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Biomedical subjects

D Felsen

Publications and source records attributed to D Felsen.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effects of temperature on tissue thermal injury and wound strength after photothermal wound closure.

BACKGROUND AND OBJECTIVES: Our goal was to determine the effect of temperature on the induction of tissue damage after laser-welded wound closure with and without albumin solder. STUDY DESIGN/MATERIALS AND METHODS: Multiple full-thickness skin incisions were made in a porcine model. Incisions were repaired by using a 1.32-microm laser at temperatures of 65 degrees C, 75 degrees C, 85 degrees C, or 95 degrees C with and without a 50% human albumin solder. The rate of apoptosis (programmed cell death) was quantified by counting the proportion of cells that stained positively for nuclear DNA fragmentation (nick end labeling). The distance that necrosis extended from the wound edge was also measured. The strength of the weld was measured with a tensiometer. RESULTS: For laser-welded repairs with solder, the amount of apoptosis at 65 degrees C and 75 degrees C was comparable to that of controls but became significantly elevated at 85 degrees C and 95 degrees C. The extent of necrosis was similar to that of controls at low temperature but also increased at 95 degrees C. Incisions repaired without solder showed increased necrosis compared with those repaired with solder at temperatures of 65 degrees C, 75 degrees C, and 95 degrees C at 0-0.5 mm from the incision. Wounds repaired at 85 degrees C and 95 degrees C showed more apoptosis in the absence of solder. The increased cell death at higher temperatures correlated with significantly decreased wound strengths at 3 days after repair in the solder group. A lower rate of cell death was observed in the solder group, which correlated with superior wound strength when compared with repairs without solder at days 0 (65-95 degrees C) and 3 (95 degrees C). CONCLUSION: Both apoptotic and necrotic cell death were used as quantitative measures of tissue injury and were accurate predictors of short-term wound strength. The addition of albumin solder decreased overall tissue injury. These results suggest that temperatures of 65-75 degrees C with solder provide the optimal conditions for maximizing acute wound strength and minimizing tissue injury.

Albumins↗
PubMed1999

Effect of laser welding with human serum albumin on the expression of P-selectin on platelets.

BACKGROUND AND OBJECTIVE: Artery repair by means of laser energy induces activation of platelets with a risk of thrombosis and local inflammatory reactions. The aim of this study was to investigate the effect of human serum albumin, the most common solder in laser surgery, on platelet activation. STUDY DESIGN/MATERIALS AND METHODS: Platelet activation was evaluated in canine blood by using two-color flow cytometry with a phycoerythrin-labeled antibody to a common platelet marker, glycoprotein IIb/IIIa and fluorescein isothiocyanate-labeled antibody to a platelet activation molecule, P-selectin. Human serum albumin was applied in vitro and in vivo, as a solder during laser reconstruction of canine arteries. RESULTS: In vitro, albumin significantly (P < 0.01) reduces the expression of P-selectin on platelets. This is most likely related to the blockage of P-selectin by albumin, which binds to the platelet surface, as confirmed by flow cytometry with fluorescein isothiocyanate-labeled albumin. In vivo, application of albumin solder tended to result in a lower percentage of P-selectin-expressing platelets in laser-repaired arteries compared to suture-repaired arteries. CONCLUSION: Albumin decreases the percentage of P-selectin-expressing platelets in vitro. Further research may allow the platelet activation inhibiting properties of albumin to be further optimized in vivo.

Animals↗
PubMed1999

Altered bladder function in transgenic mice expressing rat elastin.

The elasticity of tissues subjected to repeated deformation is provided by the presence of elastic fibers in the extracellular matrix (ECM). The most abundant component of elastic fibers is elastin, whose soluble precursor is tropoelastin. To establish the role elastin plays in the bladder, this study describes the biosynthetic, histologic, and physiologic consequences of expression of an isoform of rat tropoelastin in transgenic mouse bladder. The polymerase chain reaction (PCR) was used to determine expression of a rat tropoelastin minigene in transgenic mice. Histochemical methods were used to demonstrate changes in elastic fibers in frozen sections of bladder. Cystometric analysis was carried out in transgenic and non-transgenic mice, prior to and after 3 weeks of partial outlet obstruction. The PCR assay demonstrated that bladder tissue of transgenic mice expressed rat tropoelastin mRNA, whereas non-transgenes did not. Increased deposition of elastic fibers was demonstrated with the Verhoeff-van Gieson stain. Bladders of transgenic animals were more compliant than bladders of their non-transgenic littermates. Partial outlet obstruction resulted in increased bladder volume and more compliant bladders in non-transgenic mice. In contrast, the bladder volume and compliance in transgenes was almost unchanged by obstruction. This study demonstrates that normal elastic fiber assembly is prerequisite for the compliant properties of the bladder wall. Moreover, the response of the bladder to obstruction is critically influenced by elastin synthesis.

Animals↗
PubMed1999

BCL-2 and p53 expression in clinically localized prostate cancer predicts response to external beam radiotherapy.

PURPOSE: Clinicians have long been hampered by the inability to distinguish patients with localized prostate cancer who will and will not respond to radiotherapy. In a significant proportion of patients therapy fails as determined by increasing posttreatment serum prostate specific antigen (PSA). We evaluated the expression of 2 key regulators of apoptosis, bcl-2 and p53, relative to treatment outcomes in patients who received external beam radiotherapy for clinically organ confined carcinoma of the prostate. MATERIALS AND METHODS: Immunohistochemical staining for bcl-2 and p53 on pretreatment needle biopsies was performed in 54 patients who were treated with radiotherapy for localized prostate cancer. Expression was scored using strict criteria. Nadir PSA less than 1 ng./ml. after therapy was considered a successful treatment response. RESULTS: There was a predominance of stage T1c cancer (74%) with a mean Gleason score of 6.9 and an average pretreatment PSA of 25.3 ng./ml. Overall 54% of the patients did not have a nadir PSA of less than 1 ng./ml. Of the bcl-2 positive cases therapy ultimately failed in 85%. Similarly 88% of the patients with p53 positive biopsies had treatment failure and in all with bcl-2 as well as p53 expression radiotherapy failed. Expression of bcl-2 and p53 was an independent prognostic variable for treatment failure with odds ratios (95% confidence interval) of 7.3 and 10.8, respectively. CONCLUSIONS: Expression of bcl-2 and p53 was associated with treatment failure after external beam radiation therapy. These findings suggest that bcl-2 and p53 expression in pretreatment biopsies may be helpful for predicting response to definitive radiotherapy.

Adenocarcinoma↗
PubMed1998

Transforming growth factor-beta receptor types I and II are expressed in renal tubules and are increased after chronic unilateral ureteral obstruction.

Transforming growth factor-beta (TGF-beta) is a profibrotic cytokine which has been implicated in the renal fibrosis which follows unilateral ureteral obstruction (UUO) in the rat. TGF-beta receptor type I (TGF-RI) and TGF-beta receptor type II (TGF-RII) are part of the complex which mediates the response to TGF-beta. We sought to determine if TGF-RI and TGF-RII are found in the kidney, and if their expression is changed as a result of UUO. Polymerase chain reaction (PCR) was used to determine expression of mRNA for TGF-RI and TGF-RII in the kidney. Immunoperoxidase was used to localize and quantify the expression of these receptors at 3, 7, 14, 21 and 28 days after UUO, and in sham-operated animals. Expression of mRNA for TGF-RI and TGF-RII was demonstrated in sham operated, obstructed and contralateral unobstructed kidneys using PCR. Using immunoperoxidase, a uniform distribution of TGF-RI and TGF-RII was found in cortical tubules of sham operated kidneys, whereas medullary tubules showed a patchy TGF-RI distribution and no TGF-RII staining. After UUO, an increased tubular expression of TGF-RI and TGF-RII was noted in both obstructed and contralateral kidneys compared to sham operated kidneys. No staining for either TGF-RI or TGF-RII was noted in glomeruli, vasculature or interstitial cells. TGF-beta receptors I and II were found exclusively in renal tubules and were shown to increase in both the obstructed and contralateral kidneys relative to sham operated animals. Upregulation of TGF-beta receptors in both kidneys suggests that TGF-beta may contribute to the fibrotic response in the obstructed kidney and the hypertrophic response of the contralateral kidney.

Actins↗
PubMed1997

In vivo cystometric evaluation of progressive bladder outlet obstruction in rats.

PURPOSE: Bladder outlet obstruction in man is a common medical disorder that may result from benign prostatic hyperplasia, urethral stricture disease, or congenital anomaly. The functional changes that develop in response to obstruction include detrusor instability, elevated voiding pressures, and the presence of a residual urine. The aim of this study was to document the development of progressive bladder outlet obstruction over time in a rat model using conscious, in vivo urodynamics. MATERIALS AND METHODS: Infravesical bladder outlet obstruction was created in female rats by placing a jeweler's jump ring loosely around the proximal urethra. Gradual development of outlet obstruction was followed urodynamically in awake animals at 3, 7, 14, 21, and 28 days post obstruction using a subcutaneously implanted mediport. For each group n = 5-8 animals. RESULTS: Animals developed large capacity bladders with increased compliance, a high residual urine volume, and spontaneous activity. Bladder capacity increased from 0.20 + 0.02 ml. to 6.30 + 1.59 ml. at 28 days post obstruction (p < 0.05). Residual volume increased from 0.06 + 0.01 ml. to 5.95 + 1.54 ml. (p < 0.05). Percent void decreases from 72 + 3.7% in sham controls to 6.7 + 2.5% at 28 d (p < 0.05). Voiding pressure increased from 12 + 1.6 mm. Hg in sham animals to a maximum of 42 + 6.1 mm. Hg at 21 d (p < 0.05). Compliance was significantly higher at 28 d when compared to all other time points. 89% of obstructed animals developed bladder instability. CONCLUSIONS: This study provides clear evidence of the progressive change in bladder function which occurs following outlet obstruction. Implantation of a subcutaneous mediport allows in vivo recording of both the filling and voiding phases of micturition in awake animals that have intact neural responses. This is a precise and easily reproducible method for producing obstruction in a small animal which can provide a continuum of tissue and urodynamic data that may be used to further study the pathophysiologic changes underlying bladder outlet obstruction or other models of bladder dysfunction.

Animals↗
PubMed1996

Expression of I2-imidazoline sites in rat prostate. Effect of castration and aging.

Clonidine, idazoxan, and related imidazoline adrenergic drugs bind to non-adrenergic sites in brain and several peripheral tissues. These sites, termed imidazoline receptors, appear to exist in two major subclasses, I1 sites labeled by clonidine and I2 sites labeled by idazoxan. In this study, we investigated whether rat prostate expresses imidazoline receptors and, if so, whether their expression can be regulated by circulating testosterone. Studies in rat ventral prostate membrane revealed that [3H]idazoxan, but not [3H]p-aminoclonidine, bound to non-adrenergic sites. The binding of [3H]idazoxan was saturable (Bmax: 941 +/- 105 fmol/mg protein) and high affinity (KD: 16.4 +/- 2.3 nM). The rank order of the inhibition of binding by imidazoline ligands was cirazoline > clonidine > UK 14,304 > guanabenz, indicating an I2 subclass of imidazoline receptors. Bilateral orchiectomy increased the number of binding sites (Bmax) for [3H]idazoxan without changing the affinity (KD). Testosterone replacement, while completely restoring the plasma testosterone levels, only partially reversed the increase in Bmax. In contrast, the binding of [3H]idazoxan to prostate membranes of rats in different age groups (4, 7, and 16 months) revealed a progressive decrease in the Bmax without any change in KD. We conclude that the rat prostate expresses the I2 subclass of imidazoline receptors and that the expression is regulated by circulating testosterone.

Adrenergic Agonists↗
PubMed1996

Chronic unilateral ureteral obstruction is associated with interstitial fibrosis and tubular expression of transforming growth factor-beta.

Chronic unilateral ureteral obstruction (UUO) results in interstitial fibrosis and nephron damage associated with irreversible loss of function. Collagen is increased in UUO, but detailed studies of rat renal extracellular matrix changes in UUO have not been carried out. Acute (3-day) obstruction results in increases in renal macrophages and the fibrogenic cytokine transforming growth factor-beta (TGF-beta), but their involvement in longer-term obstruction and fibrosis has not been studied. In the present experiments, kidneys of rats after UUO of 1, 2, 3, 7, 14, 21, and 28 days' duration were used. Trichrome staining, measurement of interstitial volume, and immunohistochemical studies localizing collagens I, III, and IV; laminin; fibronectin; TGF-beta; and macrophages were carried out. We found increases in the interstitial space in both cortex and medulla that (a) were significant by day 7 after UUO and (b) were accompanied by increased deposition of collagen I and collagen III. Collagen IV, laminin, and fibronectin, normally associated with the basement membrane, were found both in a thickened basement membrane and in the interstitial space. Macrophages, not found in sham-operated kidneys, were found in the interstitial space after UUO. TGF-beta was found in sham cortical tubules, but not in medullary tubules. UUO was associated with little change in cortical TGF-beta, whereas at 14 days, TGF-beta was found in dilated medullary tubules. Immunohistochemical findings were confirmed with measurements of tissue TGF-beta. In summary, UUO is associated with interstitial fibrosis. The increase in extracellular matrix is due both to increases in the interstitial collagens I and III and the basement membrane-associated collagen IV, laminin, and fibronectin. Macrophages are increased after UUO, but do not seem to be associated with the fibrogenic cytokine TGF-beta. Medullary tubular synthesis of TGF-beta may be a contributing factor in the fibrosis associated with UUO.

Animals↗
PubMed1994

The metabolic effects of platelet-activating factor antagonism in endotoxemic man.

OBJECTIVE: To determine if the inflammatory phospholipid platelet-activating factor (PAF) participated in the symptomatologic, metabolic, and counterregulatory hormonal responses of human endotoxemia. DESIGN: In a double-blind, placebo-controlled study, five subjects received 10 mg of the PAF antagonist Ro 24-4736 orally, while five control subjects received a placebo. Eighteen hours later, all subjects were administered 4 ng/kg of endotoxin (lipopolysaccharide) intravenously. SETTING: The Clinical Research Center of The New York Hospital-Cornell Medical Center. PARTICIPANTS: Healthy male volunteers. MAIN OUTCOME MEASURES: Repeated measurements of vital signs, symptoms, cytokine and hormone levels, resting energy expenditure, platelet aggregation, and bleeding times were performed during a 24-hour period. RESULTS: Subjects who were pretreated with the PAF antagonist experienced fewer symptoms, including rigors at 1 hour (P < .05) and myalgias at 1 through 4 hours (P < .05) after administration of lipopolysaccharide. This was in concert with a diminished peak cortisol level (668 +/- 107 vs 959 +/- 159 nmol/L in controls; P < .05), epinephrine secretion (1057 +/- 165 vs 2029 +/- 431 nmol/L in controls; P < .05), and almost complete inhibition of PAF-induced platelet aggregation ex vivo. CONCLUSIONS: These findings in the face of unaltered circulating cytokines tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6, as well as the tumor necrosis factor receptor-I s, suggest that PAF may influence some endotoxin-induced, counterregulatory hormonal responses and symptoms through cytokine-independent mechanisms. This study further supports the role of PAF antagonists as an adjunct to cytokine blockade in the treatment of gram-negative sepsis.

Adult↗
PubMed1994

Inflammatory mediator profile in urine and bladder wash fluid of patients with interstitial cystitis.

Interstitial cystitis is a syndrome of urinary urgency, frequency and suprapubic pain. We investigated the role of inflammatory mediators in 96 patients with histories and symptoms consistent with interstitial cystitis, and 13 controls from The New York Hospital-Cornell Medical Center, University of Washington and University of California at San Diego. Patients were classified into either group A (meets all criteria of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases for inclusion in research studies), group B (meets all of these criteria but without glomerulations) or an "other" group. A small number of group A patients had detectable interleukin-6 in the urine. Urinary concentrations of tumor necrosis factor, prostaglandins E2, D2 and F2 alpha, and thromboxane B2 were not different among either patient groups or controls. Urine specimens contained inhibitors of the bioactivity of interleukin-6 and tumor necrosis factors but no differences between patients or controls were found. No factors chemotactic for human neutrophils were detected in a small patient sample. Bladder wash fluid concentrations of prostaglandins E2, D2 and F2 alpha, and thromboxane were much lower than urinary levels. Bladder wash fluid interleukin-6 and tumor necrosis factor were not detectable. The results suggest that while a small subset of patients may have elevated levels of interleukin-6 the majority of patients do not appear to have elevated levels of inflammatory mediators in the urine or bladder wash fluid. Evaluation of patient bladder tissue may indicate changes not detectable in urine or bladder wash fluid. Alternatively, other etiologies must be considered in those patients.

Adult↗
PubMed1994

Identification, localization and functional analysis of imidazoline and alpha adrenergic receptors in canine prostate.

In nonsurgical management of benign prostatic hyperplasia, drugs which interfere with prostate contraction mediated through the alpha-1 adrenergic receptor are used. Clonidine acts at alpha adrenergic and I1-imidazoline receptors. In the present study, we found the Kd for [3H]clonidine binding to I1 sites in canine prostate to be 4 +/- 1 nM; the Bmax was 18 +/- 2 fmol/mg of protein. Inhibition of binding by imidazolines and by brain extracts containing putative endogenous ligand confirmed the identity of these sites as I1-imidazoline. Autoradiographic studies showed localization of both I1 and alpha-2 sites to the glandular epithelium. We sought to determine whether in vivo activation of the I1-imidazoline sites by clonidine mediates its contractile action in canine prostate. Dose-response curves were generated for para-aminoclonidine in the presence of vehicle alone, yohimbine (alpha-2 antagonist), idazoxan (alpha-2/I1/I2 antagonist) and prazosin (alpha-1 antagonist). Prazosin was the most effective antagonist. Yohimbine was less effective and did not effectively discriminate between para-aminoclonidine and phenylephrine, an alpha-1-selective agonist. Idazoxan antagonized para-aminoclonidine, but by not more than 50% at any dose. These results suggest that clonidine is active primarily at alpha-1 receptors on prostate smooth muscle in vivo. Thus the function of the I1 and alpha-2 receptors in the prostate remains to be determined; however, they may be involved in epithelial cell function.

Animals↗
PubMed1993

Medical management of benign prostatic hyperplasia: a canine model comparing the in vivo efficacy of alpha-1 adrenergic antagonists in the prostate.

Medical management of benign prostatic hyperplasia (BPH) is an alternative to surgical treatment of this disease. A major target for pharmacologic therapy is the alpha-1 adrenergic receptor, since activation of this receptor by endogenous catecholamines is thought to contribute to outlet obstruction. In the present study, we compared the potency of various alpha-1 adrenergic antagonists against epinephrine-induced contraction of the canine prostate. The drugs tested were dibenzyline, prazosin, terazosin and YM617. The rank order of potency, comparing inhibitory constants (Ki's), was found to be YM617 >> prazosin > terazosin > dibenzyline. This study is the first to compare all of these drugs directly in the prostate in vivo. The rank order of potency of the drugs is similar to the rank order of potency at other alpha-1 receptors. These results demonstrate that 1) our model is useful in confirming activity of drugs at the alpha-1 receptor and 2) the prostate alpha-1 receptor is similar to other alpha-1 receptors. Whether activity at the alpha-1 adrenergic receptor is a sufficient determinant of clinical efficacy of these drugs remains to be determined.

Adrenergic alpha-Antagonists↗
PubMed1993

Toradol, an NSAID used for renal colic, decreases renal perfusion and ureteral pressure in a canine model of unilateral ureteral obstruction.

Toradol is a new parenteral, nonsteroidal anti-inflammatory drug which is efficacious in treating renal coli. In the present experiments, Toradol was administered to both control dogs and dogs with unilateral ureteral obstruction. In control dogs, Toradol had no effect on RBF or GFR, despite inhibition of renal prostaglandin synthesis (measured as urinary prostaglandin release). In contrast, RBF fell acutely by 35% (p < 0.001) within 15 minutes of Toradol administration in the setting of ureteral obstruction; contralateral RBF was unaffected. Ipsilateral ureteral pressure also fell. Changes in RBF and ureteral pressure, together with the known effects of NSAIDs on pain pathways, may contribute to the pain relief observed clinically with Toradol. However, the abrupt changes in renal hemodynamics brought on by Toradol to the obstructed kidney may compromise renal reserve, and Toradol should be used cautiously in treating renal colic.

Animals↗
PubMed1992

Evidence for a bioactive clonidine-displacing substance in peripheral tissues and serum.

Clonidine-displacing substance (CDS) from brain is biologically active in the kidney and stomach and on platelets. To determine whether CDS is contained in these and other peripheral tissues, homogenates of fresh brain, eight other organs and serum from rat were ultrafiltered (less than 10,000 mol. wt only), dried and extracted with methanol. Evaluation by radioimmunoassay (RIA) using antibodies to p-aminoclonidine showed that adrenal gland and gastric fundus (GF) contained significantly greater amounts of CDS-like radioimmunoactivity than brain; intermediate-to-low activity was present in heart, small intestine, serum, kidney and liver; lung and skeletal muscle values were near-background. RIA-positive extracts elicited well-correlated contractile activity in a GF smooth muscle bioassay; contractions persisted in the presence of antagonists of various transmitters and modulators, but were abolished by low concentrations of the calcium channel blocker verapamil. Serum levels of CDS were profoundly reduced following removal of the adrenal glands. We conclude that a CDS-like substance is present not only in brain as previously reported, but also in peripheral organs and in the circulation.

Adrenal Glands↗
PubMed1990

Identification of a novel tumor necrosis factor alpha/cachectin from the livers of burned and infected rats.

Tumor necrosis factor alpha (TNF-alpha)/cachectin is a monocyte/macrophage-derived cytokine implicated as a proximal mediator of many of the catastrophic host responses to infection or endotoxin. However, circulating levels of TNF-alpha/cachectin have only been episodically detected in hospitalized patients with life-threatening bacterial infections. In the present report, increased quantities of immune-reactive TNF-alpha/cachectin were recovered from the livers of rats 3 days following a lethal burn and infection. Two species of TNF-alpha/cachectin were detected, one of approximately 29 kd and the other 17 kd, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In murine peritoneal macrophages and rat Kupffer cells stimulated in vitro with endotoxin, a 29-kd cell-associated and 17-kd secreted form were also detected. We conclude that the increased appearance in vivo of a 29-kd form of TNF-alpha/cachectin from the livers of lethally burned and infected rats represents a novel cell-associated form of the protein.

Animals↗