Molecular mechanisms of tolerance to and withdrawal of GABAA receptor modulators

Here, we summarize recent data pertaining to the effects of GABA_A receptor modulators on the receptor gene expression in order to elucidate the molecular mechanisms behind tolerance and dependence induced by these drugs. Drug selectivity and intrinsic activity seems to be important to evidence at the molecular level the GABA_A receptor tolerance. On the contrary, we suggested that all drug tested are equally potentially prone to induce dependence. Our results demonstrate that long-lasting exposure of GABA_A receptors to endogenous steroids, benzodiazepines and ethanol, as well as their withdrawal, induce marked effects on receptor structure and function. These results suggest the possible synergic action between endogenous steroids and these drugs in modulating the functional activity of specific neuronal populations. We report here that endogenous steroids may play a crucial role in the action of ethanol on dopaminergic neurons.     

In vivo assessment of antiangiogenic activity of SU6668 in an experimental colon carcinoma model.

PURPOSE: The purpose of this research was to assess in vivo by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) the antiangiogenic effect of SU6668, an oral, small molecule inhibitor of the angiogenic receptor tyrosine kinases vascular endothelial growth factor receptor 2 (Flk-1/KDR), platelet-derived growth factor receptor, and fibroblast growth factor receptor 1. EXPERIMENTAL DESIGN: A s.c. tumor model of HT29 human colon carcinoma in athymic mice was used. DCE-MRI with a macromolecular contrast agent was used to measure transendothelial permeability and fractional plasma volume, accepted surrogate markers of tumor angiogenesis. CD31 immunohistochemical staining was used for assessing microvessels density and vessels area. Experiments were performed after 24 h, and 3, 7, and 14 days of treatment. RESULTS: DCE-MRI clearly detected the early effect (after 24 h of treatment) of SU6668 on tumor vasculature as a 51% and 26% decrease in the average vessel permeability measured in the tumor rim and core (respectively). A substantial decrease was also observed in average fractional plasma volume in the rim (59%) and core (35%) of the tumor. Histological results confirmed magnetic resonance imaging findings. After 3, 7, and 14 days of treatment, postcontrast magnetic resonant images presented a thin strip of strongly enhanced tissue at the tumor periphery; histology examination showed that this hyperenhanced ring corresponded to strongly vascularized tissue adjacent but external to the tumor. Histology also revealed a strong decrease in the thickness of peripheral viable tissue, with a greatly reduced vessel count. SU6668 greatly inhibited tumor growth, with 60% inhibition at 14 days of treatment. CONCLUSIONS: DCE-MRI detected in vivo the antiangiogenic efficacy of SU6668.     

Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients.

PURPOSE: Imatinib (Glivec) is a potent inhibitor of bcr/abl, an oncogenic fusion protein that causes chronic myelogenous leukemia (CML). alpha1 acid glycoprotein (AGP) binds to imatinib with high affinity and inhibits imatinib activity in vitro and in vivo in an animal model. A pharmacokinetics analysis of imatinib was undertaken in CML patients. EXPERIMENTAL DESIGN: Imatinib plasma concentrations were measured in 19 CML patients treated with imatinib (400 or 600 mg/day). Five patients received a concomitant short-term course of clindamycin (CLI). RESULTS: A positive correlation between AGP and imatinib plasma levels was observed. CLI administration decreased imatinib plasma concentrations, evaluated as area under the curve (AUC) and peak concentrations (C(max)). The effects of a bolus of CLI was studied in three patients on imatinib 23 h after the last imatinib dose. Within 5-10 min in three of three cases, CLI caused a decrease in imatinib plasma concentrations of 2.6-, 2.7-, and 4.7-fold, respectively. In vitro experiments using fresh blasts from CML patients showed that AGP, at concentrations observed in the patients, decreased imatinib intracellular concentrations up to 10 times and blocked imatinib activity. The incubation with CLI restored imatinib intracellular concentrations and biological activity. CONCLUSION: AGP exerts significant effects of the pharmacokinetics, plasma concentrations, and intracellular distribution of imatinib in CML patients; these data indicate that plasma imatinib levels represent unreliable indicators of the cellular concentrations of this molecule.     

An Analysis of Approaches to the Management of Endometrial Cancer in North America: A CTF Study

Objective.The aim of this study was to define the clinical–therapeutical approach to endometrial cancer now being followed in some of the most important centers of reference for gynecological cancer in North America by means of a questionnaire.Study design.The questionnaire focused on four principal areas: (1) surgical staging and therapy; (2) adjuvant treatment; (3) treatment modifications; and (4) management of advanced stages (FIGO III–IV).Results.There were 48 evaluable responses (77%) received by the end of December 1994 which were considered for this analysis. Lymphadenectomy is utilized routinely in 26/48 centers (54.2%) and in selective clinical–pathological conditions in another 21/48 centers (43.5%). In the majority of centers (31/48; 64.6%) radical surgery is utilized for selected indications such as cervical involvement. Only 3/48 (6.2%) centers consider the vaginal approach totally inappropriate. The great majority (40/48; 83.3%) of the centers considered postsurgical adjuvant therapy to be necessary in FIGO Stage Ic. Brachytherapy is routinely performed in 3 centers (6.2%) in postsurgical management of Stage I endometrial cancer, while the majority of the centers (31/48; 64.6%) perform brachytherapy of the vaginal vault in certain clinical–pathological conditions. A wide variety of treatments are used for advanced stages (FIGO III–IV).Conclusions.It emerges that some controversial aspects exist on endometrial cancer treatment, and these conflicting data need a large-scale multicenter randomized clinical trial.     

Delivery room strategies and outcomes in preterm infants with gestational age 24-28 weeks.

OBJECTIVE: To investigate the effect of different delivery room strategies on survival, short term morbidity, and outcomes in extremely premature infants. METHODS: This retrospective cohort study included all preterm infants with a gestational age between 24 and 28 weeks who were born in 1992-1997 (period A; n = 161) and in 1998-2003 (period B; n = 163). In period A, elective intubation was performed. In period B, if spontaneous breathing was present, nasal continuous positive airway pressure (nCPAP) was applied. RESULTS: Survival rate and the number of never-intubated infants significantly increased in period B. No differences were found concerning short-term morbidity. Among major outcomes, the need for retinopathy of prematurity (ROP) surgery and the length of stay were significantly lower in period B. Subgroup analysis showed no significant differences from period A to period B in infants with gestational age 24-26 weeks. In the 27-28 weeks subgroup, the never-intubated infants rate increased from 2.8% to 21.3% and survival rate increased from 63% to 79%. A reduced need for ROP surgery and a shorter hospital stay were also observed. CONCLUSIONS: Changes in delivery room strategy tending to reduce mechanical ventilation in extremely premature infants are likely to benefit essentially infants of 27-28 weeks of gestation. Extension of such benefits to premature infants at the limit of viability requires further research.     

Recurrent inflammation of accessory parotid tissue associated with unilateral parotid gland aplasia: diagnostic and therapeutic implications

Aplasia of the major salivary glands is a rare condition due to an alteration in the development of the ectodermal tissue of the oral cavity often related to other craniofacial abnormalities or alteration of structures deriving from the first or second archial branch, in particular the lacrimal glands; it can be total or partial and determine clinical states ranging from an asymptomatic condition to a severe xerostomia. The accessory parotid tissue is similar to normal parotid tissue, completely independent from the main gland and susceptible to the same pathological disorders. We describe a very unusual case of an inflammatory disorder of accessory parotid tissue in a 44-year-old male patient with concomitant, and previously unknown, aplasia of the main ipsilateral parotid gland. We also discuss the role of imaging and conservative therapeutic modalities such as botulinum toxin therapy and, in the future, minimally invasive endoscopic-assisted resection in the management of such salivary disorder.     

Is Biblioleaks Inevitable?

In 2014, the vast majority of published biomedical research is still hidden behind paywalls rather than open access. For more than a decade, similar restrictions over other digitally available content have engendered illegal activity. Music file sharing became rampant in the late 1990s as communities formed around new ways to share. The frequency and scale of cyber-attacks against commercial and government interests has increased dramatically. Massive troves of classified government documents have become public through the actions of a few. Yet we have not seen significant growth in the illegal sharing of peer-reviewed academic articles. Should we truly expect that biomedical publishing is somehow at less risk than other content-generating industries? What of the larger threat—a “Biblioleaks” event—a database breach and public leak of the substantial archives of biomedical literature? As the expectation that all research should be available to everyone becomes the norm for a younger generation of researchers and the broader community, the motivations for such a leak are likely to grow. We explore the feasibility and consequences of a Biblioleaks event for researchers, journals, publishers, and the broader communities of doctors and the patients they serve.     

Congenital nasal pyriform aperture stenosis: diagnosis and management

ABSTRACT: BACKGROUND: Congenital nasal pyriform aperture stenosis is a rare and potentially lethal form of airway obstruction in newborns. Immediate recognition and appropriate therapy are mandatory for this potentially life-threating condition. This anomaly may present as an isolated malformation or may be associated with other cranial-facial anomalies. Clinically, CNPS shows unspecific symptoms of nasal airway obstruction such as apnoic crisis, episodic cyanosis and inability to nurse. The purpose of this report is to present author's experience in the surgical management of this rare pathology in 3 patients. Patients and Methods Three cases of congenital nasal pyriform aperture stenosis were reviewed for presentation of the disorder, management and effectiveness of the surgical treatment. RESULTS: All the patients underwent a surgical correction of the pyriform aperture stenosis using a sublabial approach followed by nasal stenting. During the follow-up no cases of restenosis, respiratory failure or cyanosis were detected. CONCLUSIONS: Congenital pyriform aperture stenosis should be suspected in newborns with clinical signs of severe nasal obstruction associated with a difficulty to pass a small catheter though the anterior nasal valve. Timely recognition is mandatory to prevent a potential deadly outcome. Surgical correction of the stenosis though a sublabial approach followed by a nasal stenting revealed to be most effective treatment for these patients.