Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of γ oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.SIGNIFICANCE STATEMENT Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling promotes the maturation of inhibitory parvalbumin (PV) interneurons, neurons central to local cortical dynamics, γ rhythms, and cognition. Here, we used a novel viral approach for reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) to establish the role of BDNF/trkB signaling in adult prefrontal network activities. Reduced BDNF/trkB signaling caused pronounced morphologic alterations, reduced PV inhibition, and deficient prefrontal network dynamics. The altered network activity appeared to manifest across stimuli and brain states and was associated with aberrant local field potential (LFP) activities and increased aggression. The results demonstrate that adult BDNF/trkB signaling is essential to PV inhibition and prefrontal circuit function and directly links BDNF/trkB signaling to network integrity in the adult brain.     

A novel strategy for the determination of a rhabdovirus genome and its application to sequencing of Eggplant mottled dwarf virus

A novel strategy employing the rhabdovirus untranslated conserved intergenic regions was developed and applied successfully for the determination of the complete nucleotide sequence of Eggplant mottled dwarf virus (EMDV). The EMDV genome contains seven open reading frames with the same organization as Potato yellow dwarf virus (PYDV), the type species of the genus Nucleorhabdovirus. These two species encode five core genes [nucleocapsid (N), phosphoprotein (P), matrix (M), glycoprotein (G), and the polymerase (L)] like other viruses of the genus and an additional one (X), located between N and P, giving rise to a protein with currently unknown function. Furthermore, both EMDV and PYDV contain a gene (Y), inserted between P and M, which probably encodes the virus movement protein, in concordance with the rest of the plant-infecting rhabdoviruses. Phylogenetic analysis of the polymerase gene confirmed the classification of EMDV within the genus Nucleorhabdovirus and showed a close evolutionary relationship to PYDV. The novel sequencing strategy developed is a useful tool for the genome determination of yet uncharacterized rhabdoviruses.     

Jet or conventional local anaesthesia? A randomized controlled split mouth study

Objectives

To compare the efficacy, acceptance and preference of conventional infiltration technique with a needleless jet anaesthetic device (Comfort-In).

Materials and methods

Non-fearful healthy adult volunteers, aged 19–40 years, were recruited in the Dental School of Aristotle University of Thessaloniki, Greece. Intact maxillary premolars were selected for local anaesthesia. Both techniques were applied sequentially with 35 min time gap on either buccal side on the same day by the same operator. The quadrant and the order of administration were randomly assigned using an online randomization generator. Immediately after administration, at 1, 3, 5, 10, 15, 20, 25 and 30 min, pulp vitality and soft tissue pain reaction tests were performed. Each participant was asked 6 questions in order to assess acceptance. At the end of the session, at 24 h and 7 days, all participants were asked to report any adverse events and their preference.

Results

In 63 volunteers who were successfully followed, 63 teeth received conventional local infiltration and 63 the Comfort-In. Both techniques presented with similar anaesthetic efficacy at 1, 3, 5, 10 and 15 min, whereas the conventional technique was more efficacious at 20 min (p < 0.005). Both presented similar acceptance apart from higher pain/discomfort during administration of Comfort-In (p = 0.002). Significantly higher preference was reported for the conventional technique immediately after the session, at 24 h and at 7 days (p < 0.0005); 19 (30.2%) reported the presence of ecchymosis or lacerations at the Comfort-In site as opposed to 5 (7.9%) with the conventional method (p < 0.0001).

Conclusion

Both techniques showed similar effectiveness. Conventional infiltration was preferred to needleless anaesthesia by non-fearful adult volunteers and was associated with less adverse events.

Clinical relevance

This study enhances the advantages of conventional local anaesthesia.

Trial registration

ISRCTN17400733

     

Tumors of the labial mucosa: a retrospective study of 1045 biopsies

Background To investigate the relative frequency of localized mucosal swellings of the upper and lower labial mucosa, the clinical-pathological diagnosis agreement and whether patient’s age and gender and tumor’s site and size may raise the suspicion of neoplasm. Material and Methods Retrospective analysis was performed on upper or lower labial mucosal tumors, histopathologically diagnosed between 2009-2018. The diagnostic categories developmental/reactive tumors, benign and malignant neoplasms were associated with patient’s age and gender and tumor’s site and size; clinical-pathological diagnosis agreement was, also, evaluated. Results Overall, 1000 (95.7%) developmental/reactive tumors, 35 (3.3%) benign and 10 (1%) malignant neoplasms were found. Upper/lower lip tumor ratio was 0.14:1. The diagnostic category was significantly associated with age (p<0.0001), site (p<0.0001) and diameter (p<0.0001). Age ≥60 years, tumor’s location on the upper lip and diameter >1cm were independent predictors for neoplasms. Patients presenting 2 or 3 of these variables were 20.2 times (p < 0.0001) or 33.6 times (p <0.0001), respectively, more likely to have a neoplasm. Complete/partial agreement between clinical and pathological diagnosis was seen in 96.3% of the cases. Conclusions Most lip tumors involve the lower lip and are reactive, but upper lip tumors measuring >1cm in patients≥60 years have significantly higher probability to be neoplasms. Key words:Lip, tumor, neoplasm, carcinoma, cyst.     

Transcatheter Valve Repair for Patients With Mitral Regurgitation: 30-Day Results of the CLASP Study

ObjectivesThe authors report the procedural and 30-day results of the PASCAL Transcatheter Valve Repair System (Edwards Lifesciences, Irvine, California) in patients with mitral regurgitation (MR) enrolled in the multicenter, prospective, single-arm CLASP study.BackgroundSevere MR may lead to symptoms, impaired quality of life, and reduced functional capacity when untreated.MethodsEligible patients had grade 3+ or 4+ MR despite optimal medical therapy and were deemed appropriate for the study by the local heart team. All outcomes were assessed through 30 days post-procedure. Major adverse events (MAEs) were adjudicated by an independent clinical events committee, and echocardiographic images were assessed by a core laboratory. The primary safety endpoint was the rate of MAEs at 30 days.ResultsBetween June 2017 and September 2018, 62 patients with grade 3+ or 4+ MR were enrolled. The mean age was 76.5 years, and 51.6% of patients were in New York Heart Association functional class III or IV, with 56% functional, 36% degenerative, and 8% mixed MR etiology. At 30 days, the MAE rate was 6.5%, with an all-cause mortality rate of 1.6% and no occurrence of stroke; 98% had MR grade ≤2+, with 86% with MR grade ≤1+ (p < 0.0001); and 85% were in New York Heart Association functional class I or II (p < 0.0001). Six-minute walk distance improved by 36 m (p = 0.0018), and Kansas City Cardiomyopathy Questionnaire and EQ-5D scores improved by 17 (p < 0.0001) and 10 (p = 0.0004) points, respectively.ConclusionsThe PASCAL repair system showed feasibility and acceptable safety in the treatment of patients with grade 3+ or 4+ MR. MR severity, irrespective of etiology, was significantly reduced and accompanied by clinically and statistically significant improvements in functional status, exercise capacity, and quality of life. (The CLASP Study Edwards PASCAL Transcatheter Mitral Valve Repair System Study; NCT03170349)