Cytokine receptors

The molecular characterization of cytokine receptors has progressed rapidly over the past 5 years as a result of availability of radiolabeled cytokines, as well as the identification or creation of cell lines that express significant numbers of receptors at the cell surface. This explosion in research effort has led to establishment of multiple cytokine-receptor gene families and the realization that inhibition of cytokine function at the level of ligand-receptor interaction may be an important area for therapeutic drug development.     

Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment

The antenatal variant of Bartter's syndrome is an autosomal recessive kidney disease characterized by polyhydramnios, premature delivery, hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous, having been linked recently to mutations in an ATP- sensitive, renal outer medullary K+channel, ROMK, and earlier to mutations in the Na-K-2Cl co-transporter, NKCC2. We characterized four of the mutations reported in three heterozygous ROMK variants of antenatal Bartter's and found that each expressed a distinct phenotype in Sf9 cells. One mutation expressed normal function and appears to be an allelic polymorphism. The other three mutations produced channels with significantly reduced K+fluxes. However, the mechanisms in each case were different and reflected abnormalities in phosphorylation, proteolytic processing or protein trafficking. The different mechanisms may be important in the design of appropriate therapy for patients with this disease.      

Determination of the parent of origin in nine cases of prenatally detected chromosome aberrations found after intracytoplasmic sperm injection

Prenatal cytogenetic analysis of 71 fetuses conceived by intracytoplasmic sperm injection (ICSI) resulted in the detection of nine (12.7%) chromosome aberrations including two cases of 47,XXY, four cases involving a 45,X cell line and three autosomal trisomies. Molecular analysis of the parental origin of the deleted or supernumerary chromosome was performed by using polymorphic microsatellite markers. Six cases involving a sex chromosome abnormality were found to be of paternal origin while the two trisomic cases that could be analysed were of maternal origin. Two cases involved the same infertile couple who had two consecutive ICSI pregnancies terminated because of a chromosome abnormality. The replaced embryos in both cases originated from a single batch of ICSI fertilized oocytes of which part was used to initiate the first pregnancy and part was cryopreserved and used to initiate the second pregnancy.      

The QT interval during wake and sleep in patients with ventricular arrhythmias

Eight patients with frequent ventricular ectopy underwent continuous electrocardiographic (ECG) and polygraphic monitoring for 4 days. A complex protocol consisted of normal day-night, activity-nonactivity, cycles for 48 h (nine patients); followed by a 24-h awake bedrest; and finally by a very delayed sleep and inactivity phase in the morning before returning to a normal day-night cycle (eight patients only). ECG tracings showed that the QT intervals during rapid eye movement sleep and nonrapid eye movement sleep increased significantly when compared with active wakefulness. The Bazett's corrected QT (QTc) interval also increased from active wakefulness to rapid eye movement sleep and nonrapid eye movement sleep. Adjusted mean QT intervals computed using the RR [corrected] interval as a covariate were significantly longer during non-rapid-eye-movement (407 ms) and rapid-eye-movement (408 ms) sleep than during active wakefulness (386 ms). The RR-adjusted mean QT intervals during inactive wake were also longer (400 ms) but this clear trend did not reach statistical significance (p = 0.08). Although prolongation of the QT interval during sleep reflects inactivity that may be related to withdrawal of sympathetic tone, we postulate that sleep per se also has an effect on the interval.     

The effects in vivo of purified preparations of murine macrophage colony stimulating factor-1, recombinant murine granulocyte-macrophage colony stimulating factor and natural and recombinant murine interleukin 3 without and with pretreatment of mice with purified iron-saturated human lactoferrin

The influence of purified natural colony stimulating factor-1 (CSF-1), purified recombinant granulocyte-macrophage (GM)-CSF, purified recombinant interleukin 3 (IL3) and natural IL3 were assessed in mice that were untreated or pretreated with purified iron-saturated human lactoferrin (LF) in order to first suppress myelopoiesis in the mice. S1/S1d mice responded to recombinant GM-CSF and recombinant IL3 in a manner similar to the response of their +/+ littermates. These 4 factors increased the cycling status of hematopoietic progenitors in vivo. The effects were more noticeable if myelopoiesis was first decreased by LF. The effects do not appear to be due to endotoxin contamination. It cannot be discerned from these studies whether the effects are direct ones on the progenitor cells or indirect ones mediated through growth-factor releasing accessory cells. It is possible that effects can be both direct and indirect.     

Initial evaluation of a continuous speech recognition program for radiology

The aims of this work were to measure the accuracy of one continuous speech recognition product and dependence on the speaker's gender and status as a native or nonnative English speaker, and evaluate the product's potential for routine use in transcribing radiology reports. IBM MedSpeak/Radiology software, version 1.1 was evaluated by 6 speakers. Two were nonnative English speakers, and 3 were men. Each speaker dictated a set of 12 reports. The reports included neurologic and body imaging examinations performed with 6 different modalities. The dictated and original report texts were compared, and error rates for overall, significant, and subtle significant errors were computed. Error rate dependence on modality, native English speaker status, and gender were evaluated by performing ttests. The overall error rate was 10.3 +/- 3.3%. No difference in accuracy between men and women was found; however, significant differences were seen for overall and significant errors when comparing native and nonnative English speakers (P = .009 and P = .008, respectively). The speech recognition software is approximately 90% accurate, and while practical implementation issues (rather than accuracy) currently limit routine use of this product throughout a radiology practice, application in niche areas such as the emergency room currently is being pursued. This methodology provides a convenient way to compare the initial accuracy of different speech recognition products, and changes in accuracy over time, in a detailed and sensitive manner.     

Evaluation of the bias in using the time to the first event when the inter-event intervals have a Weibull distribution

Currently the analysis of clinical trials for treatment of paroxysmal atrial fibrillation (PAF) relies on the assumption that the events are distributed according to a Poisson distribution. We contend that the occurrence of PAF events are clearly not Poisson and tend to occur in clusters. A candidate parametric model of the inter-event interval, the Weibull distribution, is presented. When the events are distributed according to a Poisson distribution, the time to the first event (TFE) has the same distribution as the inter-event intervals (IEI) due to the 'memoryless' property of the Poisson distribution, hence the TFE can be used instead of the IEI. When the events do not form a Poisson distribution, the TFE does not have the same distribution as the IEI. We show that for the Weibull distribution, when the TFE is used to model the IEI, both the mean and the survivor distribution are biased. The bias in the survivor function is a function both of time and the parameters of the distribution. Therefore when two groups have different parameters for their distributions (as in the case of different treatment effects), the discrepancy between the survivor distribution of the IEI and the survivor distribution of the TFE is affected differentially. We demonstrate the low coverage probabilities of the mean and the survivor function which result when the underlying distribution is Weibull with shape parameter kappa < 1.0. It is likely that this problem will arise for other clustered event processes. This suggests that careful empirical investigation of the distribution of IEI for recurrent events is necessary before choosing to analyse the data using the TFE.