Reduced-intensity Transplantation For Lymphomas Using Haploidentical Related Donors Versus Hla-matched Sibling Donors: A Center For International Blood And Marrow Transplant Research Analysis

Purpose: Related donor haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplantation cyclophosphamide (PT-Cy) is increasingly used in patients lacking HLA-matched sibling donors (MSD). We compared outcomes after Haplo-HCT using PT-Cy with MSD-HCT in patients with lymphoma, using the Center for International Blood and Marrow Transplant Research registry. Materials and Methods: We evaluated 987 adult patients undergoing either Haplo-HCT (n = 180) or MSD-HCT (n = 807) following reduced-intensity conditioning regimens. The haploidentical group received graft-versus-host disease (GVHD) prophylaxis with PT-Cy with or without a calcineurin inhibitor and mycophenolate. The MSD group received calcineurin inhibitor-based GVHD prophylaxis. Results: Median follow-up of survivors was 3 years. The 28-day neutrophil recovery was similar in the two groups (95% v 97%; P = .31). The 28-day platelet recovery was delayed in the haploidentical group compared with the MSD group (63% v 91%; P = .001). Cumulative incidence of grade II to IV acute GVHD at day 100 was similar between the two groups (27% v 25%; P = .84). Cumulative incidence of chronic GVHD at 1 year was significantly lower after Haplo-HCT (12% v 45%; P < .001), and this benefit was confirmed on multivariate analysis (relative risk, 0.21; 95% CI, 0.14 to 0.31; P < .001). For Haplo-HCT v MSD-HCT, 3-year rates of nonrelapse mortality (15% v 13%; P = .41), relapse/progression (37% v 40%; P = .51), progression-free survival (48% v 48%; P = .96), and overall survival (61% v 62%; P = .82) were similar. Multivariate analysis showed no significant difference between Haplo-HCT and MSD-HCT in terms of nonrelapse mortality (P = .06), progression/relapse (P = .10), progression-free survival (P = .83), and overall survival (P = .34). Conclusion: Haplo-HCT with PT-Cy provides survival outcomes comparable to MSD-HCT, with a significantly lower risk of chronic GVHD

Frequency of 22q11.2 microdeletion in children with congenital heart defects in western poland

<p>Abstract</p> <p>Background</p> <p>The 22q11.2 microdeletion syndrome (22q11.2 deletion syndrome -22q11.2DS) refers to congenital abnormalities, including primarily heart defects and facial dysmorphy, thymic hypoplasia, cleft palate and hypocalcaemia. Microdeletion within chromosomal region 22q11.2 constitutes the molecular basis of this syndrome. The 22q11.2 microdeletion syndrome occurs in 1/4000 births. The aim of this study was to determine the frequency of 22q11.2 microdeletion in 87 children suffering from a congenital heart defect (conotruncal or non-conotruncal) coexisting with at least one additional 22q11.2DS feature and to carry out 22q11.2 microdeletion testing of the deleted children's parents. We also attempted to identify the most frequent heart defects in both groups and phenotypic traits of patients with microdeletion to determine selection criteria for at risk patients.</p> <p>Methods</p> <p>The analysis of microdeletions was conducted using fluorescence <it>in situ </it>hybridization (FISH) on metaphase chromosomes and interphase nuclei isolated from venous peripheral blood cultures. A molecular probe (Tuple) specific to the <it>HIRA (TUPLE1, DGCR1</it>) region at 22q11 was used for the hybridisation.</p> <p>Results</p> <p>Microdeletions of 22q11.2 region were detected in 13 children with a congenital heart defect (14.94% of the examined group). Microdeletion of 22q11.2 occurred in 20% and 11.54% of the conotruncal and non-conotruncal groups respectively. Tetralogy of Fallot was the most frequent heart defect in the first group of children with 22q11.2 microdeletion, while ventricular septal defect and atrial septal defect/ventricular septal defect were most frequent in the second group. The microdeletion was also detected in one of the parents of the deleted child (6.25%) without congenital heart defect, but with slight dysmorphism. In the remaining children, 22q11.2 microdeletion originated <it>de novo</it>.</p> <p>Conclusions</p> <p>Patients with 22q11.2DS exhibit wide spectrum of phenotypic characteristics, ranging from discreet to quite strong. The deletion was inherited by one child. Our study suggests that screening for 22q11.2 microdeletion should be performed in children with conotruncal and non-conotruncal heart defects and with at least one typical feature of 22q11.2DS as well as in the deleted children's parents.</p

Molecular and Functional Characterization of the Odorant Receptor2 (OR2) in the Tiger Mosquito Aedes albopictus

In mosquitoes, the olfactory system plays a crucial role in many types of behavior, including nectar feeding, host preference selection and oviposition. Aedes albopictus, known also as the tiger mosquito, is an anthropophilic species, which in the last few years, due to its strong ecological plasticity, has spread throughout the world. Although long considered only a secondary vector of viruses, the potential of its vector capacity may constitute a threat to public health. Based on the idea that an improved understanding of the olfactory system of mosquitoes may assist in the development of control methods that interfere with their behavior, we have undertaken a study aimed at characterizing the A. albopictus Odorant Receptors. Here we report the identification, cloning and functional characterization of the AalOR2 ortholog, that represents the first candidate member of the odorant receptor (OR) family of proteins from A. albopictus. AalOR2 is expressed in the larval heads and antennae of adults. Our data indicate that A. albopictus OR2 (AalOR2) shares a high degree of identity with other mosquito OR2 orthologs characterized to date, confirming that OR2 is one of the most conserved mosquito ORs. Our data indicate that AalOR2 is narrowly tuned to indole, and inhibited by (-)-menthone. In agreement with this results, these two compounds elicit two opposite effects on the olfactory-based behavior of A. albopictus larvae, as determined through a larval behavioral assay. In summary, this work has led to the cloning and de-orphaning of the first Odorant Receptor in the tiger mosquito A. albopictus. In future control strategies this receptor may be used as a potential molecular target

Acute mountain sickness.

Acute mountain sickness (AMS) is a clinical syndrome occurring in otherwise healthy normal individuals who ascend rapidly to high altitude. Symptoms develop over a period ofa few hours or days. The usual symptoms include headache, anorexia, nausea, vomiting, lethargy, unsteadiness of gait, undue dyspnoea on moderate exertion and interrupted sleep. AMS is unrelated to physical fitness, sex or age except that young children over two years of age are unduly susceptible. One of the striking features ofAMS is the wide variation in individual susceptibility which is to some extent consistent. Some subjects never experience symptoms at any altitude while others have repeated attacks on ascending to quite modest altitudes. Rapid ascent to altitudes of 2500 to 3000m will produce symptoms in some subjects while after ascent over 23 days to 5000m most subjects will be affected, some to a marked degree. In general, the more rapid the ascent, the higher the altitude reached and the greater the physical exertion involved, the more severe AMS will be. Ifthe subjects stay at the altitude reached there is a tendency for acclimatization to occur and symptoms to remit over 1-7 days

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present

Expression profile of the AalOR2 transcript in Aedes albopictus by RT-PCR.

<p>A non-quantitative RT-PCR on enriched poly(A)⁺ RNA showing the expression of AalOR2 mRNA in pre-adult stages, and in antennae from both male and female adult mosquitoes. The lanes are as follows: early larvae (EL), late larvae (LL), pupae (P), adult female antennae (F-ant), adult female carcassae (F-body), adult male antennae (M-ant), adult male carcassae (M-body), negative control obtained by using reaction mix with no cDNA (negative), 1 kb DNA marker-Fermentas (M). All RT-PCR reactions were performed with 40 cycles of amplification on cDNA, except for m-Ant, which was obtained with 35 cycles of amplification on the first-round specific amplificate. Prior to the RT-PCR, the cDNA populations were roughly normalized by RT-PCR to the amount of the AalRpL26 expression levels to ensure an equal input.</p

Table of compounds used in the Single Sensillum Recordings and Ca²⁺ imaging assays in heterologous cells.

<p>Table of compounds used in the Single Sensillum Recordings and Ca²⁺ imaging assays in heterologous cells.</p

Behavioral assay on <i>A.albopictus</i> larvae.

<p>(A, B) Third and fourth instar larvae were kept in a pirex pan containing a ball of low melting agarose with 10 mM indole and a ball of low melting agarose (the red and blue spots, respectively, in B). The number of larvae were counted each 30 seconds for a maximum of 22 minutes. The histogram shows clearly that indole has an attractive effect for <i>Aedes albopictus</i> larvae. (C,D) Third and fourth instar larvae in the presence of a ball containing 10 mM (–)-menthone and a ball of low melting agarose (the green and blue spots, respectively, in D). Again, the larvae were counted each 30 seconds for a maximum of 22 minutes. Histogram C shows clearly that (–)-menthone evoked an avoidance behavior on the larvae. The result was calculated reporting the number of larvae just at a discrete15-min time-point. These values were compared with each other and analyzed for statistical significance by using a paired, two-tailed student’s t test considering p≤0.05 as significant (df = 4 and t_0,05;4 = 44,28 for behavioral test A; df = 4 and t_0,05;4 = 27,76 for behavioral test C. *** indicate statistical significant changes (two-tailed Student’s t-test, p<0.001). Error bars indicate S.E.M. for n = 5 separate trials per odorant.</p

Dose dependent response of AalOR2 to indole.

<p>A) The firing rates of the AalOR2-“empty neuron” in response to increasing concentrations of indole ranging from 10⁻⁷ M to 2 ×10⁻² M. Indole led to an increase in spike frequency directly proportional to its concentration, suggesting its specificity of action. B) The same responses as in A) are reported in a graph. The red bars represent the means ± S.E.M. of three separate experiments (three sensilla per fly; n = 3).</p

Inhibitory effect of (–)Menthone on the AalOR2-“empty-neuron”.

<p>Representative trace of Single-Sensillum Recordings from AalOR2-ORCo in the ab3A ORN, in response to 10⁻³ M (–)-Menthone. The firing rates clearly indicate a decrease in the number of large spikes corresponding to the ab3A neuron in one second of activity. Like with the other odors, the experiments were carried out testing three independent UAST insertions and identical results were observed in all the lines. Three sensilla were analyzed per fly, for a total of three flies per each transgenic strain.</p