Squamous cell carcinomas arising from adnexal ductal cysts.

Malignant tumors arising from adnexal cysts are rare. We report 2 cases of squamous cell carcinomas that developed within cystic structures arising from adnexal ducts. An in situ hybridization technique for human papillomaviruses (HPV)-6/11, -16, -18, and -31, and immunohistochemical staining for p53 were performed. Both tumors showed focal expression of HPV-16 within areas showing squamoid changes and diffuse expression of p53 within the areas of invasive squamous cell carcinoma. Although nuclear staining for HPV has been identified in tumors of adnexal origin, to our knowledge these are the first cases in which a highly oncogenic HPV subtype, HPV-16, has been identified within squamous cell carcinomas arising from adnexal ductal structures. These cases may help explain primary cutaneous squamous cell carcinomas with no epidermal origin.     

Ammonium accumulation and chemokine decrease in culture media of Gcdh−/− 3D reaggregated brain cell cultures

Glutaric Aciduria type I (GA-I) is caused by mutations in the GCDH gene. Its deficiency results in accumulation of the key metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body tissues and fluids. Present knowledge on the neuropathogenesis of GA-I suggests that GA and 3-OHGA have toxic properties on the developing brain.We analyzed morphological and biochemical features of 3D brain cell aggregates issued from Gcdh^?/? mice at two different developmental stages, day-in-vitro (DIV) 8 and 14, corresponding to the neonatal period and early childhood. We also induced a metabolic stress by exposing the aggregates to 10 mM l-lysine (Lys).Significant amounts of GA and 3-OHGA were detected in Gcdh^?/? aggregates and their culture media. Ammonium was significantly increased in culture media of Gcdh^?/? aggregates at the early developmental stage. Concentrations of GA, 3-OHGA and ammonium increased significantly after exposure to Lys. Gcdh^?/? aggregates manifested morphological alterations of all brain cell types at DIV 8 while at DIV 14 they were only visible after exposure to Lys. Several chemokine levels were significantly decreased in culture media of Gcdh^?/? aggregates at DIV 14 and after exposure to Lys at DIV 8.This new in vitro model for brain damage in GA-I mimics well in vivo conditions. As seen previously in WT aggregates exposed to 3-OHGA, we confirmed a significant ammonium production by immature Gcdh^?/? brain cells. We described for the first time a decrease of chemokines in Gcdh^?/? culture media which might contribute to brain cell injury in GA-I.     

β-blockers reduce bone resorption marker in early postmenopausal women

Background: There is evidence to suggest that β-blockers used in the management of cardiovascular disease may also modulate bone metabolism and reduce bone fragility.

Aim: The study aimed to determine the association between β-blocker use, serum markers of bone turnover and bone loss in early postmenopausal women.

Subjects and methods: In this observational study, we evaluated β-blocker exposure in association with serum levels of C-telopeptide and bone-specific alkaline phosphatase, and rates of bone loss. β-blocker use, concomitant therapy and lifestyle were documented for 197 women (50–59 years), 175 of whom had changes in whole body bone mineral density monitored over a 2–year period.

Results: Twenty-four β-blocker users were identified at baseline. After controlling for concomitant use of hormone therapy, C-telopeptide levels were 6.7% lower among β-blocker users (p?=?0.02). No association was detected between bone-specific alkaline phosphatase and β-blocker use. Analysis of 15 β-blocker users and 152 non-users identified 2 years post-baseline showed that levels of C-telopeptide but not bone-specific alkaline phosphatase were predictors of adjusted rates of bone loss (p?=?0.008 and p>0.05, respectively). Adjusted rates of bone loss were??0.001?±?0.026?g?cm^?2 over 2 years for the users and??0.004?±?0.025?g?cm^?2 over 2 years for non-users, but this difference was not significant.

Conclusion: β-blockers might suppress bone resorption with relative preservation of bone formation. A study with greater power is required to determine whether β-blocker use is associated with lower rates of bone loss.

Résumé. Arrière plan: Il semble que les β-bloquants employés pour le traitement des maladies cardiaques, puissant aussi moduler le métabolisme osseux et réduire la fragilité de l'os.

But: Cette étude a pour objet de déterminer l'association de l'usage des β-bloquants avec les marqueurs sériques du remplacement osseux et la perte osseuse juste après la ménopause.

Sujets et méthodes:.On a évalué l'exposition aux β-bloquants en association avec les niveaux sériques de C-telopeptide et l'alcaline phosphatase osseuse spécifique ainsi qu'avec les taux de perte osseuse. L'utilisation de β-bloquants, la thérapie concomitante et le mode de vie ont été enregistrés pour 197 femmes âgée de 50 à 59 ans, parmi lesquelles 175 ont subi un contrôle suivi des changements de leur densité minérale osseuse totale sur une période de deux ans.

Résultats: 34 utilisateurs de β-bloquants ont été identifiés comme base de référence. Après contrôle de l'emploi concomitant d'une thérapie hormonale, les niveaux de C-telopeptides sont de 6,7% plus bas chez les utlilisateurs de β-bloquants (p?=?0,02). On ne trouve pas d'association entre l'alcaline-phosphatase et l'utilisation de β-bloquants. L'analyse de 15 utilisateurs de β-bloquants et de 152 non utilisateurs identifiés deux ans après la base de référence, montre que les niveaux de C-telopeptides mais non pas l'alcaline phosphatase, sont prédicateurs des taux ajustés de perte osseuse (respectivement p?=?0,008 et p?=?0,05)). Les taux ajustés de perte osseuse sur 2 ans sont de??0,001?±?0,026 g/cm^?2 pour les utilisateurs et??0,004?±?0,025?g/cm^?2 pour les non utilisateurs, mais cette différence n'est pas significative.

Conclusion: Les β-bloquants pourraient supprimer la résorption osseuse par une préservation relative de la formation de l'os. Une étude de plus vaste envergure est nécessaire afin de déterminer si les β-bloquants sont associés à des taux plus faibles de perte osseuse.

Zusammenfassung. Hintergrund: Es gibt deutliche Hinweise darauf, dass die Einnahme von β-Blockern bei der Behandlung kardiovaskulärer Erkrankungen auch den Knochenstoffwechsel beeinflussen und zu erhöhter Knochenbrüchigkeit führen können.

Ziel: Die Studie zielte auf die Bestimmung der Beziehung zwischen Einnahme von β-Blockern, Serummarkern des Knochenumsatzes und Knochenverlusts bei Frauen kurz nach der Menopause.

Probanden und Methoden: In dieser Beobachtungsstudie beurteilten wir den Zustand unter Einnahme β-Blockern in Verbindung mit Serumspiegeln von C-Telopeptiden und knochenspezifischer alkalischer Phosphatase, und Knochenabbauraten. Die Einnahme von β-Blockern, Begleittherapie und Lebensumstände wurden bei 197 Frauen (50–59 Jahre) dokumentiert, von denen 175 Veränderungen der Ganzkörperknochendichte über einen Beobachtungszeitraum von 2 Jahren aufwiesen.

Ergebnisse: Zu Beginn wurden 24 Patienten identifiziert, die β-Blocker einnahmen. Nach rechnerischem Ausschluss von Effekten, die sich durch begleitende Hormonbehandlung ergeben könnten, zeigten Patienten, die β-Blocker einnahmen, um 6,7% niedrigere C-Telopeptidspiegel (p?=?0,02). Es fand sich keine Beziehung zwischen knochenspezifischer alkalischer Phosphatase und der Einnahme von β-Blockern. Die Analyse von 15 Patienten, die β-Blocker einnahmen, und 152 Personen, die dies über einen Zeitraum von 2 Jahren nach Studienbeginn nicht taten, zeigte, dass C-Telopeptidspiegel, nicht aber die knochenspezifische alkalische Phosphatase ein Kriterium war, um korrigierte Knochenabbauraten vorherzusagen (p?=?0,008, bzw. p?>?0,05). Korrigierte Knochen-abbauraten waren –0,001?±?0,026?g?cm^?2 über 2 Jahre für Patienten, die β-Blocker einnahmen, und –0,004?±?0,025?g?cm^?2 über 2 Jahre für solche, die keine β-Blocker einnahmen, aber diese Differenz war nicht signifikant.

Zusammenfassung: β-Blocker können die Knochenresorption supprimieren, wobei die Knochenformation im Prinzip beibehalten wird. Eine Untersuchung mit größerer power ist notwendig, um zu klären, ob die Einnahme von β-Blockern mit erniedrigten Knochenabbauraten vergesellschaftet ist.

Resumen. Antecedentes: Existen evidencias que sugieren que los ß-bloqueantes usados en el tratamiento de la enfermedad cardiovascular también pueden modular el metabolismo óseo y reducir la fragilidad de los huesos.

Objetivos: El estudio trata de determinar la asociación entre el uso de ß-bloqueantes, los marcadores séricos de remodelado y la pérdida ósea, en mujeres postmenopaúsicas tempranas.

Sujetos y métodos: En este estudio de observación, evaluamos la exposición a ß-bloqueantes en asociación con los niveles séricos del telopéptido C y de la fosfatasa alcalina óseo-específica, y las tasas de pérdida ósea. La utilización de ß-bloqueantes, la terapia concomitante y el estilo de vida se documentaron en 197 mujeres (de 50 a 59 años), 175 de las cuales habían tenido cambios en la densidad mineral ósea de todo el cuerpo monitorizados durante un periodo de 2 años.

Resultados: Inicialmente se identificaron veinticuatro usuarias de ß-bloqueantes. Tras controlar el uso conjunto de la terapia hormonal, los niveles del telopéptido C fueron un 6,7% menores entre las usuarias de ß-bloqueantes (p?=?0,2). No se detectó ninguna asociación entre la fosfatasa alcalina óseo-específica y el uso de ß-bloqueantes. El análisis de 15 usuarias de ß-bloqueantes y de 152 no usuarias, identificadas durante 2 años después del inicio, mostró que los niveles del telopéptido C, pero no los de la fosfatasa alcalina óseo-específica, eran predictores de las tasas ajustadas de pérdida ósea (p?=?0,008 y p?>?0,05, respectivamente). Las tasas ajustadas de pérdida ósea fueron de –0,001?±?0,026?g?cm^?2 tras 2 años en las usuarias y de –0,004?±?0,025?g?cm^?2 tras 2 años en las no usuarias, aunque esta diferencia no fue significativa.

Conclusión: Los β-bloqueantes podrían suprimir la resorción del hueso con una relativa preservación de la formación ósea. Se requiere un estudio con mayor potencia para determinar si el uso de ß-bloqueantes está asociado con tasas más bajas de pérdida ósea.     

Effects of serine protease inhibitor,tame, on IL-1β in LPS-stimulated human monocytes: Relationship between synthesis and release of a 33-kDa precursor and the 17-kDa biologically active species

LPS stimulation of human monocytes in vitro induced release of the 17-kDa mature IL-1 (mIL-1) but did not result in release of precursor IL-1 (pIL-1). In contrast, the presence of a serine protease inhibitor, N-(p-toluene sulfonyl)-L-arginine methyl ester (TAME; 10 mM) for 6 or 18 h was associated with the LPS-stimulated release of the 33-kDa pIL-1 as well. These effects were initially discerned from observations that the fraction of the total IL-1 produced (as detected by ELISA) that was released from monocytes increased in the presence of TAME, and immunoblot assays confirmed that this fraction was predominantly 33-kDa IL-1. A global decrease in monocyte protein synthesis was also observed after prolonged (18-h) exposure to TAME and was associated with a decrease in IL-1 synthesis, predominantly affecting 31-kDa pIL-1, and a dose-dependent inhibition of TNF- production. Parallel examination of lactate dehydrogenase (LDH) release indicated thatpIL-1 release was unrelated to cell lysis. These results demonstrate that TAME-inhibitable serine proteases are probably involved in the production and eventual proteolysis of the 33-kDa pIL-1 in situ but are probably not mechanistically related to either maturation of the IL-1 molecule or signaling of IL-1 release. IL-1 release appears to be dependent on the amount of total IL-1 synthesized. Serine proteolysis may constitute a degradative pathway for excess precursor, which, if interfered with, could result in release of the higher-molecular-weight forms of IL-1.     

Potential function of TGF-β isoforms in maturation-stage ameloblasts

Objectives

To investigate potential functions of transforming growth factor-beta (TGF-β) isoforms in maturation-stage ameloblasts during amelogenesis.

Correlation of the Tei index with invasive measurements of ventricular function in a porcine model.

BACKGROUND: The Doppler myocardial performance (Tei) index has been reported to be clinically useful in assessing left ventricular systolic and diastolic function in both adults and children. However, there are limited data to compare the Tei index with invasive measurements of ventricular function. We used a porcine model to directly correlate the Tei index with invasive indices of systolic and diastolic function. METHODS: Pressure volume loops were obtained from 10 pigs (32-45 kg). A micromanometer and a conductance catheter were placed in the left ventricle to record pressure and volume, respectively. A flow probe was placed around the ascending aorta to record cardiac output. Baseline pressure volume loops were generated during preload reduction through caval occlusion. Epicardial echocardiograms were performed just before the caval occlusion. Invasive indices including preload recruitable stroke work, ventricular stiffness constant, and cardiac output were assessed, as were noninvasive echocardiographic indices including Tei index and ejection fraction. An ischemic insult, ventricular fibrillation, was induced to alter ventricular function. After cardioversion and 40 minutes of reperfusion, echocardiographic and invasive measurements were repeated. RESULTS: There was a statistically significant inverse relationship between the percent change in Tei and the percent change in preload recruitable stroke work after ventricular fibrillation (r = -0.70, P =.02), although the correlation between the actual values of Tei and preload recruitable stroke work were not statistically significant. There was a statistically significant inverse relationship between the percent change in Tei and the percent change in cardiac output (r = -0.65, P =.03). There was a direct correlation between the value of Tei and the ventricular stiffness constant at baseline (r = 0.63, P <.05). As anticipated, the value of Tei was inversely related to ejection fraction by epicardial echocardiogram at baseline (r = -0.85, P <.001). The percent change in Tei was inversely related to the percent change in ejection fraction as well (r = -0.69, P <.05). CONCLUSIONS: This animal model is one of the first studies to demonstrate a direct correlation between the Tei index and systolic and diastolic invasive measurements of ventricular function. This supports the clinical use of this index as a measure of global ventricular function.     

The Bausch and Lomb keratometer does not measure the tangential radius of curvature

The purpose of this research was to determine if the conventional keratometer measures tangential or sagittal radius. A Bausch and Lomb keratometer was modified to enable an assessment of vertex radius and p-value to be made on convex conicoidal buttons of known surface form. Calculation of these two parameters was achieved assuming that the keratometer was measuring tangential radius and then repeated assuming a sagittal measurement. The resulting values could then be compared with those obtained by Form Talysurf analysis and by the use of an autokeratometer designed to measure sagittal radius. There was good agreement between the three instruments when the modified Bausch and Lomb keratometer was assumed to measure sagittal radius. We conclude that the Bausch and Lomb keratometer makes a radius measurement closer to the sagittal than the tangential radius of a conicoid of revolution.     

Subcortical shape alterations in major depressive disorder: Findings from the ENIGMA major depressive disorder working group

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = ?0.164 to ?0.180). Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = ?0.173 to ?0.184). Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.