Establishment and characterization of a childhood T-cell acute lymphoblastic leukemia cell line, PER-255, with chromosome abnormalities involving 7q32-34 in association with T-cell receptor- beta gene rearrangement

A human leukemia cell line, PER-255, was established from the bone marrow of a 5-year-old boy with features typical of lymphomatous T- acute lymphoblastic leukemia (T-ALL). The leukemic origin of cell line PER-255 is indicated by its cytochemical and immunologic similarity to the patient's fresh leukemic cells, which correspond to immature cortical thymocytes. Southern blot analysis showed that the IgJH genes were in germline configuration, whereas both alleles of the T-cell receptor-beta (TCR-beta) gene were rearranged in PER-255 cells, with identical rearrangements present in the patient's leukemic cells. Cytogenetic analysis of the cell line revealed a single abnormal clone with the karyotype 46,XY,t(7;10)(q32-34;q24),t(9;12) (p22;p12-13). Reciprocal translocations involving chromosome bands 7q32-36, containing the gene for the TCR-beta chain, have been reported for a number of tumors of T-cell origin. Translocations involving the 7q32-36 region appear to be nonrandomly associated with childhood T-ALL, whereas abnormalities of 9p and 12p have been reported to be nonrandomly involved in ALL but not specifically associated with the T- cell phenotype.     

An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: further evidence for SMN as the primary SMA-determining gene

The gene for autosomal recessive spinal muscular atrophy (SMA) has been mapped to 5q12 in a region that contains repeated markers and genes. Three cDNAs that detect deletions in SMA patients have been reported. One of these, the survival motor neuron (SMN) cDNA, is encoded by two genes (SMNT and SMNC) which are distinguished by base changes in exons 7 and 8. Exon 7 of the SMNT gene is not detectable in approximately 95% of SMA cases, due either to deletion or sequence conversion. There is limited information on the mutations in SMA patients that have detectable SMNT, these are critical for confirmation of SMNT as the SMA gene. Using SSCP analysis of the SMN exons we screened our SMA patients that possess at least one intact SMNT allele for mutations in SMNT. We identified one type I SMA patient with an 11 bp duplication in exon 6 which causes a frameshift and premature termination of the deduced SMNT protein. Dosage and SSCP analysis of SMNT in this family indicated that the father contributed a SMNT-deleted allele to the affected child whereas the mother passed on the 11 bp exon 6 duplication SMNT allele. Analysis of RNA by RT-PCR conclusively demonstrated that the 11 bp duplication is associated with the SMNT locus and not SMNC. This mutation provides strong support for SMN as the SMA-determining gene and indicates that disruption of SMNT on its own is sufficient to produce a severe type I SMA phenotype.      

1141635071Suppressor of Cytokine Signalling 3 (SOCS3) controls trophoblast invasion and proliferation

Preterm birth is a major cause of perinatal morbidity and mortality. Intrauterine infection/inflammation is associated with a majority of preterm labor and birth cases. Despite decades of studies recognizing a strong association between infection/inflammation and preterm birth, no effective method of preventing infection-induced premature labor and delivery is yet available. Importantly, the mechanisms by which intrauterine infection/inflammation may contribute to preterm birth are not known. Based on our observations with human gestational tissue to highlight the role of IL-10 in normal and comprimised pregnancy outcomes, we have performed experiments with syngeneic and allogeneic pregnant IL-10^-/- mice or congenic wild type mice. Pregnancy outcomes were assessed in response to i.p. administration of low doses of lipopolysacchade (LPS) on gd 14. The mice were allowed to deliver or were sacrificed on gd 16 for isolation of uterine immune cells for functional studies or collected tissue for histological analysis. Attempts were made to prevent preterm parturition. LPS-treated IL-10^-/-, but not wild type mice, displayed a significant acceleration in time of delivery, on gd 16.5 compared to gd 19.6 for wild type controls. The premature delivery observed in LPS-treated IL-10^-/- mice was associated with an increase in the number of uterine NK (uNK) cells. These cells also displayed a dramatic infiltration of the placenta with a perivascular localization. uNK cells appear to be responsible for the induction of preterm birth in these mice as depletion of NK cells completely restored normal length of gestation. Moreover, neutralization TNF-α also rescued the premature delivery. Taken together, our results for the first time demonstrate that IL-10 deficiency and uterine NK cell cytotoxic activation link intrauterine inflammation to preterm parturition.     

Effect of programmed number of intervals to detect ventricular fibrillation on implantable cardioverter-defibrillator aborted and unnecessary shocks

INTRODUCTION: Detection of self-terminating arrhythmias by implantable cardioverter-defibrillators (ICDs) causes unnecessary battery depletion and unnecessary shocks. Our goal was to estimate the effect of the programmed number of intervals to detect (NID) ventricular fibrillation (VF) on ICD temporal episode rate, unnecessary shocks, and delay in detection of VF. METHODS AND RESULTS: We analyzed 773 ICD-detected VF episodes in 875 patients. The number of intervals to detect VF was programmed to 12 of 16 (NID 12) in 305 patients and 18 of 24 (NID 18) in 570 patients. For patients with NID 12, we estimated the increase of mean cumulative episode rate at 6 months since implant and decrease in detection time for VF compared with a hypothetical NID 18. For patients with NID 18, we estimated the decrease of mean cumulative episode rate and unnecessary shocks compared with a hypothetical NID 12. Patients with NID 12 had a 17% increased episode rate resulting in unnecessary capacitor charging for self-terminating arrhythmias. Patients with NID 18 had a 22% decreased episode rate. In patients with NID 12, hypothetical NID 18 would have delayed detection of 273 VF episodes in 1.8 seconds. In patients with NID 18, hypothetical NID 12 would have resulted in inappropriate delivery of 14 aborted shocks in 10% of patients with episodes. CONCLUSION: In patients with self-terminating device-detected VF, increasing the number of intervals to detect VF from 12/16 to 18/24 results in a clinically significant decrease in ICD detections and fewer unnecessary shocks with minimal incremental delay in VF detection.     

High frequency region of the snore spectra carry important information on the disease of sleep apnoea

Snoring is the most common symptom of obstructive sleep apnoea (OSA). Several researchers have reported differences between the power spectra of non-OSA and OSA snorers. The traditional approach over the years has been to record snore sounds at a bandwidth of < 5 kHz. Narrowing of the upper airways during OSA events and the resulting upward shift of snore frequencies also lend support to the idea of examining snore sounds beyond 5 kHz. In this paper, we compute the power spectra of snores in three different bands defined as: low-frequency band (LFB: < 5 kHz); middle-frequency band (MFB: 5-10 kHz) and high-frequency band (HFB: 10-20 kHz). We illustrate that there is a significant difference between non-OSA snorers (Apnoea Hypopnoea Index (AHI) < 10) and OSA snorers (AHI > 10) in the region > 5 kHz. We then develop a feature to diagnose OSA based on the spectral differences in the high frequency region and evaluate its performance on a database of 20 subjects. Our results strongly suggest that the high-frequency region of the snore sounds carry information, hitherto disregarded, on the disease of sleep apnoea.     

Impact of gender on snore-based obstructive sleep apnea screening

Obstructive sleep apnea syndrome (OSA) is a serious widespread disease in which upper airways (UA) are collapsed during sleep. OSA has marked male predominance in prevalence. Although women are less vulnerable to OSA, under-diagnosed OSA in women may associate with serious consequences. Snoring is commonly associated with OSA and one of the earliest symptoms. Snore sounds (SS) are generated due to vibration of the collapsing soft tissues of the UA. Structural and functional properties of the UA are gender dependent. SS capture these time varying gender attributed UA properties and those could be embedded in the acoustic properties of SS. In this paper, we investigate the gender-specific acoustic property differences of SS and try to exploit these differences to enhance the snore-based OSA detection performance. We developed a snore-based multi-feature vector for OSA screening and one time-measured neck circumference was augmented. Snore features were estimated from SS recorded in a sleep laboratory from 35 females and 51 males and multi-layer neural network-based pattern recognition algorithms were used for OSA/non-OSA classification. The results were K-fold cross-validated. Gender-dependent modeling resulted in an increase of around 7% in sensitivity and 6% in specificity at the decision threshold AHI = 15 against a gender-neutral model. These results established the importance of adopting gender-specific models for the snore-based OSA screening technique.     

Pitch jump probability measures for the analysis of snoring sounds in apnea

Obstructive sleep apnea (OSA) is a highly prevalent disease in which upper airways are collapsed during sleep, leading to serious consequences. The gold standard of diagnosis, called polysomnography (PSG), requires a full-night hospital stay connected to over ten channels of measurements requiring physical contact with sensors. PSG is inconvenient, expensive and unsuited for community screening. Snoring is the earliest symptom of OSA, but its potential in clinical diagnosis is not fully recognized yet. Diagnostic systems intent on using snore-related sounds (SRS) face the tough problem of how to define a snore. In this paper, we present a working definition of a snore, and propose algorithms to segment SRS into classes of pure breathing, silence and voiced/unvoiced snores. We propose a novel feature termed the 'intra-snore-pitch-jump' (ISPJ) to diagnose OSA. Working on clinical data, we show that ISPJ delivers OSA detection sensitivities of 86-100% while holding specificity at 50-80%. These numbers indicate that snore sounds and the ISPJ have the potential to be good candidates for a take-home device for OSA screening. Snore sounds have the significant advantage in that they can be conveniently acquired with low-cost non-contact equipment. The segmentation results presented in this paper have been derived using data from eight patients as the training set and another eight patients as the testing set. ISPJ-based OSA detection results have been derived using training data from 16 subjects and testing data from 29 subjects.     

Exhaustive mathematical analysis of simple clinical measurements for childhood pneumonia diagnosis

Background

Pneumonia is the leading cause of mortality for children below 5 years of age. The majority of these occur in poor countries with limited access to diagnosis. The World Health Organization (WHO) criterion for pneumonia is the de facto method for diagnosis. It is designed targeting a high sensitivity and uses easy to measure parameters. The WHO criterion has poor specificity.

Methods

We propose a method using common measurements (including the WHO parameters) to diagnose pneumonia at high sensitivity and specificity. Seventeen clinical features obtained from 134 subjects were used to create a series of logistic regression models. We started with one feature at a time, and continued building models with increasing number of features until we exhausted all possible combinations. We used a k-fold cross validation method to measure the performance of the models.

Results

The sensitivity of our method was comparable to that of the WHO criterion but the specificity was 84%-655% higher. In the 2-11 month age group, the WHO criteria had a sensitivity and specificity of 92.0%±11.6% and 38.1%±18.5%, respectively. Our best model (using the existence of a runny nose, the number of days with runny nose, breathing rate and temperature) performed at a sensitivity of 91.3%±13.0% and specificity of 70.2%±22.80%. In the 12-60 month age group, the WHO algorithm gave a sensitivity of 95.7%±7.6% at a specificity of 9.8%±13.1%, while our corresponding sensitivity and specificity were 94.0%±12.1% and 74.0%±23.3%, respectively (using fever, number of days with cough, heart rate and chest in-drawing).

Conclusions

The WHO algorithm can be improved through mathematical analysis of clinical observations and measurements routinely made in the field. The method is simple and easy to implement on a mobile phone. Our method allows the freedom to pick the best model in any arbitrary field scenario (e.g., when an oximeter is not available).

     

1141644472Surface Enhanced Laser Desorption and Ionization (SELDI) mass spectrometry for investigation of human embryo conditioned IVF culture medium

Background:  Fetal programming is the notion that adverse environmental conditions in utero can cause short term survival adaptations that may have long-term consequences, such as chronic disease in subsequent lifetime. Recently, some authors reported that the increase of allergy prevalence in childhood may be linked with fetal immune development. In this regard, literature survey inspired to study the influence of two conjugated linoleic acid (CLA)-isomers (c9,t11 and t10,c12) on parameters of the immune system in pregnancy.
Methods:  Lymphocytes from allergic and non-allergic mothers, cord blood of their newborns, and the decidual layer of term placentae were isolated and cultured for 2 days and supplemented or not with relevant allergens, c9,t11 CLA, t10,c12 CLA or linoleic acid, respectively. Expression of CD69 (activation marker) and CD71 (transferrin receptor; proliferation marker) on B and T lymphocytes and T helper cell type 1 (Th1) and Th2 cytokines in culture supernatant were analyzed.
Results:  Both CLA isomers led to an increase of the IFN-γ/IL-10 ratio in supernatants of peripheral maternal and cord blood cells from allergic patients and non-allergic-control. CLA supplementation decreased IL-10 secretion of peripheral maternal and decidual lymphocytes and the portion of CD71⁺ maternal B cells. Linoleic acid induced a similar effect.
Conclusion:  An immunological effect of CLA on maternal and fetal lymphocyte responses could be demonstrated. It would be expected that further investigations could reveal differences in effects of CLA and linoleic acid.