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PubMed1994

Drug excretion mediated by a new prototype of polyspecific transporter.

Cationic drugs of different types and structures (antihistaminics, antiarrhythmics, sedatives, opiates, cytostatics and antibiotics, for example) are excreted in mammals by epithelial cells of the renal proximal tubules and by hepatocytes in the liver. In the proximal tubules, two functionally disparate transport systems are involved which are localized in the basolateral and luminal plasma membrane and are different from the previously identified neuronal monoamine transporters and ATP-dependent multidrug exporting proteins. Here we report the isolation of a complementary DNA from rat kidney that encodes a 556-amino-acid membrane protein, OCT1, which has the functional characteristics of organic cation uptake over the basolateral membrane of renal proximal tubules and of organic cation uptake into hepatocytes. OCT1 is not homologous to any other known protein and is found in kidney, liver and intestine. As OCT1 translocates hydrophobic and hydrophilic organic cations of different structures, it is considered to be a new prototype of polyspecific transporters that are important for drug elimination.

Amino Acid Sequence↗
PubMed2000

Structural analysis of WW domains and design of a WW prototype.

Two new NMR structures of WW domains, the mouse formin binding protein and a putative 84.5 kDa protein from Saccharomyces cerevisiae, show that this domain, only 35 amino acids in length, defines the smallest monomeric triple-stranded antiparallel beta-sheet protein domain that is stable in the absence of disulfide bonds, tightly bound ions or ligands. The structural roles of conserved residues have been studied using site-directed mutagenesis of both wild type domains. Crucial interactions responsible for the stability of the WW structure have been identified. Based on a network of highly conserved long range interactions across the beta-sheet structure that supports the WW fold and on a systematic analysis of conserved residues in the WW family, we have designed a folded prototype WW sequence.

Amino Acid Sequence↗
PubMed2001

Recombinant maxi-K channels on transistor, a prototype of iono-electronic interfacing.

We report on the direct electrical interfacing of a recombinant ion channel to a field-effect transistor on a silicon chip. The ion current through activated maxi-K(Ca) channels in human embryonic kidney (HEK293) cells gives rise to an extracellular voltage between cell and chip that controls the electronic source-drain current. A comparison with patch-clamp recording shows that the channels at the cell/chip interface are fully functional and that they are significantly accumulated there. The direct coupling of potassium channels to a semiconductor on the level of an individual cell is the prototype for an iono-electronic interface of ligand-gated or G protein-coupled ion channels and the development of screening biosensors with many transfected cells on a chip with a large array of transistors.

Cell Line↗
PubMed1998

The many faces of Src: multiple functions of a prototypical tyrosine kinase.

c-src was first isolated as the normal cellular homologue of v-src, the transforming gene of Rous Sarcoma virus (Stehelin et al., 1976). As the first proto-oncogene described and one of the first molecules demonstrated to have tyrosine kinase activity, Src has provided a prototype for understanding signal transduction involving tyrosine phosphorylation. Comparison between c-src and activated or transforming mutants of Src including v-src, combined with recent data on the structure of Src family kinases has provided new insight into their regulation. In this review, I will discuss the function of the various domains of Src in light of these mutational and structural studies.

Animals↗
PubMed2001

Comparison of three-dimensional computed tomography with rapid prototype models in the management of coronoid hyperplasia.

OBJECTIVES: To compare (1) the accuracy of 3DCT with rapid prototyping (RP) models and (2) their application in the management of coronoid hyperplasia. METHODS: An adult dry skull was used to compare 3DCT and a RP model for accuracy of reproduction; Polymerisation contraction and 17 distances between 27 anatomical points were measured. Two patients with coronoid process hyperplasia were assessed by means of 3DCT and plastic models. RESULTS: Differences in measurements with the RP model and the dried skull were smaller than those with 3DCT (P=0.04). Polymerisation contraction was greater than the errors in reproduction with the RP model and approximately equal to those with the 3DCT. The coronoid process was thick and prominent in the patients with coronoid process hyperplasia and the small space and early contact between zygomatic arch and the coronoid process demonstrated. The plastic model duplicated the exostosis of the inner surface of the malar bone facing the concavity of the elongated process. The coronoid process had an anterior tilt in one case. CONCLUSION: The plastic model duplicated the relationship between the maxillofacial deformity and the coronoid process with tolerable accuracy. Trismus may be due to the direction as well as the length of the enlarged coronoid process.

Adolescent↗
PubMed1995

Two different isoschizomers of the type-II restriction endonuclease Taq I (T/CGA) within the same Thermus isolate: Tsp32 I, an enzyme with similar heat stability properties to the prototype enzyme Taq I, and Tsp32 II, a hyperthermostable isoschizomer of Taq I.

We have recently screened 112 separate isolates of the genus Thermus, collected from neutral and alkaline hot water springs on four continents, for the presence of the Type-II restriction endonuclease Taq I (T/CGA). One particular isolate from the Azores (strain 32) was found to contain high levels of a restriction endonuclease with the same recognition and cleavage site as Taq I. Initial studies revealed that the partially purified enzyme from strain 32 was considerably more resistant to heat inactivation than the prototype enzyme Taq I, being able to withstand temperatures at least 10 degrees C higher than Taq I, before showing evidence of heat inactivation. Subsequently it became clear that the partially purified extract from strain 32 contains two separate enzymes, both of which are isoschizomers of Taq I. One of the enzymes, Tsp32 I, has similar thermal stability characteristics to Taq I, whereas the second Taq I isoschizomer, Tsp32 II, found in the same Thermus isolate as Tsp32 I, is considerably more thermostable than Taq I, retaining full enzyme activity up to a temperature of 85 degrees C. Tsp32 I and Tsp32 II were further distinguished by virtue of their different requirements for magnesium ions.

Base Sequence↗
PubMed2002

Evaluation in an anaesthetic simulator of a prototype of a new drug administration system designed to reduce error.

Ten anaesthetists were observed while providing anaesthesia for two simulated surgical procedures, twice using conventional methods and twice using a prototype of a new drug administration system designed to reduce error. Aspects of each method were rated by users on 10-cm visual analogue scales (10 being best) and comments were invited. Median safety scores were 7.7 cm (range 4.3-8.9) for the new system and 4.6 cm (1.3-8.2) for conventional methods (p = 0.009). The new system was compared favourably with conventional methods in respect of safety (p = 0.005), clinical acceptability (p = 0.008), organisation and layout (p = 0.047), and acceptability for use on patients (p = 0.005). The new system saved time in the preparation of drugs both before anaesthesia (105 vs. 346 s; p < 0.001) and during anaesthesia (20 vs. 104 s; p < 0.001). Comments facilitated development of the system and the evaluation endorsed proceeding to a clinical trial.

Anesthesiology↗
PubMed2003

Monocytes and neutrophils from tuberculosis patients are insensitive to anti-inflammatory effects triggered by the prototypic formyl peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP).

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis where formyl peptides, which are cleavage products of bacterial and mitochondrial proteins, are present. In this study, we demonstrated that interferon gamma (IFN)-gamma and interleukin (IL)-10 induced the overexpression of the receptor for the Fc portion of IgG I (FcgammaRI) in monocytes from tuberculosis (TB) patients, showing that these cells respond to IFN-gamma and IL-10 signals. We also demonstrated that lower doses of IL-10 render monocytes from TB patients less responsive to higher doses of the cytokine. Although the prototypic formyl peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) is a well-known proinflammatory agonist, we have demonstrated previously that preincubation of monocytes with FMLP inhibited the up-regulation of FcgammaRI induced by IFN-gamma or IL-10. This effect was not observed in monocytes from TB patients. FMLP also induced the down-regulation of the expression of FcgammaRI in monocytes that had been activated already with IFN-gamma. However, this effect of FMLP was not observed in monocytes from TB patients and supernatants from monocytes obtained from these patients were incapable of inducing the down-regulation of FcgammaRI. In contrast to normal donors, supernatants from FMLP-treated neutrophils from TB patients did not modify the basal level of expression of FcgammaRI in monocytes from normal donors. In conclusion, in this study we demonstrated the existence of two novel mechanisms that may contribute to the pathological effects generated by M. tuberculosis: the enhancement of FcgammaRI in response to IFN-gamma and IL-10, and the unresponsiveness to the anti-inflammatory effects induced by formyl peptides.

Cells, Cultured↗
PubMed1999

Light-guided tracheal intubation using a prototype illuminated flexible catheter through the intubating laryngeal mask.

We evaluated the efficacy of a newly developed prototype illuminated flexible catheter to facilitate tracheal intubation through the intubating laryngeal mask and compared this light-guided technique with the conventional blind tracheal intubation through the intubating laryngeal mask. The illuminated flexible catheter consists of a completely flexible thin plastic catheter, a bulb attached to its distal end, a 15-mm concentric adapter at its proximal end connected with a battery and a power switch. The device is placed into a silicone tracheal tube in such a way that the bulb protrudes from the distal end of the tracheal tube. One hundred adult patients, ASA I-III, scheduled to undergo propofol/fentanyl/atracurium anaesthesia for elective surgery were studied. All participants underwent a randomized double comparative cross over trial with respect to the tracheal intubation technique through the intubating laryngeal mask. The light guided tracheal intubation was performed as follows; the tracheal tube preloaded with the illuminated flexible catheter was inserted through the intubating laryngeal mask and by observing the glow in the neck was advanced into the trachea. Whenever resistance was felt during insertion, appropriate adjusting manoeuvres were performed. The intubating laryngeal mask was inserted successfully in all patients. The success rate for the blind and light-guided technique was 91% and 100%, respectively (P = 0.003). The mean (+/- SD) duration including appropriate intubating laryngeal mask placement and tracheal intubation, was significantly lower in the light-guided tracheal intubation technique, than with the blind tracheal intubation (31 +/- 8 s vs. 43 +/- 18 s; P < 0.0001). We conclude that the use of an illuminated flexible catheter carries advantages either in optimizing the intubating laryngeal mask position in the laryngopharynx or in achieving a quick and safe light-guided advancement from laryngopharynx into the trachea.

Adult↗
PubMed1999

The performance of foreign medical graduates on the National Board of Medical Examiners (NBME) standardized patient examination prototype: a collaborative study of the NBME and the Educational Commission for Foreign Medical Graduates (ECFMG).

OBJECTIVES: The purpose of the study was to explore foreign medical graduates' (FMGs) performance on a clinical skills (SPX) examination. The National Board of Medical Examiners (NBME) is in the process of developing an SPX for potential use in the United States Medical Licensing Examination (USMLE). The Educational Commission for Foreign Medical Graduates (ECFMG) is developing the Clinical Skills Assessment (CSA) as an additional requirement for FMGs who wish to be certified by ECFMG. DESIGN: Thirty-three FMGs and 151 United States medical students (USMSs) took the SPX during the winter of 1996 as part of the ongoing pilot studies conducted by the NBME. Four clinical skill areas were assessed: history-taking, physical examination, communication and interpersonal skills. The examination used in this research consisted of 12 cases. The examination utilizes standardized patients (SPs) who are trained to document examinee behaviours and evaluate the communication component of the test. The SPs were also trained to evaluate the English proficiency of the candidates. Candidates were also administered the Test of Spoken English developed by the Educational Testing Services (ETS). SETTING: The examination was conducted in one medical school which served as an SPX centre for NBME pilot studies. SUBJECTS: Thirty-three foreign medical students and 151 US medical students. RESULTS: The indications were that the majority of candidates in both groups felt the examination was moderately fair but 78% of FMGs felt moderately pressed for time, vs. 80% of the USMSs who did not feel pressed for time. Reliabilities obtained for the various SPX components were somewhat higher for the FMGs reflecting the heterogeneity of this group. CONCLUSIONS: The NBME-ECFMG collaborative study yielded important information regarding the NBME SPX prototype as a performance measure for FMGs.

Clinical Competence↗
PubMed2003

The monolithic fetal pacemaker: prototype lead design for closed thorax deployment.

Prenatal sudden cardiac death and hydrops fetalis are often due to complete heart block. However, no pacing modality exists for intrauterine application for fetal bradycardia. A prototype lead for a novel fetal pacemaker has been developed and used in a direct pacing model. It has been demonstrated that the lead can be safely and successfully deployed using a hypochondriac and transdiaphragmatic or subxiphoid approach. Pacing with ventricular capture was evident with the widening of QRS duration from 50.2 +/- 9.8 to 95.1 +/- 12.8 ms (P = 0.0001). Further studies by echocardiogram revealed an increase in the pulse with pacing, confirming pacing. This study documents proof-of-concept for closed thorax over-the-wire deployment of a novel lead design applicable to fetal pacing. By combining the lead design with microcircuitry and a small power source, it is possible to create a monolithic fetal pacemaker system capable of being deployed in utero.

Animals↗
PubMed1996

A prototypic intracellular calcium antagonist, TMB-8, protects cultured cerebellar granule cells against the delayed, calcium-dependent component of glutamate neurotoxicity.

The effect(s) of a prototypic intracellular Ca2+ antagonist, 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8), on glutamate-induced neurotoxicity was investigated in primary cultures of mouse cerebellar granule cells. Glutamate evoked an increase in cytosolic free-Ca2+ levels ([Ca2+]i) that was dependent on the extracellular concentration of Ca2+ ([Ca2+]o). In addition, this increase in [Ca2+]i correlated with a decrease in cell viability that was also dependent on [Ca2+]o. Glutamate-induced toxicity, quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) staining, was shown to comprise two distinct components, an "early" Na+/Cl(-)-dependent component observed within minutes of glutamate exposure, and a "delayed" Ca(2+)-dependent component (ED50 approximately 50 microM) that coincided with progressive degeneration of granule cells 4-24 h after a brief (5-15 min) exposure to 100 microM glutamate. Quantitative analysis of cell viability and morphological observations identify a "window" in which TMB-8 (at > 100 microM) protects granule cells from the Ca(2+)-dependent, but not the Na+/Cl(-) -dependent, component of glutamate-induced neurotoxic damage, and furthermore, where TMB-8 inhibits glutamate-evoked increases in [Ca2+]i. These findings suggest that Ca2+ release from a TMB-8-sensitive intracellular store may be a necessary step in the onset of glutamate-induced excitotoxicity in granule cells. However, these conclusions are compromised by additional observations that show that TMB-8 (1) exhibits intrinsic toxicity and (2) is able to reverse its initial inhibitory action on glutamate-evoked increases in [Ca2+]i and subsequently effect a pronounced time-dependent potentiation of glutamate responses. Dantrolene, another putative intracellular Ca2+ antagonist, was completely without effect in this system with regard to both glutamate-evoked increases in [Ca2+]i and glutamate-induced neurotoxicity.

Animals↗
PubMed2003

Genetic approaches in the clinical investigation of complex disorders: malnutrition, inflammation, and atherosclerosis (MIA) as a prototype.

Despite major research efforts and improvements in dialysis technology, patients with end-stage renal disease (ESRD) experience an extremely high mortality, which seems to be increasingly related to cardiovascular disease. Cardiovascular disease has been linked to the presence of systemic inflammation and malnutrition (MIA syndrome), in addition to the high prevalence of traditional risk factors observed in ESRD patients. Since the mechanisms underlying the development of these complications of ESRD are largely unknown, new strategies for identification of risk factors, pathophysiologic pathways, and targets for intervention are warranted. Although the combined impact of MIA complications seems to determine the extremely poor clinical outcome in the ESRD patients, there are significant unexplained individual differences in the development of the MIA syndrome, implying that genetic differences might play a role. The vast information generated by the advances in molecular genetics offers a great opportunity to analyze the causes of differences not only in our susceptibility to (or protection from) various diseases, but also in the age of onset, severity of illness, and in the way our bodies respond to treatment. In this review, we summarize an integrated approach in the investigation of complex disorders, requiring the interactive collaboration between laboratory, clinical, and epidemiologic resources using the MIA syndrome as a prototype. We focus on the application of common genetic variations (single nucleotide polymorphisms [SNPs]) in association with studies to generate potential risk profiling using data from multiple vulnerability genes. The appropriate application of this approach may be essential in the early identification of high-risk individuals and groups of patients for whom specific therapeutic interventions are indicated, thus creating a tailor-made clinical management for the future.

Arteriosclerosis↗
PubMed2000

Computational flow study of the continuous flow ventricular assist device, prototype number 3 blood pump.

A computational fluid dynamics study of blood flow in the continuous flow ventricular assist device, Prototype No. 3 (CFVAD3), which consists of a 4 blade shrouded impeller fully supported in magnetic bearings, was performed. This study focused on the regions within the pump where return flow occurs to the pump inlet, and where potentially damaging shear stresses and flow stagnation might occur: the impeller blade passages and the narrow gap clearance regions between the impeller-rotor and pump housing. Two separate geometry models define the spacing between the pump housing and the impeller's hub and shroud, and a third geometry model defines the pump's impeller and curved blades. The flow fields in these regions were calculated for various operating conditions of the pump. Pump performance curves were calculated, which compare well with experimentally obtained data. For all pump operating conditions, the flow rates within the gap regions were predicted to be toward the inlet of the pump, thus recirculating a portion of the impeller flow. Two smaller gap clearance regions were numerically examined to reduce the recirculation and to improve pump efficiency. The computational and geometry models will be used in future studies of a smaller pump to determine increased pump efficiency and the risk of hemolysis due to shear stress, and to insure the washing of blood through the clearance regions to prevent thrombosis.

Computer Simulation↗
PubMed2002

Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia.

Preclinical models in vitro and in vivo have shown that tumor hypoxia alters the malignant cell phenotype, selecting for p53 mutations, stimulating angiogenesis and metastasis, and markedly reducing the efficacy of both radiotherapy and chemotherapy. Similarly, clinical studies measuring pretreatment tumor oxygen status confirm that the presence of hypoxia confers a negative impact on local control, disease-free survival, and overall survival. Despite these data and extensive past research efforts, the promise of developing selective hypoxic-cell sensitizers has been largely unfulfilled. In contrast, tirapazamine is the rationally designed prototype for a new class of therapeutic agents targeting tumor hypoxia: hypoxic cytotoxins. Tirapazamine is bioreductively activated in hypoxic cells and has been shown to potentiate the cytotoxicity of radiation and a number of chemotherapeutic drug classes, in particular platinum compounds and taxanes. This article reviews the preclinical and clinical development of tirapazamine, as well as current trials in non-small cell lung cancer designed to provide proof of principle for this new category of cancer therapeutics.

Carcinoma, Non-Small-Cell Lung↗
PubMed2002

Analysis of errors in medical rapid prototyping models.

Rapid prototyping (RP) is a relatively new technology that produces physical models by selectively solidifying UV-sensitive liquid resin using a laser beam. The technology has gained a great amount of attention, particularly in oral and maxillofacial surgery. An important issue in RP applications in this field is how to obtain RP models of the required accuracy. We investigated errors generated during the production of medical RP models, and identified the factors that caused dimensional errors in each production phase. The errors were mainly due to the volume-averaging effect, threshold value, and difficulty in the exact replication of landmark locations. We made 16 linear measurements on a dry skull, a replicated three-dimensional (3-D) visual (STL) model, and an RP model. The results showed that the absolute mean deviation between the original dry skull and the RP model over the 16 linear measurements was 0.62 +/- 0.35 mm (0.56 +/- 0.39%), which is smaller than values reported in previous studies. A major emphasis is placed on the dumb-bell effect. Classifying measurements as internal and external measurements, we observed that the effect of an inadequate threshold value differs with the type of measurement.

Algorithms↗
PubMed2002

[Connections between attachment prototypes and relationship patterns].

Connections between attachment styles and relationship patterns are studied on 32 female psychotherapy patients. Our study gives first hints to a connection between attachment variables, assessed by the German version of the Adult Attachment Prototype Rating (AAPR) and predominant relationship patterns, assessed by the Core Conflictual Relationship Theme Method (CCRT) developed by Luborsky, if both methods are used independently. Subsamples according to the attachment styles show differences in CCRT variables.

Adult↗
PubMed1998

Biliary stenting with a prototype expandable Teflon endoprosthesis.

BACKGROUND AND STUDY AIMS: A new balloon-expandable Teflon endoprosthesis was developed for endoscopic placement in the biliary tree. After deployment to its maximum diameter the stent is hardened by exposure to UV light. We present our preliminary results with a prototype 18 Fr prosthesis. PATIENTS AND METHODS: Three patients with a distal common bile duct obstruction due to unresectable pancreatic head carcinoma were treated with this stent. Insertion of the stent was the only palliative procedure. Patients were followed up until stent dysfunction or death. RESULTS: Stent placement was successful in all patients and no procedural complications occurred. Distal migration occurred in one patient, clogging of the stent after 149 days in another. CONCLUSION: In patients with a malignant biliary stricture this newly developed expandable endoprosthesis is effective in relieving obstructive jaundice. The technique has potential advantages over placement of current expandable metal mesh stents.

Aged↗