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Biomedical subjects

W Bowers

Publications and source records attributed to W Bowers.

At least 19 recordsLinked to original sources
PubMed2001

Ultrastructural and histological effects of exposure to CEES or heat in a human epidermal model.

Ultrastructural and terminal deoxynucleotidyl transferase nick end labeling (TUNEL) studies were conducted to compare mechanisms of 2-chloroethyl ethyl sulfide (CEES) and heat-induced injury to EpiDerm. Twenty-two hours after 2-h exposure to the monofunctional alkylating agent CEES, budding of cytoplasm, clumping of nuclear chromatin, disintegration of nuclear membranes and cytoplasmic structures, and cytoplasmic vacuolization were detected, especially in the basal cells near the pseudobasement membrane. TUNEL techniques revealed DNA fragmentation distinct from that normally associated with terminal keratinocyte differentiation. Similar evaluations 22.5 h after 90 min exposure of EpiDerm to elevated temperature (45 degrees C) produced a different pattern of cell damage. Swelling of intercellular spaces, extensive cytoplasmic vacuolization, disruption of normal nuclear shape, reduced cell membrane integrity, and release of cellular material in the basal region characterized heat injury. Heat did not alter the DNA fragmentation normally associated with keratinocyte maturation. These data suggest that CEES elicited an apoptotic mechanism of cell death with features of terminal differentiation such as nuclear membrane disintegration and loss of cytoplasmic structures. Heat, alternatively, produced changes more typical of oncotic necrosis.

Apoptosis↗
PubMed2000

Effects of CEES on inflammatory mediators, heat shock protein 70A, histology and ultrastructure in two skin models.

Chemical warfare threats require the development of diverse models for the assessment of countermeasures. Human skin products, Skin2 (differentiating keratinocytes on a fibroblast-collagen matrix) and EpiDerm (differentiating keratinocytes) were exposed (2 h) to the sulfur mustard 2-chloroethyl ethyl sulfide (CEES, 1-2 mg l(-1) min(-1)) in humidified air or to humidified air alone. Tissues were evaluated histologically, ultrastructurally and for viability 22 h later; media and tissues were also analyzed for inflammatory mediators. Histology showed that CEES induced the separation of dermal and epidermal regions in Skin2 with severe damage to basal keratinocytes. Histology and electron microscopy of both products revealed condensation of nuclear chromatin, retraction of spinous processes, collapse of the tonofibrillar network and cytoplasmic vacuolization and blebbing in those cells with loss of pseudobasement membrane integrity. Exposure of Skin2 to CEES increased extracellular interleukin-1alpha (IL-1alpha), prostaglandin-E2 (PGE2) and especially IL-1 receptor antagonist (IL-1Ra) release (56,334 vs 84,614 pg ml(-1)), but decreased interleukin-6 (IL-6, 4,755 vs 351 pg ml(-1)). Exposure of EpiDerm to CEES led to unaffected extracellular and reduced intracelluar IL-1alpha (371 vs 92 pg ml(-1)). Extracellular IL-1Ra greatly increased (2,375 vs 24,875 pg ml(-1)), whereas cellular levels decreased (16,5425 vs 96,625 pg ml(-1)). Extracellular (224 vs 68 pg ml(-1)) and intracellular (485 vs 233 pg ml(-1)) soluble interleukin-1 receptor H (sIL-1RII) decreased. Prostanglandin E2 increased (1,835 vs 2,582 pg ml(-1)), whereas heat shock protein 70A (Hsp70A) remained statistically unchanged (57,000 vs 96,000 pg ml(-1)). Failure to obtain a heat shock response to CEES may contribute to the susceptibility of tissue to the alkylating agent. Consistent and marked responses of cellular and extracellular IL-1Ra to CEES suggest a potential for use as a tissue status marker and primary antiinflammatory regulator in skin.

Biomarkers↗
PubMed2000

Il-1-related cytokine responses of nonimmune skin cells subjected to CEES exposure with and without potential vesicant antagonists.

Sulfur mustard provokes an acute inflammatory response in skin. To determine if keratinocytes regulate this response and whether three potential vesicant antagonists can counteract adverse changes, specimens of EpiDerm (MatTek Corp., Ashland, MA), a human skin model of differentiating keratinocytes, were exposed 2 h to humidified air with or without 2-chloroethyl ethyl sulfide (CEES, 1.72-1.73 mg/L/min) with or without 10 mM niacinamide, a poly (ADP-ribose) polymerase (PARP) inhibitor, 25 microM CGS9343B (calmodulin antagonist), or 8.4 mM leupeptin (cysteine protease inhibitor). After a 22-h incubation, levels of interleukin-1 alpha (IL-1alpha), its receptor antagonist (IL-1Ra), soluble type II receptor (sIL-1RII) and prostaglandin-E(2) (PGE(2)) were determined. Methylthiazole tetrazolium (MTT) viability tests and histological observations were also conducted. PGE(2) levels were abundant but unaffected by CEES regardless of antagonist presence. Total amounts (media plus lysate) of IL-1alpha, IL-1Ra, and sIL-1RII were reduced with CEES irrespective of antagonist. CEES promoted the release of IL-1Ra. Exposure of EpiDerm to CEES in the presence of the vesicant antagonists did not improve viability or counteract histological damage. We conclude CEES depresses total IL-1alpha and related cytokines, does not affect PGE(2) release, and adverse changes associated with CEES-exposed EpiDerm are not ameliorated by these particular antagonists. Dramatically increased (5- to 10-fold) release of IL-1Ra may provide a useful marker for cytotoxicity. The high level of IL-1Ra and increased release with injury suggest a primary function in down-regulating IL-1 inflammatory responses in skin.

Benzimidazoles↗
PubMed1999

Artificial human skin: cytokine, prostaglandin, Hsp70 and histological responses to heat exposure.

Artificial human skin, Skin2 (keratinocytes and fibroblasts) and EpiDerm (keratinocytes), was used to determine heat-induced release/accumulation of mediators of injury and repair. Skin2 was exposed to 37 or 41-45 degrees C for 90 min, followed by 37 degrees C for 22.5 h. Media were analyzed for interleukin-1alpha (IL-1alpha), prostaglandin-E2 (PGE2), thromboxane-B2 (TxB2) and nuclear matrix apparatus protein (NMAP, viability). Specimens were taken for microscopy. Media and lysates from Skin2 and EpiDerm (37 and 45 degrees C) were analyzed for IL-1alpha, its soluble receptor (sIL-1RII), receptor antagonist (IL-1Ra), interleukin-6 (IL-6) and heat shock protein-70A (lysates only). Significant release of IL-1alpha and PGE2 was detected only above 43 degrees C, where viability deteriorated and histological damage (especially to keratinocytes) was observed. With both skin products, sIL-1RII release was heat-depressed. IL-1alpha and IL-1Ra were elevated in media and IL-1Ra appeared to lower the bioactivity of IL-1alpha. Heat depressed IL-6 release from Skin2 fibroblasts. IL-6 production and release were negligible with EpiDerm. Heat increased Hsp-70A in both products. We conclude keratinocytes and fibroblasts are not primary cytokine and prostaglandin sources in heatstroke (< 44 degrees C) but could be in evaporative cooling failure, focal hot spots, or systemic responses. Levels of IL-1Ra, PGE2 and Hsp70A may be important markers of cell status.

Antigens, Nuclear↗
PubMed1997

Risk factors for basal cell carcinoma in the UK: case-control study in 806 patients.

Basal cell carcinoma (BCC) is the commonest malignant neoplasm in white people. We present a large UK case-control study in which conditional logistic regression analysis of age-matched and gender-matched data sets was used to compare, first, cases with controls (n = 403) and second, patients having multiple BCC with those having a single BCC (n = 278). Eye/hair colour, occupation, skin type, social class, tumour site at presentation and smoking history were assessed. Social class 1/2, skin type 1, red/blonde hair and blue/green eyes were all related to BCC risk, social class most strongly (odds ratio 2.36, P = 0.007). Truncal site at presentation was a risk factor for the development of multiple BCC (odds ratio 4.03, P = 0.002). These data support the view that genetically mediated differences in ultraviolet responsiveness are important in BCC, though the scale of their effect is small. They may be exploitable in primary and secondary prevention as well as giving insights into pathogenesis. In particular, the fact that patients presenting with a truncal tumour are at increased risk of further BCC suggests that intermittent exposure in genetically predisposed individuals may contribute to a cancer susceptibility syndrome.

Basal Cell Carcinoma↗
PubMed1995

Acute treatment response in outpatients with panic disorder: high versus low depressive symptoms.

The authors studied 75 outpatients with DSM-III-R panic disorder who had participated in a clinical trial and had been randomly assigned to receive fluvoxamine, cognitive therapy, or placebo for an 8-week period. They compared a group with high levels of depressive symptoms and a group with low levels of depressive symptoms. At baseline, patients with high levels of depressive symptoms were more likely to have severe phobic avoidance and to have higher scores on measures of anxiety, hyochondriasis, and disability. An important finding was that depressive symptoms improved at a rate which paralleled improvement in panic and anxiety. Likewise, the presence of depressive symptoms did not interfere with treatment response in panic disorder. Clinical implications of the findings are discussed.

Adult↗
PubMed1994

Predictors of short-term treatment response in 66 patients with panic disorder.

Short-term treatment response in panic disorder was studies in 66 subjects who had completed 3 weeks of treatment with fluvoxamine (n = 23), cognitive therapy (n = 20), or placebo (n = 23). Clinical and self-rated assessments were gathered at baseline, during, and after treatment. Using multiple logistic regression, treatment with fluvoxamine, a low panic attack severity score, and absence of a comorbid personality disorder were identified as significant predictors of recovery. Personality disorder was an important negative predictor to outcome with cognitive therapy. The results support the efficacy of fluvoxamine, and show that patients with low symptom severity and a normal personality respond well to treatment.

Adolescent↗
PubMed1993

A comparison of fluvoxamine, cognitive therapy, and placebo in the treatment of panic disorder.

Seventy-five outpatients with moderate to severe panic disorder were randomly assigned to receive 8 weeks of fluvoxamine, cognitive therapy, or placebo. Fifty-five patients completed the treatment protocol. Fluvoxamine was found to be an effective and well-tolerated treatment for panic using clinician- and patient-rated variables. Subjects receiving cognitive therapy also showed improvement, but this improvement did not significantly differ from the experience of the placebo-treated group for most comparisons. Fluvoxamine was superior to cognitive therapy for many ratings, but cognitive therapy was not superior to fluvoxamine on any rating. Fluvoxamine also produced improvement earlier than cognitive therapy. At the main comparison point (week 4), 57% (13/23) of patients receiving fluvoxamine were rated moderately improved or better vs 40% (8/20) of the group given cognitive therapy and 22% (5/23) of the placebo-treated group. At that point, 43% (10/23) of the fluvoxamine recipients vs 25% (5/20) of cognitive therapy and 4% (1/23) of placebo recipients were free of panic attacks.

Adolescent↗
PubMed1993

Prostaglandin E2, interleukin-1 alpha, and potassium release from artificial human skin after freeze-thaw injury.

Living skin equivalent (LSE) was used to identify nonvascular aspects of freeze-thaw injury to human skin cells. Pairs of transwell cell culture inserts, containing LSE, were washed twice for 30 min in maintenance media at 37 degrees C in a CO2 incubator and placed in two wells of a six-well assay tray (containing assay media). One specimen was maintained at room temperature. The other was cooled at 1 degrees C/min to -15 degrees C and rapidly rewarmed. Both were incubated for 24 h on fresh maintenance media at 37 degrees C in a CO2 incubator. This process was repeated producing 12 per group. Prostaglandin E2 (PGE2), interleukin-1 alpha (IL-1 alpha), and K+ were measured (mean +/- SE) in the assay medium, after the rewarming interval, and in the maintenance media after the 24-h incubation. Specimens were then processed for electron microscopy. After the rewarming interval, PGE2 (164.0 +/- 23.2 pg/0.1 ml), IL-1 alpha (24.3 +/- 2.2 pg/0.1 ml), and K+ (6.47 +/- 0.41 mM) released from frozen LSE were significantly increased compared to controls (PGE2 = 22.2 +/- 4.6 pg/0.1 ml, IL-1 alpha = 5.7 +/- 1.0 pg/0.1 ml, K+ = 4.32 +/- 0.02 mM). After the 24-h incubation, PGE2 and IL-1 alpha released by frozen LSE (PGE2 = 1126 +/- 208 pg/0.1 ml; IL-1 alpha = 80.6 +/- 6.8 pg/0.1 ml) remained significantly higher than controls (PGE2 = 229.0 +/- 45 pg/0.1 ml; IL-1 alpha = 4.9 +/- 0.7 pg/0.1 ml). At this time, K+ leakage from frozen LSE (4.39 +/- 0.03 mM) had returned to a normal range (control = 4.65 +/- 0.02 mM). Keratinocytes and, to a lesser extent, fibroblasts showed ultrastructural freeze-thaw damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Artificial Organs↗
PubMed1987

Calcium antagonists and heat-induced hepatic injury.

Several laboratories have demonstrated the value of the isolated perfused rat liver as a suitable model for heat-induced hepatic injury in vivo. Membrane changes caused by perfusion of rat livers at 42 degrees C for 90 min were similar to those induced by toxic chemicals or hypoxia. In an evaluation of several categories of drugs reported to reduce cell injury, calcium antagonists (nifedipine, dantrolene, and verapamil), were evaluated for their therapeutic potential for heat injury. Isolated rat livers were perfused at 42 degrees C for 90 min with and without calcium antagonists. Livers were also perfused at 37 degrees C. Potassium and transaminase leakage, bile production and ultrastructure were used to evaluate their responses. Neither of the three calcium antagonists significantly improved any of the functional parameters measured. However, dantrolene produced dilated or vesicular rough endoplasmic reticulum in the heated livers. These changes suggest selective intracellular action on endoplasmic reticulum of heated livers. Ring-shaped mitochondria and vesicular endoplasmic reticulum were observed in the heated, verapamil-treated livers, but these could not be quantitatively distinguished from controls. Nifedipine did not appear to alter intracellular membranes, but did increase bile production.

Animals↗
PubMed1987

Variations of norepinephrine concentrations following chronic stressor application.

Exposure to acute uncontrollable footshock increased utilization of central norepinephrine (NE), and in some brain regions, most notably the hypothalamus, a decline in amine concentrations was induced. Utilization of NE was likewise increased in mice exposed to footshock on 14 consecutive days, but the NE reduction was not evident, suggesting that the chronic stressor provoked a compensatory increase of amine synthesis. In mice that were decapitated 24 hr after the chronic shock regimen, NE concentrations exceeded those of nonshocked animals or mice decapitated immediately after the last shock session, possibly reflecting a sustained increase of amine synthesis. The altered NE utilization and concentrations associated with chronic footshock were evident irrespective of whether the stressor was applied on a predictable schedule or on an intermittent basis, although the former treatment was somewhat more effective in increasing concentrations and utilization.

Animals↗
PubMed1985

A structured interview for the DSM-III personality disorders. A preliminary report.

With few exceptions, published studies fail to indicate that the DSM-III personality disorders can be distinguished from each other with respect to etiology, prognosis, treatment response, or family history. The Structured Interview for the DSM-III Personality Disorders (SIDP) was developed to improve axis II diagnostic reliability, and hence allow validity testing of axis II. Sixty-three subjects were independently rated by two interviewers using the SIDP. The kappa coefficients for interrater agreement reached .70 or higher for histrionic, borderline, and dependent personalities. While it is impossible to separate the validity testing of the SIDP from validity testing of the DSM-III personality criteria themselves, preliminary results from 102 inpatient SIDP interviews suggest some criterion-based validity with respect to standard personality rating scales and some construct validity with respect to the dexamethasone suppression test.

Adolescent↗
PubMed1985

Differential effects of pimozide on response-rate and choice accuracy in a self-stimulation paradigm in mice.

Intracranial self-stimulation (ICSS) from the dopamine (DA) A9 cell grouping was evaluated in mice following pimozide administration in both a one hole head dipping task and a two hole discrimination paradigm. While pimozide reliably decreased response rates, choice accuracy in the discrimination paradigm was unaffected by the drug treatment. The data were taken to suggest that neuroleptics influence response rate owing to motoric disturbances, without influencing the effectiveness of cues that previously had been associated with primary reinforcement.

Animals↗
PubMed1984

Insulin and cortisol improve heat tolerance in isolated perfused rat liver.

Isolated rat livers were perfused at 37 degrees, 41 degrees, 42 degrees, and 43 degrees C with and without insulin and cortisol. Two additional groups were perfused at 42 degrees C with either hormone alone. The perfusate contained red blood cells, amino acids, and albumin in Krebs-Ringer bicarbonate. Bile flow was significantly increased by hormones at 37 degrees C. Bile flow was also increased by hormones at all other temperatures. At 41 degrees C, K+ leakage was the only parameter that indicated injury. Insulin and cortisol significantly reduced K+ leakage at this temperature compared to those without hormones. At 42 degrees C, insulin and cortisol reduced K+ leakage, increased bile flow, reduced transaminase release, and improved ultrastructural integrity. The enhanced bile flow was due primarily to insulin. A reduction in K+ leakage required both insulin and cortisol. Transaminase leakage responded to either hormone alone or in combination; however, only the cortisol-treated group showed a statistically significant reduction in transaminase leakage. At 43 degrees C, indications of irreversible injury were evident and hormones had no beneficial effects. Loss of membrane homeostasis appeared to be the initial event.

Alanine Transaminase↗
PubMed1983

A simplified ultrafiltration method for determination of serum free cortisol.

We describe the suitability of the Amicon MPS-1 centrifugal ultrafiltration device and the YMB membrane for measuring free cortisol in serum. The method combines two independent assays: total cortisol and the ultrafiltrate fraction of added [3H]cortisol. The unbound fraction is determined in 0.25-0.30 ml of ultrafiltrate collected from 0.6 to 1 ml of serum that has been equilibrated with [3H]cortisol at 37 degrees C for 20 min. The assay is rapid (less than 1 h), practical ( no more than 0.6 ml of serum is necessary) and repeatable (CV: 3.8% within-assay and 12.2% in different assays). Error introduced in free cortisol measurement due to dilution effects in dialysis is systematically defined, and the effect of tracer purity on the ultrafiltration method is examined. Dialyzed sera from normal men and women, from patients with Cushing's disease and adrenal insufficiency, and from pregnant women gave ultrafiltration results that accurately duplicated those obtained by previous dialysis.

Adsorption↗
PubMed1982

An improved ultrafiltration method for determining free testosterone in serum.

In this method, we use the Amicon MPS-1 centrifugal ultrafiltration device and the YMB membrane in measuring free testosterone in serum. Two independent assays are combined: total testosterone and the ultrafiltrable fraction of added [3H]testosterone. The unbound fraction is determined in 0.15-0.5 mL ultrafiltrates of 0.6 to 1 mL of variably diluted serum that has been equilibrated with [3H]testosterone at 37 degrees C. The assay is rapid (less than 1 h), practicable (requires 0.6 mL of serum), and reproducible (CV 3.2% within assay, 3.9% between assays). Accuracy was evaluated as the fraction of free testosterone in the ultrafiltrate of dialyzed serum vs that in a prior dialysate; they were the same confirming the validity of the free testosterone measurement. Samples from ostensibly healthy men and women and from hirsute and pregnant women gave results that agreed with those obtained by equilibrium dialysis. Total testosterone concentrations for normal and hirsute women showed considerable overlap, but data on free testosterone concentrations in these populations were better resolved.

Adult↗
PubMed1981

Integrity of perfused rat liver at different heat loads.

Isolated rat livers were perfused for 90 minutes at temperatures from 37 degrees to 43 degrees C. to evaluate the effects of heat alone on bile production, alanine aminotransferase, and asparate aminotransferase release, and light and electron microscopic structure. Bile production reached a plateau after 45 minutes at 43 degrees C. and after 60 minutes at 42 degrees C. At temperatures between 39 degrees and 41 degrees C., bile production was not significantly different from that produced at 37 degrees C. The timing and levels of alanine aminotransferase and aspartate aminotransferase released into the perfusates were similar, with increases after 45 minutes at 43 degrees C., after 60 minutes at 41 degrees and 42 degrees C. and after 75 minutes at 39 degrees and 40 degrees C. At the end of the 90-minute perfusion, light microscopy indicated vacuolization and severe dissociation of hepatocytes at 42 degrees and 43 degrees C., and pronounced centrilobular vacuolization at 41 degrees C. Electron microscopy demonstrated that hepatocytes had sustained extensive damage at 41 degrees to 43 degrees C. Mild focal and probably reversible damage occurred at 39 degrees and 40 degrees C. Since pH and O2 levels were regulated in a nonrecirculating system and perfusion rates were constant, neither acidosis, hypoxia, nor circulatory inadequacy were responsible for the alterations. Therefore, changes were attributed to the direct effects of heat, reflected a continuum from no detectable damage at 37 degrees C. to occasional necrosis of individual cells at 39 degrees to 40 degrees C. and culminated in widespread necrosis at 41 degrees to 43 degrees C. with a 90-minute exposure. These results reflect a time/temperature relationship over a range of temperatures. A hypothesis for the sequence of events in the pathogenesis of heat-induced hepatic injury is described.

Alanine Transaminase↗