Effect of lacosamide on ethanol induced conditioned place preference and withdrawal associated behavior in mice: Possible contribution of hippocampal CRMP-2

BackgroundExcessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice.MethodsThe behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured.ResultsEthanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice.ConclusionThe present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal.     

An adenovirus type 5 (AdV5) vector encoding an envelope domain III-based tetravalent antigen elicits immune responses against all four dengue viruses in the presence of prior AdV5 immunity

Dengue is a mosquito-borne viral disease caused by four antigenically distinct serotypes of dengue viruses (DENVs). This disease, which is prevalent in over a hundred tropical and sub-tropical countries of the world, represents a significant global public health problem. A tetravalent dengue vaccine capable of protecting against all four DENV serotypes has been elusive so far. Current efforts are focused on producing a tetravalent vaccine by mixing four monovalent vaccine components. In this work, we have utilized a discrete carboxy-terminal region of the major DENV envelope (E) protein, known as domain III (EDIII), which mediates virus entry into target cells and contains multiple serotype-specific neutralizing epitopes, to create a chimeric tetravalent antigen. This antigen derived by in-frame fusion of the EDIII-encoding sequences of the four DENV serotypes was expressed using a replication-defective recombinant human adenovirus type 5 (rAdV5) vaccine vector. This rAdV5 vector induced cell-mediated immune responses and virus-neutralizing antibodies specific to each of the four DENVs in mice. Interestingly, anti-AdV5 antibodies did not suppress the induction of DENV-specific neutralizing antibodies. We observed that anti-AdV5 antibodies in the sera of immunized mice could promote uptake of a rAdV5-derived reporter vector into U937 cells, suggesting that pre-existing immunity to AdV5 may in fact facilitate the uptake of rAdV5 vectored vaccines into antigen presenting cells. This work presents an alternative approach to developing a single component tetravalent vaccine that bypasses the complexities inherent in the currently adopted four-in-one physical mixture approach.     

Serum ECP levels and methacholine challenge in infants with recurrent wheezing.

BACKGROUND: High levels of serum eosinophil cationic protein (sECP) as a marker of eosinophilic airway inflammation have been described as a predictor of childhood asthma. Bronchial hyperreactivity (BHR) appears to be secondary to the release of inflammatory mediators. OBJECTIVE: We investigated the possible correlation between eosinophilic inflammation and BHR in 72 infants with recurrent wheezing. METHODS: To determine bronchial reactivity, lung function measurements with methacholine challenge were performed in 72 infants, aged 12 to 30 months, and the degree of BHR to methacholine was compared with sECP values. Patients were grouped according to low (group 1, <10 microg/L, n = 22), medium (group 2, 10 to 20 microg/L, n = 23), and high (group 3, >20 microg/L, n = 27) sECP values. RESULTS: In group 1, sECP levels ranged from 3.1 to 9.9 microg/L, mean 6.6 microg/L +/- standard deviation [SD] 2.3, in group 2, from 10.3 to 19.8 microg/L, mean 14.3 microg/L +/- SD 2.8, and in group 3 from 23.0 to 66.7 microg/L, mean 34.5 microg/L +/- SD 9.5. Distribution of provocative methacholine concentration among groups was as follows: group 1, 30 to 976 microg, mean 350.9 microg +/- SD 258.3; group 2, 36 to 752 microg, mean 340.7 microg +/- SD 226.3; group 3, 41 to 848 microg, mean 301.3 microg +/- SD 189.8 methacholine. CONCLUSION: There was no significant correlation between sECP levels and bronchial reactivity in all groups (r = -0.076, P = 0.6), indicating that these parameters reflect two independent pathogenic mechanisms in the etiology of childhood asthma.     

Effect of creatine supplementation during rapid body mass reduction on metabolism and isokinetic muscle performance capacity

Well-trained subjects (n=6) were studied before and after losing a mean 3.0%–4.3% of body mass to determine whether muscle performance could be maintained or even enhanced by dietary creatine supplementation. During a 5-day period of loss of mass the subjects were randomly assigned to a creatine or placebo supplemented diet. All the subjects were measured before and after loss of mass on both supplements for isokinetic peak torque (PT) and work at peak torque (W _PT) of knee extensors, also for intermittent high intensity working capacity of the same muscle group. The latter test consisted of submaximal isokinetic knee extensions at an angular velocity of 1.57 rad?·?s^?1 for 45 s at the rate of 30 contractions each min (submaximal work, W _{s max} ) followed by 15-s maximal effort (maximal work, W _max ). Total duration of the test was 3 min. Haematocrit was measured and haemoglobin, ammonia, lactate, glucose and urea concentrations were analysed in blood samples obtained at rest and after cessation of muscle performance tests. The results indicated that creatine supplementation in comparison with placebo treatment during rapid body mass reduction may help to maintain muscle PT and W _PT at high angular velocities, not influencing W _max and the rate of fatigue development during W _max , but affecting adversely W _{s max} . Within the limitations of the present study the reasons for the partially detrimental effect of creatine administration remain obscure, but it is suggested that impaired creatine uptake in muscle during body mass loss as well as creatine induced changes in muscle glucose and glycogen metabolism may be involved.     

Effects of growth hormone treatment on thyroid function in pediatric patients with Prader–Willi syndrome

It is unclear whether hypothyroidism is present in patients with Prader–Willi syndrome (PWS). This study aimed to clarify the state of the hypothalamic–pituitary–thyroid axis and the effects of growth hormone (GH) treatment on thyroid function in pediatric patients with PWS. We retrospectively evaluated thyroid function in 51 patients with PWS before GH treatment using a thyroid‐releasing hormone (TRH) stimulation test (29 males and 22 females; median age, 22 months). We also evaluated the effect of GH therapy on thyroid function by comparing serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels at baseline, 1 year, and 2 years after GH therapy. TSH, fT4, and fT3 levels were 2.28 μU/ml (interquartile range [IQR]; 1.19–3.61), 1.18 ng/dl (IQR; 1.02–1.24), and 4.02 pg/dl (IQR; 3.54–4.40) at baseline, respectively. In 49 of 51 patients, the TSH response to TRH administration showed a physiologically normal pattern; in two patients (4.0%), the pattern suggested hypothalamic hypothyroidism (delayed and prolonged TSH peak after TRH administration). TSH, fT4, and fT3 levels did not change significantly during 1 or 2 years after GH treatment. The TSH response to TRH showed a normal pattern in most patients, and thyroid function did not change significantly during the 2 years after initiating GH treatment.     

The association of Hospital Medicare beneficiary payer-mix,national quality rankings and outcomes following hepatopancreatic surgery

IntroductionWe sought to determine the impact of payer-mix on post-operative outcomes among Medicare beneficiaries following hepatopancreatic surgery.MethodsMedicare beneficiaries who underwent hepatopancreatic surgery were identified. Hospital quality markers were obtained from the Hospital General Information dataset. Hospitals were dichotomized (low/average vs. high) based on Medicare patient days versus all patient days irrespective of payer type.ResultsHigh Medicare patient-mix hospitals were more likely to be ranked higher than the national average relative to safety of care (29.4% vs. 38.1%) and timeliness of care (15.4% vs. 26.3%) versus low burden Medicare hospitals (both p < 0.001). However, Medicare beneficiaries who had hepatopancreatic surgery at a high Medicare patient-mix hospital were at higher risk of a complication (OR = 1.13, 95%CI 1.04–1.22), and death within 30-days (OR = 1.37, 95%CI 1.23–1.53) following surgery.ConclusionWhile hospitals caring for higher numbers of Medicare beneficiaries generally performed better on CMS quality indicators, these rankings did not equate to improved post-operative outcomes.     

ASO Visual Abstract: Impact of Race/Ethnicity and County-Level Vulnerability on Receipt of Surgery Among Older Medicare Beneficiaries Diagnosed with Early Pancreatic Cancer

Annals of Surgical Oncology -