Re: Conservative Management of Gradenigo Syndrome in a Child.
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Abducens Nerve Diseases↗
Biomedical subjects
D Mehta
Publications and source records attributed to D Mehta.
Self citations and impact factors in otolaryngology journals.
Self citation of a journal may affect its impact factor. Self citations during 1997 and 1998 were investigated in six 'general' otolaryngology journals. The citations each journal gave to other journals, including itself, and the citations each journal received from the other journals, differed significantly among the six journals (chi2= 2794, d.f. = 25, P < 0.0001). Acta Otolaryngologica and Laryngoscope had the highest self-citing rates (11.9% and 10.02%). Clinical Otolaryngology had the lowest self-citing rate (4%). There was no significant correlation between self-citing rates and impact factors for the six otolaryngology journals (r = -0.3143, P = 0.56).
Bibliometrics↗
Differential role of CD18 integrins in mediating lung neutrophil sequestration and increased microvascular permeability induced by Escherichia coli in mice.
The in vivo contributions of CD18 integrin-dependent and -independent mechanisms in mediating the increases in lung neutrophil (polymorphonuclear leukocyte; PMN) sequestration and microvascular permeability are not well understood. We determined the time course of these responses to Gram-negative sepsis in the mouse lung and addressed the specific contributions of CD18 integrins and ICAM-1. PMN sequestration in the lung was assessed by morphometric analysis, and transalveolar PMN migration was assessed by bronchoalveolar lavage. Lung tissue PMN number increased by 6-fold within 1 h after i.p. Escherichia coli challenge; this value peaked at 3 h (7-fold above control) and decreased at 12 h (3.5-fold above control). PMN migration into the airspace was delayed; the value peaked at 6 h and remained elevated up to 12 h. Saturating concentrations of anti-CD18 and anti-ICAM-1 mAbs reduced lung tissue PMN sequestration and migration; however, peak responses at 3 and 6 h were inhibited by 40%, indicating that only a small component of PMN sequestration and migration was CD18 dependent at these times. In contrast to the time-dependent decreased role of CD18 integrins in mediating PMN sequestration and migration, CD18 and ICAM-1 blockade prevented the increase in lung microvascular permeability and edema formation at all times after E. coli challenge. Thus, Gram-negative sepsis engages CD18/ICAM-1-independent mechanisms capable of the time-dependent amplification of lung PMN sequestration and migration. The increased pulmonary microvascular permeability induced by E. coli is solely the result of engagement of CD18 integrins even when PMN accumulation and migration responses are significantly CD18 independent.
Animals↗
Long-term effect of N-acetyl-seryl-aspartyl-lysyl-proline on left ventricular collagen deposition in rats with 2-kidney, 1-clip hypertension.
BACKGROUND: N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural inhibitor of pluripotent hematopoietic stem cell proliferation. Ac-SDKP plasma concentration is increased 5-fold after angiotensin-converting enzyme inhibition. Here we studied the effect of Ac-SDKP on monocyte/macrophage infiltration, fibroblast proliferation, and collagen deposition in the rat heart in renovascular hypertension. METHODS AND RESULTS: We investigated whether long-term Ac-SDKP administration would prevent left ventricular (LV) hypertrophy and interstitial collagen deposition in rats with 2-kidney, 1-clip (2K-1C) hypertension. Ac-SDKP (400 microgram. kg(-1). d(-1)) did not affect development of hypertension. Mean blood pressure was similar in rats with 2K-1C hypertension whether they were given vehicle or Ac-SDKP and was higher than in controls. Both LV weight and cardiomyocyte size were significantly increased in rats with 2K-1C hypertension compared with controls and were unaffected by Ac-SDKP. Proliferating cell nuclear antigen- and monocyte/macrophage-positive cells were increased in the LV of 2K-1C hypertensive rats; this increase was significantly blunted by Ac-SDKP (P<0.001). LV interstitial collagen fraction was also increased in 2K-1C hypertensive rats given vehicle (10.1+/-0.8%) compared with sham (5.3+/-0.1%, P<0.0001), and this increase was prevented by Ac-SDKP (5.4+/-0.4%, P<0.001). CONCLUSIONS: Ac-SDKP inhibited monocyte/macrophage infiltration, cell proliferation, and collagen deposition in the LV of hypertensive rats without affecting blood pressure or cardiac hypertrophy, suggesting that it may be partly responsible for the cardioprotective effect of angiotensin-converting enzyme inhibitors.
Animals↗
Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B(2) kinin receptor gene knockout mice.
Using B(2) kinin receptor gene knockout mice (B(2)(-/-)), we tested the hypothesis that (l) lack of B(2) receptors may affect blood pressure and cardiac function and aggravate cardiac remodeling after myocardial infarction (MI), and (2) kinins partially mediate the cardiac beneficial effect of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT(1)-ant), whereas lack of B(2) receptors may diminish this cardioprotective effect. Chronic heart failure (HF) was induced by MI, which was caused by coronary artery ligation in both B(2)(-/-) and 129/SvEvTac mice (wild-type control, B(2)(+/+)). An ACEi (ramipril, 2.5 mg/kg/d) or AT(1)-ant (L-158809, 3 mg/kg/d) was given 1 week after MI and was continued for 12 weeks. Left ventricular (LV) ejection fraction, cardiac output (CO), diastolic LV dimension (LVDd), and LV mass were evaluated by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were studied histopathologically. We found that basal blood pressure and cardiac function were similar in B(2)(+/+) and B(2)(-/-) mice. After MI, development of HF and remodeling were also similar between the 2 strains. The ACEi improved cardiac function and remodeling in both strains; however, its effects were attenuated in B(2)(-/-) mice (respective values for B(2)(+/+) versus B(2)(-/-) mice: overall increase in ejection fraction, 64+/-10% versus 21+/-5% [P<0.01]; increase in CO, 69+/-17% versus 23+/-9% [P<0.01]; overall decrease in LVDd, -24+/-3% versus -7+/-4% [P<0.01]; and decrease in LV mass, -38+/-3% versus -6+/-6% [P<0.01]). AT(1)-ant had a beneficial cardiac effect similar to that produced by ACEi, and this effect was also diminished in B(2)(-/-) mice (respective values for B(2)(+/+) versus B(2)(-/-) mice: overall increase in ejection fraction, 46+/-10% versus 25+/-9% [P<0.01]; increase in CO, 44+/-14% versus 15+/-5% [P<0.01]; overall decrease in LVDd, -14+/-4% versus -6+/-3% [P<0.01]; and decrease in LV mass, -33+/-4 versus -16+/-7% [P<0.01]). The effect of ACEi or AT(1)-ant on myocyte cross-sectional area was similar between strains; however, their effect on the interstitial collagen fraction was diminished in B(2)(-/-) mice. We concluded that (1) lack of B(2) kinin receptors does not affect cardiac phenotype or function, either under normal physiological conditions or during the development of HF; and (2) kinins acting via the B(2) receptor play an important role in the cardioprotective effect of ACEi and AT(1)-ant.
Angiotensin Receptor Antagonists↗
Protein kinase C-alpha signals rho-guanine nucleotide dissociation inhibitor phosphorylation and rho activation and regulates the endothelial cell barrier function.
The Rho-GDP guanine nucleotide dissociation inhibitor (GDI) complexes with the GDP-bound form of Rho and inhibits its activation. We investigated the role of protein kinase C (PKC) isozymes in the mechanism of Rho activation and in signaling the loss of endothelial barrier function. Thrombin and phorbol 12-myristate 13-acetate induced rapid phosphorylation of GDI and the activation of Rho-A in human umbilical venular endothelial cells. Inhibition of PKC by chelerythrine chloride abrogated the thrombin-induced GDI phosphorylation and Rho activation. Depletion of PKC prevented the thrombin-induced GDI phosphorylation and Rho activation, thereby indicating that these events occurred downstream of phorbol ester-sensitive PKC isozyme activation. The depletion of PKC or inhibition of Rho by C3 toxin also prevented the thrombin-induced decrease in transendothelial electrical resistance (a measure of increased transendothelial permeability), thus indicating that PKC-induced barrier dysfunction was mediated through Rho-dependent pathway. Using inhibitors and dominant-negative mutants, we found that Rho activation was regulated by PKC-alpha. Moreover, the stimulation of human umbilical venular endothelial cells with thrombin induced rapid association of PKC-alpha with Rho. Activated PKC-alpha but not PKC-epsilon induced marked phosphorylation of GDI in vitro. Taken together, these results indicate that PKC-alpha is critical in regulating GDI phosphorylation, Rho activation, and in signaling Rho-dependent endothelial barrier dysfunction.
Capillary Permeability↗
A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies.
Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.
Adolescent↗
Pacemakers and defibrillators for congestive heart failure.
Although medical therapy is the primary therapy for patients with heart failure, the use of pacemakers to improve cardiac hemodynamics is under investigation. Despite promising initial results, controlled studies have not verified the benefit of application of VDD or DDD pacing to a nonselected population of severely symptomatic congestive heart failure (CHF) patients to simply shorten their atrioventricular (AV) delay. There is increasing interest in pacing the left side of the heart or simultaneously pacing the right and left ventricles. Early studies suggest that these techniques may produce favorable hemodynamic effects in patients with CHF. Controlled, randomized studies are now underway. Further, it has been shown that sudden cardiac death accounts for 50% of deaths in patients with CHF. The value of an implantable cardioverter defibrillator (ICD) in secondary prevention of sudden cardiac death is well established. The use of ICD for primary prevention of sudden cardiac death in patients with CHF is being actively evaluated. Several large multicenter trials are underway, some combined with biventricular pacing, and should provide useful data in the coming years.
Death, Sudden↗
Atrial tachycardia or atrioventricular nodal reentry? An unusual case of a long RP tachycardia.
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Aged↗
Signal-averaged P-wave ECG discriminates between persistent and paroxysmal atrial fibrillation.
Atrial fibrillation (Afib) has been associated with abnormal signal-averaged P wave (SAPW) parameters but whether SAPW is associated with the time course of these arrhythmias (persistent vs. paroxysmal, frequent vs. rare episodes) remains unknown. This article assesses the significance of SAPW duration in distinguishing patients with paroxysmal from those with persistent Afib. SAPW electrocardiogram was performed with a "double triggering" software system for acquisition and analysis of data. SAPW total duration (TD), X, Y, and Z leads magnitudes and vector signal magnitudes were measured offline. Optimal cutoff value between control and patient groups was determined by using a receiver operator characteristic curve. Data were analyzed to compare controls with patients groups and between patient groups according to time course of the arrhythmic history. Fifteen age-matched patients without a history of Afib and 55 patients with a history of Afib (33 with paroxysmal and 22 with persistent arrhythmia) were studied off antiarrhythmic drugs. Patients with history of persistent arrhythmia were studied within 2 days after electrical cardioversion to sinus rhythm. SAPW TD was the only parameter consistently associated with Afib. SAPW TD was 98 +/- 6 ms (mean +/- SD) in the control group, 127 +/- 19 ms in the pooled patients group (P =.0001); 122 +/- 20 ms for paroxysmal and 133 +/- 17 ms for the persistent Afib group (P =.04). Analysis of other SAPW parameters were not statistically significant. SAPW duration is a simple method to identify patients with history of Afib. A significantly longer SAPW TD characterizes patients with a history of persistent as opposed to paroxysmal Afib. Prolongation of SAPW TD possibly reflects more advanced electrophysiological changes, creating a more stable substrate that leads to persistence of the arrhythmia.
Algorithms↗
Glucagon use for esophageal coin dislodgment in children: a prospective, double-blind, placebo-controlled trial.
OBJECTIVE: Prospective evaluation of the use of glucagon in dislodgment of impacted esophageal coins in children. METHODS: This was a double-blind, placebo-controlled study with an open-label second phase in children 1 to 8 years of age who presented to a pediatric emergency department with a radiographically confirmed single esophageal coin impaction. One milligram of glucagon or placebo was given intravenously in double-blinded fashion. Patients were placed in an upright position and asked to drink 2-3 ounces of water. A repeat radiograph was obtained to check coin position in 30-60 minutes. Patients who did not respond were given 1 mg of open-label glucagon intravenously. The glucagon and placebo groups were compared. RESULTS: Fourteen patients were enrolled in the study (the predetermined sample size was not pursued due to inefficacy). Nine patients were in the glucagon group, and five were in the placebo group. Six patients received an additional open-label glucagon dose. The two groups were not different in age (mean, 5.5 years and 4.5 years, respectively), coin position, time between ingestion and presentation (p = 0.45), or time between treatment and repeat radiograph (p = 0.29). In patients who received glucagon, two of 15 (15%) passed the coin into the stomach. In the placebo group, three of five (60%) passed the coin, an inversely significant ratio. Five of six patients who received open-label glucagon were from the initial glucagon group. There were no responders among patients in this group. CONCLUSIONS: Glucagon does not appear to be effective in the dislodgment of esophageal coins in children.
Administration, Oral↗
Requirement for Ca2+ signaling in the mechanism of thrombin-induced increase in endothelial permeability.
We compared the thrombin-activated responses in human umbilical vein endothelial cells (HUVECs) and a HUVEC-derived cell line, ECV304. Thrombin induced a 40-50% decrease in transendothelial monolayer electrical resistance and a twofold increase in 125I-albumin permeability in HUVECs, whereas it failed to alter the endothelial barrier function in ECV304 cells. Thrombin produced a brisk intracellular Ca2+ concentration transient and phosphorylation of 20-kDa myosin light chain in HUVECs but not in ECV304 cells. Thrombin-induced phosphoinositide hydrolysis was comparable in ECV304 cells and HUVECs, indicating the activation of thrombin receptors in both cell types. La3+ reduced both the thrombin-induced decrease in endothelial monolayer electrical resistance and the increase in 125I-albumin permeability in HUVECs. Because the absence of Ca2+ signaling could explain the impairment in the permeability response in ECV304 cells, we studied the effect of increasing intracellular Ca2+ concentration in ECV304 cells with thapsigargin. Exposure of ECV304 cells to thapsigargin caused decreased endothelial monolayer electrical resistance and increased 125I-albumin permeability. These results indicate that Ca2+ influx and activation of Ca2+-dependent signaling pathways are important determinants of the thrombin-induced increase in endothelial permeability.
Antigens, CD↗
Serine/threonine phosphatase 2B regulates protein kinase C-alpha activity and endothelial barrier function.
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Animals↗
Synergistic effects of tumor necrosis factor-alpha and thrombin in increasing endothelial permeability.
Because activation of the coagulation cascade and the generation of thrombin coexist with sepsis and the release of tumor necrosis factor (TNF)-alpha, we determined the effects of TNF-alpha on the mechanism of thrombin-induced increase in endothelial permeability. We assessed Ca(2+) signaling in human umbilical vein endothelial cells. In human umbilical vein endothelial cells exposed to TNF-alpha for 2 h, thrombin produced a rise in the intracellular Ca(2+) concentration ([Ca(2+)](i)) lasting up to 10 min. In contrast, thrombin alone produced a rise in [Ca(2+)](i) lasting for 3 min, whereas TNF-alpha alone had no effect on [Ca(2+)](i.) Thrombin-induced inositol 1,4,5-trisphosphate generation was not different between control and TNF-alpha-exposed cells. In the absence of extracellular Ca(2+), thrombin produced similar increases in [Ca(2+)](i) in both control and TNF-alpha-exposed cells. In TNF-alpha-exposed cells, the thrombin-induced Ca(2+) influx after intracellular Ca(2+) store depletion was significantly greater and prolonged compared with control cells. Increased Ca(2+) entry was associated with an approximately fourfold increase in Src activity and was sensitive to the Src kinase inhibitor PP1. After TNF-alpha exposure, thrombin caused increased tyrosine phosphorylation of junctional proteins and actin stress fiber formation as well as augmented endothelial permeability. These results suggest that TNF-alpha stimulation of endothelial cells results in amplification of the thrombin-induced Ca(2+) influx by an Src-dependent mechanism, thereby promoting loss of endothelial barrier function.
Albumins↗
The Mount Sinai Hospital clinicalpathological conference: a 45-year-old man with Pompe's disease and dilated cardiomyopathy.
This is an unusual case of a 45-year-old man, born in Ecuador, with evidence of profound left ventricular dysfunction, dilated cardiomyopathy and marked myocardial hypertrophy. Preceding events were advanced atrioventricular block (necessitating pacemaker implantation) and atrial flutter. The diagnosis of Pompe's disease was established by endomyocardial biopsy and appropriate staining, which indicated abnormal glycogen storage.
Cardiomyopathy, Dilated↗
Abrogation of thrombin-induced increase in pulmonary microvascular permeability in PAR-1 knockout mice.
We investigated the function of proteinase-activated receptor-1 (PAR-1) in the regulation of pulmonary microvascular permeability in response to thrombin challenge using PAR-1 knockout mice (-/-). Lungs were isolated and perfused with albumin (5 g/100 ml)-Krebs solution at constant flow (2 ml/min). Lung wet weight and pulmonary artery pressure (P(pa)) were continuously monitored. We determined the capillary filtration coefficient (K(fc)) and (125)I-labeled albumin (BSA) permeability-surface area product (PS) to assess changes in pulmonary microvessel permeability to liquid and albumin, respectively. Normal and PAR-1-null lung preparations received in the perfusate: 1) thrombin or 2) selective PAR-1 agonist peptide (TFLLRNPNDK-NH(2)). In control PAR-1 (+/+) mouse lungs, (125)I-albumin PS and K(fc) were significantly increased over baseline (by approximately 7- and 1.5-fold, respectively) within 20 min of alpha-thrombin (100 nM) challenge. PAR-1 agonist peptide (5 microM) gave similar results, whereas control peptide (5 microM; FTLLRNPNDK-NH(2)) was ineffective. At relatively high concentrations, thrombin (500 nM) or PAR-1 agonist peptide (10 microM) also induced increases in P(pa) and lung wet weight. All effects of thrombin (100 or 500 nM) or PAR-1 agonist peptide (5 or 10 microM) were prevented in PAR-1-null lung preparations. Baseline measures of microvessel permeability and P(pa) in the PAR-1-null preparations were indistinguishable from those in normal lungs. Moreover, PAR-1-null preparations gave normal vasoconstrictor response to thromboxane analog, U-46619 (100 nM). The results indicate that the PAR-1 receptor is critical in mediating the permeability-increasing and vasoconstrictor effects of thrombin in pulmonary microvessels.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Squamous cell carcinoma of maxillary sinus.
BACKGROUND: Medical records of 43 patients with histologically proved diagnosis of squamous cell carcinoma who were treated between the years 1975 and 1994 at the department of Otolaryngology Head Neck Surgery, VU Amsterdam were examined. METHODS: Tumors were restaged according to UICC classification 1997. Thirty-eight patients were treated for cure, nine were treated with chemotherapy followed by external beam radiotherapy, and 28 patients were treated with surgery followed by postoperative radiotherapy. No patient was lost to follow-up. Data with respect to survival were analyzed. RESULTS: Eighty-three percent of the tumours were in stage III or stage IV at the time of first presentation. Five-year survival after surgery and postoperative radiotherapy for all patients was 64%. For stages II, III, and IV it was 83%, 49%, and 37%, respectively. Cervical nodal metastases were present in 4.1% at the time of presentation. Thirty-seven percent of the patients survived 2 years after chemotherapy followed by radiotherapy. CONCLUSIONS: Squamous cell carcinoma continues to be diagnosed late. Surgery followed by radiotherapy remains the treatment of choice. Mandibulotomy should be considered for better clearance of retromaxillary space in T3 -T4 tumors. The eye should be preserved whenever it is oncologically safe to do so.
Adult↗
Neural reorganisation in porcine vein grafts: a potential role for endothelin-1.
Vein grafts are associated with adventitial remodelling which may influence innervation of the graft. Since there is also evidence that endothelin-1 (ET-1) plays a role in the adventitial remodelling process, we investigated neural distribution in porcine vein grafts 1 and 6 months after implantation, as well as the localisation of immunoreactive ET-1 and its receptors in the same tissues. Saphenous vein-carotid artery interposition grafting was performed in Landrace pigs. One and 6 months after surgery, vein grafts and ungrafted saphenous veins were excised; neural tissue and ET-1 were identified by immunocytochemistry and ET receptors were identified using in vitro autoradiography. In ungrafted saphenous veins, abundant perivascular nerves were located in the outer region of the media with only a few paravascular nerves in the adventitia. In vein grafts at 1 month after implantation, there was almost complete depletion of perivascular nerves in the media. In contrast, in the neoadventitia, there was an emphatic appearance of large paravascular nerve bundles and a marked increase in small paravascular nerves. These changes were more pronounced at 6 months after surgery, although the principal changes had occurred within 1 month. Immunoreactive ET-1 (index of ET-1 content) was associated with paravascular nerve bundles, appearing as a dark, dense ring at the perineurium. Furthermore, within the nerve bundles, positive ET-1 immunoreactivity was associated with positive alpha-actin staining, indicating that ET-1 is associated with (neural) microvessels. Also, dense 125I-labelled BQ3020 (ET(B)-selective) binding to nerve bundles was observed, indicating the presence of ET(B) receptor subtypes. ET(A) receptor subtypes were not detected in neural tissue. These data demonstrate neural reorganisation in vein grafts and indicate that ET-1 content and binding may play a role in this process. The functional consequences of these changes on neointima formation, a major cause of vein graft failure, remain to be determined.
Animals↗