Developmental hearing loss-induced perceptual deficits are rescued by genetic restoration of cortical inhibition.

Even a transient period of hearing loss during the developmental critical period can induce long-lasting deficits in temporal and spectral perception. These perceptual deficits correlate with speech perception in humans. In gerbils, these hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABAA and metabotropic GABAB receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABAA receptors. Therefore, we developed viral vectors to express proteins that would upregulate gerbil postsynaptic inhibitory receptor subunits (GABAA, Gabra1; GABAB, Gabbr1b) in pyramidal neurons, and an enzyme that mediates GABA synthesis (GAD65) presynaptically in parvalbumin-expressing interneurons. A transient period of developmental hearing loss during the auditory critical period significantly impaired perceptual performance on two auditory tasks: amplitude modulation depth detection and spectral modulation depth detection. We then tested the capacity of each vector to restore perceptual performance on these auditory tasks. While both GABA receptor vectors increased the amplitude of cortical inhibitory postsynaptic potentials, only viral expression of postsynaptic GABAB receptors improved perceptual thresholds to control levels. Similarly, presynaptic GAD65 expression improved perceptual performance on spectral modulation detection. These findings suggest that recovering performance on auditory perceptual tasks depends on GABAB receptor-dependent transmission at the auditory cortex parvalbumin to pyramidal synapse and point to potential therapeutic targets for developmental sensory disorders.

Transcriptomic Analysis Reveals the Inability of Recombinant AAV8 to Activate Human Monocyte-Derived Dendritic Cells.

Recombinant Adeno-Associated Virus (rAAV) is considered as one of the most successful and widely used viral vectors for in vivo gene therapy. However, host immune responses to the vector and/or the transgene product remain a major hurdle to successful AAV gene transfer. In contrast to antivector adaptive immunity, the initiation of the innate immunity towards rAAV is still poorly understood but is directly dependent on the interaction between the viral vector and innate immune cells. Here, we used a quantitative transcriptomic-based approach to determine the activation of inflammatory and anti-viral pathways after rAAV8-based infection of monocyte-derived dendritic cells (moDCs) obtained from 12 healthy human donors. We have shown that rAAV8 particles are efficiently internalized, but that this uptake does not induce any detectable transcriptomic change in moDCs in contrast to an adenoviral infection, which upregulates anti-viral pathways. These findings suggest an immunologically favorable profile for rAAV8 serotype with regard to in vitro activation of moDC model. Transcriptomic analysis of rAAV-infected innate immune cells is a powerful method to determine the ability of the viral vector to be seen by these sensor cells, which remains of great importance to better understand the immunogenicity of rAAV vectors and to design immune-stealth products.

Chemogenetic Activation of Cortical Parvalbumin-Positive Interneurons Reverses Noise-Induced Impairments in Gap Detection.

Exposure to loud noises not only leads to trauma and loss of output from the ear but also alters downstream central auditory circuits. A perceptual consequence of noise-induced central auditory disruption is impairment in gap-induced prepulse inhibition, also known as gap detection. Recent studies have implicated cortical parvalbumin (PV)-positive inhibitory interneurons in gap detection and prepulse inhibition. Here, we show that exposure to loud noises specifically reduces the density of cortical PV but not somatostatin (SOM)-positive interneurons in the primary auditory cortex in mice (C57BL/6) of both sexes. Optogenetic activation of PV neurons produced less cortical inhibition in noise-exposed than sham-exposed animals, indicative of reduced PV neuron function. Activation of SOM neurons resulted in similar levels of cortical inhibition in noise- and sham-exposed groups. Furthermore, chemogenetic activation of PV neurons with the hM3-based designer receptor exclusively activated by designer drugs completely reversed the impairments in gap detection for noise-exposed animals. These results support the notions that cortical PV neurons encode gap in sound and that PV neuron dysfunction contributes to noise-induced impairment in gap detection.SIGNIFICANCE STATEMENT Noise-induced hearing loss contributes to a range of central auditory processing deficits (CAPDs). The mechanisms underlying noise-induced CAPDs are still poorly understood. Here we show that exposure to loud noises results in dysfunction of PV-positive but not somatostatin-positive inhibitory interneurons in the primary auditory cortex. In addition, cortical PV inhibitory neurons in noise-exposed animals had reduced expression of glutamic acid decarboxylases and weakened inhibition on cortical activity. Noise exposure resulted in impaired gap detection, indicative of disrupted temporal sound processing and possibly tinnitus. We found that chemogenetic activation of cortical PV inhibitory interneurons alleviated the deficits in gap detection. These results implicate PV neuron dysfunction as a mechanism for noise-induced CAPDs.

Neoadjuvant therapy versus upfront surgery for early-stage left-sided pancreatic adenocarcinoma: A propensity-matched analysis from a national cohort of distal pancreatectomies.

BACKGROUND: There are limited data on the efficacy of neoadjuvant therapy (NAT) for early-stage distal pancreas adenocarcinoma (PDAC). Previous studies focused on adenocarcinoma of the head of the pancreas or dealt with borderline and locally advanced tumors of the body and tail. METHODS: This is a retrospective study of the National Cancer Database between 2006 and 2015. A propensity-matched analysis was performed to compare overall survival estimates between NAT and upfront resection (UR) groups. RESULTS: A total of 5003 distal pancreatectomies for PDAC were identified, of whom 408 (9%) received NAT. After 1:1 matching, 353 NAT patients were compared with 353 UR patients. NAT was associated with lower 90-day mortality. There were no differences in the number of lymph nodes retrieved, or length of stay. With matching, the NAT group had higher median overall survival compared with UR (33.0 vs. 27.0 months; p = 0.009) and adjusted overall survival (hazard ratio = 0.63, 95% confidence interval = 0.51-0.77; p < 0.001). CONCLUSION: The receipt of NAT followed by distal pancreatectomy for early-stage distal PDAC is associated with improved overall survival compared with UR. This study supports the use of NAT in the multimodal therapy paradigm of early-stage adenocarcinoma of the body and tail of the pancreas.

Predicting Conversion from Laparoscopic to Open Cholecystectomy: A Single Institution Retrospective Study.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the standard surgical treatment for benign gallbladder disease. Nevertheless, conversion to open cholecystectomy (OC) is needed in some cases. The aim of this study is to calculate our institutional conversion rate and to identify the variables that are implicated in increasing the risk of conversion (LC-OC). MATERIALS AND METHODS: We carried out a retrospective study of all cases of LC performed at the American University of Beirut Medical Center between 2000 and 2015. Each (LC-OC) case was randomly matched to a laparoscopically completed case by the same consultant within the same year of practice, as the LC-OC case, in a 1:5 ratio. Forty-eight parameters were compared between the two study groups. RESULTS: Forty-eight out of 4668 LC were converted to OC over the 15-year study period; the conversion rate in our study was 1.03%. The variables that were found to be most predictive of conversion were male gender, advanced age, prior history of laparotomy, especially in the setting of prior gunshot wound, a history of restrictive or constrictive lung disease and anemia (Hb < 9 g/dl). The most common intraoperative reasons for conversion were perceived difficult anatomy or obscured view secondary to severe adhesions or significant inflammation. Patients who were in the LC-OC arm had a longer length of hospital stay. CONCLUSION: Advance age, male gender, significant comorbidities and history of prior laparotomies have a high risk of conversion. Patients with these risk factors should be counseled for the possibility of conversion to open surgery preoperatively. Further research is needed to determine whether these high risks patients should be operated on by surgeons with more extensive experience in minimal invasive surgery.

Percutaneous closure of patent ductus arteriosus in children using amplatzer duct occluder II: relationship between PDA type and risk of device protrusion into the descending aorta.

OBJECTIVES: To compare the efficacy and safety of Amplatzer Duct Occluder II (ADOII) among the various patent ductus arteriosus (PDA) types, and to assess the association between development of aortic obstruction and the PDA type in terms of measurable parameters as the device angulation and distance of upper end protrusion into the aortic lumen. METHODS: Retrospective cohort study involving 50 consecutive subjects who underwent ADO II device closure of PDA. RESULTS: The median age and weight at intervention were 13 months (5.5 months to 18 years) and 11 (6-67) kg respectively. The median smallest ductal diameter by angiography was 3.2 (1.9-5.4) mm. Thirty two patients had type A PDA, 5 had type C, 5 had type D, and 8 had type E. Residual shunt was seen in only 1 patient who had a tubular PDA and resolved within 2 months of the procedure. No device embolization or pulmonary side protrusion were noted. There was a 16% aortic protrusion rate. The median distance of protrusion of the upper end of the device into the aortic lumen was 3.1 (0-9) mm and the median angle formed between the aortic end of the device and the PDA take-off was 10.4 (0-80.6) degrees. These latter parameters of aortic obstruction were significantly higher in the non-conical PDA group as compared to the conical PDA. Nevertheless, there was no significant coarctation due to aortic retention disc protrusion. CONCLUSION: Device closure of PDA using the ADO II is a safe procedure for chosen types of PDA. We demonstrated a novel technique for objective assessment of device protrusion into the descending aorta based on measurable parameters. ADOII device closure of non-conical PDAs warrants closer follow ups.

Novel percutaneous femoral arterial-transthoracic approach for closure of ascending aortic pseudoaneurysm with a septal occluder device in a child.

Ascending aortic pseudoaneurysms are a rare complication following cardiac surgery. Their traditional surgical management carries high morbidity and mortality, especially in patients with multiple comorbidities. Transcatheter closure of these pseudoaneurysms using a septal occluder device has been previously reported in adults as an alternative approach with fewer complications. We report the first case of a novel percutaneous femoral arterial-transthoracic approach for exclusion of an ascending aortic pseudoaneurysm with an Amplatzer atrial septal occluder device in a 9-year-old child with Takayasu's arteritis.

Research in congenital heart disease: a comparative bibliometric analysis between developing and developed countries.

Congenital heart disease (CHD) is the most common congenital anomaly, affecting 1 % of live births. The field of pediatric cardiology has witnessed major advances over the past 25 years triggered by research initiatives focusing on CHD. However, large disparities exist in research capabilities between Arab developing nations and the developed nations. This study used bibliometric analysis to assess the contribution of the Arab countries to CHD research. To identify articles on CHD published in the Arab countries, the United States, and Europe, a systematic search was run on MEDLINE, PubMed, and Scopus. The Arab countries, with an estimated population of 362 million, published 530 research articles addressing CHD in the last 25 years (average, 1.5 articles/10(6) population). This compares with 12,936 research articles published in the United States (average, 41 articles/10(6) population) and 12,260 published in Europe (average, 24.3 articles/10(6) population). Basic research relating to genetics and animal models of CHD is emerging sparsely in the Arab world, with few articles published in high-impact-factor journals. The Arab world research output in the field of CHD per capita is substantially low, estimated to be 29 times less than in developed countries. Despite the minimal increase in published research articles in global periodicals, most of the research relating to CHD continues to be far from innovative. Regional collaborations with international linkage are starting to evolve. The research facilities in the Arab countries need to increase substantially in research and infrastructure funding to keep up with the pace of research in developing countries.

Rupture of sinus of Valsalva aneurysm with aorto-biventricular fistulas and right-ventricular outflow tract obstruction: a unique association.

Sinus of Valsalva aneurysms are a rare entity. Rupture of such aneurysms is a major cause of aortocardiac fistulas usually occurring between the right sinus of Valsalva and right cardiac chambers. We report an exceptional case of a ruptured congenital sinus of Valsalva aneurysm with fistulas involving both the right- and left-ventricular outflow tracts and causing RVOT obstruction. We also demonstrate the utility of computed tomography angiography and transesophageal echocardiography in diagnosing these fistulas.

Developmental hearing loss-induced perceptual deficits are rescued by cortical expression of GABAB receptors.

Even transient periods of developmental hearing loss during the developmental critical period have been linked to long-lasting deficits in auditory perception, including temporal and spectral processing, which correlate with speech perception and educational attainment. In gerbils, hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABAA and metabotropic GABAB receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABAA receptors. We developed viral vectors to express both endogenous GABAA or GABAB receptor subunits in auditory cortex and tested their capacity to restore perception of temporal and spectral auditory cues following critical period hearing loss in the Mongolian gerbil. HL significantly impaired perception of both temporal and spectral auditory cues. While both vectors similarly increased IPSCs in auditory cortex, only overexpression of GABAB receptors improved perceptual thresholds after HL to be similar to those of animals without developmental hearing loss. These findings identify the GABAB receptor as an important regulator of sensory perception in cortex and point to potential therapeutic targets for developmental sensory disorders.

Contributions of Hearing Loss and Traumatic Brain Injury to Blast-Induced Cortical Parvalbumin Neuron Loss and Auditory Processing Deficits.

Auditory processing disorder is the most common problem affecting veterans after blast exposure, but the distinct impacts of blast-related traumatic brain injury and blast-related hearing loss are unknown. Independently, both hearing loss and blast exposure affect the entire auditory processing pathway at the molecular and physiological levels. Here, we identified distinct changes to the primary auditory cortex (AI) and temporal processing in mice following blast exposure both with and without protected hearing. Our results show that blast-exposure alone activated microglia in AI, but hearing loss was required for reductions in the density of parvalbumin-expressing interneurons. Although blast exposure impaired the temporal following response, these impairments were more severe with concurrent unilateral hearing loss, further resulting in impairments in behavioral gap detection. Taken together, these results indicate that protecting hearing during blast exposure can prevent most impairments to auditory processing but does not fully protect temporal processing.

Long-Term Enhancement of NMDA Receptor Function in Inhibitory Neurons Preferentially Modulates Potassium Channels and Cell Adhesion Molecules.

Effectively enhancing the activity of inhibitory neurons has great therapeutic potentials since their reduced function/activity has significant contributions to pathology in various brain diseases. We showed previously that NMDAR positive allosteric modulator GNE-8324 and M-8324 selectively increase NMDAR activity on the inhibitory neurons and elevates their activity in vitro and in vivo. Here we examined the impact of long-term administering M-8324 on the functions and transcriptional profiling of parvalbumin-containing neurons in two representative brain regions, primary auditory cortex (Au1) and prelimbic prefrontal cortex (PrL-PFC). We found small changes in key electrophysiological parameters and RNA levels of neurotransmitter receptors, Na+ and Ca2+ channels. In contrast, large differences in cell adhesion molecules and K+ channels were found between Au1 and PrL-PFC in drug-naïve mice, and differences in cell adhesion molecules became much smaller after M-8324 treatment. There was also minor impact of M-8324 on cell cycle and apoptosis, suggesting a fine safety profile.

Increasing endogenous activity of NMDARs on GABAergic neurons increases inhibition, alters sensory processing and prevents noise-induced tinnitus.

Selective enhancement of GABAergic inhibition is thought to impact many vital brain functions and interferes with the genesis and/or progression of numerous brain disorders. Here, we show that selectively increasing NMDA receptor activity in inhibitory neurons using an NMDAR positive allosteric modulator (PAM) elevates spiking activity of inhibitory neurons in vitro and in vivo. In vivo infusion of PAM increases spontaneous and sound-evoked spiking in inhibitory and decreases spiking in excitatory neurons, and increases signal-to-noise ratio in the primary auditory cortex. In addition, PAM infusion prior to noise trauma prevents the occurrence of tinnitus and reduction in GABAergic inhibition. These results reveal that selectively enhancing endogenous NMDAR activity on the GABAergic neurons can effectively enhance inhibitory activity and alter excitatory-inhibitory balance, and may be useful for preventing diseases that involve reduced inhibition as the major cause.

Blast Exposure Disrupts the Tonotopic Frequency Map in the Primary Auditory Cortex.

Blast exposure can cause various auditory disorders including tinnitus, hyperacusis, and other central auditory processing disorders. While this is suggestive of pathologies in the central auditory system, the impact of blast exposure on central auditory processing remains poorly understood. Here we examined the effects of blast shockwaves on acoustic response properties and the tonotopic frequency map in the auditory cortex. We found that multiunits recorded from the auditory cortex exhibited higher acoustic thresholds and broader frequency tuning in blast-exposed animals. Furthermore, the frequency map in the primary auditory cortex was distorted. These changes may contribute to central auditory processing disorders.