Glomerular hypertrophy aggravates epithelial cell injury in nephrotic rats.

Glomerular function and structure were assessed after reduction of nephron number and restriction of protein intake in rats with adriamycin nephrosis. Rats received an injection of adriamycin and were divided into three groups with similar values for albuminuria after 4 wk. Group 1 rats then served as controls, group 2 rats were subjected to four-fifths renal ablation, and group 3 rats were placed on a low protein diet (8% protein) while group 1 and group 2 rats remained on a standard diet (24% protein). Micropuncture and morphometric studies were performed 10 d later. Estimated single-nephron albuminuria (SNalb) was increased by renal ablation in group 2 and decreased by protein restriction in group 3 (group 1, 20 +/- 2 micrograms/d; group 2, 68 +/- 7 micrograms/d; group 3, 12 +/- 1 microgram/d, P less than 0.05 groups 2 and 3 vs. 1). Increased SNalb was associated with increased glomerular volume in group 2 and reduced SNalb was associated with reduced glomerular volume in group 3. (group 1, 1.44 +/- 0.04 x 10(6) microns 3; group 2, 1.66 +/- 0.08 x 10(6) microns 3; group 3, 1.26 +/- 0.03 x 10(6) microns 3, P less than 0.05 groups 2 and 3 vs. 1). Increased SNalb in group 2 was not associated with an increase in glomerular transcapillary hydraulic pressure. The area of epithelial cell detachment from the peripheral capillary wall was markedly increased in group 2 but not perceptibly altered in group 3 (group 1, 16 +/- 5 x 10(2) microns 2; group 2, 65 +/- 17 x 10(2) microns 2; group 3, 18 +/- 5 x 10(2) microns 2; P less than 0.05 group 2 vs. 1). These studies show that glomerular hypertrophy is associated with increased epithelial cell detachment from the peripheral capillary wall and with increased remnant nephron albuminuria after reduction of nephron number in rats with established nephrosis.

Podocyte loss and progressive glomerular injury in type II diabetes.

Kidney biopsies from Pima Indians with type II diabetes were analyzed. Subjects were classified clinically as having early diabetes (n = 10), microalbuminuria (n = 17), normoalbuminuria, despite a duration of diabetes equal to that of the subjects with microalbuminuria (n = 12), or clinical nephropathy (n = 12). Subjects with microalbuminuria exhibited moderate increases in glomerular and mesangial volume when compared with those with early diabetes, but could not be distinguished from subjects who remained normoalbuminuric after an equal duration of diabetes. Subjects with clinical nephropathy exhibited global glomerular sclerosis and more prominent structural abnormalities in nonsclerosed glomeruli. Marked mesangial expansion was accompanied by a further increase in total glomerular volume. Glomerular capillary surface area remained stable, but the glomerular basement membrane thickness was increased and podocyte foot processes were broadened. Broadening of podocyte foot processes was associated with a reduction in the number of podocytes per glomerulus and an increase in the surface area covered by remaining podocytes. These findings suggest that podocyte loss contributes to the progression of diabetic nephropathy.

The Human Brain Project: neuroinformatics tools for integrating, searching and modeling multidisciplinary neuroscience data.

What is neuroinformatics? What is the Human Brain Project? Why should you care? Supported by a consortium of US funding agencies, the Human Brain Project aims to bring to the analysis of brain function the same advantages of Internet-accessible databases and database tools that have been crucial to the development of molecular biology and the Human Genome Project. The much greater complexity of neural data, however, makes this a far more challenging task. As a pilot project in this new initiative, we review some of the progress that has been made and indicate some of the problems, challenges and opportunities that lie ahead.

ALFRED: an allele frequency database for diverse populations and DNA polymorphisms--an update.

ALFRED (the ALelle FREquency Database) is designed to store and disseminate frequencies of alleles at human polymorphic sites for multiple populations, primarily for the population genetics and molecular anthropology communities. Currently ALFRED has information on over 180 polymorphic sites for more than 70 populations. Since our initial release of the database we have focussed on increasing the quantity and quality of data, making reciprocal links between ALFRED and other related databases, and providing useful tools to make the data more comprehensible to the end user. ALFRED is accessible from the Kidd Lab home page (http://info.med.yale. edu/genetics/kkidd/) or from ALFRED directly (http://alfred.med.yale. edu/alfred/index.asp).

ALFRED: the ALelle FREquency Database. Update.

Elaboration of ALFRED (http://alfred.med.yale.edu) is being continued in two directions. One of which is developing tools for efficiently annotating the entries and checking the integrity of the data already in the database while the other is to increase the quantity and accessibility of data. Information contained in ALFRED such as, polymorphic sites, number of populations and frequency tables (one sample typed for one site) has significantly increased.

Reversal of glomerular hyperfiltration and renal hypertrophy by blood glucose normalization in diabetic rats.

Two groups of rats with streptozocin-induced diabetes and one group of nondiabetic control rats were studied. Group 1 diabetic rats received daily insulin to maintain blood glucose levels at 300-400 mg/dl for 44 wk. Group 2 diabetic rats received the same insulin regimen for 37 wk and then received an increased dose of insulin to return blood glucose levels close to normal for 7 wk. Group 3 nondiabetic rats were age-matched controls. Glomerular filtration rate (GFR) and kidney weight were elevated in moderately hyperglycemic group 1 rats compared with group 3 rats. Normalization of blood glucose returned both GFR (group 1, 1.83 +/- 0.04 ml/min; group 2, 1.36 +/- 0.05 ml/min; group 3, 1.45 +/- 0.07 ml/min) and kidney weight (group 1, 2.55 +/- 0.06 g; group 2, 1.82 +/- 0.05 g; group 3, 1.72 +/- 0.06 g) to normal in group 2 rats. Despite a sustained increase in GFR, group 1 rats did not exhibit any increase in glomerular volume (group 1, 2.77 +/- 0.09 x 10(6) microns3; group 2, 2.69 +/- 0.09 x 10(6) microns3; group 3, 2.81 +/- 0.7 x 10(6) microns3). Group 1 rats did, however, exhibit a significant increase in glomerular mesangial volume (group 1, 0.31 +/- 0.02 x 10(6) microns3; group 2, 0.28 +/- 0.02 x 10(6) microns3; group 3, 0.21 +/- 0.01 x 10(6) microns3), which was not reversed by normalization of blood glucose in group 2. These findings show that normalization of blood glucose can reverse established glomerular hyperfiltration and renal hypertrophy in moderately hyperglycemic diabetic rats. They further indicate that mesangial expansion is associated with sustained moderate hyperglycemia in this disease model.

Retrograde amnesia and bilateral electroconvulsive therapy. Long-term follow-up.

Memory for past events was assessed in 43 patients who had been prescribed bilateral electroconvulsive therapy (ECT) for relief of depressive illness. Four memory tests of personal or public events were administered before ECT, shortly after the fifth treatment, one week after completion of treatment, and about seven months later. The results indicated that ECT can initially disrupt recall of events that occurred many years previously, but recovery of these memories was virtually complete by seven months after treatment. It was also clear that persisting memory loss for information acquired only a few days before treatment can occur. For information acquired one to two years prior to treatment, recovery was substantial, but the results suggested that some memory problems might persist for events that occurred during this time period.

A point-addressable transfer system for automated sampling, feeding, and expansion of hybridoma cultures.

A Dynatech Autoprep liquid sampling system has been modified to perform fully automated aseptic sampling, feeding, and expansion of hybridoma cultures in standard 96- and 24-well culture plates. The system is controlled by an Apple IIe computer, and uses a single teflon probe to transfer culture medium from randomly located wells to EIA plates and deliver fresh medium to the sampled wells. An 'expansion mode' allows suspension of cells for transfer to another plate. The sampling probe may be washed with sterile medium, buffer, or water between each transfer. Any combination of up to 6 assay plates, sterile growth plates, and expansion plates may be operated on at one time, and each transaction is recorded on a floppy disk file. Experiments with various hybridoma cultures indicated that transfers were reproducible, sterility was maintained, and the washing procedure reduced cross-contamination of cultures with other cells or antibodies to negligible levels. The APPLE BASIC computer programs which perform the functions and record the transactions are described in the paper and the Appendix, and are available upon request.

Molecular genetic analysis of sperm competition in the damselfly Ischnura elegans (Vander Linden).

Sperm competition can be a powerful selective force in the evolution of mating systems. Several odonate species have attracted study to assess the extent and mechanism of last-male sperm precedence. Members of the genus Ischnura (Zygoptera) display a particularly interesting range of mating systems, and Ischnura elegans was selected for study. Polymorphic microsatellites were cloned, sequenced and used to determine paternity of I. elegans larvae, to reveal patterns of sperm precedence. More than 3000 larvae, collected from both wild and captively bred I. elegans females, were typed for one or two microsatellite loci and paternity was determined by comparison with parental genotypes. Microsatellite typing showed that most wild-caught females had mated with several males. Analysis of offspring from females which mated in captivity showed that multiple-matings result in a large proportion of last-male sperm precedence (mean value for immediate last male precedence is 0.79 +/- 0.2 (+/- s.d.; n = 11, range = 0.44-1)). There is appreciable variation in the extent and patterns of immediate and longer-term precedence, which could reflect differences in male sperm removal ability or selective use of sperm by females.

The three year course of psychiatric problems in a geriatric population.

This is a 3 year follow-up of the psychiatric status of 276 men age 65 and older who were originally seen as medical and surgical patients. Major psychiatric diagnoses were noted in 24% of the individuals, these being fairly evenly divided between active alcoholism, affective disorder, atherosclerotic dementia, or a past history of alcoholism, and a heterogeneous category, composed mostly of individuals with senile dementia. Over the 3 years, approximately one-quarter of the sample who had originally been free of psychopathology became ill, most with an affective disorder or an organic brain syndrome. A high level of diagnostic consistency was noted over 3 years for the individuals originally noted to be psychiatrically ill. The follow-up demonstrated an unexpectedly bleak prognosis for the individuals with affective disorder. The reasons for this finding are explored.

A three year follow-up of elderly alcoholics.

This a 3 year follow-up of the psychiatric status of 280 consecutive men age 65 and over who were admitted to the San Diego Veterans Administration Medical Center for medical or surgical problems. Eleven percent of the individuals were found to have active or remitted primary alcoholism. Over the 3 years only 20% of the surviving active alcoholics became abstinent. Most of the inactive alcoholics remained alcohol problem-free after 3 years. Affective disorder and dementia were common intercurrent psychiatric disorders arising during follow-up. The 3 year mortality rate was significantly higher for remitted alcoholics when compared to those without psychiatric illness.

Aspects of IAIMS implementation that require further research.

The Integrated Advanced Information Management System (IAIMS) program promotes an integrated approach to information management within a medical center. Since the IAIMS program was conceived, many of the initial IAIMS technologic needs have been quite widely achieved or are planned for implementation in many medical centers. At the same time, the IAIMS frontier is being steadily pushed to new issues that need to be addressed to achieve the full power of the IAIMS vision. The paper discusses 1) levels of integration where IAIMS has been successfully pursued to date and 2) challenging areas in which research is required to approach the full potential of the IAIMS in the future.

Opportunities at the intersection of bioinformatics and health informatics: a case study.

This paper provides a "viewpoint discussion" based on a presentation made to the 2000 Symposium of the American College of Medical Informatics. It discusses potential opportunities for researchers in health informatics to become involved in the rapidly growing field of bioinformatics, using the activities of the Yale Center for Medical Informatics as a case study. One set of opportunities occurs where bioinformatics research itself intersects with the clinical world. Examples include the correlations between individual genetic variation with clinical risk factors, disease presentation, and differential response to treatment; and the implications of including genetic test results in the patient record, which raises clinical decision support issues as well as legal and ethical issues. A second set of opportunities occurs where bioinformatics research can benefit from the technologic expertise and approaches that informaticians have used extensively in the clinical arena. Examples include database organization and knowledge representation, data mining, and modeling and simulation. Microarray technology is discussed as a specific potential area for collaboration. Related questions concern how best to establish collaborations with bioscientists so that the interests and needs of both sets of researchers can be met in a synergistic fashion, and the most appropriate home for bioinformatics in an academic medical center.

Domain-constrained generation of clinical condition sets to help test computer-based clinical guidelines.

The paper describes T/Gen, a prototype computer-based tool designed to help maintain the knowledge in a computer-based clinical practice guideline that provides patient-specific recommendations. T/Gen takes as input a set of clinical conditions to which a guideline must react, and allows the user to specify domain-specific constraints as to which combinations of conditions do not make sense or do not need to be exhaustively tested against one another. T/Gen automatically generates constrained sets of combinations of clinical conditions, each corresponding to a clinical case (or to several closely related clinical cases) that can be used to help test the computer-based guideline. The combinations can be used to test the guideline logic using T/Gen's built-in logic interpreter, or to generate a set of test cases for use in testing an operational guideline system. T/Gen has been developed and tested with five pilot guidelines, for two childhood immunization series, for influenza vaccination, for primary thyroid screening, and for embryo transplantation. The paper describes how T/Gen's approach is implemented for the five pilot guidelines, outlines the current status and future directions of the project, and discusses the design issues that arose in the course of carrying out the work.

Trade-offs in producing patient-specific recommendations from a computer-based clinical guideline: a case study.

This case study explored 1) how much online clinical data is required to obtain patient-specific recommendations from a computer-based clinical practice guideline, 2) whether the availability of increasing amounts of online clinical data might allow a higher specificity of those recommendations, and 3) whether that increased specificity is necessarily desirable. The "quick reference guide" version of the guideline for acute postoperative pain management in adults, developed by the Agency for Health Care Policy and Research, was analyzed. Patient-specific data items that might be used to tailor the computer's output for a particular case were grouped into rough categories depending on how likely they were to be available online and how readily they might be determined from online clinical data. The patient-specific recommendations were analyzed to determine to what degree the amount of text produced depended on the online availability of different categories of data. An examination of example recommendations, however, illustrated that high specificity may not always be desirable. The study provides a concrete illustration of how the richness of online clinical data can affect patient-specific recommendations, and describes a number of related design trade-offs in converting a clinical guideline into an interactive, computer-based form.

Exploring the degree of concordance of coded and textual data in answering clinical queries from a clinical data repository.

OBJECTIVE: To query a clinical data repository (CDR) for answers to clinical questions to determine whether different types of fields (coded and free text) would yield confirmatory, complementary, or conflicting information and to discuss the issues involved in producing the discrepancies between the fields. METHODS: The appropriate data fields in a subset of a CDR (5,135 patient records) were searched for the answers to three questions related to surgical procedures. Each search included at least one coded data field and at least one free-text field. The identified free-text records were then searched manually to ensure correct interpretation. The fields were then compared to determine whether they agreed with each other, were supportive of each other, contained no entry (absence of data), or were contradictory. RESULTS: The degree of concordance varied greatly according to the field and the question asked. Some fields were not granular enough to answer the question. The free-text fields often gave an answer that was not definitive. Absence of data was most logically interpreted in some cases as lack of completion of data and in others as a negative answer. Even with a question as specific as which side a hernia was on, contradictory data were found in 5 to 8 percent of the records. CONCLUSIONS: Using the data in the CDR to answer clinical questions can yield significantly disparate results depending on the question and which data fields are searched. A database cannot just be queried in automated fashion and the results reported. Both coded and textual fields must be searched to obtain the fullest assessment. This can be expected to result in information that may be confirmatory, complementary, or conflicting. To yield the most accurate information possible, final answers to questions require human judgment and may require the gathering of additional information.

PathMaster: content-based cell image retrieval using automated feature extraction.

OBJECTIVE: Currently, when cytopathology images are archived, they are typically stored with a limited text-based description of their content. Such a description inherently fails to quantify the properties of an image and refers to an extremely small fraction of its information content. This paper describes a method for automatically indexing images of individual cells and their associated diagnoses by computationally derived cell descriptors. This methodology may serve to better index data contained in digital image databases, thereby enabling cytologists and pathologists to cross-reference cells of unknown etiology or nature. DESIGN: The indexing method, implemented in a program called PathMaster, uses a series of computer-based feature extraction routines. Descriptors of individual cell characteristics generated by these routines are employed as indexes of cell morphology, texture, color, and spatial orientation. MEASUREMENTS: The indexing fidelity of the program was tested after populating its database with images of 152 lymphocytes/lymphoma cells captured from lymph node touch preparations stained with hematoxylin and eosin. Images of "unknown" lymphoid cells, previously unprocessed, were then submitted for feature extraction and diagnostic cross-referencing analysis. RESULTS: PathMaster listed the correct diagnosis as its first differential in 94 percent of recognition trials. In the remaining 6 percent of trials, PathMaster listed the correct diagnosis within the first three "differentials." CONCLUSION: PathMaster is a pilot cell image indexing program/search engine that creates an indexed reference of images. Use of such a reference may provide assistance in the diagnostic/prognostic process by furnishing a prioritized list of possible identifications for a cell of uncertain etiology.

Lessons learned from a pilot implementation of the UMLS information sources map.

OBJECTIVE: To explore the software design issues involved in implementing an operational information sources map (ISM) knowledge base (KB) and system of navigational tools that can help medical users access network-based information sources relevant to a biomedical question. DESIGN: A pilot biomedical ISM KB and associated client-server software (ISM/Explorer) have been developed to help students, clinicians, researchers, and staff access network-based information sources, as part of the National Library of Medicine's (NLM) multi-institutional Unified Medical Language System (UMLS) project. The system allows the user to specify and constrain a search for a biomedical question of interest. The system then returns a list of sources matching the search. At this point the user may request 1) further information about a source, 2) that the list of sources be regrouped by different criteria to allow the user to get a better overall appreciation of the set of retrieved sources as a whole, or 3) automatic connection to a source. RESULTS: The pilot system operates in client-server mode and currently contains coded information for 121 sources. It is in routine use from approximately 40 workstations at the Yale School of Medicine. The lessons that have been learned are that: 1) it is important to make access to different versions of a source as seamless as possible, 2) achieving seamless, cross-platform access to heterogeneous sources is difficult, 3) significant differences exist between coding the subject content of an electronic information resource versus that of an article or a book, 4) customizing the ISM to multiple institutions entails significant complexities, and 5) there are many design trade-offs between specifying searches and viewing sets of retrieved sources that must be taken into consideration. CONCLUSION: An ISM KB and navigational tools have been constructed. In the process, much has been learned about the complexities of development and evaluation in this new environment, which are different from those for Gopher, wide area information servers (WAIS), World-Wide-Web (WWW), and MOSAIC resources.

Portability issues for a structured clinical vocabulary: mapping from Yale to the Columbia medical entities dictionary.

OBJECTIVE: To examine the issues involved in mapping an existing structured controlled vocabulary, the Medical Entities Dictionary (MED) developed at Columbia University, to an institutional vocabulary, the laboratory and pharmacy vocabularies of the Yale New Haven Medical Center. DESIGN: 200 Yale pharmacy terms and 200 Yale laboratory terms were randomly selected from database files containing all of the Yale laboratory and pharmacy terms. These 400 terms were then mapped to the MED in three phases: mapping terms, mapping relationships between terms, and mapping attributes that modify terms. RESULTS: 73% of the Yale pharmacy terms mapped to MED terms. 49% of the Yale laboratory terms mapped to MED terms. After certain obsolete and otherwise inappropriate laboratory terms were eliminated, the latter rate improved to 59%. 23% of the unmatched Yale laboratory terms failed to match because of differences in granularity with MED terms. The Yale and MED pharmacy terms share 12 of 30 distinct attributes. The Yale and MED laboratory terms share 14 of 23 distinct attributes. CONCLUSION: The mapping of an institutional vocabulary to a structured controlled vocabulary requires that the mapping be performed at the level of terms, relationships, and attributes. The mapping process revealed the importance of standardization of local vocabulary subsets, standardization of attribute representation, and term granularity.