Fertility and genetic advice in diabetics

Summary The improved fertility of diabetics and the progress of diabetic morbidity imply the necessity of restricting procreation. The opposite notions of fertility and prevention may be reconciled by the genetic counselling if the pedigree, the mode of transmission of diabetes, the financial situation, ethical point of view, etc. are taken into account. Details are given concerning this advice and the arguments sustaining it, especially the number of diabetics in the pedigree and the penetrance of diabetes. The authors criticize mixed marriages which increase the number of diabetogenic genes in the population. On the contrary they advise marriage between diabetics in order to limit the number of births by «autoprophylaxis» and thus prevent the dissemination of diabetogenic genes. The arguments lending support to mixed marriages are also listed, with detailed advice for special cases. Genetic advice would be more readily accepted if diabetics were taught to draw up their pedigree and keep it up to date.

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Zusammenfassung Die verbesserte Fruchtbarkeit der Diabetiker und die vermehrte Diabetes-Morbidität bringen mit sich die Notwendigkeit, die Reproduktion der Diabetiker zu beschränken. Die entgegengesetzten Begriffe der Fruchtbarkeit und der Verhütung können durch genetische Ratschläge in Einklang gebracht werden, vorausgesetzt daß Stammbaum, Vererbungsmodus der Zuckerkrankheit, finanzielle Situation, ethische Gesichtspunkte, etc, berücksichtigt werden. Es werden Einzelheiten bezüglich dieser Beratung gegeben sowie die Überlegungen, auf welchen diese basieren, d.h. insbesondere die Anzahl der Diabetiker im Stammbaum und die Penetranz des Diabetes. Die Verfasser sind gegen Mischehen, welche die Anzahl der Diabetikergene in der Bevölkerung vermehren. Hingegen raten sie zur Eheschliessung zwischen Diabetikern, um die Geburtenzahl durch «Selbstprophylaxe» zu beschränken und somit die Aussaat der Diabetikergene zu verhüten. Es werden auch die Gründe aufgezählt, welche für die Mischehen sprechen, mit Ratschlägen für besondere Fälle. Genetische Ratschläge würden leichter angenommen werden, wenn man Diabetiker lehrte, ihren Stammbaum zu führen und ihn auf dem laufenden zu halten.

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Resumen La fertilidad mejorada de los diabéticos y el aumento de la morbosidad por diabetes evocan la necesidad de limitar la procreación. Los consejos de genética son susceptibles de conciliar las nociones opuestas de fertilidad y de prevención. Al dar esos consejos se deben considerar el análisis del árbol genealógico, el modo de trasmisión de la diabetes, la situación económica, los problemas éticos, etc. Esos consejos se exponen detalladamente justificándolos, a la vez, en relación, sobre todo, con el número de diabéticos existentes en el árbol genealógico y con la penetración de la diabetes. Los autores no son partidarios del matrimonio de individuos sanos con enfermos puesto que aumenta el número de genes diabetógenos en la población y aconsejan, por el contrario, el matrimonio entre diabéticos, con la finalidad autoprofiláctica de limitar los nacimientos e impedir de tal manera la diseminación de genes diabetógenos en la población. Se exponen también, detalladamente, los argumentos a favor de este tipo de matrimonio, dando además consejos especiales para los diversos casos. La sugerencias genéticas podrían ser aceptadas más fácilmente si se indujese a los diabéticos a elaborar y poner al día su proprio árbol genealógico.

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Résumé L'amélioration de la fertilité des diabétiques et la progression de la morbidité diabétique évoquent la nécéssité de limiter la procréation. Le conseil génétique est susceptible de concilier les notions opposées de fertilité et de prévention. Pour donner ce conseil on doit tenir compte de l'analyse de l'arbre généalogique, du mode de transmission du diabète, de la situation économique, enfin du point de vue étique, etc. Sont détaillés les conseils et leur justification, notamment par le nombre des diabétiques existant dans l'arbre généalogique et la pénétrance du diabète. Les auteurs font la critique du mariage mixte qui augmente le nombre de gènes diabétogènes dans la population. Par contre ils conseillent le mariage entre diabétiques avec l'intention de limiter les naissances par autoprophylaxie et d'empêcher ainsi la dissémination des gènes diabétogènes dans la population. Sont détaillés les arguments qui plaident en faveur de ce mariage. Des conseils détaillés sont donnés pour les cas spéciaux. Le conseil génétique serait plus facilement accepté si l'on habituait les diabétiques à dessiner et à tenir à jour leur arbre généalogique.

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Riassunto La migliorata fertilità dei diabetici e l'aumento della morbosità per diabete evocano la necessità di limitare la procreazione. I consigli di genetica sono suscettibili di conciliare le opposte nozioni di fertilità e di prevenzione. Nel fornire questi consigli si debbono considerare l'analisi dell'albero genealogico, il modo di trasmissione del diabete, la situazione economica, i problemi etici, etc. Tali consigli vengono esposti in dettaglio e di essi viene fornita la giustificazione, in rapporto soprattutto al numero di diabetici esistenti nell'albero genealogico e alla penetranza del diabete. Gli AA. fanno la critica del matrimonio misto, il quale aumenta il numero di geni diabetogeni nella popolazione. Essi consigliano, al contrario, il matrimonio tra diabetici, allo scopo di limitare le nascite per autoprofilassi e di impedire in tal modo la disseminazione di geni diabetogeni nella popolazione. Gli argomenti in favore di questo tipo di matrimonio sono esposti in modo particolareggiato. Consigli speciali vengono dati per i diversi casi. I suggerimenti genetici potrebbero essere più facilmente accettati qualora i diabetici venissero istruiti a costruire e a tenere aggiornato il proprio albero genealogico.

     

CBL mutations in myeloproliferative neoplasms are also found in the gene's proline-rich domain and in patients with the V617FJAK2

Background

Despite the discovery of the p.V617F in JAK2, the molecular pathogenesis of some chronic myeloproliferative neoplasms remains unclear. Although very rare, different studies have identified CBL (Cas-Br-Murine ecotropic retroviral transforming sequence) mutations in V617FJAK2-negative patients, mainly located in the RING finger domain. In order to determine the frequency of CBL mutations in these diseases, we studied different regions of all CBL family genes (CBL, CBLB and CBLC) in a selected group of patients with myeloproliferative neoplasms. We also included V617FJAK2-positive patients to check whether mutations in CBL and JAK2 are mutually exclusive events.

Design and Methods

Using denaturing high performance liquid chromatography, we screened for mutations in CBL, CBLB and CBLC in a group of 172 V617FJAK2-negative and 232 V617FJAK2-positive patients with myeloproliferative neoplasms not selected for loss of heterozygosity. The effect on cell proliferation of the mutations detected was analyzed on a 32D(FLT3) cell model.

Results

An initial screening of all coding exons of CBL, CBLB and CBLC in 44 V617FJAK2-negative samples revealed two new CBL mutations (p.C416W in the RING finger domain and p.A678V in the proline-rich domain). Analyses performed on 128 additional V617FJAK2-negative and 232 V617FJAK2-positive samples detected three CBL changes (p.T402HfsX29, p.P417R and p.S675C in two cases) in four V617FJAK2-positive patients. None of these mutations was found in 200 control samples. Cell proliferation assays showed that all of the mutations promoted hypersensitivity to interleukin-3 in 32D(FLT3) cells.

Conclusions

Although mutations described to date have been found in the RING finger domain and in the linker region of CBL, we found a similar frequency of mutations in the proline-rich domain. In addition, we found CBL mutations in both V617FJAK2-positive (4/232; 1.7%) and negative (2/172; 1.2%) patients and all of them promoted hypersensitivity to interleukin-3.     

Liver Sinusoid during Chronic Alcohol Consumption in the Rat: An Electron Microscopic Study

Transmission and scanning electron microscopic studies were performed on the liver sinusoid, with emphasis on sinusoidal endothelial cells, in rats fed a liquid diet containing either alcohol or dextrin (control) for 14 weeks. Animals were also treated with either Gram-negative bacterial lipopolysaccharide (LPS; 100 μg/100 g body weight, intravenously) or sterile saline (control). All specimens were prepared after perfusion fixation of the liver. Livers of rats fed dextrin-containing liquid diet displayed the ultrastructural features typical of the sinusoid and its endothelial cells. Livers from alcohol-fed animals, however, were characterized by massive loss of sieve-plate architecture of the sinusosidal endothelium, which was virtually replaced with a meshwork of enlarged openings with diameters frequently exceeding 1 urn. Morphological evidence of Kupffer cell activation could also be seen along with significant fatty infiltration of the hepatocyte. Conversely, LPS administration to dextrin-fed animals induced an apparent decrease in fenestration of the sinusoidal endothelial cell, accompanied by morphological evidence of enhanced endocytotic activity and cytoplasmic swelling. The changes seen 3 hr after LPS administration were markedly advanced at 24 hr. LPS administration to alcohol-fed rats accentuated the alterations observed after alcohol treatment alone. Additionally, the presence of platelets in the sinusoid as well as adhering to the hepatocyte microvilli in the space of Disse, along with the presence of Ito and Kupffer cell activation, greater than that observed in the alcohol-treated rats, is morphological evidence consistent with the disruption of vascular integrity in the liver. Interestingly, LPS treatment did not reverse the effects of alcohol on the sinusoidal endothelial cell fenestration. The possible functional consequences of alcohol- and LPS-induced ultrastructural alterations of the sinusoidal endothelial cell, and of the hepatic sinusoid in general, are evaluated in light of the available data on scavenging function of the sinusoidal endothelial cell.     

De novo isochromosome 18p in two patients: cytogenetic diagnosis and confirmation by chromosome painting

This report concerns two patients with clinical features typical for tetrasomy 18p syndrome. Chromosomal analysis revealed a male karotype in both cases, with an additional small metacentric marker chromosome, putatively an i(18p). Fluorescent in situ hybridization with a chromosome 18-specific paint confirmed that the marker chromosome consisted of chromosome 18 material in both cases.     

Anticoagulation in transradial percutaneous coronary intervention

Transradial percutaneous coronary intervention (PCI) is associated with significant reductions in access site complications and major bleeding as compared with the transfemoral approach. Bivalirudin is now the most commonly used anticoagulant for transradial PCI in the United States, while weight adjusted unfractionated heparin remains the most common choice outside the United States. A growing number of reports suggest that transradial intervention may offer improved outcomes across a variety of clinical situations, including those at the highest risk of bleeding complications, such as those with acute myocardial infarction. The following review provides an overview of the studies evaluating anticoagulation in transradial PCI and a rationale for the combination of the transradial approach to coronary interventions with an optimal anticoagulant strategy to reduce both access site and nonaccess site‐related bleeding. © 2013 Wiley Periodicals, Inc.     

The role of interferon in the resistance of C57BL/6 mice to various doses of herpes simplex virus type 1

C57BL/6 (B6) mice are relatively resistant to infection with herpes simplex virus type 1 (HSV-1). Paradoxically, B6 mice were resistant to 250 LD50 (50% lethal dose) of HSV-1 but were killed by 25 or 2.5 LD50 of HSV-1 injected intraperitoneally. At the injection site 250 LD50 of virus induced high titers of interferon (IFN) (greater than 1,000 international units) that reached maximal levels 2-4 hr after inoculation, whereas 25 or 2.5 LD50 of HSV-1 generated only borderline levels of IFN (15-40 international units). Simultaneous inoculation of 250 LD50 of HSV-1 and antiserum to mouse IFN (MuIFN) rendered B6 mice susceptible to infection; however, treatment with antiserum to MuIFN did not increase susceptibility to 1 LD50 of virus. Injections of MuIFN given 2 hr before and 2 hr after inoculation with virus protected B6 mice against 25 LD50 of virus. Thus, endogenous IFN induced after injection with 250 LD50 of HSV-1 protects B6 mice, whereas low doses of virus kill the animals because they do not generate a detectable IFN response at the infection site.     

Effect of Acute and Chronic Alcohol Administration to Rats on the Expression of Interleukin-6 Cell-Surface Receptors of Hepatic Parenchymal and Nonparenchymal Cells

Rats were treated with alcohol either acutely (continuous, 7-hr intravenous infusion; blood alcohol levels ～35 mM) or chronically (liquid diet, 12–14 weeks). Three hr before killing, the animals received Gram-negative bacterial lipopolysaccharide (LPS) or saline. Hepatocytes, Kupffer cells, and liver sinusoidal endothelial cells were isolated by liver collagenase perfusion and centrifugal elutriation, and used for measurements of recombinant human [¹²⁵I]interleukin-6 binding. Dissociation constant (K_d) and the amount of cell-surface receptors (B_max) were measured on whole cells, at 4°C. Two binding sites were detected on all three cell types: high-affinity (K_d1, from 20 to 125 PM) and low-affinity (K_d2, from 0.2 to 2 nM), with low B_max (B_max from 0.4 to 12 fmol/10⁶ cells) and high B_max (B_max2, from 10 to 210 fmol/10⁶ cells). Hepatocytes displayed an 8-fold higher binding capacity for high-affinity sites (B_max1) than the other two cell types. Acute ethanol treatment induced the following significant changes in the binding parameters: a decrease in K_d1 for hepatocytes and Kupffer cells, an increase in B_max2 for hepatocytes, and a decrease in B_max1 for Kupffer cells. Although the control (nonalcoholic) liquid diet per se completely suppressed the high-affinity binding sites, alcohol-containing diet induced only one change: a significant increase in K_d2 for hepatocytes. No changes in the binding parameters were seen after LPS administration to the chronically treated group. In the acute group, LPS mimicked alcohol action on hepatocyte binding parameters. Alcohol blunted LPS effects. No changes were observed in the cytokine binding to Kupffer cells after LPS injection. The results show that alcohol alters interleukin-6 cell-surface receptor properties and receptor amount on hepatocytes and Kupffer cells. By demonstrating the presence of interleukin-6 receptors on non-parenchymal liver cells, our data also suggest that these cells may be involved in an autocrine loop-like response, which could be a target for alcohol action on the liver.