Evidence for a feeding related association between melanocortin in the NTS and Neuropeptide-Y in the PVN.

Melanocortin and neuropeptide-Y (NPY) are both involved in feeding and energy regulation, and they have opposite effects in the paraventricular nucleus of the hypothalamus (PVN). The present study examined an interaction between melanocortin in the nucleus of the solitary tract (NTS) and NPY in the PVN. Male Sprague-Dawley rats were implanted with cannulae in the injection sites of interest. In Experiment 1, subjects received either the melanocortin 3/4-receptor (MC3/4) antagonist SHU9119 (0, 10, 50 and 100 pmol/0.5 µl) or the MC3/4 agonist MTII (0, 10, 50, 100 and 200 pmol/0.5 µl) into the NTS. Food intake was measured at 1, 2, 4, 6 and 24-h post-injection. Administration of SHU9119 into the NTS significantly and dose-dependently increased food intake at 1, 2, 4, 6 and 6-24-h, and administration of MTII into the NTS significantly and dose-dependently decreased 24-h free feeding. In Experiment 2, subjects received the MC3/4 agonist MTII (0, 10, 50, 100 and 200 pmol/0.5 µl) into the NTS just prior to NPY (0 and 1µg/0.5 µl) in the PVN. PVN injection of NPY stimulated feeding, and administration of MTII (50, 100 and 200 pmol) into the NTS significantly and dose-dependently decreased NPY-induced feeding at 2, 4, 6 and 6-24-h. These data suggest that there could be a neuronal association between melanocortin in the NTS and NPY in the PVN, and that the melanocortin system in the NTS has an antagonistic effect on NPY-induced feeding in the PVN.

Correlation of the antiproliferative action of diphenylmethane-derivative antiestrogen binding site ligands with antagonism of histamine binding but not of protein kinase C-mediated phosphorylation.

The nonestrogen receptor-mediated antiproliferative action of antiestrogen binding site (AEBS) ligands, including triphenylethylene antiestrogens and phenothiazines, has been linked to their ability to inhibit protein kinase C (PKC). Recent studies indicate that some diphenylmethane derivatives inhibit growth, are potent AEBS ligands, and antagonize histamine binding at an AEBS-related histamine site different from H1 and H2. Three novel diphenylmethane derivatives, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCI (DPPE), 4-decanoyl-DPPE (dec-DPPE), and 4-benzylphenyl decanoate (BPD) were studied in an attempt to determine whether PKC or histamine interactions best correlate with their antiproliferative effects. Platelet aggregation and the phosphorylation of a platelet Mr 47,000 protein (p47) induced by phorbol-12-myristate-13-acetate (PMA) represent two processes mediated by PKC. DPPE inhibits PMA-induced aggregation [50% inhibitory concentration (IC50) = 31.2 +/- 2.4 (SEM) x 10(-6) M] but does not significantly inhibit either PMA-induced phosphorylation of Mr 47,000 protein (IC50 greater than 500 x 10(-6) M), or binding of [3H]phorbol dibutyrate to platelets. dec-DPPE is a more potent inhibitor of PMA-induced platelet aggregation (IC50 = 18.8 +/- 0.7 x 10(-6) M), a weak inhibitor of Mr 47,000 phosphorylation (IC50 = 80-200 x 10(-6) M), but is without effect on [3H]phorbol dibutyrate binding. BPD, which lacks the alkylaminoethoxy side chain necessary for binding to the AEBS/DPPE site, is devoid of anti-PMA effects. These results are compared to the inhibition of [3H]histamine binding in rat cortex membranes (Ki value for DPPE = 0.83 +/- 0.62 x 10(-6) M; Ki value for dec-DPPE = 6.6 +/- 3.5 x 10(-6) M; BPD is inactive) and growth inhibition of MCF-7 cells (IC50 value for DPPE = 4.5 x 10(-6) M; IC50 value for dec-DPPE = 1.5 x 10(-5) M; BPD is ineffective at all concentrations tested). Thus, while dec-DPPE is a more potent inhibitor of PKC-mediated phosphorylation, DPPE is a more potent inhibitor of histamine binding and is correspondingly more antiproliferative than dec-DPPE. The results support a relationship between antagonism of histamine binding and growth inhibition but argue against an association between the antiproliferative effects of DPPE and dec-DPPE and inhibition of PKC. The findings for DPPE suggest that platelet response to PMA, antagonized by diphenylmethane-type AEBS-ligands, may be mediated, at least in part, by mechanisms other than activation of protein kinase C-dependent phosphorylation.

Dexamethasone increases hepatic insulin-like growth factor binding protein-1 (IGFBP-1) mRNA and serum IGFBP-1 concentrations in the rat.

Glucocorticoid excess is associated with growth retardation in both man and experimental animals. We have previously reported that dexamethasone (DXM) inhibits growth hormone induction of insulin-like growth factor-I (IGF-I) mRNA in the hypophysectomized rat and reduces steady-state IGF-I mRNA levels in the intact rat. However, in these experiments, DXM had surprisingly little effect on serum IGF-I concentrations. Here, we have examined the effect of DXM on hepatic insulin-like growth factor binding protein-1 (IGFBP-1) mRNA levels and on serum IGFBP-1 concentrations. After a single ip injection of DXM, 6 micrograms/100 g body wt, IGFBP-1 mRNA increased 2.24 +/- 0.25-fold, P less than 0.05 at 1 h and declined to normal levels in 6-12 h. A dose-dependent increase in increased hepatic IGFBP-1 mRNA abundance was seen in rats killed 1 h after an ip injection of DXM, 0.1 to 60 micrograms/100g body wt. As little as 1 microgram/100g body wt, significantly enhanced hepatic IGFBP-1 mRNA levels; 2.02- +/- 0.38-fold, P less than 0.05. This effect appeared to be post-transcriptional, since IGFBP-1 transcription in hepatic nuclei from rats treated with DXM was not significantly different from untreated rats. When DXM, 1 microgram/rat, was administered daily for 6 days a significant increase in IGFBP-1 mRNA was detected; 2.02 +/- 0.39-fold, P less than 0.05. A more marked increase was seen with 6 and 60 micrograms/rat of DXM; 4.47 +/- 1.08- and 10.61 +/- 0.31-fold, respectively. Serum was analyzed by sodium dodecyl sulfate-plyacrylamide gel electrophoresis and immunoblotting using antisera raised against a synthetic peptide derived from the predicted sequence of rat IGFBP-1. The antisera recognized a doublet of approximately 30 kDa. A dose-dependent increase in the abundance of these BPs were seen in the serum from rats treated chronically with DXM. The observations reported here clearly demonstrate that DXM increases hepatic IGFBP-1 mRNA and serum IGFBP-1 concentrations. If IGFBP-1 functions to decrease the bioavailability of IGF-1 in vivo the enhanced expression of IGFBP-1 may be an additional mechanism whereby glucocorticoid excess results in growth retardation.

Enhanced expression of insulin-like growth factor-binding protein-I in the fasted rat: the effects of insulin and growth hormone administration.

The effect of fasting on insulin-like growth factor-binding protein-1 (IGFBP-1) expression was examined in the rat. Food deprivation for a period of 24 h resulted in a 9.5 +/- 2.0-fold increase in hepatic IGFBP-1 mRNA abundance (P less than 0.001). An increase in circulating IGFBP-1 in sera from fasted rats was demonstrated by immunoblotting, and an increased abundance of a 30-kDa IGFBP in sera from fasted rats was apparent when [125I]IGF-I was used in ligand blotting experiments. Refeeding resulted in a prompt decline in hepatic IGFBP-1 mRNA. Administration of insulin (0.5-4 U, ip) to fasted rats resulted in profound hypoglycemia, but either increased or had no significant effect on hepatic IGFBP-1 mRNA abundance. In contrast, administration of human GH (hGH; 100 micrograms, ip) resulted in a prompt decline in hepatic IGFBP-1 mRNA, followed by a late rebound in IGFBP-1 mRNA to levels greater than those in fasted controls. Furthermore, hepatic IGFBP-1 mRNA levels were significantly lower in hGH-treated (100 micrograms every 8 h) food-deprived rats than in saline-treated food-deprived rats (2.25 +/- 1.55- vs. 8.99 +/- 3.80-fold increase; P less than 0.005). Similar changes were observed when serum IGFBP-1 was quantitated by immunoblotting. The effects of GH could not be explained by secondary hyperinsulinism, since no significant increase in insulin levels was observed in GH-treated rats. From these observations we conclude the enhanced expression of IGFBP-1 in the food-deprived rat may be a consequence of GH deficiency rather than insulin deficiency.

Interaction of neuroleptic drugs with a synthetic calcium-binding peptide analog of site III of rabbit skeletal troponin C. Phenothiazine selective binding.

The effects of nine drugs on the CD spectra of a synthetic calcium binding analog of site III of rabbit skeletal troponin C, can generally be divided into 3 groups: (1) that consisting of haloperidol, benperidol, molindone and promethazine, had no effect on the CD spectrum or calcium sensitivity of the apopeptide; (2) that composed of structurally rigid thioxanthenes, induced CD-detectable structural change in the apopeptide but prevented Ca2+-induced structural change; (3) that consisting of chlorpromazine, trifluoperazine and fluphenazine, induced structural change in the peptide but had no effect on the Ca2+-induced structural change.

Turner-Warwick urethroplasty and urethral stricture. Results in 60 patients.

Sixty patients with urethral strictures at the bulbous and membranous levels were treated with Turner-Warwick urethroplasty. Initially, there were significant difficulties with restenosis of either the proximal or distal st-ma following the first-stage urethroplasty. Use of nitrofurazone-hydrocortisone (Furacin-Hc) urethral suppositories practically eliminated recurrent stomal stenosis after the first stage. Several additional modifications were made in the original technique; these included placement of urethral sutures prior to scrotal mobilization and abandonment of the suprapublic cystotomy for frainage at the second stage of the procedure. These modifications increased the chances of achieving a successful result while facilitating the actual surgery and improving the patients' comfort. The over-all success rate was approximately 90 per cent. Patients with urethral stricture surgery subsequent to prostatectomy had problems with urinary control, but not so if prostatectomy was done after the first stage of urethroplasty. It appears that the Turner-Warwick urethroplasty is good one, and predictably good results can be expected on selected patients with urethral strictures.

Simplified nonrefluxing ileovesical anastomosis. Experimental study and clinical application.

A simplified ileovesical anastomosis is herein described. It prevents vesicoileal reflux and allows for unimpeded efflux of urine into the bladder. The technique involves implanting 3 inches of distal ileum into a denuded muscular bed in the bladder. Vesical mucosa grows over the ileum creating an effective valvular mechanism. Experimental work done on the canine bladder and the use of this technique in 2 patients is described.

Unusual case of renal Candida fungus balls.

Renal fungus balls are rare in the adult population. A case of asymptomatic renal pelvic fungus balls is presented, and several approaches to treatment are discussed.

Unstable bladder: urodynamic diagnosis and observations in evaluating urinary incontinence in the female.

Unstable bladder in the female has been the subject of controversy with regard to its etiology, identification, and treatment. One hundred thirty consecutive female patients referred with incontinence were evaluated as to their symptoms and urodynamic findings. A stress cystometrogram, systematically done, was introduced and observations were made regarding certain findings on the urodynamic examination. These criteria were used subsequently for making a diagnosis of unstable bladder. Forty per cent of these patients were found to have an unstable bladder. History of frequency and urgency correlated best with a diagnosis in 70 to 80 per cent of our cases, and the new stress cystometrogram proved to be the most sensitive urodynamic test (78%) for detecting this condition. A systematic approach such as we describe is advocated as a first step toward gaining a better understanding of this puzzling entity.

Influence of indwelling urinary tract stones on twenty-four-hour urine chemistries.

Twenty-two patients with ureteral stones underwent twenty-four-hour urinary excretion studies of calcium, phosphorus, and uric acid before and after stone elimination from the urinary tract. Comparison of pre- and post-stone elimination studies showed no significant differences suggesting that the presence of stones in the urinary tract has little influence on the twenty-four-hour urinary excretion of calcium, phosphorus, and uric acid.

On percutaneous drainage of retroperitoneal collections: when is primary surgical drainage preferable?

Percutaneous drainage of retroperitoneal collections is a method employed with an ever-increasing frequency. The indication for primary surgical drainage of these collections is rapidly decreasing. Herein we describe what we consider to be the indications for primary surgical drainage of retroperitoneal collections illustrated by the recurrence of the abscess in 3 of our patients following adequate primary percutaneous drainage.

Role of urodynamics in management of urethral diverticulum in females.

This report deals with 10 female patients with urethral diverticula, 8 of whom were also found to have findings of stress incontinence. This association was proved by urodynamic studies. Three patients were seen with incontinence postdiverticulectomy. Seven patients were evaluated prior to diverticulectomy, and of these 5 had anatomic changes of stress urinary incontinence. Those patients in whom the preoperative evaluation considered them to be at risk for development of stress incontinence postdiverticulectomy were treated with a prophylactic urethropexy. Patients so treated were continent and voided well and were probably spared having a postoperative problem with incontinence. The role of urodynamic techniques in the detection of any association between the diverticulum and a possible risk of postdiverticulectomy incontinence, and how to recognize the problem and its correction before it becomes clinically manifest are the stated purposes of this report.

Is there a urodynamic equivalence to anterior urethra in the male?

To evaluate the role of the anterior urethra in the male in micturition dynamics, 9 patients with urethral strictures who were undergoing a two-stage Turner-Warwick urethroplasty were evaluated with flow and pressure flow measurements, pre- and post-second-stage urethroplasty. Any decrease in flow or increase in resistance after closure would suggest an anterior "urethral effect." None was found, indicating that the anterior urethra in the male functions as an inert conduit.

Sex-dependent variations in natural history of transitional cell carcinoma of bladder.

The records of 196 patients with transitional cell carcinoma of the bladder diagnosed up to 1975 were analyzed for age, sex, tumor histology, and survival parameters. Analysis of the series as a whole showed it to be comparable to literature controls in the male to female ratio, average age at presentation, and in survival data. Sex stratification combined with parametric analysis showed that females had longer recurrence-free survivals and died less frequently of bladder cancer than their male counterparts. In addition, the incidence of high-grade tumors was lower in females. These facts and the comments that follow point to a probable less aggressive natural history of transitional cell carcinoma of the bladder in females.

Urachal remnants in adults.

Urachal disorders are uncommon and present with varied appearances. Three cases of urachal disease, one congenital and two acquired, are reported. Each case is representative of the symptoms and findings of its respective category. A review of the literature is presented. A basic understanding of urachal development is necessary to suspect a diagnosis of urachal disease.

Androgen receptors in bladder tumors.

Cytosol androgen receptor content of transitional cell bladder cancer tissue was found to be substantially higher than its content in normal bladder mucosa and lower than in control benign prostatic hypertrophy tissue. Tumors arising in female patients had a lower androgen receptor content than those arising in male patients. High-grade tumors had a lower androgen receptor content than low-grade tumors.

Ileal segment replacement of ureter. I. Effects on kidney of refluxing vs nonrefluxing ileovesical anastomosis.

Unilateral partial ureteral obstruction was induced in 32 dogs followed by total ileal replacement of the obstructed ureter. The morphologic and functional effects on the kidney using a freely refluxing versus a nonrefluxing ileovesical anastomosis were compared, as well as the effect of total tapering of the reimplanted ileal segment. The tapered ileovesical anastomosis proved more reliable for prevention of reflux than the nontapered technique. Reflux prevention does not appear necessary for maintaining renal morphology and function when bladder function is normal and the observation period short. Total tapering of the ileal segment did not prove to be advantageous in protecting against hyperchloremic acidosis in this short-term canine study.

Ileal segment replacement of ureter. II. Dynamic characteristics of refluxing, nonrefluxing, and totally tapered ileal ureter.

The pressure characteristics and cinefluoroscopic appearances of a refluxing, nonrefluxing, and totally tapered ileal " neoureter " were compared in 22 dogs with normal bladder function. The totally tapered ileal segment with a reflux preventing ileovesicostomy simulates normal ureteral peristalsis most closely on cinefluoroscopic evaluation. Pressure gradients across the ileovesical junction though were similar in refluxing and nonrefluxing ileovesicostomies , as well as in totally tapered ureters.