2-Phenyl-imidazo[1,2-a]pyridine derivatives as ligands for peripheral benzodiazepine receptors: stimulation of neurosteroid synthesis and anticonflict action in rats.

Selective activation of peripheral benzodiazepine receptors (PBRs) in adrenal cells and brain oligodendrocytes promotes steroidogenesis. Three 2-phenyl-imidazo[1,2-a]pyridine derivatives (CB 34, CB 50 and CB 54) have now been investigated with regard to their selectivity for PBRs and their ability to stimulate central and peripheral steroidogenesis in rats. The three CB compounds (10(-10)-10(-4) M) potently inhibited the binding of the PBR ligand [3H]-PK 11195 to brain and ovary membranes in vitro, without substantially affecting [3H]-flunitrazepam binding to central benzodiazepine receptors. These compounds (10(-7)-10(-4) M) also had little or no marked effects on GABA-evoked Cl- currents in voltage-clamped Xenopus oocytes expressing human alpha1beta2gamma2S GABA(A) receptors. In addition, they failed to affect ligands binding to GABA(B), D1/D2 dopamine, muscarinic acetylcholine, N-methyl-D-aspartic acid and opiate receptors. Intraperitoneal administration of CB compounds (3-50 mg kg(-1)) induced a dose-dependent increase in the concentrations of neuroactive steroids in plasma and brain. The brain concentrations of pregnenolone, progesterone, allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC) showed maximal increases in 96+/-3, 126+/-14, 110+/-12 and 70+/-13% above control, respectively, 30 to 60 min after injection of CB 34 (25 mg kg(-1)). CB 34 also increased the brain concentrations of neuroactive steroids in adrenalectomized-orchiectomized rats, although to a lesser extent than in sham-operated animals, suggesting that CB compounds stimulate brain steroidogenesis independently of their effects on peripheral tissues. The increase in brain and plasma neurosteroid content induced by CB 34 was associated with a marked anticonflict effect in the Vogel test. Our results indicate that the three CB compounds tested are specific and potent agonists at peripheral benzodiazepine receptors, and that they stimulate steroidogenesis in both the brain and periphery.     

Morpholinylanthracyclines: cytotoxicity and antitumor activity of differently modified derivatives

Summary The relationship between different chemical modifications on morpholinylanthracyclines and their ability to overcome multidrug resistance (MDR) has been evaluated testing all compounds in vitro on LoVo and LoVo/DX human colon adenocarcinoma cells and in vivo on disseminated P388 and P388/DX murine leukemias.Results obtained led us to the following conclusions: 1) the insertion of the morpholinyl or the methoxymorpholinyl group on position 3 of the sugar moiety confers the ability to overcome MDR in vitro and in vivo; conversely, 4 morpholinyl compounds are effective on MDR cells only in vitro and result inactive in vivo on DX-resistant leukemia; 2) all chemical modifications performed on 3 morpholinyl or methoxymorpholinyl derivatives, that is substitutions on the aglycone or on position 2 of the morpholino ring, do not interfere with the activity of the compounds: all derivatives present in fact the same efficacy on sensitive and resistant models.It is concluded that position 3 in the sugar moiety plays a crucial role in the ability of morpholinylanthracyclines to overcome MDR.     

HIV-permissive cells from solid tissues: Cytokine induction and effects

Summary HIV-1 is a polytropic virus that, apart from hematopoietic cells, can replicate in several cells from solid tissues. Virus yields vary widely, closely resembling differences in HIV binding to the cells; the latter phenomenon appears mainly related to the extent of CD4 expression, even though other molecules have been implied in virus-cell interactions, the expression of which on the cell membrane can be modulated by several stimuli. During the course of HIV replication, a series of cytokines is produced and released in parallel to virus growth, particularly IL-6 and TNF-. In fact, exposure of fibroblasts or epithelial cells to these HIV-in-duced cytokines causes an increase of CD4 expression, HIV adsorption to uninfected cells, and release of infectious virions by infected cells. In cells exposed to interferon-, IL-6 and TNF- allow the virus to bypass interferon inhibition of virus release. The fact that HIV-1 adsorption and spread can be mediated by HIV-induced cytokines may be relevant in AIDS pathogenesis, accelerating virus transmission both within the organ and to infiltrating cells, activating a self-maintaining mechanism of infection.     

Long-term follow-up of surgical correction of Madelung's deformity with conservation of the distal radioulnar joint in teenagers

Eleven wrists with painful Madelung deformity in seven patients were corrected during adolescence by a closing wedge osteotomy of the radius and a shortening osteotomy of the ulna, with conservation of the distal radioulnar joint. At late follow-up (9.7 years) function was considerably improved. When the ulnar head was correctly relocated during operation, a new distal radioulnar space developed. Shortening of the ulna must be generous and combined with slight flexion at the osteotomy.     

Value of P-glycoprotein and clinicopathologic factors as the basis for new treatment strategies in high-grade osteosarcoma of the extremities.

PURPOSE: To evaluate the prognostic value of P-glycoprotein and clinicopathologic parameters in a large series of high-grade osteosarcoma (OS) patients treated at the Rizzoli Institute. PATIENTS AND METHODS: With the use of immunohistochemistry, P-glycoprotein was assessed in 149 patients with primary, nonmetastatic, high-grade OS who were homogeneously treated with chemotherapy protocols based on doxorubicin, high-dose methotrexate, and cisplatin and the addition of ifosfamide in the postoperative phase. RESULTS: P-glycoprotein positivity was found in 47 of 149 cases (32%) and was significantly associated with a higher incidence of relapse and a worse outcome, as was age younger than 12 years and tumor volume greater then 150 mL at diagnosis. Multivariate analysis further confirmed the prognostic value of these parameters, which all were independent adverse prognostic factors. Event-free survival and proportional hazards regression analyses confirmed that overexpression of P-glycoprotein at clinical onset is the most important adverse prognostic factor for high-grade OS patients treated with these chemotherapy protocols. CONCLUSION: Increased P-glycoprotein levels, together with tumor volume and age, should be taken into consideration to identify, at time of diagnosis, subgroups of OS patients with a higher risk of recurrence. This subgroup identification will constitute the basis for drawing individualized treatment protocols on the basis of risk evaluation, with the aim of using more aggressive chemotherapy, or combination chemotherapy with other adjuvants, only in those patients for which more aggressive regimens are strictly necessary and warranted.     

Lack of effect of dietary nucleotide supplementation on erythrocyte 2,3-diphosphoglycerate concentration. A study on preterm neonates.

BACKGROUND: Recently we demonstrated an increased 2,3-diphosphoglycerate (2,3-DPG) erythrocyte concentration in rat pups subjected to nucleotide-enriched artificial feeding. DESIGN: The present study was carried out to test the hypothesis that a possible increase in 2,3-DPG concentration can also be obtained in human neonates who are fed nucleotide-enriched formula. Preterm neonates born or referred to the neonatal intensive care unit of the G. Gaslini Hospital, Genoa University, with a gestational age >30 weeks and <37 weeks were enrolled in our randomized trial. Recruitment took place within 48-72 hours from birth. Only newborns of mothers deciding not to breast-feed were eligible to be randomized for the supplemented group (FN) or non-supplemented group (RF). Breast-fed newborns were considered the control group (C). The study window (for supplementation and blood samples) was restricted to the first two weeks following birth (from the 2nd (t1) to the 16th (t2) day of life). At the end of our study, only 21 neonates were eligible for statistical analysis. RESULTS: The stimulating action of dietary nucleotides on 2,3-DPG concentration failed to be demonstrated; increases in 2,3-DPG concentration that were observed in newborns fed with nucleotide supplemented formula (FN) were comparable to those observed in newborns fed with regular formula (RF) and breast-fed newborns. CONCLUSIONS: The EC recommendation for the amount of nucleotides allowed in formula milk does not seem to be high enough to have positive effects on 2,3-DPG synthesis. Whether this possible 'pharmacological' effect can be achieved by a higher intake of ingested nucleotides and/or a change in the proportions of single nucleotides contained in milk formulas remain interesting end points to be elucidated.     

Cytological aspects of the nasal respiratory epithelium in reproductive-age women taking oral contraceptives.

OBJECTIVE: To determine the effects of monophasic oral contraceptives on the nasal respiratory epithelium in premenopausal women. DESIGN: Prospective open clinical trial. SETTING: Outpatient Family Planning Centre. PATIENT(S): Eighty-eight premenopausal women, with ovulatory cycle, who were planning to take oral contraceptives. INTERVENTION(S): Baseline endovaginal ultrasound examination and blood test to measure serum progesterone to confirm ovulatory cycle. Thirty-eight women on pill containing 30 microg ethinylestradiol (EE) plus 75 microg gestodene, and 35 women on pill containing 15 microg ethinylestradiol plus 60 microg gestodene. MAIN OUTCOMES/MEASURE(S): Cytological changes on the nasal respiratory epithelium evaluated with the maturation index performed during the follicular, periovular, and luteal phases of the menstrual cycle, and on the sixth cycle of pill intake. RESULT(S): Hematoxylin-eosin staining for the maturation index showed similar trophic cytological aspects between the nasal and vaginal epithelium during the menstrual cycle and pill usage. Both the nasal and vaginal cytological samples showed higher maturation indexes during both the follicular and the periovular phases than during the luteal phase. Women on pill containing 15 microg EE showed lower trophic aspects in the nasal cytological samples compared with those on pill with 30 microg EE. CONCLUSION(S): Along with the vaginal cells, the nasal respiratory epithelium is an ovarian steroid target. The maturation index of the nasal respiratory epithelium seems to depend on the variation of the ovarian steroids during the menstrual cycle and on the iatrogenic effects of oral contraceptives.