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PubMed2001

Application of virtual microscopy in clinical cytopathology.

Virtual microscopy (VM) refers to the use of an automated microscope and digital imaging technology to scan, store, and view glass slides. VM systems allow the user to view a scanned image of the entire slide at multiple magnifications on a computer screen. We tested VM to evaluate its possible utility in diagnostic cytopathology. Ten cervical-vaginal monolayered preparations (AutoCyte preparation) were scanned using a BLISS (Bacus Laboratories Inc. Slide Scanner) system. Approximately 20-30% of the cellular area of each slide was imaged. The cases were randomly chosen to include examples ranging from benign cellular changes (BCC) to high-grade squamous intraepithelial lesions (HSIL). The computer performed image tiling and fusing of multiple JPEG images to create a high-quality VM slide. Six examiners (two each of cytopathologists, senior residents, and cytotechnologists) blindly evaluated the VM slides using an image server program (WebSlide Browser thin client software). The cytopathologic diagnoses made on the VM slide were then compared to the original glass slide diagnoses. BLISS took 36-100 min (avg. 58.4 min) to scan the selected fields in a glass slide with file sizes ranging from 23.1-83.6 MB. Time taken by the examiners to render a diagnosis ranged from 1-15 min (avg. 4.1 min) per case. The combined diagnostic accuracy was 98.3%. Only one case of LSIL was missed by one examiner. VM is a promising new tool, which gives a user the feel and simulated experience of an actual microscopic examination and provides a useful alternative to a glass slide in diagnostic cytopathology. Possible applications include: 1) second opinion consultation without transporting the glass slide, 2) education, 3) VM proficiency tests / board exams, and 4) telepathology. Shortcomings include 1) expensive initial setup, 2) inability to maintain an adequate focus in a thick smear with multiple levels, 3) large storage size of the VM slide, and 4) relatively long time needed to scan a slide.

Female↗
PubMed1994

Evaluation of the role of exogenous pathogens on the incidence of embryo loss during early pregnancy in mice.

The mating of CBA/j female mice (H2k) by DBA/2j male mice (H2d) typically results in an elevated incidence of spontaneous embryo loss thus providing an ideal genetically controlled laboratory model for the study of the factors causing early embryo loss during pregnancy. There is now considerable data on the cells and factors involved in fetal resorption but little is known about the events which activate this process. While the activation of the maternal response to the fetal implant could have endogenous or genetic origins, a role for exogenous factors including microbial pathogens could also be involved. In order to investigate these possibilities, the reproductive success of CBA/j female x DBA/2j male matings in a conventional animal care facility were compared with matings in a specific pathogen free (SPF) animal facility. All animals housed under these conditions were routinely screened by immunoassay and culture, for the presence of a number of viral and bacterial pathogens of mice. The incidence of spontaneous embryo loss in specific pathogen free CBA female mice mated by DBA and other male strains was found to be virtually identical to that of CBA female mice infected with multiple viral pathogens and housed under otherwise identical conditions (non-SPF). However, the numbers of implantation per pregnancy was significantly greater in an SPF facility. Therefore, exposure of mating mice to exogenous viral and bacterial pathogens did not appear to alter the overall incidence of spontaneous embryo resorption. It was concluded that the immunomodulatory effects of infection by common murine pathogens neither augmented nor reduced post-implantation embryo losses.

Abortion, Veterinary↗
PubMed2026

Functional screening and single-cell cultivation of marine CO2-fixing bacteria via flow-mode Raman-activated cell sorting.

Most marine CO2-fixing microorganisms remain uncultivated due to strong culture bias and low throughput of conventional approaches, which fail to link in situ function with isolated strains and render slow-growing or low-abundance taxa virtually inaccessible. This study presents an integrated single-cell workflow that incorporates 13C-NaHCO3 labeling, high-throughput flow-mode Raman-activated cell sorting (RACS) and microwell cultivation for the isolation of active CO2-fixing bacteria from the Yellow Sea. Function-guided sorting was achieved by monitoring the 13C-induced Raman shifts of carotenoids (ν1 band: ∼1507 to ∼ 1503.78 cm-1 at 24 h). Genomic and physiological analyses identified Paraburkholderia aromaticivorans FR-4 as a novel facultative chemoautotrophic nitrite-oxidizing bacterium (NOB). Its genome encodes complete nitrite oxidation and Calvin cycle pathways, together with key carbon acquisition genes (carbonic anhydrase, bicarbonate transporter). FR-4 grows autotrophically using NO2- as the electron donor and CO2/HCO3- as the carbon source, confirming its ability to couple nitrite oxidation with carbon fixation, while retaining metabolic flexibility for heterotrophic growth. By directly linking in situ carbon-fixing activity, genotype, and phenotype, this workflow provides a targeted strategy for exploring elusive marine CO2-fixing bacteria and overcomes critical limitations of conventional cultivation.

Carbon-fixing↗
PubMed2004

Identification, genetic diversity and prevalence of Theileria and Babesia species in a sheep population from Northern Spain.

The genetic diversity and prevalence of virtually all Theileria and Babesia species in a sheep population were studied using a specifically designed reverse line blot macroarray. The amplified hypervariable V4 region of the 18S rRNA gene was hybridised against generic and species-specific probes. In a first screening (Study I), 320 apparently healthy animals corresponding to 32 flocks located in the Basque Country (Northern Spain) were analysed. The survey demonstrated a high prevalence of subclinical infections (64.7%). Three Theileria genotypes were identified, sharing 96.7-97.0% similarity between their 18S rRNA gene sequences: Theileria ovis, Theileria sp. OT1 (99.6% similarity with the recently described pathogenic piroplasm Theileria sp. China 1), and Theileria sp. OT3. Two Babesia species sharing 91.5% similarity were also detected: Babesia ovis and Babesia motasi. The complete 18S rRNA gene sequences of these and other piroplasm species were phylogenetically analysed. Prevalence of piroplasms was also investigated in a second group of 80 sheep from 16 flocks reared in mountain areas that had been heavily exposed to ticks and had suffered a recent abortion episode (Study II). The screening revealed a significantly higher (P < 0.05) prevalence (78.7%) of piroplasm infections compared to Study I. Although the prevalence rates for some piroplasm species were significantly related to abortion (e.g. Theileria sp. OT3), decreases in the red cell parameters were not significant. The widespread distribution of Theileria spp. in the studied sheep population suggests that the parasites involved are of relatively low pathogenicity, in contrast to what has been reported for Theileria sp. China 1 in other countries.

Animals↗
PubMedDate not supplied

Effect of pH on infectivity and morphology of ecotropic moloney murine leukemia virus.

A number of factors affect the infectivity of retroviruses. The effect of pH on infectivity and morphology of ecotropic moloney murine leukemia virus (MoMuLV) was determined in this work. The ecotropic MoMuLVs were found to remain infectious at a narrow pH range from 5.5 to 8.0. Our experiments indicated that the viruses were inactivated swiftly at lower or higher pH. Within 5 min of exposure to pH 4 about 95% of the viruses lost infectiousness. The viruses were completely inactivated after exposure to pH < 3 or pH >11 for 5 min. The inactivation of MoMuLV was irreversible. Electron microscopy revealed that ecotropic MoMuLV remained round-shaped at pH between 7.0 and 5. They became irregular with a convex head at pH < 4. At pH 2, virtually all virion particles were penetrated by stains, causing the accumulation of heavy metals inside the particles. The penetration of heavy metal inside the particles indicated the disassociation of the lipid bilayer of the viruses at low pH. A FACS-based screening strategy for selecting high-titer retrovirus producing cell lines is also presented in this report.

3T3 Cells↗
PubMed2003

Differential proteomic analysis of the mouse retina: the induction of crystallin proteins by retinal degeneration in the rd1 mouse.

We have applied proteomic analysis to the degeneration of photoreceptors. In the rd1 mouse, a recessive mutation in the PDE6B gene leads to rapid loss of rods through apoptosis. By 5 wk postnatal, virtually all rod photoreceptors have degenerated, leaving one row of cones that degenerates secondarily. In order to assess comparative protein expression, proteins extracted from whole retina were resolved on a two-dimensional gel and identified by mass spectrometry combined with database screening. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry coupled to peptide mass fingerprinting was sufficient to identify most of the proteins, the remaining being identified with additional sequence information obtained by nano-electrospray ionization tandem mass spectrometry or liquid chromatography tandem mass spectrometry. The study revealed 212 spots, grouped into 109 different proteins. Differential analysis showed loss of proteins involved in the rod-specific phototransduction cascade, as well as induction of proteins from the crystallin family, in response to retinal degeneration. Identification of such pathways may contribute to new therapeutic approaches.

Amino Acid Sequence↗
PubMed2006

The expression of pituitary gland genes in laying geese.

The purpose of this study was to detect differential expression of genes in the pituitary gland in laying geese by suppression subtractive hybridization (SSH). Pituitary glands from prelaying and laying geese were dissected for mRNA extraction. The cDNA from pituitary glands of prelaying geese was subtracted from the cDNA from the pituitary glands of laying geese (forward subtraction); the reverse subtraction was also performed. We screened 384 clones with possible differentially expressed gene fragments by differential screening. Sixty-five clones from the differential screening results were subjected to gene sequencing and further analysis. We found that at least 19 genes were highly expressed in the pituitary glands of laying geese compared with prelaying geese. Among these, 6 genes (including 4 novel genes) were confirmed by virtual Northern analysis. We found that prolactin and visinin-like protein were highly expressed in the pituitary glands of laying geese compared with prelaying geese (P < 0.05). Further investigation is needed to demonstrate specific functions of the novel genes discovered in the current study.

Animals↗
PubMed1981

Hyperparathyroidism in the elderly.

A survey was made on the records of 40 patients aged 60 or older who were operated on at Boston University Medical Center over a 10-year period for suspected primary hyperparathyroidism. Mild or "asymptomatic" presentation was virtually the rule, with many patients having become accustomed to some degree of decreased well-being. The findings were compared with those in other reviews of the clinical manifestations of hyperparathyroidism, in both general and elderly populations of patients. Issues of screening for mild or asymptomatic disease, especially among the elderly, are discussed.

Aged↗
PubMed2005

Colonization of Bacillus spp. on seeds and in plant rhizoplane.

Seed coating, dipping and Scanning Electron Microscopy (SEM) were employed to study bacterial and fungal colonization of the seeds and rhizoplane of maize (Zea mays L.) during the early stages of growth. Isolation of Bacillus spp. entailed screening soil bacteria with potential growth stimulation and plant pathogen suppressive abilities isolated from the rhizospheres and rhizoplanes of vegetable crops. The bacterial colonization of the spermosphere was 90%. When the coated seeds were fully germinated, bacteria moved to the emerging radicle. Virtually no bacteria occurred on the root tip both for the treated and untreated. However, colonization was 20% in the basal portion of the roots close to the seed-root junction. SEM observations showed that the bacterial cells were arranged linearly and laterally on the growing root axis. This phenomenon was more noticeable in the seedlings dipped in the bacterial culture on the 3rd day after germination. The results indicate that attachment to the seed coat and the rhizoplane by the plant growth-promoting rhizobacterium (PGPR) is an important factor in the successful colonization of the rhizoplane. The significance of the work is to ascertain that the inoculated Bacillus spp. adhered to and established in the rhizoplane of maize. It can therefore be used as a PGPR and as a biocontrol agent.

Bacillus↗
PubMed2005

Segmented crystalline scintillators: an initial investigation of high quantum efficiency detectors for megavoltage x-ray imaging.

Electronic portal imaging devices (EPIDs) based on indirect detection, active matrix flat panel imagers (AMFPIs) have become the technology of choice for geometric verification of patient localization and dose delivery in external beam radiotherapy. However, current AMFPI EPIDs, which are based on powdered-phosphor screens, make use of only approximately 2% of the incident radiation, thus severely limiting their imaging performance as quantified by the detective quantum efficiency (DQE) (approximately 1%, compared to approximately 75% for kilovoltage AMFPIs). With the rapidly increasing adoption of image-guided techniques in virtually every aspect of radiotherapy, there exist strong incentives to develop high-DQE megavoltage x-ray imagers, capable of providing soft-tissue contrast at very low doses in megavoltage tomographic and, potentially, projection imaging. In this work we present a systematic theoretical and preliminary empirical evaluation of a promising, high-quantum-efficiency, megavoltage x-ray detector design based on a two-dimensional matrix of thick, optically isolated, crystalline scintillator elements. The detector is coupled with an indirect detection-based active matrix array, with the center-to-center spacing of the crystalline elements chosen to match the pitch of the underlying array pixels. Such a design enables the utilization of a significantly larger fraction of the incident radiation (up to 80% for a 6 MV beam), through increases in the thickness of the crystalline elements, without loss of spatial resolution due to the spread of optical photons. Radiation damage studies were performed on test samples of two candidate scintillator materials, CsI(Tl) and BGO, under conditions relevant to radiotherapy imaging. A detailed Monte Carlo-based study was performed in order to examine the signal, spatial spreading, and noise properties of the absorbed energy for several segmented detector configurations. Parameters studied included scintillator material, septal wall material, detector thickness, and the thickness of the septal walls. The results of the Monte Carlo simulations were used to estimate the upper limits of the modulation transfer function, noise power spectrum and the DQE for a select number of configurations. An exploratory, small-area prototype segmented detector was fabricated by infusing crystalline CsI(Tl) in a 2 mm thick tungsten matrix, and the signal response was measured under radiotherapy imaging conditions. Results from the radiation damage studies showed that both CsI(Tl) and BGO exhibited less than approximately 15% reduction in light output after 2500 cGy equivalent dose. The prototype CsI(Tl) segmented detector exhibited high uniformity, but a lower-than-expected magnitude of signal response. Finally, results from Monte Carlo studies strongly indicate that high scintillator-fill-factor configurations, incorporating high-density scintillator and septal wall materials, could achieve up to 50 times higher DQE compared to current AMFPI EPIDs.

Computer Simulation↗
PubMed2002

Screening for colorectal cancer: the cost to find an advanced adenoma.

OBJECTIVE: Cancer Care Ontario has recommended a program to screen for colorectal cancer using fecal occult blood testing (FOBT). Patients who test positive on FOBT will require further investigation. We examined the cost of finding an advanced adenoma in these patients using four different strategies. METHODS: Using decision analysis software (DATA 3.5, TreeAge Software, Boston, MA), we considered four strategies for evaluating patients referred for a positive FOBT: 1) flexible sigmoidoscopy to the splenic flexure, 2) flexible sigmoidoscopy with air contrast barium enema (ACBE), 3) virtual colonoscopy, and 4) colonoscopy. If an adenoma was found in any of the first three methods, colonoscopy and polypectomy were performed. An advanced adenoma was defined as a villous adenoma, tubular adenoma > or = 10 mm, high grade dysplasia, or cancer. Values for probabilities, test characteristics and costs ($CDN) were estimated from a MEDLINE literature review, local costs, and OHIP fee codes. Patients with adenomas identified as well as direct medical costs from a third party payer perspective were calculated. RESULTS: Assuming a probability of adenoma of 16.9%, the cost for each strategy (compared to no investigation) was as follows: flexible sigmoidoscopy to the splenic flexure, $226; flexible sigmoidoscopy with ACBE, $424; virtual colonoscopy, $597; and colonoscopy, $387. The cost to clear a patient of adenoma(s) was $1,930, $2,840, $3,681, and $2,290, respectively. Despite being most cost-effective, the sigmoidoscopy strategy was predicted to detect 69% of cases of advanced adenomas. The radiological strategies would be less expensive if ACBE cost less than $115 or virtual colonoscopy cost less than $291. The colonoscopy strategy was more cost-effective if the probability of an adenoma was > or = 33.5%. When the incremental costs were considered to investigate 1000 patients, virtual colonoscopy and sigmoidoscopy with ACBE were both more costly then colonoscopy, and neither detected as many cases of advanced adenomas. CONCLUSION: Improved access to colonoscopy seems to be the preferred approach to deal with increased referrals.

Adenoma↗
PubMed1992

A common ancestor of the mammalian transcription factors TCF-1 and TCF-1 alpha/LEF-1 expressed in chicken T cells.

Several mammalian T cell-specific transcription factors have been cloned recently. Two of these, TCF-1 and TCF-1 alpha/LEF-1, display a moderate level of overall sequence similarity, and contain virtually identical versions of a novel type of DNA-binding domain, the HMG box. To study evolutionary aspects of the TCF transcription factors in relation to lymphoid differentiation, we have isolated chicken TCF clones from a spleen cDNA library. Low-stringency screening with human probes as well as a polymerase chain reaction-aided strategy resulted in the cloning of a single chicken TCF (chTCF) gene. Sequence comparison revealed that chTCF contained a TCF-1 alpha-like N terminus, and a TCF-1-like C terminus. Furthermore, TCF-1 and TCF-1 alpha were more homologous to chTCF than to each other. We postulate that chTCF is the direct descendant of a single ancestral gene, which has been duplicated in mammals to yield TCF-1 and TCF-1 alpha.

Amino Acid Sequence↗
PubMed1995

Characterization of a putative molluscan insulin-related peptide receptor.

In the pond snail Lymnaea stagnalis (Ls), growth and associated processes are likely to be controlled by a family of molluscan insulin-related peptides (MIP). Here we report on the cloning of a cDNA encoding a putative receptor for these MIP. This cDNA was isolated from Ls via PCR with degenerate oligodeoxynucleotides corresponding to conserved parts of the tyrosine kinase domain of the human insulin receptor and its Drosophila homologue. Many of the typical insulin-receptor features, including a cysteine-rich domain, a single transmembrane domain and a tyrosine-kinase domain are conserved in the predicted, 1607-amino acid (aa) protein. Comparison of the aa sequence of the molluscan receptor to other insulin-receptor sequences revealed strong variations in the percentage of sequence identity for the different domains, ranging from 70% sequence identity in the tyrosine-kinase domain to virtually no sequence identity in the C-terminal sequence. Striking differences are the absence of a clear tetrabasic cleavage site, and the extremely long C-terminus of 308 aa that contains seven Tyr residues. Southern blot analyses at varying stringencies, extensive screening of cDNA- and genomic libraries, and PCR experiments indicate the presence of a single putative MIP receptor. This suggests that the four different MIP may exert their functional role in Ls by binding to the same receptor.

Amino Acid Sequence↗
PubMed2004

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.

Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.

Acetamides↗
PubMed1994

The signs and symptoms of poor nutritional status.

Many signs and symptoms suggest poor nutritional status, and some have been categorized by consensus of the Nutrition Screening Initiative as "major indicators"; this term implies that, if certain standards of change from the norm in that parameter have occurred, poor nutritional status as a cause must be considered and appropriate steps taken to correct such poor nutritional status if confirmed. Virtually all of the signs and symptoms of poor nutritional status are nonspecific and may be caused or exacerbated by other medical conditions. However, by categorizing them as major or minor indicators and summarizing them, the hope is that practicing health professionals will more frequently note these commonly observed changes, appreciate their nutritional significance, and implement nutritional interventions to correct the problems thus preventing the increased morbidity and mortality known to occur in the malnourished older individual.

Aged↗
PubMed1993

Old and new mechanisms of antiepileptic drug actions.

At the present time, between 30% and 50% of individuals with epilepsy continue to have seizures and among those who are considered "controlled", a good many unpleasant side effects are endured. It is clear that we need more and better antiepileptic drugs. The virtual explosion in knowledge about the cellular and molecular mechanisms underlying both normal and pathological reactions of the brain provides encouragement that we are on the right path towards developing new, effective and safe agents. Whether we continue to use "model-based" screening or "mechanism-based screening", or both, we must not go another 14 years without the introduction of a new antiepileptic drug. The problem is too large, our patients are too impatient and our responsibilities are clear.

Animals↗
PubMed1996

Utility of the Pediatric Symptom Checklist as a psychosocial screen to meet the federal Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) standards: a pilot study.

OBJECTIVE: To examine the usefulness of the Pediatric Symptom Checklist (PSC) as the psychosocial screening measure to meet federal Medicaid/Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) standards in a low-income Hispanic community. DESIGN AND SETTING: Three hundred seventy-nine children (aged 6 to 16 years) were screened with the PSC in a 10-month period during well child visits to three clinics in Ventura and San Mateo counties in California. The PSC was available in English and Spanish and was administered both in written (paper-and-pencil) and oral formats. Follow-up services were provided for children identified as needing evaluation. RESULTS: The Cronbach alpha was high (r = 0.91) for the PSC in the whole sample and virtually identical for English, Spanish, oral, and written formats. All the PSC items were significantly associated with total score on the PSC in English, Spanish, oral, and written formats. Overall, the PSC identified 10.6% of the sample as at risk for psychosocial problems. Thirty-six children (9.5% of sample) were referred for mental health follow-up. Public health data from Ventura County showed a statistically significant increase in referrals for psychologic problems during the study period in two locations using the PSC: from 0.5% to 2.9% of the school-aged children seen. CONCLUSION: The PSC provides a feasible, well-accepted method for screening for psychosocial problems during EPSDT examinations of school-aged children. Psychosocial screening using a validated instrument such as the PSC, as well as increased efforts to refer positive screening results, track outcomes, and assess cost benefits should be essential requirements in capitated Medicaid approaches to caring for poor children.

Adolescent↗
PubMed1998

[3D navigation for interstitial stereotaxic brachytherapy].

AIM: The aim of this paper is to describe the adaption of 3D-navigation for interstitial brachytherapy. The new method leads to prospective and therefore improved planning of the therapy (position of the needle and dose distribution) and to the possibility of a virtual simulation (control if vessels or nerves are on the pathway of the needle). MATERIAL AND METHODS: The EasyGuide Neuro navigation system (Philips) was adapted in the way, that needles for interstitial brachytherapy were made connectable to the pointer and correctly displayed on the screen. To determine the positioning accuracy, several attempts were performed to hit defined targets on phantoms. Two methods were used: "free navigation", where the needle was under control of the navigation system, and the "guided navigation" where an aligned template was used additionally to lead the needle to the target. In addition a mask system was tested, whether it met the requirements of stable and reproducible positioning. The potential of applying this method in clinical practice was tested with an anatomical specimen. RESULTS: About 91% of all attempts lied within 5 mm. There were even better results on the more rigid table (94% < 4 mm). No difference could be seen between both application methods ("free navigation" and "navigation with template"), they showed the same accuracy. CONCLUSIONS: The accuracy of the phantom experiments and the confirmation by the experiment with the anatomical specimen showed that excellent results can be expected in clinical practice using rigid tables and patient supporting systems.

Brachytherapy↗