Multivariate study of the Open Field Drink Test using undernourished rats and desipramine as an antipanic drug

Approach-avoidance animal models are useful as initial screens for drugs affecting anxiety, but the components of anxiety assessed by these models remain poorly defined. Complex models of evaluation allow more complete inferences than those which are obtained when only one behavior is evaluated. Previous studies demonstrate that the tricyclic-antidepressant desipramine exerts a selective anticonflict effect on adult rats submitted to a protein deprivation schedule at perinatal age, in parameters of spontaneous behavior (elevated plus-maze) and conditioned intake (Geller Seifter). These deprived rats show alterations in noradrenergic neurotransmission that resembled the generalized activation of noradrenergic system displayed by patients suffering from panic attacks. The desipramine anticonflict activity was evaluated by a test of ethological conflict: the Open Field Drink Test, without discarding any behavior a priori under a multivaried approach. This approach has not been considered in previous studies with the open field and antipanic drugs. Considering the four variables selected by factorial analysis, desipramine (10 mg/kg/day) administered IP during just 7 days produced a significant diet x drug interaction which was consistent with previous studies. That interaction was independent of the effects of both treatments on weight or intake and was expressed, on deprived rats, as a decrease in all the behaviors, except for the time of drinking, with respect to the control rats, which displayed, in general, a decrease in all the behaviors except for the frequency of grooming.     

A Meta‐Analysis of the Association of Fracture Risk and Body Mass Index in Women

Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20–105) years and follow up of 2.2 million person‐years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m²) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non‐obese women. Compared to a BMI of 25 kg/m², the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m² was 0.87 (95% confidence interval [CI], 0.85–0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09–1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored. © 2014 American Society for Bone and Mineral Research.     

Outcomes of junctional ectopic tachycardia ablation in adult population—a multicenter experience

Purpose

Idiopathic junctional ectopic tachycardia (JET) is typically refractory to antiarrhythmic agents. Catheter ablation for JET is feasible but is associated with high risk of unintended atrioventricular (AV) block. There is limited data on the appropriate procedural technique and clinical outcomes with catheter ablation for idiopathic JET in adults.

Methods

This is a multicenter, retrospective study of all adult patients (age?≥?18 years) who underwent catheter ablation for idiopathic JET. Patient, procedural characteristics, and long-term outcomes were evaluated.

Results

Fifteen patients [radiofrequency ablation (RF)?=?14 and cryoablation?=?1) were treated with catheter ablation. The median age was 58 years with 67% males. All patients underwent mapping of the right atrium and the aortic cusps prior to energy delivery. The location of earliest activation in relation to the atrioventricular (AV) node was postero-superior in 73% (11/15), posterior in 13% (2/15), and superior in 13% (2/15) respectively. Acute success was 100%. Arrhythmia recurrence occurred in 53% (8/15) all of whom underwent a repeat ablation. High-grade AV block requiring permanent pacemaker occurred in 20% (3/15). At 12-month follow-up in the redo-ablation group, 37.5% (3/8) had recurrence of the arrhythmia two of which underwent a third ablation procedure.

Conclusion

Catheter ablation of idiopathic JET in adults is associated with a high rate of recurrence requiring multiple procedures and high risk of AV block requiring a permanent pacemaker. Mapping and ablation of the non-coronary cusp can be considered as the arrhythmia was controlled in 3 patients with no inadvertent AV block.

     

Somatostatin receptors 1, 2, and 5 cooperate in the somatostatin inhibition of C6 glioma cell proliferation in vitro via a phosphotyrosine phosphatase-eta-dependent inhibition of extracellularly regulated kinase-1/2

Somatostatin inhibits cell proliferation through the activation of five receptors (SSTR1-5) expressed in normal and cancer cells. We analyzed the role of individual SSTRs in the antiproliferative activity of somatostatin in C6 rat glioma cells. Somatostatin dose-dependently inhibited C6 proliferation, an effect mimicked, with different efficacy or potency, by BIM-23745, BIM-23120, BIM-23206 (agonists for SSTR1, -2, and -5) and octreotide. The activation of SSTR3 was ineffective, although all SSTRs are functionally active, as demonstrated by the inhibition of cAMP production. All SSTRs induced cytostatic effects through the activation of the phosphotyrosine phosphatase PTPeta and the inhibition of ERK1/2. For possible synergism between SSTR subtypes, we tested the effects of the combined treatment with two agonists (SSTR1+2 or SSTR2+5) or bifunctional compounds. The simultaneous activation of SSTR1 and SSTR2 slightly increased the efficacy of the individual compounds with an IC50 in between the single receptor activation. SSTR2+5 activation displayed a pattern of response superimposable to that of the SSTR5 agonist alone (low potency and higher efficacy, as compared with BIM-23120). The simultaneous activation of SSTR1, -2, and -5 resulted in a response similar to somatostatin. In conclusion, the cytostatic effects of somatostatin in C6 cells are mediated by the SSTR1, -2, and -5 through the same intracellular pathway: activation of PTPeta and inhibition of ERK1/2 activity. Somatostatin is more effective than the individual agonists. The combined activation of SSTR1 and -2 shows a partial synergism as far as antiproliferative activity, whereas SSTR2 and -5 activation results in a response resembling the SSTR5 effects.     

A point mutation in the MET oncogene abrogates metastasis without affecting transformation

The MET oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF), known to stimulate invasive growth of epithelial cells. MET is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis. To investigate whether this oncogene is directly responsible for the acquisition of the metastatic phenotype, we exploited a single-hit oncogenic version of MET, able to transform and to confer invasive and metastatic properties to nontumorigenic cells, both in vitro and in nude mice. We mutagenized the signal transducer docking site of Met (Y¹³⁴⁹VHVX₃Y¹³⁵⁶VNV), which has the uncommon property of binding and activating multiple src homology region 2 (SH2)-containing intracellular effectors. Notably, a point mutation (H¹³⁵¹ → N) increased the transforming ability of the oncogene but abolished its metastatic potential. This mutation duplicates the Grb2 binding site, super-activating the Ras pathway and preventing the binding of the other intracellular transducers. Complementation in trans with another nonmetastatic mutant (N¹³⁵⁸ → H), recruiting all the transducers downstream to Met except Grb2, rescued the invasive–metastatic phenotype. It is concluded that the metastatic potential of the MET oncogene relies on the properties of its multifunctional docking site, and that a single point mutation affecting signal transduction can dissociate neoplastic transformation from metastasis.     

Clinical prediction of normotension in borderline hypertensive men--a 10 year study

OBJECTIVE: To investigate 24-h ambulatory blood pressure measurements (ABPM) as a tool for long-term prediction of future blood pressure (BP) status in high normal and low stage 1 hypertensives. DESIGN, SETTING AND PARTICIPANTS: A total of 165 men from a population screening program with diastolic BP (DBP) 85-94 mmHg and a systolic BP (SBP) < 150 mmHg performed a 24-h ABPM. Ten years later, 120 participants (73%) returned for renewed measurements. MAIN OUTCOME MEASURES: Blood pressure status at 10 years. RESULTS: At the 10-year follow-up, 53% of the participants were classified as hypertensive (HT) (BP > or = 140/90 or taking anti-hypertensive medication) and 47% were classified as normotensive (NT) (BP < 140/90 mmHg). There was no significant baseline differences in office SBP levels between those who were normotensive or hypertensive at follow-up (136/91 versus 138/92 mmHg), whereas both SBP and DBP night-time levels were significantly lower in the future normotensives as compared to the future hypertensives (107/69 versus 112/74 mmHg, P < 0.01). Using recommended normalcy night-time ABP levels of < 120/75 mmHg in addition to office BP (140/90) at baseline, over 85% of the subjects were correctly classified provided they met both clinic and ambulatory night-time criteria for HT and NT classification at baseline. CONCLUSION: The use of ABPM in addition to office BP's in patients with borderline hypertension greatly increases the possibility of identifying those individuals who are at a very small risk of developing future hypertension. This could potentially lead to considerable savings in both patient anxiety, physician time and resource consumption.     

Cardiac Aspergillosis with pedunculated mass in the left ventricle

Immunosuppression can allow organisms that are not usually pathogenetic to cause disease; under such circumstances, Aspergillus species frequently form large masses of fungal elements. We describe the case of a 12-year-old girl with hematologic remission of leukemia. She had a left ventricular pedunculated mass that was detected by echocardiographic study; at surgery, the presence of Aspergillus terreus was confirmed.     

Human Infection with Highly Pathogenic A(H7N7) Avian Influenza Virus,Italy, 2013

During an influenza A(H7N7) virus outbreak among poultry in Italy during August–September 2013, infection with a highly pathogenic A(H7N7) avian influenza virus was diagnosed for 3 poultry workers with conjunctivitis. Genetic analyses revealed that the viruses from the humans were closely related to those from chickens on affected farms.