Serological studies in the elderly.

Sera from 108 elderly patients in psychiatric and general hospitals were tested for antibodies to seven viruses. Measles virus antibody levels were significantly higher in patients from the psychiatric hospital, regardless of diagnosis, than in those from other hospitals. Demented patients, regardless of their hospital, had significantly higher levels of antibody to adenovirus than control patients.     

Vasodilatation with captopril and prazosin in chronic heart failure: double blind study at rest and on exercise

A double blind cross over study was performed to compare the long term hormonal, haemodynamic, and clinical responses to specific inhibition of the renin-angiotensin-aldosterone system (captopril) and of the alpha 1 adrenoceptors of the sympathetic system (prazosin) both at rest and during upright exercise in patients with chronic heart failure. Sixteen patients completed one month's treatment with each drug. During conventional diuretic treatment (control) plasma renin activity, aldosterone, and noradrenaline were increased at rest and on exercise. Control left ventricular filling pressures were raised, and correlated significantly with plasma renin activity both at rest and on exercise. Systemic vascular resistance was increased at rest, and its reduction during exercise correlated inversely with the increase in plasma renin activity and plasma noradrenaline. After one month's treatment with captopril there were reductions in plasma aldosterone, weight, left ventricular filling pressure, and systemic vascular resistance at rest and on exercise. Dyspnoea was relieved and exercise capacity increased. The greater fall in systemic vascular resistance on exercise no longer correlated with the increase in plasma renin activity. During treatment with prazosin there were increases in plasma noradrenaline and, transiently, in plasma aldosterone. Fluid retention occurred, and left ventricular filling pressure was unchanged. Compared with control values systemic vascular resistance was reduced at rest but not on exercise. Dyspnoea and exercise capacity did not improve. In chronic heart failure, vasodilatation by inhibition of the alpha adrenergic system with prazosin causes compensatory stimulation of the renin-angiotensin-aldosterone system and does not result in clinical benefit. Inhibition of the renin-angiotensin-aldosterone system with captopril causes secondary vasodilatation at rest and on exercise and results in improvement in symptoms and exercise capacity.     

Hereditary pancreatic endocrine tumours.

The two main types of hereditary pancreatic neuroendocrine tumours are found in multiple endocrine neoplasia type 1 (MEN-1) and von Hippel-Lindau disease (VHL), but also in the rarer disorders of neurofibromatosis type 1 and tuberous sclerosis. This review considers the major advances that have been made in genetic diagnosis, tumour localization, medical and surgical treatment and palliation with systemic chemotherapy and radionuclides. With the exception of the insulinoma syndrome, all of the various hormone excess syndromes of MEN-1 can be treated medically. The role of surgery however remains controversial ranging from no intervention (except enucleation for insulinoma), intervening for tumours diagnosed only by biochemical criteria, intervening in those tumours only detected radiologically (1-2 cm in diameter) or intervening only if the tumour diameter is > 3 cm in diameter. The extent of surgery is also controversial, although radical lymphadenectomy is generally recommended. Pancreatic tumours associated with VHL are usually non-functioning and tumours of at least 2 cm in diameter should be resected. Practice guidelines recommend that screening in patients with MEN-1 should commence at the age of 5 years for insulinoma and at the age of 20 years for other pancreatic neuroendocrine tumours and variously at 10-20 years of age for pancreatic tumours in patients with VHL. The evidence is increasing that the life span of patients may be significantly improved with surgical intervention, mandating the widespread use of tumour surveillance and multidisciplinary team management.     

COX-2-dependent cardiac failure in Gh/tTG transgenic mice

Gh is a GTP binding protein that couples to the thromboxane receptor (TP), but also functions as tissue transglutaminase II (tTG). A transgenic mouse model was generated in which Gh was overexpressed (GhOE) in ventricular myocytes under the control of the alpha-myosin heavy chain promoter. Heart rate was elevated and both blood pressure and left ventricular ejection fraction were depressed in GhOEs. Left ventricular mass was increased, consistent with genetic and ultrastructural evidence of hypertrophy. Fibrosis and apoptosis were also augmented. Survival declined disproportionately in older GhOEs. Cardiomyocyte expression of COX-2, thromboxane synthase (TxS), and the receptors for TxA2 (the TP), PGF2alpha (the FP), and PGI2 (the IP) were upregulated and urinary 8,12-iso-iPF2alpha-VI,2,3-dinor-6-keto-PGF1alpha and 2,3-dinor-thromboxane B2 were increased in GhOEs, reflecting increased lipid peroxidation and cyclooxygenase (COX) activation. Selective COX-2 inhibition, TP antagonism, and suppression of lipid peroxidation each rescued the cardiac phenotype. Infusion of an FP agonist exacerbated the phenotype, whereas administration of an IP agonist improved cardiac function. Directed cardiac overexpression of Gh/tTG causes both TG activation and increased TP/Gh-dependent signaling. The COX-2-dependent increase in TxA2 generation augments cardiac hypertrophy, whereas formation of PGI2 by the same isozyme ameliorates the phenotype. Oxidant stress may contribute, via regulation of COX-2 expression and/or ligation of the TP and the FP by isoprostanes. Gh/tTG activation regulates expression of COX-2 and its products may differentially modulate cardiomyocyte commitment to cell death or survival.     

Doppler echocardiographic comparison of the Carpentier and Duran anuloplasty rings versus no ring after mitral valve repair for mitral regurgitation

To compare the hemodynamic results of different anuloplasty techniques of primary valve repair for mitral regurgitation, 122 patients were prospectively studied with Doppler echocardiograms 5 to 10 days after operation. Seventy-seven patients had mitral valve prolapse, 27 had coronary artery disease, 13 patients had rheumatic mitral valve lesions and 5 patients had infective endocarditis. Forty-eight patients received the flexible Duran ring, 46 received the more rigid Carpentier ring and 28 patients received no ring. Doppler echocardiography demonstrated a significant decrease in mitral valve area estimated by the pressure half-time method in patients who received either a Carpentier (2.6 +/- 0.8 cm2) or Duran ring (2.8 +/- 0.8 cm2) when compared with patients who received no ring (3.2 +/- 0.7 cm2) (p = 0.01). No significant differences were observed for peak transmitral diastolic velocity, peak transmitral diastolic gradient, or the grade of mitral regurgitation by color flow Doppler mapping between patients with and without rings. The etiology of mitral disease and concomitant surgical procedures accompanying mitral valve repair did not significantly influence mitral valve area, peak velocity or peak gradient. These data suggest that Carpentier and Duran rings decrease the hemodynamic mitral valve area; however, the decrease in valve area is small and not associated with a clinically important increase in transvalvular gradient.     

Comparative assessment of right, left, and biventricular pacing in patients with permanent atrial fibrillation.

AIMS: Left ventricular (LV) and biventricular (BiV) pacing are potentially superior to right ventricular (RV) apical pacing in patients undergoing atrioventricular (AV) junction ablation and pacing for permanent atrial fibrillation. METHODS AND RESULTS: Prospective randomized, single-blind, 3-month crossover comparison between RV and LV pacing (phase 1) and between RV and BiV pacing (phase 2) performed in 56 patients (70+/-8 years, 34 males) affected by severely symptomatic permanent atrial fibrillation, uncontrolled ventricular rate, or heart failure. Primary endpoints were quality of life and exercise capacity. Compared with RV pacing, the Minnesota Living with Heart Failure Questionnaire (LHFQ) score improved by 2 and 10% with LV and BiV pacing, respectively, the effort dyspnoea item of the Specific Symptom Scale (SSS) changed by 0 and 2%, the Karolinska score by 6 and 14% (P<0.05 for BiV), the New York Heart Association (NYHA) class by 5 and 11% (P<0.05 for BiV), the 6-min walked distance by 12 (+4%) and 4 m (+1%), and the ejection fraction by 5 and 5% (P<0.05 for both). BiV pacing but not LV pacing was slightly better than RV pacing in the subgroup of patients with preserved systolic function and absence of native left bundle branch block. Compared with pre-ablation measures, the Minnesota LHFQ score improved by 37, 39, and 49% during RV, LV, and BiV pacing, respectively, the effort dyspnoea item of the SSS by 25, 25, and 39%, the Karolinska score by 39, 42, and 54%, the NYHA class by 21, 25, and 30%, the 6-min walking distance by 35 (12%), 47 (16%), and 51 m (19%) and the ejection fraction by 5, 10, and 10% (all differences P<0.05). CONCLUSIONS: Rhythm regularization achieved with AV-junction ablation improved quality of life and exercise capacity with all modes of pacing. LV and BiV pacing provided modest or no additional favourable effect compared with RV pacing.     

Exploring the utility of whole‐exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness

The advent of whole‐exome next‐generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½‐year old female patient with a 2‐year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work‐up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di‐deoxy sequencing. WES revealed a de novo non‐synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.     

Toward resolution of the debate regarding purported crypto-Jews in a Spanish-American population: Evidence from the Y chromosome

Background: The ethnic heritage of northernmost New Spain, including present-day northern New Mexico and southernmost Colorado, USA, is intensely debated. Local Spanish-American folkways and anecdotal narratives led to claims that the region was colonized primarily by secret- or crypto-Jews. Despite ethnographic criticisms, the notion of substantial crypto-Jewish ancestry among Spanish-Americans persists. Aim: We tested the null hypothesis that Spanish-Americans of northern New Mexico carry essentially the same profile of paternally inherited DNA variation as the peoples of Iberia, and the relevant alternative hypothesis that the sampled Spanish-Americans possess inherited DNA variation that reflects Jewish ancestry significantly greater than that in present-day Iberia. Subjects and Methods: We report frequencies of 19 Y-chromosome unique event polymorphism (UEP) biallelic markers for 139 men from across northern New Mexico and southern Colorado, USA, who self-identify as ‘Spanish-American’. We used three different statistical tests of differentiation to compare frequencies of major UEP-defined clades or haplogroups with published data for Iberians, Jews, and other Mediterranean populations. We also report frequencies of derived UEP markers within each major haplogroup, compared with published data for relevant populations. Results: All tests of differentiation showed that, for frequencies of the major UEP-defined clades, Spanish-Americans and Iberians are statistically indistinguishable. All other pairwise comparisons, including between Spanish-Americans and Jews, and Iberians and Jews, revealed highly significant differences in UEP frequencies. Conclusion: Our results indicate that paternal genetic inheritance of Spanish-Americans is indistinguishable from that of Iberians and refute the popular and widely publicized scenario of significant crypto-Jewish ancestry of the Spanish-American population.

Résumé. Arrière plan:?L’héritage ethnique de la partie la plus septentrionale de la Nouvelle Espagne, incluant aux USA l’actuel nord du Nouveau-Mexique et le sud du Colorado, est intensément discuté. Des traditions hispano-américaines locales et des anecdotes tendent à proclamer que cette région a été colonisée primitivement par des crypto-juifs. En dépit de critiques ethnographiques, la notion d’ancestralité substantielle crypto-juive persiste chez les hispano-américains.

But:?Tester l‘hypothèse nulle que les hispano-américains du Nouveau-Mexique septentrional présentent essentiellement le même profil de variation d’ADN paternel que les populations de la péninsule ibérique et l’hypothèse alternative que les hispano-américains échantillonnés possèdent une variation d’ADN qui reflète significativement plus l’ancestralité juive que l’ibérique.

Sujets et méthodes:?On reporte les fréquences de 19 polymorphismes uniques du chromosome Y (PU-Y) de marqueurs bi-alléliques chez 139 hommes du nord du Nouveau-Mexique et du sud du Colorado qui s’auto-identifient comme hispano-américains. On utilise trois tests statistiques de différenciation afin de comparer les fréquences des clades ou haplogroupes de PU-Y majeurs, ainsi que les fréquences des marqueurs PU-Y singularisés à l’intérieur de chaque haplogroupe majeur, avec les données publiées pour les espagnols, les juifs et d’autres populations méditerranéennes.

Résultats:?Tous les tests de différenciation montrent que les hispano-américains et les ibères sont statistiquement indistincts pour les fréquences des clades majeurs à définition PU-Y. Toutes les autres comparaisons deux à deux incluant hispano-américains et juifs et ibères et juifs, montrent des différences hautement significatives des fréquences PU-Y.

Conclusion: Nos résultats indiquent que l’hérédité paternel des hispano-américains ne peut être distinguée de celle des ibères et réfute le scénario populaire et largement diffusé, de l’existence d’une origine significative crypto-juive de la population hispano-américaine.

Zusammenfassung. Hintergrund:?Das ethnische Erbe des nördlichsten Teils von Neuspanien, einschliess;lich des heutigen New Mexico und des südlichen Colorado, USA, unterliegt intensiven Diskussionen. Lokale spanisch-amerikanische Traditionen und Anekdoten haben zu Behauptungen beigetragen, dass diese Region hauptsächlich von Geheimjuden beziehungsweise sogenannten crypto-jews kolonialisiert worden war. Trotz ethnographischer Kritik an dieser Theorie, hält sich die Vorstellung, dass ein bedeutender Anteil der heutigen in dieser Region lebenden Spanisch-Amerikaner von crypto-Jewish Vorfahren abstammen.

Ziel:?Wir untersuchen die Nullhypothese, die besagt, dass die Spanisch-Amerikaner des nördlichen New Mexico im Wesentlichen dasselbe Profil väterlich vererbter DNS-Variationen zeigen wie die Bevälkerung der Iberischen Halbinsel, und die entsprechende Alternativhypothese, die besagt, dass die getesteten Spanisch-Amerikaner DNS-Variationen besitzen, die ein signifikant höheres Mass; an jüdischer Herkunft widerspiegelen als die, die heute auf der Iberischen Halbinsel vorgefunden werden.

Probanden und Methoden:?Für 139 Männer aus dem nördlichen New Mexico und südlichen Colorado, USA, die sich selbst als, Spanisch-Amerikaner“ bezeichnen, wurde eine Genotypisierung auf dem Y-Chromosom anhand von 19 verschiedenen biallelischen Markern (unique event polymorphism, UEP) vorgenommen. Drei verschiedene statistische Tests wurden ausgeführt, um mögliche Unterschiede bei den Häufigkeiten der wesentlichen UEP-definierten Stämme oder Haplogruppen mit denen von bisher veröffentlichten Daten von Bewohnern der Iberischen Halbinsel, Juden sowie anderen mediterranen Völkern vergleichen zu können. Auss;erdem berichten wir die Häufigkeiten von abgeleiteten UEP-Markern innerhalb einer jeden Haupt-Haplogruppe und vergleichen diese mit publizierten Daten für die entsprechenden Populationen.

Ergebnisse:?Alle Untersuchungen auf Unterschiede zeigten für die Häufigkeiten der wesentlichen UEP-definierten Stämme, dass sich die der Spanisch-Amerikaner und der Bewohner der Iberischen Halbinsel statistisch nicht unterscheiden. Alle anderen paarweisen Vergleiche, einschliess;lich derer zwischen zum einen Spanisch-Amerikanern und Juden und zum anderen Bewohnern der Iberischen Halbinsel und Juden, zeigten signifikante Unterschiede in den jeweiligen UEP-Häufigkeiten.

Zusammenfassung:?Unsere Ergebnisse legen nahe, dass die väterliche genetische Vererbung bei Spanisch-Amerikanern nicht von der der iberischen Bevölkerung zu unterscheiden ist. Das populäre und oft publizierte Szenario einer signifikanten crypto-Jewish Abstammung, unter der heutigen spanisch-amerikanischen Bevölkerung wird damit widerlegt.

Resumen. Antecedentes:?La herencia étnica de la Nueva España situada más al norte, que incluye el norte del actual Nuevo México y el sur de Colorado, E.E.U.U., es objeto de un intenso debate. El modo de vida y las narraciones anecdóticas locales hispanoamericanas conducen a afirmar que la región fue colonizada inicialmente por judíos secretos o cripto-judíos. A pesar de las críticas etnográficas, persiste aún la noción de una ascendencia cripto-judía substancial entre los hispanoamericanos.

Objetivo:?Comprobamos la hipótesis nula de que los hispano-americanos del norte de Nuevo México portan esencialmente el mismo perfil de variación de ADN heredada por vía paterna que los pueblos de la Península Ibérica, así como la hipótesis alternativa relevante de que los hispanoamericanos estudiados poseen una variación de ADN heredada que refleja su ascendencia judía de forma mucho más perceptible que en la actual Península Ibérica.

Sujetos y métodos:?Presentamos las frecuencias de 19 marcadores bialélicos de polimorfismo de evento único (UEP) del cromosoma Y, de 139 varones procedentes de la zona situada entre el norte de Nuevo México y el sur de Colorado (E.E.U.U.), quienes se identifican a sí mismos como “hispanoamericanos”. Utilizamos tres pruebas estadísticas distintas de diferenciación para comparar las frecuencias de los principales clados o haplogrupos de UEP, definidos mediante datos publicados sobre ibéricos, judíos y otras poblaciones mediterráneas. También presentamos las frecuencias derivadas de los marcadores UEP dentro de cada haplogrupo principal, comparadas con los datos publicados sobre poblaciones relevantes.

Resultados:?todos los tests de diferenciación mostraron que, para las frecuencias de los principales clados de UEP definidos, hispanoamericanos e ibéricos son estadísticamente indistinguibles. El resto de pares comparados, incluyendo hispanoamericanos y judíos, e ibéricos y judíos, revelaron diferencias altamente significativas en las frecuencias de los UEP.

Conclusión:?nuestros resultados indican que la herencia genética paterna de los hispanoamericanos es indistinguible de la de los ibéricos y refuta el escenario popular y ampliamente publicitado de una significativa ascendencia cripto-judía de la población hispanoamericana.