Effects of alcohol and lorazepam during extinction of alcohol self-administration in rats

Systemic injections of alcohol have previously been reported to 'prime' or to reinstate self-administration of alcohol in rats, and it has been suggested that the priming effects of drugs are related to their stimulus properties. We tested this hypothesis by investigating the effects of lorazepam, which cross-generalizes with alcohol in animal drug-discrimination studies, in rats trained to self-administer 7% alcohol in an operant paradigm. Once animals were trained, extinction tests were carried out twice weekly, before which rats were injected with either vehicle, alcohol (0.063-0.5 g/kg, i.p.) or lorazepam (0.03-0.25 mg/kg, i.p.). Alcohol did not increase responding for alcohol during extinction. Doses of 0.25 and 0.5 g/kg reduced alcohol-appropriate lever pressing (p < 0.05 versus 0 g/kg), with the largest dose also suppressing general activity (p < 0.02 versus 0 g/kg). Lorazepam also reduced alcohol-appropriate responding, in a behaviourally specific manner; doses of 0.03 mg/kg and above decreased lever pressing (p < 0.05 versus 0 mg/kg), whereas general activity was depressed at 0.06 mg/kg and larger doses (p < 0.05 versus 0 mg/kg). Although lorazepam mimicked the effect of alcohol at doses predicted to do so on the basis of their relative potency in drug discrimination studies, neither alcohol nor lorazepam primed rats to respond for alcohol. By contrast, the pattern of results suggested that, in this model, they 'satiated' or substituted for alcohol, resulting in a reduced motivation to respond.     

Altered receptor trafficking in Huntingtin Interacting Protein 1-transformed cells

The clathrin-associated protein, Huntingtin Interacting Protein 1 (HIP1), is overexpressed in multiple human epithelial tumors. Here, we report that HIP1 is a novel oncoprotein that transforms cells. HIP1-transformed cells, in contrast to RasV12-transformed cells, have dysregulation of multiple receptors involved in clathrin trafficking. Examples include upregulation of the epidermal growth factor receptor (EGFR) and the transferrin receptor. Furthermore, accumulation of transferrin and EGF in the HIP1-transformed cells was increased, and breast tumors that had EGFR expressed also had HIP1 upregulated. Thus, HIP1 overexpression promotes tumor formation and is associated with a general alteration in receptor trafficking. HIP1 is the first endocytic protein to be directly implicated in tumor formation.     

A whole genome association study in Icelandic multiple sclerosis patients with 4804 markers

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) with a complex genetic background. Here we use a genome-wide association strategy with 4804 microsatellite markers successfully typed in separately pooled DNA from 200 patients and 200 controls. A total of 91 markers showed evidence of association. When compared to our in-house physical map of the genome, six 2-Mb regions containing at least two of these markers were detected. Of those, three regions have one or more markers among the 20 most strongly associated: chromosomes 3q25, 6p21.3 (the MHC region) and 19q13.     

A whole genome association study in multiple sclerosis patients from north Portugal

Genetic factors are known to influence susceptibility to multiple sclerosis (MS) but the genes involved are largely undefined. Here, we report an association study based on 200 patients and 200 controls from the Porto region in Portugal. A total of 3974 markers were successfully typed from which we have identified 46 markers showing evidence of association. When compared to a physical map three regions were found with two of these markers less than 1.5 Mb apart: chromosomes 6p21.3 (the MHC region), 6q14.1 and 7q34.     

Comparison of three treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome

The aim of the study was to compare the treatment regimen of three natural surfactants of different extraction and formulation (Alveofact [Surfactant A = SA], Poractant [Surfactant B = SB] and Beractant [Surfactant C = SC]) in neonatal respiratory distress syndrome (RDS). Premature infants of /=0.3 were randomly assigned to receive at least two doses of SA, SB or SC (100 mg/kg per dose). Infants who remained dependent on artificial ventilation with a FiO2 >/=0.3 received up to two additional doses. There were no differences among the groups regarding the necessity for more than two doses. The SA and the SB groups spent fewer days on a ventilator (p-value SA/SB 0.7, SA/SC 0.05, SB/SC 0.043) compared with the SC group, needed fewer days of oxygen administration (p-value SA/SB 0.14, SA/SC 0.05, SB/SC 0.04) and spent fewer days in hospital (p-value SA/SB 0.65, SA/SC 0.04, SB/SC 0.027). There were no statistically significant differences in the incidence of mortality, chronic lung disease, air leaks, necrotising enterocolitis, retinopathy of prematurity and intraventricular haemorrhage among the three groups. CONCLUSION: The Alveofact and Poractant groups spent fewer days on the ventilator, needed fewer days of oxygen administration and spent fewer days in hospital compared with the Beractant group but no differences were observed among the three groups with regards to mortality and morbidity.     

Emergency obstetric hysterectomy

BACKGROUND: All cases of obstetric hysterectomies that were performed in our hospital during a seven-year study period were reviewed in order to evaluate the incidence, indications, risk factors, and complications associated with emergency obstetric hysterectomy. METHODS: Medical records of 45 patients who had undergone emergency hysterectomy were scrutinized and evaluated retrospectively. Maternal age, parity, gestational age, indication for hysterectomy, the type of operation performed, estimated blood loss, amount of blood transfused, complications, and hospitalization period were noted and evaluated. The main outcome measures were the factors associated with obstetric hysterectomy as well as the indications for the procedure. RESULTS: During the study period there were 32,338 deliveries and 9,601 of them (29.7%) were by cesarean section. In this period, 45 emergency hysterectomies were performed, with an incidence of 1 in 2,526 vaginal deliveries and 1 in 267 cesarean sections. All of them were due to massive postpartum hemorrhage. The most common underlying pathologies was placenta accreta (51.1%) and placenta previa (26.7%). There was no maternal mortality. CONCLUSIONS: Obstetric hysterectomy is a necessary life-saving procedure. Abnormal placentation is the leading cause of emergency hysterectomy when obstetric practice is characterized by a high cesarean section rate. Therefore, every attempt should be made to reduce the cesarean section rate by performing this procedure only for valid clinical indications.     

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma

Introduction: The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment.

Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings. Additionally, published case series/case reports were screened for information on AEs.

Expert opinion: Even though almost every patient (98%) under combination therapy with dabrafenib and trametinib experiences at least one adverse event, these are generally mild to moderate, reversible and can be managed with dose reductions or interruptions. However, due to an increased life expectancy, there is a substantial need to prevent and treat also mild adverse events, as they play a central role for the quality of life of patients. Ongoing clinical trials will have to demonstrate the efficacy as well as safety of triple combination with anti-PD-1/anti-PD-L1 antibodies.     

Cardiovascular safety of oncologic agents: a double-edged sword even in the era of targeted therapies – Part 2

Introduction: Patients with cancer are subject to the cardiotoxic effects of cancer therapy. Improved cancer treatments lead to more cancer-survivors, who though are exposed to various forms of cardiovascular (CV) disease (CVD) as they age. Aging patients are at increased risk of developing both malignancy and CVD or they may have survived some form of CVD as a result of effective CV treatments. Furthermore, patients with CVD may develop cancer and require treatment (and vice versa), all contributing to increased morbidity and mortality. The prevalence of both malignancy and CVD will increase due to the trend toward a longer lifespan.

Areas covered: In part 2 of this review, the discussion of the CV effects of specific oncology drugs is completed with inclusion of additional immunological agents, current hormonal and other agents. Early detection and monitoring of cardiotoxicity, use of biomarkers and other imaging and diagnostic methods and prevention and treatment options are also discussed.

Expert opinion: As outlined in part 1 of this review, oncologists need to be aware of the CV adverse-effects of their treatments and make careful and expectant clinical decisions, especially in patients with preexisting CVD or CV risk factors. Similarly, cardiologists should consider a detailed previous history of treatment for malignant disease, including prior chemotherapy exposure, dose(s) received, and/or combined modality therapy with chest radiotherapy. Both specialists should collaborate in order to minimize the impact of these two ubiquitous diseases (cancer and CVD) and mitigate the adverse effects of treatment modalities.