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Calcium-modulating cyclophilin ligand (Caml) is a ubiquitously expressed cytoplasmic protein that is involved in multiple signaling and developmental pathways. An observation in our laboratory of a protein-protein interaction between Caml and the cytoplasmic region of Cadherin23 led us to speculate that Caml might be important in the inner ear and play a role in the development and/or function of hair cells. To address this question, we generated a mouse line in which Caml expression was eliminated in Atoh1-expressing cells of the inner ear upon administration of tamoxifen. Tamoxifen was administered immediately after birth to neonates to assess the effect of loss of Caml in the inner ear during postnatal development. Hearing in treated animals was tested by auditory brain stem response (ABR) analysis and cochlear pathology was evaluated by light microscopy. Lack of Caml expression in the inner ear leads to severe loss of cochlear hair cells and complete deafness. Elucidating the role of Caml in the inner ear will aid our understanding of the molecular pathways important for auditory development and function.

There is now a growing body of evidence supporting the use of fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in gynaecological malignancies. Although this molecular imaging technique is becoming increasingly available, PET/CT remains an expensive imaging tool. It is essential to be familiar with the circumstances in which FDG-PET/CT can add value and contribute to patient management and indeed to know when it is unlikely to be of benefit. It is also important to understand and recognize the potential pitfalls. FDG-PET/CT has been most widely adopted for staging patients with suspected advanced disease or in suspected recurrence, offering a whole-body imaging approach. However, there is great potential for this technique to act as a predictive biomarker of response to treatment, as well as a prognostic biomarker. In addition, FDG-PET images may now be incorporated into radiotherapy planning in order to refine the delineation of dose according to metabolically active sites of disease. This article reviews the literature that provides the evidence for the use of FDG-PET in gynaecological malignancies, identifies areas of real benefit and future potential, and highlights circumstances where there is limited value.

Objective: To determine whether a structured, behavior-based applicant interview predicts future success in an obstetrics and gynecology residency program., Study Design: Using a modified pre-post study design, we compared behavior-based interview scores of our residency applicants to a postmatch evaluation completed by the applicant's current residency program director. Applicants were evaluated on the following areas: academic record, professionalism, leadership, trainability/suitability for the specialty, and fit for the program., Results: Information was obtained for 45 (63%) applicants. The overall interview score did not correlate with overall resident performance. Applicant leadership subscore was predictive of leadership performance as a resident (P = .042). Academic record was associated with patient care performance as a resident (P = .014), but only for graduates of US medical schools. Five residents changed programs; these residents had significantly lower scores for trainability/suitability for the specialty (P = .020)., Conclusion: Behavioral interviewing can provide predictive information regarding success in an obstetrics and gynecology training program., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Erythropoietin (EPO) is a 30.4 kDa glycoprotein produced by the kidney, and is mostly well-known for its physiological function in regulating red blood cell production in the bone marrow. Accumulating evidence, however, suggests that EPO has additional organ protective effects, which may be useful in the prevention or treatment of acute kidney injury. These protective mechanisms are multifactorial in nature and include inhibition of apoptotic cell death, stimulation of cellular regeneration, inhibition of deleterious pathways, and promotion of recovery.In this article, we review the physiology of EPO, assess previous work that supports the role of EPO as a general tissue protective agent, and explain the mechanisms by which it may achieve this tissue protective effect. We then focus on experimental and clinical data that suggest that EPO has a kidney protective effect.

In nature, micro organisms experience numerous environmental stresses and generally grow poorly most of the time. In the last two decades it has become evident that mutations arise not only in actively dividing cells but also in non-replicating or slowly replicating cells starved for nutrients. In yeast, precise base selection and proofreading by replicative DNA polymerases δ and ε keep starvation-associated mutagenesis (SAM) at basal levels. Less is known about the role of replicative DNA polymerase α (Pol α). Here we provide evidence that Pol α is involved in the control of SAM in yeast cells starved for adenine by participation in sporadic replication and/or DNA repair under these conditions.

Objective: To compare visual inspection with acetic acid (VIA) with conventional cervical cytology as a follow-up cervical cancer screening method in women who had been treated previously with cryotherapy., Methods: Salvadoran women screened with VIA and treated with cryotherapy within 3 years were eligible to participate. Study participants were rescreened with VIA, Pap smear, colposcopy, 4-quandrant biopsy, and endocervical curettage., Results: Of 147 women enrolled in the study, post-cryotherapy VIA was positive in 39 women (26.5%; 95% CI, 19.6%-34.4%). Of these 39, 1 woman had CIN 1 or higher on biopsy. Post-cryotherapy Pap smear was positive (ASCUS or higher) in 6 women (4.1%; 95% CI, 1.5%-8.7%). Of these 6, 2 women had CIN 1 or higher on biopsy. Post-cryotherapy specificity was significantly higher for Pap compared with VIA (95.8% [138/144]; 95% CI, 91.2%-98.5% vs 73.6% [106/144]; 95% CI, 65.6%-80.6%; P<0.001)., Conclusion: As the single-visit approach for cervical cancer screening gains popularity, more women will have been treated with cryotherapy. Appropriate follow-up screening is therefore vital. Cytology may be a more suitable screening method than VIA in low-resource settings for women treated previously with cryotherapy., (Copyright © 2010. Published by Elsevier Ireland Ltd.)

Background: Strengthening primary health care is critical to reducing health inequity between Indigenous and non-Indigenous Australians. The Audit and Best practice for Chronic Disease Extension (ABCDE) project has facilitated the implementation of modern Continuous Quality Improvement (CQI) approaches in Indigenous community health care centres across Australia. The project demonstrated improvements in health centre systems, delivery of primary care services and in patient intermediate outcomes. It has also highlighted substantial variation in quality of care. Through a partnership between academic researchers, service providers and policy makers, we are now implementing a study which aims to 1) explore the factors associated with variation in clinical performance; 2) examine specific strategies that have been effective in improving primary care clinical performance; and 3) work with health service staff, management and policy makers to enhance the effective implementation of successful strategies., Methods/design: The study will be conducted in Indigenous community health centres from at least six States/Territories (Northern Territory, Western Australia, New South Wales, South Australia, Queensland and Victoria) over a five year period. A research hub will be established in each region to support collection and reporting of quantitative and qualitative clinical and health centre system performance data, to investigate factors affecting variation in quality of care and to facilitate effective translation of research evidence into policy and practice. The project is supported by a web-based information system, providing automated analysis and reporting of clinical care performance to health centre staff and management., Discussion: By linking researchers directly to users of research (service providers, managers and policy makers), the partnership is well placed to generate new knowledge on effective strategies for improving the quality of primary health care and fostering effective and efficient exchange and use of data and information among service providers and policy makers to achieve evidence-based resource allocation, service planning, system development, and improvements of service delivery and Indigenous health outcomes.

This was a nurse-driven, hospital-based, prospective cohort study of data collected in 19 hospitals in San Bernardino and Riverside counties by California Perinatal Services Network on all mothers (n = 21 842) who delivered a singleton infant (37-40 weeks gestation) between July 2005 through June 2006. Multivariate ordinal logistic regression showed that maternal infant-feeding method intention (measured prior to birth), sociodemographic characteristics, intrapartum variables, and early skin-to-skin mother-infant contact during the first 3 hours following birth (controlling for delivery hospital) were correlated with exclusive breastfeeding during the maternity hospitalization. Compared with mothers with no early skin-to-skin contact, exclusive breastfeeding was higher in mothers who experienced skin-to-skin contact for 1 to 15 minutes (odds ratio [OR] 1.376; 95% confidence interval [CI], 1.189-1.593), 16 to 30 minutes (OR 1.665; 95% CI, 1.468-1.888), 31 to 59 minutes (OR 2.357; 95% CI, 2.061-2.695), and more than 1 hour (OR 3.145; 95% CI, 2.905-3.405). The results demonstrate a dose-response relationship between early skin-to-skin contact and breastfeeding exclusivity.

Purpose: Changes in glycosylated hemoglobin (HbA(1c)) levels, blood pressure measurements, and utilization metrics among diabetic patients managed by a clinical pharmacist were studied., Summary: This pharmacist intervention model was developed by Polk County, Florida, to engage patients with diabetes in managing their health based on the Asheville Project's framework. The diabetes program was implemented in February 2005, with an on-site clinical pharmacist to counsel participants with diabetes. The on-site pharmacist individualized each patient's care. After the initial assessment, educational deficiencies were noted and addressed as needed. Outcomes measured included changes in HbA(1c), blood glucose, and blood pressure values and utilization metrics, such as hospitalization and emergency room visit rates, from baseline to one year after pharmacist intervention. Of the 564 participants who enrolled in the program, 477 were enrolled at the end of one year and were included in the analysis. Results showed that HbA(1c) values steadily decreased over the one-year study period. At baseline, there were 55% of participants with an average HbA(1c) value of < or =7%. After one year, 72% of participants had HbA(1c) values of < or =7%. Participants' mean systolic and diastolic blood pressure values were lower at the end of one year compared with the baseline. Participants also had a 30% reduction in hospital admissions, and the number of emergency room visits during the one-year period decreased by 24%., Conclusion: An employer-based pharmacist intervention model for patients with diabetes improved HbA(1c) levels, reduced systolic and diastolic blood pressure values, and decreased hospitalizations and emergency room visits after one year.

STUDENT RESEARCHERS USED ACTION research both to study the relationship between university researchers and the ethics committee, and also to explore the ethics committee's approach to protocols involving action research and other qualitative methods. We review the existing literature on relationships between university faculty and their ethics committees and briefly discuss the basic tenets of action research. We then describe our research process and the specific recommendations that resulted from this work. Finally, we consider the ways in which action research can be used to better understand and address institutional problems through effective collaboration and dialogue.

Since the isolation of respiratory syncytial virus (RSV) in 1956, its significance as an important human pathogen in infants, the elderly and the immunocompromised has been established. Many important mechanisms contributing to RSV infection, replication and disease pathogenesis have been uncovered; however, there is still insufficient knowledge in these and related areas, which must be addressed to facilitate the development of safe and effective vaccines and therapeutic treatments. A better understanding of the molecular pathogenesis of RSV infection, particularly the host-cell response and transcription profiles to RSV infection, is required to advance disease intervention strategies. Substantial information is accumulating regarding how RSV proteins modulate molecular signaling and regulation of cytokine and chemokine responses to infection, molecular signals regulating programmed cell death, and innate and adaptive immune responses to infection. This review discusses RSV manipulation of the host response to infection and related disease pathogenesis.

Background: The majority of alcohol related problems in the community are managed in general practice. Screening and provision of brief interventions by general practitioners can impact on morbidity and mortality. General practitioners also play a central role in the management of alcohol dependence., Objective: This article discusses risky drinking and the prevalence of alcohol problems. It describes evidence based approaches to alcohol related problems in primary care., Discussion: Opportunistic screening and brief interventions in the general practice setting can have a sizeable impact on alcohol consumption rates among hazardous and harmful drinkers. They are low cost and easy and quick to implement. Patients with alcohol dependence will usually require a period of abstinence and more intensive treatment. They may benefit from alcohol pharmacotherapy, although the effects may be modest. Combining pharmacotherapy with referral to a psychologist for cognitive behavioural therapy may result in better outcomes than pharmacotherapy alone.

Topical corticosteroids remain the most common treatment for eczema; however, it is uncertain whether long-term use of these agents has any adverse effect on bone mass. Cyclosporin is very useful in patients with severe atopic dermatitis who have failed conventional therapy. It has been shown to induce bone loss. We compared 43 children with severe eczema who were using topical corticosteroids with 73 healthy children. Of the 43 patients, six were also taking cyclosporin. Bone mineral density was measured in the lumbar spine and in the femoral neck using dual-energy X-ray absorptiometry. In multivariate analysis, subjects with eczema had lower lumbar spine bone mineral density (-0.03 g/cm(2); p = 0.015) and bone mineral apparent density (-0.01 g/cm(3); p = 0.008) but higher FN BMAD (+0.02 g/cm(3); p = 0.029) compared with controls. Patients with eczema on topical corticosteroids who had used cyclosporin had lower lumbar spine bone mineral apparent density (-0.01; p = 0.006) compared with those only on topical corticosteroids in both adjusted and unadjusted analysis. In conclusion, children with severe eczema have decreased lumbar spine bone mass, which is primarily mediated by cyclosporin use rather than by topical corticosteroid use. This effect is likely to lead to a modest increase in the risk of wrist and forearm fractures in children using this agent.

Objective: The aim of this study was to investigate the feasibility of adapting group-based interpersonal psychotherapy (IPT-G) for patients with chronic post traumatic stress disorder (PTSD)., Methods: Thirteen subjects with DSM-IV-defined PTSD, with symptom duration greater than 12 months, entered the study, an 8-week treatment programme conducted in a clinical setting using IPT-G modified for the treatment of PTSD. Data obtained were analysed qualitatively and quantitatively., Results: All 13 subjects completed the treatment programme and showed significant improvement in social functioning, general wellbeing and depressive symptoms. Treatment completers demonstrated a moderate reduction in the avoidant symptom cluster of PTSD. These improvements appeared stable at 3-month follow-up. Benefits appeared to be associated with perceived intra-therapy progress in resolving identified IPT problem areas. Qualitative analysis found that themes of 'reconnection' and 'interpersonal efficacy' were core parts of the experience of the treatment., Conclusion: IPT-G modified for PTSD appears to be of modest symptomatic benefit, but may lead to improvement in social functioning, general psychological wellbeing and enhanced interpersonal functioning. Further studies are indicated.

Angiogenesis is a critical element for adaptation to low levels of oxygen and occurs following long-term exposure to mild hypoxia in rats. To test whether a similar response in mice occurs, CD1, 129/Sv, C57Bl/6, and Balb/c mice were exposed to 10% oxygen for up to 3 wk. All mice showed significant increases in the percentage of packed red blood cells, and CD1 and 129/Sv mice showed increased respiration frequency and minute volume, common physiological measures of hypoxia. Significant angiogenesis was observed in all strains except Balb/c following 3-wk exposure to chronic hypoxia. CD1 hypoxic mice had the largest increase (88%), followed by C57Bl/6 (48%), 129/Sv (41%), and Balb/c (12%), suggesting that some mice undergo more remodeling than others in response to hypoxia. Protein expression analysis of vascular endothelial growth factor (VEGF), angiopoietin (Ang)-1 and Ang2, and Tie2 were examined to determine whether regulation of different angiogenic proteins could account for the differences observed in hypoxia-induced angiogenesis. CD1 mice showed the strongest upregulation of VEGF, Ang2, Ang1, and Tie2, whereas Balb/c had only subtle increases in VEGF and no change in the other proteins. C57Bl/6 mice showed a regulatory response that fell between the CD1 and Balb/c mice, consistent with the intermediate increase in angiogenesis. Our results suggest that genetic heterogeneity plays a role in angiogenesis and regulation of angiogenic proteins and needs to be accounted for when designing and interpreting experiments using transgenic mice and when studying in vivo models of angiogenesis.

Ns (neuroserpin) is a member of the serpin (serine protease inhibitor) gene family that is primarily expressed within the central nervous system. Its principal target protease is tPA (tissue plasminogen activator), which is thought to contribute to synaptic plasticity and to be secreted in a stimulus-dependent manner. In the present study, we demonstrate in primary neuronal cultures that Ns co-localizes in LDCVs (large dense core vesicles) with the regulated secretory protein chromogranin B. We also show that Ns secretion is regulated and can be specifically induced 4-fold by secretagogue treatment. A novel 13-amino-acid sorting signal located at the C-terminus of Ns is identified that is both necessary and sufficient to target Ns to the regulated secretion pathway. Its deletion renders Ns no longer responsive to secretagogue stimulation, whereas PAI-Ns [Ns (neuroserpin)-PAI-1 (plasminogen activator inhibitor-1) chimaera appending the last 13 residues of Ns sequence to the C-terminus of PAI-1] shifts PAI-1 secretion into a regulated secretory pathway.

Background: This article discusses the importance of screening students in schools for emotional/behavioral problems., Methods: Elements relevant to planning and implementing effective mental health screening in schools are considered. Screening in schools is linked to a broader national agenda to improve the mental health of children and adolescents. Strategies for systematic planning for mental health screening in schools are presented., Results: Mental health screening in schools is a very important, yet sensitive, agenda that is in its very early stages. Careful planning and implementation of mental health screening in schools offers a number of benefits including enhancing outreach and help to youth in need, and mobilizing school and community efforts to promote student mental health while reducing barriers to their learning., Conclusions: When implemented with appropriate family, school, and community involvement, mental health screening in schools has the potential to be a cornerstone of a transformed mental health system. Screening, as part of a coordinated and comprehensive school mental health program, complements the mission of schools, identifies youth in need, links them to effective services, and contributes to positive educational outcomes valued by families, schools, and communities.

The report from President George W. Bush's New Freedom Commission on Mental Health (NFC), Achieving the Promise: Transforming Mental Health Care in America(2003), proposes goals and recommendations for improving mental health services. This report has significant implications for the delivery of mental health services through the schools. A focused discussion of the potential opportunities and challenges of implementing NFC recommendations related to school-based mental health is presented. Strategies for addressing five key areas at the intersection of school mental health and the Commission's recommendations include: stigma reduction, suicide prevention, expansion and improvement of school mental health, and screening and treatment of co-occurring mental health and substance abuse disorders.

The No Child Left Behind Act of 2001 was signed into law by President George W. Bush in January 2002 and is regarded as the most significant federal education policy initiative in a generation. The primary focus of the No Child Left Behind Act is on promoting educational success for all children; however, the legislation also contains opportunities to advance school-based mental health. Unfortunately, the complexities of the provisions of the No Child Left Behind Act have made it difficult for educators, stakeholders, and mental health professionals to understand the legal and practical interface between No Child Left Behind and the school mental health movement. Therefore, the goals of this article are to (1) raise awareness about the challenges educators and school mental health professionals face as a result of the implementation of No Child Left Behind and (2) provide ideas and recommendations to advance the interface between No Child Left Behind and school mental health, which will support key provisions of the act and the growth of the field.

SUMMARY The role of food allergy in atopic dermatitis is controversial. This study presents results of skin prick tests to 31 different food allergens in a selected population of predominantly breast-fed young infants who had moderate to severe generalized atopic dermatitis. Of the 59 infants (22 female, mean age 26.5 weeks) tested, 54 infants (91.5%) had positive responses to one or more foods, 53 infants (90%) were positive to one or more of the five common food allergens (egg white, cow's milk, peanuts, wheat or soy) and 80% were positive to egg white, which was by far the most common positive test. A total of 37 infants had strongly positive responses to one or more foods, with 33 of these 37 having strongly positive responses to egg white. The significance of these responses is discussed. It is concluded that positive skin prick tests to foods, particularly to egg white, are very common in this selected population of breast-fed infants with moderate to severe atopic dermatitis.

Alagille syndrome is an autosomal-dominant disorder characterized by hepatic, cardiac, ocular, skeletal, and facial abnormalities. The disease gene, Jaggedl (JAG]), was identified by molecular analyses of chromosomal alterations involving chromosome 20p. Total gene deletions (3-7%) and intragenic mutations (70%) of JAG] have been identified in Alagille patients. Identifying JAG] mutations is challenging, given its size of 26 exons. Methods to identify both whole-gene deletions and intragenic mutations of JAG] are described in detail, including fluorescence in situ hybridization (FISH), conformation-sensitive gel electrophoresis (CSGE), and complementary DNA (cDNA) sequencing.

Access to health services in rural Australia has been particularly problematic because of the vast geographical areas and the sparse population distribution across the inland. The focus on health servicing has been very much on primary health care with most attention being giving to the distribution of doctors in rural Australia. This study takes a closer look at rural health servicing through the eyes of women in rural Australia. Drawing on a survey of 820 women, the study revealed that a focus on primary health care may be resulting in a lack of attention to women's health in areas, such as maternity models of care, domestic violence and mental health. The study also reveals the disquiet of Australian rural women at the poor state of health services.

Background: Some older drivers may have a higher crash risk than others. Because many of these drivers have not received formal driving training, we evaluated the effectiveness of a re-training program for older drivers as it is currently being offered. Specifically, we examined if older drivers who received the training would have better scores on a driving evaluation than drivers who did not receive the training., Methods: We used a randomized controlled trial. Participants first took part in on-road driving evaluations (possible scores ranged from 0 to 100), after which they were block randomized into training (treatment) or waiting (control) groups based on the driving evaluation results, age, and sex. Individuals in the treatment group attended driver re-training sessions, and were tested once more with the on-road test. Those in the control group completed their second driving evaluation and were then offered the re-training sessions. The second evaluations took place approximately two months after the first evaluations., Results: Sixty-five participants completed two driving evaluations. Despite the overall improvement in driving scores (3.73, SD = 6.87, p = 0.001), we found no statistically significant difference between the control and treatment groups. The mean improvement for the control group was 3.46 (SD=6.72) compared to 4.02 (SD=7.11) for the treatment group (p = 0.747). Drivers' age was related to overall driving scores (r = -0.55, p = 0.001) but not changes between the first and second evaluations (r = 0.01, p = 0.955)., Interpretation: Although we have not demonstrated a statistically significant impact of the intervention, the overall increase suggests that an initial driving evaluation may underestimate the actual driving ability of many older drivers. Furthermore, although older drivers may have lower driving scores initially, they have the ability to improve on these scores. These findings should encourage us to explore diverse approaches to improve driving safety.

Ank is a 492-amino acid multipass transmembrane protein involved in the regulation of extracellular inorganic pyrophosphate levels and the control of tissue calcification. Previous Northern blot hybridization experiments revealed that Ank mRNA was expressed in the brain, but there have been no reports describing the anatomical sites or specific cell types in the brain that express Ank protein. In this study, we demonstrate that Ank is expressed primarily in human brain neurons, with the highest levels of expression observed in the thalamus, the III and V cortical layers, the Purkinje cells of the cerebellum, clusters of cells in the dorsal portion of the pons and midbrain, and neurons of the anterior horn of the spinal cord. In primary mouse neuronal cell cultures, Ank is detected on both the cell body and on cell extensions, mainly dendrites. In the rat brain, Ank mRNA is expressed at relatively high levels in the thalamus, midbrain, and spinal cord, and the Ank protein expression pattern is similar to that observed in the human brain. Finally, we observed a significant increase in Ank immunoreactivity in the rat amygdala, the CA-2 and CA-3 layers of the hippocampus, and the cerebral cortex after the induction of seizure activity. Ank regulation of ATP and/or inorganic pyrophosphate release from neurons may function to modulate the membrane excitability and cell death associated with seizure activity.

Purpose: Accurate anatomical delineation of the gross tumour volume (GTV) is crucial for effective radiotherapy (RT) treatment of prostate cancers. Although reference to pelvic magnetic resonance (MR) for improved delineation of the prostate is a regular practice in some clinics, MR has not replaced CT due to its geometrical distortions and lack of electron-density information. The possibility and practicality of using MR only for RT treatment planning were studied., Materials and Methods: The addition of electron-density information to MR images for conformal radiotherapy (CRT) planning of the prostate was quantified by comparing dose distributions created on the homogeneous density- and bulk-density assigned images to original CT for four patients. To quantify the MR geometrical distortions measurements of a phantom imaged in CT (Siemens Somatom Plus 4) and FLASH 3D T1-weighted MR (1.5 T whole body Siemens Magnetom Vision) were compared. Dose statistics from CRT treatment plans made on CT and MR for five patient data were compared to determine if MR-only treatment plans can be made., Results: The differences between dose-plans on bulk-density assigned images when compared to CT were less than 2% when water and bone values were assigned. Dose differences greater than 2% were observed when images of homogeneous-density assignment were compared to the CT. Phantom measurements showed that the distortions in the FLASH 3D T1-weighted MR averaged 2 mm in the volume of interest for prostate RT planning. For the CT and MR prostate planning study, doses delivered to the planning target volume (PTV) in CT and MR were always inside a 93-107% dose range normalised to the isocentre. Also, the doses to the organs-at-risk in the MR images were similar to the doses delivered to the volumes in the registered CT image when the organ volumes between the two images were similar., Conclusions: Negligible differences were observed in dose distribution between CRT plans using bone+water CT number bulk-assigned image and original CT. Also, the MR distortions were reduced to negligible amounts using large bandwidth MR sequence for prostate CRT planning. MR treatment planning was demonstrated using a large bandwidth sequence and bulk-assigned images. The development of higher quality, low distortion MR sequence will allow regular practice of this technique.

Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase expressed in the CNS during events that require neuronal plasticity. In this study we demonstrate that endogenous tPA mediates the progression of kainic acid-induced (KA-induced) seizures by promoting the synchronization of neuronal activity required for seizure spreading, and that, unlike KA-induced cell death, this activity is plasminogen-independent. Specifically, seizure induction by KA injection into the amygdala induces tPA activity and cell death in both hippocampi, and unilateral treatment of rats with neuroserpin, a natural inhibitor of tPA in the brain, enhances neuronal survival in both hippocampi. Inhibition of tPA within the hippocampus by neuroserpin treatment does not prevent seizure onset but instead markedly delays the progression of seizure activity in both rats and wild-type mice. In tPA-deficient mice, seizure progression is significantly delayed, and neuroserpin treatment does not further delay seizure spreading. In contrast, plasminogen-deficient mice show a pattern of seizure spreading and a response to neuroserpin that is similar to that of wild-type animals. These findings indicate that tPA acts on a substrate other than plasminogen and that the effects of neuroserpin on seizure progression and neuronal cell survival are mediated through the inhibition of tPA.