Biomedical subjects
Publications and source records attributed to J R Porter.
Acyclic, disulphide derivatives of cysteine have been identified as moderately potent antagonists of alpha4beta1-mediated leukocyte cell adhesion to VCAM. This communication describes how they were discovered from a simple L-cystine derivative and using the structure-activity data of C*DThioPC* related cyclic peptides.
Using disulphide cysteine-based inhibitors as lead structures, this communication describes our strategy for identifying more stable, potent antagonists of the alpha4beta1 integrin. These studies ultimately discovered potent, low molecular weight inhibitors based on D-thioproline-L-tyrosine.
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High free fatty acid (FFA) levels are common in obesity and in diseases such as diabetes that are associated with the obese state. Dehydroepiandrosterone (DHEA) decreases dietary fat consumption, body fat content, and insulin levels in the obese Zucker rat (ZR), a genetic model of human youth-onset obesity and type 2 diabetes mellitus. This study was conducted to investigate the effects of DHEA on lean and obese ZR serum, adipose, and hepatic tissue fatty acid (FA) profiles and serum FFA levels. Because DHEA is known to decrease fat consumption and body fat, we postulate that DHEA may also alter FA profiles and FFA levels of the obese ZR such that they more closely resemble the profiles and levels of their lean siblings. In this study there was a DHEA and a pair-fed (PF) group (n = 6) for 12 lean and 12 obese ZR. The diet of the treatment groups was supplemented with 0.6% DHEA, and PF groups were given the same average calories consumed by their corresponding DHEA group for 30 d. Fasted animals were sacrificed, and FA profiles and FFA levels were measured. Serum FFA levels were higher in obese (approximately 1 mmol/L) compared to lean rats (approximately 0.6 mmol/L). After 30 d of DHEA treatment, FFA levels were lower (P < 0.05) in both lean and obese groups. Although several significant differences in FA profile of serum, hepatic, and adipose lipid components were observed between lean and obese ZR, DHEA-related changes were only observed in the serum phospholipid (PL) and liver PL and triglyceride fractions. The slight but significant decrease in serum FFA levels may be reflected by changes in serum PL FA profiles. Specific hepatic FA profile alterations may be related to DHEA's known effects in inducing hepatic peroxisomes. We speculate that such FA changes may give insight into a mechanism for the action of DHEA.
To understand the mechanism(s) of appetite modulation by DHEA, we have undertaken a series of studies to examine the effects of DHEA on neurotransmitters and neuropeptides known to affect appetitive behavior. Here, we report the effect of DHEA on serum enterostatin-VPDPR or E, a pentapeptide known to cause selective diminution in fat intake. Four-week-old lean (fa/+) and obese (fa/fa) Zucker rats were divided into control and treatment groups. DHEA-treated groups received powdered chow containing 0.6% DHEA ad lib for 16 weeks. Another group of obese rats was pair fed to match the intake of the obese DHEA-treated rats. At the end of this period, trunk blood was collected from fasted rats for assay of E-like immunoreactivity (E-LI) by ELISA. DHEA treatment caused a significant diminution in circulating E-LI in both lean (control: 2030 +/- 226; treated: 752 +/- 145 ng/mL; n = 10, p < 0.0001) and obese (control: 2489 +/- 391, n = 6; treated: 1123 +/- 185 ng/mL, n = 7; p = 0.0003) rats. Because DHEA treatment decreases caloric intake and body weight, we examined the effect of caloric intake and body weight on E-LI levels. Serum ELI levels were lower in the obese DHEA-treated group compared to that of obese pair fed (pair fed: 1589 +/- 313, n = 6; DHEA: 1123 +/- 185 ng/mL, n = 7), but the differences were statistically insignificant (p = 0.185). Also, both weight-matched lean and obese control rats had significantly (p < 0.008) higher E-LI than their DHEA-treated counterparts. To examine whether the decrease in serum E-LI following DHEA treatment could be due to increased peptide metabolism, the rate of disappearance of endogenous E-LI from serum (obese control and DHEA-treated) at 37 degrees C was evaluated. The results show an attenuation of peptide metabolism in serum from DHEA-treated rats, a finding contrary to our expectations. In summary, DHEA treatment lowers serum E-LI levels both in lean and obese Zucker rats. This decrement in peptide level is not secondary to changes in body weight or caloric intake due to DHEA, or due to altered serum peptide metabolism. Although DHEA appears to be a potent modulator of E-LI levels, the relationship between DHEA and E-LI in relation to appetitive behavior remains to be clarified.
The obese Zucker rat has a genetically flawed leptin system and is a model of hyperphagia, obesity, hyperlipidemia, and markedly elevated leptin levels. Dehydroepiandrosterone (DHEA) administration reduces hyperphagia, hyperlipidemia, and obesity in Zucker rats. Since serum leptin levels are associated with body fat, we wondered what the effects of fat pad weight reduction from DHEA administration would have on leptin levels. This experiment investigated the effects of DHEA on intra-abdominal fat pads, serum lipids, and peripheral leptin in male lean and obese Zucker rats that were administered DHEA in their food from 4 weeks of age to 20 weeks. Lean and obese rats received plain chow or chow containing DHEA. Additional chow-fed groups of lean and obese weight-matched controls and obese pair-fed rats helped to control for the reduced body weight, food intake, and fat pad weights seen with DHEA administration. DHEA administration to lean Zucker rats reduced body weight and fat pad weights, but leptin levels showed a lower trend. Among obese rats, both DHEA treatment and pair-feeding reduced body weight and fat pad weights, but only DHEA lowered leptin levels. The weight-matched controls had reductions in fat pad weights similar to the DHEA-treated group, but with increased leptin levels. Thus, DHEA may exert a small, independent effect on leptin levels in this animal model, but the reduction is less than what would be expected.
PURPOSE: We present our experience with computerized tomography (CT) cystography for diagnosing bladder rupture in patients with blunt abdominal and pelvic trauma, and compare the results of CT cystography with those of surgical exploration. MATERIALS AND METHODS: We identified all patients with blunt trauma diagnosed with bladder rupture from 1992 to September 1998. We reviewed the radiology computerized information system for all CT cystography performed to evaluate blunt trauma during the same period. We also reviewed the medical records and pertinent radiographic studies of patients with bladder rupture who underwent CT cystography as part of the hospital admission evaluation. Operative and radiographic findings were compared. RESULTS: CT cystography was performed in 316 patients as part of the initial evaluation of blunt trauma. Of the 44 patients with the ultimate diagnosis of bladder rupture CT cystography revealed bladder rupture in 42, while 23 of the 28 (82%) who underwent formal bladder exploration had operative findings that exactly matched the CT cystography interpretation in terms of the presence and type of rupture. In the 316 patients CT cystography detected bladder rupture with an overall sensitivity and specificity of 95% and 100%, respectively. For intraperitoneal rupture sensitivity was 78% and specificity was 99%. CONCLUSIONS: CT cystography provides expedient evaluation of bladder rupture due to blunt trauma and has accuracy comparable to that reported for plain film cystography. We recommend CT cystography over plain film cystography in patients undergoing CT for other injuries associated with blunt trauma.
Fasted obese, female Zucker rats accustomed to eating a single high fat meal within 1 h a day were treated with intraperitoneal injections of dehydroepiandrosterone (DHEA) and dextrofenfluramine (d-fen), either individually or in combination. Caloric intake was measured over a 1-h period 2 h after drug administration, and results compared to that of vehicle-treated controls. At 50 mg/kg body weight, DHEA did not affect food intake. At doses of < or = 2 mg/kg d-fen did not affect food intake. Together, however, DHEA 50 mg/kg and d-fen < or = 2 mg/kg significantly decreased food intake. At doses of > or = 3 mg/kg d-fen diminished caloric intake by itself, and the addition of DHEA significantly augmented this effect. Neurotransmitter levels in select regions of the hypothalamus of animals treated using a similar drug protocol showed several changes in the levels of serotonin and its metabolite 5 hydroxyindole acetic acid (5-HIAA). It is hypothesized that DHEA augments the production of serotonin while d-fenfluramine enhances its release, and together these two actions may account for the synergistic action of DHEA and d-fenfluramine.
The free beta-subunit of human chorionic gonadotrophin (hCGbeta) is well recognised as a product of many epithelial tumours. Recently, it has been shown that this ectopic production may have a functional relationship to tumour growth. The growth-promoting activity of hCGbeta may be explained by its structural similarity to a family of growth factors which all contain the same distinct topological fold known as the cystine-knot motif. Since the other members of this family all exhibit their activities as homo- and heterodimers, it is possible that the same may be true for hCGbeta. Using size-exclusion chromatography, low stringency SDS-PAGE and matrix assisted laser desorption/ionisation (MALDI) time-of-flight (TOF) mass spectrometry (MS) we have shown that pure preparations of hCGbeta contain hCGbetabeta homodimers. Size-exclusion chromatography revealed asymmetric elution profiles with a forward peak corresponding to the size-exclusion characteristic of a globular protein with an approximate mass of 44-54 kDa and a late shoulder centered around an elution position expected for a globular protein of approximately 29 kDa. Two immunoreactive hCGbeta species, of approximately 32 and 64 kDa, were clearly resolved by SDS-PAGE and Western blotting. When analysed by MALDI-TOF MS a |mf23 kDa monomer and a |mf46 kDa dimer were identified. Formation of hCGbetabeta homodimers is consistent with the behaviour of other cystine-knot growth factors and strengthens the inclusion of the glycoprotein hormones within this superfamily. It has yet to be determined whether it is this dimeric molecular species that is responsible for growth-promoting activity of hCGbeta preparations in tumours.
Volume-array coils offer increased signal-to-noise ratio (SNR) over standard volume coils near the array elements while preserving the SNR at the center of the volume. As the number of array elements is increased, the SNR advantage as well as the complexity of actually constructing the array increases also. In this study, a 16-channel receive-only array for imaging of the brain is demonstrated and compared to a circularly polarized (CP) head coil of similar shape and diameter. The array was formed from a 2 x 8 grid of square elements placed on a cylindrical form. Mutual coupling was minimized by a combination of overlapping element placement and current-reducing matching networks. Simultaneous data acquisition from the 16 individual elements was performed using a four-channel receiver system with each channel time domain multiplexed by a factor of 4. Theoretical and experimental comparisons between the array and a standard CP head coil show that the array offers an increase in SNR of nearly a factor of 3 near its surface while maintaining a comparable SNR to that of the CP head coil in the center of the region of interest.
Dehydroepiandrosterone (DHEA) is the major adrenal steroid of young adults; however, its physiologic functions, if any, are not known. The purpose of this review is to evaluate the current literature in which DHEA was administered to either humans or experimental animals to discern what these functions might be. Reports are divided into five areas: neurologic, immunologic, cardiovascular, oncologic, and metabolic. Particular attention is paid to the dosage and route of administration. This type of analysis shows that at the lowest doses, DHEA has effects on neurologic and immunologic tissues, suggesting that these two sites may be physiologic targets. DHEA also affects cardiologic and metabolic functions as well as tumor growth, but such actions require higher doses and may reflect 'pharmacologic' activities. It is proposed that DHEA's pattern of activity represents a new class of steroid hormones, the "Regnantoids." Further progress in the endocrinology of this family of steroids may only come when synthetic, long-acting analogs of DHEA are available for in vitro studies to allow correlations between hormone action and receptor binding.
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Dehydroepiandrosterone (DHEA) has been shown to alter hypothalamic monoamines and reduce energy intake (EI) in Zucker rats (ZRs). We hypothesized that a metabolite of DHEA, delta 4-Androstenedione (delta 4), may mediate these effects. Male lean and obese ZRs (LZR, OZR) were fed control chow (CC) for 7 days, during which basal EI was recorded, various concentrations of delta 4 for 7 days, during which 0.6 and 0.3% delta 4 reduced EI significantly, and CC for 7 days, which resulted in a return of EI to basal levels. After delta 4 administration, neurotransmitter contents of various hypothalamic areas were determined. Serotonin (5-HT) has been shown to be correlated with feeding inhibition, and we have shown DHEA to increase lateral hypothalamic 5-HT synthesis; however, after 1 day and 7 days of delta 4, the OZR exhibited an increased metabolism, not synthesis, of 5-HT in the lateral and paraventricular hypothalamus, respectively, delta 4 was compared to DHEA in a macronutrient self-selection study with female OZRs. One group was injected intraperitoneally (IP) with sesame oil (control), another with DHEA (100 mg/kg), and another with delta 4 (100 mg/kg). Previous studies have shown that DHEA decreases both EI and % calories from fat. In this study, delta 4 decreased % calories from fat, but did not decrease total EI. Contrary to DHEA's effect of reducing serum insulin through 28 days of treatment, delta 4 in chow reduced insulin only acutely (1 day). We conclude, based on these differences, that DHEA has unique effects not mediated by its metabolite, delta 4-Androstenedione.
In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.
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PURPOSE: We determined the success of early urethral realignment using magnetic urethral catheters. MATERIALS AND METHODS: We retrospectively reviewed the records of 13 patients with complete urethral disruption treated with endourological realignment 0 to 11 days after injury using coaxial magnetic urethral catheters. RESULTS: Urethral realignment was established in 11 of the 13 patients (85%) using magnetic urethral catheters. Of the 10 patients for whom followup was available urethral strictures developed in 5 (50%) a mean of 6.1 months after realignment, necessitating a mean of 1.4 corrective procedures per patient. Impotence was noted in 1 of 7 patients (14%) and no urinary incontinence developed after realignment. CONCLUSIONS: Urethral realignment within 2 weeks of injury using magnetic urethral catheters is a safe and simple technique with minimal morbidity. The stricture formation, impotence and incontinence rates of this technique are comparable to those reported for delayed urethroplasty. We advocate early realignment using magnetic urethral sounds as an alternative treatment for traumatic urethral disruption.
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Several studies suggest a role for endogenous cyclo(His-Pro) or CHP in appetite regulation. In the present study, we have examined the regional brain distribution of CHP in hyperphagic obese Zucker rats and their lean littermates. The data show a significant elevation in the levels of CHP in many brain regions, including hypothalamus of the obese rat. Within the hypothalamus, the lateral hypothalamic (LH) nucleus of obese rats had significantly higher levels of CHP when compared to that of the lean littermates. Administration of dehydroepiandrosterone, a steroid hormone known to decrease food intake and body weight gain, to obese rats led to decrease in the levels of CHP in the LH. These data further suggest a role for the endogenous CHP in attenuating food intake.