The ineffectiveness of applying moisture to the ear on the incidence and severity of otic barotrauma for air passengers.

OBJECTIVE: The application of moisture to the ear is anecdotally claimed to relieve the pain from otic barotrauma that can arise during aircraft descent. This claim was tested in a randomised double-blind study on an aircraft with eight participants heavily predisposed to barotrauma. METHODS: On the outward flight, half the participants wore 'active' devices that applied moisture to the external ear; the remainder wore placebo devices that contained no moisture, but were otherwise identical. On the return flight, the groups were reversed. Participants wore the devices from just before descent until landing, unless they experienced symptoms of barotrauma, in which case they switched to what they knew was an active device. RESULTS: There were no significant differences between conditions regarding the appearance of the tympanic membrane on landing or the discomfort levels immediately before and after any switch. CONCLUSION: Applying moisture is ineffective for passengers heavily predisposed to otic barotrauma.

A phenomenological model of myelinated nerve with a dynamic threshold.

To evaluate coding strategies for cochlear implants a model of the human cochlear nerve is required. Nerve models based on voltage-clamp experiments, such as the Frankenhaeuser-Huxley model of myelinated nerve, can have over forty parameters and are not amenable for fitting to physiological data from a different animal or type of nerve. Phenomenological nerve models, such as leaky integrate-and-fire (LIF) models, have fewer parameters but have not been validated with a wide range of stimuli. In the absence of substantial cochlear nerve data, we have used data from a toad sciatic nerve for validation (50 Hz to 2 kHz with levels up to 20 dB above threshold). We show that the standard LIF model with fixed refractory properties and a single set of parameters cannot adequately predict the toad rate-level functions. Given the deficiency of this standard model, we have abstracted the dynamics of the sodium inactivation variable in the Frankenhaeuser-Huxley model to develop a phenomenological LIF model with a dynamic threshold. This nine-parameter model predicts the physiological rate-level functions much more accurately than the standard LIF model. Because of the low number of parameters, we expect to be able to optimize the model parameters so that the model is more appropriate for cochlear implant simulations.

Stimulus-dependent refractoriness in the Frankenhaeuser-Huxley model.

Phenomenological neural models, such as the leaky integrate-and-fire model, normally have a fixed refractory time-course that is independent of the stimulus. The recovery of threshold following an action potential is typically based on physiological experiments that use a two-pulse paradigm in which the first pulse is suprathreshold and causes excitation and the second pulse is used to determine the threshold at various intervals following the first. In such experiments, the nerve is completely unstimulated between the two pulses. This contrasts the receptor stimuli in normal physiological systems and the electrical stimuli used by cochlear implants and other neural prostheses. A numerical study of the Frankenhaeuser-Huxley conductance-based model of nerve fibre was therefore undertaken to investigate the effect of stimulation on refractoriness. We found that the application of a depolarizing stimulus during the later part of what is classically regarded as the absolute refractory period could effectively prolong the absolute refractory period, while leaving the refractory time-constants and other refractory parameters largely unaffected. Indeed, long depolarizing pulses, which would have been suprathreshold if presented to a resting nerve fibre, appeared to block excitation indefinitely. Stimulation during what is classically regarded as the absolute refractory period can therefore greatly affect the temporal response of a nerve. We conclude that the classical definition of absolute refractory period should be refined to include only the initial period following an action potential when an ongoing stimulus would not affect threshold; this period was found to be about half as long as the classical absolute refractory period. We further conclude that the stimulus-dependent nature of the relative refractory period must be considered when developing a phenomenological nerve model for complex stimuli.

Does communication skills training make a difference to patients' experiences of consultations in oncology and palliative care services?

There is much evidence supporting the efficacy of communication skills training; however, very little of this evidence comes from patient feedback. The primary aim of this pilot study was to evaluate whether the advanced communications skills training improves patients' experience of consultations. Healthcare professionals working in oncology and palliative care services from the North East of England were invited to participate in this study. Interactions between healthcare professionals (n = 21) and patients (n = 1103) were evaluated using the Consultation and Relational Empathy (CARE) Measure, which is a brief questionnaire designed to assess the patients' perceptions of relational empathy in the consultation. Additional demographic variables, such as patient age, length of consultation, familiarity with healthcare professional and overall satisfaction with consultation, were also collected. Healthcare professionals were either part of the intervention group who attended a 3-day communication skills training course or part of the control group who were on the waiting list for training. No differences in the patients' ratings on the CARE measure were found between Time 1 (before training) and Time 2 (after training) for the intervention group. Possible explanations for the findings are explored and implications for communication skills training are discussed.

Prognostic value of coronary multidetector CT angiography in patients with an intermediate probability of significant coronary heart disease.

The aim of this study was to determine the prognostic value of coronary multidetector CT angiography (MDCTA) in patients with an intermediate pre-test probability of significant coronary artery disease (CAD). Patients who underwent 64-slice coronary MDCTA and met the selection criteria were identified and assessed for intermediate pre-test probability. Coronary MDCTA scans were preceded by calcium scoring, whereas all MDCTA scans were interrogated for the presence of plaque composition and the distribution and degree of stenosis. Significant stenosis was classified as being >50% of the luminal diameter. All patients were followed up for the occurrence of (i) cardiac death, (ii) non-fatal myocardial infarction, (iii) unstable angina requiring hospital admission and (iv) revascularisation. 138 patients were included (follow-up of 19.9 months); of these, 8 had a cardiac event (all revascularisations) and all had a positive coronary MDCTA. Patients with normal coronary arteries or non-significant stenosis suffered no cardiac events during follow-up. There were significant differences between the two groups regarding the presence of significant stenosis (p<0.001), the presence of plaque (p = 0.011) and a calcium score >10 (p = 0.003); 36.4% of patients with significant stenosis underwent revascularisation. In conclusion, this is the first UK study to investigate survival data in a population of intermediate-risk patients with no prior history of CAD who were investigated with coronary MDCTA. Coronary MDCTA can confidently rule out significant CAD in the intermediate-risk population and guide risk factor modification in patients with demonstrated coronary atheroma.

Enhanced information transmission with signal-dependent noise in an array of nonlinear elements.

We have investigated information transmission in an array of threshold units that have signal-dependent noise and a common input signal. We demonstrate a phenomenon similar to stochastic resonance and suprathreshold stochastic resonance with additive noise and show that information transmission can be enhanced by a nonzero level of noise. By comparing system performance to one with additive noise we also demonstrate that the information transmission of weak signals is significantly better with signal-dependent noise. Indeed, information rates are not compromised even for arbitrary small input signals. Furthermore, by an appropriate selection of parameters, we observe that the information can be made to be (almost) independent of the level of the noise, thus providing a robust method of transmitting information in the presence of noise. These result could imply that the ability of hair cells to code and transmit sensory information in biological sensory systems is not limited by the level of signal-dependent noise.

Neuropsychological functioning following systemic treatment in women treated for breast cancer: a review.

The aim of this review was to evaluate the effect of treatment and illness-related factors on neuropsychological functioning in women treated for breast cancer. Eight studies were identified examining neuropsychological test performance following systemic treatment. Six of the eight studies suggest that neuropsychological functioning may be impaired following treatment. However, there are a number of important methodological issues which limit interpretation of these results. Therefore, it is unclear whether neuropsychological outcome differs according to a range of treatment, biomedical and psychological factors. Larger samples with longitudinal follow-up are required in order to examine the treatment-related factors that best predict cognitive deficits.

Unusual complications of thyroid carcinoma.

Thyroid carcinomas are the most frequent endocrine malignancies. Complications may arise from an established malignancy and these may lead to the initial clinical presentation or cause subsequent problems. In this case report two elderly patients with differentiated and undifferentiated thyroid carcinomas who suffered unusual medical complications are described. The incidence and treatment of thyroid carcinoma is discussed and the importance of fine needle aspiration of thyroid nodules and the recognition of iodine containing radiographic contrast media in the causation of iodine induced thyrotoxicosis is highlighted.

TrialDB: A web-based Clinical Study Data Management System.

Clinical Study Data Management Systems (CSDMSs) are a class of software that support centralized management of data generated during the conduct of clinical studies. Commercial CSDMSs include Oracle Clinical, ClinTrial and MetaTrial. Such systems, which are typically deployed at an institutional or organizational level, must accommodate diverse types of data from different clinical domains that is generated by different groups of clinical investigators. Large-scale CSDMSs typically employ a high-end database engine that is usually accessed over an intranet or the Internet using Web-based technologies. CSDMSs in institution-wide use for a variety of clinical domains are best served by entity-attribute-value (EAV) modeling for the clinical data: all the commercial CSDMSs that we are aware of use EAV design. However, de novo development of EAV databases for data management is a challenging task. A large body of generic metadata-driven code must be developed before a basic EAV application can be written. Clearly, the availability of pre-existing software with the requisite functionality would be very valuable. We will discuss the benefits of such software being in open-source form.

Human herpesvirus 6 limbic encephalitis after stem cell transplantation.

Central nervous system complications are common in stem cell transplant recipients, but selective involvement of the medial temporal area is unusual. The 5 patients reported here presented after stem cell transplantation with increased hippocampal T2 signal on magnetic resonance imaging and increased hippocampal glucose uptake on [F-18]fluorodeoxyglucose-positron emission tomography (FDG-PET) associated with short-term memory loss, insomnia, and temporal lobe electrographic seizure activity. The initial scalp electroencephalograms (EEGs) failed to detect seizure activity in these patients, although the memory dysfunction along with the magnetic resonance imaging and FDG-PET findings suggested subcortical seizure activity. However, extended EEG monitoring revealed repetitive temporal lobe electrographic seizure activity. Follow-up MRIs in 2 patients and postmortem findings on 1 patient suggested that hippocampal sclerosis had developed following the clinical syndrome. Cerebrospinal fluid studies revealed the presence of human herpesvirus 6, variant B, DNA in all of 3 patients who had lumbar punctures. Immunohistochemical staining for the P41 and P101 human herpesvirus 6 protein antigens showed numerous immunoreactive astrocytes and neurons in the hippocampus of 1 of the patients who died from other causes. Because of its subtle clinical presentation, this syndrome may be underrecognized, but can be diagnosed with appropriate magnetic resonance imaging techniques, EEG monitoring, and cerebrospinal fluid viral studies.

The measurement of quality of life in children: past and future perspectives.

Quality of life (QoL) is central to pediatric practice. Where it is possible to manage but not cure a disease, it is important to determine how far treatment and disease compromise the child's QoL. In this way, informed judgments can be made about whether or not treatment is appropriate, and, where there is a choice, which choice might be the best option for the child. In this review, we consider different approaches to measuring child QoL, report a methodological review of measures currently available, evaluate the quality of these measures, and finally consider the implications for the future development and use of QoL measures. Computer searches identified 269 potentially relevant articles, of which 137 were included in the review. Of these, 43 were primarily concerned with the development of a new measure of QoL, 79 reported subsequent development of these same measures, and 15 used a battery approach to measure QoL. All currently available measures have limitations (e.g., limited psychometric data, lack of parallel forms for children and proxy raters, and insufficient attention to children's ability to complete paper-and-pencil measures). However, recommendations are made on the basis of those considered to be most satisfactory. It is essential that attempts be made to use QoL measures in research (e.g., evaluation of clinical trials and alternative treatments) to gain experience that will guide development of a second generation of more sophisticated measures. Despite the practical difficulties identified, measurement of QoL remains of central interest to all those concerned with the well-being of children.

Issues in measuring quality of life in childhood cancer: measures, proxies, and parental mental health.

The relationship between child- and parent-reported quality of life (QOL) and the effects of parental mental health, illness stressors, and child vulnerability was explored using two measures of QOL: the Pediatric Cancer Quality Life-32 (Varni et al., 1998a) and the Disquol (Eiser, Cotter, Oades, Seamark, & Smith, 1999). Thirty-two children with acute lymphoblastic leukaemia (mean age = 8.92 years) and 36 parents completed measures of QOL when attending routine clinic. In addition, parents also completed the General Health Questionnaire (GHQ-28), perception of the child's vulnerability, and illness-related stressors. Significant correlations were found between the overall scores on the two child-completed QOL measures, with a range of poor, moderate to good correlations found between the individual subscales. Poor to moderate concordance was found between child and parent reports. Children who self-reported poorer QOL had mothers who were more depressed. Parents who reported poorer QOL for their child reported more illness stressors and perceived their child as being more vulnerable. Assumptions that concordance between child and parent ratings of QOL is a necessary requirement for new measures of QOL are challenged.

The N-terminal and C-terminal domains of RAP1 are dispensable for chromatin opening and GCN4-mediated HIS4 activation in budding yeast.

Repressor activator protein 1 (RAP1) assists GCN4-mediated HIS4 activation by overcoming some repressive aspect of chromatin structure to facilitate GCN4 binding. RAP1 also participates in other nuclear processes, and discrete domains of RAP1 have been shown to have specific properties including DNA binding, DNA bending, transcriptional activation, and silencing and telomere functions. To investigate whether specific domains of RAP1 are required to "open" chromatin and help GCN4 to activate the HIS4 gene, we examined the abilities of different truncated RAP1 proteins to perturb positioned nucleosomes via a nucleosomal RAP1 site in a yeast episome in vivo, and we tested HIS4 activation in yeast strains harboring truncated RAP1 mutants. We found that neither the DNA bending domain nor the putative activation domain of RAP1 is required for its ability to perturb the chromatin structure of a plasmid containing a RAP1 site. Similarly, neither the putative activation domain nor the N-terminal DNA-bending domain was required for GCN4-mediated activation of HIS4. We also used a rap1(ts) mutant to show that continuous occupancy of the HIS4 promoter by RAP1 is required for GCN4-mediated gene activation.

GCN5 dependence of chromatin remodeling and transcriptional activation by the GAL4 and VP16 activation domains in budding yeast.

Chromatin-modifying enzymes such as the histone acetyltransferase GCN5 can contribute to transcriptional activation at steps subsequent to the initial binding of transcriptional activators. However, few studies have directly examined dependence of chromatin remodeling in vivo on GCN5 or other acetyltransferases, and none have examined remodeling via nucleosomal activator binding sites. In this study, we have monitored chromatin perturbation via nucleosomal binding sites in the yeast episome TALS by GAL4 derivatives in GCN5(+) and gcn5Delta yeast cells. The strong activator GAL4 shows no dependence on GCN5 for remodeling TALS chromatin, whereas GAL4-estrogen receptor-VP16 shows substantial, albeit not complete, GCN5 dependence. Mini-GAL4 derivatives having weakened interactions with TATA-binding protein and TFIIB exhibit a strong dependence on GCN5 for both transcriptional activation and TALS remodeling not seen for native GAL4. These results indicate that GCN5 can contribute to chromatin remodeling at activator binding sites and that dependence on coactivator function for a given activator can vary according to the type and strength of contacts that it makes with other factors. We also found a weaker dependence for chromatin remodeling on SPT7 than on GCN5, indicating that GCN5 can function via pathways independent of the SAGA complex. Finally, we examine dependence on GCN5 and SWI-SNF at two model promoters and find that although these two chromatin-remodeling and/or modification activities may sometimes work together, in other instances they act in complementary fashion.

Point prevalence of alcoholism in hospitalized patients: continuing challenges of detection, assessment, and diagnosis.

OBJECTIVE: To measure a 1-day point prevalence of alcohol dependence among hospitalized patients and to assess practices of detection, evaluation, and diagnosis of alcohol problems. PATIENTS AND METHODS: On April 27, 1994, a total of 795 adult inpatients at 2 midwestern teaching hospitals were asked to complete a survey that included the Self-administered Alcoholism Screening Test (SAAST). The records of SAAST-positive patients were reviewed to determine the numbers of patients receiving laboratory screening for alcoholism, addiction consultative services, and a discharge diagnosis of alcoholism. RESULTS: The survey response rate was 84% (667/795). Of the 569 patients who provided SAAST information, 42 (7.4%) had a positive SAAST score and thus were identified as alcohol dependent. Thirteen (31%) of the 42 alcoholic patients received addiction or psychiatric consultative services during their hospitalization. Serum gamma-glutamyltransferase was measured in 4 (11%) of the 38 actively drinking alcoholic patients. Three (7%) of 42 alcoholic patients received a discharge diagnosis of alcohol abuse or dependence. CONCLUSIONS: The alcoholism prevalence rate was lower than those observed in several other US hospitals. Laboratory testing may be underutilized in identifying hospitalized patients who may be addicted to alcohol. Physician use of consultative services and diagnosis of alcohol dependence had not improved from similar observations more than 20 years earlier. These findings may indicate persistent problems in physician detection, assessment, and diagnosis of alcoholism.

Structure of Cry2Aa suggests an unexpected receptor binding epitope.

BACKGROUND: Genetically modified (GM) crops that express insecticidal protein toxins are an integral part of modern agriculture. Proteins produced by Bacillus thuringiensis (Bt) during sporulation mediate the pathogenicity of Bt toward a spectrum of insect larvae whose breadth depends upon the Bt strain. These transmembrane channel-forming toxins are stored in Bt as crystalline inclusions called Cry proteins. These proteins are the active agents used in the majority of biorational pesticides and insect-resistant transgenic crops. Though Bt toxins are promising as a crop protection alternative and are ecologically friendlier than synthetic organic pesticides, resistance to Bt toxins by insects is recognized as a potential limitation to their application. RESULTS: We have determined the 2.2 A crystal structure of the Cry2Aa protoxin by multiple isomorphous replacement. This is the first crystal structure of a Cry toxin specific to Diptera (mosquitoes and flies) and the first structure of a Cry toxin with high activity against larvae from two insect orders, Lepidoptera (moths and butterflies) and Diptera. Cry2Aa also provides the first structure of the proregion of a Cry toxin that is cleaved to generate the membrane-active toxin in the larval gut. CONCLUSIONS: The crystal structure of Cry2Aa reported here, together with chimeric-scanning and domain-swapping mutagenesis, defines the putative receptor binding epitope on the toxin and so may allow for alteration of specificity to combat resistance or to minimize collateral effects on nontarget species. The putative receptor binding epitope of Cry2Aa identified in this study differs from that inferred from previous structural studies of other Cry toxins.

NK cell-mediated lysis of autologous human oligodendrocytes.

Although considered an autoimmune disease, the mechanisms underlying oligodendrocyte (OL)/myelin injury in multiple sclerosis (MS) remain to be established. We utilized in vitro assays to demonstrate that human OLs, as well as other glial elements (astrocytes, microglia), were susceptible to injury mediated by peripheral blood-derived mononuclear cell preparations (MNCs) enriched for natural killer (NK cells) by depleting CD3(+) +/- CD19(+) cells through use of either magnetic beads or cell sorting. Cytotoxic effects of the NK cell-enriched effectors were dependent on pre-exposure of these cells to IL-2. Furthermore, we found that autologous OLs were as susceptible to injury mediated by IL-2 activated NK cells as were heterologous OLs. In context of the tissue injury that occurs in MS, our results suggest that the inflammatory milieu in MS lesions could provide conditions required for NK cell activation and that such effector cells can bypass the putative protective effects of self-MHC class I molecules that may be expressed on OLs.

Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial.

PURPOSE: Infantile glycogen storage disease type II (GSD-II) is a fatal genetic muscle disorder caused by deficiency of acid alpha-glucosidase (GAA). The purpose of this study was to investigate the safety and efficacy of recombinant human GAA (rhGAA) enzyme therapy for this fatal disorder. METHODS: The study was designed as a phase I/II, open-label, single-dose study of rhGAA infused intravenously twice weekly in three infants with infantile GSD-II. rhGAA used in this study was purified from genetically engineered Chinese hamster ovary (CHO) cells overproducing GAA. Adverse effects and efficacy of rhGAA upon cardiac, pulmonary, neurologic, and motor functions were evaluated during 1 year of the trial period. The primary end point assessed was heart failure-free survival at 1 year of age. This was based on historical control data that virtually all patients died of cardiac failure by 1 year of age. RESULTS: The results of more than 250 infusions showed that rhGAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all three infants. These infants have well passed the critical age of 1 year (currently 16, 18, and 22 months old) and continue to have normal cardiac function. Improvements of skeletal muscle functions were also noted; one patient showed marked improvement and currently has normal muscle tone and strength as well as normal neurologic and Denver developmental evaluations. Muscle biopsies confirmed that dramatic reductions in glycogen accumulation had occurred after rhGAA treatment in this patient. CONCLUSIONS: This phase I/II first study of recombinant human GAA derived from CHO cells showed that rhGAA is capable of improving cardiac and skeletal muscle functions in infantile GSD-II patients. Further study will be needed to assess the overall potential of this therapy.