DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 3 2008
Hiroko Matsui
During heart development at the gastrula stage, inhibition of bone morphogenetic protein (BMP) activity affects the heart specification but does not impair the expression of smooth muscle , -actin (SMA), which is first expressed in the heart mesoderm and recruited into initial heart myofibrils. Interaction of tissues between posterior epiblast and hypoblast at the early blastula stage is necessary to induce the expression of SMA, in which Nodal and Chordin are thought to be involved. Here we investigated the role of fibroblast growth factor-8 (FGF8) in the expression of SMA. In situ hybridization and reverse transcription,polymerase chain reaction showed that Fgf8b is expressed predominantly in the nascent hypoblast. Anti-FGF8b antibody inhibited the expression of SMA, cTNT, and Tbx5, which are BMP-independent heart mesoderm/early cardiomyocyte genes, but not Brachyury in cultured posterior blastoderm, and combined FGF8b and Nodal, but neither factor alone induced the expression of SMA in association with heart specific markers in cultured epiblast. Although FGF8b did not induce the upregulation of phospho-Smad2, anti-FGF8b properties suppressed phospho-Smad2 in cultured blastoderm. FGF8b was able to reverse the BMP-induced inhibition of cardiomyogenesis. The results suggest that FGF8b acts on the epiblast synergistically with Nodal at the pregastrula stage and may play a role in the expression of SMA during early cardiogenesis. [source]

Man1, an inner nuclear membrane protein, regulates left,right axis formation by controlling nodal signaling in a node-independent manner

DEVELOPMENTAL DYNAMICS, Issue 12 2008
Akihiko Ishimura
Abstract Man1, an inner nuclear membrane protein, regulates transforming growth factor , signaling by interacting with receptor-associated Smads. In Man1 -deficient (Man1,/,) embryos, vascular remodeling is perturbed by misregulation of Smad activity. Here, we show that Man1,/, embryos exhibit abnormal heart morphogenesis including the looping abnormality. We searched for the molecular basis underlying the heart abnormalities and found that the left side-specific genes responsible for left,right (LR) asymmetry, Nodal, Lefty2, and Pitx2, were expressed bilaterally in the lateral plate mesoderm and that their expression was enhanced significantly in mutants. Notably, Lefty1, a marker for the midline barrier, was maintained in Man1,/, mutants. Crossing Man1,/+ with Nodal hypomorphs (Nodalneo/+), in which Nodal signaling in the node is disrupted, to generate double homozygous embryos (Man1,/,; Nodalneo/neo) revealed that the bilateral Nodal was retained in Man1,/,; Nodalneo/neo embryos. These results suggest that Man1 regulates LR asymmetry by controlling Nodal signaling in a node-independent manner. Developmental Dynamics 237:3565,3576, 2008. © 2008 Wiley-Liss, Inc. [source]

Xnr2 and Xnr5 unprocessed proteins inhibit Wnt signaling upstream of dishevelled

DEVELOPMENTAL DYNAMICS, Issue 4 2005
Yasuko Onuma
Abstract Nodal and Nodal-related proteins activate the Activin-like signal pathway and play a key role in the formation of mesoderm and endoderm in vertebrate development. Recent studies have shown additional activities of Nodal-related proteins apart from the canonical Activin-like signal pathway. Here we report a novel function of Nodal-related proteins using cleavage mutants of Xenopus nodal-related genes (cmXnr2 and cmXnr5), which are known to be dominant-negative inhibitors of nodal family signaling. cmXnr2 and cmXnr5 inhibited both BMP signaling and Wnt signaling without activating the Activin-like signal in animal cap assays. Pro region construct of Xnr2 and Xnr5 did not inhibit Xwnt8, and pro/mature region chimera mutant cmActivin - Xnr2 and cmActivin- Xnr5 also did not inhibit Xwnt8 activity. These results indicate that the pro domains of Xnr2 and Xnr5 are necessary, but not sufficient, for Wnt inhibition, by Xnr family proteins. In addition, Western blot analysis and immunohistochemistry analysis revealed that the unprocessed Xnr5 protein is stably produced and secreted as effectively as mature Xnr5 protein, and that the unprocessed Xnr5 protein diffused in the extracellular space. These results suggest that unprocessed Xnr2 and Xnr5 proteins may be involved in inhibiting both BMP and Wnt signaling and are able to be secreted to act on somewhat distant target cells, if these are highly produced. Developmental Dynamics 234:900,910, 2005. © 2005 Wiley-Liss, Inc. [source]

Roles of nodal-lefty regulatory loops in embryonic patterning of vertebrates

GENES TO CELLS, Issue 11 2001
Hou Juan
Nodal is a signalling molecule that belongs to the transforming growth factor,, superfamily of proteins, and Lefty proteins are antagonists of Nodal signalling. The nodal and lefty genes form positive and negative regulatory loops that resemble the reaction-diffusion system. As a pair, these genes control various events of vertebrate embryonic patterning, including left-right specification and mesoderm formation. In this review, we will focus on recent studies that have addressed the roles of nodal and lefty in mouse development. [source]

Nodal sampling in pancreaticoduodenectomy: does it change our management?

HPB, Issue 6 2007
ROOZBEH RASSADI
Abstract Background. Lymph node involvement in periampullary malignancy is the single most important factor in predicting survival in pancreaticoduodenectomy (PD). The role of nodal sampling in PD has not been well evaluated. This study evaluates the utility of nodal sampling of nodal stations 8 and 12, which are easily dissected early in PD, in overall final nodal status. Patients and methods. Fifty patients underwent PD at a single institution by a one surgeon over a 15 month period. Nodal stations 8 and 12 were sent separately for pathologic evaluation. Twenty-eight patients had a final diagnosis of periampullary malignancy. Demographic and pathologic data were collected retrospectively from patient charts. Positive and negative predictive values of nodes 8 and 12 were evaluated. Results. Eighteen of 28 patients with a diagnosis of periampullary malignancy had pathologically negative nodes 8 and 12, and a final nodal status (all peripancreatic lymph nodes) negative for nodal involvement. Nine of 28 patients had a negative nodal sampling result, but a positive final nodal status for metastatic tumor. The remaining four patients had both positive nodal sampling and final nodal status for metastatic tumor. The negative predictive value of negative nodes 8 and 12 was 0.625. Conclusion. The negative predictive of a negative node 8 and 12 of 0.625 suggests that the decision to proceed with or abort PD should not be based on intraoperative evaluation of these nodes. Performance of PD should be undertaken if technically feasible, and not based on intraoperative nodal assessment. [source]

Utilization of Retrograde Right Bundle Branch Block to Differentiate Atrioventricular Nodal from Accessory Pathway Conduction

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2009
SURAJ KAPA M.D.
Introduction: Defining whether retrograde ventriculoatrial (V-A) conduction is via the AV node (AVN) or an accessory pathway (AP) is important during ablation procedures for supraventricular tachycardia (SVT). With the introduction of ventricular extrastimuli (VEST), retrograde right bundle branch block (RBBB) may occur, prolonging the V-H interval, but only when AV node conduction is present. We hypothesized that when AP conduction was present, the V-A interval would increase less than the V-H interval, whereas with retrograde nodal conduction, the V-A interval would increase at least as much as the V-H interval. Methods and Results: We retrospectively reviewed the electrophysiological studies of patients undergoing ablation for AVN reentrant tachycardia (AVNRT) (55) or AVRT (50), for induction of retrograde RBBB during the introduction of VEST, and the change in the measured V-H and V-A intervals. Results were found to be reproducible between independent observers. Out of 105 patients, 84 had evidence of induced retrograde RBBB. The average V-H interval increase with induction of RBBB was 53.7 ms for patients with AVRT and 54.4 ms for patients with AVNRT (P = NS). The average V-A interval increase with induction of RBBB was 13.6 ms with AVRT and 70.1 ms with AVNRT (P < 0.001). All patients with a greater V-H than V-A interval change had AVRT, and those with a smaller had AVNRT. Conclusions: Induction of retrograde RBBB during VEST is common during an electrophysiological study for SVT. The relative change in the intervals during induction of RBBB accurately differentiates between retrograde AVN and AP conduction. [source]

Connexin40-Deficient Mice Exhibit Atrioventricular Nodal and Infra-Hisian Conduction Abnormalities

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 11 2000
BRIAN A. VANDERBRINK B.S.
AV Nodal and Infra-Hisian Conduction in Cx40 Mice. Introduction: Previous electrophysiologic investigations have described AV conduction disturbances in connexin4(Cx40)-deficient mice. Because expression or(Cx40 occurs predominantly in the atria and His-Purkinje system of the mouse heart, the AV conduction disturbances were thought to be secondary to disruption in His-Pnrkinje function. However, the lack of a His-bundle electrogram recording in the mouse has limited further investigation of the importance of Cx40. Using a novel technique to record His-bundle recordings in Cx40-deficient mice, we define the physiologic importance of defciencies in Cx40. Methods and Results: Ten Cx40 -/- mice and 11 Cx40+/+ controls underwent a blinded, in vivo, closed chest electrophysiology study at 9 to 12 weeks of age. In the Cx40+/+ mice, the PR interval was significantly longer compared with Cx40+/+ mice (44.6 ± 6.4 msec vs 36.0 ± 4.1 msec, P = 0.002). Not only the HV interval (14.0 ± 3.0 msec vs 10.4 ± 1.2 msec, P = 0.003) but also the AH interval (33.2 ± 4.8 msec vs 27.1 ± 3.7 msec, P = 0.006), AV Wenckebach cycle lengths, and AV nodal effective and functional refractory periods were prolonged in Cx40 -/- compared with Cx40+/+ mice. Conclusion: Cx40-deficient mice exhibit significant delay not only in infra-Hisian conduction, as would be expected from the expression of Cx40 in the His-Purkinje system but also in the electrophysiologic parameters that reflect AV nodal conduction. Our data suggest a significant role of Cx40 in atrionodal conduction and/or in proximal His-bundle conduction, [source]

Atrial, SA Nodal, and AV Nodal Electrophysiology in Standing Horses: Normal Findings and Electrophysiologic Effects of Quinidine and Diltiazem

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2007
Colin C. Schwarzwald
Background: Although atrial arrhythmias are clinically important in horses, atrial electrophysiology has been incompletely studied. Hypotheses: Standard electrophysiologic methods can be used to study drug effects in horses. Specifically, the effects of diltiazem on atrioventricular (AV) nodal conduction are rate-dependent and allow control of ventricular response rate during rapid atrial pacing in horses undergoing quinidine treatment. Animals: Fourteen healthy horses. Methods: Arterial blood pressure, surface electrocardiogram, and right atrial electrogram were recorded during sinus rhythm and during programmed electrical stimulation at baseline, after administration of quinidine gluconate (10 mg/kg IV over 30 minutes, n = 7; and 12 mg/kg IV over 5 minutes followed by 5 mg/kg/h constant rate infusion for the remaining duration of the study, n = 7), and after coadministration of diltiazem (0.125 mg/kg IV over 2 minutes repeated every 12 minutes to effect). Results: Quinidine significantly prolonged the atrial effective refractory period, shortened the functional refractory period (FRP) of the AV node, and increased the ventricular response rate during atrial pacing. Diltiazem increased the FRP, controlled ventricular rate in a rate-dependent manner, caused dose-dependent suppression of the sinoatrial node and produced a significant, but well tolerated decrease in blood pressure. Effective doses of diltiazem ranged from 0.125 to 1.125 mg/kg. Conclusions and Clinical Importance: Standard electrophysiologic techniques allow characterization of drug effects in standing horses. Diltiazem is effective for ventricular rate control in this pacing model of supraventricular tachycardia. The use of diltiazem for rate control in horses with atrial fibrillation merits further investigation. [source]

Atrioventricular Nodal versus Atrioventricular Supraventricular Reentrant Tachycardias: Characterization by an Integrated Doppler Electro-physiological Hemodynamic Study

PACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 12 2000
DONATO MELE
During reentrant Supraventricular tachycardias involving the atrioventricular node (A VN-SVT) or an A V bypass tract (AV-SVT), atrial pressure increases. While in AVN-SVT this increase relates to atrial contraction during ventricular systole, the mechanism remains unclear in AV-SVT. This study sought to clarify this mechanism. During 11 AVN-SVTs and 9 AV-SVTs. anterograde flow through the AV valves and retrograde flow in the pulmonary and hepatic veins were studied by pulsed- wave (PW) Doppler measuring the time interval between the ECG-R wave and (1) the end of venous retrograde flows, and (2) the beginning of valvular anterograde flows. The positive or negative difference between these two time intervals guided recognizing the atrial contraction against open or closed A V valves. Intracavitary pressures and cardiac index were also measured. During AVN-SVTs, venous retrograde flows always ended before the anterograde valvular flows, indicating atrial contraction against closed AV valves. During A V-SVTs, pulmonary retrograde flow ended before the beginning of mitral anterograde flow in five cases, began before but ended during the anterograde flow in three cases, and overlapped to the anterograde flow in one case. A corresponding behavior was observed at the right side of the heart. In both SVTs, atrial pressures increased and end-dias-tolic ventricular pressure and cardiac index decreased similarly. During AVN-SVT, the atrial contraction always occurs against closed A V valves, and during A V-SVT it generally occurs against totally or partially closed A V valves, explaining similar atrial pressure and cardiac index changes in both SVTs. [source]

Involvement of different risk factors in clinically severe large joint osteoarthritis according to the presence of hand interphalangeal nodes

ARTHRITIS & RHEUMATISM, Issue 9 2010
Ana M. Valdes
Objective To quantify the differences in risk factors influencing total hip replacement (THR) and total knee replacement (TKR) based on the presence versus absence of multiple interphalangeal nodes in 2 or more rays of the fingers of each hand in patients with large joint osteoarthritis (OA). Methods A group of 3,800 patients with large joint OA who underwent total joint replacement (1,201 of whom had the nodal phenotype) and 1,906 control subjects from 2 case,control studies and a population-based cohort in the UK were studied. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for the risk of total joint replacement in association with age, sex, body mass index (BMI), height, and prevalence of the T allele in the GDF5 rs143383 polymorphism. ORs for total joint replacement were compared between cases of nodal OA and cases of non-nodal OA and between patients who underwent TKR and those who underwent THR. Results Age, sex, and BMI had significantly higher ORs for an association with total joint replacement in nodal OA cases than in non-nodal OA cases. The GDF5 polymorphism was significantly associated with THR in cases of nodal OA, but not in cases of non-nodal OA, and increased height was a risk factor for THR in non-nodal OA cases only. Female sex was a protective risk factor for TKR in non-nodal OA cases (OR 0.60, 95% CI 0.52,0.70) but was predisposing for TKR in the nodal form of OA (OR 1.83, 95% CI 1.49,2.26). The nodal phenotype was associated with a significantly higher risk of undergoing both THR and TKR (OR 1.46, 95% CI 1.09,1.94) and also a significantly higher risk of bilateral TKR (OR 1.70, 95% CI 1.37,2.11), but, paradoxically, was associated with a lower risk of bilateral THR (OR 0.72, 95% CI 0.56,0.91). Conclusion Nodal and non-nodal forms of large joint OA have significantly different risk factors and outcomes, indicating a different etiology for the 2 forms of OA. With regard to the likelihood of undergoing THR, this appears to be, at least in part, genetically determined. [source]

Sentinel Lymph Node Excision and PET-CT in the Initial Stage of Malignant Melanoma: A Retrospective Analysis of 61 Patients with Malignant Melanoma in American Joint Committee on Cancer Stages I and II

DERMATOLOGIC SURGERY, Issue 4 2010
JOACHIM KLODE MD
BACKGROUND AND OBJECTIVES Sentinel lymph node excision (SLNE) for the detection of regional nodal metastases and staging of malignant melanoma has resulted in some controversies in international discussions. Positron emission tomography with computerized tomography (PET-CT), a noninvasive imaging procedure for the detection of regional nodal metastases, has increasingly become of interest. Our study is a direct comparison of SLNE and PET-CT in patients with early-stage malignant melanoma. MATERIALS AND METHODS We retrospectively analyzed data from 61 patients with primary malignant melanoma with a Breslow index greater than 1.0 mm. RESULTS Metastatic SLNs were found in 14 patients (23%); 17 metastatic lymph nodes were detected overall, only one of which was identified preoperatively using PET-CT. Thus, PET-CT showed a sensitivity of 5.9% and a negative predictive value of 78%. CONCLUSION SLNE is much more sensitive than PET-CT in discovering small lymph node metastases. We consider PET-CT unsuitable for the evaluation of early regional lymphatic tumor dissemination in this patient population and recommend that it be limited to malignant melanomas of American Joint Committee on Cancer stages III and IV. We therefore recommend the routine use of SLNE for tumor staging and stratification for adjuvant therapy of patients with stage I and II malignant melanoma. The authors have indicated no significant interest with commercial supporters. [source]

Sentinel Lymph Node Biopsy in Cutaneous Squamous Cell Carcinoma: A Systematic Review of the English Literature

DERMATOLOGIC SURGERY, Issue 11 2006
AMY SIMON ROSS MD
BACKGROUND Although most cutaneous squamous cell carcinoma (SCC) is curable by a variety of treatment modalities, a small subset of tumors recur, metastasize, and result in death. Although risk factors for metastasis have been described, there are little data available on appropriate workup and staging of patients with high-risk SCC. OBJECTIVE We reviewed reported cases and case series of SCC in which sentinel lymph node biopsy (SLNB) was performed to determine whether further research is warranted in developing SLNB as a staging tool for patients with high-risk SCC. METHODS The English medical literature was reviewed for reports of SLNB in patients with cutaneous SCC. Data from anogenital and nonanogenital cases were collected and analyzed separately. The percentage of cases with a positive sentinel lymph node (SLN) was calculated. False negative and nondetection rates were tabulated. Rates of local recurrence, nodal and distant metastasis, and disease-specific death were reported. RESULTS A total of 607 patients with anogenital SCC and 85 patients with nonanogenital SCC were included in the analysis. A SLN could not be identified in 3% of anogenital and 4% of nonanogenital cases. SLNB was positive in 24% of anogenital and 21% of nonanogenital patients. False-negative rates as determined by completion lymphadenectomy were 4% (8/213) and 5% (1/20), respectively. Most false-negative results were reported in studies from 2000 or earlier in which the combination of radioisotope and blue dye was not used in the SLN localization process. Complications were reported rarely and were limited to hematoma, seroma, cutaneous lymphatic fistula, wound infection, and dehiscence. CONCLUSIONS Owing to the lack of controlled studies, it is premature to draw conclusions regarding the utility of SLNB in SCC. The available data, however, suggest that SLNB accurately diagnoses subclinical lymph node metastasis with few false-negative results and low morbidity. Controlled studies are needed to demonstrate whether early detection of subclinical nodal metastasis will lead to improved disease-free or overall survival for patients with high-risk SCC. [source]

In-Transit Metastasis From Primary Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients and Nonimmunosuppressed Patients: Clinical Characteristics, Management, and Outcome in a Series of 21 Patients

DERMATOLOGIC SURGERY, Issue 4p2 2004
John A. Carucci MD
Background. In-transit metastases from cutaneous squamous cell carcinoma (SCC) may occur in organ transplant recipients and may indicate aggressive disease and poor prognosis. Objective. The objective of this study was to describe in-transit metastases from cutaneous SCC and to identify factors associated with this phenomenon in a series of 21 patients. We also attempted to evaluate outcome with respect to status as an organ transplant recipient or nonorgan transplant recipient. Methods. A multicenter case series of patients was reviewed; factors included clinical presentation, management, and outcome. Results. Twenty-one patients, 15 organ transplant recipients, and 6 nontransplant recipients with in-transit metastases were reviewed. In-transit metastases presented most commonly as discrete, dermal papules distinct from but in the vicinity of the primary tumor site. Histologic differentiation was variable. At a mean follow up of 24 months, 33% the transplant patients had no evidence of disease compared with 80% of nontransplant patients. Thirty-three percent were dead from disease and 33% were alive with nodal or distant metastases. In contrast, 80% of nonimmunosuppressed patients had no evidence of disease and none had died at mean follow-up of 24 months. Conclusion. In-transit metastasis from cutaneous SCC is a unique presentation of metastatic SCC, more commonly described in organ transplant recipients, and is associated with poor prognosis in that group. This description represents the largest experience with in-transit metastases from cutaneous SCC in the literature. [source]

Man1, an inner nuclear membrane protein, regulates left,right axis formation by controlling nodal signaling in a node-independent manner

Roles of nodal-lefty regulatory loops in embryonic patterning of vertebrates

Ireland's Foreign-Owned Technology Sector: Evolving Towards Sustainability?

GROWTH AND CHANGE, Issue 3 2008
PATRICK COLLINS
ABSTRACT For some, Ireland's pursuit of an exogenous-led development model has proved to be the cornerstone of recent economic success. Others point to recent high-profile closures and argue that foreign-owned operations are attracted to Ireland solely because of the advantageous tax breaks and lucrative grants scheme offered by the Irish government. We pay tribute to both arguments by pushing the level of enquiry beyond that of supply and backward linkages to try and gauge the actual performance of affiliates themselves. This brings some interesting facets of the Irish foreign direct investment scene to light. We highlight complexity of process, attainment of broader investment remits, and the emergence of a managerial class as integral to the ability of affiliates to adapt to and exploit organisational change. By examining 10 case studies and making use of media searches and company interviews, we highlight evidence of Ireland's largest technology transnational corporation affiliates showing positive performance advances. With these movements come, what we term, increased nodal significance of Irish operations within the global production network of their corporations. We argue against policy and theories that see these movements as linear and provide evidence of how some Irish operations have leveraged control and gained significant regional and global remits that have resulted in their growing significance, both in the corporation and in the country in which they are based. In the same line we argue that embeddedness in terms of supply linkages does not fit the Irish case and instead employ the term "network anchoring" of affiliates as they increase their nodal weighting through increased mandates. [source]

Molecular characterization of epstein-barr virus and oncoprotein expression in nasopharyngeal carcinoma in Korea

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 7 2004
Yoon Kyung Jeon MD
Abstract Background. We evaluated the characteristics of nasopharyngeal carcinoma in Korea, including its clinical, pathologic, and molecular features, especially emphasizing on the EBV strains involved, latent membrane protein 1 (LMP1) expression, and the alterations of matrix metalloproteinase 9 (MMP9) and E-cadherin expression. Methods. The presence of EBV was evaluated by EBER in situ hybridization, and the expression of LMP1, MMP9, and E-cadherin by immunohistochemistry. The characterization of EBV type and LMP1 variant was performed by PCR. Results. EBER was detected in 55 of 57 cases (96%) of nonkeratinizing carcinoma (NKC) and undifferentiated carcinoma, but in only four of nine cases (44%) of squamous cell carcinoma (SCC). EBER positivity was much higher in the group with nodal metastases (p = .003). The predominant strain of EBV infection was type A (81%) and a 30-bp deletion LMP1 variant (77%). All EBER-positive SCCs were infected with EBV type A. LMP1 expression was detected in 36 of 59 (61%) patients with latent EBV infection and MMP9 in 41 of these 59 (69%). LMP1 positivity was much higher among the patients aged 50 years and younger. MMP9 expression was associated with LMP1 expression (p = .008), and nodal and distant metastasis (p = .019, p = .045). Loss of E-cadherin expression was correlated with MMP9 and nodal metastasis. The survival rate was much lower in patients with a higher TNM classification, stage, and a histology of SCC. EBER positivity was associated with a better prognosis in the Kaplan-Meier test, but had no prognostic value by Cox regression analysis. Loss of E-cadherin expression and nodal metastasis were also correlated with local recurrence and distant metastasis. Conclusion. EBV type and LMP1 variant had no significant influence on the clinicopathologic properties of tumor. However, there was a tendency toward a better survival in the EBV type B group. Histology and clinical staging were the two most important prognostic factors. © 2004 Wiley Periodicals, Inc. Head Neck26: 573,583, 2004 [source]

Clinical relevance of three subtypes of primary sinonasal lymphoma characterized by immunophenotypic analysis

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 7 2004
Gwi Eon Kim MD
Abstract Background. The purpose of this study was to investigate the clinical relevance of subtypes categorized by immunophenotypic analysis in primary sinonasal lymphomas. Methods. Eighty patients with localized non-Hodgkin's lymphoma involving the nasal cavity and/or paranasal sinuses were divided into three subtypes on the basis of their immunohistochemical findings: (A) B-cell lymphoma (n = 19), (B) T-cell lymphoma (n = 27), and (C) natural killer (NK)/T-cell lymphoma (n = 34). The clinicopathologic profiles, immunophenotypic data, patterns of treatment failure, and survival data among the three patient groups were retrospectively compared. Results. The nasal cavity was the predominant site of involvement in T-cell and NK/T-cell lymphoma, whereas sinus involvement without nasal disease was common in B-cell lymphoma. Systemic B symptoms were frequently observed in NK/T-cell lymphoma. Almost all patients with NK/T-cell lymphoma showed a strong association with the Epstein-Barr virus by in situ hybridization studies. Sixty-five patients (81%) patients achieved complete remission after initial treatment, but 36 (55%) of these subsequently experienced treatment failure. Although there were no significant differences in locoregional failure rates among the patients of the three groups, distant failure was far more common in B-cell or NK/T-cell lymphoma than in T-cell lymphoma (p = .005). Most B-cell lymphoma cases showed a predilection for sites of systemic failure in the nodal and extranodal sites below the diaphragm, such as the paraaortic lymph nodes or the gastrointestinal (GI) tract, whereas patients with NK/T-cell lymphoma showed an increased risk of systemic dissemination to the skin, testes, or GI tract, including the development of hemophagocytic syndrome. The 5-year actuarial and disease-free survival rates for all patients were 57% and 51%, respectively. Of the three subtypes of primary sinonasal lymphomas, T-cell lymphoma seemed to carry the most favorable prognosis and NK/T-cell lymphoma the worst. (The 5-year actuarial survival rate was 57% for B-cell lymphoma, 80% for T-cell lymphoma, 37% for NK/T-cell lymphoma; p = .02, log-rank.) By univariate and multivariate analyses, immunophenotype was identified as the most important prognostic factor. Conclusions. Our data indicate that the three subtypes of primary sinonasal lymphomas classified by immunohistochemical studies exhibit different clinical profiles, different patterns of failure, and different treatment outcomes. Given these observations, it is concluded that the recognition of these distinct subsets, diagnosed on the basis of immunophenotypic study, is very important and clinically relevant in predicting their potential behavior and prognosis. © 2004 Wiley Periodicals, Inc. Head Neck26: 584,593, 2004 [source]

Feasibility and long-term results of autologous PBSC transplantation in recurrent undifferentiated nasopharyngeal carcinoma

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 9 2001
Mario Airoldi MD
Abstract Background Recurrent undifferentiated nasopharyngeal carcinoma (UNPC) is a chemosensitive illness. Here we report long-term results of high-dose chemotherapy (HDC) as late intensification, with autologous peripheral blood stem cell (PBSC) support. Methods Six patients (5 men, 1 woman; median age 41years; median ECOG PS = 0) with recurrent UNPC (local, 2; local + nodal, 2; bone metastasis, 2) have been enrolled. All patients had been previously treated with neoadjuvant chemotherapy and radiotherapy; 3 of 4 local relapses had received a re-irradiation. Every patient received three courses of cisplatin + epirubicin and 1 cycle of epirubicin followed by PBSC collection. A median of 7.2 × 106/kg (range, 4.5,18) CD34+ cells were reinfused. HDC was according ICE scheme: ifosfamide, 2.5 g/m2/d, + carboplatin, 300 mg/m2/d, + VP-16, 300 mg/m2/d days 1 through 4. Results After conventional chemotherapy, we had 1 CR (16%), 3 PR (50%), and 2 NC (34%). After HDC, we had 4 CR (66%) ,1 PR (17%), and 1 MR (17%). Toxicity was manageable. After a median follow-up of 30 months (range, 14,50), two patients are alive without disease (34%), one is alive with bone disease (16%), and three (50%) died of disease at 16, 18, and 24 months. Conclusions HDC has an acceptable toxicity, can convert PR in CR, and seems effective, with long-lasting CRs. © 2001 John Wiley & Sons, Inc. Head Neck 23: 799,803, 2001. [source]

Suppression of liver regeneration and hepatocyte proliferation in hepatocyte-targeted glypican 3 transgenic mice,

HEPATOLOGY, Issue 3 2010
Bowen Liu
Glypican 3 (GPC3) belongs to a family of glycosylphosphatidylinositol-anchored, cell-surface heparan sulfate proteoglycans. GPC3 is overexpressed in hepatocellular carcinoma. Loss-of-function mutations of GPC3 result in Simpson-Golabi-Behmel syndrome, an X-linked disorder characterized by overgrowth of multiple organs, including the liver. Our previous study showed that GPC3 plays a negative regulatory role in hepatocyte proliferation, and this effect may involve CD81, a cell membrane tetraspanin. To further investigate GPC3 in vivo, we engineered transgenic (TG) mice overexpressing GPC3 in the liver under the control of the albumin promoter. GPC3 TG mice with hepatocyte-targeted, overexpressed GPC3 developed normally in comparison with their nontransgenic littermates but had a suppressed rate of hepatocyte proliferation and liver regeneration after partial hepatectomy. Moreover, gene array analysis revealed a series of changes in the gene expression profiles in TG mice (both in normal mice and during liver regeneration). In unoperated GPC3 TG mice, there was overexpression of runt related transcription factor 3 (7.6-fold), CCAAT/enhancer binding protein alpha (2.5-fold), GABA A receptor (2.9-fold), and wingless-related MMTV integration site 7B (2.8-fold). There was down-regulation of insulin-like growth factor binding protein 1 (8.4-fold), Rab2 (5.6-fold), beta-catenin (1.7-fold), transforming growth factor beta type I (3.1-fold), nodal (1.8-fold), and yes-associated protein (1.4-fold). Changes after hepatectomy included decreased expression in several cell cycle,related genes. Conclusion: Our results indicate that in GPC3 TG mice, hepatocyte overexpression of GPC3 suppresses hepatocyte proliferation and liver regeneration and alters gene expression profiles, and potential cell cycle,related proteins and multiple other pathways are involved and affected. (HEPATOLOGY 2010;52:1060,1067) [source]

BCL2 gene abnormalities define distinct clinical subsets of follicular lymphoma

HISTOPATHOLOGY, Issue 3 2006
J R Goodlad
Aims:, Follicular lymphoma (FL) arising primarily in the skin has recently been proposed as a distinct entity on the basis of a low incidence of t(14;18)(q32;q21) and bcl-2 expression, with a very high percentage of patients surviving more than 5 years. However, cases of t(14;18)(q32;q21)-positive primary cutaneous FL (PCFL) and examples of t(14;18)(q32;q21)-negative FL at nodal and other extranodal sites, are well documented. The aim of this study was to test the hypothesis that there is a subtype of FL lacking t(14;18)(q32;q21), which preferentially involves certain sites but is not restricted by anatomical location. Methods and results:, A cohort of 47 stage 1 FL was stratified according to the presence or absence of t(14;18)(q32;q21) using conventional cytogenetics, polymerase chain reaction and interphase fluorescence in situ hybridization. Compared with t(14;18)(q32;q21)-positive cases, FL lacking the translocation were less likely to express CD10 or bcl-2 (P < 0.01), made up a significantly greater proportion of cases arising at extranodal sites (P < 0.001) and had a significantly better overall and disease-specific 5-year survival (P < 0.01). Conclusions:, These results support the concept of a subtype of FL lacking t(14;18)(q32;q21), characterized by low-intensity bcl-2 expression, a predilection for extranodal sites, particularly the skin, and a more favourable outcome than t(14;18)(q32;q21)-positive FL. [source]

Nodal sampling in pancreaticoduodenectomy: does it change our management?

Block diagonalization of Laplacian matrices of symmetric graphs via group theory

INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 5 2007
A. Kaveh
Abstract In this article, group theory is employed for block diagonalization of Laplacian matrices of symmetric graphs. The inter-relation between group diagonalization methods and algebraic-graph methods developed in recent years are established. Efficient methods are presented for calculating the eigenvalues and eigenvectors of matrices having canonical patterns. This is achieved by using concepts from group theory, linear algebra, and graph theory. These methods, which can be viewed as extensions to the previously developed approaches, are illustrated by applying to the eigensolution of the Laplacian matrices of symmetric graphs. The methods of this paper can be applied to combinatorial optimization problems such as nodal and element ordering and graph partitioning by calculating the second eigenvalue for the Laplacian matrices of the models and the formation of their Fiedler vectors. Considering the graphs as the topological models of skeletal structures, the present methods become applicable to the calculation of the buckling loads and the natural frequencies and natural modes of skeletal structures. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Improved implementation and robustness study of the X-FEM for stress analysis around cracks

INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 8 2005
E. Béchet
Abstract Numerical crack propagation schemes were augmented in an elegant manner by the X-FEM method. The use of special tip enrichment functions, as well as a discontinuous function along the sides of the crack allows one to do a complete crack analysis virtually without modifying the underlying mesh, which is of industrial interest, especially when a numerical model for crack propagation is desired. This paper improves the implementation of the X-FEM method for stress analysis around cracks in three ways. First, the enrichment strategy is revisited. The conventional approach uses a ,topological' enrichment (only the elements touching the front are enriched). We suggest a ,geometrical' enrichment in which a given domain size is enriched. The improvements obtained with this enrichment are discussed. Second, the conditioning of the X-FEM both for topological and geometrical enrichments is studied. A preconditioner is introduced so that ,off the shelf' iterative solver packages can be used and perform as well on X-FEM matrices as on standard FEM matrices. The preconditioner uses a local (nodal) Cholesky based decomposition. Third, the numerical integration scheme to build the X-FEM stiffness matrix is dramatically improved for tip enrichment functions by the use of an ad hoc integration scheme. A 2D benchmark problem is designed to show the improvements and the robustness. Copyright © 2005 John Wiley & Sons, Ltd. [source]

A general high-order finite element formulation for shells at large strains and finite rotations

INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 15 2003
Y. Ba
Abstract For hyperelastic shells with finite rotations and large strains a p -finite element formulation is presented accommodating general kinematic assumptions, interpolation polynomials and particularly general three-dimensional hyperelastic constitutive laws. This goal is achieved by hierarchical, high-order shell models. The tangent stiffness matrices for the hierarchical shell models are derived by computer algebra. Both non-hierarchical, nodal as well as hierarchical element shape functions are admissible. Numerical experiments show the high-order formulation to be less prone to locking effects. Copyright © 2003 John Wiley & Sons, Ltd. [source]

Topological aspects of meshless methods and nodal ordering for meshless discretizations

INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 9 2001
Arash Yavari
Abstract The meshless element-free Galerkin method (EFGM) is considered and compared to the finite-element method (FEM). In particular, topological aspects of meshless methods as the nodal connectivity and invertibility of matrices are studied and compared to those of the FE method. We define four associated graphs for meshless discretizations of EFGM and investigate their connectivity. The ways that the associated graphs for coupled FE-EFG models might be defined are recommended. The associated graphs are used for nodal ordering of meshless models in order to reduce the bandwidth, profile, maximum frontwidth, and root-mean-square wavefront of the corresponding matrices. Finally, the associated graphs are numerically compared. Copyright © 2001 John Wiley & Sons, Ltd. [source]

Lymphoproliferative disorders in autoimmune diseases in Japan: Analysis of clinicopathological features and Epstein-Barr virus infection

INTERNATIONAL JOURNAL OF CANCER, Issue 3 2004
Yoshihiko Hoshida
Abstract Lymphoproliferative disorders (LPD) occasionally develop in individuals with immune deficiencies such as immunosuppressive conditions and autoimmune diseases (AID). In our study, the clinicopathologic features and virus status were analyzed in 53 cases with LPD developing in rheumatoid arthritis (RA) and other AID. AID in only 4 of 53 patients had been treated with some sort of immunosuppressive therapy, including methotrexate. Median age at the diagnosis of LPD in AID was 60 years old with marked female predominance (M/F = 0.4). The median interval between the onset of AID and LPD development was 45 months, and longer in RA patients than in other AID (p < 0.01). The primary site of lymphoma was nodal in 21 cases and extra-nodal in 24, with clinical Stage I in 17, II in 5, III in 13, and IV in 13. Immunohistochemistry showed that 39 cases were B cell type, 10 were T cell type and 4 were Hodgkin lymphoma (HL). Then majority of B cell cases were diffuse large B cell lymphomas, and 2 were diffuse polymorphic type. EBER-1 in situ hybridization for Epstein-Barr virus (EBV) showed positive signals in tumor cells in 16 of 53 (30.2%) cases. The EBV-positive rate in T cell LPD (70%) was much higher than that in B cell LPD (12.8%) (p < 0.01). All 4 cases of HL were EBV-positive. Immunohistochemistry showed a latency II pattern of EBV infection (LMP-1+ and EBNA-2,). Five-year overall survival rate was 33%. Multivariate analysis showed that only type of AID was an independent factor for survival of patients, i.e., LPD in RA showed the most favorable prognosis. In conclusion, LPD in AID generally shared common features with sporadic LPD except for a much higher EBV-positive rate in T cell LPD. © 2003 Wiley-Liss, Inc. [source]

Clinical usage of the squamous cell carcinoma antigen in patients with penile cancer

INTERNATIONAL JOURNAL OF UROLOGY, Issue 2 2007
Stavros Touloupidis
Background: We present our initial experience with the use of the squamous cell carcinoma (SCC) antigen (SCCAg) in 16 men with penile SCC (SCC group), in four men with condyloma acuminatum (benign group), and in 32 blood donors (control group). Methods: The SCCAg levels were measured at presentation and every 6 months (upper limit was 2 ng/mL). The mean follow-up time was 4 years. Results: All non-SCC patients had normal SSCAg serum levels in contrast with the SCC patients. The presence of nodal and/or distant metastases resulted in statistically significant higher SCCAg levels, both at presentation and during the follow-up. In patients undergoing lymph node dissection with elevated SCCAg levels prior to the procedure, there was a statistically significant decrease of the SCCAg levels after the operation. Conclusion: The SCCAg level could be a serum marker that holds promise for clinical use in penile SCC. Sequential monitoring of SCCAg level might indicate developing of nodal and/or distant metastases and could be useful in following the response to treatment. [source]

Phytanic Acid Accumulation Is Associated with Conduction Delay and Sudden Cardiac Death in Sterol Carrier Protein-2/Sterol Carrier Protein-x Deficient Mice

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 11 2004
GEROLD MÖNNIG M.D.
Introduction: The sterol carrier protein-2 gene encodes two functionally distinct proteins: sterol carrier protein-2 (SCP2, a peroxisomal lipid carrier) and sterol carrier protein-x (SCPx, a peroxisomal thiolase known as peroxisomal thiolase-2), which is involved in peroxisomal metabolism of bile acids and branched-chain fatty acids. We show in this study that mice deficient in SCP2 and SCPx (SCP2null) develop a cardiac phenotype leading to a high sudden cardiac death rate if mice are maintained on diets enriched for phytol (a metabolic precursor of branched-chain fatty acids). Methods and Results: In 210 surface and 305 telemetric ECGs recorded in wild-type (C57BL/6; wt; n = 40) and SCP2 null mice (n = 40), no difference was observed at baseline. However, on diet, cycle lengths were prolonged in SCP2 null mice (262.9 ± 190 vs 146.3 ± 43 msec), AV conduction was prolonged (58.3 ± 17 vs 42.6 ± 4 ms), and QRS complexes were wider (19.1 ± 5 vs 14.0 ± 4 ms). In 11 gene-targeted Langendorff-perfused hearts isolated from SCP2 null mice after dietary challenge, complete AV blocks (n = 5/11) or impaired AV conduction (Wenckebach point 132 ± 27 vs 92 ± 10 msec; P < 0.05) could be confirmed. Monophasic action potentials were not different between the two genotypes. Left ventricular function studied by echocardiography was similar in both strains. Phytanic acid but not pristanic acid accumulated in the phospholipid fraction of myocardial membranes isolated from SCP2 null mice. Conclusion: Accumulation of phytanic acid in myocardial phospholipid membranes is associated with bradycardia and impaired AV nodal and intraventricular impulse conduction, which could provide an explanation for sudden cardiac death in this model. [source]

Total Atrioventricular Nodal Ablation Increases Atrial Fibrillation Burden in Patients with Paroxysmal Atrial Fibrillation Despite Continuation of Antiarrhythmic Drug Therapy

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 12 2003
RIK WILLEMS M.D.
Introduction: Total atrioventricular nodal (TAVN) ablation and pacing is an accepted and safe treatment for patients with drug-refractory paroxysmal atrial fibrillation (AF). Many patients develop permanent AF within the first 6 months after TAVN ablation. This usually is ascribed to the cessation of antiarrhythmic drug therapy. We hypothesized that TAVN ablation itself creates an atrial substrate prone to AF. Methods and Results: Patients participating in the Atrial Pacing Periablation for Paroxysmal Atrial Fibrillation (PA3) study who remained on stable antiarrhythmic drug therapy throughout follow-up were included in this analysis. AF burden and the development of persistent AF in the preablation period were compared to two consecutive postablation periods. Echocardiographic changes also were evaluated. Twenty-two patients remained on stable drug therapy (9 men and 13 women, age 59 ± 3 years). One patient developed persistent AF preablation compared to 10 postablation (P < 0.05). AF burden preablation was 3.0 ± 1.2 hours/day and increased to 10.4 ± 2.2 hours/day and 11.8 ± 2.3 hours/day in the two postablation follow-up periods (P < 0.05). In patients with fractional shortening (FS) >30% prior to ablation, FS decreased significantly from 39.4%± 1.3% to 36.4%± 1.7% (P < 0.05). In contrast, in patients with a FS ,30% prior to ablation, FS increased from 27%± 0.8% to 33.6 ± 1.7% (P < 0.05). Conclusion: TAVN ablation increases AF burden and facilitates the development of persistent AF in patients with paroxysmal AF despite the continuation of antiarrhythmic drugs. Loss of AV and/or interventricular synchrony may lead to altered cardiac hemodynamics resulting in atrial stretch and increasing AF burden. (J Cardiovasc Electrophysiol, Vol. 14, pp. 1296-1301, December 2003) [source]