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(1/1800) Is early post-operative treatment with 5-fluorouracil possible without affecting anastomotic strength in the intestine?

Early post-operative local or systemic administration of 5-fluorouracil (5-FU) is under investigation as a means to improve outcome after resection of intestinal malignancies. It is therefore quite important to delineate accurately its potentially negative effects on anastomotic repair. Five groups (n = 24) of rats underwent resection and anastomosis of both ileum and colon: a control group and four experimental groups receiving daily 5-FU, starting immediately after operation or after 1, 2 or 3 days. Within each group, the drug (or saline) was delivered either intraperitoneally (n = 12) or intravenously (n = 12). Animals were killed 7 days after operation and healing was assessed by measurement of anastomotic bursting pressure, breaking strength and hydroxyproline content. In all cases, 5-FU treatment from the day of operation or from day 1 significantly (P<0.025) and severely suppressed wound strength; concomitantly, the anastomotic hydroxyproline content was reduced. Depending on the location of the anastomosis and the route of 5-FU administration, even a period of 3 days between operation and first dosage seemed insufficient to prevent weakening of the anastomosis. The effects of intravenous administration, though qualitatively similar, were quantitatively less dramatic than those observed after intraperitoneal delivery. Post-operative treatment with 5-FU, if started within the first 3 days after operation, is detrimental to anastomotic strength and may compromise anastomotic integrity.  (+info)

(2/1800) Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist.

1. We designed and synthesized several novel cyclic MSH analogues and tested their affinities for cells expressing the MC1, MC3, MC4 and MC5 receptors. 2. One of the substances HS028 (cyclic [AcCys11, dichloro-D-phenylalanine14, Cys18, Asp-NH2(22)]-beta-MSH11-22) showed high affinity (Ki of 0.95nM) and high (80 fold) MC4 receptor selectivity over the MC3 receptor. HS028 thus shows both higher affinity and higher selectivity for the MC4 receptor compared to the earlier first described MC4 receptor selective substance HS014. 3. HS028 antagonised a alpha-MSH induced increase in cyclic AMP production in transfected cells expressing the MC3 and MC4 receptors, whereas it seemed to be a partial agonist for the MC1 and MC5 receptors. 4. Chronic intracerebroventricularly (i.c.v.) administration of HS028 by osmotic minipumps significantly increased both food intake and body weight in a dose dependent manner without tachyphylaxis for a period of 7 days. 5. This is the first report demonstrating that an MC4 receptor antagonist can increase food intake and body weight during chronic administration providing further evidence that the MC4 receptor is an important mediator of long term weight homeostasis.  (+info)

(3/1800) Intraperitoneal insemination of the guinea pig with synchronized estrus induced by progesterone implant.

Female guinea pigs with synchronized ovulation by means of implantation of progesterone-filled tubing (P-tube) followed by a progesterone injection, were inseminated by intraperitoneal injection with sperm suspension. First, to obtain the optimum conditions for insemination, the females were inseminated singly over the range of 1-10 x 10(7) spermatozoa before and after the synchronized ovulation. The incidence of conception and implantation was 100% in the females given more than 5 x 10(7)/animal at 9:00 h on the 5th day after removal of the P-tube. Second, the reproductive ability of the inseminated females under this optimal condition was observed throughout the pregnancy to delivery. Inseminated females had a mean +/- S.D. gestation period of 68.7 +/- 0.5 days, a litter size of 2.8 +/- 0.6 pups and body weight of 110 +/- 14 g. These data were comparable to those of naturally-mated females. Our findings suggest that the artificial insemination by intraperitoneal injection in combination with the synchronized estrus technique is very useful for production control in a small colony of guinea pigs.  (+info)

(4/1800) Cefamandole: in vitro and clinical pharmacokinetics.

Cefamandole has a broader spectrum and greater potency than the other cephalosporins. It includes Haemophilus influenzae, most strains of Enterobacter, and many strains of indole-positive Proteus and Bacteroides, with a lower minimal inhibitory concentration for Escherichia coli, Klebsiella, etc. Concentrations of drug in the serum after the parenteral injection of cefamandole exceed manyfold the minimal inhibitory concentrations of over 82% of the bacteria studied. Approximately 65 to 85% is excreted in a biologically active form in the urine. This antibiotic offers advantages of antibacterial effectiveness and at the same time retains the safety of penicillin G and cephalothin in animals.  (+info)

(5/1800) Apparent loss and hypertrophy of interneurons in a mouse model of neuronal ceroid lipofuscinosis: evidence for partial response to insulin-like growth factor-1 treatment.

The neuronal ceroid lipofuscinoses (NCL) are progressive neurodegenerative disorders with onset from infancy to adulthood that are manifested by blindness, seizures, and dementia. In NCL, lysosomes accumulate autofluorescent proteolipid in the brain and other tissues. The mnd/mnd mutant mouse was first characterized as exhibiting adult-onset upper and lower motor neuron degeneration, but closer examination revealed early, widespread pathology similar to that seen in NCL. We used the autofluorescent properties of accumulated storage material to map which CNS neuronal populations in the mnd/mnd mouse show NCL-like pathological changes. Pronounced, early accumulation of autofluorescent lipopigment was found in subpopulations of GABAergic neurons, including interneurons in the cortex and hippocampus. Staining for phenotypic markers normally present in these neurons revealed progressive loss of staining in the cortex and hippocampus of mnd/mnd mice, with pronounced hypertrophy of remaining detectable interneurons. In contrast, even in aged mutant mice, many hippocampal interneurons retained staining for glutamic acid decarboxylase. Treatment with insulin-like growth factor-1 partially restored interneuronal number and reduced hypertrophy in some subregions. These results provide the first evidence for the involvement of interneurons in a mouse model of NCL. Moreover, our findings suggest that at least some populations of these neurons persist in a growth factor-responsive state.  (+info)

(6/1800) A nerve growth factor mimetic TrkA antagonist causes withdrawal of cortical cholinergic boutons in the adult rat.

Cholinergic neurons respond to the administration of nerve growth factor (NGF) in vivo with a prominent and selective increase of choline acetyl transferase activity. This suggests the possible involvement of endogenous NGF, acting through its receptor TrkA, in the maintenance of central nervous system cholinergic synapses in the adult rat brain. To test this hypothesis, a small peptide, C(92-96), that blocks NGF-TrkA interactions was delivered stereotactically into the rat cortex over a 2-week period, and its effect and potency were compared with those of an anti-NGF monoclonal antibody (mAb NGF30). Two presynaptic antigenic sites were studied by immunoreactivity, and the number of presynaptic sites was counted by using an image analysis system. Synaptophysin was used as a marker for overall cortical synapses, and the vesicular acetylcholine transporter was used as a marker for cortical cholinergic presynaptic sites. No significant variations in the number of synaptophysin-immunoreactive sites were observed. However, both mAb NGF30 and the TrkA antagonist C(92-96) provoked a significant decrease in the number and size of vesicular acetylcholine transporter-IR sites, with the losses being more marked in the C(92-96) treated rats. These observations support the notion that endogenously produced NGF acting through TrkA receptors is involved in the maintenance of the cholinergic phenotype in the normal, adult rat brain and supports the idea that NGF normally plays a role in the continual remodeling of neural circuits during adulthood. The development of neurotrophin mimetics with antagonistic and eventually agonist action may contribute to therapeutic strategies for central nervous system degeneration and trauma.  (+info)

(7/1800) Intraperitoneal gene therapy with adenoviral-mediated p53 tumor suppressor gene for ovarian cancer model in nude mouse.

In an effort to develop a method for better local control of advanced ovarian cancers, we have established a peritoneal tumor model of ovarian cancer in the nude mouse and applied intraperitoneal gene therapy with the recombinant adenoviral-mediated wild-type p53 tumor suppressor gene (Avp53). The results indicate that: (a) the recombinant adenoviral vector system effectively infected the tumor and normal cells in the peritoneal cavity; and (b) Avp53 treatment effectively suppressed the growth of peritoneal tumors and prolonged the survival of the treated group, especially when the tumor burden was less. These results suggest that intraperitoneal gene therapy using Avp53 is potentially useful as an adjuvant therapeutic modality in human ovarian cancer.  (+info)

(8/1800) Many LH peaks are needed to physiologically stimulate testosterone secretion: modulation by fasting and NPY.

The pulsatile luteinizing hormone (LH) and testosterone secretions were studied during serial blood collections performed at 7-min time intervals in the male rat. In fed rats, a discontinuous pattern of LH secretion was observed. Periods without secretion alternated with active secretory episodes consisting in trains of three to four LH peaks that triggered testosterone secretion usually 1-2 h later. The magnitude of the testosterone response was not correlated with the amplitude of the LH peaks. Isolated, single peaks of LH did not evoke clear testosterone responses. Forty-eight hours after initiation of fasting, testosterone secretion was markedly decreased, but integrated LH secretion was only partly reduced. Chronic infusion of neuropeptide Y (NPY; 18 microgram/day, icv) reduced testosterone secretion to very low levels and abolished pulsatile LH secretion or testosterone response to isolated LH peaks. In conclusion, the stimulation of testosterone secretion by LH necessitates several LH peaks organized in a proper sequence, and the testosterone response is not immediate. Low testosterone secretion in fasting rats appears to result from disappearance of coordinated, multiple LH peaks of sufficient size. Inhibition of the gonadotropic axis achieved by central NPY administration is due to either absence of LH peak "clusters" or occurrence of nonfunctional single LH peaks.  (+info)