Beyond overlap: Considering habitat preference and fitness outcomes in the umbrella species concept.

Umbrella species and other surrogate-species approaches to conservation provide an appealing framework to extend the reach of conservation efforts beyond single species. For the umbrella species concept to be effective, populations of multiple species of concern must persist in areas protected on behalf of the umbrella species. Most assessments of the concept, however, focus exclusively on geographic overlap among umbrella and background species, and not measures that affect population persistence (e.g., habitat quality or fitness). We quantified the congruence between the habitat preferences and nesting success of a high-profile umbrella species (greater sage-grouse, Centrocercus urophasianus, hereafter "sage-grouse"), and three sympatric species of declining songbirds (Brewer's sparrow Spizella breweri, sage thasher Oreoscoptes montanus, and vesper sparrow Pooecetes gramineus) in central Wyoming, USA during 2012 - 2013. We used machine-learning methods to create data-driven predictions of sage-grouse nest-site selection and nest survival probabilities by modeling field-collected sage-grouse data relative to habitat attributes. We then used field-collected songbird data to assess whether high-quality sites for songbirds aligned with those of sage-grouse. Nest sites selected by songbirds did not coincide with sage-grouse nesting preferences, with the exception that Brewer's sparrows preferred similar nest sites to sage-grouse in 2012. Moreover, the areas that produced higher rates of songbird nest survival were unrelated to those for sage-grouse. Our findings suggest that management actions at local scales that prioritize sage-grouse nesting habitat will not necessarily enhance the reproductive success of sagebrush-associated songbirds. Measures implemented to conserve sage-grouse and other purported umbrella species at broad spatial scales likely overlap the distribution of many species, however, broad-scale overlap may not translate to fine-scale conservation benefit beyond the umbrella species itself. The maintenance of microhabitat heterogeneity important for a diversity of species of concern will be critical for a more-holistic application of the umbrella species concept.

A mesoscale finite element modeling approach for understanding brain morphology and material heterogeneity effects in chronic traumatic encephalopathy.

Chronic Traumatic Encephalopathy (CTE) affects a significant portion of athletes in contact sports but is difficult to quantify using clinical examinations and modeling approaches. We use an in silico approach to quantify CTE biomechanics using mesoscale Finite Element (FE) analysis that bridges with macroscale whole head FE analysis. The sulci geometry produces complex stress waves that interact with one another to create increased shear stresses at the sulci depth that are significantly larger than in analyses without sulci (from 0.5 to 18.0 kPa). Sulci peak stress concentration regions coincide with experimentally observed CTE sites documented in the literature. HighlightsSulci introduce stress localizations at their depth in the gray matterSulci stress fields interact to produce stress concentration sites in white matterDifferentiating brain tissue properties did not significantly affect peak stresses.

Molecular dynamics simulations showing 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) membrane mechanoporation damage under different strain paths.

Continuum finite element material models used for traumatic brain injury lack local injury parameters necessitating nanoscale mechanical injury mechanisms be incorporated. One such mechanism is membrane mechanoporation, which can occur during physical insults and can be devastating to cells, depending on the level of disruption. The current study investigates the strain state dependence of phospholipid bilayer mechanoporation and failure. Using molecular dynamics, a simplified membrane, consisting of 72 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) phospholipids, was subjected to equibiaxial, 2:1 non-equibiaxial, 4:1 non-equibiaxial, strip biaxial, and uniaxial tensile deformations at a von Mises strain rate of 5.45 × 108 s-1, resulting in velocities in the range of 1 to 4.6 m·s-1. A water bridge forming through both phospholipid bilayer leaflets was used to determine structural failure. The stress magnitude, failure strain, headgroup clustering, and damage responses were found to be strain state-dependent. The strain state order of detrimentality in descending order was equibiaxial, 2:1 non-equibiaxial, 4:1 non-equibiaxial, strip biaxial, and uniaxial. The phospholipid bilayer failed at von Mises strains of .46, .47, .53, .77, and 1.67 during these respective strain path simulations. Additionally, a Membrane Failure Limit Diagram (MFLD) was created using the pore nucleation, growth, and failure strains to demonstrate safe and unsafe membrane deformation regions. This MFLD allowed representative equations to be derived to predict membrane failure from in-plane strains. These results provide the basis to implement a more accurate mechano-physiological internal state variable continuum model that captures lower length scale damage and will aid in developing higher fidelity injury models.

Leader preference in Neoconocephalus ensiger katydids: a female preference for a nonheritable male trait.

Female preferences for males producing their calls just ahead of their neighbours, leader preferences, are common in acoustically communicating insects and anurans. While these preferences have been well studied, their evolutionary origins remain unclear. We tested whether females gain a fitness benefit by mating with leading males in Neoconocephalus ensiger katydids. We mated leading and following males with random females and measured the number and quality of F1 , the number of F2 and the heritability of the preferred male trait. We found that females mating with leaders and followers did not differ in the number of F1 or F2 offspring. Females mating with leading males had offspring that were in better condition than those mating with following males suggesting a benefit in the form of higher quality offspring. We found no evidence that the male trait, the production of leading calls, was heritable. This suggests that there is no genetic correlate for the production of leading calls and that the fitness benefit gained by females must be a direct benefit, potentially mediated by seminal proteins. The presence of benefits indicates that leader preference is adaptive in N. ensiger, which may explain the evolutionary origin of leader preference; further tests are required to determine whether fitness benefits can explain the phylogenetic distribution of leader preference in Neoconocephalus. The absence of heritability will prevent leader preference from becoming coupled with or exaggerating the male trait and prevent females from gaining a 'sexy-sons' benefit, weakening the overall selection for leader preference.

Impact of the OATP1B1 c.521T>C single nucleotide polymorphism on the pharmacokinetics of exemestane in healthy post-menopausal female volunteers.

WHAT IS KNOWN AND OBJECTIVE: OATP1B1 mediates the transport of a diverse range of amphiphilic organic compounds that include bile acids, steroid conjugates and hormones. This retrospective pharmacogenetic study was conducted to assess the impact of the OATP1B1 c.521T>C single nucleotide polymorphism (SNP) on the pharmacokinetics of the steroidal aromatase inhibitor drug exemestane in healthy volunteers. METHODS: Exemestane (25 mg) was administered orally to 14 healthy post-menopausal women. All of the 14 subjects were sampled for pharmacokinetic (PK) analyses and retrospectively genotyped for OATP1B1 c.521T>C (rs 4149056). RESULTS AND DISCUSSION: Of the 14 subjects enrolled in the study, five were carriers of the minor C allele (OATP1B1 c.521TC+CC) and the remaining nine were carriers of the OATP1B1 c.521TT genotype. PK was assessed over 8 hours post-dosing. Our results showed statistically significant differences (P=.04) in the plasma exemestane AUC0-8 between the OATP1B1 genotype groups. Our data also showed statistically significant differences (P=.04) in the plasma AUC0-8 of 17-hydroexemestane (the major biologically active metabolite) between the OATP1B1 genotype groups. WHAT IS NEW AND CONCLUSION: Our data suggest that the OAPTP1B1 c.521T>C SNP may influence exemestane pharmacokinetics in humans.

Current concepts and future potential in neoadjuvant chemotherapy for esophageal cancer.

Many trials have evaluated preoperative chemotherapy for the treatment of locally advanced esophageal cancer (LAEC). Most studies were small with conflicting results and no clear evidence of survival advantage. However, two large trials that included squamous cell carcinomas and adenocarcinomas of the esophagus produced opposite outcomes with one showing limited benefit and the other showing none. Recent meta-analyses suggest only a modest benefit from induction chemotherapy in the treatment of LAEC. Two factors associated with prolonged survival are: (1) an R0 resection and (2) pathological complete remission. Preoperative chemotherapy is preferred in Europe for adenocarcinomas; however, chemoradiation has been the treatment of choice in the US. The individualization and optimization of therapy for esophageal cancer patients may come from an in-depth understanding of molecular biology and the development of predictive biomarkers. The use of targeted and immunotherapy agents in the preoperative setting are also promising and warrant further evaluation.

Elevational speciation in action? Restricted gene flow associated with adaptive divergence across an altitudinal gradient.

Evolutionary theory predicts that divergent selection pressures across elevational gradients could cause adaptive divergence and reproductive isolation in the process of ecological speciation. Although there is substantial evidence for adaptive divergence across elevation, there is less evidence that this restricts gene flow. Previous work in the boreal chorus frog (Pseudacris maculata) has demonstrated adaptive divergence in morphological, life history and physiological traits across an elevational gradient from approximately 1500-3000 m in the Colorado Front Range, USA. We tested whether this adaptive divergence is associated with restricted gene flow across elevation - as would be expected if incipient speciation were occurring - and, if so, whether behavioural isolation contributes to reproductive isolation. Our analysis of 12 microsatellite loci in 797 frogs from 53 populations revealed restricted gene flow across elevation, even after controlling for geographic distance and topography. Calls also varied significantly across elevation in dominant frequency, pulse number and pulse duration, which was partly, but not entirely, due to variation in body size and temperature across elevation. However, call variation did not result in strong behavioural isolation: in phonotaxis experiments, low-elevation females tended to prefer an average low-elevation call over a high-elevation call, and vice versa for high-elevation females, but this trend was not statistically significant. In summary, our results show that adaptive divergence across elevation restricts gene flow in P. maculata, but the mechanisms for this potential incipient speciation remain open.

IgG in cervicovaginal mucus traps HSV and prevents vaginal herpes infections.

IgG is the predominant immunoglobulin in cervicovaginal mucus (CVM), yet how immunoglobulin G (IgG) in mucus can protect against infections is not fully understood. IgG diffuses rapidly through cervical mucus, slowed only slightly by transient adhesive interactions with mucins. We hypothesize that this almost unhindered diffusion allows IgG to accumulate rapidly on pathogen surfaces, and the resulting IgG array forms multiple weak adhesive crosslinks to mucus gel that effectively trap (immobilize) pathogens, preventing them from initiating infections. Here, we report that herpes simplex virus serotype 1 (HSV-1) readily penetrated fresh, pH-neutralized ex vivo samples of CVM with low or no detectable levels of anti-HSV-1 IgG but was trapped in samples with even modest levels of anti-HSV-1 IgG. In samples with little or no endogenous anti-HSV-1 IgG, addition of exogenous anti-HSV-1 IgG, affinity-purified from intravenous immunoglobulin, trapped virions at concentrations below those needed for neutralization and with similar potency as endogenous IgG. Deglycosylating purified anti-HSV-1 IgG, or removing its Fc component, markedly reduced trapping potency. Finally, a non-neutralizing IgG against HSV-gG significantly protected mice against vaginal infection, and removing vaginal mucus by gentle lavage abolished protection. These observations suggest that IgG-Fc has a glycan-dependent "muco-trapping" effector function that may provide exceptionally potent protection at mucosal surfaces.

Engineering a multimodal nerve conduit for repair of injured peripheral nerve.

Injury to nerve tissue in the peripheral nervous system (PNS) results in long-term impairment of limb function, dysaesthesia and pain, often with associated psychological effects. Whilst minor injuries can be left to regenerate without intervention and short gaps up to 2 cm can be sutured, larger or more severe injuries commonly require autogenous nerve grafts harvested from elsewhere in the body (usually sensory nerves). Functional recovery is often suboptimal and associated with loss of sensation from the tissue innervated by the harvested nerve. The challenges that persist with nerve repair have resulted in development of nerve guides or conduits from non-neural biological tissues and various polymers to improve the prognosis for the repair of damaged nerves in the PNS. This study describes the design and fabrication of a multimodal controlled pore size nerve regeneration conduit using polylactic acid (PLA) and (PLA):poly(lactic-co-glycolic) acid (PLGA) fibers within a neurotrophin-enriched alginate hydrogel. The nerve repair conduit design consists of two types of PLGA fibers selected specifically for promotion of axonal outgrowth and Schwann cell growth (75:25 for axons; 85:15 for Schwann cells). These aligned fibers are contained within the lumen of a knitted PLA sheath coated with electrospun PLA nanofibers to control pore size. The PLGA guidance fibers within the nerve repair conduit lumen are supported within an alginate hydrogel impregnated with neurotrophic factors (NT-3 or BDNF with LIF, SMDF and MGF-1) to provide neuroprotection, stimulation of axonal growth and Schwann cell migration. The conduit was used to promote repair of transected sciatic nerve in rats over a period of 4 weeks. Over this period, it was observed that over-grooming and self-mutilation (autotomy) of the limb implanted with the conduit was significantly reduced in rats implanted with the full-configuration conduit compared to rats implanted with conduits containing only an alginate hydrogel. This indicates return of some feeling to the limb via the fully-configured conduit. Immunohistochemical analysis of the implanted conduits removed from the rats after the four-week implantation period confirmed the presence of myelinated axons within the conduit and distal to the site of implantation, further supporting that the conduit promoted nerve repair over this period of time. This study describes the design considerations and fabrication of a novel multicomponent, multimodal bio-engineered synthetic conduit for peripheral nerve repair.

Dietary fat intake and risk of ovarian cancer in the NIH-AARP Diet and Health Study.

BACKGROUND: Fat intake has been postulated to increase risk of ovarian cancer, but previous studies have reported inconsistent results. METHODS: The NIH-AARP Diet and Health Study, a large prospective cohort, assessed diet using a food frequency questionnaire at baseline in 1995-1996. During an average of 9 years of follow-up, 695 ovarian cancer cases were ascertained through the state cancer registry database. The relative risks (RRs) and 95% confidence interval (CI) were estimated using a Cox proportional hazard model. RESULTS: Women in the highest vs the lowest quintile of total fat intake had a 28% increased risk of ovarian cancer (RR(Q5 vs Q1)=1.28, 95% CI: 1.01-1.63). Fat intake from animal sources (RR(Q5 vs Q1)=1.30; 95% CI: 1.02-1.66), but not from plant sources, was positively associated with ovarian cancer risk. Saturated and monounsaturated fat intakes were not related to risk of ovarian cancer, but polyunsaturated fat intake showed a weak positive association. The association between total fat intake and ovarian cancer was stronger in women who were nulliparous or never used oral contraceptives. CONCLUSION: Fat intake, especially from animal sources, was related to an increased risk of ovarian cancer. The association may be modified by parity and oral contraceptive use, which warrants further investigation.

Relationships between migration rates and landscape resistance assessed using individual-based simulations.

Linking landscape effects on gene flow to processes such as dispersal and mating is essential to provide a conceptual foundation for landscape genetics. It is particularly important to determine how classical population genetic models relate to recent individual-based landscape genetic models when assessing individual movement and its influence on population genetic structure. We used classical Wright-Fisher models and spatially explicit, individual-based, landscape genetic models to simulate gene flow via dispersal and mating in a series of landscapes representing two patches of habitat separated by a barrier. We developed a mathematical formula that predicts the relationship between barrier strength (i.e., permeability) and the migration rate (m) across the barrier, thereby linking spatially explicit landscape genetics to classical population genetics theory. We then assessed the reliability of the function by obtaining population genetics parameters (m, F(ST) ) using simulations for both spatially explicit and Wright-Fisher simulation models for a range of gene flow rates. Next, we show that relaxing some of the assumptions of the Wright-Fisher model can substantially change population substructure (i.e., F(ST) ). For example, isolation by distance among individuals on each side of a barrier maintains an F(ST) of ∼0.20 regardless of migration rate across the barrier, whereas panmixia on each side of the barrier results in an F(ST) that changes with m as predicted by classical population genetics theory. We suggest that individual-based, spatially explicit modelling provides a general framework to investigate how interactions between movement and landscape resistance drive population genetic patterns and connectivity across complex landscapes.

Parecoxib for analgesia after craniotomy.

BACKGROUND: Pain after craniotomy is often under-treated. Opiates carry distinct disadvantages. Non-steroidal anti-inflammatory drugs have an anti-platelet action and carry a bleeding risk. Cyclo-oxygenase 2 inhibitors such as parecoxib are not associated with a bleeding risk and would be welcome analgesics if shown to be effective. METHODS: In a prospective double-blind, randomized, placebo-controlled study, we investigated the analgesic effect of a single dose of parecoxib 40 mg given at dural closure in 82 patients undergoing elective craniotomies. Remifentanil was used intraoperatively, and i.v. morphine was titrated to the requirement in the post-anaesthetic unit. On the ward, i.m. morphine 5 mg as required and regular acetaminophen was prescribed. Morphine use and visual analogue pain scores were recorded at 1, 6, 12, and 24 h after surgery. RESULTS: Parecoxib reduced pain scores at 6 h and morphine use at 6 and 12 h after operation. However, overall, it had only minimal impact on postoperative analgesia. We found a wide variability in analgesic requirements where 11% of patients required no opioids and 16% required more than 15 mg i.v. morphine 1 h after the surgery. CONCLUSIONS: We found only limited evidence to support parecoxib as an analgesic after craniotomy.

Is arteriovenous shunting involved in the development of varicosities? A study of the intraluminal pressure and oxygen content in varicose veins.

OBJECTIVES: Arteriovenous (AV) shunting has been postulated as the underlying cause of varicose veins. The aim of this study was to analyse pressure and oxygen content in primary varicose veins in order to determine evidence of arterial shunting. METHODS: Thirty-nine patients with varicose veins underwent cannulation of varicosities. The pressure and the blood oxygen content within varicosities were measured in different positions and during exercise. Similar measurements were made in the long saphenous veins of 10 control subjects without venous disease. RESULTS: Mean pressure in varicose veins in the supine position was 12.3 mmHg (Standard deviation [SD] 3.6 mmHg). Control subjects had similar pressures measured in the long saphenous vein. No pulsatile pressure tracings were obtained. Varicosity pressures in the erect position averaged 66 mmHg (SD 9 mmHg). In all cases, the pressure correlated with the distance of the varicosity from the heart. Pressure reduction in varicosities after exercise was significantly less than that in control subjects. Recovery time (RT 90) was also significantly shorter than in the control group. Mean venous pO2 in varicosities was 4.5 kPa (SD 1.0) in the supine position dropping to 3.9 kPa (SD 0.9) on standing; these values were not significantly different to samples from control subjects. CONCLUSIONS: AV shunting is unlikely to be a causative factor in the development of primary varicose veins.

Tube structures of probable microbial origin in the Neoarchean Carawine Dolomite, Hamersley Basin, Western Australia.

The approximately 2.63 Ga Carawine Dolomite, Hamersley Basin, Western Australia, preserves tube structures of probable microbial origin that formed in a low energy environment. The tubes are 0.4-1.8 cm in diameter and at least 10-16 cm long in outcrop. The tubes are defined by dark, 45-microm-thick dolomicritic walls, whereas the tube fill and host rock are composed of 30 microm, cloudy dolomite crystals and rare 170- to 425-microm-wide, dark well-sorted clasts. Closely spaced, rarely discontinuous laminae coat the insides of tubes; less closely spaced, peaked, discontinuous laminae coat the outsides of tubes. The laminae on the outsides of tubes are often intercalated with mammilate structures. The presence of probable microbial coatings on both the insides and the outsides of the tube walls requires that the tubes formed above the sediment-water interface. These tube structures probably formed during gas-charged fluid escape, similar to tubes observed in ancient and modern hydrocarbon seeps and cylindrical water transfer structures in sandstones. The laminae that coat the tubes have very similar geometries to modern biofilms that form in both turbulent and laminar flow, and their geometries probably reflect flow conditions during the fluid escape. The identification of these structures suggests that the preserved interaction between fluid escape and microbial growth in carbonates may be more common than previously thought.

Nasal hyperreactivity in allergic and non-allergic rhinitis: a potential risk factor for non-specific building-related illness.

UNLABELLED: Self-reported non-allergic nasal symptom triggers in non-allergic ('vasomotor') rhinitis overlap with commonly identified environmental exposures in non-specific building-related illness. These include extremes of temperature and humidity, cleaning products, fragrances, and tobacco smoke. Some individuals with allergic rhinitis also report non-allergic triggers. We wished to explore the phenotypic overlap between allergic and non-allergic rhinitis by ascertaining self-reported non-allergic nasal symptom triggers among allergic rhinitics. Sixty subjects without work-related respiratory exposures or symptoms, aged 19-68 years, stratified by age, gender and (skin test-proven) allergic rhinitis status, were queried with regard to self-reported non-allergic nasal symptom triggers (aggregate score 0-8). In this sample, the number of self-reported non-allergic triggers was bimodal, with peaks at 1 and 5. Forty-two percent of seasonal allergic rhinitic subjects reported more than three non-allergic triggers, compared with only 3% of non-allergic non-rhinitics (P < 0.01). Subjects over 35 years were more likely to report one or more non-allergic triggers, particularly tobacco smoke (P < 0.05). Allergic rhinitics reported more non-allergic symptom triggers than did non-allergic, non-rhinitics. As indexed by self-reported reactivity to non-specific physical and chemical triggers, both non-allergic rhinitics and a subset of allergic rhinitics may constitute susceptible populations for non-specific building-related illness. PRACTICAL IMPLICATIONS: Judging by self-report, a substantial subset of individuals with allergic rhinitis--along with all individuals with nonallergic rhinitis (by definition)--are hyperreactive to non-allergic triggers. There is overlap between these triggers (elicited in the process of obtaining a clinical diagnosis) and environmental characteristics associated with ''problem buildings.'' Since individuals with self-identified rhinitis report an excess of symptoms in most epidemiologic studies of problem buildings (even in the absence of unusual aeroallergen levels), rhintics may be acting as a ''sentinel'' subgroup when indoor air quality is suboptimal. Together, non-allergic rhinitics plus allergic rhinitics with prominent non-allergic triggers, are thought to constitute approximately one-sixth of the US population.

Fast track open aortic surgery: reduced post operative stay with a goal directed pathway.

OBJECTIVE: Open aortic aneurysm repair is traditionally associated with an extended hospital stay. The aim of this study was to examine the feasibility of reducing post-operative stay through the implementation of a fast-track, goal directed, clinical pathway for elective open aortic surgery. METHODS: A fast-track clinical pathway for aortic surgery was introduced in a regional vascular unit in September 2005. The pathway has daily goals and targets discharge for all patients on the 3rd post operative day. This study compares thirty consecutive discharges of unselected patients undergoing elective infra-renal aortic surgery following introduction of the pathway to the thirty consecutive cases preceding its introduction. Reasons for prolonged hospital stay were recorded. RESULTS: Six of thirty patients achieved discharge by Day 3. The median hospital stay reduced from 9 (range 4 to 17 days) to 5 days (range 2 to 12 days) following introduction of the pathway. There was one readmission within 30 days and no complications attributable to the pathway implementation. Cardiac complications and home planning were the most common causes of delayed discharge. CONCLUSION: Post-operative stay in patients undergoing standard elective open infra-renal aortic surgery can be safely reduced with the introduction of a goal directed pathway.

Putting the "landscape" in landscape genetics.

Landscape genetics has emerged as a new research area that integrates population genetics, landscape ecology and spatial statistics. Researchers in this field can combine the high resolution of genetic markers with spatial data and a variety of statistical methods to evaluate the role that landscape variables play in shaping genetic diversity and population structure. While interest in this research area is growing rapidly, our ability to fully utilize landscape data, test explicit hypotheses and truly integrate these diverse disciplines has lagged behind. Part of the current challenge in the development of the field of landscape genetics is bridging the communication and knowledge gap between these highly specific and technical disciplines. The goal of this review is to help bridge this gap by exposing geneticists to terminology, sampling methods and analysis techniques widely used in landscape ecology and spatial statistics but rarely addressed in the genetics literature. We offer a definition for the term "landscape genetics", provide an overview of the landscape genetics literature, give guidelines for appropriate sampling design and useful analysis techniques, and discuss future directions in the field. We hope, this review will stimulate increased dialog and enhance interdisciplinary collaborations advancing this exciting new field.

Seizures, not hippocampal neuronal death, provoke neurogenesis in a mouse rapid electrical amygdala kindling model of seizures.

PURPOSE: Proliferation of neural precursors adjacent to the granule cell layer of the dentate gyrus has been identified in previous epilepsy models. Convincingly demonstrating that seizure activity is the stimulant for neurogenesis, rather than neuronal death or other insults inherent to seizure models, is difficult. To address this we derived a rapid electrical amygdala kindling model in mice known to be resistant to seizure-induced neuronal death as an experimental model of focal seizures and to analyze subsequent neurogenesis. METHODS: Mice were implanted with bipolar electrodes in the left amygdala and given electrical stimulation (3 s, 100 Hz, 1 ms monophasic square wave pulses every 5 min, 40 in total) while being observed and graded for the development of seizures. Neurogenesis in the hippocampus was assessed by counting bromodeoxyuridine-immunoreactive cells co-labeled for astrocyte (glial fibrillary acidic protein) and neuronal nuclear markers. RESULTS: Bromodeoxyuridine-reactive cell numbers were three-fold higher in stimulated mice compared with controls at 1 week in the subgranular region and at three weeks extensive co-labeling with neuronal nuclear was noted in cells which had migrated into the body of the granule cell layer, while mice receiving stimulation but failing to kindle did not differ significantly from controls. No increase in neuronal death was detected by terminal deoxynucleotidyl transferase-mediated digoxigenin-11-dUTP nick end labeling, Fluorojade or fluorescent examination of hematoxylin and eosin-stained sections in any inter-group comparison. CONCLUSIONS: We propose that this kindling paradigm, not previously applied to mice, demonstrates more convincingly than previously the surge in neurogenesis in response to seizures, and the effects of seizures alone in regard to neuronal injury and regeneration.