A 26-year-old man with shoulder pain

The acute effects of flumazenil, a benzodiazepine (BZD) receptor antagonist in long-term BZD users were used as a possible test to detect physiological dependence. Thirty-four subjects (20 females, 14 males) aged 26-48 years (mean + SD, 42.4+/-8.5 years), all chronic users of low doses of diazepam (5-20 mg/day, 14.2+/-4.8 mg/day) for 5 to 28 years (10.5+/-6 years), received a single 1-mg i.v. flumazenil dose or saline, infused slowly under double-blind conditions. Physiological dependence was suggested as all patients receiving flumazenil developed an anxiety reaction while the placebo group did not. Flumazenil triggered a qualitatively different reaction amounting to a panic attack during infusion in nine out of 15 patients. These patients had a diagnosis of panic disorder or a history of panic attacks. Caution should be exercised when giving flumazenil to panic patients who are taking BZDs as maintenance treatment.     

The effects of aging on mu and delta opioid receptors in the spinal cord of Fischer-344 rats

The lordosis-inhibiting effects of the 5-HT1A receptor agonist, (+/-)8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), were examined in ovariectomized rats, hormone primed with 2.5, 7.5, or 25 micrograms estradiol benzoate plus 500 micrograms progesterone. 8-OH-DPAT (50, 100 or 200 ng per bilateral site) infused into the ventromedial nucleus of the hypothalamus (VMN), inhibited lordosis behavior in all hormone-treated conditions. However, animals primed with 2.5 micrograms estradiol benzoate were significantly more affected by the infusion than rats primed with 7.5 or 25 micrograms of the hormone. These findings strengthen prior speculations that 5-HT1A receptor function is modulated by estrogen.     

Transgenic animals in toxicology

Recent advances have been made in the characterization of a number of transgenic animal models. These animal models have provided a powerful toxicological tool for studying in vivo chemical effects and have increased our understanding of the role of specific genetic alterations as predisposing factors for chemical carcinogenesis. The goal of this symposium was to introduce the development of transgenic animals and the utilization of transgenics in toxicology research focusing on understanding tissue-specific mutation, chemical effects, and cancer. The production of transgenic animals, including gene insertions and gene knockouts, and the utilization of transgenic technology for studying multistage carcinogenesis and tumor suppressor genes are described. Data on the application and implications of transgenics as a genetic endpoint are also discussed. The use of transgenic animals in toxicology should improve our understanding of the role of specific genetic alterations in the carcinogenic process and lead to improved estimations of human health risks.     

Permanent open shunt as a reason for impotence or reduced potency after surgical treatment of priapism in 26 patients

A permanent open shunt as a cause of impotence or impaired potency after a shunt operation for priapism is an unusual situation. In this series we studied the persistence of an open shunt in 26 patients who had developed impotence or impaired potency after operative treatment for priapism. All patients had been examined by cavernosography on the suspicion of an open shunt, giving a positive finding in five of 26 cases, in all of which impotence was cured by closure of the shunt. In five patients without a permanent open shunt potency returned to normal only after 6-12 months.     

Opposing effects by glucocorticoid and bone morphogenetic protein-2 in fetal rat bone cell cultures

Glucocorticoid in excess produces bone loss in vivo. Consistent with this, it reduces the stimulatory effect of transforming growth factor beta (TGF-beta) on collagen synthesis in osteoblast-enriched cultures in vitro, where it also suppresses TGF-beta binding to its type I receptors. Analogous studies with bone morphogenetic protein-2 (BMP-2) show directly opposite results. These findings prompted us to assess the effect of glucocorticoid on BMP-2 activity in cultured bone cells, and whether either agent had a dominant influence on TGF-beta binding or function. BMP-2 activity was retained in part in osteoblast-enriched cultures pre-treated or co-treated with cortisol, and was fully evident when glucocorticoid exposure followed BMP-2 treatment. In addition, BMP-2 suppressed the effects of cortisol on TGF-beta activity, on TGF-beta binding, and on gene promoter activity directed by a glucocorticoid sensitive transfection construct. While BMP-2 also alters the function of less-differentiated bone cells, it only minimally prevented cortisol activity in these cultures. Our studies indicate that BMP-2 can oppose certain effects by cortisol on differentiated osteoblasts, and may reveal useful ways to diminish glucocorticoid-dependent bone wasting.     

In vitro and in vivo antipseudomonal activity, acute toxicity, and mode of action of a newly synthesized fluoroquinolonyl ampicillin derivative

Compounds N-(6,7-difluoroquinolonyl)-ampicillin (AU-1) and N-(6-fluoroquinolonyl)-ampicillin (FQ-1), synthesized by coupling of the carboxyl group of 6,7-difluoroquinolone (FP-3) and 6-fluoroquinolone (FP4), respectively, with the alpha-amino-group of ampicillin side chain, exhibit antipseudomonal activity similar to and lower acute toxicity than that of norfloxacin, whereas neither ampicillin nor the fluoroquinolone moieties, compound FP-3 or FP4, alone have such activity. Also, AU-1 and FQ-1 are active against tested clinical isolates of Pseudomonas aeruginosa that are highly resistant to norfloxacin, gentamicin, or both. The therapeutic efficacies of FQ-1 and norfloxacin were assessed and compared in neutropenic mice infected with a 90% lethal dose of P aeruginosa. Mice intraperitoneally administered FQ-1 (10 mg/kg) 4, 8, 24, and 48 hours after infection had survival rates as high as 80%, comparable to those of mice treated with norfloxacin at the same dosage and dosing schedule. The study of protoplast formation revealed that FQ-1 did not inhibit cell-wall biosynthesis but did induce cell filamentation of Bacillus subtilis at a level close to its minimal inhibition concentration. Both AU-1 and FQ-1 were able to intercalate into the double-stranded DNA. However, that FQ-1 lost such activity after it was treated with penicillinase suggests that the lactam-ring structure in ampicillin moiety of FQ-1 was hydrolyzed by penicillinase and that the hydrolyzed structure of FQ-1 does not own DNA-intercalation activity.     

Increased prevalence of hypertension and long-term arsenic exposure

A possible role of endothelin (ET)-1 in mediating hypoxic pulmonary vasoconstriction (HPV) was examined by comparing haemodynamic differences between ET-1-induced vasoconstriction and HPV in isolated perfused rat lungs. An ETA receptor antagonist (BQ123) was also employed to assess the effects of ET-1. The pulmonary arterial pressure (Ppa) was significantly increased by alveolar hypoxia (3% O2) and by ET-1 (5 nM). The pulmonary microvascular pressure was not changed by hypoxia, but increased more than two-fold by ET-1 (P < 0.01). Hypoxia significantly increased pulmonary arterial resistance (P < 0.01) while ET-1 significantly increased pulmonary venous resistance (P < 0.01), and slightly increased arterial resistance. Lung weight was increased by ET-1 and decreased by hypoxia, accompanied by similar Ppa responses in both cases. BQ123 (10(-6) M and 10(-5) M) did not influence the changes in Ppa and lung weight induced by hypoxia or angiotensin II (0.3 micrograms). BQ123 did, however, suppress (P < 0.05) the increase in Ppa and lung weight induced by 5 nM ET-1. Thus, it appears unlikely that ET-1 is involved in changes in pulmonary vascular tone during acute HPV.