Multimodal imaging for a theranostic approach in a murine model of B-cell lymphoma with engineered nanoparticles

Nanoparticles (NPs) are a promising tool for in vivo multimodality imaging and theranostic applications. Hyaluronic acid (HA)-based NPs have numerous active groups that make them ideal as tumor-targeted carriers. The B-lymphoma neoplastic cells express on their surfaces a clone-specific immunoglobulin receptor (Ig-BCR). The peptide A20-36 (pA20-36) selectively binds to the Ig-BCR of A20 lymphoma cells. In this work, we demonstrated the ability of core-shell chitosan-HA-NPs decorated with pA20-36 to specifically target A20 cells and reduce the tumor burden in a murine xenograft model. We monitored tumor growth using high-frequency ultrasonography and demonstrated targeting specificity and kinetics of the NPs via in vivo fluorescent reflectance imaging. This result was also confirmed by ex vivo magnetic resonance imaging and confocal microscopy. In conclusion, we demonstrated the ability of NPs loaded with fluorescent and paramagnetic tracers to act as multimodal imaging contrast agents and hence as a non-toxic, highly specific theranostic system.     

Effects of the potassium ion channel modulators BMS-204352 Maxipost and its R-enantiomer on salicylate-induced tinnitus in rats

Currently, there are no effective pharmacological therapies for chronic tinnitus despite a number of efforts from clinical studies and more recently, studies in animals using compounds to enhance endogenous inhibition or reduce central hyperactivity. The purpose of the current study was to evaluate the therapeutic efficacy of a novel anxiolytic with potassium channel activity in suppressing salicylate induced tinnitus in animals. Kv7 potassium channels are present in the peripheral and central auditory system where they are believed to modulate neural activity. Maxipost, a compound which attenuates hyperexcitability via positive modulation of Kv7.2-Kv7.5 channels, was administered to rats with behavioral evidence of salicylate induced tinnitus. Tinnitus was measured using our previously established animal model, Schedule Induced Polydipsia Avoidance Conditioning, a paradigm where rats were conditioned to drink only during quiet and suppress drinking in the presence of sound. Salicylate alone significantly suppressed licks in quiet but had no effect on licks in sound; results consistent with the presence of tinnitus. Maxipost at 10 mg/kg suppressed behavioral evidence of tinnitus as it completely reversed salicylate's suppression of licks in quiet. Unexpectedly, the R-enantiomer of Maxipost, R-Maxipost, which has no anxiolytic effects and negatively modulates Kv7.2-Kv7.5, also suppressed behavioral evidence of tinnitus. Our original hypothesis was that Kv7.2-Kv7.5 channels might play a key role in tinnitus generation and that Maxipost but not R-Maxipost would suppress tinnitus; however, it appears that a shared mechanism between Maxipost and R-xMaxipost, such as inhibition of Kv7.1 channels or activation of BK channels or some novel mechanism common to both compounds, underlies salicylate induced tinnitus as both compounds completely abolished behavioral evidence of tinnitus in a dose-dependent manner. Further studies with specific BK channel agonists/antagonists are necessary to determine the contribution of these channels to other forms of tinnitus or determine novel targets that could be related to tinnitus.     

Nocturnal hyperactivity, increased social novelty preference and delayed extinction of fear responses in post-weaning socially isolated mice

When rodents are reared in isolation from young age onwards, they manifest a number of behavioural alterations in adulthood. Since some of these alterations resemble symptoms of psychiatric disorders, the post-weaning social isolation (ISO) manipulation is often applied to create rodent models of these disorders. In rats, ISO effects have been thoroughly characterised, but in mice they are less well documented. Therefore, we further evaluated behaviour of adult ISO mice with a test battery that focussed on abnormalities relevant to schizophrenia. We found that ISO mice were hyperactive during the dark phase. Also, ISO mice showed alterations in magnitude, habituation and prepulse-inhibition of the acoustic startle reflex, increased anxiety, increased social preference and changes in extinction of fear responses. We did not observe increased sensitivity to locomotor-activating effects of amphetamine. It is concluded that ISO of mice might serve as a useful model to test further hypotheses regarding pathogenesis occurring at specific developmental timeframes.     

Vglut2 haploinsufficiency enhances behavioral sensitivity to MK-801 and amphetamine in mice

Recently developed mouse models have implicated the vesicular glutamate transporter 2 (VGLUT2) in psychostimulant-induced hyperactivity, a behavioral assay that is often applied to evaluate mouse behavior related to positive schizophrenia (SCZ) symptomatology. In present research, we wanted to evaluate further the role of subtle VGLUT2 impairment as a factor underlying SCZ symptomatology. To this end, we evaluated Vglut2 haploinsufficient (Vglut2^+/−) mice and their wildtype littermates in a test battery assessing behaviors related to positive, negative and cognitive SCZ symptom domains. We found in Vglut2^+/− mice an increased locomotor response to amphetamine and an increased sensitivity to the startle-disrupting effects of MK-801, but no impairment in sensorimotor gating. Further on, minor alterations in tests assessing cognitive and negative symptom-related behavior were observed. Possible neurobiological mechanisms of these observations are discussed.     

Increase in Lactate Without Change in Nutritive Blood Flow or Glucose at Active Trigger Points Following Massage: A Randomized Clinical Trial

Objective

To investigate changes in nutritive blood flow as well as interstitial glucose and lactate within an active myofascial trigger point (MTrP) following massage.

Hypercaloric diets differing in fat composition have similar effects on serum leptin and weight gain in female subjects with anorexia nervosa

Weight regain in subjects with anorexia nervosa is associated with an increase in serum leptin concentrations that is hypothesized to impair full weight restoration. As diets rich in n-3 polyunsaturated fatty acids (PUFA) have been described to lower serum leptin concentrations, we tested the hypothesis that consumption of a hypercaloric diet rich in n-3 PUFA is associated with an attenuated increase in serum leptin and a higher efficiency of body weight gain in subjects with anorexia nervosa. Twenty-five female subjects with anorexia nervosa were enrolled into this controlled dietary intervention study. Four subjects discontinued therapy or participation in the study prematurely, and six were excluded. 15 subjects completed the study. Subjects consumed hypercaloric diets rich in either saturated fatty acids (SFA, n = 8) or n-3 PUFA (n = 7) for 5 weeks. Primary endpoints were the change in serum leptin concentrations and body weight gain relative to energy consumed. Serum leptin concentrations increased distinctly throughout the study (P < .001), and to a similar extend in both groups [+2.9 (SD 2.4) vs. +2.8 (SD 3.4) ng/mL in the SFA- and n-3 PUFA group, respectively; P = .487]. The efficiency of body weight gain also did not differ significantly between groups, with a body weight gain of 63.1 (SD 12.4) vs. 79.2 (SD 26.0) g per 4.2 MJ (1000 kcal) consumed in the SFA- and n-3 PUFA group, respectively (P = .132). Hypercaloric diets rich in either SFA or n-3 PUFA do not differ in their effects on serum leptin concentrations and the efficiency of body weight gain in female subjects with anorexia nervosa.     

A comparison of the speech recognition and pitch ranking abilities of children using a unilateral cochlear implant, bimodal stimulation or bilateral hearing aids

Objective

The present study compared the speech recognition and pitch ranking abilities of normally hearing children (n = 15) to children using a cochlear implant (CI) alone (n = 8), bilateral hearing aids (HAs) (n = 6), or bimodal stimulation (BMS) (n = 9). It was hypothesised that users of BMS would score higher on tasks of speech and pitch perception than children using a CI alone, but not children using HAs.

Methods

Participants were assessed on tasks of monosyllabic word recognition in quiet, sentence recognition in quiet and noise (10 dB signal-to-noise ratio), and a pitch ranking task using pairs of sung vowels one, half, and a quarter of an octave apart.

Results

There were no significant differences between the mean percentage-correct scores of the four participant groups for either words in quiet or sentences in quiet and noise. However, the proportion of bimodal users who scored >80% correct (80%) was significantly greater than the proportion of high-scoring unilateral CI (25%) or bilateral HA users (17%). Contrary to expectations, there was also no significant difference between the pitch ranking scores of users of BMS and users of a CI alone for all three interval sizes (p < 0.05, RM-ANOVA). However participants using only acoustic hearing (i.e. the NH and HA groups) scored significantly higher than participants using electrical stimulation (i.e. the CI and BMS groups) on the pitch ranking task (p < 0.05; RM-ANOVA).

Conclusions

Contrary to findings in postlingually deafened adults, we found no significant bimodal advantage for pitch perception in prelingually deafened children. However, the performance of children using electrical stimulation was significantly poorer than children using only acoustic stimulation. Further research is required to investigate the contribution of the non-implanted ears of users of BMS to pitch perception, and the effect of hearing loss on the development of pitch perception in children.