Child abuse with multiple sharp foreign bodies penetrating the chest wall causing hemothorax and cardiac tamponade in two separate occasions: Case report.

We present a case of repeated child abuse causing left-sided hemothorax and cardiac tamponade on two separate occasions. A 14-year-old cerebral palsy male presented with left-sided hemothorax and multiple metallic foreign bodies in the chest wall managed by small limited incision, removal of the foreign bodies and chest tube. One week later, he came to our emergency department (ER) with multiple chest wall foreign bodies and tamponade managed by median sternotomy, removal of the foreign bodies, one of them was in the LAD. He had a smooth postoperative course and the case is under investigation.

VGLUT3 Deletion Rescues Motor Deficits and Neuronal Loss in the zQ175 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease characterized by progressive motor and cognitive impairments, with no disease-modifying therapies yet available. HD pathophysiology involves evident impairment in glutamatergic neurotransmission leading to severe striatal neurodegeneration. The vesicular glutamate transporter-3 (VGLUT3) regulates the striatal network that is centrally affected by HD. Nevertheless, current evidence on the role of VGLUT3 in HD pathophysiology is lacking. Here, we crossed mice lacking Slc17a8 gene (VGLUT3 -/-) with heterozygous zQ175 knock-in mouse model of HD (zQ175:VGLUT3 -/-). Longitudinal assessment of motor and cognitive functions from 6 to 15 months of age reveals that VGLUT3 deletion rescues motor coordination and short-term memory deficits in both male and female zQ175 mice. VGLUT3 deletion also rescues neuronal loss likely via the activation of Akt and ERK1/2 in the striatum of zQ175 mice of both sexes. Interestingly, the rescue in neuronal survival in zQ175:VGLUT3 -/- mice is accompanied by a reduction in the number of nuclear mutant huntingtin (mHTT) aggregates with no change in the total aggregate levels or microgliosis. Collectively, these findings provide novel evidence that VGLUT3, despite its limited expression, can be a vital contributor to HD pathophysiology and a viable target for HD therapeutics.SIGNIFICANCE STATEMENT Dysregulation of the striatal network centrally contributes to the pathophysiology of Huntington's disease (HD). The atypical vesicular glutamate transporter-3 (VGLUT3) has been shown to regulate several major striatal pathologies, such as addiction, eating disorders, or L-DOPA-induced dyskinesia. Yet, our understanding of VGLUT3's role in HD remains unclear. We report here that deletion of the Slc17a8 (Vglut3) gene rescues the deficits in both motor and cognitive functions in HD mice of both sexes. We also find that VGLUT3 deletion activates neuronal survival signaling and reduces nuclear aggregation of abnormal huntingtin proteins and striatal neuron loss in HD mice. Our novel findings highlight the vital contribution of VGLUT3 in HD pathophysiology that can be exploited for HD therapeutic management.

VGLUT3 Ablation Differentially Modulates Glutamate Receptor Densities in Mouse Brain.

Type 3 vesicular glutamate transporter (VGLUT3) represents a unique modulator of glutamate release from both nonglutamatergic and glutamatergic varicosities within the brain. Despite its limited abundance, VGLUT3 is vital for the regulation of glutamate signaling and, therefore, modulates the activity of various brain microcircuits. However, little is known about how glutamate receptors are regulated by VGLUT3 across different brain regions. Here, we used VGLUT3 constitutive knock-out (VGLUT3-/-) mice and explored how VGLUT3 deletion influences total and cell surface expression of different ionotropic and metabotropic glutamate receptors. VGLUT3 deletion upregulated the overall expression of metabotropic glutamate receptors mGluR5 and mGluR2/3 in the cerebral cortex. In contrast, no change in the total expression of ionotropic NMDAR glutamate receptors were observed in the cerebral cortex of VGLUT3-/- mice. We noted significant reduction in cell surface levels of mGluR5, NMDAR2A, NMDAR2B, as well as reductions in dopaminergic D1 receptors and muscarinic M1 acetylcholine receptors in the hippocampus of VGLUT3-/- mice. Furthermore, mGluR2/3 total expression and mGluR5 cell surface levels were elevated in the striatum of VGLUT3-/- mice. Last, AMPAR subunit GluA1 was significantly upregulated throughout cortical, hippocampal, and striatal brain regions of VGLUT3-/- mice. Together, these findings complement and further support the evidence that VGLUT3 dynamically regulates glutamate receptor densities in several brain regions. These results suggest that VGLUT3 may play an intricate role in shaping glutamatergic signaling and plasticity in several brain areas.

Optineurin deletion disrupts metabotropic glutamate receptor 5-mediated regulation of ERK1/2, GSK3ß/ZBTB16, mTOR/ULK1 signaling in autophagy.

Optineurin (OPTN) is a multifunctional protein that mediates a network of cellular processes regulating membrane trafficking, inflammatory responses and autophagy. The OPTN-rich interactome includes Group I metabotropic glutamate receptors (mGluR1 and 5), members of the Gαq/11 protein receptor family. Recent evidence has shown that mGluR5, in addition to its canonical Gαq/11 protein-coupled signaling, regulates autophagic machinery via mTOR/ULK1 and GSK3ß/ZBTB16 pathways in both Alzheimer's and Huntington's disease mouse models. Despite its potential involvement, the role of OPTN in mediating mGluR5 downstream signaling cascades remains largely unknown. Here, we employed a CRISPR/Cas9 OPTN-deficient STHdhQ7/Q7 striatal cell line and global OPTN knockout mice to investigate whether Optn gene deletion alters both mGluR5 canonical and noncanonical signaling. We find that OPTN is required for mGluR5-activated Ca2+ flux and ERK1/2 signaling following receptor activation in STHdhQ7/Q7 cells and acute hippocampal slices. Deletion of OPTN impairs both GSK3ß/ZBTB16 and mTOR/ULK1 autophagic signaling in STHdhQ7/Q7 cells. Furthermore, mGluR5-dependent regulation of GSK3ß/ZBTB16 and mTOR/ULK1 autophagic signaling is impaired in hippocampal slices of OPTN knockout mice. Overall, we show that the crosstalk between OPTN and mGluR5 can have major implication on receptor signaling and therefore potentially contribute to the pathophysiology of neurodegenerative diseases.

Targeting Vesicular Glutamate Transporter Machinery: Implications on Metabotropic Glutamate Receptor 5 Signaling and Behavior.

Cross talk between both pre- and postsynaptic components of glutamatergic neurotransmission plays a crucial role in orchestrating a multitude of brain functions, including synaptic plasticity and motor planning. Metabotropic glutamate receptor (mGluR) 5 exhibits promising therapeutic potential for many neurodevelopmental and neurodegenerative disorders as a consequence of its modulatory control over diverse neuronal networks required for memory, motor coordination, neuronal survival, and differentiation. Given these crucial roles, mGluR5 signaling is under the tight control of glutamate release machinery mediated through vesicular glutamate transporters (VGLUTs) that ultimately dictate glutamatergic output. A particular VGLUT isoform, VGLUT3, exhibits an overlapping, but unique, distribution with mGluR5, and the dynamic cross talk between mGluR5 and VGLUT3 is key for the function of specific neuronal networks involved in motor coordination, emotions, and cognition. Thus, aberrant signaling of the VGLUT3-mGluR5 axis is linked to various pathologies including, but not limited to, Parkinson disease, anxiety disorders, and drug addiction. We argue that a comprehensive profiling of how coordinated VGLUT3-mGluR5 signaling influences overall glutamatergic neurotransmission is warranted. SIGNIFICANCE STATEMENT: Vesicular glutamate receptor (VGLUT) 3 machinery orchestrates glutamate release, and its distribution overlaps with metabotropic glutamate receptor (mGluR) 5 in regional brain circuitries, including striatum, hippocampus, and raphe nucleus. Therefore, VGLUT3-mGluR5 cross talk can significantly influence both physiologic and pathophysiologic glutamatergic neurotransmission. Pathological signaling of the VGLUT3-mGluR5 axis is linked to Parkinson disease, anxiety disorders, and drug addiction. However, it is also predicted to contribute to other motor and cognitive disorders.

Heme oxygenase byproducts variably influences myocardial and autonomic dysfunctions induced by the cyclosporine/diclofenac regimen in female rats.

We recently reported that exposure to cyclosporine (CSA) plus diclofenac causes hypertension and impairs left ventricular (LV) and cardiac autonomic functions in female rats. Here, we tested the hypothesis that these effects could be mitigated by facilitated heme oxygenase (HO) signaling. Experiments were performed in female rats to assess the effects of 10-day treatment with CSA (25 mg/kg/day)/diclofenac (1 mg/kg/day) regimen on cardiovascular functions in absence and presence of maneuvers that upregulate HO or its enzymatic products. The CSA/diclofenac-induced hypertension and impairment in cardiac sympathovagal balance (i.e. reduced low-frequency/high-frequency spectral ratio) were blunted upon concurrent treatment with hemin (HO-1 inducer), tricarbonyldichlororuthenium (II) dimer (CORM-2, carbon monoxide-releasing molecule), or bilirubin. While none of the latter treatments affected the CSA/diclofenac-evoked decrease in isovolumic relaxation constant (Tau, a measure of diastolic function), the increased LV contractility (dP/dtmax) and attenuated reflex bradycardia in CSA/diclofenac-treated rats was abolished by bilirubin only. Paradoxically, the CSA/diclofenac-evoked attenuation in reflex tachycardia was improved in presence of hemin or CORM-2, but not bilirubin. The favorable hemin effects were abrogated after inhibition of HO (ZnPP) or nitric oxide synthase (NOS, l-NAME). These finding highlights NOS-dependent modulatory roles for HO and its enzymatic products in improving the worsened cardiovascular profile in CSA/diclofenac-treated female rats.

Role of NADPHox/Rho-kinase signaling in the cyclosporine-NSAIDs interactions on blood pressure and baroreflexes in female rats.

AIMS: The hypertensive effect of the immunosuppressant drug cyclosporine (CSA) is paralleled, and probably triggered, by impaired arterial baroreceptor sensitivity (BRS). Here we asked if these effects of CSA are influenced by co-administration of nonsteroidal antiinflammatory drugs (NSAIDs) and if the oxidative NADPH-oxidase (NADPHox)/Rho-kinase (ROCK) pathway mediates this interaction. MATERIALS AND METHODS: Female rats were treated for 10days with CSA (25mg/kg/day), diclofenac (DIC, COX-1/COX-2 inhibitor, 1mg/kg/day), celecoxib (COX-2 inhibitor, 10mg/kg/day), or their combinations. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed and slopes of the curves were taken as measures of BRS. KEY FINDINGS: Compared with control rats, CSA increased BP and reduced reflex chronotropic responses as indicated by the significantly smaller BRSPE and BRSSNP values. Similar effects were observed in rats treated with diclofenac alone or combined with CSA. Whereas CSA hypertension was maintained after selective COX-2 inhibition by celecoxib, the concomitant BRS reductions were largely eliminated. NADPHox inhibition by diphenyleneiodonium (DPI) blunted the CSA/DIC-evoked increases and decreases in BP and BRSPE, respectively. By contrast, fasudil (ROCK inhibitor) had no effect on CSA/DIC hypertension but reversed the associated reductions in both BRSPE and BRSSNP. SIGNIFICANCE: Depending on the nature of the cardiovascular response, NADPHox and ROCK contribute variably to the worsened cardiovascular profile in CSA/DIC-treated rats. Further, celecoxib rather than diclofenac could be a better choice as an add-on therapy to CSA in autoimmune arthritic conditions.

Modulation by NADPH oxidase of the chronic cardiovascular and autonomic interaction between cyclosporine and NSAIDs in female rats.

Cyclosporine (CSA) and nonsteroidal antiinflammatory drugs (NSAIDs) are used together to manage arthritic disorders with an immune component. Previous reports showed contrasting effects for NSAIDs on CSA nephrotoxicity and acute elevations in blood pressure. Both effects were ameliorated or exaggerated after selective cyclooxygenase-2 (COX2) and nonselective COX inhibition, respectively. Here we investigated: (i) the interaction of CSA with NSAIDs possessing variable COX1/COX2 selectivities on hemodynamic, left ventricular (LV) and cardiac autonomic and histologic profiles, and (ii) role of NADPH-oxidase (NOX)/Rho-kinase (ROCK) pathway in the interaction. Female rats were pre-instrumented with femoral catheters and treated for 10 days with CSA (25mg/kg/day), diclofenac (nonselective NSAIDs, 1mg/kg/day), celecoxib (COX2 inhibitor, 10mg/kg/day), or their combinations. CSA-mediated hypertension was maintained upon co-administration of either NSAID whereas the concomitant reductions in time- and frequency-domain indices of heart rate variability (HRV) were accentuated in presence of diclofenac but not celecoxib. The isovolumic relaxation time (Τau), a measure of diastolic function, was reduced by all regimens whereas LV contractility (dP/dtmax) remained unaffected. The CSA/diclofenac regimen, but not individual treatments, increased cardiac NOX2 expression and caused more cardiac structural damage. The inhibition of NOX by diphenyleneiodonium reversed CSA/diclofenac-evoked increases in MAP, decreases in HRV and Tau, cardiac structural damage, and increased NOX2 expression. No such effects were observed after ROCK inhibition by fasudil, despite concomitant decreases in NOX2 expression. In conclusion, CSA/diclofenac-treated female rats exhibit exacerbated hemodynamic, autonomic, LV, and histopathologic disturbances via ROCK-independent NOX2 upregulation.

Opposite Modulatory Effects of Selective and Non-Selective Cyclooxygenase Inhibition on Cardiovascular and Autonomic Consequences of Cyclosporine in Female Rats.

Non-steroidal anti-inflammatory drugs (NSAIDs) and the immunosuppressant drug cyclosporine (CSA) are concurrently administered in arthritis. Here, we investigated whether diclofenac (non-selective inhibitor of cyclooxygenase-1 and 2, COX-1/COX-2), celecoxib (selective COX-2 inhibitor) or SC560 (selective COX-1 inhibitor) interact variably with haemodynamic effects of CSA in conscious female rats. Changes caused by CSA (10 mg/kg i.v.) in blood pressure (BP), heart rate (HR), HR variability (HRV) and myocardial contractility were assessed in the absence and presence of individual NSAIDs (10 mg/kg each). Compared with vehicle values, CSA caused immediate and sustained (i) increases in BP and decreases in pulse pressure index (PPI) and HR, (ii) elevations in left ventricular (LV) contractility (dP/dtmax ) and isovolumic relaxation constant (Τau) and (iii) increases in the time- and frequency-domain indices of HRV and shifted the cardiac sympathovagal balance towards parasympathetic dominance. CSA hypertension was abolished in rats pre-treated with celecoxib and intensified in the presence of diclofenac or SC560. Alternatively, the CSA-evoked decreases in PPI, increases in HRV indices and cardiac parasympathetic dominance were blunted by celecoxib in contrast to no effect for diclofenac or SC560. Similarly, celecoxib, but not other NSAIDs, eliminated the elevated LV contractility (dP/dtmax ) and isovolumic relaxation constant (Τau, τ), which reflect cardiac systolic and diastolic function, respectively, that accompanied the CSA-induced pressure load. The data underscore the preferential capacity of selective COX-2 inhibition by celecoxib to mitigate CSA hypertension and consequent alterations in cardiac performance and autonomic balance. By contrast, CSA effects are preserved or even exacerbated after COX-1 inhibition.