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PubMed1991

Descending noradrenergic influences on pain.

Multiple separate and distinct supraspinally organized descending inhibitory systems have been identified which are capable of powerfully modulating spinal nociceptive transmission. Until recently, brainstem sites known to be involved in the centrifugal modulation of spinal nociceptive transmission were few in number, being limited to midline structures in the midbrain and medulla (e.g., periaqueductal gray and nucleus raphe magnus). However, with continued investigation, that number has increased and brainstem sites previously thought to be primarily involved in cardiovascular function and autonomic regulation (e.g., nucleus tractus solitarius; locus coeruleus/subcoeruleus (LC/SC); A5 cell group; lateral reticular nucleus) also have been demonstrated to play a role in the modulation of spinal nociceptive transmission. Spinal monoamines (norepinephrine (NE) and serotonin) have been shown to mediate stimulation-produced descending inhibition of nociceptive transmission from these brainstem sites. The majority of NE-containing fibers and terminations in the spinal cord arise from supraspinal sources; thus, the LC/SC, the parabrachial nuclei, the Kölliker-Fuse nucleus and the A5 cell group have all been suggested as possible sources of the spinal noradrenergic (NA) innervation involved in the centrifugal modulation of spinal nociceptive transmission. Several lines of evidence suggest that the LC/SC plays a significant role in a functionally important descending inhibitory NA system. Focal electrical stimulation in the LC produces an antinociception and increases significantly the spinal content of NA metabolites. The inhibition of the nociceptive tail-flick withdrawal reflex produced by electrical stimulation in the LC/SC has been demonstrated to be mediated by postsynaptic alpha 2-adrenoceptors in the lumbar spinal cord. Similarly, electrical or chemical stimulation given in the LC/SC inhibits noxious-evoked dorsal horn neuronal activity. Thus, results reported in electrophysiological experiments confirm those reported in functional studies and the NA coeruleospinal system appears to play a significant role in spinal nociceptive processing.

Adrenergic Fibers↗
PubMed1985

Effect of host immune status on the spontaneous metastasis of cloned cell lines of the 13762NF rat mammary adenocarcinoma.

The importance of host immune status on the spontaneous metastasis of cloned cell lines of the 13762NF rat mammary adenocarcinoma was examined. Cell lines MTLn3 (high metastatic potential), MTF7 and MTLn2 (intermediate metastatic potential) and MTC (low metastatic potential) were subjected to a series of in vivo assays designed to assess how manipulation of the immune system in the syngeneic F344 host would affect the ability of these cells to metastasise. Treatment of tumour bearing rats with the immunosuppressive agents cyclosporin A or cyclophosphamide had little influence on metastasis in this system. Growth of tumours in congenitally athymic nude rats resulted in reduction of observed metastases. In addition, humoral immune response was not detectable during a 23-day period of tumour growth in F344 rats. Excision of the tumour growing in situ reduced the number of metastases when the tumours were resected early (less than 10 days), but at later times tumour resection did not influence the incidence of metastasis. The importance of initial lymphatic rather than haematogenous routes of dissemination was confirmed in experiments where the draining inguinal and axillary lymph nodes were removed at different times either before, or after, subcutaneous mammary fat pad injection of metastatic tumour cells.

Adenocarcinoma↗
PubMed2004

The mannose-binding lectin-pathway is involved in complement activation in the course of renal ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) is an important cause of acute renal failure (ARF). The complement system appears to be essentially involved in I/R injury. However, via which pathway the complement system is activated and in particular whether the mannose-binding lectin (MBL)-pathway is activated is unclear. This tempted us to study the activation and regulation of the MBL-pathway in the course of experimental renal I/R injury and in clinical post-transplant ARF. Mice subjected to renal I/R displayed evident renal MBL-depositions, depending on the duration of warm ischemia, in the early reperfusion phase. Renal deposition of C3, C6 and C9 was observed in the later reperfusion phase. The deposition of MBL-A and -C completely co-localized with the late complement factor C6, showing that MBL is involved in complement activation in the course of renal I/R injury. Moreover, the degree of early MBL-deposition correlated with complement activation, neutrophil-influx, and organ-failure observed in the later reperfusion phase. In serum of mice subjected to renal I/R MBL-A, levels increased in contrast to MBL-C levels, which dropped evidently. In line, liver mRNA levels for MBL-A increased, whereas MBL-C levels decreased. Renal MBL mRNA levels rapidly dropped in the course of renal I/R. Finally, in human biopsies, MBL-depositions were observed early after transplantation of ischemically injured kidneys. In line with our experimental data, in ischemically injured grafts displaying post-transplant organ-failure extensive MBL depositions were observed in peritubular capillaries and tubular epithelial cells. In conclusion, in experimental renal I/R injury and clinical post-transplant ARF the MBL-pathway is activated, followed by activation of the complement system. These data indicate that the MBL-pathway is involved in ischemia-induced complement activation.

Animals↗
PubMed1990

Differential effects of 12-O-tetradecanoylphorbol 13-acetate on cytochrome P-450-dependent monooxygenase activities in rat hepatoma cells: induction of P-450I and suppression of P-450II.

We have studied the effects of the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) on cytochrome P-450-dependent monooxygenase activities in several differentiated and dedifferentiated Reuber rat hepatoma cell lines using aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH), ethoxyresorufin O-deethylase (EROD), and aldrin epoxidase (AE) as test systems. The following results were obtained: (1) Exposure of cultures to 400 nM TPA for 18-24 h increased AHH activities in the differentiated lines 2sFou, H41IEC3/G- and Fao as well as in the dedifferentiated line 5L, 1.5-2.5-fold. The phorbol ester did not affect AHH activity in the dedifferentiated line H5. (2) EROD, a marker for P-450I, was induced by the phorbol ester to a similar degree as AHH. (3) A monoclonal antibody directed against P-450I strongly inhibited the AHH activity induced by TPA. (4) The onset of AHH or EROD induction by TPA was much later than that elicited by benz[a]anthracene. (6) In contrast to the induction of AHH and EROD, TPA decreased AE activity, a marker for P-450II, by about 50% in all the cell lines containing this monooxygenase activity. (7) The half-maximum-effect concentration of TPA for inducing or suppressing AHH and AE, respectively, was approximately 20 nM. (8) TPA did not interfere with AHH induction by benz[a]anthracene. However, the phorbol ester moderately decreased AHH induction and markedly suppressed AE induction by dexamethasone. The results indicate that TPA simultaneously induces P-450I and suppresses P-450II forms in rat hepatoma cells. P-450I induction by TPA in these cells did not appear to depend on their status of differentiation. Furthermore, the results suggest that the mechanism of P-450I induction by TPA differs from that elicited by polycyclic aromatic hydrocarbons or glucocorticoids.

Animals↗
PubMed1995

Partition of aminoacyl-tRNA synthetases in two different structural classes dating back to early metabolism: implications for the origin of the genetic code and the nature of protein sequences.

We describe, on the molecular level, a possible fuzzy and primordial translation apparatus capable of synthesizing polypeptides from nucleic acids in a world containing a mixture of coevolving molecules of RNA and proteins already arranged in metabolic cycles (including cofactors). Close attention is paid to template-free systems because they are believed to be the immediate ancestors of this primordial translation apparatus. The two classes of aminoacyl-tRNA synthetases (aaRSs), as seen today, are considered as the remnants of such a simple imprecise translation apparatus and are used as guidelines for the construction of the model. Earlier theoretical work by Bedian on a related system is invoked to show how specificity and stability could have been achieved automatically and rather quickly, starting from such an imprecise system, i.e., how the encoded synthesis of proteins could have appeared. Because of the binary nature of the underlying proto-code, the first genetically encoded proteins would then have been alternating copolymers with a high degree of degeneracy, but not random. Indeed, a clear signal for alternating hydrophobic and hydrophilic residues in present-day protein sequences can be detected. Later evolution of the genetic code would have proceeded along lines already discussed by Crick. However, in the initial stages, the translation apparatus proposed here is in fact very similar to the one postulated by Woese, only here it is given a molecular framework. This hypothesis departs from the paradigm of the RNA world in that it supposes that the origin of the genetic code occurred after the apparition of some functional (statistical) proteins first. Implications for protein design are also discussed.

Amino Acid Sequence↗
PubMed2005

Quantitative trait loci controlling root growth and architecture in Arabidopsis thaliana confirmed by heterogeneous inbred family.

Arabidopsis thaliana provides a scientifically attractive and simple model for studying root growth and architecture and, subsequently, for discovering new genes involved in the control of these characters in plants. We have used the natural variation available in Arabidopsis accessions and mapped quantitative trait loci (QTLs) for primary root length (PRL), lateral root number (LRN) and density (LRD) and for total length of the lateral root system (LRL) in the Bay-0 x Shahdara population. Total phenotypic variation was very large, and despite the importance of the environmental component we were able to map 13 QTLs and one epistatic interaction between QTLs. Our results highlight the biological relevance and genetic control of lateral root density in this material. We were also able to show that variation in the extent of the lateral root system depends mainly on the growth of the existing lateral roots rather than in a change in LRN. Factors controlling lateral root growth seemed to have no major effect on primary root growth. Moreover, Shahdara QTL alleles always increased the length of the lateral roots, which may be taken as an adaptation to its very dry natural environment in Tadjikistan. A QTL for PRL was confirmed using a type of near-isogenic line called a heterogeneous inbred family (HIF), and this QTL is a candidate for further fine-mapping and cloning.

Arabidopsis↗
PubMed2002

Two illusions of perceived orientation: one fools all of the people some of the time; the other fools all of the people all of the time.

In a series of three separate experiments, we studied two different orientation illusions, in both of which vertical lines appear tilted as a result of being set against a tilted background pattern. The 'simultaneous tilt illusion' (STI), in which a target grating is viewed within an abutting tilted grating surround, is thought to originate early in the cortical processing of visual contours. In contrast, the 'rod-and-frame' illusion (RFI), which is induced by a distant tilted frame, is thought to originate much later in the perceptual processing system. In the first two experiments we found that orientation-guided action was virtually impervious to the RFI, whereas both perceptual experience and action were equally influenced by the STI. In the third experiment, in which the two illusions were pitted one against the other, an opposite pattern of effects emerged, such that visuomotor performance was now deceived by the illusion much more than was perceptual experience. This pattern of association and dissociation in the effects of visual illusions on perception versus action can best be explained within a two-visual-systems model of cortical processing.

Feedback↗
PubMed2006

Automatic attention orienting by social and symbolic cues activates different neural networks: an fMRI study.

Visual attention can be automatically re-oriented by another person's non-predictive gaze as well as by symbolic arrow cues. We investigated whether the shifts of attention triggered by biologically relevant gaze cues and biologically non-relevant arrow cues rely on the same neural systems by comparing the effects of gaze-cued and arrow-cued orienting on blood oxygenation level-dependent (BOLD) signal in humans. Participants detected laterally presented reaction signals preceded by centrally presented non-predictive gaze and arrow cues. Directional gaze cues and arrow cues were presented in separate blocks. Furthermore, two separate control blocks were run in which non-directional cues (straight gaze or segment of a line) were used. The BOLD signals during the control blocks were subtracted from those during the respective blocks with directional cues. Behavioral data showed that, for both cue types, reaction times were shorter on congruent than incongruent trials. Imaging data revealed three foci of activation for gaze-cued orienting: in the left inferior occipital gyrus and right medial and inferior occipital gyri. For arrow-cued orienting, a much more extensive network was activated. There were large postcentral activations bilaterally including areas in the medial/inferior occipital gyri and medial temporal gyri and in the left intraparietal area. Interestingly, arrow cuing also activated the right frontal eye field and supplementary eye field. The results suggest that attention orienting by gaze cues and attention orienting by arrow cues are not supported by the same cortical network and that attention orienting by symbolic arrow cues relies on mechanisms associated with voluntary shifts of attention.

Adult↗
PubMed2004

Lymphatic malformation of the sphenoid sinus in a pediatric patient.

UNLABELLED: Lymphatic malformation is a benign vascular lesion resulting from lymphatic tissue being isolated from the remainder of the lymphatic system. They are present at birth and up to 90% are diagnosed by 2 years of age. More aggressive lesions are usually diagnosed earlier, with low-grade lesions presenting later with fewer complications. These lesions are hamartomas and not true neoplasms. The term hamartoma is used to describe an abnormally large mass of histologically normal tissue in a normal location. The lymphatic malformation is composed of lymph-filled channels lined with a single layer of flat endothelial cells on a basement membrane. They present with either generalized edema and poorly defined borders (microcystic) or a localized area of multilocular cysts (macrocystic). The term lymphatic malformation has replaced many other outdated terms, such as lymphangioma, cystic hygroma, lymphangioma circumscriptum, and lymphangiomatosis. In this study, we present a case report of a pediatric lymphatic malformation of the sphenoid sinus. To our knowledge, this lesion has not been described in the pediatric population and has been described only once in an adult in the German literature. EBM RATING: C.

Child↗
PubMedDate not supplied

Cyclooxygenase and 5-lipoxygenase inhibitors protect against mononuclear phagocyte neurotoxicity.

Neuroinflammation and oxidative stress are believed to be contributing factors to neurodegeneration in normal aging, as well as in age-related neurological disorders. Reactive microglia are found in increased numbers in aging brain and are prominently associated with lesions in such age-related degenerative conditions as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). In vitro, stimulated microglia or microglial-like cells secrete neurotoxic materials and are generators of free radicals through their respiratory burst system. Agents that suppress microglial activation are therefore candidates for neuroprotection. We have developed quantitative in vitro assays for measuring neurotoxicity of microglia or other mononuclear phagocytes. Neuronal like SH-SY5Y cells are cultured in supernatants from activated cells of the human monocytic THP-1 line and their survival is followed. Respiratory burst is directly measured on the activated cells. We tested inhibitors of the cyclooxygenase (COX) or the 5-lipoxygenase (5-LOX) pathways as possible neuroprotective agents. The COX pathway generates inflammatory prostaglandins, while the 5-LOX pathway generates inflammatory leukotrienes. We found that inhibitors of both these pathways suppressed neurotoxicity in a dose-dependent fashion. They included the COX-1 inhibitor indomethacin; the COX-2 inhibitor NS-398; the mixed COX-1/COX-2 inhibitor ibuprofen; the nitric oxide (NO) derivatives of indomethacin, ibuprofen and flurbiprofen; the 5-LOX inhibitor REV 5901; and the 5-LOX activating protein (FLAP) inhibitor MK-886. The FLAP inhibitor also reduced respiratory burst activity in a more potent manner than indomethacin. Combinations of COX and 5-LOX inhibitors were more effective than single inhibitors. The data suggest that both COX inhibitors and 5-LOX inhibitors may be neuroprotective in vivo by suppressing toxic actions of microglia/macrophages, and that combinations of the two might have greater therapeutic potential than single inhibitors of either class.

Aging↗
PubMed2002

Prediction of intestinal absorption: comparative assessment of GASTROPLUS and IDEA.

We have assessed two commercial software tools employing physiologically based models for prediction of intestinal absorption in human. IDEA 2.0 and GASTROPLUS 3.1.0 were compared both in their ability to predict fraction absorbed for a set of 28 drugs and in terms of the functionality offered. The emphasis was placed on the practical usefulness to pharmaceutical drug discovery. Predictions were assessed for three levels of input data (i) pure in silico input, (ii) thermodynamic solubility and in silico permeability, (iii) thermodynamic solubility and human colon carcinoma cell line (CACO-2) permeability. We found the pure in silico prediction ability of the tools to be comparable with 70% correct classification rate. With measured input data the IDEA prediction rate improved to 79% while GASTROPLUS stayed at 70%. In terms of functionality GASTROPLUS is a powerful system for the trained user. Open access to model parameters, diagnostic tools and the ability to integrate data make it particularly suitable for the later stages of discovery and development. IDEA is web based and presents a simple interface suitable for widespread use with minimal training. However the limited functionality and inconvenient handling of multiple compound batches currently restrict the usefulness of version 2.0 for drug discovery.

Intestinal Absorption↗
PubMedDate not supplied

Ghostbursting: a novel neuronal burst mechanism.

Pyramidal cells in the electrosensory lateral line lobe (ELL) of weakly electric fish have been observed to produce high-frequency burst discharge with constant depolarizing current (Turner et al., 1994). We present a two-compartment model of an ELL pyramidal cell that produces burst discharges similar to those seen in experiments. The burst mechanism involves a slowly changing interaction between the somatic and dendritic action potentials. Burst termination occurs when the trajectory of the system is reinjected in phase space near the "ghost" of a saddle-node bifurcation of fixed points. The burst trajectory reinjection is studied using quasi-static bifurcation theory, that shows a period doubling transition in the fast subsystem as the cause of burst termination. As the applied depolarization is increased, the model exhibits first resting, then tonic firing, and finally chaotic bursting behavior, in contrast with many other burst models. The transition between tonic firing and burst firing is due to a saddle-node bifurcation of limit cycles. Analysis of this bifurcation shows that the route to chaos in these neurons is type I intermittency, and we present experimental analysis of ELL pyramidal cell burst trains that support this model prediction. By varying parameters in a way that changes the positions of both saddle-node bifurcations in parameter space, we produce a wide gallery of burst patterns, which span a significant range of burst time scales.

Action Potentials↗
PubMed1997

Gene therapy for peritoneal dissemination of pancreatic cancer by liposome-mediated transfer of herpes simplex virus thymidine kinase gene.

Peritoneal dissemination is one of the most common complications of the malignancies of the digestive system, such as gastric or pancreatic cancers. Yet, no effective therapy has been established so far to alleviate this devastating and often fatal end-stage condition. Here we describe a novel approach of intraperitoneal (i.p.) lipofection of a suicidal gene to the pancreatic cancer cells in a mouse peritoneal dissemination model. A human pancreatic cancer cell line, PSN-1, was inoculated into the peritoneal cavity of nude mice. Eight days later, a herpes simplex virus thymidine kinase (HSV-TK) gene expression plasmid under a potent hybrid promoter CAG was injected as a DNA-lipopolyamine complex. Ganciclovir (GCV) was then administered for 8 days, and the mice were examined for tumor development at the 24th day after the tumor inoculation. Although all 24 control mice showed macroscopic peritoneal dissemination and solid tumors on the pancreas, 8 of the 14 mice treated with HSV-TK and GCV were free of tumors, and only a few small tumors were observed in the remaining 6 mice. Treatment-related toxicity was not observed. The semiquantitative reverse transcription polymerase chain reaction (RT-PCR) analysis suggested that the HSV-TK transgene was expressed in about 10% of tumor cells but not in the normal pancreas or in the small intestine. When the lacZ gene was transduced in place of the HSV-TK gene, the blue-stained cells were identified only in tumor nodules and not in normal organs. This preclinical study suggests the therapeutic feasibility of the i.p. lipofection-based suicidal gene/prodrug strategy for peritoneal dissemination of pancreatic cancer.

Animals↗
PubMed2006

Two and three-dimensional computed tomography for the classification and management of distal humeral fractures. Evaluation of reliability and diagnostic accuracy.

BACKGROUND: Complex fractures of the distal part of the humerus can be difficult to characterize on plain radiographs and two-dimensional computed tomography scans. We tested the hypothesis that three-dimensional reconstructions of computed tomography scans improve the reliability and accuracy of fracture characterization, classification, and treatment decisions. METHODS: Five independent observers evaluated thirty consecutive intra-articular fractures of the distal part of the humerus for the presence of five fracture characteristics: a fracture line in the coronal plane; articular comminution; metaphyseal comminution; the presence of separate, entirely articular fragments; and impaction of the articular surface. Fractures were also classified according to the AO/ASIF Comprehensive Classification of Fractures and the classification system of Mehne and Matta. Two rounds of evaluation were performed and then compared. Initially, a combination of plain radiographs and two-dimensional computed tomography scans (2D) were evaluated, and then, two weeks later, a combination of radiographs, two-dimensional computed tomography scans, and three-dimensional reconstructions of computed tomography scans (3D) were assessed. RESULTS: Three-dimensional computed tomography improved both the intraobserver and the interobserver reliability of the AO classification system and the Mehne and Matta classification system. Three-dimensional computed tomography reconstructions also improved the intraobserver agreement for all fracture characteristics, from moderate (average kappa [kappa2D] = 0.554) to substantial agreement (kappa3D = 0.793). The addition of three-dimensional images had limited influence on the interobserver reliability and diagnostic characteristics (sensitivity, specificity, and accuracy) for the recognition of specific fracture characteristics. Three-dimensional computed tomography images improved intraobserver agreement (kappa2D = 0.62 compared with kappa3D = 0.75) but not interobserver agreement (kappa2D = 0.24 compared with kappa3D = 0.28) for treatment decisions. CONCLUSIONS: Three-dimensional reconstructions improve the reliability, but not the accuracy, of fracture classification and characterization. The influence of three-dimensional computed tomography was much more notable for intraobserver comparisons than for interobserver comparisons, suggesting that different observers see different things in the scans-most likely a reflection of the training, knowledge, and experience of the observer with regard to these relatively uncommon and complex injuries.

Adult↗
PubMed1985

Effects of divalent cations on the interaction of platelets with tumor cells: aggregation and perfusion studies with two homologous human systems.

The effects of chelation of divalent cations in the interaction of platelets and tumor cells has been studied in a homologous human system using human platelet-rich plasma and two tumor cell lines of human origin: SKNMC (neuroblastoma) cells, which cause platelet aggregation by an adenosine diphosphate-dependent mechanism, and U87MG (glioblastoma) cells, which function by a thrombin-dependent mechanism. When added at zero time, citrate 14 mmol/L completely abolished aggregation in heparinized (5 U/ml) platelet-rich plasma by either cell line, but the degree of inhibition was reduced by later addition of the chelating agent. Calcium citrate 8 mmol/L reduced by only 10%, indicating that citrate anion was not responsible for the inhibition. Addition of Ca++ or Mg++ alone or in combination at concentrations up to 1.5 mmol/L did not reverse the inhibition. Addition of higher concentrations of Ca++ (2 mmol/L) caused immediate clotting, whereas concentrations of Mg++ up to 6 mmol/L were without effect. Inhibition could be reversed by washing the platelets free of citrate and resuspending in heparinized platelet-rich plasma. Aggregation by either cell line was inhibited by EDTA and EGTA. In the Baumgartner perfusion apparatus, platelet interaction with subendothelium was increased about 50-fold in the presence of SKNMC cells, but this effect was also abolished after addition of citrate. After addition of U87MG cells to heparinized PRP, there was a 400-fold increase in platelet interaction with subendothelium, and complex thrombi containing red cells, white cells, and fibrin were formed. This stimulation was reduced to control levels by addition of citrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Platelets↗
PubMed1995

Isokinetic cycle ergometer--application in sports medicine.

Paper deals with application of fully computerized isokinetic cycle ergometer with on-line registration of effective crank force in sports medicine, namely in functional diagnostic and rehabilitation. The system allows to carry out the time and position course analyses of effective pedal force and power produced at various revolution rates. Maximal or mean values of force and power produced by action of right and left leg may be used for the estimation of strength as well as for detection and quantitative assessment of lateral functional deficit for example due to injury. Short term bouts on isokinetic cycle ergometer may be applied as an effective means for the improvement of strength of lower extremities in patients as well as in competitive cyclists. The estimation of individual fluctuation of effective force (i.e. differences between maxima at horizontal and minima at vertical crank position) may be used for the evaluation of pedalling technique. Short term all-out efforts at various cadences allow to register not only peak and mean force and power at particular revolution rates, but also to estimate an optimal individual revolution rate, i.e. those allowing to produce highest power output. Such information can be employed for diagnostic assessment of anaerobic capabilities, namely in cyclists. Isokinetic cycling with self-controlled effort may be also used as a comfortable aerobic exercise. It may be concluded that isokinetic cycle ergometer represents a valuable diagnostic as well as therapeutic tool, which may be utilized in several areas of sports medicine.

Adult↗
PubMed1991

Cultured proliferating rat mammary epithelial cells.

Normal epithelial cells from the rat mammary gland proliferated in culture when plated with lethally irradiated cells of the LA7 rat mammary tumor line. Proliferation of the normal rat cells occurred as the LA7 cells slowly died from the radiation. By labeling the cultures with 3H-thymidine it was determined that most of the proliferating rat cells were those adjacent to the LA7 feeder cells. The epithelial cells from the primary culture proliferated after subsequent passages if the cells were plated at each subculture with newly irradiated LA7 cells. If the cells were plated at a ratio of approximately 1:8 rat:LA7 a confluent layer of normal rat cells covered the plastic substrate after 6 to 7 wk. The cells have so far been carried up through Passage 7, which amounted to approximately 19 doublings in cell number, and still proliferate vigorously. The growth medium for this culture system was Dulbecco's modified Eagle's medium:Ham's F12 1:1 supplemented with fetal bovine serum, insulin, and antibiotics. The presence in the cells of keratin, desmosomes, and cell junctions attested to their epithelial origin. The cultures were composed of cells with diploid or near diploid chromosome numbers. Samples of the cultured cells were implanted into the cleared fat pads of nude mice. Most of the implants from Passage 2 formed normal mammary ductal structures, but the incidence of outgrowths decreased significantly with later passages until no outgrowths resulted from the implantation of cells from Passage 5. The one unusual, feeder-independent cell line that arose from a primary culture seemed to be immortal in culture, contained a hyperdiploid chromosome complement, and formed abnormal structures when implanted into cleared fat pads.

Animals↗
PubMed1998

[Asynchrony of ventricular contraction and relaxation--pathophysiologically recognized phenomenon, now can be clinically assessed].

When regional myocardial dysfunction is present, the physiological pattern of ventricular filling and contraction is impaired. During acute coronary occlusion, characteristic changes are observed in the ischemic myocardial segment: the amplitude of the systolic wall thickening is reduced (hypokinesia), then virtually absent (akinesia) and finally replaced by a paradoxical outward motion (dyskinesia). The maximum amplitude is reached in early diastole ("post-ejection thickening"). Since hyperkinesis develops in the normal region, the ischemic and the normal region contract asynchronously. Experimentally left ventricular asynchrony can be detected by means of subendo- and subepicardially implanted ultrasonic crystals ("sonomicrometry") or by the analysis of the phase difference of the first Fourier harmonic of dysfunctional versus control myocardial wall motion. In the clinical setting, digitized cineventriculography, radionuclide angiography and digitized M-mode echocardiography were used to assess left ventricular asynchrony in patients with coronary artery disease and hypertrophic cardiomyopathy. However, these imaging modalities are time-consuming and require complicated off-line analysis. Tissue Doppler echocardiography (TDE) is a new ultrasound modality that is based on color Doppler principles and allows for quantification of myocardial wall motion velocity by detection of consecutive phase shifts of the ultrasound signal reflected from the myocardium. The Doppler signals are displayed as a color or pulsed Doppler image by rejecting low-amplitude echoes from the blood pool due to changes in thresholding and filtering algorithms. In addition, the ability to measure low velocity is improved in the TDE system so that the lowest measurable velocity is 0.2 cm/s, a velocity level associated with cardiac tissue motion (Table 1). Due to its high temporal and spatial resolution, TDE provides valuable information on regional myocardial wall motion during different intervals of the cardiac cycle. In healthy subjects, patients with coronary artery disease and patients with hypertrophic cardiomyopathy, tissue Doppler echocardiography was used to assess myocardial synchrony/asynchrony on a 2-fold temporal and spatial analysis. Peak myocardial velocities in different myocardial regions were detected during rapid ejection, isovolumic relaxation, rapid filling and atrial contraction (Figure 1). In the apical view, during the isovolumic relaxation time (IVRT) healthy subjects showed slow, synchronous outward motion of the septum and the lateral wall with homogeneous color-encoding (blue/green, Figure 2). Analysis of peak velocities revealed low, negative velocities in both the septum and the lateral wall (Figure 3). In patients with a significant luminal narrowing of the LAD myocardial asynchrony was detected during the isovolumic relaxation period: while the septum was moving inwards (red color-encoding with low, positive velocities), the lateral wall was moving outwards (blue/green encoding, low, negative velocities). A representative example of a patient with CAD is given in Figure 4. The M-mode analysis of the abnormally contracting interventricular septum reveals positive peak tissue velocities during the isovolumic relaxation period (Figure 5). In hypertrophic cardiomyopathy, TDE was able to detect an abnormal inward motion of the interventricular septum during IVRT and a delay in the onset of rapid filling (Figure 6). Thus, tissue Doppler echocardiography is a feasible method for the on-line detection of myocardial asynchrony. Sensitivity and specificity of the findings have to be explored in further, prospectively randomized trials.

Cardiomyopathy, Hypertrophic↗