Evidence for involvement of 5-HT1C and 5-HT2 receptors in the food intake suppressant effects of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)

Administration of various doses of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) to rats produced dose-related decreases in 1-h food intake in the food-deprived paradigm. Pretreatment with spiperone (5-HT_1A/5-HT₂/D₂ antagonist), propranolol or CGP361A (-adrenoceptor antagonists that also have binding affinities for 5-HT_1A and 5-HT_1B sites) and MDL-72222 (5-HT₃ antagonist) did not attenuate DOI-induced suppression of food intake. In contrast, pretreatment with metergoline (5-HT₁/5-HT₂ antagonist) completely blocked whereas mesulergine, mianserin and ritanserin (5-HT_1C/5-HT₂ antagonists) partially blocked DOI's effect on food intake. On the other hand, pretreatment with MDL-72222 but not with m-chlorophenylpiperazine (m-CPP) significantly potentiated DOI-induced suppression of food intake. Furthermore, the food intake suppressant effects of various doses of DOI were found to be similar in the Fawn-Hooded (FH) rat strain as compared to the Wistar rat strain. These findings suggest that DOI-induced suppression of food intake is mediated by stimulation of both 5-HT_1C and 5-HT₂ receptors.     

Evaluation of the toxicity,pathology, and treatment of cyclohexylmethylphosphonofluoridate (CMPF) poisoning in rhesus monkeys

Cyclohexylmethylphosphonofluoridate (CMPF) is an organophosphate cholinesterase inhibitor with military significance. The purpose of these studies was 1) to determine the acute toxicity of CMPF in the male rhesus monkey, 2) to evaluate the efficacy of pyridostigmine (PYR) pretreatment plus atropine and oxime (2-PAM or HI6) treatment, and 3) to evaluate the pathological consequences of acute poisoning. An i. m. LD₅₀ of CMPF was estimated using an up-and-down dose selection procedure and 12 animals. The 48-h and 7-day LD₅₀ was 46.6 g/kg, i.m. In the protection experiments, pyridostigmine (0.3–0.7 mg/kg/24 h) was administered by surgically implanted osmotic minipumps for 3–12 days resulting in 21–65% inhibition of erythrocyte acetylcholinesterase activity. Animals were challenged with 5 × LD₅₀ CMPF (233 g/kg) and treated with atropine (0.4 mg/kg) and either 2-PAM (25.7 mg/kg) or HI6 (37.8 mg/kg) at the onset of signs or 1 min after challenge. Osmotic pumps were removed within 30 min after agent challenge. Pyridostigmine, atropine, and either 2-PAM or HI6 were completely effective against CMPF, saving ten of ten animals in each group. In comparison, three of five animals challenged with 5 × LD₅₀ of soman and treated with atropine and 2-PAM survived 7 days. The primary histologic lesions in the acute toxicity group were neuronal degeneration/necrosis and spinal cord hemorrhage. The CMPF treated groups (total of 20 animals) had minimal nervous system changes with no significant lesion difference resulting from the different oxime therapies. The primary non-neural lesions were degenerative cardiomyopathy and skeletal muscle degeneration which occasionally progressed to necrosis and mineralization. The results indicate that PYR pretreatment in conjunction with atropine and oxime treatment is an effective regimen against battlefield relevant levels (5 × LD₅₀) of CMPF.The experiments reported here were conducted according to the Guide for Care and Use of Laboratory Animals (1985), as prepared by the Committee on Care and Use of Laboratory Animals, National Research Council, NIH Publication No. 85-23. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting views of the Department of the Army or the Department of Defense.     

Predicting genitourinary toxicity in patients receiving cisplatin-based combination chemotherapy: a cancer and leukemia group B study

Summary Assessment of renal function prior to cisplatin chemotherapy has long been based on measurement of creatinine clearance by 24-hour urine collection (CrC _meas). Estimated creatinine clearance (CrC _est) as calculated from the patient's age, weight, and serum creatinine level has been suggested as an adequate surrogate for CrC _meas, as it provides advantages of improved convenience, decreased cost, and possibly increased accuracy. We studied 847 patients receiving cisplatin-based chemotherapy on Cancer and Leukemia Group B (CALGB) protocols to determine whether the CrC _meas, CrC _est, or serum creatinine value or the age of the patient would predict the subsequent genitourinary (GU) toxicity. Both CrC _meas (P=0.001) and CrC _est (P=0.02) were predictive of subsequent grade 2+GU toxicity, with CrC _meas being a slightly better predictor. Patient age also influenced subsequent GU toxicity, with the risk increasing with age (P=0.0008). When patients were classified by age group and by CrC _meas, distinct subgroups were identified, with differences in the risk for grade 2+GU toxicity ranging from 14% to 32%. Using a logistic model to assess the probability of grade 2+GU toxicity, we found that an age of60 years (P=0.005), a CrC _meas value of <75 ml/min (P=0.004), and the risk characteristics of the individual cisplatin trial were important, whereas CrC _est was not. Furthermore, CrC _est proved to be a poor predictor of a CrC _meas value of <75 ml/min, misclassifying nearly half of the patients to a lower-risk subgroup. In summary, both CrC _meas and the patient's age independently provided predictive information concerning cisplatin GU toxicity. Our data support the continued clinical usefulness of determining the CrC _meas value prior to the administration of cisplatin-based chemotherapy to most patients.This study is supported by the following NIH grants: CA 26806, CA 33601, CA 11789, CA 31983, USAThe opinions or assertations contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense of the United States of America     

Transthyretin is an inhibitor of monocyte and endothelial cell interleukin-1 production

Human serurn was found to contain an inhibitor of constitutive interleukin 1 (IL-1) production by human umbilical vein endothelial cells (ECs). Purification of the serum activity by anion exchange chromatography, molecular sieve HPLC, and hydroxyl apatite chromntography yielded material 82% pure with a molecular weight of 17 kDa by SDS-PAGE. Amino acid sequencing revealed the purified inhibitor to be transthyretin (TTR). a liver-derived protein. There was a 42.6% reduction in the production of spontaneous IL-1 activity in EC supernatants after coculture with 10g/ml TTR. TTR was subsequently found by ELISA to inhibit LPS-stimulated IL-1 production by cells of the human monocytic leukemia line THP-1 by 47.1 ± 9.4%, whereas a less striking but still significant inhibition of monocyte-derived IL-1 production was also observed. Inhibition of IL-1 secretion correlated with increased IL-1 mRNA synthesis in both THP-1 cells and monocytes. Furthermore, TTR was associated with increased intracellulaf concentrations of IL-1. These data suggest that TTR functions by inhibiting processing of newly synthesized peptide for secretion. This novel inhibitory effect of TTR on the production of IL-1 activity suggests a previously unrecognized endogenous antiinflammatory mediator.     

Intravesical Evans strain BCG therapy: quantitative immunohistochemical analysis of the immune response within the bladder wall.

Previous studies have demonstrated that is is the local immune response which is of importance for the anti-tumour activity of BCG therapy. We have investigated this by quantitative immunohistochemical analysis of serial bladder mucosal biopsies taken before, during and after an eight week course of intravesical Evans strain BCG therapy and three monthly thereafter in 16 patients (15 extensive CIS and one extensive G2pTa papillary tumour). This particular group of patients had a 67% complete response rate at six months post-treatment. The main findings on immunohistochemical analysis were the universal induction of MHC Class II antigens by urothelial cells which was statistically significant up to 6 months after completion of therapy, coupled with a T cell dominated cystitis. Increases in CD3+ T cell infiltration of the lamina propria and that of the CD4+ "Helper" subset which predominated were significant up to 3 months post-therapy and these cells showed evidence of increased immunological activation as shown by increased interleukin-2 receptor and MHC Class II antigen expression. There were also significant increases in CD68+ macrophage and the incidence of CD22+ B cell aggregates but CD57+ NK cells were sparse both before and after therapy. The degree of mononuclear cell infiltration for all markers examined (except CD57) was significantly greater in those biopsies in which the urothelial cells expressed MHC Class II antigens than in those that did not. Also the degree of T cell infiltration (CD3, CD4 and CD8) was significantly greater in the eight patients deemed to have had a complete response compared to those seven with a partial response or treatment failure. These results are discussed in terms of possible mechanisms of action for BCG therapy and in particular the role of enhanced antigen presentation by tumour cells.     

The neuromuscular effects of sevoflurane and isoflurane alone and in combination with vecuronium or atracurium in the rat

Sevoflurane was compared to isoflurane anesthesia alone and in combination with atracurium or vecuronium in 84 rats using the sciatic nerve—anterior tibialis muscle preparation. Both bolus injection and infusion rate techniques were used to evaluate these drug interactions. The ED₅₀ (dose which produced a 50% depression of twitch tension) of atracurium was 311 ± 31 and 360 ± 32µg·kg^–1 during 1.25MAC sevoflurane and isoflurane anesthesia respectively. The ED₅₀ of vecuronium was 190 ± 27 and 149 ± 14µg·kg^–1 during 1.25MAC sevoflurane and isoflurane anesthesia respectively. The mean infusion rates of atracurium and vecuronium required to maintain a 50% depression of twitch tension were 5.04 ± 0.7 and 2.02 ± 0.3mg·kg^–1·hr^–1. These infusion rates were 5.04 ± 0.7 and 2.02 ± 0.3mg·kg^–1·hr^–1 during 1.25MAC sevoflurane and 3.73 ± 0.3 and 1.81 ± 0.4mg·kg^–1·hr^–1 during 1.25MAC isoflurane anesthesia respectively. With both atracurium and vecuronium, the infusion rate required to maintain a 50% depression twitch of tension was inversely related to the concentrations of isoflurane and sevoflurane. The authors conclude that sevoflurane is similar in potency to that of isoflurane in augmenting a vecuronium or atracurium induced neuromuscular blockade in a dose-dependent manner.(Shin YS, Miller RD, Caldwell JE, et al.: The neuromuscular effects of sevoflurane and isoflurane alone and in combination with vecuronium or atracurium in the rat. J Anesth 6: 1–8, 1992)     

The effect of growth hormone on the growth failure of chronic renal failure

To investigate the effects of growth hormone (GH) on the reversal of growth failure in uremia, recombinant human GH (rhGH) was administered to rats with chronic renal failure (CRF). The dosage of rhGH was 3 IU/day (i.p.) for 13 days after the induction of CRF by 5/6 nephrectomy. Animals were classified into four groups: untreated nephrectomized rats (NX,n=40), GH-treated nephrectomized rats (NX+GH,n=18), sham-operated rats fed ad libitum (SHAMAL,n=27), and sham-operated rats pair-fed with 10 NX rats (SHAMPF,n=10). NX and NX+GH rats developed a similar and moderate degree of CRF, serum urea nitrogen being (mean±SEM) 49±3 and 54±4 mg/dl, respectively, compared with 16±4 and 19±0 mg/dl in SHAMAL and SHAMPF groups. Weight (56.0±3.3 g) and length (3.5±0.1 cm) gains of NX rats were lower than those of SHAMAL rats (94.2±4.0 g,P<-0.0001 and 4.1±0.2 cm,P<-0.01). Growth of the SHAMPF group and the matched NX rats was not significantly different. Weight (56.2±5.0 g) and length (3.4±0.2 cm) gains of NX+GH and NX rats were similar, the beneficial effect of GH therapy on growth being observed in only those animals with more severe degrees of uremia. This growth-promoting action resulted from greater food efficiency and not from stimulated food intake. The hypercholesterolemia seen in NX rats, 81±2 mg/dl versus 55±3 mg/dl in SHAMAL (P0.0001), was not increased in the NX+GH group, 87±3 mg/dl. There was a positive and significant correlation between serum cholesterol and serum urea nitrogen values in NX and NX+GH animals. This study suggests that growth impairment of mild CRF is mainly due to malnutrition and is refractory to GH administration. GH therapy improves the growth rate of animals with advanced CRF without aggravating their lipid abnormalities.     

Observations on Nine Personal Cases Where Esophagitis Has Appeared as a Complication of a Functioning Vertical Gastroplasty

This paper is based on observations on a personal series of patients who presented with severe ulcerating esophagitis, unresponsive to medical treatment following a vertical stapled gastroplasty. With one exception this was a late complication in an effective weight loss procedure. The therapeutic modalities chosen to treat this problem depended on patient choice, as well as personal experience with treating earlier cases. Unfortunately, I could find little guidance in the literature or from my colleagues on how to treat this problem. Conversion to a Roux-Y gastric bypass seemed the most satisfactory solution to the problem, relieving the symptoms and maintaining the weight loss.     

Nasal symmetry: a 10-year comparison between the Pigott and McComb nasal correction.

The objective assessment of the symmetry of the cleft lip nose has not been properly evaluated. A simple technique using enlarged photographs and area assessment is described. Two different techniques were assessed, the Pigott "alar leapfrog" technique and the McComb alar lift technique. The children were assessed at 10 years of age. The results show no differences in the linear measurements or when the symmetry is assessed in the frontal view. In the worm's eye view, the Pigott correction was shown to produce a more asymmetric nose when compared with the McComb technique. Both corrections produce significant asymmetry when compared with a control group.     

Use of a Calibration Balloon Tube to Size the Pouch and Channel in Gastroplasty Procedures

Gastroplasty is currently one of the most common surgical procedures performed on the morbidly obese for weight loss. An adequate result can be assured only if the pouch that is created is less than 30 ml and the channel that connects that pouch to the distal stomach is approximately 1 cm in diameter. The current method to size the pouch is to occlude the esophagus and the outlet of the pouch and to measure with a manometer through a naso-gastric tube. We contend this method is both time consuming and adds to the potential of complications. Through the use of a calibration balloon tube the size of the pouch can be quickly and safely estimated. It can also be used to size the channel between the pouch and the distal stomach and check for leaks. The technique of how this tube has been used over the past 6 years is described. By the use of a calibration balloon tube, three problem areas in gastric stapling surgery for morbid obesity are avoided, namely: inappropriate pouch size, inappropriate channel size and postoperative leaks.