally present in the hindlimb vascular bed. These data also suggest that kinin B1 and B2 receptor-mediated vasodilator responses are mediated by the release of nitric oxide and that the activation of K+ATP channels or muscarinic receptors, or the release of vasodilator prostaglandins play little if any role in mediating responses to kallidin, DABK, or DAK in the hindlimb vascular bed of the cat.

Adamantane↗
PubMed1995

Immunohistochemical localization of the 11 beta-hydroxysteroid dehydrogenase type II enzyme in human kidney and placenta.

It has been proposed that the inactivation of glucocorticoids by the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) is an obligatory step in the kidney, permitting binding of aldosterone to the mineralocorticoid receptor, and in the placenta, protecting the fetus from high circulating levels of maternal glucocorticoids. Both low and high affinity isoforms of 11 beta HSD are known to exist, with evidence accumulating that the former species (11 beta HSD1) does not fulfill criteria that would allow it to perform these physiological functions. We have recently cloned a high affinity isoform of the enzyme (11 beta HSD2) from a human kidney library and have shown this species to possess all of the characteristics predicted from whole cell studies. In the present study we have raised a polyclonal antibody (HUH23) to a synthetic peptide deduced from the carboxy-terminus of the protein. The immunopurified antibody recognized a single band at 41,000 daltons on Western blots of mammalian cells transfected with an expression plasmid containing 11 beta HSD2, slightly smaller than the predicted 44,140 daltons protein. A single band of identical size was also seen in blots of human kidney and placenta, suggesting post-translational processing of the enzyme. Immunohistochemical studies on frozen sections of human kidney showed strong 11 beta HSD2 immunoreactivity in the cortical distal convoluted tubules and collecting ducts. Strong staining was also observed in medullary tubules, which had the appearance of collecting ducts and the thick ascending limb of Henle's loop. Staining of medium intensity was observed in vascular smooth muscle cells. Epithelial cells of glomeruli showed weak but detectable reactivity with HUH23. In the placenta, HUH23 antibody immunoreactivity was restricted to syncytial trophoblast cells in which strong staining was observed. These results suggest that the 11 beta HSD2 enzyme colocalizes with the mineralocorticoid receptor in the distal nephron where it allows aldosterone to occupy its physiological receptor. Furthermore, 11 beta HSD2 is also ideally situated in the placenta to protect the fetus from high circulating levels of maternal glucocorticoids.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Insulin-like growth factor-I promotes cell proliferation in the absence of modulation of collagen phenotypes and utilizes IRS-1, not PLC-gamma 1, in corneal endothelial cells.

Corneal endothelial cells are differentiated cells and are thus incapable of physiologic regeneration. In a search for a growth factor that would promote optimal proliferation of corneal endothelial cells in the absence of other modulating activities, the effect of insulin-like growth factor-I (IGF-I) on rabbit corneal endothelial cells was studied. In addition, cellular effector molecules responsible for the signal pathway for IGF-I were studied. IGF-I at 50 ng/ml stimulated corneal endothelial cell proliferation after at least 8 h of treatment. IGF-I did not change cell shape of corneal endothelial cells: the cells treated with IGF-I at 50 ng/ml maintained polygonal morphology regardless of the duration of exposure. IGF-I did not alter collagen phenotypes either qualitatively or quantitatively: the treated cells continued to synthesize types IV and VIII collagen, as did the control cells. The steady-state levels of alpha 2(I) collagen RNA and alpha 2(IV) RNA were not altered by IGF-I treatment. Immunohistochemical analysis showed that IGF-I is present in corneal endothelium in vivo, while the underlying Descemet's membrane demonstrated no staining. Corneal endothelial cells also produce IGF binding protein-2 (IGFBP-2), which appears to bind IGF-I that has been introduced exogenously in the medium. Further investigation as to how the signals of IGF-I were transmitted for the biological activities demonstrated that the expression of insulin receptor substrate-1 (IRS-1) is up-regulated by IGF-I treatment, while PLC-gamma 1 expression is not altered by this growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Chronic blepharitis: a review.

Although blepharitis is one of the most common ocular disorders encountered in clinical practice, it may constitute a diagnostic and therapeutic enigma. Attempts to classify this disorder are difficult because of the complex mechanisms underlying its pathogenesis. Clinical and laboratory investigations have clearly established bacteria and meibomian gland abnormalities as major etiologic determinants. In addition, changes in tear film dynamics and underlying dermatologic abnormalities appear to contribute to pathogenesis. The clinical manifestations primarily occur along the lid margin, and the predominant symptoms are itching and burning. Currently there is no cure for this condition. In the case of staphylococcal blepharitis, for example, there is no long-term cure because patients are likely susceptible to the causative organism(s), and thus become reinfected. Therapy is aimed then at bringing the disease process under control. A therapeutic regimen consisting of lid hygiene, topical or systemic antibiotics, and tear replacement seems to be most effective in alleviating symptoms and maintaining disease control but requires prolonged treatment.

Bacteria↗
PubMed1995

A phase II trial of paclitaxel in squamous cell carcinoma of the head and neck with correlative laboratory studies.

Head and neck cancer is a major cause of cancer-related deaths. In general, early stage head and neck cancers are effectively treated with either radiation or surgery. More advanced tumors often require combined-modality therapy with both radiation therapy and surgery. Recent investigations indicate that the addition of chemotherapy may be helpful. One of the newer chemotherapy agents that appears to have significant activity against head and neck cancer is paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). Paclitaxel, originally derived from the western yew Taxus brevifolia, acts by increasing the stability of microtubules and preventing mitosis. Recent evidence indicates that the microtubule system is vital to the release of various cytokines and that modulation of cytokine release may play a major role in the drug's antitumor activity. We report a phase II trial of paclitaxel in patients with head and neck cancer, not only to evaluate its clinical effects, but also to study its effect on cytokine release. We assessed interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha production by using a sensitive enzyme-linked immunosorbent assay to assess the serum of patients receiving paclitaxel and to detect cytokine release in vitro. The objective response rate was 36%, with 12% complete responses and 24% partial responses. No IL-1 beta or tumor necrosis factor-alpha was detected in patient serum at any time during the infusion of paclitaxel or after overnight incubation with patient monocytes. No proIL-1 beta was detected in in vitro cultures of paclitaxel-treated patient monocytes. When monocytes were stimulated with endotoxin, IL-1 beta production was greatest at 48 hours, suggesting that paclitaxel can prime cells to produce greater quantities of cytokines after a second stimulus.

Adult↗
PubMed1995

Endoscopic evaluation of iron deficiency anemia. A guide to diagnostic strategy in older patients.

Gastrointestinal blood loss is the primary cause of iron deficiency anemia in older adults. Bidirectional endoscopy (combined colonoscopy and esophagogastroduodenoscopy) is highly sensitive and specific in its ability to locate gastro-intestinal lesions resulting in iron deficiency anemia. Although the diagnostic yield of esophagogastroduodenoscopy is higher than that of colonoscopy, the possibility of malignant disease dictates that initial colonoscopy be performed in all but a few cases involving distinct upper gastrointestinal risk factors and symptoms. If neither colonoscopy nor esophagogastroduodenoscopy identifies a source of blood loss, a safe course is to observe the patient and provide supplemental iron. Patients who fail to respond to supplemental iron or who become transfusion-dependent require further evaluation. Small-bowel evaluation has a role in selected patients.

Aged↗
PubMed1995

Changing indications for penetrating keratoplasty, 1989-1993.

The purpose of this study was to identify new trends in the changing indications for penetrating keratoplasty. We retrospectively reviewed the clinical and pathologic diagnoses of 1,104 corneal buttons that had been submitted to the Estelle Doheny Eye Pathology Laboratory, Los Angeles, during the 5-year period 1989-1993. The leading indications, in order of decreasing frequency, were pseudophakic corneal edema (24.8%), regrafts (21.3%), scarring with or without chronic inflammation (11.1%), keratoconus (7.1%), aphakic corneal edema (6.4%), and ulcerative conditions (5.8%). The incidence of pseudophakic corneal edema remained stable over the study period and was actually surpassed by regraft in the last year of the study. Although pseudophakic corneal edema remains the predominant indication for penetrating keratoplasty, our findings suggest that its occurrence rate has begun to level off.

Adolescent↗
PubMed1995

Determinants of blood pressure in Sowetan infants.

A study of the effect of different variables on the blood pressure of Sowetan infants was undertaken with the Birth-to-Ten (BTT) cohort as the study population. Variables studied at 1 year included anthropometric indices, aspects of feeding practices and relationship to maternal blood pressure. Systolic blood pressure was recorded in 792 infants at 1 year; 29,3% of the variance was determined by weight, upper arm circumference, age at which formula feeds were started, length and volume of formula feeds (in order of significance). Amount of salt added to diet approached statistical significance. Data available for 353 of the 752 infants showed a correlation between the infants' and the mothers' blood pressure. The maternal blood pressure only accounted for an additional 2% of the variance; approximately 70% of blood pressure variance is therefore still unexplained. Firm recommendations with regard to use of formula feeds and the addition of salt to infants' diet are difficult to make on the basis of this limited follow-up.

Anthropometry↗
PubMed1994

Inhibition of platelet activity by S-nitrosoglutathione during coronary angioplasty.

Platelet activation is associated with acute vessel occlusion and chronic restenosis after percutaneous transluminal coronary angioplasty (PTCA). Organic nitrates, which act by releasing the vasodilator and anti-platelet agent nitric oxide (NO), have a predominantly vasodilator action and cause hypotension at doses required to inhibit platelet activation. S-nitrosoglutathione (GSNO) is an NO donor with a preferential action on platelets. We investigated platelet activation in patients undergoing PTCA and the effect of GSNO. Blood was sampled from the coronary sinus to measure platelet surface expression of P-selectin and glycoprotein IIb/IIIa as indices of platelet activation. In 7 control patients, PTCA caused a rise in platelet surface expression of P-selectin and glycoprotein IIb/IIIa, which was maximal 5 minutes after PTCA, indicating increased platelet activation despite treatment with aspirin, glyceryl trinitrate, and heparin. 6 patients received an intracoronary infusion of GSNO, starting 10 min before PTCA. GSNO significantly inhibited the PTCA-induced increase in platelet surface expression of P-selectin and glycoprotein IIb/IIIa without altering blood pressure. These findings show that platelets are activated following PTCA and that GSNO can prevent this activation.

Aged↗
PubMed1994

Production and function of murine macrophage inflammatory protein-1 alpha in bleomycin-induced lung injury.

We investigated the role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in bleomycin-induced lung injury, a model of interstitial lung disease. Bleomycin stimulates a T cell-dependent pulmonary inflammatory response characterized by an increase in leukocyte infiltration, fibroblast proliferation, and collagen synthesis. Intratracheal challenge of CBA/J mice with bleomycin resulted in a significant time-dependent increase in MIP-1 alpha protein levels both in whole-lung homogenates and bronchoalveolar lavage fluid. The kinetics of MIP-1 alpha expression were biphasic, with the first peak occurring at 2 days postinstillation and the second peak at 16 days. These levels of Ag expression temporally correlated with the accumulation of granulocytes, lymphocytes, and mononuclear phagocytes in the lung. In addition, immunohistochemical staining identified alveolar macrophages and bronchial epithelial cells as the primary cellular sources of MIP-1 alpha production. Interestingly, passive immunization of bleomycin-challenged mice with anti-MIP-1 alpha Abs significantly reduced pulmonary mononuclear phagocyte accumulation and fibrosis. These experiments establish that MIP-1 alpha protein is expressed in the lungs of bleomycin-treated mice and provide evidence that MIP-1 alpha promotes leukocyte accumulation and activation. Furthermore, these findings support the notion that leukocyte accumulation and activation are linked to fibrosis.

Animals↗
PubMed1994

Dipeptide phosphonates as inhibitors of dipeptidyl peptidase IV.

A series of dipeptides which contained phosphonate analogs of proline and piperidine-2-carboxylic acid (homoproline) have been synthesized and tested as inhibitors of DPP-IV. The rates of inhibition of DPP-IV by these compounds are moderate, but the inhibitors are quite specific. The best inhibitor in the series is Ala-PipP(OPh-4-Cl)2 (13), which has a k(inact) of 0.353 s-1 and KI of 236 microM. The DPP-IV inhibitors Ala-ProP(OPh)2 (6), Ala-ProP(OPh-4-Cl)2 (12), and Ala-PipP(OPh-4-Cl)2 (13) do not inhibit trypsin, human leukocyte elastase (HLE), porcine pancreatic elastase (PPE), acetylcholinesterase, papain, and cathepsin B. However, compounds 12 and 13 inhibited chymotrypsin slowly. Most of these dipeptides containing a homoproline phosphonate residue (PipP) or a Pro phosphonate residue (ProP) at the P1 site are stable in a pH 7.8 buffer with half-lives of several hours to several days. DPP-IV inhibited by 6, 7 (Ala-PipP(OPh)2), 12, or 13 is quite stable, and no enzyme activity was recovered after removal of excess inhibitor and incubation in buffer for 1 day. Since the phosphonate inhibitors are specific toward DPP-IV and the inhibited enzymes are stable, they should be useful in establishing the biological functions of DPP-IV and may be useful therapeutically in the prevention of the rejection of transplanted tissue.

Buffers↗