Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia.

PURPOSE: Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) [inv(3)/t(3;3)] is recognized as a distinctive entity in the WHO classification. Risk assignment and clinical and genetic characterization of AML with chromosome 3q abnormalities other than inv(3)/t(3;3) remain largely unresolved. PATIENTS AND METHODS: Cytogenetics, molecular genetics, therapy response, and outcome analysis were performed in 6,515 newly diagnosed adult AML patients. Patients were treated on Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research (HOVON/SAKK; n = 3,501) and German-Austrian Acute Myeloid Leukemia Study Group (AMLSG; n = 3,014) protocols. EVI1 and MDS1/EVI1 expression was determined by real-time quantitative polymerase chain reaction. RESULTS: 3q abnormalities were detected in 4.4% of AML patients (288 of 6,515). Four distinct groups were defined: A: inv(3)/t(3;3), 32%; B: balanced t(3q26), 18%; C: balanced t(3q21), 7%; and D: other 3q abnormalities, 43%. Monosomy 7 was the most common additional aberration in groups (A), 66%; (B), 31%; and (D), 37%. N-RAS mutations and dissociate EVI1 versus MDS1/EVI1 overexpression were associated with inv(3)/t(3;3). Patients with inv(3)/t(3;3) and balanced t(3q21) at diagnosis presented with higher WBC and platelet counts. In multivariable analysis, only inv(3)/t(3;3), but not t(3q26) and t(3q21), predicted reduced relapse-free survival (hazard ratio [HR], 1.99; P < .001) and overall survival (HR, 1.4; P = .006). This adverse prognostic impact of inv(3)/t(3;3) was enhanced by additional monosomy 7. Group D 3q aberrant AML also had a poor outcome related to the coexistence of complex and/or monosomal karyotypes and cryptic inv(3)/t(3;3). CONCLUSION: Various categories of 3q abnormalities in AML can be distinguished according to their clinical, hematologic, and genetic features. AML with inv(3)/t(3;3) represents a distinctive subgroup with unfavorable prognosis.

Polymorphisms in TLR2 are associated with increased viral shedding and lesional rate in patients with genital herpes simplex virus Type 2 infection.

Clinical and virologic manifestations of genital herpes simplex virus type 2 (HSV-2) infection vary widely. We examined frequencies of single-nucleotide polymorphisms (SNPs) in Toll-like receptors (TLRs) 2, 3, 4, and 9 in a prospective cohort of 128 HSV-2-infected persons whose viral shedding and lesion frequency was measured by daily sampling from genital secretions. Two TLR2 haplotypes (2 and 4) were associated with increased lesional (P=.008 and P=.03) and shedding (P=.02 and P=.001) rates. An SNP in haplotype 2 (-15607A/G) was also associated with shedding (P=.01) and lesional (P=.008) rates. Polymorphisms in TLR2 may be in part responsible for differences in the severity of HSV-2 infection.

Le type chromosomique A des Sorex du groupe araneus: Sorex coronatus Millet, 1828 (Mammalia, Insectivora)

Après avoir complété la nomenclature par lettres des différents caryotypes des musaraignes du genre Sorex rattachées au groupe araneus, lequel est caractérisé par un trivalent sexuel, les auteurs discutent le statut taxonomique du type A. Sur la base de l'examen cytologique et morphologique de 3 individus, récoltés dans la localité type de Sorex coronatus Millet, 1828,ils proposent ce nom pour désigner l'espèce chromosomique A. Sorex gemellus Ott, 1968 tombe alors en synonymie. L'espèce est décrite et le statut des sous-espèces reconnues dans son aire de distribution examiné.

Mucosal but not parenteral immunization with purified human papillomavirus type 16 virus-like particles induces neutralizing titers of antibodies throughout the estrous cycle of mice.

We have recently shown that nasal immunization of anesthetized mice with human papillomavirus type 16 (HPV16) virus-like particles (VLPs) is highly effective at inducing both neutralizing immunoglobulin A (IgA) and IgG in genital secretions, while parenteral immunization induced only neutralizing IgG. Our data also demonstrated that both isotypes are similarly neutralizing according to an in vitro pseudotyped neutralization assay. However, it is known that various amounts of IgA and IgG are produced in genital secretions along the estrous cycle. Therefore, we have investigated how this variation influences the amount of HPV16 neutralizing antibodies induced after immunization with VLPs. We have compared parenteral and nasal protocols of vaccination with daily samplings of genital secretions of mice. Enzyme-linked immunosorbent assay analysis showed that total IgA and IgG inversely varied along the estrous cycle, with the largest amounts of IgA in proestrus-estrus and the largest amount of IgG in diestrus. This resulted in HPV16 neutralizing titers of IgG only being achieved during diestrus upon parenteral immunization. In contrast, nasal vaccination induced neutralizing titers of IgA plus IgG throughout the estrous cycle, as confirmed by in vitro pseudotyped neutralization assays. Our data suggest that mucosal immunization might be more efficient than parenteral immunization at inducing continuous protection of the female genital tract.

Glucose sensing and the pathogenesis of obesity and type 2 diabetes.

The control of body weight and of blood glucose concentrations depends on the exquisite coordination of the function of several organs and tissues, in particular the liver, muscle and fat. These organs and tissues have major roles in the use and storage of nutrients in the form of glycogen or triglycerides and in the release of glucose or free fatty acids into the blood, in periods of metabolic needs. These mechanisms are tightly regulated by hormonal and nervous signals, which are generated by specialized cells that detect variations in blood glucose or lipid concentrations. The hormones insulin and glucagon not only regulate glycemic levels through their action on these organs and the sympathetic and parasympathetic branches of the autonomic nervous system, which are activated by glucose or lipid sensors, but also modulate pancreatic hormone secretion and liver, muscle and fat glucose and lipid metabolism. Other signaling molecules, such as the adipocyte hormones leptin and adiponectin, have circulating plasma concentrations that reflect the level of fat stored in adipocytes. These signals are integrated at the level of the hypothalamus by the melanocortin pathway, which produces orexigenic and anorexigenic neuropeptides to control feeding behavior, energy expenditure and glucose homeostasis. Work from several laboratories, including ours, has explored the physiological role of glucose as a signal that regulates these homeostatic processes and has tested the hypothesis that the mechanism of glucose sensing that controls insulin secretion by the pancreatic beta-cells is also used by other cell types. I discuss here evidence for these mechanisms, how they integrate signals from other nutrients such as lipids and how their deregulation may initiate metabolic diseases.

Botulinum neurotoxin type A blocks the morphological changes induced by chemical stimulation on the presynaptic membrane of Torpedo synaptosomes.

The action of botulinum neurotoxin on acetylcholine release, and on the structural changes at the presynaptic membrane associated with the transmitter release,was studied by using a subcellular fraction of cholinergic nerve terminals (synaptosomes) isolated from the Torpedo electric organ. Acetylcholine and ATP release were continuously monitored by chemiluminescent methods.To catch the membrane morphological changes, the quick-freezing method was applied. Our results show that botulinum neurotoxin inhibits the release of acetylcholine from these isolated nerve terminals in a dose-dependent manner, whereas ATP release is not affected. The maximal inhibition (70%) is achieved at neurotoxin concentrations as low as 125 pM with an incubation time of 6 min. This effect is not linked to an alteration of the integrity of the synaptosomes since, after poisoning by botulinum neurotoxin type A, they show a nonmodified occluded lactate dehydrogenase activity. Moreover, membrane potential is not altered by the toxin with respect to the control, either in resting condition or after potassium depolarization. In addition to acetylcholine release inhibition, botulinum neurotoxin blocks the rearrangement of the presynaptic intramembrane particles induced by potassium stimulation. The action of botulinum neurotoxin suggests that the intramembrane particle rearrangement is related to the acetylcholine secretion induced by potassium stimulation in synaptosomes isolated from the electric organ of Torpedo marmorata.

Rate, type, and cost of adverse drug reactions in emergency department admissions.

Background: Adverse drug reactions (ADRs) are a threat to patients' health and quality of life, and can generate significant expenses. They are generally underreported, with different rates in different health care systems. Methods: We conducted a 6-month survey of all primary admissions to the medical emergency department of a university hospital and assessed the rate, characteristics, avoidability, and marginal costs of ADRs. Results: A total of 7% of all admissions were mainly caused by ADRs. The most frequent were gastrointestinal bleeding (22.3%) and febrile neutropenia (14.4%). Anticancer drugs were involved in 22.7% of the cases, and anticoagulants, analgesics, and non-steroidal anti-inflammatory drugs in 8% each. Physicians had prescribed 70% of these drugs. Patients were predominantly treated in intermediate care units and ordinary wards. The mean cost per case amounted to CHF 3586+/-342, or a total of CHF 821204 over the 6-month-period (1 CHF=0.56 US$=0.87 Euro). A total of 67% were considered definitely imputable to drug effects and 32% were retrospectively regarded as avoidable. Conclusions: Interventions aimed at reducing the incidence of ADRs should be directed towards both patient education and physician training. This could save hospitals admissions and money, and could be used as an indicator of prescription quality.

Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2(Akita/+) mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2(Akita/+) and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2(Akita/+) mice and sex-matched littermate controls. Our phenotypic analysis of Ins2(Akita/+) mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM.

Identification of novel and cell type enriched cofactors of the transcription activation domain of RelA (p65 NF-kappaB).

RelA (NF-kappaB) is a transcription factor inducible by distinct stimuli in many different cell types. To find new cell type specific cofactors of NF-kappaB dependent transcription, we isolated RelA transcription activation domain binding proteins from the nuclear extracts of three different cell types. Analysis by electrophoresis and liquid chromatography tandem mass spectrometry identified several novel putative molecular partners. Some were strongly enriched in the complex formed from the nuclear extracts of specific cell types.

Entry and transcription as key determinants of differences in CD4 T-cell permissiveness to human immunodeficiency virus type 1 infection.

Isolated primary human cells from different donors vary in their permissiveness-the ability of cells to be infected and sustain the replication of human immunodeficiency virus type 1 (HIV-1). We used replicating HIV-1 and single-cycle lentivirus vectors in a population approach to identify polymorphic steps during viral replication. We found that phytohemagglutinin-stimulated CD4(+) CD45RO(+) CD57(-) T cells from healthy blood donors (n = 128) exhibited a 5.2-log-unit range in virus production. For 20 selected donors representing the spectrum of CD4 T-cell permissiveness, we could attribute up to 42% of the total variance in virus production to entry factors and 48% to postentry steps. Efficacy at key intracellular steps of the replicative cycle (reverse transcription, integration, transcription and splicing, translation, and budding and release) varied from 0.71 to 1.45 log units among donors. However, interindividual differences in transcription efficiency alone accounted for 64 to 83% of the total variance in virus production that was attributable to postentry factors. While vesicular stomatitis virus G protein-mediated fusion was more efficacious than CCR5/CD4 entry, the latter resulted in greater transcriptional activity per proviral copy. The phenotype of provirus transcription was stable over time, indicating that it represents a genetic trait.

Achondrogenesis Type 1B.

DISEASE CHARACTERISTICS: Clinical features of achondrogenesis type 1B (ACG1B) include extremely short limbs with short fingers and toes, hypoplasia of the thorax, protuberant abdomen, and hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton. The face is flat, the neck is short, and the soft tissue of the neck may be thickened. Death occurs prenatally or shortly after birth. DIAGNOSIS/TESTING: The diagnosis of ACG1B rests on a combination of clinical, radiologic, and histopathologic features. SLC26A2 (DTDST) is the only gene known to be associated with ACG1B. Molecular genetic testing is available on a clinical basis. MANAGEMENT: Treatment of manifestations: palliative care for liveborn neonates. GENETIC COUNSELING: ACG1B is inherited in an autosomal recessive manner. At conception, each sib of a proband with ACG1B has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both disease-causing alleles in the family are known and the carrier status of the parents has been confirmed. Ultrasound examination after 14-15 weeks' gestation can be diagnostic.

Nanocrystalline M-type hexaferrite powders: preparation, geometric and magnetic propertiess

Co-Ti-Sn-Ge substituted M-type bariumhexaferrite powders with mean grain sizes between about 10 nm and about 1 ¿m and a narrow size distribution were prepared reproducibly by means of a modified glass crystallization method. At annealing temperatures between 560 and 580°C of the amorphous flakes nanocrystalline particles grow. They behave superparamagnetically at room temperature and change into stable magnetic single domains at lower temperatures. The magnetic volume of the powders is considerably less than the geometric one. However, the effective anisotropy fields are larger by a Factor of two to three.

Recovery of paraplegia after type B dissection due to spinal collateral recruitment.

Acute paraplegia could be a symptom of aortic dissection due to sudden compromise of arterial spinal cord blood supply. Complete spontaneous neurologic recovery is possible and was observed in the present case 3 hours after symptom onset. Spontaneous spinal cord reperfusion after acute type B dissection was probably due to two main mechanisms. Reperfusion of false lumen and collateral vascular network recruitment, recently confirmed by anatomic animal studies, serve as potential explanations. Favorable evolution of acute paraplegia after aortic dissection exists, but prognosis is uncertain, probably due to individual variable anatomic distribution of spinal cord blood supply.

Contrôle glycémique du diabète de type 2: intensif ou classique ?: revue Cochrane pour le praticien

Cet article présente les résultats de la revue systématique: Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal T, Hemmingsen C, Wetterslev J. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2011 Jun 15;(6):CD008143. DOI: 10.1002/14651858.CD008143.pub2. PMID: 21678374.