Detection of candidate biomarkers of prostate cancer progression in serum: a depletion-free 3D LC/MS quantitative proteomics pilot study.

BACKGROUND: Prostate cancer (PCa) is the most common male cancer in the United Kingdom and we aimed to identify clinically relevant biomarkers corresponding to stage progression of the disease. METHODS: We used enhanced proteomic profiling of PCa progression using iTRAQ 3D LC mass spectrometry on high-quality serum samples to identify biomarkers of PCa. RESULTS: We identified >1000 proteins. Following specific inclusion/exclusion criteria we targeted seven proteins of which two were validated by ELISA and six potentially interacted forming an 'interactome' with only a single protein linking each marker. This network also includes accepted cancer markers, such as TNF, STAT3, NF-κB and IL6. CONCLUSIONS: Our linked and interrelated biomarker network highlights the potential utility of six of our seven markers as a panel for diagnosing PCa and, critically, in determining the stage of the disease. Our validation analysis of the MS-identified proteins found that SAA alongside KLK3 may improve categorisation of PCa than by KLK3 alone, and that TSR1, although not significant in this model, might also be a clinically relevant biomarker.

Detection of lipoprotein(a) in intraparenchymal cerebral vessels: correlation with vascular pathology and clinical history.

Serum levels of lipoprotein(a), Lp(a), have been shown to be associated with increased risk of atherosclerosis (AS) and AS-related diseases such as myocardial and ischemic cerebral infarcts (ICI). Lp(a) has been detected in the vascular wall of the aorta and coronary vessels, and we documented the presence of apo(a) in cerebral vessels of the Circle of Willis, associated with AS changes. In this study we further investigated and characterized the biochemical nature of Lp(a) detected in both large and small cerebral parenchymal vessels. Autopsy specimens of cerebral vessels of 51 patients were examined by immunohistochemistry with monoclonal antibodies against apo(a), apoB, and plasminogen. Lp(a) was detected in cerebral capillaries and arterioles. All of the 8 patients with ICI expressed Lp(a) in parenchymal vessels, generally (6/8) in both capillaries and arterioles. Of 43 patients without ICI only 25 had Lp(a) detected. Among the patients without ICI, there was a slightly increased incidence of parenchymal Lp(a) in those patients who had severe hypoxic brain damage (12/20) compared to those patients without severe hypoxic damage (9/23). Thus, the presence of Lp(a) in small cerebral parenchymal vessels may reflect the role of Lp(a) in ICI.

Gene expression of apolipoprotein(a) within the wall of human aorta and carotid arteries.

Atherosclerosis is associated with arterial deposition of low density lipoprotein (LDL) and lipoprotein(a), Lp(a). Both lipoproteins have been detected in atherosclerotic vessels; however, while LDL has been shown to be only blood-derived, it is not clear whether Lp(a) is also produced within the vessel wall. In the present investigation we studied gene expression of apo(a) and apoB in human blood vessels. Aorta, carotid arteries and liver specimens from 29 adult and pediatric autopsy cases were studied by RT-PCR and Southern blot analysis with primers and probes specific for apo(a), apoB and GAPDH (a control housekeeping gene). The mRNA of apo(a), but not apoB, was found within the vessel wall in both adult atherosclerotic arterial vessels and in pediatric non atherosclerotic vessels. Neither apo(a) nor apoB mRNA was detected in femoral veins. To verify the nature of the detected transcripts, we cloned the 162 base pair (bp) RT-PCR product derived from the arterial wall total RNA. Nucleotide sequencing revealed 100% homology with the apo(a) gene. Thus, while LDL in atherosclerotic arteries is exclusively blood-derived, the accumulation of Lp(a) within the artery may be due in part to in situ production of apo(a) within the vessel wall.

Effects of microphone type on acoustic measures of voice.

Acoustic measures provide an objective means to describe pathological voices and are a routine component of the clinical voice examination. Because the voice sample is obtained using a microphone, microphone characteristics have the potential to influence the values of parameters obtained from a voice sample. This project examined how the choice of microphone affects key voice parameters and investigated how one might compensate for such microphone effects through filtering or by including additional parameters in the decision process. A database of 53 normal voice samples and 100 pathological voice samples was used in four experiments conducted in an anechoic chamber using four different microphones. One omnidirectional microphone and three cardioid microphones were used in these experiments. The original voice samples were presented to each microphone through a speaker located in an anechoic chamber, and the output of each microphone sampled to computer disk. Each microphone modified the frequency spectrum of the voice signal; this, in turn, affected the values of the voice parameters obtained. These microphone effects reduced the accuracy with which acoustic measures of voice could be used to discriminate pathological from normal voices. Discrimination performance improved when the microphone output was filtered to compensate for microphone frequency response. Performance also improved when spectral moment coefficient parameters were added to the vocal function parameters already in use.

Managing migraine: strategies for successful patient outcomes.

This article highlights information from the 2000 National Conference for Nurse Practitioners symposium held in Washington, D.C., on November 9, 2000. It was sponsored by The Nursing Institute of Springhouse Corporation and funded by an unrestricted educational grant from Merck & Co., Inc. The firsttopic, "Overview of Migraine: Compelling Effects on Patients and Society," was presented for Dedie Downey Russell, CNP, ANP/GNP, MS. The second topic, "Understanding Pathophysiology: Evolving from Traditional to Current Therapeutic Options," was presented by Dara G. Jamieson, MD. Maureen Moriarty-Sheehan, MS, CRNP, who also served as chairperson, presented the third topic, "Developing a Management Plan for Optimal Patient Benefit."

Deriving robust operating rules for the interim control of the Kirazdere reservoir.

A methodology is developed for deriving robust operating rules for the interim control of a multipurpose reservoir. The methodology includes the generation of policies using optimisation models, the derivation of robust operating rules using artificial neural networks and the evaluation of the identified policies through simulation. The approach developed is demonstrated through an application to the Kirazdere Reservoir located on the Kiraz River in Turkey.

Acoustic discrimination of pathological voice: sustained vowels versus continuous speech.

We investigated the ability of acoustic measures to discriminate between normal and pathological talkers. Two groups of measures were compared: (a) those extracted from sustained vowels and (b) those based on continuous speech samples. Nine acoustic measures, which include fundamental frequency and amplitude perturbation measures, long term average spectral measures, and glottal noise measures were extracted from both sustained vowel and continuous speech samples. Our experiments were performed on a published database of 53 normal talkers and 175 talkers with a pathological voice. The classification performance of the nine acoustic measures was quantified using linear discriminant analysis and receiver operating characteristic (ROC) curve analysis. When individual measures were considered in isolation, classification was more accurate for measures extracted from sustained vowels than for those based on continuous speech samples. Classification accuracy improved when combinations of acoustic parameters were considered. For such combinations of measures, classification results were comparable for measures extracted from continuous speech samples and for those based on sustained vowels.

Identification of pathological voices using glottal noise measures.

We investigated the abilities of four fundamental frequency (F0)-dependent and two F0-independent measures to quantify vocal noise. Two of the F0-dependent measures were computed in the time domain, and two were computed using spectral information from the vowel. The F0-independent measures were based on the linear prediction (LP) modeling of vowel samples. Tests using a database of sustained vowel samples, collected from 53 normal and 175 pathological talkers, showed that measures based on the LP model were much superior to the other measures. A classification rate of 96.5% was achieved by a parameter that quantifies the spectral flatness of the unmodeled component of the vowel sample.

Rizatriptan. Comparative trial results.

Four drugs in the triptan class are now available for the treatment of acute migraine--sumatriptan, rizatriptan, naratriptan, and zolmitriptan. For clinicians prescribing these drugs, data on the comparative advantages and disadvantages of each medication can aid in drug selection. For example, in 2 recently conducted clinical trials, rizatriptan was found to have several advantages over naratriptan and zolmitriptan. Compared with both drugs, rizatriptan provided more rapid relief of headache pain and associated nausea, and allowed patients to return to normal activities more quickly. These are important advantages for patients, particularly when migraine affects their ability to function on the job or at home.

A comparison of high precision F0 extraction algorithms for sustained vowels.

Perturbation analysis of sustained vowel waveforms is used routinely in the clinical evaluation of pathological voices and in monitoring patient progress during treatment. Accurate estimation of voice fundamental frequency (F0) is essential for accurate perturbation analysis. Several algorithms have been proposed for fundamental frequency extraction. To be appropriate for clinical use, a key consideration is that an F0 extraction algorithm be robust to such extraneous factors as the presence of noise and modulations in voice frequency and amplitude that are commonly associated with the voice pathologies under study. This work examines the performance of seven F0 algorithms, based on the average magnitude difference function (AMDF), the input autocorrelation function (AC), the autocorrelation function of the center-clipped signal (ACC), the autocorrelation function of the inverse filtered signal (IFAC), the signal cepstrum (CEP), the Harmonic Product Spectrum (HPS) of the signal, and the waveform matching function (WM) respectively. These algorithms were evaluated using sustained vowel samples collected from normal and pathological subjects. The effect of background noise and of frequency and amplitude modulations on these algorithms was also investigated, using synthetic vowel waveforms.

Acute stroke teams: results of a national survey. National Acute Stroke Team Group.

BACKGROUND AND PURPOSE: The sensitivity of the brain to brief periods of profound ischemia or prolonged periods of modest ischemia mandates an aggressive approach to acute stroke care. Past studies have shown that many stroke patients do not receive acute care in an urgent and timely fashion. The formation of acute stroke teams (AST) is one approach that can be used to accelerate the delivery of acute stroke care. METHODS: We conducted a survey of major stroke program directors and neurovascular experts throughout the United States. The survey focused on issues related to the presence of AST, their staffing, operational features, and utilization at the surveyed programs and hospitals. RESULTS: Surveys were returned from 45 of 60 centers. Ninety-one percent of the respondents indicated that they currently had an AST, with 66% formed between 1995 and 1997. Staffing of ASTs consisted of attending physicians (95%), nurses or study coordinators (73%), fellows (49%), and residents (46%). In almost all cases (98%), the AST was led by a neurologist or neurosurgeon, and 98% of the ASTs operated on a 24-hours-per-day, 7-days-per-week basis. The most common call frequency was 2 to 3 times per week (41%), followed by >5 calls per week (29%). In 59% of the cases, the teams cost

Defensin stimulates the binding of lipoprotein (a) to human vascular endothelial and smooth muscle cells.

There is evidence to suggest that elevated plasma levels of lipoprotein (a) [Lp(a)] represent a risk factor for the development of atherosclerotic vascular disease, but the mechanism by which this lipoprotein localizes to involved vessels is only partially understood. In view of studies suggesting a link between inflammation and atherosclerosis and our previous finding that leukocyte defensin modulates the interaction of plasminogen and tissue-type plasminogen activator with cultured human endothelial cells, we examined the effect of this peptide on the binding of Lp(a) to cultured vascular endothelium and vascular smooth muscle cells. Defensin increased the binding of Lp(a) to endothelial cells approximately fourfold and to smooth muscle cells approximately sixfold. Defensin caused a comparable increase in the amount of Lp(a) internalized by each cell type, but Lp(a) internalized as a consequence of defensin being present was not degraded, resulting in a marked increase in the total amount of cell-associated lipoprotein. Abundant defensin was found in endothelium and in intimal smooth muscle cells of atherosclerotic human cerebral arteries, regions also invested with Lp(a). These studies suggest that defensin released from activated or senescent neutrophils may contribute to the localization and persistence of Lp(a) in human vessels and thereby predispose to the development of atherosclerosis.

Ketoprofen and carotico-cavernous fistula.

Whilst treating a patient with traumatic direct carotico-cavernous fistula, pain relief was difficult to achieve. Adequate doses of ibuprofen and codeine were ineffective, but single doses of ketoprofen alleviated pain in a reproducible manner. Although similar in analgesic efficacy to codeine, and a potent inhibitor of cyclooxygenase like ibuprofen, ketoprofen has other actions which may account for the differential response seen. This observation may help elucidate the nature of local mediators involved in the pathogenesis of vascular headache pain.

Apolipoprotein(a) deposition in atherosclerotic plaques of cerebral vessels. A potential role for endothelial cells in lesion formation.

Atherosclerosis is the leading cause of death and serious morbidity in economically developed societies through its sequelae of coronary artery and cerebrovascular disease. The causes and mechanisms of atherosclerosis are still largely unknown. Serum levels of a lipoprotein, Lp(a), have been shown, in retrospective and some prospective clinical studies, to be associated with increased risk of myocardial and cerebral infarction. The active part of Lp(a), apo(a), has > 80% homology with plasminogen; thus it may competitively inhibit the thrombolytic action of plasminogen and enhance thrombogenesis. Lp(a) has been shown to be deposited in the vascular wall of the aorta and coronary vessels, but its presence in the cerebral vessels has not yet been shown. Autopsy specimens of vessels of the circle of Willis from 23 patients were examined for degree of atherosclerosis and deposition of apo(a) by immunohistochemistry with apo(a)-specific monoclonal antibodies. The amount of apo(a) deposition in cerebral vessels correlated well with the degree of cerebral atherosclerosis. Arterial deposition of apo(a) was found entirely within the endothelial cell and subendothelial cell layers. There was no staining within the media and adventitia, with the exception of staining within the endothelial cells of the vasa vasorum. Correlation between the morphology of apo(a) deposition and plaque stage was found suggesting that detection of apo(a) in endothelial cells is an early event in the development of the atherosclerotic plaque of cerebral vessels.

Evaluation of a speech enhancement strategy with normal-hearing and hearing-impaired listeners.

An adaptive digital signal processing procedure was applied to various speech signals in three noise backgrounds. The procedure uses a modified approach to Wiener filtering to estimate a noise suppression filter which reduces the signal at frequencies most likely to be corrupted by noise. Speech intelligibility was compared with and without processing, for speech presented in three types of background noise: multitalker babble, wide-band noise, and narrow-band noise. The speech signals used were six spondaic words spoken by a male talker; 20 consonants, in an intervocalic environment, spoken by a female talker; and a passage of continuous discourse read by a female talker. Adaptive speech reception threshold (ASRT) testing was used to estimate the minimum SNR at which the spondaic words could be identified 70.7% of the time. With this test, signal processing improved performance by 11 dB in narrow-band noise for normal-hearing listeners; no statistically significant improvement was observed when listening in a background of wide-band or speech babble noise. Five of the six hearing-impaired listeners also had improved performance when listening in narrow-band noise, but minimal changes in wide-band or speech babble noise. With the consonant targets, a closed-set nonsense syllable testing procedure demonstrated that processing did not change or slightly reduced performance for all listeners. With continuous discourse all listeners demonstrated a strong preference for processed signals under most listening conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

The input/output formula: a theoretical approach to the fitting of personal amplification devices.

There is a growing trend for hearing aids to incorporate wide dynamic range compression. The input/output (I/O) hearing aid formula, presented in this report, is a general frequency-specific mathematical approach which describes the relationship between the input level of a signal delivered to a hearing aid and the output level produced by the hearing aid. The I/O formula relates basic psychoacoustic parameters, including hearing threshold level and uncomfortable listening level, to the electroacoustic characteristics of hearing aids. The main design goal of the I/O formula was to fit the acoustic region corresponding to the "extended" normal auditory dynamic range into the hearing-impaired individual's residual auditory dynamic range. The I/O approach can be used to fit hearing aids utilizing linear gain, linear compression or curvilinear compression to a hearing-impaired individual's residual auditory area.

Waking effectiveness of visual alerting signals.

People who are unable to hear acoustic alarm signals because they have a complete or partial hearing loss must rely on visual or tactile signals to warn them in the event of an emergency. However, consumers report that personal smoke detector devices which provide a visual alarm do not wake people reliably. We examined the ability of visual alerting devices to wake people from the deepest stages of sleep: slow wave sleep (SWS) and rapid-eye-movement sleep (REM). These results were related to the physical (optical) characteristics of devices currently on the market. In Experiment 1, a range of strobe intensities and locations were investigated. Experiment 2 confirmed the results of this pilot study on an independent set of subjects. On each trial, the strobe was allowed to run at a constant intensity until the subject awoke, or a maximum of 5 min had elapsed. Even though a diffuse light remained directly over the subject's face for each trial, subjects did not wake consistently. Under the favorable optical (smoke-free) conditions of the present study, the most intense of the devices presently offered for sale in Canada cannot be relied on to wake a sleeping person in the event of a fire. It remains unclear whether any visual alerting device can be expected to safely wake a sleeper in an emergency situation.

Effect of screening for syphilis on the management of patients with cerebrovascular disease.

Although meningovascular syphilis may result in cerebral ischemia, the effect of syphilis screening on the management of patients with ischemic stroke is unclear. This is due to the variability in syphilis incidence and prevalence, as well as the diverse manifestations that vary with stage of infection. We prospectively screened patients with cerebrovascular disease (CVD) for syphilis and analyzed seropositivity rates as well as assessed the impact of screening on patient management. There were relatively high rates of seropositivity in both CVD (12.5%, n = 104) and control (9.9%, n = 211) populations without a significant difference between groups. Overall, syphilis screening had little impact on the management of the patients with CVD. No cerebral event was attributed to meningovascular syphilis, and there was no identifiable group in which syphilis screening was more likely to result in treatment for meningovascular syphilis, although there were significantly (p < 0.001) higher rates of seropositivity in black patients than whites. The relatively high incidence of seropositivity in both groups is representative of local syphilis prevalence and suggests that screening is warranted in patients with neurological disease, but not necessarily as part of the evaluation for cerebral ischemia.

Congenital endplate acetylcholinesterase deficiency.

Endplate acetylcholinesterase (AChE) consists of globular catalytic subunits attached to the basal lamina by a collagen-like tail. Different genes encode the catalytic subunit and the tail portion of the enzyme. Endplate AChE deficiency was reported previously in a single case (Engel et al., 1977, patient 1). We describe here our observations in four additional patients (patients 2-5). Three cases were sporadic; patients 2 and 3 were sisters. All had generalized weakness increased by exertion but ophthalmoparesis was not a constant feature. All had mild slowing of the pupillary light reflex; other dysautonomic features were absent. None benefited from anticholinesterase therapy. All patients had a decremental electromyogram response; in four of the five patients, single nerve stimuli evoked a repetitive response. Miniature endplate potential amplitude was reduced in patient 5 only. Endplate amplitudes and currents were prolonged but the open-time of the acetylcholine receptor ion channel was normal. In patients 1-4 the quantal content of the endplate potential was reduced due to a reduced number of readily releasable quanta. Quantitative electron microscopy revealed abnormally small nerve terminals, abnormal encasement of the presynaptic membrane by Schwann cells and degeneration of junctional folds and of organelles in the junctional sarcoplasm. Acetylcholinesterase was absent from all endplates of all patients by cytochemical and immunocytochemical criteria. Density gradient ultracentrifugation of muscle extracts from patients 1, 3, 4 and 5 revealed an absence of the collagen-tailed form of the enzyme in patients 1, 3 and 4 but not in patient 5. The kinetic properties of the residual AChE in muscle were normal. Erythrocyte AChE activity and Km values, determined in three patients, were also normal. Studies of the catalytic subunit gene of AChE in patients 2 and 3 revealed no abnormality in those exons that encode the domain to which the tail subunit binds. In patients 1-4 the molecular defect is likely to reside in the gene encoding the tail subunit of AChE, or in a protein necessary to assemble the catalytic and tail subunits. In patient 5, the absence of AChE from the endplate may be due to a faulty tail subunit, a defect in the basal lamina site that binds the tail subunit or failure of transport of the assembled asymmetric enzyme from the cell interior to the basal lamina. The cause of the weakness in these patients is not fully understood but possible mechanisms are discussed.

Studies of respiratory stridor in young children: acoustical analyses and tests of a theoretical model.

Non-invasive procedures are proposed to aid the diagnosis of childhood laryngotracheal pathology and to monitor the course of such disease. The procedures capitalize on the one-to-one relationship which exists between the acoustic phenomena (stridors) associated with respiration and the configuration of the respiratory tract. Careful analysis of these acoustic patterns can thus assist in identifying and localizing constrictions, in diagnosis, and in monitoring disease severity. Based on the acoustical analysis of the stridor generated by children with congenital stridor, subglottal laryngitis, and trachea stenosis, the present paper demonstrates that a close relationship exists between the specific pathology and the spectrum of the associated respiratory stridor.