An encyclopedia of mouse genes.

The laboratory mouse is the premier model system for studies of mammalian development due to the powerful classical genetic analysis possible (see also the Jackson Laboratory web site, http://www.jax.org/) and the ever-expanding collection of molecular tools. To enhance the utility of the mouse system, we initiated a program to generate a large database of expressed sequence tags (ESTs) that can provide rapid access to genes. Of particular significance was the possibility that cDNA libraries could be prepared from very early stages of development, a situation unrealized in human EST projects. We report here the development of a comprehensive database of ESTs for the mouse. The project, initiated in March 1996, has focused on 5' end sequences from directionally cloned, oligo-dT primed cDNA libraries. As of 23 October 1998, 352,040 sequences had been generated, annotated and deposited in dbEST, where they comprised 93% of the total ESTs available for mouse. EST data are versatile and have been applied to gene identification, comparative sequence analysis, comparative gene mapping and candidate disease gene identification, genome sequence annotation, microarray development and the development of gene-based map resources.

[Rehabilitee-management-categories (RMK)--results of the development phase and of the first clinical implementation in alcohol rehabilitation centres]. / Rehabilitanden-Management-Kategorien (RMK)--Entwicklungsprozess und ausgewählte Ergebnisse am Beispiel der Suchtrehabilitation.

BACKGROUND: Due to the introduction of lump sum reimbursement systems for acute-care settings (DRGs), patient classification systems have been developed in Germany during the last 15 years to adapt a case-based lump sum system to the field of medical rehabilitation. The concept of Rehabilitee-Management-Categories (RMK), developed by the Charité - Universitätsmedizin Berlin, classifies rehabilitees primarily by their relevant impairments of activity and participation, as these factors mainly determine treatment needs and resources required in rehabilitation. It can, inter alia, be used to optimize the demand-related allocation of treatment services in the rehabilitation centres as well as lead to more transparency in the allocation process. RMK results are reported on the example of inpatient rehabilitation of alcohol dependence. METHODS: Utilizing internationally established assessments, an RMK-assessment was developed that allows the assessment of rehab treatment needs of patients undergoing alcohol dependence rehabilitation. The RMK-assessment was completed by n=731 rehabilitees. Latent class analysis was applied to find groups of cases. To facilitate the RMK-patient classification a software-based algorithm was developed and implemented in 12 rehabilitation centres (implementation study). To validate the results of the first study phase, the data collected during implementation (n=1,533) was again analyzed using latent class analysis. Combined standardized and qualitative user surveys were conducted at the end of the implementation study. RESULTS: On the basis of 15 needs-related patient characteristics, 4 comparable case groups (AL-1 to AL-4) each were identified in 2 independent samples, groups that differed significantly in their degree of dependence-related, psychological and social impairment. The user survey confirmed the basic clinical plausibility of the 4 different case groups as well as the feasibility of the instruments applied in a rehabilitation setting. CONCLUSIONS: The RMK-concept offers a new approach for a demand-related patient classification in medical rehabilitation. The RMK-instruments allow a standardized initial assessment of impairment and treatment needs in alcohol rehabilitation and can hence be used for objective comparisons between rehabilitation centres. The results of the RMK-assessment provide relevant information about demand-related treatment requirements, which is a matter of great interest in the context of limited resources. Appropriate treatment requirements for the 4 RMK-case groups will be defined and verified in the next step of the RMK-concept. A financial evaluation of the RMK is possible in principal, will however require more extensive development, not least in order to model and evaluate the health-economic implications involved.

Study on the antimicrobial effect of silver-containing inner liners in refrigerators.

AIMS: To investigate the effect of silver-based antimicrobial material incorporated in the inner liners of refrigerators on food safety and quality. METHODS AND RESULTS: In the first stage, the bactericidal effect was tested in the laboratory. Silver-containing samples and control plates were inoculated with different bacterial suspensions and stored at various temperatures. After defined storage periods the bacterial reduction was calculated by comparing viable cell count on reference plates and on silver-containing plates. The reduction caused by the silver-containing material varied between 1.0 and 5.9 log(10) units, depending on bacterial strain, incubation time and temperature. In the second stage, food storage experiments have been carried out. Thus, perishable foods were stored in coated and untreated refrigerators. After certain time periods the products were analysed for their sensorial and microbiological characteristics. A clear drop in viable counts both on the refrigerator wall and on the food was demonstrated using the silver-based antimicrobial material. CONCLUSIONS: Silver prevents refrigerators from being a hot spot for contaminants that could be transferred upon contact with food. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides original results regarding the antimicrobial activity of silver-containing refrigerator surfaces.

Chest dynamics asymmetry facilitates earlier detection of pneumothorax.

Pneumothorax is usually diagnosed when signs of life-threatening tension pneumothorax develop. The case report describes novel data derived from miniature superficial sensors that continuously monitored the amplitude and symmetry of the chest wall tidal displacement (TDi) in a premature infant that suffered from pneumothorax. Off-line analysis of the TDi revealed slowly progressing asymmetric ventilation that could be detected 38 min before the diagnosis was made. The TDi provides novel and valuable information that can assist in early detection and decision making.

Monitoring the respiratory rate by miniature motion sensors in premature infants: a comparative study.

OBJECTIVE: Existing respiratory rate (RR) monitors suffer from inaccuracy. The study assesses the accuracy of a novel modality that monitors lung ventilation with miniature motion sensors. STUDY DESIGN: RR was measured by three methods: impedance technology, motion sensors and visual count, in babies (n=9) that breathed spontaneously or with respiratory support and babies (n=12) that received high-frequency oscillatory ventilation (HFOV). RESULTS: A line close to equality (slope=0.96, r(2)=0.83) was obtained between the motion sensor and the visual count of the RR with narrow 95% limits of agreements (<14.0 b.p.m.). The relationship between the impedance and the visual count showed a lower correlation (r(2)=0.65) and wider 95% limits of agreements (21.4 b.p.m.). The motion sensor- and the ventilator-determined RRs demonstrated a good agreement during HFOV, whereas the impedance failed to measure the RR during HFOV. CONCLUSION: Monitoring RR with motion sensors is more accurate compared with the impedance, in infants, in all ventilation modes.

The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation.

The vesiculo-vacuolar organelle (VVO) is a recently described organelle found in the cytoplasm of endothelial cells that line tumor microvessels and normal venules. VVOs are grape-like clusters of interconnecting uncoated vesicles and vacuoles, bounded by trilaminar unit membranes, that span the entire thickness of vascular endothelium, thereby providing a potential trans-endothelial connection between the vascular lumen and the extravascular space. Macromolecular tracers preferentially cross hyperpermeable tumor microvessels through VVOs. The present investigation was undertaken to elucidate further the ultrastructure and function of VVOs in a murine ovarian carcinoma (MOT) and in normal venules. Morphometry revealed that VVOs were enormous cytoplasmic structures (median area, 0.12-0.14 microns2 in single electron micrographs). Moreover, the individual vesicles and vacuoles that comprised VVOs were on average substantially larger than capillary caveolae and followed a non-normal distribution that was skewed to the right. Specimen tilting provided conclusive evidence that individual VVO vesicles and vacuoles communicated with each other and with the endothelial cells' plasma membranes by stomata, some of which were closed by diaphragms composed of a single membrane. Studies with two tracers, ferritin (FE, diameter approximately 11 nm) and horseradish peroxidase (HRP, diameter approximately 5 nm), revealed that passage of macromolecules through VVOs was regulated at the level of stomatal diaphragms, thereby demonstrating a mechanism for controlling the passage of macromolecules across endothelial cells. Thus, compared with tumor microvessels, little circulating FE and HRP entered the VVOs of normal venular endothelium because stomata joining vesicles and vacuoles to each other and to the lumen and ablumen were closed. VVOs and their component vesicles/vacuoles were readily distinguished from endosomal organelles such as coated vesicles and multivesicular bodies, which also accumulated FE and HRP. Our findings indicate that VVOs provide a major pathway for the extravasation of circulating macromolecules across endothelia taller than capillary endothelium and suggest that upregulated VVO function accounts for the well-known hyperpermeability of tumor blood vessels.

Impaired spelling in Alzheimer's disease: a linguistic deficit?

Different kinds of real words and pronounceable pseudowords (PWs) were presented for writing to dictation to patients with the diagnosis of probable Alzheimer's disease (AD) and to age- and education-matched healthy controls. Though spelling less accurately on all tasks, AD patients responded in a manner generally qualitatively similar to controls. Except for a slightly enhanced effect of spelling regularity in real word writing accuracy, AD patients showed the same sensitivity to various lexical, orthographic and phonological variables as controls. Both groups showed no difference in spelling accuracy for words and PWs with regular vs ambiguous spelling patterns, and groups also showed similar orthographic preferences when spelling PWs having several different acceptable pronunciations. Finally, AD patients and controls produced similar types of errors when spelling real words. Dementia severity was related to the overall accuracy, but not to the pattern, of spelling responses. It is suggested that the decline in response accuracy in cognitively demanding writing tasks in patients with more advanced dementia is most likely due to semantic impairment and impairments of nonlinguistic functions of attention, executive control and praxis, rather than to a disturbance within language specific processes.

Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome.

The Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by: (1) at least a single sebaceous gland tumor (either an adenoma, an epithelioma, or a carcinoma) and (2) a minimum of one internal malignancy. To date, 120 patients with MTS have been reported. The most commonly associated neoplasms were colorectal (51%) and genitourinary (25%). Unlike colorectal neoplasms in the general population, the majority (58%) of these tumors in MTS patients occurred proximal to or at the splenic flexure. Nearly half of the MTS patients had more than one primary malignancy. Cutaneous lesions occurred before or concurrent with the diagnosis of the initial cancer in 41% of these patients. The median age for the appearance of the skin lesions was 53 years (range, 23 to 89 years); the median age for the detection of the initial visceral neoplasm was 50 years (range, 23 to 81 years). The cancers appear to have an indolent course in many of the MTS patients; the median survival has not been reached and the median follow-up is 10+ years. Patients with an MTS-associated cutaneous lesion should have a complete evaluation for gastrointestinal or genitourinary cancers. Although the penetrance of this disease is variable, its autosomal dominant inheritance suggests that relatives should be examined for sebaceous gland tumors and internal malignancy.

Radiofrequency hyperthermia: the design of coil transducers for local heating.

Simple and complex coils have been designed and built for use as radiofrequency transducers for local and regional hyperthermia. The heating from such coils is produced by currents generated in the dielectric by the electromagnetic field radiated from the coil elements. The heating rate profile, as a function of phantom depth, is dependent upon the size and geometry of the coil, its proximity to the dielectric, and the transducer current. Since the fields of simple pancake coils are inhomogeneous, either complex geometries or some method of smoothing is required. A simple solution is to move the coil over the region to be heated or to use multiple applicators. However, many satisfactory heating patterns have been derived for stationary coils designed to heat well-defined subcutaneous volumes to a depth of 3-5 cm. Thermometry studies in static saline-gelatin phantoms demonstrate extensive heating ranges and flexibility since the coils couple with the dielectric through air.

The blood-tissue barrier of human brain tumors: correlation of scintigraphic and ultrastructural findings: concise communication.

Through the first 2 hr, uptake of [Tc-99m]pertechnetate and of Co-57 bleomycin were assessed in 29 brain tumors and were correlated with the ultrastructure of the tumor's capillary endothelium. No difference in uptake was found between the two tracers. Permeability of brain tumors to these agents was found to be governed by the same ultrastructural features that determine permeability in experimental brain tumors: the type of junction between contiguous endothelial cells in the capillaries. Meningiomas, which showed very high uptake of the radiotracers, demonstrated open or punctate junctions with short fusion of apposed membranes. They also showed a large number of pinocytotic vesicles and fenestrae. Capillaries of tumors without uptake had a small number of short tight junctions (less than 0.25 mu) between adjacent endothelial cells and a relatively large number of long junctions (greater than 0.5 mu). In intracerebral tumors that showed relatively high uptake, the reverse was true: most of the junctions were short and only a few long junctions were found. That uptake of [Tc-99m]pertechnetate and of Co-57 bleomycin depends on tumor capillary ultrastructure (which determines the permeability) suggests the possibility of the use of radiopharmaceuticals as in vivo indicators of tumor permeability. Brain scintigraphy may help to asses brain-tumor availability to non-lipid-soluble chemotherapeutic drugs.

A method for the measurement of fibrinolytic activity based on one dimensional diffusion using small glass tubes. II. With special reference to the differences between the use of plasminogen-rich fibrinogen and that of plasminogen-free fibrinogen as the substrates.

The optimal conditions for the measurement of the fibrinolytic factors of plasma were examined using human and bovine plasminogen-rich fibrinogen or plasminogen-free fibrinogen as the substrates using the one dimensional diffusion method. The results were as follows: 1. There was no essential difference found between using human or bovine fibrinogen. 2. The levels of proactivator-plasminogen and plasminogen could be measured while using either plasminogen-rich or plasminogen-free fibrinogen. But, in using the latter, the proactivator-plasminogen level could not be measured, if a final concentration of more than 2,000 Christensen units of streptokinase were employed. 3. When using plasminogen-rich fibrinogen, anti-plasmin(s) and anti-activator(s) could be measured while using urokinase and plasmin, but not while using streptokinase. However, further study should be given to the measurement of the inhibitors, when using plasminogen-free fibrinogen.

The interaction between heparin and plasmin on amidolysis.

The effect of the interaction between heparin and plasmin not only on fibrinolytic, caseinolytic and esterolytic activities but also on amidolytic activity, since plasmin has amidolytic or amidase activity, was investigated. Following were the results obtained from these investigations: 1. Heparin enhanced amidolytic activity of a fixed level of plasmin which was prepared by activating plasminogen with urokinase within the range from 2 to 64 units/ml of the final concentration of heparin. 2. Heparin also enhanced amidolytic activity of a fixed level of plasmin which was prepared by converting plasminogen with insolubilized urokinase. 3. Heparin did not enhance or inhibit fibrinolytic, caseinolytic and esterolytic activities of a fixed level of plasmin which was prepared by activating plasminogen with urokinase, in the fibrinolytic activity within the range from 0.032 to 125 units/ml, in the caseinolytic activity within the range from 0.0125 to 100 units/ml, and in the esterolytic activity within the range from 0.016 to 128 units/ml, of the final concentration of heparin respectively.

Randomized, controlled trial comparing once daily and three times daily gentamicin in children with urinary tract infections.

OBJECTIVE: To undertake population pharmacokinetic modeling and to determine the safety and efficacy of once daily (OD) gentamicin dosing in children with severe urinary tract infections (UTI). METHODS: An open, randomized, controlled trial comparing OD with three times daily (TD) gentamicin dosing in hospitalized children ages 1 month to 12 years with UTI. Daily doses (milligrams per kg per day) of gentamicin in both groups were 7.5 (<5 years old), 6.0 (5 to 10 years old) and 4.5 (>10 years old). RESULTS: There were 179 children enrolled (90 OD, 89 TD). Baseline clinical characteristics and pathogens were similar, except that circulatory compromise and renal cortical scintigraphic defects were more common in the OD group. Median gentamicin treatment durations were 3.0 (OD) and 2.7 (TD) days. Mean peak gentamicin concentrations were 17.3 (OD) vs. 6.4 (TD) mg/l; 99% of peak concentrations were >7 mg/l in the OD group whereas 16% of peak concentrations were <5 mg/l in the TD group. Mean trough concentrations were 0.35 (OD) vs. 0.55 (TD) mg/l. In the OD group 4% of trough concentrations were > or = 2 mg/l, whereas in the TD group only 0.7% were > or = 2 mg/l. Age or prior elevated peak concentrations did not predict high trough concentrations. Population pharmacokinetic modeling of the data fitted a one-compartment model with first order elimination. There were no clinical or bacteriologic failures. The two disease-related complications were confined to the OD group. No nephro- or ototoxicity was identified. CONCLUSIONS: With age-appropriate dosing and measurement of serum trough concentrations before the second dose, OD gentamicin is safe and effective for the treatment of UTI requiring parenteral treatment in children aged 1 month to 12 years.

Epidermal Langerhans' cells in Behçet's disease.

Langerhans' cells were studied in the epidermis of two patients with active Behçet's disease and compared with those in two normal controls. Ultrastructural morphology and the percentage of Langerhans' cells found were similar in patients' (1.88%) and the control epidermis (1.79%). The density of Langerhans' cells in adjacent sites of the same epidermis was not homogeneous, being in the range of 0.8-2.8% in Behçet's disease and 0.6-4% in the controls. In the controls, Langerhans' cells were distributed unevenly. Some were located near the basal layer of the epidermis while the rest were in the mid and upper layers. In Behçet's disease most Langerhans' cells were in the mid-epidermis, but some were immediately beneath the stratum granulosum. In the Behçet's disease epidermis the area occupied by Langerhans' cells was increased by about 25% and the number of granules found increased by about 44%. It is suggested that in Behçet's disease the Langerhans' cells are in a more active state.

Rapid dose calculations for stereotactic radiosurgery.

A three-dimensional dose calculation algorithm is described for stereotactic radiosurgery using multiple noncoplanar beam arcs. Precalculated dose libraries of 20-deg arc segments, or mini arcs, are stored in computer memory which permits rapid calculation of complete, high resolution, three-dimensional isodose distributions and dose volume histograms. Three-dimensional patient contours and target volumes are obtained from CT scans and angiographic x rays. Rapid dose calculations are made possible by the use of arc libraries and an improved algorithm for mapping beam doses to the dose calculation grid. This permits more flexibility in designing optimum treatment plans, as five-six complete plans can be generated in less than 1 h. Thus many possible treatment options can be tested in the 3-4-h time period typically available in stereotactic procedures between CT scanning and treatment.

Lexical-phonological processing of functors: evidence from fluent aphasia.

The purpose of this study was to investigate how functors are processed at the lexical-phonological level. Four fluent aphasics with impaired ability to fully activate entries in the phonological lexicon, as revealed by their noun production, were asked to repeat and read aloud individual functors. Similarities between their functor and noun production (e.g., level of performance, production of phonological errors) indicated that functors are stored along with content words in the phonological lexicon, and are stored with a similar abstract structure. We also considered whether the sentence-planning system can facilitate the phonological encoding of functors presented in isolation.

The relationship between oral spelling and phonological breakdown in a conduction aphasic.

Unsolicited oral spelling has been observed in conduction aphasics during word-production difficulty (Kohn, 1985), but has never been examined systematically. In the present study, the possible role of oral spelling in the word-production process of a conduction aphasic (JM) is explored. Oral spelling occurred much more frequently during picture naming than during either oral reading or repetition, and it seemed to be operating as a strategy to lessen the phonemic output deficit often observed in this syndrome.

Consonant harmony as a compensatory mechanism in fluent aphasic speech.

This study addresses how fluent aphasics construct complete phonological representations, given the premise that their phonological speech errors result from faulty information about stored lexical representations. We explored whether consonant harmony, a common rule-governed process of feature copying, operates as a compensatory device for completing phonological representations in fluent aphasia. This was examined in a corpus of phonemic paraphasias (n = 543) produced by 8 fluent aphasics during picture naming. Consonant substitutions due to a single feature change (n = 143) were analyzed for the properties of consonant harmony predicted by the phonological principles embodied in a Universal Markedness version of Underspecification Theory (e.g., Chomsky and Halle, 1968). Results indicated that harmony constrained the feature substitution errors involving the feature class of voice (e.g., calendar-->/[symbol: see text]/), but not place of articulation (e.g., igloo-->/idlu/); substitutions due to an error in manner were rare. These findings were used to argue that for English-speaking fluent aphasics a consonant harmony rule for the feature voice is incorporated into a compensatory output mechanism that is used to complete faulty lexical-phonological representations.

Verb finding in aphasia.

Word finding for nouns and verbs was examined in a heterogeneous group of aphasics (N = 9) by comparing the ability to generate synonyms and sentences for the same set of 20 nouns and 20 verbs. Synonym Generation performance resembled that of an age-matched group of normal control subjects (n = 9): In both groups, some subjects produced comparable numbers of synonyms for nouns and verbs while other subjects produced significantly fewer synonyms for verbs. Essentially the same two patterns were displayed on Sentence Generation using the frequency of "empty" nouns (e.g., 'it', 'man') and "empty" verbs (e.g., 'is', 'do') as an index of word-finding difficulty: In both groups, some subjects produced comparable numbers of empty nouns and verbs, while other subjects produced significantly more empty verbs. However, the Sentence Generation performance of one aphasic subject stood out overall by her tendency to avoid empty verbs and produce incomplete sentences. This pattern of performance was interpreted as a breakdown in an early stage of sentence planning that may be directly related to her diagnosis of transcortical motor aphasia.

Repetition of single words and nonwords in Alzheimer's disease.

Repetition of single words and pronounceable nonwords (pseudowords) was assessed in Alzheimer's Disease (AD) patients to evaluate how lexical phonological processing might be accomplished when semantic and conceptual knowledge is impaired. AD patients performed significantly worse than healthy elderly controls on all repetition tasks. However, repetition abilities and dementia severity were not correlated, and AD patients produced the same distribution of error types as controls. Furthermore, despite their semantic problems, AD patients, like controls, showed a significant advantage for repeating real words compared to pseudowords, even when repeating low frequency phonologically complex words whose meaning is not likely to have been retained. The results support the postulated existence of a lexical phonological system that is used to repeat both known and novel words and that processes linguistic information independent of its meaning.