Construction of a pseudolarynx after laryngectomy and radical neck dissection. A preliminary report

Oxytocin analogues which combine high oxytocic activities with negligible antidiuretic and pressor activities have been studied. [4-Threonine,7-glycine]oxytocin, [1-(L-2-hydroxy-3-mercaptopropionic acid),4-threonine,7-glycine]oxytocin, and [1-(L-2-hydroxy-3-mercaptopropionic acid)]oxytocin were found to possess the following specific biological activities respectively: rat uterotonic, 270 +/- 10, 337 +/- 23, 1542 +/- 0.4; rat antidiuretic, 0.002 +/- 0.0008, 0.048 +/- 0.005, 40.3 +/- 2.4. The results are analyzed from a conformation-activity viewpoint in a continued attempt to evaluate the scope and limitations of this approach in comparison to structure-activity studies.     

"High-load" polyethylene glycol-polystyrene (PEG-PS) graft supports for solid-phase synthesis

In the rat dorsal hippocampus and dorsal raphe nucleus, the microiontophoretic application of ergotamine and 5-HT suppressed the firing activity of CA3 pyramidal neurons and 5-HT neurons, an effect antagonized by selective 5-HT1A receptor antagonists. Co-application of ergotamine prevented the inhibitory action of 5-HT on the firing activity of CA3 pyramidal neurons but not of 5-HT neurons, indicating that ergotamine acted as a partial 5-HT1A receptor agonist in the dorsal hippocampus and as a full agonist at 5-HT1A autoreceptors. Ergotamine decreased, in a concentration-dependent manner, the electrically evoked release of [3H]5-HT in preloaded rat and guinea pig hypothalamus slices; this effect was prevented by the nonselective 5-HT receptor antagonist methiothepin but not by the selective 5-HT1B/1D receptor antagonist GR 127935 or the alpha 2-adrenoceptor antagonist idazoxan. Although body temperature in humans remained unchanged following inhaled ergotamine, in the rat, subcutaneously injected ergotamine produced a hypothermia that was prevented by a pretreatment with the 5-HT1A/1B receptor/beta-adrenoceptor antagonist pindolol. Finally in humans, ergotamine did not alter prolactin or adrenocorticotropic hormone levels, but increased growth hormone level, which was prevented by pindolol. Cortisol level was increased in humans by ergotamine, but this enhancement was unaltered by pindolol. In conclusion, the present results suggest that ergotamine acted in the rat brain as a 5-HT1A receptor agonist and as an agonist of terminal 5-HT autoreceptor of a yet undefined subtype. In humans, ergotamine also displayed some 5-HT1A receptor activity but, probably because of lack of receptor selectivity, it did not present the same profile as other 5-HT1A receptor agonists.     

Thyroid hormone export regulates cellular hormone content and response

Actions of thyroid hormones (THs) are determined by intracellular free hormone concentration. Here we report that enhanced TH extrusion via a saturable, cold-sensitive mechanism lowers intracellular TH and causes TH resistance in hepatoma cells. Since these cells overexpress multidrug resistance P-glycoproteins and TH extrusion and resistance are blunted by verapamil, P-glycoproteins may mediate this resistance. Verapamil-inhibitable TH efflux was also found in primary hepatocytes, cardiocytes, and fibroblasts. These findings demonstrate that TH extrusion can modulate TH availability and action in mammalian cells.     

Gonadal hormones influence the immune response to PLP 139-151 and the clinical course of relapsing experimental autoimmune encephalomyelitis

Rotational atherectomy is effective acutely in treating complex coronary disease, but less is known about its long-term clinical outcome. We examined the acute results and late clinical outcome in 178 patients undergoing treatment with this device. Rotational atherectomy was used to treat 240 lesions in 178 individual patients. Nineteen percent had multilesion or staged multivessel procedures, and 71% had AHA-ACC Type B2/C lesions. The procedure was completed successfully in 94% of patients. Major complications occurred in 6% (death 1%, Q-MI 2.8%, and emergency bypass surgery 2.2%). Clinical follow-up was available for 167 (94%) patients at 13+/-6 months. Thirty-five percent required additional catheterization because of recurrent symptoms or an abnormal stress test. Clinical restenosis was confirmed in 18%, and an additional 2.2% of patients had progression of disease in previously untreated segments. At the end of 1 year, 14% had undergone repeat target vessel revascularization. Cumulatively at follow-up, approximately 80% had avoided an acute major complication and repeat revascularization for restenosis. Rotational atherectomy provides excellent acute and good late clinical results. At 1 year follow-up, the likelihood of developing clinical restenosis or significant progression of disease was 1 in 5, and patients had a 1 in 7 chance of requiring revascularization because of restenosis. These findings are encouraging and indicate that rotational atherectomy can be performed safely and with a high degree of acute and late clinical success in complex coronary disease characterized by multivessel or multilesion involvement and a predominance of B2 and C lesions.     

Cardioprotective effects of the novel adenosine A1/A2 receptor agonist AMP 579 in a porcine model of myocardial infarction

This study examined the cardioprotective effects and pharmacology of the novel adenosine A1/A2 receptor agonist ([1S-[1a,2b,3b, 4a(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-methylpropyl]amino]-3H-imida zo[4,5-b] pyridyl-3-yl] cyclopentane carboxamide) (AMP 579), in a model of myocardial infarction. Experiments were performed in pentobarbital-anesthetized pigs in which myocardial infarction was induced by a 40-min occlusion of the left anterior descending coronary artery, followed by 3 hr of reperfusion. This procedure resulted in approximately 20% of the left ventricle being made ischemic in all test groups. In untreated animals, an infarct size equal to 56 +/- 5% of the ischemic area was observed. Preconditioning, with two cycles of 5 min of ischemia followed by 10-min reperfusion, resulted in a 70% reduction in infarct size (17 +/- 5%) relative to risk area. Administration of AMP 579 30 min before ischemia (3 microg/kg i.v. followed by 0.3 microg/kg/min i.v. through 1 hr of reperfusion) did not change blood pressure, HR or coronary blood flow but resulted in marked cardioprotection: a 98% reduction in infarct size (1 +/- 1%) relative to risk area. Moreover, whereas approximately 90% of control pigs suffered ventricular fibrillation during ischemia, no fibrillation was observed in animals treated with AMP 579. Further experiments determined the effects of AMP 579 when administered 30 min after the onset of myocardial ischemia, 10 min before reperfusion. Two doses were studied: a low hemodynamically silent dose (3 microg/kg + 0.3 microg/kg/min through 1 hr of reperfusion) and a 10-fold higher dose that did cause reductions in blood pressure and HR. Both doses of AMP 579 produced a comparable cardioprotective effect, reducing infarct size to approximately 50% of that observed in control animals. The cardioprotective effect of AMP 579 was a consequence of adenosine receptor stimulation, because it was completely inhibited by pretreatment with the specific adenosine receptor antagonist CGS 15943 (1 mg/kg i.v.). However, the selective A1 receptor agonist GR 79236 (3 microg/kg + 0.3 microg/kg/min i.v.) did not reduce infarct size, which suggests that under these experimental conditions, stimulation of adenosine A2 receptors is important for the cardioprotective effect of AMP 579. The adenosine-regulating agent acadesine (5 mg/kg + 0.5 mg/kg/min i.v.) also failed to reduce infarct size. In conclusion, the novel adenosine A1/A2 receptor agonist AMP 579 produces marked cardioprotection whether administered before myocardial ischemia or reperfusion. Cardioprotection is not dependent on changes in afterload or myocardial oxygen demand and is a consequence of adenosine receptor stimulation. The pharmacological profile of AMP 579 in this model is consistent with its potential utility in the treatment of acute myocardial infarction.     

FhuF, an iron-regulated protein of Escherichia coli with a new type of [2Fe-2S] center

We previously used fhuF as a sensitive reporter gene of the iron status of Escherichia coli. In this report, the fhuF gene was identified as open reading frame f262b at 99.2 min on the genome sequence map of E. coli K-12. The FhuF protein was labeled with a His-tag and then purified to electrophoretic homogeneity. Based on sulfur determinations and M?ssbauer and EPR spectroscopy, FhuF was identified as a [2Fe-2S] protein. The g values (gx = 1.886, gy = 1.961, gz = 1.994) and some of the M?ssbauer parameters of FhuF obtained [oxidized protein as isolated: delta EQ,4.2K = 0.474 mm s-1; Fe3+ (reduced protein): delta EQ = 0.978 mm s-1] are not typical of common [2Fe-2S] proteins and indicate that FhuF has unusual structural properties. The primary sequence of FhuF does not show any sequence similarities to known [2Fe-2S] proteins. By site-directed mutagenesis, each of the six cysteines of FhuF was replaced by serine. EPR of the six reduced mutant proteins revealed that the terminal cysteine residues 244, 245, 256, and 259 form the [2Fe-2S]Cys4 cluster. Mutants having the Cys-to-Ser replacement at positions 244, 245, 256, or 259 did not complement a fhuF mutant. The motif Cys-Cys-Xaa10-Cys-Xaa2-Cys in FhuF differs considerably from the motif Cys-Xaa2-Cys-Xaa9-15-Cys-Xaa2-Cys found in other [2Fe-2S] proteins. The unusual Cys-Cys terminal group of the cluster may explain the atypical EPR and M?ssbauer spectroscopic properties of the FhuF protein; possibly the tetrahedral symmetry at the ferric ion site is distorted. The phenotype of fhuF mutants and the structural features of the FhuF protein suggest that FhuF is involved in the reduction of ferric iron in cytoplasmic ferrioxamine B.     

Induction of atypical squamous metaplasia with benzo[a]pyrene in cultured hamster tracheas

Areas of hyperplasia were produced in hamster tracheal epithelium maintained in vitro by exposure to a suspension of benzo[a]pyrene (BP) in gelatin. Typical and atypical epiodermoid metaplasia were seen by 2 weeks. In atypical areas, cell nuclei were enlarged with prominent nucleoli, the cytoplasm contained dense bundles of tonofilaments and the cells were joined by numerous desmosomes. The peak response to the carcinogen was reached 4 weeks after the application of BP and consisted of extensive atypical epidermoid metaplasia. Tracheas treated with gelatin alone maintained a columnar epithelium for 6 weeks of culture. The characteristics of the metaplastic changes in vitro are essentially identical to those described after exposure of the hamster tracheobronchial epithelium to benzo[a]pyrene-ferric oxide in vivo.     

Extracts of porcine pancreas prevent progression of hypercalcemia and cachexia and prolong survival in nude mice bearing a human squamous carcinoma

Porcine pancreatic extracts (PXs) have previously been shown to decrease blood ionized calcium in BALB/c mice (T. Yoneda, Y. Takaoka, and G. R. Mundy. FEBS Lett., 278: 171-174, 1991). In the present study, we show that the PX is effective in preventing progression of hypercalcemia and decreasing osteoclastic bone resorption associated with a human squamous carcinoma in nude mice. PX inhibited osteoclast-like cell formation in mouse bone marrow cultures and bone resorption in organ cultures of fetal rat long bones which had been stimulated by serum-free culture supernatants of this cancer. In addition, PX increased food intake, decreased weight loss, and prevented development of cachexia. In parallel with these effects, PX prolonged survival of tumor-bearing animals. PX might have therapeutic potential for management of hypercalcemia and cachexia associated with malignancy.     

Recognising Simple Behaviours Using Time-Delay RBF Networks

This paper presents experiments using a radial basis function variant of the time-delay neural network with image sequences of human faces. The network is shown to be able to learn simple behaviours based on y-axis head rotation and generalise on different data. The network model's suitability for future dynamic vision applications is discussed.