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PubMed2006

Simulating properties of in vitro epithelial cell morphogenesis.

How do individual epithelial cells (ECs) organize into multicellular structures? ECs are studied in vitro to help answer that question. Characteristic growth features include stable cyst formation in embedded culture, inverted cyst formation in suspension culture, and lumen formation in overlay culture. Formation of these characteristic structures is believed to be a consequence of an intrinsic program of differentiation and de-differentiation. To help discover how such a program may function, we developed an in silico analogue in which space, events, and time are discretized. Software agents and objects represent cells and components of the environment. "Cells" act independently. The "program" governing their behavior is embedded within each in the form of axioms and an inflexible decisional process. Relationships between the axioms and recognized cell functions are specified. Interactions between "cells" and environment components during simulation give rise to a complex in silico phenotype characterized by context-dependent structures that mimic counterparts observed in four different in vitro culture conditions: a targeted set of in vitro phenotypic attributes was matched by in silico attributes. However, for a particular growth condition, the analogue failed to exhibit behaviors characteristic of functionally polarized ECs. We solved this problem by following an iterative refinement method that improved the first analogue and led to a second: it exhibited characteristic differentiation and growth properties in all simulated growth conditions. It is the first model to simultaneously provide a representation of nonpolarized and structurally polarized cell types, and a mechanism for their interconversion. The second analogue also uses an inflexible axiomatic program. When specific axioms are relaxed, growths strikingly characteristic of cancerous and precancerous lesions are observed. In one case, the simulated cause is aberrant matrix production. Analogue design facilitates gaining deeper insight into such phenomena by making it easy to replace low-resolution components with increasingly detailed and realistic components.

Cell Shape↗

PubMed2026

Environmental benzene exposure induces a conserved neutrophil degranulation program across species.

Immune systems have evolved under constant pressure from pathogens and environmental challenges, leading to the emergence of conserved defense mechanisms across diverse organisms. Evidence indicates that environmental exposures perturb immune regulatory networks, particularly during development, when transcriptional programs governing hematopoiesis, immune cell differentiation, and inflammatory signaling are highly dynamic and sensitive to external stressors. Volatile organic compounds represent an important but incompletely understood source of immunological perturbation. Among these, benzene is a ubiquitous environmental contaminant associated with hematotoxicity and immune dysregulation; however, transcriptional responses to environmentally relevant low-level exposures during development remain poorly characterized. To determine whether benzene exposure engages conserved cross-species immune regulatory pathways, we performed a comparative transcriptomic analysis integrating developmental tissues from 3 vertebrate systems: human placenta, murine placenta, and zebrafish larvae. Bulk RNA sequencing datasets were analyzed to identify transcriptional responses associated with benzene exposure in experimental models (≤5 ppm) and with benzene adduct levels in maternal plasma for human samples. Because placental gene expression exhibits strong sexual dimorphism, murine datasets were stratified by fetal sex. Pathway- and network-level analyses were used to identify conserved biological responses. We observed a striking convergence on activation of innate immune pathways associated with neutrophil degranulation, IL-8 signaling, and Rho GTPase-mediated inflammatory responses. Further, network analyses identified CXCL8 and ERK1/2 as shared regulatory hubs linking transcriptional responses across datasets. Together, these findings uncover an evolutionarily conserved innate immune signature associated with benzene exposure during vertebrate development, suggesting that environmental chemical perturbations may disrupt fundamental immune regulatory programs across species.

Animals↗

PubMedDate not supplied

Social factors associated with pediatric emergency department visits for caries-related dental pain.

PURPOSE: This study was performed to describe and relate sociodemographic factors and management of visits to a pediatric hospital emergency department for caries-related dental pain. METHODS: Retrospective chart review of cases with a verifiable chief complaint of caries-related dental pain in 1998, was conducted using established protocol and trained reviewers. RESULTS: Three hundred of 984 hospital ED dental emergencies met the study's selection criteria and 109 children were six years old or younger. Almost two-thirds (66%) came from single parent families. Fifty-eight percent were self-pay or covered by government programs and the rest had some insurance. African-American children were 45% of cases. Over 80% were from within Franklin County, OH. Only 4 children (1%) had been seen for the same tooth previously. Lower primary molars were most often affected. Race, insurance, parental marital status were not significantly related to follow-up attendance at the facility (P > 0.05). Those living outside Franklin County and under 5 years of age were more likely to attend follow-up appointments (P < 0.05). When compared to the catchment population of Franklin County, this ED sample had six times as many uninsured children, two and a half times more African-Americans, and came from single parent families four and a half times more often. CONCLUSIONS: Children seen in the ED were predominantly poor, from single-parent families, and disproportionately minority, and were different from the catchment area population. These social risk factors were not related to attendance at follow-up.

Adolescent↗

PubMed2003

Physician, public, and policymaker perspectives on chronic conditions.

BACKGROUND: Chronic conditions are the leading reason why people seek medical care, yet the current financing and delivery system has been criticized for not promoting ongoing care. The perceptions of physicians, policymakers, and the general public were compared on how well the current system addresses the needs of people with chronic conditions. METHODS: National surveys of 1238 physicians and 1663 Americans and a convenience sample of 155 policymakers were compared. All 3 groups were given the same definition of a chronic condition and asked similar questions. RESULTS: There was strong agreement that chronic medical conditions affect men and women of all ages, ethnicities, and income levels (>90% strongly or somewhat agree). However, compared with the public and physicians, policymakers were less likely to respond that people with chronic conditions usually receive adequate medical care, that health insurance pays for most needed services, or that government programs are adequate. The public was most positive about the current system and policymakers the least. A majority of all 3 groups agreed that it is somewhat or very difficult for people with chronic conditions to obtain adequate care from primary care physicians, medical specialists, and other health care professionals. CONCLUSIONS: A majority of physicians, policymakers, and the general public are concerned that the current health care system is not addressing the needs of people with chronic conditions. Changes in how medical care is financed and delivered are necessary to respond to these concerns.

Adult↗

PubMed1997

Measuring quality of care in neurology.

Neurologists are being asked to incorporate methods into daily practice that measure quality of care. Standards of care are increasingly being defined using evidence-based assessments of neurological literature. To evaluate quality of care, a widely accepted and useful model considers the structure, process, and outcomes of care. Outcomes, the impact of care on patients' health, should include measures of mortality, morbidity, disability, patient functioning and well-being (health-related quality of life), and patient satisfaction with care. A variety of private organizations and government programs exist to encourage documentation and promotion of high quality of care. This explosion in quality information is not yet standardized, so that much confusion exists about appropriate data elements to be measured. The challenge is to collect, summarize, and disseminate practical data useful to neurologists and the purchasers and consumers of our services.

Evidence-Based Medicine↗

PubMed2000

Selective referral to high-volume hospitals: estimating potentially avoidable deaths.

CONTEXT: Evidence exists that high-volume hospitals (HVHs) have lower mortality rates than low-volume hospitals (LVHs) for certain conditions. However, few employers, health plans, or government programs have attempted to increase the number of patients referred to HVHs. OBJECTIVES: To determine the difference in hospital mortality between HVHs and LVHs for conditions for which good quality data exist and to estimate how many deaths potentially would be avoided in California by referral to HVHs. DESIGN, SETTING, AND PATIENTS: Literature in MEDLINE, Current Contents, and First-Search Social Abstracts databases from January 1, 1983, to December 31, 1998, was searched using the key words hospital, outcome, mortality, volume, risk, and quality. The highest-quality study assessing the mortality-volume relationship for each given condition was identified and used to calculate odds ratios (ORs) for in-hospital mortality for LVHs vs HVHs. These ORs were then applied to the 1997 California database of hospital discharges maintained by the California Office of Statewide Health Planning and Development to estimate potentially avoidable deaths. MAIN OUTCOME MEASURES: Deaths that potentially could be avoided if patients with conditions for which a mortality-volume relationship had been treated at an HVH vs LVH. RESULTS: The articles identified in the literature search were grouped by condition, and predetermined criteria were applied to choose the best article for each condition. Mortality was significantly lower at HVHs for elective abdominal aortic aneurysm repair, carotid endarterectomy, lower extremity arterial bypass surgery, coronary artery bypass surgery, coronary angioplasty, heart transplantation, pediatric cardiac surgery, pancreatic cancer surgery, esophageal cancer surgery, cerebral aneurysm surgery, and treatment of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). A total of 58,306 of 121,609 patients with these conditions were admitted to LVHs in California in 1997. After applying the calculated ORs to these patient populations, we estimated that 602 deaths (95% confidence interval, 304-830) at LVHs could be attributed to their low volume. Additional analyses were performed to take into account emergent admissions and distance traveled, but the impact of loss of continuity of care for some patients and reduction in the availability of specialists for patients remaining at LVHs could not be assessed. CONCLUSIONS: Initiatives to facilitate referral of patients to HVHs have the potential to reduce overall hospital mortality in California for the conditions identified. Additional study is needed to determine the extent to which selective referral is feasible and to examine the potential consequences of such initiatives.

California↗

PubMed1997

Living on the edge: dietary strategies of economically impoverished women in Cali, Colombia.

Economically impoverished women in Cali, Colombia, have restricted access to food in a city where food is abundant. Ethnographic observations, interviews and 2 day food records were used to better understand the coping strategies used by a group of these women (n = 85) to maintain adequate levels of energy intake. Anthropometric indicators of nutritional status were normal for the group. Interview data revealed that the ability to purchase food was a concern for 58% of the women. When faced with a restricted ability to purchase food, the women indicated they made compromises in meal composition, reduced portion sizes, and/or reduced the number of meals. They also relied on relatives, friends, neighbors, store credit, or local government programs for access to food. Changes in meal composition were identified in 17.1% of all diet records (n = 509). Low energy intake (defined as energy intake < or = 1.27 x BMR) was identified in 17.1% of all diet records. Carbohydrate consumption was significantly greater on low-energy intake days. The adequate nutritional status of this group of women suggests that their coping strategies are usually adequate to maintain energy intake, but the presence of uncertainty, the frequency of compromises in diet composition, and the frequency of low-energy intake days suggest that these women are at risk for undernutrition.

Adaptation, Psychological↗

PubMed2006

Physiology and pathology of notch signalling system.

Notch proteins encode a family of transmembrane receptors that are part of a signalling transduction system known as Notch signalling, an extremely conserved and widely used mechanism regulating programs governing growth, apoptosis and differentiation in metazoans. Notch signalling begins when the Notch receptor binds ligands and ends when the Notch intracellular domain enters the nucleus and activates transcription of target genes. This core pathway is subjected to a wide array of regulatory influences and protein-protein interactions and is correlated with other signalling pathway. This review will summarize recent findings concerning the physiology and pathology of Notch signalling in vascular development and homeostasis. Moreover, the clinical phenotypes of Notch3 signalling system pathology will be described, with particular regard to CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) for which the most recent pathogenetic hypotheses are reported.

Animals↗

PubMed2000

Influence of mRNA self-structure on hybridization: computational tools for antisense sequence selection.

Antisense targeting, an innovative technology based on preventing biosynthesis through sequence-specific hybridization of mRNA to synthetic oligodeoxynucleotides (ODNs), is used to selectively and transiently downregulate the expression of any gene product. Its potential applications are both investigative (neurobiology and related disciplines) and therapeutic (oncology, virology, genetic diseases), and several antisense-based drugs are currently undergoing clinical trials. However, the reported efficiencies vary and there is still a lack of clarity in the underlying mechanisms of action. A critical factor of antisense efficiency is the issue of target site selection, as both mRNA and ODN molecules exhibit a significant amount of highly heterogeneous self-structure and the region selected for targeting may well be sterically or energetically inaccessible. Because of the prohibitively large chain length, mRNA structural information is not accessible by X-ray crystallography or NMR, making a modeling approach indispensable. I outline how the latest molecular modeling techniques can be employed to establish the secondary (2D) and tertiary (3D) structures into which a given mRNA folds during and after transcription. The aim should be to integrate 2D prediction results achieved by (a) free-energy minimization, (b) kinetic folding simulations, (c) iterative population breeding by genetic algorithms, and (d) phylogenetic comparison techniques. These results can form the input of a 3D structure prediction paradigm based on constraint-satisfying programming, governed by experimental molecular mechanical constraints, and refined by molecular dynamics simulations. Finally, the automated docking (by simulated annealing) of ODN molecules to the mRNA structure can provide information about the accessibility of target mRNA regions for hybridization. To date, the great majority of studies that employ antisense as a tool select their target sequences more or less randomly. Although the wealth of molecular interactions that take place within a cell makes complete predictability unrealistic, the kind of information that can be extracted from such techniques is of relevance to every application of antisense technology, both investigative and therapeutic.

Algorithms↗

PubMedDate not supplied

Infections in intraabdominal surgery. The EURESI Project. European Research Network on Surgical Infections.

The situation of clinical research in Europe must be improved substantially according to statements of scientists, managers and politicians. The analysis of requirements is available; however, there are no indications that the conclusion of the analysis is being converted into actual facts. Government programs, although originally conceived to improve the situation of clinical research, are used to maintain the status quo. The European Research Network on Surgical Infections (EURESI) concept has been developed by scientists and clinicians from European institutions and university hospitals to make the first steps possible in a new cooperation in European research. With regard to the essentials for clinical research, formulated according to a survey among research-oriented pharmaceutical companies, EURESI was successful in the following objectives: 1) competence in clinical research, 2) capacity for clinical studies, 3) internal quality control, 4) special know-how relevant to clinical studies, 5) performance according to a time plan, 6) interdisciplinianism, 7) contract partnership, 8) organization of research meetings. This special addendum includes presentations at the EURESI meeting in Heidelberg/Weinheim with special reference to the requirements for clinical studies in intraabdominal infections to further stimulate contact with the network.

Abdomen↗

PubMed2002

Voluntary toe-walking gait initiation: electromyographical and biomechanical aspects.

This study was carried out to investigate the biomechanical constraints of toe-walking gait initiation and the associated changes in motor program compared to the well documented heel-toe walking gait initiation. Seven healthy subjects volunteered for this study. Gait was initiated on a force platform, at three self-selected speed conditions, from an erect spontaneous posture in the control situation (CS) and from a posture with heels raised in the test situation (TS). Surface electromyographical (EMG) activities of muscles soleus (Sol) and tibialis anterior (TA) were recorded on both limbs. We analysed the consequences of the heel-off posture on EMG patterns and biomechanical activities. Whatever the speed condition, the centre of foot pressure was initially located more ahead of the ankle axis in TS than in CS, with an increased Sol and TA EMG activity. The EMG pattern which expresses the motor program governing gait initiation was modified in TS in comparison to CS and induced adaptations of the anticipatory postural adjustments (APA) that precede toe-off of the stepping limb. A lengthening of the APA duration allowed the subjects in TS to reach a gait velocity similar to the one obtained in CS at the end of the anticipatory movements and also at the end of the first step. In TS, the velocity of the centre of gravity at time of toe-off covaried, as in CS, with CG velocity at the end of the first step, still resulting from TA muscular actions during the APA but also probably from other combined muscular actions.

Adaptation, Physiological↗

PubMed2004

Projecting large-scale area changes in land use and land cover for terrestrial carbon analyses.

One of the largest changes in US forest type areas over the last half-century has involved pine types in the South. The area of planted pine has increased more than 10-fold since 1950, mostly on private lands. Private landowners have responded to market incentives and government programs, including subsidized afforestation on marginal agricultural land. Timber harvest is a crucial disturbance affecting planted pine area, as other forest types are converted to planted pine after harvest. Conversely, however, many harvested pine plantations revert to other forest types, mainly due to passive regeneration behavior on nonindustrial private timberlands. We model land use and land cover changes as a basis for projecting future changes in planted pine area, to aid policy analysts concerned with mitigation activities for global climate change. Projections are prepared in two stages. Projected land use changes include deforestation due to pressures to develop rural land as the human population expands, which is a larger area than that converted from other rural lands (e.g., agriculture) to forestry. In the second stage, transitions among forest types are projected on land allocated to forestry. We consider reforestation, influences of timber harvest, and natural succession and disturbance processes. Baseline projections indicate a net increase of about 5.6 million ha in planted pine area in the South over the next 50 years, with a notable increase in sequestered carbon. Additional opportunities to expand pine plantation area warrant study of landowner behavior to aid in designing more effective incentives for inducing land use and land cover changes to help mitigate climate change and attain other goals.

Carbon↗

PubMed1997

Environmental Awareness, Economic Orientation, and Farming Practices: A Comparison of Organic and Conventional Farmers

/ This study examines similarities and differences between organic and conventional farmers. We explore the factors that underlie farmers' conservation attitudes and behaviors, including demographic and farm characteristics, awareness of and concern for environmental problems associated with agriculture, economic orientation toward farming, and self-reported conservation practices. A series of intensive personal interviews was conducted with 25 farmers in Washtenaw County, Michigan, USA, using both qualitative and quantitative survey methods. The findings indicate that both groups of farmers share a concern for the economic risks associated with farming, although the organic farmers reported a significantly greater concern for long-term sustainability and a greater willingness to incur present risk to gain future benefits. Organic farmers expressed a greater awareness of and concern for environmental problems associated with agriculture. Organic farmers also scored significantly higher on a multifaceted measure of conservation practices, although both groups had a fairly high adoption rate. Implications of these findings are discussed, relative to economic risks of farming, implications for new farmers, effectiveness of conservation education and government programs, and impact of farm size and crop diversity.KEY WORDS: Environmental attitudes; Conservation behaviors; Organic farming; Agricultural sustainability

Journal Article↗

PubMed1997

A species-specific recognition system directs haustorium development in the parasitic plant Triphysaria (Scrophulariaceae).

Parasitic plants use host molecules to trigger development programs essential for parasitism. One such program governs the initiation, development, and function of haustoria, parasite-specific organs responsible for attachment and invasion of host tissues. Haustoria development can be initiated by several different molecules produced by appropriate host species. We are interested in understanding how these signals are interpreted by two related facultative parasites, Triphysaria eriantha (Benth). Chuang and Heckard, and T. versicolor Fischer and C. Meyer, to distinguish their own roots from those of potential hosts. We used an in vitro bioassay to determine what proportion of different Triphysaria populations formed haustoria in the presence and absence of closely related and unrelated host species. We found that the proportion of plants with haustoria was the same whether the plants were grown in isolation or with a conspecific host. In contrast, a significantly higher proportion of plants made haustoria when the host was a congeneric Triphysaria. Plants with haustoria neither enhanced nor inhibited other plants' propensity to form haustoria. Together these results indicate that qualitative differences exist in haustorium-inducing factors exuded by closely related species. The highest proportion of Triphysaria had haustoria when growth with Arabidopsis thaliana (L.) Heynh. Even in this case, however, some Triphysaria failed to develop haustoria. Interestingly, the percentage of haustoria that had vessel elements was higher when connections were made with Arabidopsis than with another Triphysaria. These results demonstrate that host recognition can be manifested at multiple points in haustorium development.

Arabidopsis↗

PubMed1990

Acute hospital costs of pediatric trauma in the United States: how much and who pays?

National estimates of the numbers and expenditures associated with hospitalization due to injury among children (aged 0 to 14) were derived using data from the 1984, 1985, and 1986 National Hospital Discharge Surveys (NHDS) and the 1980 National Medical Care Utilization and Expenditures Study (NMCUES). In this report, age- and sex-specific estimates of the numbers of hospital admissions and expenditures are reported for subgroup of patients defined by external cause of the injury and by nature and severity of the injury. In 1985, over 266,000 children sustained a traumatic injury resulting in hospitalization (rate of 51 per 10,000 children). Expenditures totaled nearly $1 billion. Over 80% of the hospitalizations and two thirds of total expenditures were for minor (Maximum AIS = 1.2) trauma. Moderate (Maximum AIS = 3) and severe (Maximum AIS = 4,5) trauma accounted for 18% and 2% of admissions and 31% and 8% of expenditures, respectively. Falls ranked first in expenditures and admissions (36% of the total). Motor vehicle-related injuries accounted for 19% of trauma admissions and 24% of expenditures. Other less common causes included bicycle injuries, penetrating injuries and injuries caused by the child being hit by an object or person. An estimated 28% of the total hospital charges were paid for by public sources (15% from federal government programs, 13% from state and local programs). An additional 63% of total expenditures were paid for by private sources, with the remaining 9% considered uninsured care.(ABSTRACT TRUNCATED AT 250 WORDS)

Accidental Falls↗

PubMed1982

Disease epidemiology and earthquake disaster. The example of Southern Italy after the 23 November 1980 earthquake.

This paper describes aspects of the epidemiological situation following the November 1980 earthquake disaster in Campania and Basilicata, southern Italy. First, population displacements and the fluctuating state of homelessness after the catastrophe are described. Secondly, the level of medical provision prior to the disaster is assessed and damage caused by the earthquake to the medical care and sanitation infrastructures is outlined. Thirdly, the publicity given by news media to the threat of disease is examined and compared with the official government reaction, which took the form of emergency medical provision and intervention against the supposed threat of disease. The national epidemiological surveillance system, which was set up during the aftermath of the disaster, is outlined and some of its results, describing the post-impact epidemiological situation in the disaster zone, are examined. Despite the chaotic situation following the earthquake and the publicity given to the threat of disease outbreaks, there were no serious epidemics and the hospital system was able to cope with the aftermath. The government program of vaccinating survivors and relief volunteers can therefore be seen as an over-reaction to the prevailing situation, although continuing disease surveillance was probably a wise precaution.

Communicable Disease Control↗

PubMed1985

Health care expenditure containment in the United States: strategies at the state and local level.

The current status of state and local strategies to contain health care expenditures in the United States is described. These strategies are classified as predominantly regulatory, competitive or voluntary. The actions of two major groups of purchasers of care--state government programs for the indigent and private employers--in support of expenditure containment strategies are discussed as well. The large number of approaches to expenditure containment currently being attempted, and their diverse character, are hypothesized to be a result not only of increased health care inflation and the concern it causes purchasers of care, but also of fundamental changes in the health care industry in the United States which have realigned traditional provider interest groups.

Budgets↗

PubMed2026

Tissue-derived extracellular matrix hydrogels instruct epigenetic adaptation in metastatic colonization.

The extracellular matrix (ECM) plays a central role in regulating tumor progression and metastatic colonization by providing biochemical and mechanical signals that shape cancer cell fate. However, most organoid culture systems rely on basement membrane extracts that fail to reproduce the tissue-specific extracellular environments encountered during metastasis. Here, we develop tissue-derived decellularized matrix hydrogels to reconstruct organ-specific microenvironments and investigate epigenetic adaptation to ECM cues during metastatic colonization. Patient-derived colorectal cancer organoids cultured in colon-derived matrices exhibited enhanced maintenance of stem-like phenotypes and colon-specific chromatin accessibility landscapes compared with cultures grown in basement membrane extracts, demonstrating improved physiological relevance for primary tumor modeling. When exposed to matrices derived from secondary organs, the organoids showed distinct growth phenotypes accompanied by rapid, tissue-dependent chromatin accessibility remodeling, indicating that ECM composition alone can reshape regulatory programs governing metastatic adaptation. Notably, liver-derived matrices selectively activated hepatocyte nuclear factor 4 alpha (HNF4A)-associated transcriptional networks and created a context-specific dependence on c-MET signaling for survival. Functional perturbation of HNF4A or c-MET signaling confirmed that both are required for organoid formation specifically within the liver matrix environment. Together, these findings establish tissue-derived matrix hydrogels as instructive bioactive materials that actively regulate cancer cell epigenetic states and reveal microenvironment-specific therapeutic vulnerabilities during early metastatic colonization.

Journal Article↗