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PubMed1984

Prognostic value of Q waves, R/S ratio, loss of R wave voltage, ST-T segment abnormalities, electrical axis, low voltage and notching: correlation of electrocardiogram and left ventriculogram.

Data on the correlation of left ventricular segmental wall motion and electrocardiographic findings are, except for Q waves and ST segment elevation, still controversial. Therefore, in addition to Q waves and ST segment elevation, eight features of the electrocardiogram were studied in 265 patients, 61 with normal coronary arteries and 204 with coronary artery disease. Patients with a QRS duration of 0.12 second or greater were excluded. Left ventricular wall motion was assessed in the 30 degrees right anterior oblique and the 60 degrees left anterior oblique projections and analyzed by the Stanford method and a modification of that method, respectively. Asynergy of a particular segment correlated well with the presence of Q waves in the corresponding electrocardiographic lead or leads, but was also found in other segments. There was a significant (p less than 0.001) correlation between the number of leads with Q waves and the degree of extension of asynergy. The R/S ratio in lead V1 and Q waves in lead V6 appeared to be the most informative about the posterior wall. Loss of R wave voltage had a lower predictive value for segmental asynergy than did Q waves in the same lead. Among patients with electrocardiographic findings of an infarct, asynergy was found in 83 to 94%. Patients having Q waves in combination with ST segment elevation manifested more severe asynergy than did patients whose Q waves were not associated with ST elevation. New data are presented for lateral and posterior infarction. Patients having left-axis deviation, low voltage and QRS notching had severe asynergy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Arthroscopic assessment of the posterior compartments of the knee via the intercondylar notch: the arthroscopist's field of view.

This study was undertaken to assess the adequacy of visualization, limits of arthroscopic field of view (FOV), and potential "blind spots" at the periphery of the meniscocapsular junction using standard arthroscopic instrumentation. Five human cadaveric knees were assessed arthroscopically via standard anteromedial and anterolateral portal. Access to the posterior compartments was obtained via the intercondylar notch. FOV was maximized with first a 30 degrees and then a 70 degrees arthroscope, and the farthest point of visualization was marked with a holmium:yttrium-aluminum-garnet (YAG) laser. FOV was calculated as a percentage of the total meniscocapsular periphery. For the lateral compartment, FOV averaged 100.2% with the 30 degrees versus 116.6% with the 70 degrees arthroscope. In all knees, the entire periphery of the lateral meniscocapsular junction could be visualized with the 30 degrees arthroscope anteriorly combined with the 70 degrees arthroscope posteriorly. Medially, FOV averaged 68.9% with a 30 degrees and 88.1% with a 70 degrees arthroscope. A "blind spot" was present in all knees, averaging 21.5% of the meniscocapsular periphery with a 30 degrees arthroscope anteriorly and a 70 degrees arthroscope posteriorly.

Arthroscopy↗
PubMedDate not supplied

Suprascapular nerve entrapment at the spinoglenoid notch caused by a ganglion cyst.

A 34-year-old man had right infraspinatus muscle palsy and posterior aching of the shoulder caused by electromyographically confirmed suprascapular nerve entrapment. Sonography and magnetic resonance imaging revealed a cystic lesion at the spinoglenoid notch; this lesion was diagnosed as a ganglion. Operative removal led to immediate pain relief and incomplete recovery of the compressed branches of the suprascapular nerve.

Adult↗
PubMed2002

APP, Notch, and presenilin: molecular pieces in the puzzle of Alzheimer's disease.

Deposition of the amyloid-beta protein (Abeta) in the form of cerebral plaques is a defining pathological feature of Alzheimer's disease (AD), and all AD-causing genes identified to date affect Abeta production or deposition. For these reasons, the two proteases, beta- and gamma-secretases, that cut out Abeta from the amyloid-beta precursor protein (APP) are considered important targets for the development of therapeutics for AD. AD-causing mutations in the presenilin genes alter y-secretase activity, increasing production of the more deleterious 42-residue form of Abeta. Pharmacological profiling, site-directed mutagenesis, knockout studies, affinity labeling, and activity-dependent chromatography all strongly support the hypothesis that presenilin is an integral component of gamma-secretase, a founding member of an emerging class of polytopic membrane proteases. Gamma-Secretase/ presenilin also cleaves other proteins that are important for critical signaling events (the Notch family of receptors), raising concerns about mechanism-based toxicities that might arise as a consequence of inhibiting this protease. In light of these findings, the potential of gamma-secretase vis-à-vis beta-secretase as therapeutic targets for the prevention or treatment of AD will be discussed.

Alzheimer Disease↗
PubMed1988

Thyroid cartilage at the suprasternal notch with low situated thyroid gland.

The thyroid cartilage and thyroid gland forming a lump at the suprasternal notch is a surprising congenital anomaly which I believe has not been previously reported. A case with co-existent low hyoid bone, pharyngo-oesophageal junction and intrathoracic cricoid cartilage with no cervical trachea is presented. Its pathogenesis is suggested and its surgical importance is discussed.

Abnormalities, Multiple↗
PubMed2002

A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing.

Proteolytic processing of the transmembrane domain of the amyloid precursor protein (APP) is a key component of Alzheimer's disease pathogenesis. Using C-terminally tagged APP derivatives, we have identified by amino-terminal sequencing a novel cleavage site of APP, at Leu-49, distal to the gamma-secretase site. This was termed -cleavage. Brefeldin A treatment and pulse-chase experiments indicate that this cleavage occurs late in the secretory pathway. The level of -cleavage is decreased by expression of presenilin-1 mutants known to impair Abeta formation, and it is sensitive to the gamma-secretase inhibitors MDL28170 and L-685,458. Remarkably, it shares similarities with site 3 cleavage of Notch-1: membrane topology, cleavage before a valine, dependence on presenilins, and inhibition profile.

Alzheimer Disease↗
PubMed2003

Nuclear magnetic resonance structure of a prototype Lin12-Notch repeat module from human Notch1.

Notch1 is a member of a conserved family of large modular heterodimeric type 1 transmembrane receptors that control differentiation in multicellular animals. Receptor maturation is accompanied by a furin-dependent cleavage that converts the Notch1 precursor polypeptide into a heterodimer consisting of an extracellular ligand-binding subunit (NEC) and a transmembrane signaling subunit (NTM). Binding of a physiologic ligand to NEC induces signaling by triggering additional proteolytic cleavages in NTM, which allow its intracellular region to translocate to the nucleus where it participates in a transcriptional activation complex. In the absence of ligand, the three conserved LNR modules of the NEC subunit participate in maintaining the receptor in its resting conformation. Here, we report the solution structure of the first LNR module (LNR_A) of human Notch1, and identify residues of LNR_A perturbed by the presence of the adjacent module LNR_B. LNR_A is held together by a unique arrangement of three disulfide bonds and a single bound Ca(2+) ion, and adopts a novel fold that falls in the general class of irregular disulfide-bonded structures. Residues perturbed by the presence of the adjacent LNR_B module are predominantly hydrophobic, and lie on one face of the module. These studies represent an initial step toward understanding the structural interrelationships among the three contiguous LNR modules required for proper regulation of Notch signaling.

Amino Acid Sequence↗
PubMedDate not supplied

Similarity between cell-cycle genes of budding yeast and fission yeast and the Notch gene of Drosophila.

The HO gene of Saccharomyces cerevisiae encodes the endonuclease that initiates mating-type switching. To prevent inopportune switching, HO transcription is restricted to a specific period in the haploid cell cycle, which is just after, and dependent on, the start of the mitotic cell cycle. A repeated promoter element (CACGA4) (refs 7-9) and two trans-acting activators (SWI4 and SWI6) have been identified, which are responsible for the periodic and start-dependent transcription of HO. To understand further the link between start and HO transcription, the SWI6 gene has been cloned and sequenced. The SWI6 protein is similar to the protein in Schizosaccharomyces pombe that is encoded by cdc10 an essential gene specifically required at the start of the cell cycle. The similarity between the SWI6 and cdc10 products, and their common involvement with 'start', suggest that they may share a common mechanism for sensing or executing this critical control step in the cell cycle. The SWI6 and cdc10 proteins also contain two copies of a repeated motif that occurs at least five times in the cytoplasmic domain of the Notch protein of Drosophila melanogaster.

Amino Acid Sequence↗
PubMed1988

The Caenorhabditis elegans lin-12 gene encodes a transmembrane protein with overall similarity to Drosophila Notch.

The lin-12 gene seems to control certain binary decisions during Caenorhabditis elegans development, from genetic and anatomical studies of lin-12 mutants that have either elevated or reduced levels of lin-12 activity. We report here the complete DNA sequence of lin-12: 13.5 kilobases (kb) derived from genomic clones and 4.5 kb from complementary DNA clones. It is of interest that the predicted product is a putative transmembrane protein, given that many of the decisions controlled by lin-12 activity require cell-cell interactions for the correct choice of cell fate. In addition, the predicted lin-12 product may be classified into several regions, based on amino acid sequence similarities to other proteins. These include extensive overall sequence similarity to the Drosophila Notch protein, which also is involved in cell-cell interactions that specify cell fate; a repeated motif found in proteins encoded by the yeast cell-cycle control genes cdc10 (Schizosaccharomyces pombe) and SWI6 (Saccharomyces cerevisiae); and a repeated motif exemplified by epidermal growth factor, found in many mammalian proteins.

Animals↗
PubMed2005

Notch 2-positive progenitors with the intrinsic ability to give rise to pancreatic ductal cells.

Pancreatic adenocarcinomas display foci of duct-like structures that are positive for markers of pancreatic ductal cells. The development of these tumors is promoted by conditions leading to acinar-to-ductal metaplasia, a process by which acinar cells are replaced by ductal cells. Acinar-to-ductal metaplasia has recently been shown to proceed through intermediary cells expressing Nestin. To create an in vitro system to study pancreatic adenocarcinomas, we had used an hTERT cDNA to immortalize primary cells of the human pancreas. In this report, we show that the immortalized cells, termed hTERT-HPNE cells, have the ability to differentiate to pancreatic ductal cells. Exposing hTERT-HPNE cells to sodium butyrate and 5-aza-2'-deoxycytidine lead to the formation of pancreatic ductal cells marked by the expression of MDR-1, carbonic anhydrase II, and the cytokeratins 7, 8, and 19. hTERT-HPNE cells were found to have properties of the intermediary cells formed during acinar-to-ductal metaplasia, which included their undifferentiated phenotype, expression of Nestin, evidence of active Notch signaling, and ability to differentiate to pancreatic ductal cells. These results provide further evidence for the presence in the adult pancreas of a precursor of ductal cells. hTERT-HPNE cells should provide a useful model to study acinar-to-ductal metaplasia and the role played by this process in pancreatic cancer development.

Adenocarcinoma↗
PubMed2004

Membrane-bound delta-4 notch ligand reduces the proliferative activity of primitive human hematopoietic CD34+CD38low cells while maintaining their LTC-IC potential.

To examine the role of the Notch ligand Delta-4 on hematopoietic stem cells, human CD34+CD38low cord blood cells were cocultured on S17 cells transduced with transmembrane Delta-4 (mbD4/S17) or an empty vector (C/S17). By the end of a 3-week culture, mbD4/S17 induced a 25-fold reduction in nucleated cell production, as compared to C/S17, by maintaining a higher proportion of cells in G0/G1 phase. A specific retention of a high proportion of CD34+ cells throughout the culture was observed with mbD4/S17, contrary to C/S17. Although mbD4/S17 promoted expansion of cells with the phenotype of committed lymphoid precursors (CD34+CD7+CD45RA+), these cells still retained their myeloid differentiation potential. mbD4/S17 maintained a higher LTC-IC frequency in output CD34+ cells, compared to C/S17, as in the subsets of cells having completed the same number of divisions on mbD4/S17. A Delta4-Fc protein (extracellular part of human Delta4 fused to Fc human IgG1 portion), immobilized on plastic, also reduced cell production and retained the LTC-IC potential. Transplantation of cells grown on mbD4/S17 into NOD/SCID mice showed no significant enhancement of the long-term repopulating ability. Thus, Delta4 appears to inhibit hematopoietic stem cell proliferation, in association with the maintenance of short-term lymphoid and myeloid repopulation capacity.

ADP-ribosyl Cyclase↗
PubMed2006

Stable expression of intracellular Notch suppresses v-Src-induced transformation in avian neural cells.

Understanding how disruption of differentiation contributes to the cancer cell phenotype is required to identify alterations essential for malignant transformation and provide experimental basis for their correction. We investigated whether primary quail neuroretina cells, transformed by a conditional v-Src mutant (QNR/v-src(ts)), could revert to a normal phenotype, in response to the stable expression of constitutively active Notch1 intracellular domain (ICN). This model system was chosen because Notch signaling plays an instructive role in cell fate determination during NR development, and because the intrinsic capacity of QNR cultures to differentiate is blocked by v-Src. We report that stable ICN expression results in suppression of QNR/v-src(ts) cell transformation in the presence of an active oncoprotein. This phenotypic reversion coincides with a major switch in cell identity, as these undifferentiated cells acquire glial differentiation traits. Both changes appear to be mediated by CBF, a transcription factor that binds to ICN and activates target genes. Cells restored to a normal and differentiated phenotype have undergone changes in the functioning of signaling effectors, essentially regulating cell morphology and cytoskeleton organization. This dominant interference may be partially mediated by an autocrine/paracrine mechanism, as revertant cells secrete a factor(s), which inhibits transformation properties of QNR/v-src(ts) cells.

Animals↗
PubMed1989

Static acoustic-admittance measures in normal ears: a combined analysis for ears with and without notched tympanograms.

A preliminary database of acoustic-immittance measures in normal adults was provided in an earlier publication (Wiley, Oviatt, & Block, 1987). Here, an additional analysis of static acoustic-admittance measures, based on the original database, is provided. Specifically, compensated static acoustic-admittance data for a 220-Hz probe signal are provided for 239 ears including those that did (N = 55) and did not (N = 184) demonstrate tympanometric notching for a 660-Hz probe signal.

Acoustic Impedance Tests↗
PubMed2001

Maternal diastolic function in asymptomatic pregnant women with bilateral notching of the uterine artery waveform at 24 weeks' gestation: a pilot study.

OBJECTIVE: To study second-trimester maternal cardiac adaptation in asymptomatic patients at risk, on the basis of abnormal uterine artery Doppler, for the development of gestational hypertension or having a small-for-gestational age fetus. Fetal and maternal outcomes were verified at the end of pregnancy. METHODS: Thirty-six normotensive women with abnormal uterine artery waveforms underwent maternal echocardiographic examination at 24 weeks' gestation. RESULTS: Twenty-one women (58.3%) subsequently showed normal outcome; 12 patients developed gestational hypertension (33.3%) and three (8.3%) had small-for-gestational age newborns. Left ventricular outflow tract, left ventricular diastolic dimensions and atrial and ventricular function were significantly lower in the pathological outcome group. Diastolic function parameters were significantly different between the two groups: peak mitral E-wave and A-wave and A-wave duration showed lower values in the pathological outcome group. Isovolumetric relaxation time of the left ventricle was significantly longer in the pathological outcome group. The prevalence of an altered geometric pattern was 14.3% (3/21) in the normal and 80% (12/15) in the pathological outcome groups (P < 0.001). CONCLUSIONS: Women who subsequently develop a complication of pregnancy tend to display abnormal cardiac adaptation. An abnormal placentation process, expressed by an elevated resistance index and the presence of notches in the uterine artery waveform, are likely to cause an adaptative mechanism involving the whole cardiovascular system. A pathological outcome of pregnancy is associated with the failure of this process.

Adult↗
PubMed2001

p48 subunit of mouse PTF1 binds to RBP-Jkappa/CBF-1, the intracellular mediator of Notch signalling, and is expressed in the neural tube of early stage embryos.

BACKGROUND: Development of the pancreas and the nervous tissues is regulated by common transcription factors. A basic helix-loop-helix protein, p48 of pancreas transcription factor 1 (PTF1), is essential for differentiation of the exocrine acinar cells. RESULTS: We isolated PTF1 p48 from 9.5-day mouse embryos as a binding protein of RBP-Jkappa, a mediator of Notch signalling. p48 bound to RBP-Jkappa more strongly than and in a distinct way from Notch1. In 9.5-12.5 day embryos, p48 was expressed in the dorsal part of the neural tube as well as in the pancreatic buds. Two lines of evidence suggested functions of p48 in neurogenesis: (i) expression of p48 was induced in P19 cells when they committed to neural fate upon retinoic acid treatment, and (ii) p48 over-expressed in Xenopus embryos repressed the development of neuronal precursors. p48 inhibited the MASH1-activated transcription from the E-box, while p48 stimulated transcription from the PTF1 motif synergistically with E47. The p48/E47-activated transcription from the PTF1 motif was stimulated further by RBP-Jkappa and RBP-Jkappa derivatives that mimicked the active RBP-Jkappa/Notch complex. CONCLUSIONS: In developing embryos, p48 is expressed in both the nervous system and the pancreas. p48 inhibits neuronal differentiation. We propose possible mechanisms for this inhibition.

3T3 Cells↗
PubMed2004

Symbolic reachable set computation of piecewise affine hybrid automata and its application to biological modelling: Delta-Notch protein signalling.

Hybrid automata are an eminently suitable modelling framework for biological protein regulatory networks, as the protein concentration dynamics inside each biological cell are modelled using linear differential equations; inputs activate or deactivate these continuous dynamics through discrete switches, which themselves are controlled by protein concentrations reaching given thresholds. This paper proposes an iterative refinement algorithm for computing discrete abstractions of a class of hybrid automata with piecewise affine continuous dynamics and forced discrete transitions, defined completely in terms of symbolic variables and parameters. Furthermore, these discrete abstractions are utilised to compute symbolic parametric backward reachable sets from the equilibria of the hybrid automata, that are guaranteed to be exact or conservative under-approximations. The algorithm is then implemented using MATLAB and QEPCAD, to compute reachable sets for the biologically observed equilibria of the multiple cell Delta-Notch protein signalling automaton with symbolic parameters. The results are analysed to show that novel, non-intuitive, and biologically interesting properties can be deduced from the reachability computation, thus demonstrating the utility of the algorithm.

Algorithms↗
PubMed2006

[Early systolic notched peripheral Doppler flow pattern as an indicator of functional obstruction of the common iliac artery after iatrogenic aortic dissection: a case report].

We report on a 57-year-old male patient with typical claudication localised in the right thigh, following aortic valve replacement. The ankle brachial index under resting conditions is within normal range on both sides. A conspicuous monomorphic double-humped peripheral Doppler flow pattern with an early systolic notch extending to the baseline can be registered in all the arteries of the right lower limb. The flow patterns of all other peripheral arteries are properly configured and of triphasic morphology. As the underlying cause of the pathologically altered Doppler flow morphology, aortic dissection Type A can be detected, extending from the former cannulation site of the ascending aorta into the right common iliac artery. Its dissection membrane functionally occludes the right common iliac artery in the early systole, the effect being brief and reversible. The pathogenesis of this morphologically altered Doppler flow pattern and potential differential diagnoses are discussed in this case report, also considering the current literature.

Aortic Dissection↗