An overview of malingering and deception in neuropsychiatric cases.

Forensic practitioners must shoulder special responsibilities when evaluating over-stated pathology (e.g., malingering) as well as simulated adjustment. Such determinations may modify or even override other clinical findings. As a result, practitioners must be alert to their own misassumptions that may unintentionally bias their conclusions about response styles. Detection strategies for malingering-based on unlikely or markedly amplified presentations-are highlighted in this article. Given page constraints, assessment methods for feigning are succinctly presented with their applications to administrative, civil, and criminal referrals.

Chemogenetic activation of ventral medullary astrocytes enhances feeding and corticosterone release in response to mild glucoprivation.

To investigate the role of glial cells in the regulation of glucoprivic responses in rats, a chemogenetic approach was used to activate astrocytes neighboring catecholamine (CA) neurons in the ventromedial medulla (VLM) where A1 and C1 CA cell groups overlap (A1/C1). Previous results indicate that activation of CA neurons in this region is necessary and sufficient for feeding and corticosterone release in response to glucoprivation. However, it is not known whether astrocyte neighbors of CA neurons contribute to glucoregulatory responses. Hence, we made nanoinjections of AAV5-GFAP-hM3D(Gq)-mCherry to selectively transfect astrocytes in the A1/C1 region with the excitatory designer receptor exclusively activated by designer drugs (DREADDs), hM3D(Gq). After allowing time for DREADD expression, we evaluated the rats for increased food intake and corticosterone release in response to low systemic doses of the antiglycolytic agent, 2-deoxy-d-glucose (2DG), alone and in combination with the hM3D(Gq) activator clozapine-n-oxide (CNO). We found that DREADD-transfected rats ate significantly more food when 2DG and CNO were coadministered than when either 2DG or CNO was injected alone. We also found that CNO significantly enhanced 2DG-induced FOS expression in the A1/C1 CA neurons, and that corticosterone release also was enhanced when CNO and 2DG were administered together. Importantly, CNO-induced activation of astrocytes in the absence of 2DG did not trigger food intake or corticosterone release. Our results indicate that during glucoprivation, activation of VLM astrocytes cells markedly increases the sensitivity or responsiveness of neighboring A1/C1 CA neurons to glucose deficit, suggesting a potentially important role for VLM astrocytes in glucoregulation.

Characterization and surgical management of aberrant subclavian arteries.

OBJECTIVE: Aberrant subclavian arteries (aSCAs), with or without aortic pathology, are uncommon. The purpose of the present study was to review our experience with the surgical management of aSCA. METHODS: We performed a retrospective review of patients who had undergone surgery for an aSCA between 1996 and 2020. Symptomatic and asymptomatic patients were included. The primary end points were ≤30-day and late mortality. The secondary end points were ≤30-day complications, graft patency, and reinterventions. RESULTS: A total of 46 symptomatic and 3 asymptomatic patients with aSCA had undergone surgery (31 females [62%]; median age, 45 years). An aberrant right subclavian artery was present in 38 (78%) and an aberrant left subclavian artery in 11 patients (22%). Of the 49 patients, 41 (84%) had had a Kommerell diverticulum (KD) and 11 (22%) had had a concomitant distal arch or proximal descending thoracic aortic aneurysm. Symptoms included dysphagia (56%), dyspnea (27%), odynophagia (20%), and upper extremity exertional fatigue (16%). Five patients (10%) had required emergency surgery. The aSCA had been treated by transposition in 32, a carotid to subclavian bypass in 11, and an ascending aorta to subclavian bypass in 6. The KD was treated by resection and oversewing in 19 patients (39%). Fifteen patients (31%) had required distal arch or proximal descending thoracic aortic replacement for concomitant aortic disease and/or KD treatment. Thoracic endovascular aortic repair was used to exclude the KD in six patients (12%). Seven patients (14%) had undergone only bypass or transposition. The 30-day complications included one death from pulseless electrical activity arrest secondary to massive pulmonary embolism. The 30-day major complications (14%) included acute respiratory failure in three, early mortality in one, stroke in one, non-ST-elevation myocardial infarction in one, and temporary dialysis in one patient. The other complications included chylothorax/lymphocele (n = 5; 10%), acute kidney injury (n = 2; 4%), pneumonia (n = 2; 4%), wound infection (n = 2; 4%), atrial fibrillation (n = 2; 4%), Horner syndrome (n = 2; 4%), lower extremity acute limb ischemia (n = 1; 2%), and left recurrent laryngeal nerve injury (n = 1; 2%). At a median follow-up of 53 months (range, 1-230 months), 40 patients (82%) had had complete symptom relief and 9 (18%) had experienced improvement. Six patients had died at a median of 157 months; the deaths were not procedure or aortic related. The primary patency was 98%. Reintervention at ≤30 days had been required for two patients (4%) for ligation of lymphatic vessels and bilateral lower extremity fasciotomy after proximal descending thoracic aorta replacement. One patient had required late explantation of an infected and occluded carotid to subclavian bypass graft, which was treated by cryopreserved allograft replacement. CONCLUSIONS: Surgical treatment of the aSCA can be accomplished with low major morbidity and mortality with excellent primary patency and symptom relief.

Fenestrated/branched endovascular aortic repair using unilateral femoral access in patients with iliac occlusive disease.

OBJECTIVE: Fenestrated/branched endovascular aortic repair (F/BEVAR) in patients with occluded iliac arteries is challenging owing to limited access for branch vessel catheterization and increased risk for leg and spinal ischemic complications. The aim of this study was to analyze technical strategies and outcomes of F/BEVAR in patients with unilateral iliofemoral occlusive disease. METHODS: We performed a retrospective review of all consecutive patients treated by F/BEVAR in two institutions (2003-2021). Patients with unilateral iliofemoral occlusive disease were included in the analysis. All patients had one patent iliac artery that was used for advancement of the fenestrated-branch component. Preloaded catheter/guidewire systems or steerable sheaths were used as adjuncts to facilitate catheterization. Primary endpoints were technical success, mortality, major adverse events (stroke, spinal cord injury, dialysis or decrease in the glomerular filtration rate of more than 50%, bowel ischemia, myocardial infarction, or respiratory failure), primary iliac patency, and freedom from reinterventions. RESULTS: There were 959 patients treated with F/BEVAR. Of these, 15 patients (1.56%; mean age, 74 years; 80% male) had occluded iliac arteries and 1 patent iliofemoral access and were treated for a thoracoabdominal aortic aneurysm (n = 8) or juxtarenal abdominal aortic aneurysm (n = 7). Brachial access was used in 14 of the 15 patients and preloaded systems in 7 of the 15 patients (47%). The remaining 53% had staggered deployment of stent grafts. There were seven physician-modified endovascular grafts, seven custom-made devices, and one off-the-shelf device used. Thirteen patients (87%) had distal seal using aortouni-iliac stent grafts and two (13%) had distal seal in the infrarenal aorta. Concomitant femoral crossover bypass (FCB) was performed in two patients and six patients had a prior FCB. Technical success was 100%. There were no intraoperative complications or early lower extremity ischemic complications, and all FCB were preserved. There was one mortality (7%) within 30 days owing to retrograde type A dissection. Major adverse events occurred in 20% of patients. The median follow-up was 12 months (range, 0-85 months). Two patients (13%) required three reinterventions. One patient required proximal stent graft extension for an acute type B dissection (3 months) and another required iliac extension for type Ib endoleak of an aortouni-iliac graft (21 months) and thrombolysis of that extension (50 months). At last follow-up, all patients had primary graft patency except one with secondary graft patency without new claudication. One patient had a single renal artery stent occlusion at follow-up with no r-intervention. The overall survival rate was 60%, without aortic-related deaths. CONCLUSIONS: Although challenging, F/BEVAR with unilateral femoral/brachial approach is feasible in patients with occluded iliac limbs, with an important rate of ischemic complications, but satisfactory outcomes.

Contemporary outcomes after treatment of aberrant subclavian artery and Kommerell's diverticulum.

OBJECTIVE: Aberrant subclavian artery (ASA) and Kommerell's diverticulum (KD) are rare vascular anomalies that may be associated with lifestyle-limiting and life-threatening complications. The aim of this study is to report contemporary outcomes after invasive treatment of ASA/KD using a large international dataset. METHODS: Patients who underwent treatment for ASA/KD (2000-2020) were identified through the Vascular Low Frequency Disease Consortium, a multi-institutional collaboration to investigate uncommon vascular disorders. We report the early and mid-term clinical outcomes including stroke and mortality, technical success, and other operative outcomes including reintervention rates, patency, and endoleak. RESULTS: Overall, 285 patients were identified during the study period. The mean patient age was 57 years; 47% were female and 68% presented with symptoms. A right-sided arch was present in 23%. The mean KD diameter was 47.4 mm (range, 13.0-108.0 mm). The most common indication for treatment was symptoms (59%), followed by aneurysm size (38%). The most common symptom reported was dysphagia (44%). A ruptured KD was treated in 4.2% of cases, with a mean diameter of 43.9 mm (range, 18.0-100.0 mm). An open procedure was performed in 101 cases (36%); the most common approach was ASA ligation with subclavian transposition. An endovascular or hybrid approach was performed in 184 patients (64%); the most common approach was thoracic endograft and carotid-subclavian bypass. A staged operative strategy was employed more often than single setting repair (55% vs 45%). Compared with endovascular or hybrid approach, those in the open procedure group were more likely to be younger (49 years vs 61 years; P < .0001), female (64% vs 36%; P < .0001), and symptomatic (85% vs 59%; P < .0001). Complete or partial symptomatic relief at 1 year after intervention was 82.6%. There was no association between modality of treatment and symptom relief (open 87.2% vs endovascular or hybrid approach 78.9%; P = .13). After the intervention, 11 subclavian occlusions (4.5%) occurred; 3 were successfully thrombectomized resulting in a primary and secondary patency of 95% and 96%, respectively, at a median follow-up of 39 months. Among the 33 reinterventions (12%), the majority were performed for endoleak (36%), and more reinterventions occurred in the endovascular or hybrid approach than open procedure group (15% vs 6%; P = .02). The overall survival rate was 87.3% at a median follow-up of 41 months. The 30-day stroke and death rates were 4.2% and 4.9%, respectively. Urgent or emergent presentation was independently associated with increased risk of 30-day mortality (odds ratio [OR], 19.8; 95% confidence interval [CI], 3.3-116.6), overall mortality (OR, 3.6; 95% CI, 1.2-11.2) and intraoperative complications (OR, 8.3; 95% CI, 2.8-25.1). Females had a higher risk of reintervention (OR, 2.6; 95% CI, 1.0-6.5). At an aneurysm size of 44.4 mm, receiver operator characteristic curve analysis suggested that 60% of patients would have symptoms. CONCLUSIONS: Treatment of ASA/KD can be performed safely with low rates of mortality, stroke and reintervention and high rates of symptomatic relief, regardless of the repair strategy. Symptomatic and urgent operations were associated with worse outcomes in general, and female gender was associated with a higher likelihood of reintervention. Given the worse overall outcomes when symptomatic and the inherent risk of rupture, consideration of repair at 40 mm is reasonable in most patients. ASA/KD can be repaired in asymptomatic patients with excellent outcomes and young healthy patients may be considered better candidates for open approaches versus endovascular or hybrid modalities, given the lower likelihood of reintervention and lower early mortality rate.

International Multi-Institutional Experience with Presentation and Management of Aortic Arch Laterality in Aberrant Subclavian Artery and Kommerell's Diverticulum.

BACKGROUND: Aberrant subclavian artery (ASA) with or without Kommerell's diverticulum (KD) is a rare anatomic aortic arch anomaly that can cause dysphagia and/or life-threatening rupture. The objective of this study is to compare outcomes of ASA/KD repair in patients with a left versus right aortic arch. METHODS: Using the Vascular Low Frequency Disease Consortium methodology, a retrospective review was performed of patients ≥18 years old with surgical treatment of ASA/KD from 2000 to 2020 at 20 institutions. RESULTS: 288 patients with ASA with or without KD were identified; 222 left-sided aortic arch (LAA), and 66 right-sided aortic arch (RAA). Mean age at repair was younger in LAA 54 vs. 58 years (P = 0.06). Patients in RAA were more likely to undergo repair due to symptoms (72.7% vs. 55.9%, P = 0.01), and more likely to present with dysphagia (57.6% vs. 39.1%, P < 0.01). The hybrid open/endovascular approach was the most common repair type in both groups. Rates of intraoperative complications, death within 30 days, return to the operating room, symptom relief and endoleaks were not significantly different. For patients with symptom status follow-up data, in LAA, 61.7% had complete relief, 34.0% had partial relief and 4.3% had no change. In RAA, 60.7% had complete relief, 34.4% had partial relief and 4.9% had no change. CONCLUSIONS: In patients with ASA/KD, RAA patients were less common than LAA, presented more frequently with dysphagia, had symptoms as an indication for intervention, and underwent treatment at a younger age. Open, endovascular and hybrid repair approaches appear equally effective, regardless of arch laterality.

Falling through the cracks: Failing to identify compromised Miranda abilities for defendants with limited cognitive capacities.

Custodial suspects must be informed of their Miranda rights (Miranda v. Arizona, 1966) prior to police questioning. Since this landmark decision, scholars have rigorously studied Miranda comprehension and reasoning among vulnerable groups including those with intellectual disabilities (ID). However, the focus on ID has left arrestees with limited cognitive capacities (i.e., LCCs with IQs between 70 and 85) entirely overlooked. The current dataset addressed this oversight using a large (N = 820) sample of pretrial defendants who had completed the Standardized Assessment of Miranda Abilities (SAMA). Traditional (i.e., ID and no-ID) criterion groups were first analyzed with the standard error of measurement (SEM) removed. Second, a nuanced three-group framework included defendants with LCCs. Results indicate that LCC defendants are vulnerable to impaired Miranda comprehension (i.e., limited recall of the Miranda warning and deficits in Miranda-related vocabulary knowledge). Not surprisingly, their waiver decisions were often impaired by crucial misconceptions (e.g., seeing the investigating officers as beneficently on their side). The practical implications of these findings were underscored with respect to Constitutional safeguards for this critically important group, who have appeared to fall through the cracks in the criminal justice system.

Forensic assessment instruments: Their reliability and applicability to criminal forensic issues.

Forensic evaluations have advanced considerably with the development of specialized measures validated on forensic and correctional samples. Prior to this progress, such evaluations relied heavily on extrapolations from general psychological tests to crucial, legally relevant questions. Since then, decades of empirical work have produced forensic assessment instruments (FAIs) addressing psycholegal standards in addition to forensically relevant instruments (FRIs) examining issues central to forensic practice (e.g., malingering) but not the standards themselves. This article provides a critical examination of the development, validation, and modern applications of six published FAIs that each address one of three broad criminal forensic issues (i.e., insanity, competency to stand trial, and Miranda abilities and waivers). Evaluations of the measures' reliability and validity particularly in forensic samples are highlighted. To complement FAIs, FRIs related to response styles are briefly explored. As a primary goal, forensic practitioners are provided with the knowledge and background about FAIs to enhance their criminal forensic practices.

Dynamin-related protein 1 regulates substrate oxidation in skeletal muscle by stabilizing cellular and mitochondrial calcium dynamics.

Mitochondria undergo continuous cycles of fission and fusion to promote inheritance, regulate quality control, and mitigate organelle stress. More recently, this process of mitochondrial dynamics has been demonstrated to be highly sensitive to nutrient supply, ultimately conferring bioenergetic plasticity to the organelle. However, whether regulators of mitochondrial dynamics play a causative role in nutrient regulation remains unclear. In this study, we generated a cellular loss-of-function model for dynamin-related protein 1 (DRP1), the primary regulator of outer membrane mitochondrial fission. Loss of DRP1 (shDRP1) resulted in extensive ultrastructural and functional remodeling of mitochondria, characterized by pleomorphic enlargement, increased electron density of the matrix, and defective NADH and succinate oxidation. Despite increased mitochondrial size and volume, shDRP1 cells exhibited reduced cellular glucose uptake and mitochondrial fatty acid oxidation. Untargeted transcriptomic profiling revealed severe downregulation of genes required for cellular and mitochondrial calcium homeostasis, which was coupled to loss of ATP-stimulated calcium flux and impaired substrate oxidation stimulated by exogenous calcium. The insights obtained herein suggest that DRP1 regulates substrate oxidation by altering whole-cell and mitochondrial calcium dynamics. These findings are relevant to the targetability of mitochondrial fission and have clinical relevance in the identification of treatments for fission-related pathologies such as hereditary neuropathies, inborn errors in metabolism, cancer, and chronic diseases.

Automated multi-attribute method sample preparation using high-throughput buffer exchange tips.

RATIONALE: The multi-attribute method (MAM) has become a valuable mass spectrometry (MS)-based tool that can identify and quantify the site-specific product attributes and purity information for biotherapeutics such as monoclonal antibodies (mAbs) and fusion molecules in recent years. As we expand the use of the MAM at various stages of drug development, it is critical to enhance the sample preparation throughput without additional chemical modifications and variability. METHODS: In this study, a fully automated MAM sample preparation protocol is presented, where rapid desalting in less than 15 minutes is achieved using miniaturized size-exclusion chromatography columns in pipette tips on an automated liquid handler. The peptide samples were analyzed using an electrospray ionization (ESI) orbitrap mass spectrometer coupled to an ultra-high-performance liquid chromatography (UHPLC) system with a dual column switching system. RESULTS: No significant change was observed in product attributes and their quantities compared with manual, low-artifact sample preparation. The sample recovery using the buffer exchange tips was greatly enhanced over the manual spin cartridges while still demonstrating excellent reproducibility for a wide variety of starting sample concentrations. Unlike a plate desalting system, the individual columns provide flexibility in the number of samples prepared at a time and sample locations within plates. CONCLUSIONS: This automated protocol enables the preparation of up to 96 samples with less "at-bench" time than the manual preparation of a smaller batch of samples, thereby greatly facilitating support of process development and the use of the MAM in quality control.

"Outside the Skin": The Persistence of Black-White Disparities in U.S. Early-Life Mortality.

Research on Black-White disparities in mortality emphasizes the cumulative pathways through which racism gets "under the skin" to affect health. Yet this framing is less applicable in early life, when death is primarily attributable to external causes rather than cumulative, biological processes. We use mortality data from the National Vital Statistics System Multiple Cause of Death files and population counts from the Surveillance, Epidemiology, and End Result Program to analyze 705,801 deaths among Black and White males and females, ages 15-24. We estimate age-standardized death rates and single-decrement life tables to show how all-cause and cause-specific mortality changed from 1990 to 2016 by race and sex. Despite overall declines in early-life mortality, Black-White disparities remain unchanged across several causes-especially homicide, for which mortality is nearly 20 times as high among Black as among White males. Suicide and drug-related deaths are higher among White youth during this period, yet their impact on life expectancy at birth is less than half that of homicide among Black youth. Critically, early-life disparities are driven by preventable causes of death whose impact occurs "outside the skin," reflecting racial differences in social exposures and experiences that prove harmful for both Black and White adolescents and young adults.

How good are inpatients at feigning Miranda abilities?: An investigation of the Miranda Quiz, Inventory of Legal Knowledge, and Structured Inventory of Malingered Symptomatology.

The current study represents the first investigation into feigned Miranda abilities using an inpatient population. We investigated the use of a very generic measure (i.e., the Structured Inventory of Malingered Symptomatology, or SIMS) as well as two specialized forensic feigning measures: the Miranda Quiz (MQ) and Inventory of Legal Knowledge (ILK). With a quasi-random assignment, 82 acute inpatients were evenly distributed to "feigning" and "genuine" groups. The recommended SIMS cut score > 14 performed poorly, misclassifying three-quarters of the genuine group as feigning. In general, sensitivities on the specialized scales were constrained by the general lack of severe decrements for the feigning group. However, specificities were strong to outstanding. In particular, the MQ floor effect showed some promise but was limited by its small number of items. The strongest potential was observed for the revised ILK scales, especially the Revised Clinical ILK (RC-ILK). When using single-point cut scores on two prior correctional samples, the RC-ILK produced excellent sensitivities (0.94 and 0.96) and outstanding specificities (0.98 and 0.99). Methodological issues and professional implications were discussed in the context of feigned Miranda abilities.

Identifying Mental Disorders in Primary Care: Diagnostic Accuracy of the Connected Mind Fast Check (CMFC) Electronic Screen.

Primary care physicians (PCPs) often daily address diagnoses and treatment of mental disorders in their practices. The current study examined the Connected Mind Fast Check (CMFC), a two-tiered electronic screen, assessing six common mental disorders. The eight-item Initial Screen assesses possible symptoms, whereas SAM modules establish provisional diagnoses and areas of clinical concern. With 234 patients from five independent PCP offices, diagnostic accuracy was tested with the SCID-5-RV as the external criterion. Concerningly, many patients were unaware of their current mental disorders and comorbidities. The CMFC Initial Screen evidenced strong sensitivity, identifying with very few missing diagnoses. About two-thirds of provisional SAM diagnoses were confirmed with high specificities. Bipolar Disorder posed the most challenges at both tiers. Importantly, the suicide screen identified all patients with suicide plans and three-fourths with ideation. In general, the CMFC effectively identified provisional diagnoses, impairment, and potential suicidality.

The National Death Index as a Source of Homicide Data: A Methodological Exposition of Promises and Pitfalls for Criminologists.

Criminologists largely rely on national de-identified data sources to study homicide in the United States. The National Death Index (NDI), a comprehensive and well-established database compiled by the National Center for Health Statistics, is an untapped source of homicide data that offers identifiable linkages to other data sources while retaining national coverage. This study's five aims follow. First, we review the data sources in articles published in Homicide Studies over the past decade. Second, we describe the NDI, including its origins, procedures, and uses. Third, we outline the procedures for linking a police gang intelligence database to the NDI. Fourth, we introduce the St. Louis Gang Member-Linked Mortality Files database, which is composed of 3,120 police-identified male gang members in the St. Louis area linked to NDI records. Finally, we report on preliminary cause-of-death findings. We conclude by outlining the benefits and drawbacks of the NDI as a source of homicide data for criminologists.

Loss of excitatory amino acid transporter restraint following chronic intermittent hypoxia contributes to synaptic alterations in nucleus tractus solitarii.

Peripheral viscerosensory afferent signals are transmitted to the nucleus tractus solitarii (nTS) via release of glutamate. Following release, glutamate is removed from the extrasynaptic and synaptic cleft via excitatory amino acid transporters (EAATs), thus limiting glutamate receptor activation or over activation, and maintaining its working range. We have shown that EAAT block with the antagonist threo-ß-benzyloxyaspartic acid (TBOA) depolarized nTS neurons and increased spontaneous excitatory postsynaptic current (sEPSC) frequency yet reduced the amplitude of afferent (TS)-evoked EPSCs (TS-EPSCs). Interestingly, chronic intermittent hypoxia (CIH), a model of obstructive sleep apnea (OSA), produces similar synaptic responses as EAAT block. We hypothesized EAAT expression or function are downregulated after CIH, and this reduction in glutamate removal contributes to the observed neurophysiological responses. To test this hypothesis, we used brain slice electrophysiology and imaging of glutamate release and TS-afferent Ca2+ to compare nTS properties of rats exposed to 10 days of normoxia (Norm; 21%O2) or CIH. Results show that EAAT blockade with (3S)-3-[[3-[[4-(trifluoromethyl)benzoyl]-amino]phenyl]methoxy]-l-aspartic acid (TFB-TBOA) in Norm caused neuronal depolarization, generation of an inward current, and increased spontaneous synaptic activity. The latter augmentation was eliminated by inclusion of tetrodotoxin in the perfusate. TS stimulation during TFB-TBOA also elevated extracellular glutamate and decreased presynaptic Ca2+ and TS-EPSC amplitude. In CIH, the effects of EAAT block are eliminated or attenuated. CIH reduced EAAT expression in nTS, which may contribute to the attenuated function seen in this condition. Therefore, CIH reduces EAAT influence on synaptic and neuronal activity, which may lead to the physiological consequences seen in OSA and CIH.NEW & NOTEWORTHY Removal of excitatory amino acid transporter (EAAT) restraint increases spontaneous synaptic activity yet decreases afferent [tractus solitarius (TS)]-driven excitatory postsynaptic current (EPSC) amplitude. In the chronic intermittent hypoxia model of obstructive sleep apnea, this restraint is lost due to reduction in EAAT expression and function. Thus EAATs are important in controlling elevated glutamatergic signaling, and loss of such control results in maladaptive synaptic signaling.

Thrombin action on astrocytes in the hindbrain of the rat disrupts glycemic and respiratory control.

Severe trauma can produce a postinjury "metabolic self-destruction" characterized by catabolic metabolism and hyperglycemia. The severity of the hyperglycemia is highly correlated with posttrauma morbidity and mortality. Although no mechanism has been posited to connect severe trauma with a loss of autonomic control over metabolism, traumatic injury causes other failures of autonomic function, notably, gastric stasis and ulceration ("Cushing's ulcer"), which has been connected with the generation of thrombin. Our previous studies established that proteinase-activated receptors (PAR1; "thrombin receptors") located on astrocytes in the autonomically critical nucleus of the solitary tract (NST) can modulate gastric control circuit neurons to cause gastric stasis. Hindbrain astrocytes have also been implicated as important detectors of low glucose or glucose utilization. When activated, these astrocytes communicate with hindbrain catecholamine neurons that, in turn, trigger counterregulatory responses (CRR). There may be a convergence between the effects of thrombin to derange hindbrain gastrointestinal control and the hindbrain circuitry that initiates CRR to increase glycemia in reaction to critical hypoglycemia. Our results suggest that thrombin acts within the NST to increase glycemia through an astrocyte-dependent mechanism. Blockade of purinergic gliotransmission pathways interrupted the effect of thrombin to increase glycemia. Our studies also revealed that thrombin, acting in the NST, produced a rapid, dramatic, and potentially lethal suppression of respiratory rhythm that was also a function of purinergic gliotransmission. These results suggest that the critical connection between traumatic injury and a general collapse of autonomic regulation involves thrombin action on astrocytes.

Evidence that hindbrain astrocytes in the rat detect low glucose with a glucose transporter 2-phospholipase C-calcium release mechanism.

Astrocytes generate robust cytoplasmic calcium signals in response to reductions in extracellular glucose. This calcium signal, in turn, drives purinergic gliotransmission, which controls the activity of catecholaminergic (CA) neurons in the hindbrain. These CA neurons are critical to triggering glucose counter-regulatory responses (CRRs) that, ultimately, restore glucose homeostasis via endocrine and behavioral means. Although the astrocyte low-glucose sensor involvement in CRR has been accepted, it is not clear how astrocytes produce an increase in intracellular calcium in response to a decrease in glucose. Our ex vivo calcium imaging studies of hindbrain astrocytes show that the glucose type 2 transporter (GLUT2) is an essential feature of the astrocyte glucosensor mechanism. Coimmunoprecipitation assays reveal that the recombinant GLUT2 binds directly with the recombinant Gq protein subunit that activates phospholipase C (PLC). Additional calcium imaging studies suggest that GLUT2 may be connected to a PLC-endoplasmic reticular-calcium release mechanism, which is amplified by calcium-induced calcium release (CICR). Collectively, these data help outline a potential mechanism used by astrocytes to convert information regarding low-glucose levels into intracellular changes that ultimately regulate the CRR.

Astrocytic glutamate transporters reduce the neuronal and physiological influence of metabotropic glutamate receptors in nucleus tractus solitarii.

Astrocytic excitatory amino acid transporters (EAATs) are critical to restraining synaptic and neuronal activity in the nucleus tractus solitarii (nTS). Relief of nTS EAAT restraint generates two opposing effects, an increase in neuronal excitability that reduces blood pressure and breathing and an attenuation in afferent [tractus solitarius (TS)]-driven excitatory postsynaptic current (EPSC) amplitude. Although the former is due, in part, to activation of ionotropic glutamate receptors, there remains a substantial contribution from another unidentified glutamate receptor. In addition, the mechanism(s) by which EAAT inhibition reduced TS-EPSC amplitude is unknown. Metabotropic glutamate receptors (mGluRs) differentially modulate nTS excitability. Activation of group I mGluRs on nTS neuron somas leads to depolarization, whereas group II/III mGluRs on sensory afferents decrease TS-EPSC amplitude. Thus we hypothesize that EAATs control postsynaptic excitability and TS-EPSC amplitude via restraint of mGluR activation. To test this hypothesis, we used in vivo recording, brain slice electrophysiology, and imaging of glutamate release and TS-afferent Ca2+. Results show that EAAT blockade in the nTS with (3S)-3-[[3-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]-l-aspartic acid (TFB-TBOA) induced group I mGluR-mediated depressor, bradycardic, and apneic responses that were accompanied by neuronal depolarization, elevated discharge, and increased spontaneous synaptic activity. Conversely, upon TS stimulation TFB-TBOA elevated extracellular glutamate to decrease presynaptic Ca2+ and TS-EPSC amplitude via activation of group II/III mGluRs. Together, these data suggest an important role of EAATs in restraining mGluR activation and overall cardiorespiratory function.

Exceptional mortality risk among police-identified young black male gang members.

Gang membership is associated with many risky behaviors but is often overlooked as a source of mortality among young Americans. Gang Member-Linked Mortality Files (GM-LMFs) match St. Louis, Missouri gang members listed in a law enforcement gang database to mortality records in the National Death Index. We created three analytic samples composed of black males aged 15-35 years by merging cases of the GM-LMFs with National Vital Statistics System and Census data in years 1993-2016. Mortality rates standardized to the 15-35-year-old 2010 U.S. male population were estimated for all-cause (1477.4, 99% CI = 1451.5-1503.3), homicide (950.1, 99% CI = 932.2-967.9), non-homicide injury (314.0, 99% CI = 308.8-319.2), and non-injury (213.3, 99% CI = 202.3-224.4) deaths in the GM-LMFs. We fitted Poisson rate models to estimate mortality rate ratios (RR) between gang members and demographically-matched comparison groups. Black male gang members in St. Louis were at an elevated mortality risk from all causes of death, and homicides contributed substantially to this risk. Compared to black males in St. Louis, gang members experienced greater relative risk of all-cause (RR = 2.9, 99% CI = 2.4-3.5), homicide (RR = 3.2, 99% CI = 2.5-4.1), and non-homicide injury (RR = 4.0, 99% CI = 2.8-5.8) mortality between 1993 and 2016. Relative risk was greater when compared to black males in St. Louis MSA, Missouri, and the USA. These results identify a key source of excess mortality among young black Americans. Health policies and interventions may be most efficacious when they acknowledge, address, and incorporate information about and target high-risk populations, including gang members, that contribute to relatively high mortality risk in the USA.

Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia.

CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain.