Conservation of neuron-astrocyte coordinated activity among sensory processing centers of the developing brain.

Afferent neurons in developing sensory organs exhibit a prolonged period of burst firing prior to the onset of sensory experience. This intrinsically generated activity propagates from the periphery through central processing centers to promote the survival and physiological maturation of neurons and refine their synaptic connectivity. Recent studies in the auditory system indicate that these bursts of action potentials also trigger metabotropic glutamate receptor-mediated calcium increases within astrocytes that are spatially and temporally correlated with neuronal events; however, it is not known if this phenomenon occurs in other sensory modalities. Here we show using in vivo simultaneous imaging of neuronal and astrocyte calcium activity in awake mouse pups that waves of retinal ganglion cell activity induce spatially and temporally correlated waves of astrocyte activity in the superior colliculus that depend on metabotropic glutamate receptors mGluR5 and mGluR3. Astrocyte calcium transients reliably occurred with each neuronal wave, but peaked more than one second after neuronal events. Despite differences in the temporal features of spontaneous activity in auditory and visual processing regions, individual astrocytes exhibited similar overall calcium activity patterns, providing a conserved mechanism to synchronize neuronal and astrocyte maturation within discrete sensory domains.

Long-Term Potentiation Produces a Sustained Expansion of Synaptic Information Storage Capacity in Adult Rat Hippocampus.

Long-term potentiation (LTP) has become a standard model for investigating synaptic mechanisms of learning and memory. Increasingly, it is of interest to understand how LTP affects the synaptic information storage capacity of the targeted population of synapses. Here, structural synaptic plasticity during LTP was explored using three-dimensional reconstruction from serial section electron microscopy. Storage capacity was assessed by applying a new analytical approach, Shannon information theory, to delineate the number of functionally distinguishable synaptic strengths. LTP was induced by delta-burst stimulation of perforant pathway inputs to the middle molecular layer of hippocampal dentate granule cells in adult rats. Spine head volumes were measured as predictors of synaptic strength and compared between LTP and control hemispheres at 30 min and 2 hr after the induction of LTP. Synapses from the same axon onto the same dendrite were used to determine the precision of synaptic plasticity based on the similarity of their physical dimensions. Shannon entropy was measured by exploiting the frequency of spine heads in functionally distinguishable sizes to assess the degree to which LTP altered the number of bits of information storage. Outcomes from these analyses reveal that LTP expanded storage capacity; the distribution of spine head volumes was increased from 2 bits in controls to 3 bits at 30 min and 2.7 bits at 2 hr after the induction of LTP. Furthermore, the distribution of spine head volumes was more uniform across the increased number of functionally distinguishable sizes following LTP, thus achieving more efficient use of coding space across the population of synapses.

Cell-specific regulation of gene expression using splicing-dependent frameshifting.

Precise and reliable cell-specific gene delivery remains technically challenging. Here we report a splicing-based approach for controlling gene expression whereby separate translational reading frames are coupled to the inclusion or exclusion of mutated, frameshifting cell-specific alternative exons. Candidate exons are identified by analyzing thousands of publicly available RNA sequencing datasets and filtering by cell specificity, conservation, and local intron length. This method, which we denote splicing-linked expression design (SLED), can be combined in a Boolean manner with existing techniques such as minipromoters and viral capsids. SLED can use strong constitutive promoters, without sacrificing precision, by decoupling the tradeoff between promoter strength and selectivity. AAV-packaged SLED vectors can selectively deliver fluorescent reporters and calcium indicators to various neuronal subtypes in vivo. We also demonstrate gene therapy utility by creating SLED vectors that can target PRPH2 and SF3B1 mutations. The flexibility of SLED technology enables creative avenues for basic and translational research.

Dendritic Spine Density Scales with Microtubule Number in Rat Hippocampal Dendrites.

Microtubules deliver essential resources to and from synapses. Three-dimensional reconstructions in rat hippocampus reveal a sampling bias regarding spine density that needs to be controlled for dendrite caliber and resource delivery based on microtubule number. The strength of this relationship varies across dendritic arbors, as illustrated for area CA1 and dentate gyrus. In both regions, proximal dendrites had more microtubules than distal dendrites. For CA1 pyramidal cells, spine density was greater on thicker than thinner dendrites in stratum radiatum, or on the more uniformly thin terminal dendrites in stratum lacunosum moleculare. In contrast, spine density was constant across the cone shaped arbor of tapering dendrites from dentate granule cells. These differences suggest that thicker dendrites supply microtubules to subsequent dendritic branches and local dendritic spines, whereas microtubules in thinner dendrites need only provide resources to local spines. Most microtubules ran parallel to dendrite length and associated with long, presumably stable mitochondria, which occasionally branched into lateral dendritic branches. Short, presumably mobile, mitochondria were tethered to microtubules that bent and appeared to direct them into a thin lateral branch. Prior work showed that dendritic segments with the same number of microtubules had elevated resources in subregions of their dendritic shafts where spine synapses had enlarged, and spine clusters had formed. Thus, additional microtubules were not required for redistribution of resources locally to growing spines or synapses. These results provide new understanding about the potential for microtubules to regulate resource delivery to and from dendritic branches and locally among dendritic spines.

Reducing Challenges in Organic Synthesis with Stereoselective Hydrogenation and Tandem Catalysis.

Tandem catalysis enables the rapid construction of complex architectures from simple building blocks. This Perspective shares our interest in combining stereoselective hydrogenation with transformations such as isomerization, oxidation, and epimerization to solve diverse challenges. We highlight the use of tandem hydrogenation for preparing complex natural products from simple prochiral building blocks and present tandem catalysis involving transfer hydrogenation and dynamic kinetic resolution. Finally, we underline recent breakthroughs and opportunities for asymmetric hydrogenation.

Enantioselective Addition of α-Nitroesters to Alkynes.

By using Rh-H catalysis, we couple α-nitroesters and alkynes to prepare α-amino-acid precursors. This atom-economical strategy generates two contiguous stereocenters, with high enantio- and diastereocontrol. In this transformation, the alkyne undergoes isomerization to generate a RhIII -π-allyl electrophile, which is trapped by an α-nitroester nucleophile. A subsequent reduction with In powder transforms the allylic α-nitroesters to the corresponding α,α-disubstituted α-amino esters.

Modified Manikin for Tracheoinnominate Artery Fistula.

Audience: This simulator is designed to instruct emergency medicine residents in tracheostomy training that involves bleeding from the tracheostomy site. Any resident, fellow, or attending physician who cares for patients with complications from their tracheostomy might benefit from this innovation. Introduction: The emergency medicine provider must maintain proficiency in caring for patients with complications from their tracheostomy. In the United States, over 110,000 patients receive tracheostomies per year.1 A rare but catastrophic complication of tracheostomies, usually within the first month of placement, is a tracheoinnominate artery fistula (TIAF). This complication occurs in 0.7% of tracheostomy patients and carries a 50-70% mortality.1,2 We modified a low-fidelity tracheostomy manikin to instruct learners in the stepwise management of hemorrhage from a TIAF. Educational Objectives: By the end of this educational session, learners will be able to:Perform a focused history and physical exam on any patient who presents with bleeding from the tracheostomy site.Describe the differential diagnosis of bleeding from a tracheostomy site, including a TIAF.Demonstrate the stepwise management of bleeding from a suspected TIAF, including cuff hyperinflation and the Utley Maneuver.Verify that definitive airway control via endotracheal intubation is only feasible in the tracheostomy patient when it is clear, upon history and exam, that the patient can be intubated from above.Demonstrate additional critical actions in the management of a patient with a TIAF, including early consultation with otolaryngology and cardiothoracic surgery as well as emergent blood transfusion and activation of a massive transfusion protocol. Educational Methods: This modified manikin is a useful training tool for any healthcare provider who is involved in the treatment and stabilization of a variety of tracheostomy emergencies, from bleeding to infection to obstruction or dislodgement. Our case was presented on two separate occasions, to otolaryngology interns (PGY-1), and emergency medicine residents (PGY 1-3). It involved the care of a patient with a sentinel bleed and subsequent hemorrhage from a tracheoinnominate artery fistula (TIAF). This low-fidelity tracheostomy manikin provides the ideal platform for any complex, tracheostomy case, particularly where ongoing bleeding from the tracheostomy site might permanently damage the electrical circuitry of a high-fidelity model. We initially fashioned this modified manikin for tracheostomy training during a simulation "boot camp" for otolaryngology PGY-1 residents. Our use of this modified manikin for tracheostomy training was a useful teaching tool during our otolaryngology intern "boot camp." As a result, we organized a subsequent simulation training session with our PGY 1-3 emergency medicine residents to provide similar instruction in management of a TIAF. Research Methods: We provided a pre- and a post-simulation survey for the 33 emergency medicine residents who participated in the TIAF simulation with our modified tracheostomy manikin. There were 11 residents from each of the PGY-1, PGY-2, and PGY-3 year-groups. Thirty-two residents (97%) completed the pre-simulation survey, and 33 residents (100%) completed the post-simulation survey. We used a 6-point Likert Scale from "strongly agree" to "strongly disagree" to assess a resident's knowledge of multiple learning objectives within this simulation. Results: The pre- and post-simulation survey supported this simulation and manikin innovation as a useful teaching tool for tracheostomy emergencies such as a TIAF. Discussion: This was a useful innovation for emergency provider training in the recognition and management of a TIAF, a rare but emergent tracheostomy complication. In addition to this bleeding complication, this innovation might be useful for a variety of tracheostomy emergencies such as site infection, obstruction, and tube dislodgement. We highly recommend the involvement of both an emergency medicine and otolaryngology content expert in the design and debriefing of tracheostomy cases with this modified manikin. In our experience, a facilitated debriefing by an experienced clinician and educator from both fields provided a diverse perspective for challenging cases such as bleeding from a TIAF. Topics: Difficult airway, tracheostomy, tracheoinnominate fistula, hemorrhagic shock, tracheostomy complications, Utley Maneuver.

Non-canonical glutamate signaling in a genetic model of migraine with aura.

Migraine with aura is a common but poorly understood sensory circuit disorder. Monogenic models allow an opportunity to investigate its mechanisms, including spreading depolarization (SD), the phenomenon underlying migraine aura. Using fluorescent glutamate imaging, we show that awake mice carrying a familial hemiplegic migraine type 2 (FHM2) mutation have slower clearance during sensory processing, as well as previously undescribed spontaneous "plumes" of glutamate. Glutamatergic plumes overlapped anatomically with a reduced density of GLT-1a-positive astrocyte processes and were mimicked in wild-type animals by inhibiting glutamate clearance. Plume pharmacology and plume-like neural Ca2+ events were consistent with action-potential-independent spontaneous glutamate release, suggesting plumes are a consequence of inefficient clearance following synaptic release. Importantly, a rise in basal glutamate and plume frequency predicted the onset of SD in both FHM2 and wild-type mice, providing a novel mechanism in migraine with aura and, by extension, the other neurological disorders where SD occurs.

In Vitro Evaluation of a Novel Synthetic Bilirubin Analog as an Antioxidant and Cytoprotective Agent for Pancreatic Islet Transplantation.

Bilirubin is a natural cytoprotective agent and physiologic doses have proven to be beneficial in various models of organ and cellular transplantation. Recently, we showed that bilirubin has protective effects in models of pancreatic islet transplantation, preventing cell death associated with islet stress and suppressing the release of damage-associated molecular patterns. Despite these promising therapeutic attributes, the natural bilirubin used in these research studies is animal-derived (porcine), making it unsuitable for clinical application. In the current study, we synthesized two bilirubin analogs that can be produced without the use of animal-derived products. Antioxidant activity for the analogs was measured using the ferric-reducing-ability-of-plasma (FRAP) and 2,2V-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) assays. Dose-dependent cytotoxicity and cytoprotective effects were then demonstrated in isolated rat islets. Compound 1 showed similar antioxidant activity to natural bilirubin. Dose-dependent cytotoxicity was seen following treatment with Compound 1 and natural bilirubin at doses >40 µM, resulting in significantly increased cell death when compared to control islets (P < 0.05) or islets treated with doses ≤20 µM (P < 0.05). Following hypoxic challenge, islet cell death was reduced in islets treated with Compound 1 at 10 µM (17.27% ± 0.26%) compared to natural bilirubin at 10 µM (51.36% ± 0.71%; P < 0.0001) or 20 µM (59.02% ± 0.83%; P < 0.0001) and control islets (36.51% ± 0.44%; P < 0.0001). Compound 1 was found to have promising antioxidant and cytoprotective effects, limiting islet cell death in a model of islet transplantation hypoxic stress. Compound 1 may serve as a synthetic drug lead for clinical islet transplantation and further evaluation of this molecule and its analogs is warranted.

Shifting patterns of polyribosome accumulation at synapses over the course of hippocampal long-term potentiation.

Hippocampal long-term potentiation (LTP) is a cellular memory mechanism. For LTP to endure, new protein synthesis is required immediately after induction and some of these proteins must be delivered to specific, presumably potentiated, synapses. Local synthesis in dendrites could rapidly provide new proteins to synapses, but the spatial distribution of translation following induction of LTP is not known. Here, we quantified polyribosomes, the sites of local protein synthesis, in CA1 stratum radiatum dendrites and spines from postnatal day 15 rats. Hippocampal slices were rapidly fixed at 5, 30, or 120 min after LTP induction by theta-burst stimulation (TBS). Dendrites were reconstructed through serial section electron microscopy from comparable regions near the TBS or control electrodes in the same slice, and in unstimulated hippocampus that was perfusion-fixed in vivo. At 5 min after induction of LTP, polyribosomes were elevated in dendritic shafts and spines, especially near spine bases and in spine heads. At 30 min, polyribosomes remained elevated only in spine bases. At 120 min, both spine bases and spine necks had elevated polyribosomes. Polyribosomes accumulated in spines with larger synapses at 5 and 30 min, but not at 120 min. Small spines, meanwhile, proliferated dramatically by 120 min, but these largely lacked polyribosomes. The number of ribosomes per polyribosome is variable and may reflect differences in translation regulation. In dendritic spines, but not shafts, there were fewer ribosomes per polyribosome in the slice conditions relative to in vivo, but this recovered transiently in the 5 min LTP condition. Overall, our data show that LTP induces a rapid, transient upregulation of large polyribosomes in larger spines, and a persistent upregulation of small polyribosomes in the bases and necks of small spines. This is consistent with local translation supporting enlargement of potentiated synapses within minutes of LTP induction.

Long-term potentiation expands information content of hippocampal dentate gyrus synapses.

An approach combining signal detection theory and precise 3D reconstructions from serial section electron microscopy (3DEM) was used to investigate synaptic plasticity and information storage capacity at medial perforant path synapses in adult hippocampal dentate gyrus in vivo. Induction of long-term potentiation (LTP) markedly increased the frequencies of both small and large spines measured 30 minutes later. This bidirectional expansion resulted in heterosynaptic counterbalancing of total synaptic area per unit length of granule cell dendrite. Control hemispheres exhibited 6.5 distinct spine sizes for 2.7 bits of storage capacity while LTP resulted in 12.9 distinct spine sizes (3.7 bits). In contrast, control hippocampal CA1 synapses exhibited 4.7 bits with much greater synaptic precision than either control or potentiated dentate gyrus synapses. Thus, synaptic plasticity altered total capacity, yet hippocampal subregions differed dramatically in their synaptic information storage capacity, reflecting their diverse functions and activation histories.

Synthesis of Quaternary-Substituted Thiazolines via Halocyclization of S-Allyl Thioimidate Salts.

An efficient synthesis of S-allyl thioimidate hydrobromide salts via coupling of thioamides with allyl bromide derivatives is described. A range of mono-, di-, and trisubstituted olefins as well as alkyl- and arylthioamides with variations in electronics are tolerated. A rapid anti-diastereoselective halocyclization of these salts provides a variety of substituted alkyl- and arylthiazolines. Initial development of an efficient enantioselective synthesis of quaternary-substituted thiazolines through the organo-catalyzed halocyclization of sulfonate thioimidate salts is also described.

Seminal vesicle sperm aspiration from wounded warriors.

OBJECTIVE: To assess whether seminal vesicle sperm aspiration (SVSA) is an option for wounded warriors with severe genital and testicular injuries, with the goal of cryopreservation to use in future assisted reproductive technology (ART) cycles. DESIGN: Retrospective case series. SETTING: Tertiary care military hospital. PATIENT(S): Six wounded warriors. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Seminal vesicle fluid analysis after harvest, after thaw analysis, fertilization rates, pregnancy rates (PRs), live birth. RESULT(S): Six patients with lower extremity, pelvic, and genital injuries from dismounted improvised explosive devices underwent SVSA within 5-12 days of the initial injury. Sperm retrieved were analyzed (volume, 0.4-1.8 mL; concentration, 40-2,200 K; motility, 0-5%), washed, and cryopreserved. Two patients underwent IVF/intracytoplasmic sperm injection (ICSI) cycles using their samples. In one couple, fertilization rate was 38%. One grade V embryo was transferred with a negative pregnancy test. The second couple underwent two cycles. In their first cycle, fertilization rate was 44%, with one blastocyst transferred and a negative pregnancy test. In the second cycle, fertilization rate was 47%. Two blastocysts were cryopreserved due to ovarian hyperstimulation syndrome (OHSS) concerns. One blastocyst was later transferred in a frozen cycle resulting in a live birth. CONCLUSION(S): The SVSA is a reasonable option to retrieve sperm in wounded warriors or trauma patients with extensive genital injuries.

Susceptibility of Primary Sensory Cortex to Spreading Depolarizations.

UNLABELLED: Spreading depolarizations (SDs) are recognized as actors in neurological disorders as diverse as migraine and traumatic brain injury (TBI). Migraine aura involves sensory percepts, suggesting that sensory cortices might be intrinsically susceptible to SDs. We used optical imaging, MRI, and field potential and potassium electrode recordings in mice and electrocorticographic recordings in humans to determine the susceptibility of different brain regions to SDs. Optical imaging experiments in mice under isoflurane anesthesia showed that both cortical spreading depression and terminal anoxic depolarization arose preferentially in the whisker barrel region of parietal sensory cortex. MRI recordings under isoflurane, ketamine/xylazine, ketamine/isoflurane, and urethane anesthesia demonstrated that the depolarizations did not propagate from a subcortical source. Potassium concentrations showed larger increases in sensory cortex, suggesting a mechanism of susceptibility. Sensory stimulation biased the timing but not the location of depolarization onset. In humans with TBI, there was a trend toward increased incidence of SDs in parietal/temporal sensory cortex compared with other regions. In conclusion, SDs are inducible preferentially in primary sensory cortex in mice and most likely in humans. This tropism can explain the predominant sensory phenomenology of migraine aura. It also demonstrates that sensory cortices are vulnerable in brain injury. SIGNIFICANCE STATEMENT: Spreading depolarizations (SDs) are involved in neurologic disorders as diverse as migraine and traumatic brain injury. In migraine, the nature of aura symptoms suggests that sensory cortex may be preferentially susceptible. In brain injury, SDs occur at a vulnerable time, during which the issue of sensory stimulation is much debated. We show, in mouse and human, that sensory cortex is more susceptible to SDs. We find that sensory stimulation biases the timing but not the location of the depolarizations. Finally, we show a relative impairment of potassium clearance in sensory cortex, providing a potential mechanism for the susceptibility. Our data help to explain the sensory nature of the migraine aura and reveal that sensory cortices are vulnerable in brain injury.

LTP enhances synaptogenesis in the developing hippocampus.

In adult hippocampus, long-term potentiation (LTP) produces synapse enlargement while preventing the formation of new small dendritic spines. Here, we tested how LTP affects structural synaptic plasticity in hippocampal area CA1 of Long-Evans rats at postnatal day 15 (P15). P15 is an age of robust synaptogenesis when less than 35% of dendritic spines have formed. We hypothesized that LTP might therefore have a different effect on synapse structure than in adults. Theta-burst stimulation (TBS) was used to induce LTP at one site and control stimulation was delivered at an independent site, both within s. radiatum of the same hippocampal slice. Slices were rapidly fixed at 5, 30, and 120 min after TBS, and processed for analysis by three-dimensional reconstruction from serial section electron microscopy (3DEM). All findings were compared to hippocampus that was perfusion-fixed (PF) in vivo at P15. Excitatory and inhibitory synapses on dendritic spines and shafts were distinguished from synaptic precursors, including filopodia and surface specializations. The potentiated response plateaued between 5 and 30 min and remained potentiated prior to fixation. TBS resulted in more small spines relative to PF by 30 min. This TBS-related spine increase lasted 120 min, hence, there were substantially more small spines with LTP than in the control or PF conditions. In contrast, control test pulses resulted in spine loss relative to PF by 120 min, but not earlier. The findings provide accurate new measurements of spine and synapse densities and sizes. The added or lost spines had small synapses, took time to form or disappear, and did not result in elevated potentiation or depression at 120 min. Thus, at P15 the spines formed following TBS, or lost with control stimulation, appear to be functionally silent. With TBS, existing synapses were awakened and then new spines formed as potential substrates for subsequent plasticity.

A resource from 3D electron microscopy of hippocampal neuropil for user training and tool development.

Resurgent interest in synaptic circuitry and plasticity has emphasized the importance of 3D reconstruction from serial section electron microscopy (3DEM). Three volumes of hippocampal CA1 neuropil from adult rat were imaged at X-Y resolution of ~2 nm on serial sections of ~50-60 nm thickness. These are the first densely reconstructed hippocampal volumes. All axons, dendrites, glia, and synapses were reconstructed in a cube (~10 µm(3)) surrounding a large dendritic spine, a cylinder (~43 µm(3)) surrounding an oblique dendritic segment (3.4 µm long), and a parallelepiped (~178 µm(3)) surrounding an apical dendritic segment (4.9 µm long). The data provide standards for identifying ultrastructural objects in 3DEM, realistic reconstructions for modeling biophysical properties of synaptic transmission, and a test bed for enhancing reconstruction tools. Representative synapses are quantified from varying section planes, and microtubules, polyribosomes, smooth endoplasmic reticulum, and endosomes are identified and reconstructed in a subset of dendrites. The original images, traces, and Reconstruct software and files are freely available and visualized at the Open Connectome Project (Data Citation 1).

Transcriptional landscape of the prenatal human brain.

The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.

An anatomically comprehensive atlas of the adult human brain transcriptome.

Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ∼900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography-the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.

Prostate cancer in men less than the age of 50: a comparison of race and outcomes.

OBJECTIVE: To compare clinicopathologic features and survival outcomes for men 50 years of age in relation to other age groups stratified by race to further define prostate cancer (CaP) in young men. Controversy exists regarding the appropriate age to undergo CaP screening, outcomes for early intervention, and whether there is unique age-associated tumor biology. We compared clinicopathologic features and survival outcomes for men <50 years of age in relation to other age groups stratified by race to further define CaP in young men. METHODS: A multi-institutional review of 12,081 records of patients diagnosed with CaP from 1989-2009 was conducted. Patients were stratified by age group, race, and decade of treatment. Demographic and clinicopathologic characteristics were compared across age groups using chi-square tests and analysis of variance. The primary study endpoints, time to biochemical recurrence and all-cause mortality, were compared across age groups using Kaplan-Meier estimation and univariable and multivariable Cox proportional hazards analysis. RESULTS: Only 4.5% of the study sample was <50 years of age. A higher percentage of African Americans diagnosed were <50 compared with Caucasians (8.3% vs 3.3%, P<.0001). Positive family history was more prevalent in the <50 cohort (36.1% vs 22.0%, P<.0001). Despite these findings, both racial subgroups for men<50 years of age demonstrated improved clinicopathologic features than other age quartiles. Furthermore, both Kaplan-Meier and Cox proportional hazard analysis demonstrated that the <50 cohort had a lower incidence of biochemical recurrence and greater overall survival. CONCLUSIONS: Race and family history appear to play a significant role in the incidence of CaP in younger men. Younger age at diagnosis is associated with more favorable outcomes and indicates that population-based screening at younger ages could potentially lead to improved survival for high-risk groups.

Prostate cancer in men 70 years old or older, indolent or aggressive: clinicopathological analysis and outcomes.

PURPOSE: Currently there is a lack of consensus on screening recommendations for prostate cancer with minimal guidance on the cessation of screening in older men. We defined the clinicopathological features and outcomes for men 70 years old or older who were diagnosed with prostate cancer. MATERIALS AND METHODS: The Center for Prostate Disease Research database was queried for all men diagnosed with prostate cancer from 1989 to 2009. The patients were stratified into age quartiles and by race. Cox proportional hazard models were used to compare clinicopathological features across patient stratifications. Kaplan-Meier analysis was used to compare biochemical recurrence-free, prostate cancer specific and overall survival. RESULTS: Of the 12,081 men evaluated 3,650 (30.2%) were 70 years old or older. These men had a statistically significant higher clinical stage, biopsy grade and prediagnosis prostate specific antigen velocity (p < 0.0001). For those patients who underwent prostatectomy, pathological stage, grade and surgical margin status were all significantly higher in men 70 years old or older. Biochemical recurrence and secondary treatment were also more common in this age group (p < 0.0001). Multivariate analysis revealed age 70 years or older as a significant predictor of biochemical recurrence after prostatectomy (HR 1.45, p = 0.0054). Overall survival was lowest in men age 70 years or older who had surgery, but interestingly the mean time to death was comparable regardless of age. CONCLUSIONS: Our findings indicate that as men age, parameters consistent with more aggressive disease become more prevalent. The etiology of this trend is unknown. However, these data may have implications for current screening and treatment recommendations.