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Femoral intercondylar notch stenosis and correlation to anterior cruciate ligament injuries. A prospective study.

To evaluate the possible relationship between femoral intercondylar notch stenosis and anterior cruciate ligament injuries in pivoting and cutting sports, a 2-year prospective study was performed on intercollegiate athletes at a Division I university. Daily practice times and athlete participation in practices and games were recorded for each sport during the 2-year period. Bilateral intercondylar notch view radiographs were taken of all athletes enrolled in the study. The notch width index, a ratio that measures the width of the anterior outlet of the intercondylar notch divided by the total condylar width at the level of the popliteal groove, was measured for each knee. A total of 213 athletes, representing 415 anterior cruciate ligament-intact knees, were enrolled in the study. There were 7 anterior cruciate ligament tears. Statistical analysis demonstrated a correlation between femoral intercondylar notch stenosis and anterior cruciate ligament injuries. No statistical difference was found between the sex of the athlete and notch width indices or rate of anterior cruciate ligament tears. Athletes with intercondylar notch stenosis appear to be at increased risk for noncontact anterior cruciate ligament injuries.

Adult↗
PubMed2006

Reverse transcription-polymerase chain reaction on pooled samples to detect bovine viral diarrhea virus by using fresh ear-notch-sample supernatants.

Ear-notch samples from 3,599 yearling heifers were collected to detect persistently infected (PI) animals with suspect bovine viral diarrhea virus (BVDV). Individual immunohistochemistry (IHC), individual antigen-capture enzyme-linked immmunosorbent assay (AC-ELISA), and reverse transcription-polymerase chain reaction (RT-PCR) tests with pooled ear-notch supernatants were compared with samples from 3,016 heifers, whereas RT-PCR ear-notch pools and individual AC-ELISA tests were compared with samples from all 3,599 heifers. Four heifers were identified positive by both IHC and AC-ELISA, whereas the remaining heifers were identified negative by both tests. When supernatant from ear notches from 100 animals was randomly pooled and RT-PCR was accomplished on each pool, RT-PCR identified 2 pools that contained 1 positive AC-ELISA sample and 1 pool that contained 2 positive AC-ELISA samples. Further evaluation of the pooled RT-PCR ear-notch supernatant detected 100% (n = 36) samples spiked with supernatant from a single randomly selected positive AC-ELISA ear notch. Although follow-up confirmatory tests were not completed, all 3 methods correlated 100% in detecting suspect PI animals, with a kappa value of 1. The use of RT-PCR on pooled ear-notch supernatant could provide an initial, rapid, cost-effective method of screening cattle herds for BVDV PI animals. Subsequent serial testing with an AC-ELISA to evaluate individual samples included in the positive pool could minimize the length of time other animals are exposed to the virus.

Animals↗
PubMed2001

The Notch ligand, Delta-1, inhibits the differentiation of monocytes into macrophages but permits their differentiation into dendritic cells.

Notch-mediated cellular interactions are known to regulate cell fate decisions in various developmental systems. A previous report indicated that monocytes express relatively high amounts of Notch-1 and Notch-2 and that the immobilized extracellular domain of the Notch ligand, Delta-1 (Delta(ext-myc)), induces apoptosis in peripheral blood monocytes cultured with macrophage colony-stimulating factor (M-CSF), but not granulocyte-macrophage CSF (GM-CSF). The present study determined the effect of Notch signaling on monocyte differentiation into macrophages and dendritic cells. Results showed that immobilized Delta(ext-myc) inhibited differentiation of monocytes into mature macrophages (CD1a+/-CD14+/- CD64+) with GM-CSF. However, Delta(ext-myc) permitted differentiation into immature dendritic cells (CD1a+CD14-CD64-) with GM-CSF and interleukin 4 (IL-4), and further differentiation into mature dendritic cells (CD1a+CD83+) with GM-CSF, IL-4, and tumor necrosis factor-alpha (TNF-alpha). Notch signaling affected the differentiation of CD1a-CD14+ macrophage/dendritic cell precursors derived in vitro from CD34+ cells. With GM-CSF and TNF-alpha, exposure to Delta(ext-myc) increased the proportion of precursors that differentiated into CD1a+CD14- dendritic cells (51% in the presence of Delta(ext-myc) versus 10% in control cultures), whereas a decreased proportion differentiated into CD1a-CD14+ macrophages (6% versus 65%). These data indicate a role for Notch signaling in regulating cell fate decisions by bipotent macrophage/dendritic precursors.

Antigens, Differentiation↗
PubMed2001

Delta-Notch signaling and lateral inhibition in zebrafish spinal cord development.

BACKGROUND: Vertebrate neural development requires precise coordination of cell proliferation and cell specification to guide orderly transition of mitotically active precursor cells into different types of post-mitotic neurons and glia. Lateral inhibition, mediated by the Delta-Notch signaling pathway, may provide a mechanism to regulate proliferation and specification in the vertebrate nervous system. We examined delta and notch gene expression in zebrafish embryos and tested the role of lateral inhibition in spinal cord patterning by ablating cells and genetically disrupting Delta-Notch signaling. RESULTS: Zebrafish embryos express multiple delta and notch genes throughout the developing nervous system. All or most proliferative precursors appeared to express notch genes whereas subsets of precursors and post-mitotic neurons expressed delta genes. When we ablated identified primary motor neurons soon after they were born, they were replaced, indicating that specified neurons laterally inhibit neighboring precursors. Mutation of a delta gene caused precursor cells of the trunk neural tube to cease dividing prematurely and develop as neurons. Additionally, mutant embryos had excess early specified neurons, with fates appropriate for their normal positions within the neural tube, and a concomitant deficit of late specified cells. CONCLUSIONS: Our results are consistent with the idea that zebrafish Delta proteins, expressed by newly specified neurons, promote Notch activity in neighboring precursors. This signaling is required to maintain a proliferative precursor population and generate late-born neurons and glia. Thus, Delta-Notch signaling may diversify vertebrate neural cell fates by coordinating cell cycle control and cell specification.

Animals↗
PubMed2005

Two contrasting roles for Notch activity in chick inner ear development: specification of prosensory patches and lateral inhibition of hair-cell differentiation.

Lateral inhibition mediated by Notch is thought to generate the mosaic of hair cells and supporting cells in the inner ear, but the effects of the activated Notch protein itself have never been directly tested. We have explored the role of Notch signalling by transiently overexpressing activated Notch (NICD) in the chick otocyst. We saw two contrasting consequences, depending on the time and site of gene misexpression: (1) inhibition of hair-cell differentiation within a sensory patch; and (2) induction of ectopic sensory patches. We infer that Notch signalling has at least two functions during inner ear development. Initially, Notch activity can drive cells to adopt a prosensory character, defining future sensory patches. Subsequently, Notch signalling within each such patch mediates lateral inhibition, restricting the proportion of cells that differentiate as hair cells so as to generate the fine-grained mixture of hair cells and supporting cells.

Animals↗
PubMed1992

Notch2: a second mammalian Notch gene.

Notch is a cell surface receptor that mediates a wide variety of cellular interactions that specify cell fate during Drosophila development. Recently, homologs of Drosophila Notch have been isolated from Xenopus, human and rat, and the expression patterns of these vertebrate proteins suggest that they may be functionally analogous to their Drosophila counterpart. We have now identified a second rat gene that exhibits substantial nucleic and amino acid sequence identity to Drosophila Notch. This gene, designated Notch2, encodes a protein that contains all the structural motifs characteristic of a Notch protein. Thus, mammals differ from Drosophila in having more than one Notch gene. Northern and in situ hybridisation analyses in the developing and adult rat identify distinct spatial and temporal patterns of expression for Notch1 and Notch2, indicating that these genes are not redundant. These results suggest that the great diversity of cell-fate decisions regulated by Notch in Drosophila may be further expanded in vertebrates by the activation of distinct Notch proteins.

Amino Acid Sequence↗
PubMed2000

Activation of the Notch pathway in the hair cortex leads to aberrant differentiation of the adjacent hair-shaft layers.

Little is known about the mechanisms underlying the generation of various cell types in the hair follicle. To investigate the role of the Notch pathway in this process, transgenic mice were generated in which an active form of Notch1 (Notch(DeltaE)) was overexpressed under the control of the mouse hair keratin A1 (MHKA1) promoter. MHKA-Notch(DeltaE) is expressed only in one precursor cell type of the hair follicle, the cortex. Transgenic mice could be easily identified by the phenotypes of curly whiskers and wavy, sheen pelage hair. No effects of activated Notch on proliferation were detected in hair follicles of the transgenic mice. We find that activating Notch signaling in the cortex caused abnormal differentiation of the medulla and the cuticle, two neighboring cell types that did not express activated Notch. We demonstrate that these non-autonomous effects are likely caused by cell-cell interactions between keratinocytes within the hair follicle and that Notch may function in such interactions either by directing the differentiation of follicular cells or assisting cells in interpreting a gradient emanating from the dermal papilla.

Animals↗
PubMed2002

her1 and the notch pathway function within the oscillator mechanism that regulates zebrafish somitogenesis.

Somite formation is thought to be regulated by an unknown oscillator mechanism that causes the cells of the presomitic mesoderm to activate and then repress the transcription of specific genes in a cyclical fashion. These oscillations create stripes/waves of gene expression that repeatedly pass through the presomitic mesoderm in a posterior-to-anterior direction. In both the mouse and the zebrafish, it has been shown that the notch pathway is required to create the stripes/waves of gene expression. However, it is not clear if the notch pathway comprises part of the oscillator mechanism or if the notch pathway simply coordinates the activity of the oscillator among neighboring cells. In the zebrafish, oscillations in the expression of a hairy-related transcription factor, her1 and the notch ligand deltaC precede somite formation. Our study focuses on how the oscillations in the expression of these two genes is affected in the mutants aei/deltaD and des/notch1, in 'morpholino knockdowns' of deltaC and her1 and in double 'mutant' combinations. This analysis indicates that these oscillations in gene expression are created by a genetic circuit comprised of the notch pathway and the notch target gene her1. We also show that a later function of the notch pathway can create a segmental pattern even in the absence of prior oscillations in her1 and deltaC expression.

Animals↗
PubMed2001

Implication of APP secretases in notch signaling.

Signaling via notch receptors and their ligands is an evolutionary ancient and highly conserved mechanism governing cell-fate decisions throughout the animal kingdom. Upon ligand binding, notch receptors are subject to a two-step proteolysis essential for signal transduction. First, the ectodomain is removed by an enzyme cleaving near the outer-membrane surface ("site2"). Consecutively, the notch intracellular domain is liberated by a second protease cutting within the transmembrane sequence ("site3"). The intracellular domain is then transferred to the nucleus to act as a transcriptional coactivator. The proteases involved in notch receptor activation are shared with other proteins undergoing regulated intramembrane proteolysis, with intriguing parallels to APP. Specifically, site3 cleavage of Notch, as well as gamma-secretase processing of APP depend both critically on presenilins 1 and 2. Moreover, ADAM 10 and ADAM 17, the proteases proposed to perform site2 cleavage, are also the most probable candidate alpha-secretases to cleave APP. While the biological significance of APP processing remains to be further elucidated, interference with notch signaling has been shown to have severe consequences both in small animal models as well as in humans. Thus, a growing number of long known genetic syndromes like Alagille syndrome or Fallot's tetralogy can be caused by mutations of genes relevant for the notch signaling pathway. Likewise, the anticipated interference of gamma-secretase inhibitors with site3 cleavage may turn out to be a major obstacle for this therapeutic approach to Alzheimer's disease.

ADAM Proteins↗
PubMed2003

Aspects of mandibular morphology, with specific reference to the antegonial notch and the curve of Spee.

The purpose of this investigation was to determine whether particular metrical traits of the mandibular antegonial notches are associated with specific mandibular growth patterns, and also with the mean depth of the curve of Spee. Thirty pre-treatment lateral cephalometric radiographs belonging to a randomly selected group of patients treated in the orthodontic clinic at the SUNY at Buffalo were digitized. The surface areas of the mandibular antegonial notches, as well as some sagittal facial dimensions were measured on each radiograph. The curve of Spee was measured directly from the pre-treatment mandibular study cast of each patient included in this study. An analysis of variance showed no statistically significant difference (p < 0.01) between the measurements recorded by the two examiners who conducted this study. The results of this study showed a statistically significant positive correlation between the surface areas of the antegonial notches and the lower anterior facial heights (r = 0.87, P < 0.001). At the same time a statistically significant negative correlation was found between the surface areas of the antegonial notches and the lengths of the mandibular bodies (r = -0.9, P < 0.001). A significant negative statistical relationship was shown to exist between the lower anterior facial heights and the lengths of the corresponding mandibular bodies, and also between the depths of the curves of Spee and the surface area of the respective antegonial notches (r = -0.85, P < 0.002). The results of this study indicate that an increase in the areas of the antegonial notches is associated with a tendency for greater vertical growth of the mandible. The results further suggest that the depth of the curve of Spee and the length of the mandibular body are decreased when there is an increase in the surface areas of the antegonial notches.

Adolescent↗
PubMed2003

[Study on the location of mandibular foramen and the measurement of sigmoid notch and ramus].

OBJECTIVE: To compare the location of mandibular foramen in male and female,ang to observe and measure the sigmoid notch and ramus. METHODS: The mandibles of 74 male and 79 female adults from Shanghai were used for the study. The vertical dimension from the center of mandibular foramen to the lowest point of sigmoid notch and the horizontal distance to the posterior margin of ramus were measured,including the depth and the width of sigmoid notch and the height of ramus. The figures were compared between male and female adults. RESULTS: The average distance of mandibular foramen to ramus and sigmoid notch in men and women were 16.75mm,24.50mm and 16.08mm,23.13mm. The average width and depth of sigmoid notch in men and women were 34.20mm,15.33mm and 32.69mm,14.49mm. The average height of ramus in men and women were 61.62mm,57.19mm. CONCLUSION: The difference of vertical dimension from the center of mandibular foramen to the lowest point of sigmoid notch and the horizontal distance to the posterior margin of ramus between male and female adults was not significant, and that of the depth and the width of sigmoid notch and the height of ramus between male and female adults was not significant,either.

Adult↗
PubMed2001

[A comparative study of craniofacial morphologic differences between groups with shallow and deep antegonial notch depth].

OBJECTIVE: To evaluate the correlation between craniofacial morphology and antegonial notch depth of the mandible. METHODS: 42 patients of ear ly permanent dentition from Nanchang city, 21 with shallow and 21 with deep antegonial notch were selected. Lateral cephalometric film before treatment were taken. Hard tissue angular and linear measurement were performed. The correlation between antegonial notch depth and craniofacial morphology were analysed statistically. RESULTS: The angular measurements of SN-GoGn, S-ArGo, FH-GoMe,and ANS-Xi-Pm were significantly greater in the deep antegonial notch group. Other angles as SNB, SNP-BaN-CCGn, FH-NPg and MD-AA were significantly greater in the shallow antegonial notch group. For the linear measurements, those items as N-Me, ANS-Me,Convexity and LM-GoGn were significantly greater in the deep antegonial notch group. CONCLUSION: The deep antegonial notch group showed steeper mandibular plane, smaller chin, greater anterior facial height and gonial angle, and has a mandible with more backward and downward growth.

English Abstract↗
PubMed1991

Auditory brainstem response to clicks in quiet, notch noise, and highpass noise.

Auditory brainstem responses to clicks in quiet, notch noise, and highpass noise were recorded from 10 normal-hearing adults. Contrary to some reports, the latency of wave V increased as the center frequency of the notch decreased. Response identifiability and wave V amplitudes were similar for the notch and highpass noises. Thus, the additional frequencies below the notch did not contribute sufficiently to the response to alter identifiability or amplitude. Notch noise, as compared to the highpass noise, is advantageous because of the increased frequency-specificity provided by the low-frequency masking noise. Presenting clicks in highpass or notch noise centered at 500 Hz is of limited value for assessing auditory sensitivity. This is because the range of testable hearing levels is restricted by (1) a high normal ABR threshold (approximately 65 dB nHL) and (2) the high noise levels required to mask the click. This limited dynamic range for assessing hearing loss is a major limitation of click in noise testing, particularly for 500 Hz. Generating a two-point audiogram by presenting clicks in noise with notches centered around 1000 Hz and 4000 Hz may prove promising for assessing auditory sensitivity.

Acoustic Stimulation↗
PubMed2006

Why is delta endocytosis required for effective activation of notch?

A number of recent studies have shown that endocytosis of Notch ligands is required for activation of Notch. There are at least two broad models that account for how Delta endocytosis in one cell might contribute to activation of Notch in the neighboring cell. The first class of models is related to the possibility that Delta endocytosis facilitates S2 cleavage and removal of the Notch extracellular domain, a critical step in Notch activation. A second class of models is related to the possibility that Delta ubiquitylation and endocytosis facilitates interactions between Delta and Notch. In the second set of models, Delta undergoes endocytosis and its subsequent trafficking back to the surface, following modifications or some change in the context in which it is presented, makes Delta a more effective ligand. Though it is still not clear how either or both mechanisms contribute, recent evidence points to the importance of both endocytosis and recycling in Delta signaling.

Animals↗
PubMed2005

Notch1 co-localizes with CD4 on activated T cells and Notch signaling is required for IL-10 production.

The effector function of activated CD4(+) T cells and secretion of cytokines are important in the establishment of productive immune responses and tolerance. We identified expression by CD4(+) T cells of Notch receptors and ligands and enhanced Notch signaling upon activation. Notch1 expression was up regulated and co-localized with CD4 upon T cell stimulation. Disruption of Notch signaling did not affect proliferation, but attenuated cytokine secretion following CD3 ligation in the absence of anti-CD28 antibody. Notch signaling was absolutely necessary for transcription of IL-10 by stimulated CD4(+) T cells. CD4(+) T cells transfected with constitutively active Notch1 failed to proliferate, but exhibited enhanced cytokine secretion upon stimulation. Our data indicates that Notch receptor signaling can influence both proliferative and cytokine responses of CD4(+) T cells. In addition, the finding that Notch signaling is required for production of IL-10 may allude to a role in immune regulation.

Animals↗
PubMed2006

Making a Notch in the lymphocyte kit.

The receptor tyrosine kinase c-Kit plays crucial roles in lymphocyte development but there is little information on the molecular circuitry enforcing c-Kit expression. In addition to growth factors, Notch signaling is essential for T cell development. In this issue of the European Journal of Immunology, evidence is provided for an interesting link between c-Kit and Notch. The primary 'test subjects' were a Pax5-deficient 'pro-B cell' line, blocked in its B cell potential, and its non-mutated counterpart, a bone marrow-derived early progenitor with lymphoid and myeloid potential (EPLM). Similar to common lymphoid progenitors, EPLM have a 'B cell-biased' potential, yet show multipotency under appropriate conditions. Following Notch signaling, c-Kit expression was very rapidly upregulated and the development into T cells was found to be c-Kit-dependent. In the absence of Notch signals, c-Kit expression remained low. Development into non-T cell fates (NK or myeloid) was found to be c-Kit-independent. It remains to be determined whether c-Kit is a 'direct' target of the Notch signal transduction pathway; however, these findings, together with those of others, strongly suggest that Notch can contribute to the proper cytokine receptor pattern required for commitment and expansion of early intrathymic progenitors.

Animals↗
PubMed2006

Transient Notch signaling induces NK cell potential in Pax5-deficient pro-B cells.

Unlike early B/T cell development, NK cell lineage commitment is not well understood, with a major limitation being the lack of a robust culture system to assay NK cell progenitors. Here we have exploited the multi-lineage potential of Pax5(-/-) pro-B cells to establish an effective system to direct differentiation of progenitors into the NK cell lineage. Cultivation of Pax5(-/-) pro-B cells on OP9 cells expressing the Notch ligand Delta-Like1 (OP9-DL1) in the presence of IL-7 efficiently induced T and NK cell potential. For NK cells, Notch was only transiently required, as prolonged signaling decreased NK and increased T cell development. Pure NK cell populations could be obtained by the culture of these Notch signal-experienced cells onto OP9 stroma and IL-15. A similar transient exposure to Notch was also compatible with the differentiation of NK cells from hematopoietic progenitors, while sustained Notch signaling impaired NK cell generation. Pax5(-/-) pro-B cell-derived NK cells were cytotoxic, secreted cytokines and expressed all the expected NK cell-specific surface markers examined except the Ly49 family, a phenotype similar to fetal NK cells. These data indicate that Notch signaling induces T/NK cell differentiation in Pax5(-/-) pro-B cells that is strikingly similar to early thymopoiesis.

Animals↗
PubMed2002

Genetic screen for modifiers of the rough eye phenotype resulting from overexpression of the Notch antagonist hairless in Drosophila.

Hairless was identified as antagonist in the Notch signaling pathway based on genetic interactions. Molecularly, Hairless inhibits Notch target gene activation by directly binding to the Notch signal transducer Su(H). Additional functional domains apart from the Su(H) binding domain, however, suggest additional roles for the Hairless protein. To further our understanding of Hairless functions, we have performed a genetic screen for modifiers of a rough eye phenotype caused by overexpression of Hairless during eye development. A number of enhancers were identified that comprise mutations in components of Notch- and EGFR-signaling pathways, some unknown genes and the gene rugose. Mutant alleles of rugose display manifold genetic interactions with mutants in Notch and EGFR signaling pathway components. Accordingly, the rugose eye phenotype is rescued by Hairless and enhanced by Delta. Molecularly, interactions might occur at the protein level because rugose appears not to be a direct transcriptional target of Notch.

A Kinase Anchor Proteins↗