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PubMedDate not supplied

Current status of tumor markers in large bowel cancer.

The aim of a primary screening system is to detect premalignant lesions and carcinomas when amenable to "curative" surgery. Although a number of "classical" tumor markers have acquired potential for clinical management, none is presently adequate for presymptomatic diagnosis or screening. In colorectal carcinoma, the screening potential of carcinoembryonic antigen (CEA), the gastrointestinal-related antigen, CA19-9, and other more recently characterized "biochemical markers" is virtually nonexistent, even in patients at high risk to develop the disease. Promising new leads are beginning to emerge from somatic cell genetic and molecular biological approaches. In common with other epithelial neoplasms, perturbations in oncogene expression have been demonstrated in colorectal cancers, and probably reflect important events in malignant transformation and progression. Studies of oncogene expression have, however, not yet yielded clinically useful information. Recently, an intensive search for specific chromosomal and gene abnormalities in the hereditary colon cancer syndromes led to the location of the familial adenomatous polyposis (FAP) gene at chromosome 5q21-q22. Significant is that the loss of alleles on chromosome 5 has also been observed in the tumor cells of at least 20% of sporadic colon cancer patients. This type of association between constitutional genetic change and genetic aberration in the cells of sporadic tumors is reminiscent of other malignant diseases with a genetic component (e.g., retinoblastoma and Wilms' tumor).(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers, Tumor↗
PubMed1988

An assay that predicts the ability of monoclonal antibodies to form potent ricin A chain-containing immunotoxins.

In this report, we describe an assay for screening monoclonal antibodies for their cytotoxic potential as ricin A chain-containing immunotoxins. The assay involves treating cells with dilutions of the test antibody followed by a Fab fragment of a secondary antibody coupled to ricin A chain ("indirect assay"). The cytotoxicity of the indirect assay is compared to that of the direct assay where the monoclonal antibody is coupled to ricin A chain. Indirect and direct assays were carried out using 14 antibodies and a panel of 8 human and mouse cell types. The two assays showed virtually 100% correlation. The indirect assay, therefore, predicts the potency of a given monoclonal antibody to make an effective immunotoxin and should be useful in screening monoclonal antibodies for use as immunotoxins.

Antibodies, Monoclonal↗
PubMed2002

Glucose-6-phosphate dehydrogenase deficiency: a potential source of severe neonatal hyperbilirubinaemia and kernicterus.

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is a commonly occurring enzyme defect that can lead to severe neonatal hyperbilirubinaemia and kernicterus. Both increased haemolysis, sometimes due to an identifiable chemical trigger or to infection, and diminished bilirubin conjugation, the result of an interaction between G-6-PD deficiency and Gilbert's syndrome, contribute to the pathogenesis of the jaundice. Phototherapy is the mainstay of treatment, with exchange transfusion held in reserve for those neonates who do not respond to phototherapy. Pharmacological agents such as Sn-mesoporphyrins, which prevent bilirubin production by inhibiting the enzyme heme oxygenase, can limit hyperbilirubinaemia and possibly prevent the need for exchange transfusion. Predischarge serum total bilirubin screening is useful in predicting which neonates are at high risk for developing hyperbilirubinaemia. Migration patterns make G-6-PD deficiency a condition which may nowadays be encountered in virtually any corner of the globe and a high degree of physician awareness is essential.

Bilirubin↗
PubMed1988

The bacterial flora of neonates in intensive care-monitoring and manipulation.

Unlike healthy babies, newborns hospitalized in the neonatal intensive care unit (NICU) are colonized with bacterial flora that reflects their exposure to pathogens in the NICU, not bacterial acquired from mother in the perinatal period. For example, nosocomial Gram-negative bacilli, such as klebsiella, enterobacter, and citrobacter but not Escherichia coli tend to colonize the gastrointestinal tract. Colonization with Gram-negative bacilli generally is a prerequisite for nosocomial infection with these pathogens, but surveillance cultures may not be a cost effective approach to predicting which babies will ultimately become ill. However, screening cultures to detect the emergence of antibiotic-resistant Gram-negative bacilli facilitate containment and guide empiric antibiotic therapy, and surveillance cultures are necessary to detect colonized babies when nosocomial Gram-negative bacilli become epidemic in the NICU. Such cultures are inexpensive and easy to perform if appropriate selective media are used. Surveillance cultures to detect coagulase-negative staphylococci, which numerous investigators claim are increasingly important NICU pathogens, are of little value since colonization is virtually universal in the first week of life. Documentation of colonization with group B streptococci or Staphylococcus aureus also cannot be justified on a routine basis. Screening for methicillin-resistant S. aureus, however, may be indicated since early detection of these strains can limit dissemination in the NICU. Research aimed at restoring colonization resistance with elements of normal bacterial flora or preventing colonization by nosocomial pathogens is in its infancy.

Bacteriological Techniques↗
PubMed1981

Electrostatic control by lipids upon the membrane-bound (Na+ + K+)-ATPase.

In this paper, the membrane-bound (Na+ + K+)-ATPase from bovine brain is shown to be controlled by electrostatic alterations of the charged lipids surrounding the enzyme. The properties under investigation are the enzymatic activity, activation energy and the response of the enzymatic system to temperature. Arrhenius plots of the ATPase activity are biphasic with a break at temperature Ti. The temperature Ti, the activation energies at temperatures above and below Ti, and the enzymatic activity at any constant temperature have been shown to depend upon the concentrations of alkali and alkaline-earth metal ions in the solution. These electrolyte dependencies are ascribed to changes of electrostatic conditions at the lipids surrounding the ATPase. If the higher electrostatic screening ability of divalent ions is taken into account, the results in the presence of mono- and divalent ions become virtually the same. As a result of this work, it is concluded that electrostatic alterations are transmitted to the ATPase from the lipids of the membrane in which the enzyme is embedded. Inhibition and activation of the enzyme by mono-and divalent metal ions may thus be explained without any auxiliary hypothesis, particularly without postulating specific binding sites for the different ionic species at the protein. In addition, the specific lipid requirement of the ATPase may be understood better in the light of this interpretation.

Animals↗
PubMed2006

The effect of rhythmic somatosensory cueing on gait in patients with Parkinson's disease.

BACKGROUND AND AIMS: Gait and gait related activities in patients with Parkinson's disease (PD) can be improved with rhythmic auditory cueing (e.g. a metronome). In the context of a large European study, a portable prototype cueing device was developed to provide an alternative for rhythmic auditory cueing: rhythmic somatosensory cueing (RSC, a miniature vibrating cylinder attached to the wrist). We investigated whether PD patients could adapt their walking pattern using RSC under conditions of changing walking speed and the presence of potentially distracting visual flow while walking on a treadmill. METHODS: A total of 17 patients with PD participated (mean age 63.4+/-10.3 years; Hoehn-Yahr score 2.5+/-0.9, mean Unified Parkinson's Disease Rating Scale score 49.8+/-13.7, mean disease duration 7.7+/-5.1 years). They performed systematic walking speed manipulations under 4 conditions in a random order: (1) no cue, no visual flow, (2) no cue, visual flow, (3) cue, no visual flow and (4) cue, visual flow. Visual flow in the form of a virtual corridor that moved at the current walking speed was projected on a 2 x 2 m rear-projection screen. The cueing rhythm was set at -10% of preferred stride frequency at each speed. Stride frequency was assessed using peaks in the trajectories of thigh sagittal plane segmental angles. RESULTS: Walking with RSC resulted in lower stride frequencies, and thus larger step lengths (p-values <0.05), regardless of walking speed. The presence of visual flow did not impair the use of RSC, as evidenced by the lack of differences between conditions 3 and 4 (p>0.05). CONCLUSION: Rhythmic somatosensory cueing may be a viable alternative for auditory cueing and is robust to changes in walking speed and visual distractors.

Aged↗
PubMed1999

Active manual control of object views facilitates visual recognition.

Active exploration of large-scale environments leads to better learning of spatial layout than does passive observation [1] [2] [3]. But active exploration might also help us to remember the appearance of individual objects in a scene. In fact, when we encounter new objects, we often manipulate them so that they can be seen from a variety of perspectives. We present here the first evidence that active control of the visual input in this way facilitates later recognition of objects. Observers who actively rotated novel, three-dimensional objects on a computer screen later showed more efficient visual recognition than observers who passively viewed the exact same sequence of images of these virtual objects. During active exploration, the observers focused mainly on the 'side' or 'front' views of the objects (see also [4] [5] [6]). The results demonstrate that how an object is represented for later recognition is influenced by whether or not one controls the presentation of visual input during learning.

Adolescent↗
PubMed2006

FK506-binding protein ligands: structure-based design, synthesis, and neurotrophic/neuroprotective properties of substituted 5,5-dimethyl-2-(4-thiazolidine)carboxylates.

Structure-based design and discovery of novel neuroimmunophilin FK506-binding protein (FKBP) ligands were pursued in the present study. The binding mode of the known FKBP ligand 1 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate) in complex with FKBP12 was investigated using LUDI simulation and upon which a novel scaffold structure predicted to possess improved binding affinity was designed. A virtual combinatorial library composed of diverse combinations of two substituted groups was constructed using Project Library, followed by an automated screening of the library against the ligand binding site on FKBP52 using DOCK. Forty-three candidate compounds that displayed favorable binding with the receptor were identified and synthesized. The neurotrophic activity of the candidate compounds was evaluated on chick dorsal root ganglion cultures in vitro. As a result, 15 compounds exhibited positive effects on ganglion neurite outgrowth in the presence of 0.15 ng/mL NGF, among which 7 compounds at testing concentrations of 1 pM and 100 pM showed greater efficacy than 1 at 100 pM. Compound 18 (3-(3-pyridyl)-1-propyl (2S)-5,5-dimethyl-1-(3,3-dimethyl-1,2-dioxobutyl)-2-(4-thiazolidine)carboxylate) afforded the most potent effect in promoting the processes of neurite outgrowth and which was in a concentration-dependent manner from 1 pM to 100 pM. Half-maximal effect occurred at about 10 pM. Moreover, 18 at a dosage of 10 mg/kg was found to be significantly neuroprotective in a mouse peripheral sympathetic nerve injury model induced by 8 mg/kg 6-hydroxydopamine. This study further suggests the clinical potential of novel FKBP ligands as a new therapeutic approach in the treatment of neurodegenerative disorders, such as Parkinson's disease.

Animals↗
PubMed2006

Design and synthesis of 5-aryl-pyridone-carboxamides as inhibitors of anaplastic lymphoma kinase.

Anaplastic lymphoma kinase (ALK) is a promising new target for therapy of certain cancers such as anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT). We have identified a series of novel pyridones as kinase inhibitors of ALK by application of a stepwise process involving in vitro screening of a novel targeted library followed by iterative template modification based on medicinal chemistry insights and computational ranking of virtual libraries. Using this process, we discovered ALK-selective inhibitors with improved potency and selectivity. Herein the details of the design process and synthesis of these novel pyridones, along with their enzymatic and cell-based activity, are discussed.

Amides↗
PubMed2003

Prenatal typing of Rh and Kell blood group system antigens: the edge of a watershed.

Knowledge of the molecular basis of the blood group systems has enabled the development of assays for blood group genotyping. At this time, polymerase chain reaction (PCR)-based assays validated on fetal material obtained by invasive means (chorionic villus sampling or amniocentesis) are available for all clinically relevant fetal blood groups, However, only Rh typing (D, C, c, E, and e) and K1 genotyping assays are discussed in this review. Importantly, one must remember that results of genotyping assays will not always be concordant with serological typing. Thus, the RhD genotyping assays have to be modified in response to increased understanding of the molecular biology of this blood group system. RhD typing assays should produce negative results when tested on the black RhD-negative RHD alleles, RHDpsi and r's. PCR-based assays can be used to determine paternal zygosity. For RhD zygosity testing, the real-time quantitative PCR approach and the direct detection of the hybrid Rhesus box, which is the result of the deletion of the RHD gene are available. Recently, methods for noninvasive prenatal genotyping have been investigated. The use of fetal cells circulating in the maternal circulation has been explored; however, the scarcity of circulating fetal cells has limited the use of this approach. More promising are the results obtained with RhD typing assays with cell-free fetal DNA, which is present in the maternal circulation in a concentration of 25 genomic equivalents per milliliter of maternal blood in early pregnancy increasing to 100 copies per milliliter in the third trimester, which is cleared from the circulation within a few hours of delivery. The positive predictive value of this approach is virtually 100%, but false-negative results are (infrequently) encountered. Therefore, this assay can at present only be used for screening of RhD-negative women to make the use of antenatal prophylaxis more targeted and hence more cost-effective. For the clinical management of the pregnancies of alloimmunized women, the development of a control for the presence and the amplification of fetal DNA is needed, which is at present only available in male pregnancies. Assays for the genotyping of the other Rh antigens or Kell antigens with cell-free fetal DNA have not yet been described.

Blood Group Antigens↗
PubMed1997

Vertical distribution and phylogenetic characterization of marine planktonic Archaea in the Santa Barbara Channel.

Newly described phylogenetic lineages within the domain Archaea have recently been found to be significant components of marine picoplankton assemblages. To better understand the ecology of these microorganisms, we investigated the relative abundance, distribution, and phylogenetic composition of Archaea in the Santa Barbara Channel. Significant amounts of archaeal rRNA and rDNA (genes coding for rRNA) were detected in all samples analyzed. The relative abundance of archaeal rRNA as measured by quantitative oligonucleotide hybridization experiments was low in surface waters but reached higher values (20 to 30% of prokaryotic rRNA) at depths below 100 m. Probes were developed for the two major groups of marine Archaea detected. rRNA originating from the euryarchaeal group (group II) was most abundant in surface waters, whereas rRNA from the crenarchaeal group (group I) dominated at depth. Clone libraries of PCR-amplified archaeal rRNA genes were constructed with samples from 0 and 200 m deep. Screening of libraries by hybridization with specific oligonucleotide probes, as well as subsequent sequencing of the cloned genes, indicated that virtually all archaeal rDNA clones recovered belonged to one of the two groups. The recovery of cloned rDNA sequence types in depth profiles exhibited the same trends as were observed in quantitative rRNA hybridization experiments. One representative of each of 18 distinct restriction fragment length polymorphism types was partially sequenced. Recovered sequences spanned most of the previously reported phylogenetic diversity detected in planktonic crenarchaeal and euryarchaeal groups. Several rDNA sequences appeared to be harbored in archaeal types which are widely distributed in marine coastal waters. In total, data suggest that marine planktonic crenarchaea and euryarchaea of temperate coastal habitats thrive in different zones of the water column. The relative rRNA abundance of the crenarchaeal group suggests that its members constitute a significant fraction of the prokaryotic biomass in subsurface coastal waters.

Animals↗
PubMed1998

Differences in contributing factors to tuberculosis incidence in U.S. -born and foreign-born persons.

To determine the factors contributing to tuberculosis incidence in the U.S.-born and foreign-born populations in San Francisco, California, and to assess the effectiveness of tuberculosis control efforts in these populations, we performed a population-based molecular epidemiologic study using 367 patients with strains of Mycobacterium tuberculosis recently introduced into the city. IS6110-based and PGRS-based restriction fragment length polymorphism (RFLP) analyses were performed on M. tuberculosis isolates. Patients whose isolates had identical RFLP patterns were considered a cluster. Review of public health and medical records, plus patient interviews, were used to determine the likelihood of transmission between clustered patients. None of the 252 foreign-born cases was recently infected (within 2 yr) in the city. Nineteen (17%) of 115 U. S.-born cases occurred after recent infection in the city; only two were infected by a foreign-born patient. Disease from recent infection in the city involved either a source or a secondary case with human immunodeficiency virus (HIV) infection, homelessness, or drug abuse. Failure to identify contacts accounted for the majority of secondary cases. In San Francisco, disease from recent transmission of M. tuberculosis has been virtually eliminated from the foreign-born but not from the U.S.-born population. An intensification of contact tracing and screening activities among HIV-infected, homeless, and drug-abusing persons is needed to further control tuberculosis in the U.S.-born population. Elimination of tuberculosis in both the foreign-born and the U.S. -born populations will require widespread use of preventive therapy.

AIDS-Related Opportunistic Infections↗
PubMed1995

Relaxation effect of an audiovisual system on dental patients. Part 2. Palus-amplitude.

Dental care services include relaxation of patients to reduce their displeasure at and tension during treatment. For this purpose, it is common to use audio or audiovisual programs, that is, to let them listen to music or watch TV. However, the former utilizes only the auditory sense, and the latter is disadvantageous in that a TV set is a rather large-scale unit. In the present study, we determined the relaxation effect of an audiovisual instrument on dental patients. The instrument, which gives virtual vision, was composed of a lightweight eyeset of the snow goggle type that has a built-in TV screen, with earphone and accessories. The relaxation effect was determined using a polygraph.

Adult↗
PubMed1991

A serine esterase released by human alveolar macrophages is closely related to liver microsomal carboxylesterases.

We identified a 60-kDa diisopropylfluorophosphate-(DFP) reactive protein in human bronchoalveolar lavage fluid, at a yield of 50-100 pmol/lavage. The protein is associated with the cell-free lavage fluid sediment, which consists mainly of surfactant. [3H]DFP labeling is inhibited by heating to 56 degrees C, 2 mM phenylmethylsulfonylfluoride and 1 mM bis(4-nitrophenyl)-phosphate. An identical 60-kDa [3H]DFP-reactive protein is present in the insoluble fraction of alveolar macrophage-conditioned culture medium and in total membrane preparations of alveolar macrophages. The [3H]DFP-labeled protein was purified approximately 30-fold from lavage fluid sediment by size-exclusion (Sephacryl S-200) and ion-exchange (Mono-Q) chromatography. Cyanogen bromide treatment of the partially purified protein produced a major labeled peptide of 14 kDa with an NH2-terminal sequence 90% identical to a region of form 1 rabbit liver microsomal carboxylesterase. Esterase activity in unlabeled starting material, detected using p-nitrophenyl valerate as substrate, copurified with the [3H]DFP-labeled enzyme. Degenerate oligonucleotide primers were designed based on the partial amino acid sequence and on a highly conserved region of known liver carboxylesterase sequences. Polymerase chain reaction using these primers and reverse-transcribed human alveolar macrophage mRNA yielded a 354-base pair product which was then used to screen a human alveolar macrophage cDNA library. A complete esterase sequence was obtained from two incomplete, overlapping clones, and is virtually identical to human liver carboxylesterase partial sequences. Northern blot analysis demonstrated a single approximately 1.7-kilobase transcript in human monocytes and alveolar macrophages, with much higher levels in the latter. These data indicate that human alveolar macrophages both contain and release a serine esterase that is apparently identical to liver microsomal carboxylesterase. Its enzymatic profile suggests it is a major component of alveolar macrophage-nonspecific esterase activity. We hypothesize that it acts as a detoxication enzyme in the lung.

Adult↗
PubMed1979

[Diagnosis and treatment of sarcoidosis (author's transl)].

With only a few exceptions, in sarcoidosis the lung is virtually always, the liver mostly and the spleen only occasionally involved. Therefore, thorax-X-ray is the most important screening procedure. Histological verification by laparoscopy, bronchoscopy (transbronchial lung biopsy and bronchial mucosa biopsy) or mediastinoscopy is essential. In order to decide the therapeutic regimen, particularly the use of corticosteroids, the staging according to Wurm seems less suitable than pulmonary function testing (pneumotachograph, plethysmograph, CO-transfer, compliance). Futher clinical trials will have to find out, whether enzyme analysis (ACE) is apt to monitor progression of disease or to diagnose sarcoidosis in clinical routine use.

Adult↗
PubMed1995

Comparative 2D-electrophoretic mapping of human and rodent hepatic stress proteins as potential biomarkers.

Toxicologic studies in rodents demonstrate that two-dimensional polyacrylamide gel electrophoresis of proteins (2DE) is very useful in the detection and evaluation of chemical toxicity by providing information regarding cellular status at the molecular level. Identification of a set of specific biomarkers of exposure or effect, with a proclivity for both a particular rodent and human target tissue, is required for development of an electrophoretically based testing system. In this regard, stress proteins, such as the heat shock and glucose-regulated proteins (Hsp and Grp), are appropriate candidates. The present investigation was undertaken to identify these stress proteins on conventional two-dimensional electrophoretic gel patterns of human and rat liver homogenates. The following stress proteins were identified, their x, y coordinate positions mapped, and abundances determined, and these data statistically analyzed and compared: Hsp25, Hsp32, Hsp60, Hsc70, Hsp70, Hsp90, Grp75, Grp78, Grp94, protein disulfide isomerase (PDI), and ER-60. With the exception of Hsp25 and Hsp32, the stress proteins examined were constitutively expressed at detectable levels in both unstressed human and rat liver; in virtually identical patterns. Based on our results, the human hepatic 2DE stress protein pattern seems well-suited to toxicologic screening particularly in in vitro applications and via extrapolations from rodent exposures.

Animals↗
PubMed2002

Flexsim-R: a virtual affinity fingerprint descriptor to calculate similarities of functional groups.

Methods to describe the similarity of fragments occurring in drug-like molecules are of fundamental importance in computational drug design. In the early phase of lead discovery, they can help to select diverse building blocks for combinatorial compound libraries intended for broad screening. In lead optimization, such methods can guide bioisosteric replacements of one functional group by another or serve as descriptors for QSAR calculations. In this paper, we outline the development of a novel 3D descriptor, termed Flexsim-R, which is a further extension of our virtual affinity fingerprint idea. Descriptors are calculated based on docking of small fragments such as building blocks for combinatorial chemistry or functional groups of drug-like molecules into a reference panel of protein binding sites. The method is validated by examining the neighborhood behavior of the affinity fingerprints and by deriving predictive QSAR models for a couple of literature peptide data sets.

Algorithms↗
PubMed1999

Virtual reality and anthropology.

Since the discovery of the Tyrolean Iceman in 1991 advanced imaging and post processing techniques were successfully applied in anthropology. Specific techniques include spiral computed tomography and 3-dimensional reconstructions including stereolithographic and fused deposition modeling of volume data sets. The Iceman's skull was the first to be reproduced using stereolithography, before this method was successfully applied in preoperative planning. With the advent of high-end graphics workstations and biomedical image processing software packages, 3-dimensional reconstructions were established as a routine tool for analyzing volume data sets. These techniques opened totally new insights in the field of physical anthropology. Computed tomography became the ideal research tool to access the internal structures of various precious fossils without damaging or even touching them. Many of the most precious specimens from the species Autralopithecus (1.8-3.5 Myears), Homo heidelbergensis (200-600 kyears) or Homo neanderthalensis (40-100 kyears) were scanned during the last 5 years. Often the fossils are filled with a stone matrix or other materials. During the postprocessing routines highly advanced algorithms were used to remove virtually these incrustations. Thus it was possible to visualize the morphological structures that lie beneath the matrix. Some specimen were partially destroyed, so the missing parts were reconstructed on computer screen in order to get estimations of the brain volume and endocranial morphology, both major fields of interest in physical anthropology. Moreover the computerized form of the data allows new descriptions of morphologic structures by the means of 'geometric morphometrics'. Some of the results may change aspects and interpretations in human evolution. The introduction of new imaging and post processing techniques created a new field of research: Virtual Anthropology.

Algorithms↗