Distinctive gene expression profiles by cDNA microarrays in endometrioid and serous carcinomas of the endometrium.

Endometrial carcinomas are classified by their morphology into two major subtypes. Endometrioid carcinomas (type I) are generally estrogen dependent, well-differentiated, superficially invasive, and have a good outcome. Serous carcinomas (type II) are hormone independent, frequently deeply invasive and widely metastatic, and have a poor prognosis. Microarray technology and analysis allows us to determine if the global gene expression profiles of these two subtypes correlate with their morphologic phenotype. Fresh tissue from 18 endometrial carcinomas was studied: 7 well-, 2 moderately, and one poorly differentiated endometrioid, 4 serous carcinomas, and 4 high-grade mixed endometrioid-serous carcinomas. Labeled cDNA probes were synthesized (Cy5 for tumor, Cy3 for reference) and applied to microarrays containing 18,098 cDNA clones or ESTs. A pool of equal amounts of total RNA from each tumor served as the reference RNA. By unsupervised cluster analysis, the endometrioid carcinomas clustered together and were separate from the serous carcinomas. The high-grade mixed carcinomas clustered with the serous carcinomas. Using a statistical algorithm based on gene expression pattern and conducting a supervised analysis of the two defined groups, we have identified 315 genes that statistically differentiate type I from type II endometrial carcinomas. In addition to corroborating the predicted overexpression of known markers (e.g., ras and catenin in endometrioid carcinomas), the cDNA microarray technique has revealed novel alterations in gene expression relevant to cell cycle, cell adhesion, signal transduction, apoptosis, and tumor progression not previously implicated in endometrial carcinomas. For serous carcinomas, these include aldolase, desmoplakin, integrin-linked kinase, PKC, and metallopeptidase. In conclusion, the gene expression profiles of type I and type II endometrial carcinomas are different. Refinement of these profiles will permit more accurate diagnostic tumor classification and the development of prognosis assays.     

A parallel algorithm for simulation of large neural networks

The simulation of biologically realistic neural networks requires the numerical solution of very large systems of differential equations. Variables within the system can be changing at rates that vary by orders of magnitude, not only at different times of the solution, but at the same time in different parts of the network. Therefore, an efficient implementation must be able to vary the solution step size, and do so independently in different subsystems. A single processor algorithm is presented in which each neuron can be solved with its own step size by using a priority queue to integrate them in the correct order. But this leaves the problem of how communication and synchronisation between neurons should be managed when executing in parallel. The proposed solution uses an algorithm based on waveform relaxation, which allows groups of neurons on different processors to be solved independently and hence in parallel, for substantial parts of the computation. Realistic test problems were run on a distributed memory parallel computer and results show that speedups of 10 using 16 processors are achievable, and indicate that further speedups may be possible.     

Alterations in respiratory behavior, brain neurochemistry and receptor density induced by pharmacologic suppression of sleep in the neonatal period

The present study examined if drug suppression of active sleep (AS) in the neonate affected the development and expression of respiratory behavior. Secondly, we assessed brain neurochemistry and receptor density in specific supra-medullary brain regions to identify coincident biochemical alterations. Sprague-Dawley newborn rat pups were randomized and divided among six rat mothers (n=10/mother/group), each mother housed separately. Two untreated control (UC) groups received either no interventions or were fed milk vehicle twice daily and were handled similarly to the drug intervention animals. Pharmacological disruption of sleep was achieved by administration (2 groups of each) of either clonidine (CLO) 100 microm/kg, or scopolamine (SCO) 800 microm/kg, given orally twice daily for the first 7 days of life. On postnatal (P) days P10 and P19 of life, pups were assessed for metabolism, minute ventilation (VE), tidal volume (Vt) and frequency (f). On P21 (14 days after the end of drug exposure), pups from each condition were sacrificed and punch biopsies of the frontal cortex, hypothalamus, and hippocampus were examined for hydroxytryptophan (5-HT), and norepinepherine (NE) by HPLC. An equal number of pups were sacrificed and brains examined for muscarinic acetylcholine (mAch), alpha2-adrenergic and I1-imidazoline receptor density. RESULTS: Both CLO and SCO exposed animals had a lower V(t) and respiratory quotient than UC animals (p<0.01). CLO animals exhibited a higher f (p<0.01) and both CLO and SCO exhibited a lower V(t) (p<0.05) than the UC groups; VE was reduced in the SCO groups, compared with CLO and UC groups (p<0.01). Pattern of breathing in response to brief hypoxia exposure was altered for CLO and SCO. The normal decline in VE during sleep was not observed in CLO rats. Both drug exposures resulted in a comparable reduction in hypothalamic NE and 5-HT levels (p<0.05), while in the frontal cortex, and the hippocampus variable changes in NE and 5-HT, occurred. In CLO and SCO rats mAch receptors were increased in cortex, and reduced in hypothalamus; I1-imidazoline receptors were increased in hypothalamus and decreased in hippocampus (p<0.05 for each). In contrast, alpha2-adrenergic receptors were increased in cortex for both CLO and SCO, decreased in hypothalamus for CLO, and decreased in hippocampus for SCO (p<0.05 for each). CONCLUSIONS: these data show that drug-induced neonatal sleep suppression will alter ventilatory pattern, metabolism, and site-specific concentrations of adrenergic neurotransmitters and in receptor density, perhaps as a result of suppression of neonatal AS.     

Does gastrostomy tube feeding in children with cerebral palsy increase the risk of respiratory morbidity?

BACKGROUND: Children with severe neurological impairment may have significant oral motor dysfunction and are at increased risk of nutritional deficiencies, poor growth, and aspiration pneumonia. Gastrostomy tube feeding is increasingly being used for nutritional support in these children. AIM: To examine the occurrence of respiratory morbidity before and after gastrostomy feeding tube insertion in children with severe neurological disabilities. METHODS: This study was nested in a longitudinal, prospective, uncontrolled, multicentre cohort study designed to investigate the outcomes of gastrostomy tube feeding in 57 children with severe neurological disabilities. Parents completed a questionnaire prior to (visit 1) and 6 and 12 months (visits 2 and 3) following the gastrostomy, detailing number of chest infections requiring antibiotics and/or hospital admission. RESULTS: Mean number of chest infections requiring antibiotics was 1.8 on visit 1 and 0.9 on visit 3. Hospital admissions for chest infections fell significantly from 0.5 to 0.09. CONCLUSION: This study provides no evidence for an increase in respiratory morbidity following insertion of a feeding gastrostomy in children with cerebral palsy.     

Physiologic implications of helium as a carrier gas for inhaled nitric oxide in a neonatal model of Bethanecol-induced bronchoconstriction.

OBJECTIVE: To compare heliox to nitrogen-oxygen (nitrox) as a carrier gas for inducible nitric oxide (iNO) in the presence of pharmacologically inhaled bronchoconstriction. We hypothesized that respiratory resistance and gas exchange would improve when iNO is delivered with heliox. DESIGN: Interventional laboratory study. SETTING: An academic medical research facility in the northeastern United States. SUBJECTS: Sedated, ventilated newborn piglets. INTERVENTIONS: Newborn piglets (n = 16; 2.3 +/- 0.1 kg) were placed on a flow-controlled ventilator and given intravenous Bethanecol (2 x 1 mg/kg followed by 1 mg/kg/hr) to induce bronchoconstriction. Piglets were randomized to heliox or nitrox (Fio2 = 0.3) and given 80 ppm iNO. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, blood chemistry, and pulmonary mechanics were recorded at 30-min intervals for 2 hrs. Bethanecol dosing increased inspiratory respiratory resistance (cm H2O/L/min; p < .01) and decreased respiratory compliance (mL/cm H2O/kg; p < .01). Following carrier gas assignment, hemodynamics and respiratory compliance were similar between groups and respiratory resistance decreased (p < .01) in the heliox group. Over 2 hrs with iNO therapy, Paco2 increased (p < .01) whereas blood pH decreased (p < .01) in the heliox group. Respiratory resistance trended downward, oxygenation index improved (p < .01), and blood methemoglobin levels trended higher for nitrox compared with heliox. CONCLUSIONS: The INOvent was effective for controlling heliox delivery of iNO. Despite marked reduction in respiratory resistance with heliox gas ventilation in a neonatal model of pharmacologic bronchoconstriction, nitrox might perform better as a delivery vehicle for iNO.     

The Hardy Effect.

PURPOSE: The late James C. Hardy completed an extensive investigation of respiratory muscle activity during speech production. The data set that resulted was probably the most comprehensive and instructive that has ever existed. One aspect of the data puzzled Hardy and caused him to question the validity of his findings and withhold his observations from publication. METHOD: This research note chronicles Hardy's thinking at the time (based on personal communications) and points out how the aspect of the data that puzzled him turned out to be a seminal discovery of a fundamental mechanism of speech breathing. CONCLUSION: It is proposed that, in his honor, this discovery be referred to as the Hardy Effect.     

Flat-panel volume computed tomography for cochlear implant electrode array examination in isolated temporal bone specimens.

HYPOTHESIS: Flat-panel based volume computed tomography could improve cochlear implant electrode evaluation in comparison with multislice computed tomography. BACKGROUND: Flat-panel based volume computed tomography offers higher spatial resolution and less metal artifacts than multislice computed tomography. Both characteristics could improve the evaluation of challenging but important questions in cochlear implantation assessment, such as an exact imaging of cochlea, osseous spiral lamina, electrode array position, and single electrode contacts. These questions are not currently fully answered by multislice computed tomography. METHODS: Four isolated temporal bone specimens were scanned in a current multislice computed tomography scanner and in two experimental flat-panel based volume computed tomography scanners before and after cochlea implantation. To compare flat-panel based volume computed tomography and multislice computed tomography, four features were rated according to the following criteria: 1) visibility of the cochlea; 2) visibility of the osseous spiral lamina; 3) discernibility of individual electrode contacts; and 4) the ability to determine the electrode array position relative to scala tympani and scala vestibuli. Layer-by-layer microgrinding pictures were used as the ground truth for verification of imaging findings. RESULTS: Flat-panel based volume computed tomography was superior to multislice computed tomography in all four features rated. The cochlea and facial nerve canal were much better delineated in flat-panel based volume computed tomography. The osseous spiral lamina and single electrode contacts were only visible in flat-panel based volume computed tomography. Assessment of implant position with regard to the cochlear spaces was considerably improved by flat-panel based volume computed tomography. CONCLUSION: Cochlear implantation assessment could be improved by flat-panel based volume computed tomography and, therefore, would be highly beneficial for cochlea implantation research and for clinical evaluation. However, these first results were shown by scanning isolated temporal bone specimens; scanning whole human skull bases might be more challenging.     

The auditory midbrain implant: a new auditory prosthesis for neural deafness-concept and device description.

The auditory midbrain implant (AMI) is a new central auditory prosthesis designed for penetrating stimulation of the human inferior colliculus. The major group of candidates for the AMI consists of neurofibromatosis type 2 (NF2) patients who develop neural deafness because of growth and/or surgical removal of bilateral acoustic neuromas. Because of the absence of a viable auditory nerve, these patients cannot benefit from cochlear implants. An alternative solution has been the auditory brainstem implant (ABI), which stimulates the cochlear nucleus. However, speech perception performance in NF2 ABI patients has been limited. The fact that the ABI is able to produce high levels of speech perception in nontumor patients (with inaccessible cochleae or posttraumatic damage to the cochlear nerve) suggests that limitations in ABI performance in NF2 patients may be associated with cochlear nucleus damage caused by the tumors or the tumor removal process. Thus, stimulation of the auditory midbrain proximal to the damaged cochlear nucleus may be a better alternative for hearing restoration in NF2 patients. We propose the central nucleus of the inferior colliculus (ICC) as the potential site. A penetrating electrode array aligned along the well-defined tonotopic gradient of the ICC should selectively activate different frequency regions, which is an important elementfor supporting good speech understanding. The goal of this article is to present the ICC as an alternative site for an auditory implant for NF2 patients and to describe the design of the first human prototype AMI. Practical considerations for implementation of the AMI will also be discussed.     

Hypertrophic perineurial dysplasia in multifocal and generalized peripheral neuropathies

Two cases are described, one with a multifocal cranial and limb neuropathy of adult onset associated with optic neuropathy, and the other with a diffuse demyelinating neuropathy characterized by congenital cataract, mental retardation and progressive lower limb paresis with an onset in childhood. Extensive investigation in both failed to establish the causation. No family history of similar disorder was obtained in either case. Nerve biopsy in both showed similar perineurial abnormalities, the endoneurium being compartmentalized by hypertrophic perineurial cells that exhibited dysplastic features. The appearances resemble those described in a previously reported case of multifocal neuropathy and probably represent an unusual but non-specific response to a peripheral neuropathy.