Epidemiology and factors associated with mortality among pediatric major trauma patients in Nova Scotia: A 17-year retrospective analysis.

BACKGROUND: Major traumatic injury in the pediatric population requires further evaluation to improve patient outcomes. Relatively few Canadian studies have investigated pediatric trauma using population-based data. Our objectives were to describe the epidemiology of pediatric major trauma in Nova Scotia and identify factors associated with in-hospital mortality. METHODS: Retrospective cohort study of pediatric major trauma patients (age <18 years) injured in Nova Scotia over a 17-year period (April 2001-March 2018). Data were collected from the Nova Scotia Trauma Registry. Characteristics were compared between patient subgroups using t-tests, chi-square analyses and Fisher's exact test. Temporal trends were evaluated using the Mann-Kendall test. Incidence and mortality rates were mapped using ArcGIS Pro. A multivariate logistic regression model was created to assess for factors associated with in-hospital mortality. RESULTS: A total of 1258 injuries were observed over the 17-year study period. The incidence of pediatric major trauma was 41.7 per 100,000 person-years. Most patients were male (819/1258; 65.1 %) and resided in urban areas (764/1258; 60.7 %). Blunt trauma accounted for 86.2 % (1084/1258) of injuries, and motor vehicle collisions were the most common cause (448/1258; 35.6 %). Incidence and mortality rates were highest in the 15-17 year age group, with a trend towards increasing incidence among females (p = 0.011). Mortality was 17.2 % (217/1258) of patients; 10.9 % (137/1258) died pre-hospital. No trends were detected in mortality rates. The regression model showed increased odds of in-hospital mortality for every point increase in the ISS (OR 1.05; 95 % CI 1.02 to 1.09) and for every unit decrease in scene GCS (OR 0.63; 95 % CI 0.56-0.71). Rural patients were 2 times more likely to die in-hospital versus urban patients (OR 2.40; 95 % CI 1.01-5.69), and patients injured at home were 6 times more likely to die compared to those injured in other locations (OR 6.19; 95 % CI 1.01-38.11). CONCLUSION: Pediatric trauma remains a major public health issue in Canada and beyond. Greater efforts are required to expand our understanding of trauma epidemiology and develop targeted injury prevention strategies, especially for rural inhabitants.

Pre-hospital mortality among pediatric trauma patients in Nova Scotia.

OBJECTIVES: Limited data exist on pre-hospital pediatric trauma mortality in Canada. The Nova Scotia Trauma Registry is a provincial population-based registry that captures data from the Medical Examiner Service. This study examined the characteristics of pediatric trauma patient mortality in the pre-hospital and in-hospital settings. METHODS: We conducted a cohort study of major pediatric traumas recorded in our provincial database from April 1, 2001 to March 31, 2018. Characteristics of pre-hospital and in-hospital deaths were compared with t tests and Chi-square analyses. Multivariate regression modeling was used to identify predictors of pre-hospital mortality. The geographic distribution of pre-hospital trauma was assessed using choropleth maps. RESULTS: We identified 1,258 pediatric traumas, resulting in 217 deaths (137 pre-hospital, 80 in-hospital). Males accounted for 62.7% of fatalities. The 15-17 age group accounted for most deaths in both groups (pre-hospital 61.3%; in-hospital 41.3%). Injuries sustained in rural areas resulted in 74.7% of all deaths. For both groups, blunt trauma was the predominant injury type and motor vehicle collisions, the most prevalent injury mechanism. Patients who died pre-hospital had a higher mean age (13.3 vs. 10.7, p = 0.002) and a greater proportion were intentional injuries (23.4% vs. 15%; p = 0.02). Urban residency was more frequently observed in in-hospital deaths (57.5% vs. 36.5%, p < 0.001). Pre-hospital mortality was associated with increasing age (OR 1.1), higher injury severity score (OR 1.1), and intentional injury (OR 15.6). CONCLUSION: Over 10% of major pediatric traumas resulted in pre-hospital death, primarily from motor vehicle collisions in rural areas. Compared to in-hospital mortality, patients who died pre-hospital were older with more severe injuries and more likely to have intentionally injured themselves. These results underscore the importance for emergency physicians and EMS systems to consider geographic factors and injury patterns, advocate for improved injury prevention programs, mental health supports, and delivery of on-scene critical care services.

RéSUMé: OBJECTIFS: Il existe peu de données sur la mortalité liée aux traumatismes pédiatriques pré-hospitaliers au Canada. La Nouvelle-Écosse. Le registre des traumatismes est un registre provincial fondé sur la population qui saisit les données du Medical Examiner Service. Cette étude a examiné les caractéristiques des traumatismes pédiatriques la mortalité des patients en milieu pré-hospitalier et hospitalier. MéTHODES: Nous avons mené une étude de cohorte des traumatismes pédiatriques majeurs enregistrés dans notre province base de données du 1er avril 2001 au 31 mars 2018. Caractéristiques des services pré-hospitaliers et les décès hospitaliers ont été comparés aux tests-t et aux analyses du chi carré. La modélisation multivariée de régression a été utilisée pour identifier les prédicteurs de la mortalité pré-hospitalière. La répartition géographique des traumatismes pré-hospitaliers a été évaluée à l'aide de cartes choroplèthes. RéSULTATS: Nous avons identifié 1258 traumatismes pédiatriques, entraînant 217 décès (137 pré-hospitaliers, 80 hospitalier les hommes représentaient 62,7% des décès. Le groupe des 15 à 17 ans représentait la plupart des décès dans les deux groupes (avant l'hôpital 61,3%; à l'hôpital 41,3%). Blessures subies dans les régions rurales ont entraîné 74,7% de tous les décès. Pour les deux groupes, le traumatisme contondant était le type de blessure prédominant et les collisions de véhicules à moteur, les blessures les plus fréquentes. Les patients décédés avant l'hospitalisation avaient un âge moyen plus élevé (13,3 vs 10,7, p = 0,002) et une plus grande proportion étaient des blessures intentionnelles (23,4% contre 15%; p = 0,02). La résidence en milieu urbain était plus fréquemment observée dans les décès à l'hôpital (57,5% contre 36,5%, p < 0.001). La mortalité pré-hospitalière était associée à une augmentation de l'âge (CP 1.1) le score de gravité des blessures (CP 1.1) et les blessures intentionnelles (CP 15.6). CONCLUSIONS: Plus de 10% des traumatismes pédiatriques majeurs ont entraîné un décès avant l'hôpital, principalement à cause de troubles moteurs les collisions de véhicules dans les régions rurales. Comparativement à la mortalité à l'hôpital, les patients qui sont décédés avant. les établissements de soins palliatifs étaient plus âgés et plus susceptibles d'avoir intentionnellement subi des blessures plus graves. Ces résultats soulignent l'importance pour les médecins d'urgence et les systèmes de SMU pour tenir compte des facteurs géographiques et des tendances en matière de blessures, préconiser amélioration des programmes de prévention des blessures, du soutien en santé mentale et de la prestation sur place services de soins intensifs.

Post-COVID-19 Condition in Children 6 and 12 Months After Infection.

Importance: There is a need to understand the long-term outcomes among children infected with SARS-CoV-2. Objective: To quantify the prevalence of post-COVID-19 condition (PCC) among children tested for SARS-CoV-2 infection in pediatric emergency departments (EDs). Design, Setting, and Participants: Multicenter, prospective cohort study at 14 Canadian tertiary pediatric EDs that are members of the Pediatric Emergency Research Canada network with 90-day, 6-month, and 12-month follow-up. Participants were children younger than 18 years who were tested for SARS-CoV-2 infection between August 2020 and February 2022. Data were analyzed from May to November 2023. Exposure: The presence of SARS-CoV-2 infection at or within 14 days of the index ED visit. Main Outcomes and Measures: Presence of symptoms and QoL reductions that meet the PCC definition. This includes any symptom with onset within 3 months of infection that is ongoing at the time of follow-up and affects everyday functioning. The outcome was quantified at 6 and 12 months following the index ED visit. Results: Among the 5147 children at 6 months (1152 with SARS-CoV-2 positive tests and 3995 with negative tests) and 5563 children at 12 months (1192 with SARS-CoV-2 positive tests and 4371 with negative tests) who had sufficient data regarding the primary outcome to enable PCC classification, the median (IQR) age was 2.0 (0.9-5.0) years, and 2956 of 5563 (53.1%) were male. At 6-month follow-up, symptoms and QoL changes consistent with the PCC definition were present in 6 of 1152 children with positive SARS-CoV-2 tests (0.52%) and 4 of 3995 children with negative SARS-CoV-2 tests (0.10%; absolute risk difference, 0.42%; 95% CI, 0.02% to 0.94%). The PCC definition was met at 12 months by 8 of 1192 children with positive SARS-CoV-2 tests (0.67%) and 7 of 4371 children with negative SARS-CoV-2 tests (0.16%; absolute risk difference, 0.51%; 95% CI, 0.06 to 1.08%). At 12 months, the median (IQR) PedsQL Generic Core Scale scores were 98.4 (90.0-100) among children with positive SARS-CoV-2 tests and 98.8 (91.7-100) among children with negative SARS-CoV-2 tests (difference, -0.3; 95% CI, -1.5 to 0.8; P = .56). Among the 8 children with SARS-CoV-2 positive tests and PCC at 12-month follow-up, children reported respiratory (7 of 8 patients [88%]), systemic (3 of 8 patients [38%]), and neurologic (1 of 8 patients [13%]) symptoms. Conclusions and Relevance: In this cohort study of children tested for SARS-CoV-2 infection in Canadian pediatric EDs, although children infected with SARS-CoV-2 reported increased chronic symptoms, few of these children developed PCC, and overall QoL did not differ from children with negative SARS-CoV-2 tests.

Mental health adverse events with cannabis use diagnosed in the Emergency Department: what are we finding now and are our findings accurate?

We have previously reviewed the types and numbers of cannabis-associated adverse events that have mental health presentations that are encountered in the Emergency Department. A particular challenge in examining these events is disentangling cannabis use adverse events from adverse events associated with use of multiple recreational substances. Since that review was published, cannabis legalization for recreational use has greatly expanded world-wide and with these changes in the legal climate has come clearer information around the frequency of adverse events seen in the Emergency Department. However, as we examined the current state of the literature, we also examined some of research designs and the biases that may be impacting the validity of the data in this field. The biases both of clinicians and researchers as well as research approaches to studying these events may be impacting our ability to assess the interaction between cannabis and mental health. For example, many of the studies performed examining cannabis-related admissions to the Emergency Department were administrative studies that relied on front line clinicians to identify and attribute that cannabis use was associated with any particular admission. This narrative review provides an overview on what we currently know about mental health adverse events in the Emergency Department with a focus on the mental health impacts both for those with and without a history of mental illness. The evidence that cannabis use can adversely impact genders and sexes differently is also discussed. This review outlines what the most common adverse events related to mental health with cannabis use are; as well as noting the most concerning but much rarer events that have been reported. Additionally, this review suggests a framework for critical evaluation of this field of study going forward.

Comparison of Symptoms Associated With SARS-CoV-2 Variants Among Children in Canada.

Importance: Clinical manifestations of SARS-CoV-2 variants have not been systematically compared in children. Objective: To compare symptoms, emergency department (ED) chest radiography, treatments, and outcomes among children with different SARS-CoV-2 variants. Design, Setting, and Participants: This multicenter cohort study was performed at 14 Canadian pediatric EDs. Participants included children and adolescents younger than 18 years (hereinafter referred to as children) tested for SARS-CoV-2 infection in an ED between August 4, 2020, and February 22, 2022, with 14 days of follow-up. Exposure(s): SARS-CoV-2 variants detected on a specimen collected from the nasopharynx, nares, or throat. Main Outcomes and Measures: The primary outcome was presence and number of presenting symptoms. The secondary outcomes were presence of core COVID-19 symptoms, chest radiography findings, treatments, and 14-day outcomes. Results: Among 7272 participants presenting to an ED, 1440 (19.8%) had test results positive for SARS-CoV-2 infection. Of these, 801 (55.6%) were boys, with a median age of 2.0 (IQR, 0.6-7.0) years. Children with the Alpha variant reported the fewest core COVID-19 symptoms (195 of 237 [82.3%]), which were most often reported by participants with Omicron variant infection (434 of 468 [92.7%]; difference, 10.5% [95% CI, 5.1%-15.9%]). In a multivariable model with the original type as the referent, the Omicron and Delta variants were associated with fever (odds ratios [ORs], 2.00 [95% CI, 1.43-2.80] and 1.93 [95% CI, 1.33-2.78], respectively) and cough (ORs, 1.42 [95% CI, 1.06-1.91] and 1.57 [95% CI, 1.13-2.17], respectively). Upper respiratory tract symptoms were associated with Delta infection (OR, 1.96 [95% CI, 1.38-2.79]); lower respiratory tract and systemic symptoms were associated with Omicron variant infection (ORs, 1.42 [95% CI, 1.04-1.92] and 1.77 [95% CI, 1.24-2.52], respectively). Children with Omicron infection most often had chest radiography performed and received treatments; compared with those who had Delta infection, they were more likely to have chest radiography performed (difference, 9.7% [95% CI, 4.7%-14.8%]), to receive intravenous fluids (difference, 5.6% [95% CI, 1.0%-10.2%]) and corticosteroids (difference, 7.9% [95% CI, 3.2%-12.7%]), and to have an ED revisit (difference, 8.8% [95% CI, 3.5%-14.1%]). The proportions of children admitted to the hospital and intensive care unit did not differ between variants. Conclusions and Relevance: The findings of this cohort study of SARS-CoV-2 variants suggest that the Omicron and Delta variants were more strongly associated with fever and cough than the original-type virus and the Alpha variant. Children with Omicron variant infection were more likely to report lower respiratory tract symptoms and systemic manifestations, undergo chest radiography, and receive interventions. No differences were found in undesirable outcomes (ie, hospitalization, intensive care unit admission) across variants.

A Case of Septic Portal Vein Thrombosis in a 71-Year-Old Female.

Portal vein thrombosis (PVT) is a relatively rare condition that is characterized by partial or complete occlusion of the portal vein. The most common risk factors for developing PVT are a result of a low intra-hepatic vein flow or pro-thrombotic states, including underlying liver disease, coagulopathies, infection, and malignancy. Patients with PVT can present asymptomatically, while others are in profound shock. Clinical manifestations vary based on the location of the thrombus, degree of occlusion, and if it has become infected. Although an uncommon source of sepsis in the emergency department (ED), maintaining a high degree of clinical suspicion for septic PVT is critical as there are additional treatment considerations apart from early antibiotic therapy as in general sepsis. The following case report focuses on a 71-year-old woman with a septic PVT who presented to the ED with fever and hypotension in the absence of known risk factors. Current management guidelines and evidence regarding treatment strategies for septic PVT are also discussed in further detail.

Treatment-Resistant Wide-Complex Tachycardia in a Three-Year-Old Girl.

Wide-complex, monomorphic tachycardias represent a range of tachyarrhythmias. Such patients can present asymptomatically and hemodynamically stable, while others are in shock. The etiology of the rhythm can be difficult to determine in the emergency department, and although electrocardiogram findings may be helpful, a workup after stabilization may be necessary to determine the cause. Treatment is therefore dependent on hemodynamic status and follows a stepwise approach, as initial therapies may be ineffective. We present the case of a three-year-old girl with wide-complex tachycardia which was exceedingly refractory to preliminary treatments and required trials of multiple treatment approaches to achieve conversion to normal sinus rhythm.

Effect of the COVID-19 Pandemic on Patient Volumes, Acuity, and Outcomes in Pediatric Emergency Departments: A Nationwide Study.

OBJECTIVES: The aim of this study was to quantify the effect of the COVID-19 pandemic on pediatric emergency department (ED) utilization and outcomes. METHODS: This study is an interrupted-time-series observational study of children presenting to 11 Canadian tertiary-care pediatric EDs. Data were grouped into weeks in 3 study periods: prepandemic (January 1, 2018-January 27, 2020), peripandemic (January 28, 2020-March 10, 2020), and early pandemic (March 11, 2020-April 30, 2020). These periods were compared with the same time intervals in the 2 preceding calendar years. Primary outcomes were number of ED visits per week. The secondary outcomes were triage acuity, hospitalization, intensive care unit (ICU) admission, mortality, length of hospital stay, ED revisits, and visits for trauma and mental health concerns. RESULTS: There were 577,807 ED visits (median age, 4.5 years; 52.9% male). Relative to the prepandemic period, there was a reduction [-58%; 95% confidence interval (CI), -63% to -51%] in the number of ED visits during the early-pandemic period, with concomitant higher acuity. There was a concurrent increase in the proportion of ward [odds ratio (OR), 1.39; 95% CI, 1.32-1.45] and intensive care unit (OR, 1.20; 95% CI, 1.01-1.42) admissions, and trauma-related ED visits among children less than 10 years (OR, 1.51; 95% CI, 1.45-1.56). Mental health-related visits in children declined in the early-pandemic period (in <10 years, -60%; 95% CI, -67% to -51%; in children ≥10 years: -56%; 95% CI, -63% to -47%) relative to the pre-COVID-19 period. There were no differences in mortality or length of stay; however, ED revisits within 72 hours were reduced during the early-pandemic period (percent change: -55%; 95% CI, -61% to -49%; P < 0.001). CONCLUSIONS: After the declaration of the COVID-19 pandemic, dramatic reductions in pediatric ED visits occurred across Canada. Children seeking ED care were sicker, and there was an increase in trauma-related visits among children more than 10 years of age, whereas mental health visits declined during the early-pandemic period. When faced with a future pandemic, public health officials must consider the impact of the illness and the measures implemented on children's health and acute care needs.

When Cannabis Use Goes Wrong: Mental Health Side Effects of Cannabis Use That Present to Emergency Services.

Cannabis use is a modifiable risk factor for the development and exacerbation of mental illness. The strongest evidence of risk is for the development of a psychotic disorder, associated with early and consistent use in youth and young adults. Cannabis-related mental health adverse events precipitating Emergency Department (ED) or Emergency Medical Services presentations can include anxiety, suicidal thoughts, psychotic or attenuated psychotic symptoms, and can account for 25-30% of cannabis-related ED visits. Up to 50% of patients with cannabis-related psychotic symptoms presenting to the ED requiring hospitalization will go on to develop schizophrenia. With the legalization of cannabis in various jurisdiction and the subsequent emerging focus of research in this area, our understanding of who (e.g., age groups and risk factors) are presenting with cannabis-related adverse mental health events in an emergency situation is starting to become clearer. However, for years we have heard in popular culture that cannabis use is less harmful or no more harmful than alcohol use; however, this does not appear to be the case for everyone. It is evident that these ED presentations should be considered another aspect of potentially harmful outcomes that need to be included in knowledge mobilization. In the absence of a clear understanding of the risk factors for mental health adverse events with cannabis use it can be instructive to examine what characteristics are seen with new presentations of mental illness both in emergency departments (ED) and early intervention services for mental illness. In this narrative review, we will discuss what is currently known about cannabis-related mental illness presentations to the ED, discussing risk variables and outcomes both prior to and after legalization, including our experiences following cannabis legalization in Canada. We will also discuss what is known about cannabis-related ED adverse events based on gender or biological sex. We also touch on the differences in magnitude between the impact of alcohol and cannabis on emergency mental health services to fairly present the differences in service demand with the understanding that these two recreational substances may impact different populations of individuals at risk for adverse events.

Corticothalamic Projection Neuron Development beyond Subtype Specification: Fog2 and Intersectional Controls Regulate Intraclass Neuronal Diversity.

Corticothalamic projection neurons (CThPN) are a diverse set of neurons, critical for function of the neocortex. CThPN development and diversity need to be precisely regulated, but little is known about molecular controls over their differentiation and functional specialization, critically limiting understanding of cortical development and complexity. We report the identification of a set of genes that both define CThPN and likely control their differentiation, diversity, and function. We selected the CThPN-specific transcriptional coregulator Fog2 for functional analysis. We identify that Fog2 controls CThPN molecular differentiation, axonal targeting, and diversity, in part by regulating the expression level of Ctip2 by CThPN, via combinatorial interactions with other molecular controls. Loss of Fog2 specifically disrupts differentiation of subsets of CThPN specialized in motor function, indicating that Fog2 coordinates subtype and functional-area differentiation. These results confirm that we identified key controls over CThPN development and identify Fog2 as a critical control over CThPN diversity.

Identification of radial glia-like cells in the adult mouse olfactory bulb.

Immature neurons migrate tangentially within the rostral migratory stream (RMS) to the adult olfactory bulb (OB), then radially to their final positions as granule and periglomerular neurons; the controls over this transition are not well understood. Using adult transgenic mice with the human GFAP promoter driving expression of enhanced GFP, we identified a population of radial glia-like cells that we term adult olfactory radial glia-like cells (AORGs). AORGs have large, round somas and simple, radially oriented processes. Confocal reconstructions indicate that AORGs variably express typical radial glial markers, only rarely express mouse GFAP, and do not express astroglial, oligodendroglial, neuronal, or tanycyte markers. Electron microscopy provides further supporting evidence that AORGs are not immature neurons. Developmental analyses indicate that AORGs are present as early as P1, and are generated through adulthood. Tracing studies show that AORGs are not born in the SVZa, suggesting that they are born either in the RMS or the OB. Migrating immature neurons from the adult SVZa are closely apposed to AORGs during radial migration in vivo and in vitro. Taken together, these data indicate a newly-identified population of radial glia-like cells in the adult OB that might function uniquely in neuronal radial migration during adult OB neurogenesis.

Proliferation and expression of progenitor and mature retinal phenotypes in the adult mammalian ciliary body after retinal ganglion cell injury.

PURPOSE: Despite the identification of a small population of cells residing in the ciliary body (CB) of the adult mammalian eye that have the capacity to generate retina-like cells in vitro, their activity in vivo remains quiescent. The authors sought to identify whether the predictable and time-dependent death of retinal ganglion cells (RGCs) results in activation of progenitor-like cells within the CB. METHODS: RGC injury was induced by optic nerve axotomy in adult mice. Thymidine-analogue lineage tracing and immunocytochemistry were used to identify dividing cells and the phenotype of newly generated progeny. RESULTS: Two populations of nestin-expressing cells are present in the CB of the uninjured eye. One population resides in periendothelial cells of blood vessels, and a second resides in the ciliary epithelium. Axotomy increases proliferation in the CB, a response that begins before the onset of RGC death and continues during a time that corresponds with the peak in RGC death. In addition, a subpopulation of nestin-positive cells in the CB upregulates the homeodomain protein Chx10. Finally, recoverin, the expression of which is normally restricted to photoreceptors and bipolar cells of the retina, is upregulated in the CB in a manner that is independent of proliferation. CONCLUSIONS: Together, these results suggest that progenitorlike cells of the CB respond to cues associated with the loss of a single retinal cell type and that a subpopulation of those cells may differentiate into a cell that bears phenotypic resemblance to those seen in the retina.

Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells.

Recent work in neuroscience has shown that the adult central nervous system (CNS) contains neural progenitors, precursors and stem cells that are capable of generating new neurons, astrocytes and oligodendrocytes. While challenging the previous dogma that no new neurons are born in the adult mammalian CNS, these findings bring with them the future possibilities for development of novel neural repair strategies. The purpose of this review is to present the current knowledge about constitutively occurring adult mammalian neurogenesis, highlight the critical differences between 'neurogenic' and 'non-neurogenic' regions in the adult brain, and describe the cardinal features of two well-described neurogenic regions-the subventricular zone/olfactory bulb system and the dentate gyrus of the hippocampus. We also provide an overview of presently used models for studying neural precursors in vitro, mention some precursor transplantation models and emphasize that, in this rapidly growing field of neuroscience, one must be cautious with respect to a variety of methodological considerations for studying neural precursor cells both in vitro and in vivo. The possibility of repairing neural circuitry by manipulating neurogenesis is an intriguing one, and, therefore, we also review recent efforts to understand the conditions under which neurogenesis can be induced in non-neurogenic regions of the adult CNS. This work aims towards molecular and cellular manipulation of endogenous neural precursors in situ, without transplantation. We conclude this review with a discussion of what might be the function of newly generated neurons in the adult brain, and provide a summary of present thinking about the consequences of disturbed adult neurogenesis and the reaction of neurogenic regions to disease.

Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis.

The misfolding of the prion protein (PrP(c)) is a central event in prion diseases, yet the normal function of PrP(c) remains unknown. PrP(c) has putative roles in many cellular processes including signaling, survival, adhesion, and differentiation. Given the abundance of PrP(c) in the developing and mature mammalian CNS, we investigated the role of PrP(c) in neural development and in adult neurogenesis, which occurs constitutively in the dentate gyrus (DG) of the hippocampus and in the olfactory bulb from precursors in the subventricular zone (SVZ)/rostral migratory stream. In vivo, we find that PrP(c) is expressed immediately adjacent to the proliferative region of the SVZ but not in mitotic cells. In vivo and in vitro studies further find that PrP(c) is expressed in multipotent neural precursors and mature neurons but is not detectable in glia. Loss- and gain-of-function experiments demonstrate that PrP(c) levels correlate with differentiation of multipotent neural precursors into mature neurons in vitro and that PrP(c) levels positively influence neuronal differentiation in a dose-dependent manner. PrP(c) also increases cellular proliferation in vivo; in the SVZ, PrP(c) overexpresser (OE) mice have more proliferating cells compared with wild-type (WT) or knockout (KO) mice; in the DG, PrP(c) OE and WT mice have more proliferating cells compared with KO mice. Our results demonstrate that PrP(c) plays an important role in neurogenesis and differentiation. Because the final number of neurons produced in the DG is unchanged by PrP(c) expression, other factors must control the ultimate fate of new neurons.

Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS.

Astroglia comprise an extremely morphologically diverse cell type that have crucial roles in neural development and function. Nonetheless, distinct regions of the CNS have traditionally been defined by the phenotypic characteristics and connectivity of neuros. In a complementary fashion, we present evidence that discrete regions of the adult CNS can be delineated based solely on the morphology, density and proliferation rates of astroglia. We used transgenic hGFAP-GFP mice in which robust expression of GFP in adult astroglia enables detailed morphological characterization of this diversely heterogeneous cell population with 3D confocal microscopy. By using three complementary methods for labeling adult astroglia (hGFAP-GFP expression, and GFAP and S100beta immunostaining), we find that there is a remarkably diverse, regionally stereotypical array of astroglial morphology throughout the CNS, and that discrete anatomical regions can be defined solely on the morphology of astroglia within that region. Second, we find that the density of astroglia varies dramatically across the CNS, and that astroglial density effectively delineates even the sub-regions of complex structures, such as the thalamus. We also find that regional astroglial density varies depending on how astroglia are labeled. To quantify and illustrate these broad differences in astroglial density, we generated an anatomical density atlas of the CNS. Third, the proliferation rate, or mitotic index, of astroglia in the adult CNS also effectively defines anatomical regions. These differences are present regardless of the astroglial-labeling method used. To supplement our atlas of astroglial density we generated an atlas of proliferation density for the adult CNS. Together, these studies demonstrate that the morphology, density and proliferation rate of astroglia can independently define the discrete cytoarchitecture of the adult mammalian CNS, and support the concept that regional astroglial heterogeneity reflects important molecular and functional differences between distinct classes of astroglia, much like the long-accepted heterogeneity of neuronal populations.

Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells.

Recent work in neuroscience has shown that the adult central nervous system contains neural progenitors, precursors, and stem cells that are capable of generating new neurons, astrocytes, and oligodendrocytes. While challenging previous dogma that no new neurons are born in the adult mammalian CNS, these findings bring with them future possibilities for the development of novel neural repair strategies. The purpose of this review is to present current knowledge about constitutively occurring adult mammalian neurogenesis, to highlight the critical differences between "neurogenic" and "non-neurogenic" regions in the adult brain, and to describe the cardinal features of two well-described neurogenic regions-the subventricular zone/olfactory bulb system, and the dentate gyrus of the hippocampus. We also provide an overview of currently used models for studying neural precursors in vitro, mention some precursor transplantation models, and emphasize that, in this rapidly growing field of neuroscience, one must take caution with respect to a variety of methodological considerations for studying neural precursor cells both in vitro and in vivo. The possibility of repairing neural circuitry by manipulating neurogenesis is an intriguing one, and, therefore, we also review recent efforts to understand the conditions under which neurogenesis can be induced in non-neurogenic regions of the adult CNS. This work aims toward molecular and cellular manipulation of endogenous neural precursors in situ, without transplantation. We conclude this review with a discussion of what the function might be of newly generated neurons in the adult brain and provide a summary of current thinking about the consequences of disturbed adult neurogenesis and the reaction of neurogenic regions to disease.