Multimodal decoding of human liver regeneration.

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

Participatory Action Planning to Address the Opioid Crisis in a Rural Virginia Community Using the SEED Method.

The SEED Method is a multi-stakeholder approach that was created to involve diverse stakeholders in the development and prioritization of research questions using community-based participatory research (CBPR) principles. Here we describe an adaptation of the SEED Method that focuses on developing and prioritizing strategies for addressing a health problem and bringing stakeholders together to develop and implement community action plans based on those strategies. We describe steps for implementing the SEED Method for community action planning and the results of a case study in a rural Virginia community with high opioid prescription and mortality rates. A participatory research team worked with three groups of Topic stakeholders to gather data, develop conceptual models, and create and prioritize strategies for reducing prescription and non-prescription opioid misuse and overdoses. Each group came up with 19 to 25 strategies and prioritized their top five, which included actions, services or programs, strategies, policies, and system changes. Attendees at community action planning meetings reviewed the 15 prioritized strategies, proposed three additional strategies, and prioritized their top choices. Community stakeholders started four work groups to implement the selected strategies in collaboration with the research team.

[Traumatic Turf-Toe: challenging diagnosis and controversial treatment]. / Turf-Toe traumático: diagnóstico desafiante y tratamiento controvertido.

INTRODUCTION: Turf-Toe includes a wide variety of traumatic injuries of the metatarsophalangeal joint of the first toe (MTF1). It is a potentially severe injury and there is no consensus for surgical management. The objective of this case report was to describe a patient with traumatic Turf-Toe injury grade III with a sesamoid fracture treated surgically. CLINICAL CASE: 24-year-old male with motorcycle fall with hyperflexion of the MTF1 joint, presented pain, edema and functional limitation; the radiographs showed soft tissue edema, lateral displacement of lateral sesamoid with fracture. Traumatic Turf-Toe was established. The ultrasound of the MTF1 joint showed breakage of the plantar plate and collateral ligaments. Patient was surgically managed with sesamoid reduction and plantar plate repair; postoperative evolution was satisfactory. At 8 weeks the patient was assessed with the AOFAS forefoot scale, obtaining 82 points, SF-12 with 87% and VAS of two and returned to his daily activities. CONCLUSION: We describe a patient with traumatic Turf Toe grade III injury, not related to sports practice; first report in the literature of the use of ultrasound in the evaluation of patients with lesion of the metatarso-phalangic joint of the first toe.

INTRODUCCIÓN: Turf-Toe incluye una gran variedad de lesiones traumáticas de la articulación metatarsofalángica del primer dedo del pie (MTF1). Es una lesión potencialmente grave y no existe consenso para el manejo quirúrgico. El objetivo de este reporte fue describir el caso de un paciente con lesión Turf-Toe traumática grado III con fractura sesamoidea tratado quirúrgicamente. CASO CLÍNICO: Masculino de 24 años con caída de motocicleta con hiperflexión de la articulación MTF1 presentó dolor, edema y limitación funcional; las radiografías mostraron edema de tejidos blandos, desplazamiento lateral de sesamoideo lateral con fractura. Se estableció el diagnóstico de Turf-Toe traumático. En el ultrasonido de la articulación MTF1, se demostró rotura de la placa plantar y ligamentos colaterales. Se manejó quirúrgicamente con reducción del sesamoideo y reparación de la placa plantar. La evolución postoperatoria fue satisfactoria; a las ocho semanas el paciente fue valorado con escala AOFAS­ de antepié obteniendo 82 puntos, SF-12 con 87% y EVA de 2 y retornó a sus actividades cotidianas. CONCLUSIÓN: Describimos un paciente con lesión Turf-Toe traumática grado III, no relacionada con la práctica deportiva. Primer reporte en la literatura del uso del ultrasonido en la evaluación de pacientes con lesión de la articulación metatarso-falángica del primer dedo del pie.

Creating a Workplace Culture of Preventive Health: Process and Outcomes of the Colon Cancer-Free Zone at Virginia Cooperative Extension.

Colorectal cancer is the third leading cause of cancer death in the USA, yet is highly preventable and detectable at an early stage through screening. Virginia Cooperative Extension (VCE) implemented a worksite colon cancer awareness program to increase colorectal cancer screening rates and preventive lifestyle behaviors among its employees. The Colon Cancer-Free Zone program is designed using best practice principles of worksite health programs and includes information sessions covering the topics of colorectal cancer, screening guidelines, insurance coverage, and preventive lifestyle behaviors. It is conducted in a campaign format that includes a strategic communication strategy targeting relevant screening barriers and facilitators, peer champions, and incentives. The program was implemented with VCE employees statewide utilizing a web-based system for the information sessions, and resulted in broad participation, a significant increase in screening self-efficacy (4.15 ± 0.64 vs 3.81 ± 0.76, ρ = 0.006), changes in diet and physical activity (50% and 40% of participants, respectively), and a 20.6% increase in the employee colorectal cancer screening rate. A Colon Cancer-Free Zone toolkit was developed for use by Extension Agents to implement the program at worksites in their service communities.

A lung cancer research agenda that reflects the diverse perspectives of community stakeholders: process and outcomes of the SEED method.

PLAIN ENGLISH SUMMARY: There is a need for methods that engage lay people and other stakeholders, such as patients and healthcare providers, in developing research questions about health issues important to them and their communities. Involving stakeholders helps ensure that funding goes to research that addresses their concerns. The SEED Method engages stakeholders in a systematic process to explore health issues and develop research questions. Diverse groups of stakeholders participate at three levels: as collaborators that lead the process throughout, as participants who use their expertise to develop the questions, and as consultants who provide additional perspectives about the health topic. We used the SEED Method to engage 61 stakeholders from different socioeconomic and professional backgrounds to create research questions on lung cancer outcomes. Participants included cancer patients and caregivers, healthcare providers and administrators, and policymakers from a rural Virginia community. They developed causal models that diagrammed factors that influence lung cancer outcomes and the relationships between them. They used these models to develop priority research questions. The questions reflect the participants' diverse perspectives and address different areas of inquiry related to lung cancer outcomes, including access to care, support systems, social determinants of health, and quality of care. Participants felt well prepared to perform the project tasks because they had the opportunity to review lung cancer information, receive causal model and research question development training, and participate in facilitated group activities. The SEED Method can be used in a variety of settings and applied to any health topic of interest to stakeholders. ABSTRACT: Background Engagement of stakeholders in prioritization of health research can help ensure that funding is directed to research that reflects their concerns and needs. The Stakeholder Engagement in quEstion Development and Prioritization (SEED) Method is a multi-stakeholder methodology that uses principles of community engagement and causal modeling to develop health research questions that reflect the priorities of patients, clinicians, and other community stakeholders. We conducted a demonstration of the SEED Method to generate research questions on lung cancer outcomes, and to evaluate the process, outcomes, and effectiveness of the method for generating a research agenda that reflects diverse stakeholder perspectives. Methods The SEED Method engages community members at three levels: collaboration, participation, and consultation. We conducted a demonstration project from November, 2015 to July, 2016, in a rural Virginia community that was experiencing a significant disparity in lung cancer outcomes. A community research team led the project and selected three distinct stakeholder groups (Topic groups, TG) for participatory engagement in analysis of the health issue, causal modeling, and research question development. We evaluated the quality of stakeholder engagement and compared TG causal models and research questions to evaluate the diversity of stakeholder perspectives resulting from the methodology. Results The resulting research agenda poses questions on how a broad range of topics including access to care, support systems and coping mechanisms, social determinants of health, and quality of care impacts lung cancer outcomes. Participants felt well prepared for the tasks they were asked to perform due to the technical trainings and facilitated modeling and question development activities that are part of the SEED Method. The causal models and research questions developed by the Topic Groups reflected the diverse perspectives of the stakeholders. Conclusions The SEED Method has the potential to generate relevant stakeholder-centered research agendas on a variety of health-related topics, and to create community capacity for sustained research engagement.

[Clinical and functional results of the Broström-Gould technique for lateral ankle instability: evaluation with three scales]. / Resultados clínicos y funcionales de la plastía Broström-Gould para inestabilidad lateral de tobillo: evaluación con tres escalas.

BACKGROUND: The most frequent sequel to the ankle sprain is the instability of the lateral ligament complex; the results of surgical treatment have not been evaluated with multiple scales simultaneously. The objective of the study was to assess the clinical and functional results with three scales in patients with lateral instability of ankle undergoing Broström-Gould technique, using for fixation, anchors with suture to distal fibula. MATERIAL AND METHODS: The design of the study was cross-sectional and descriptive; we included patients with lateral instability of ankle and partial or complete rupture of the APA or CP ligament subject to repair with Broström-Gould technique. Magnetic resonance imaging was performed to confirm the diagnosis; clinical and functional outcomes were determined with three scales: EVA, SF-36 and AOFAS. Patients were evaluated at six months, or more, after the surgical procedure. RESULTS: We included 13 patients; quality of life (SF-36 questionnaire) showed a good result with average score of 90; 10 (77%) patients showed excellent results in function, absence of pain and alignment of the ankle (AOFAS 90-100). Also found significant improvement in pain (presurgical EVA: 6, compared with 1 in the postoperative period). CONCLUSIONS: The surgical procedure showed excellent results, in the short term with resolution of pain and ankle stability.

ANTECEDENTES: La secuela más frecuente del esguince de tobillo es la inestabilidad del complejo ligamentario lateral; los resultados del tratamiento quirúrgico no han sido evaluados con varias escalas simultáneamente. El objetivo del estudio fue evaluar los resultados clínicos y funcionales con tres escalas en pacientes con inestabilidad lateral de tobillo sometidos a plastía de Broström-Gould, utilizando para su fijación anclas con sutura al peroné distal. MATERIAL Y MÉTODOS: El diseño del estudio fue transversal y descriptivo; se incluyeron pacientes con inestabilidad lateral de tobillo y ruptura parcial o completa del ligamento PAA y/o PC, sometidos a reparación con plastía de Broström-Gould. Se realizó resonancia magnética nuclear para confirmar el diagnóstico; los resultados clínicos y funcionales se determinaron con tres escalas: EVA, SF-36 y AOFAS. Los pacientes fueron evaluados a los seis meses o más posteriores al procedimiento quirúrgico. RESULTADOS: Se incluyeron 13 pacientes; la calidad de vida (cuestionario SF-36) arrojó un resultado bueno con promedio de 90; 10 (77%) pacientes mostraron resultados excelentes en la función, ausencia de dolor y alineación del tobillo (AOFAS 90-100). Asimismo, se observó mejoría importante en el dolor (EVA prequirúrgico: 6, comparado con 1 en el período postquirúrgico). CONCLUSIONES: El procedimiento quirúrgico demostró excelentes resultados en el corto plazo con resolución del dolor y estabilidad del tobillo.

Fracture risk assessment after BMD examination: whose job is it, anyway?

UNLABELLED: Fracture risk assessments on bone mineral density reports guide family physicians' treatment decisions but are subject to inaccuracy. Qualitative analysis of interviews with 22 family physicians illustrates their pervasive questioning of reported assessment accuracy and independent assumption of responsibility for assessment. Assumption of responsibility is common despite duplicating specialists' work. INTRODUCTION: Fracture risk is the basis for recommendations of treatment for osteoporosis, but assessments on bone mineral density (BMD) reports are subject to known inaccuracies. This creates a complex situation for referring physicians, who must rely on assessments to inform treatment decisions. This study was designed to broadly understand physicians' current experiences with and preferences for BMD reporting; the present analysis focuses on their interpretation and use of the fracture risk assessments on reports, specifically METHODS: A qualitative, thematic analysis of one-on-one interviews with 22 family physicians in Ontario, Canada was performed. RESULTS: The first major theme identified in interview data reflects questioning by family physicians of reported fracture risk assessments' accuracy. Several major subthemes related to this included questioning of: 1) accuracy in raw bone mineral density measures (e.g., g/cm(2)); 2) accurate inclusion of modifying risk factors; and 3) the fracture risk assessment methodology employed. A second major theme identified was family physicians' independent assumption of responsibility for risk assessment and its interpretation. Many participants reported that they computed risk assessments in their practice to ensure accuracy, even when provided with assessments on reports. CONCLUSIONS: Results indicate family physicians question accuracy of risk assessments on BMD reports and often assume responsibility both for revising and relating assessments to treatment recommendations. This assumption of responsibility is common despite the fact that it may duplicate the efforts of reading physicians. Better capture of risk information on BMD referrals, quality control standards for images and standardization of risk reporting may help attenuate some inefficiency.

Measuring intravascular migration of mouse Ly6C(low) monocytes in vivo using intravital microscopy.

This unit describes methods for intravital imaging of monocytes in the vasculature of the dermis and the mesentery in vivo using fluorescent reporter mice, fluorescent dyes, and antibodies. Cx3cr1(gfp/gfp (or +)), Rag2(-/-), Il2rg(-/-) mice expressing eGFP at the locus of the Cx3cr1 gene, on the Rag2(-/-) Il2rg(-/-) C57Bl/6 background, are used. Although aimed at specifically tracking Ly6C(low) monocytes, these protocols could readily be adapted to investigate the interaction of other blood leukocytes with the vascular endothelium by use of other fluorescent reporter mice and fluorescently labeled antibodies.

[Modification of Scarf osteotomy for the treatment of hallux valgus]. / Modificación de la osteotomía de Scarf para el tratamiento del hallux valgus: experiencia en el Instituto Nacional de Rehabilitación.

OBJECTIVES: To show that the modified scarf osteotomy for hallux valgus surgery provides a greater basal contact surface, which results in more stability and less complications for the management of the metatarsus primus varus, and helps define its indications. MATERIAL AND METHODS: Longitudinal, ambispective trial conducted between 2005 and January 2012 in patients with hallux valgus and metatarsus primus varus, with a statistical analysis using Student's T test to compare the preoperative and postoperative values of the American Orthopaedic Foot & Ankle Society scale. RESULTS: 58 modified scarf osteotomies were performed in 46 patients; there were 12 bilateral patients. Mean age was 45 years; 43 patients were females (93.47%) and 3 were males (6.53%). Of the 58 scarf osteotomies, 54 feet did well (93.10%), 3 feet had relapse of the deformity (5.17%), and one had arthrosis of the metatarso-phalangeal joint (1.72%). The American Orthopaedic Foot & Ankle Society classification increased significantly from 40.65 to 82.26 (p < 0.0001). CONCLUSIONS: The modified scarf osteotomy provides greater contact surface in its inverted basal aspect, thus providing more basal stability and therefore less complications. It is therefore a safe procedure capable of correcting the essential components of the hallux valgus and the metatarsus primus varus, provided the indications are precise, like cuneometatarsal instability, joint stiffness and hindfoot alteration, as this leads to hallux valgus relapse.

[Platelet-rich plasma for managing calcaneus tendon tendinopathy and plantar fasciitis]. / Plasma rico en plaquetas para el manejo de tendinopatía del tendón calcáneo y fascitis plantar.

INTRODUCTION: Non-surgical treatment of Achilles tendinopathies ad plantar fasciitis has shown good results in up to 90% of cases. However, the remaining 10% of patients with these conditions represent a true challenge for the orthopedic surgeon. New technologies for the development of orthobiologic materials make it possible to use platelet-rich plasma (PRP) as an alternative to treat cases that have been refractory to prior treatment and that have a chronicity exceeding 12 months. MATERIAL AND METHODS: Prospective, analytical study. Patients with diagnosis of Achilles tendinopathy, plantar fasciitis or both, with a course of more than 12 months, previously treated with non-surgical alternatives, without any clinical improvement. The AOFAS hindfoot scale was used, together with the Visual Analog Scale (VAS) for pain, and photographic documentation at 2, 4, 8 and 12 months after infiltration. A treatment program that included immobilization, NSAIDs, eccentric exercises for the Achilles-calcaneal-plantar system and strengthening of the sural triceps was established. The statistical analysis included measurements of the central trend and scatter with the SPSS 15. RESULTS: A sample consisting of 10 patients (12 feet) that met the diagnostic and inclusion criteria was obtained. Mean age at the time of presentation was 43 years (range 23-56), with females being predominant (70%) and 50% laterality for the right and left feet. The initial AOFAS score was 39 (range 28-68) and the VAS score was 9 (range 7-10). By week 16 the AOFAS score had increased to 97 (range 88-99) and the VAS score was 2 (range 1-4). All patients resumed independent gait. CONCLUSION: The use of PRP in patients with Achilles tendinopathy and plantar fasciitis is an effective and safe alternative for the management of patients with a poor response to conventional non-surgical treatment. Other non-surgical modalities are recommended besides PRP for the treatment of these patients to achieve appropriate results.

Time-lapse FRET microscopy using fluorescence anisotropy.

We present recent data on dynamic imaging of Rac1 activity in live T-cells. Förster resonance energy transfer between enhanced green and monomeric red fluorescent protein pairs which form part of a biosensor molecule provides a metric of this activity. Microscopy is performed using a multi-functional high-content screening instrument using fluorescence anisotropy to provide a means of monitoring protein-protein activity with high temporal resolution. Specifically, the response of T-cells upon interaction of a cell surface receptor with an antibody coated multi-well chamber was measured. We observed dynamic changes in the activity of the biosensor molecules with a time resolution that is difficult to achieve with traditional methodologies for observing Förster resonance energy transfer (fluorescence lifetime imaging using single photon counting or frequency domain techniques) and without spectral corrections that are normally required for intensity based methodologies.

Mammographic densities in a one-year isoflavone intervention.

The estrogenic and antiestrogenic effects of isoflavones, phytoestrogens contained in soy foods, have been proposed as mechanisms for the possible involvement of soy products in the development of breast cancer. We investigated the hypothesis that isoflavones reduce mammographic density, a predictor of breast cancer risk. We conducted a double-blind randomized trial in premenopausal women who received a daily 100 mg isoflavone supplement or a placebo over 12 months. Compliance with the study regimen was confirmed by urinary isoflavones and tablet counts. We used a computer-assisted method to measure mammographic density and paired t-tests to assess changes in mammographic characteristics from baseline to follow-up mammogram. Complete sets of mammograms were available for 30 women. The two groups differed by age and mammographic density at baseline, but were similar in body weight and nutritional intakes. We detected no significant changes either in the size of the dense areas or in the per cent densities. A non-significant decrease in breast area among intervention group subjects was probably the result of methodological issues in comparing mammograms taken under different conditions. In conclusion, our findings do not support the hypothesis that isoflavones decrease mammographic density during a one-year intervention. Although this exploratory study had limited power, it appears that isoflavones do not exert an estrogenic effect similar to hormone replacement therapy on mammographic density.

Intercellular transfer and supramolecular organization of human leukocyte antigen C at inhibitory natural killer cell immune synapses.

After accumulation of target cell human leukocyte antigen (HLA)-C at inhibitory natural killer (NK) cell immune synapses, some HLA-C transfers from target cells to NK cell plasma membranes and cytoplasm. This unexpected intercellular transfer of HLA-C is dependent on NK receptor recognition, since HLA-Cw6 or -Cw4 but not -Cw3 transfer to an NK transfectant expressing killer Ig-like receptor (KIR)2DL1. Strikingly, live-cell time-lapse laser scanning confocal microscopy shows vesicles containing target cell green fluorescent protein-tagged HLA-C migrating away from immune synapses into NK cells. Unlike clustering of HLA-C at the immune synapse, intercellular transfer of HLA-C is dependent on NK cell ATP, but not target cell ATP. However, the intercellular transfer of HLA-C is not dependent on active polymerization of the actin cytoskeleton. In addition, different arrangements of HLA-C are seen at inhibitory NK immune synapses, and these alter as NK synapses mature, but in a fashion distinct from that seen upon T cell activation.

Demographic contexts and the adaptive role of mother-infant attachment : A hypothesis.

Currently much debate surrounds the significance of cross-cultural variation in mother-infant attachment. Is only one form of attachment "healthy," or are different types of attachment adaptations to local socioecological conditions? Juvenile mortality rates have been promoted as important features of local environments that shape attachment, which in turn affects later reproductive strategies. To this we add fertility. Fertility changes the environment of a child by influencing the number of potential caregivers and competitors for care, and the cultural ethos regarding the rights of children. Different combinations of fertility and mortality will likely give rise to different attachment forms, and only under one regime (low fertility and mortality) do we expect exclusivity in attachment.

Remembering and forgetting childhood sexual abuse.

Out of a large number of university students who responded to a questionnaire about childhood sexual abuse (CSA), approximately a quarter reported that they had an experience in childhood that qualified. The majority of students who reported a CSA experience refused, elsewhere in the questionnaire, to classify themselves as 'sexually abused'. Moreover, those who claimed lack of understanding of the event at the time it occurred also reported that they thought about the event less often in the intervening years and that they conceivably would have not remembered the event even if asked directly about it. Lack of understanding at the time of encoding leads to less reported memory. These observations are discussed in terms of possible mechanisms for how genuine sexual abuse experiences might be temporarily forgotten--even for extended periods--and subsequently remembered.

Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits.

Cholinergic markers, neuropeptides, and amines and their metabolites were sampled from identical specimens across 10 neocortical regions in a large sample of Alzheimer's disease (AD) cases and controls. Levels of choline acetyltransferase, acetylcholinesterase, somatostatin, corticotropin-releasing factor, serotonin, and 5-hydroxyindoleacetic acid were significantly reduced in AD versus controls. After data reduction, the most descriptive neurochemical indices were used to examine the relationship of neurochemical measures and dementia severity within the AD sample, controlling for age effects. Dementia severity ratings were based on antemortem assessments (46.9% of AD sample) and postmortem chart review (53.1% of the AD sample). Choline acetyltransferase activity was highly correlated with clinical dementia ratings across the neocortex of the AD cases. Somatostatin and corticotropin-releasing factor levels were correlated with dementia severity only when control cases were included in the analyses. None of the amines, their metabolites, or the neuropeptides quantified related significantly to dementia severity in the AD cohort. These data (a) confirm the strong association of cholinergic deficits with functional impairment in AD and show that this association is independent of age and (b) suggest that of all the neurochemical species quantified, the cholinergic indices may be unique in their association with dementia severity.

Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer's disease.

OBJECTIVE: To determine the relationships between dementia severity and the extent of histopathologic lesions in a variety of brain regions. Neocortical and hippocampal ratings for neurofibrillary tangles (NFTs) and senile plaques (SPs) were compared in 70 cases of clinically and neuropathologically confirmed Alzheimer's disease. DESIGN: Neuropathologic case series. Dementia severity was assessed by postmortem chart review with use of the extended Clinical Dementia Rating Scale (CDR). Linear association between CDR scores and NFT and SP scores were assessed by partial correlation, controlling for age at death. SETTING: Studies were conducted at the Alzheimer's Disease Research Center of the Mount Sinai Medical Center, New York, NY. MAIN OUTCOME MEASURE: Association between CDR scores and neuropathologic changes assessed with the Consortium to Establish a Registry for Alzheimer's Disease semiquantitative scale. RESULTS: Among these lesion scores, only NFTs showed a significant association with CDR score, and only for neocortical regions. In particular, NFT densities in the superior temporal cortex were most strongly correlated with dementia severity, followed by those in the inferior parietal and midfrontal cortex. No such correlations were apparent for the amygdala, hippocampus, or entorhinal cortex. Medial temporal lobe structures displayed high NFT scores, even in cases of mild dementia. Senile plaques did not correlate significantly with CDR score in any region. CONCLUSIONS: These data support the notion that neocortical neuronal degeneration, as indicated by NFT formation, is a critical determinant of the clinical progression of Alzheimer's disease and suggest that medial temporal lobe structures may represent the initial site of NFT formation. While SP density correlates with age at death, there is no correlation between SP counts and dementia severity. These results further suggest that the clinical presentation of dementia may be closely related to neurodegeneration in neocortical regions within the temporal lobe.