Important Tool In Clinical Research Research Articles

Analytical profile, in vitro metabolism and behavioral properties of the lysergamide 1P‐AL‐LAD

Lysergic acid diethylamide (LSD) is known to induce powerful psychoactive effects in humans, which cemented its status as an important tool for clinical research. A range of analogues and derivatives has been investigated over the years, including those classified as new psychoactive substances. This study presents the characterization of the novel lysergamide N,N‐diethyl‐1‐propanoyl‐6‐(prop‐2‐en‐1‐yl)‐9,10‐didehydroergoline‐8β‐carboxamide (1P‐AL‐LAD) using various mass spectrometric, gas‐ and liquid chromatographic and spectroscopic methods. In vitro metabolism studies using pooled human liver microsomes (pHLM) confirmed that 1P‐AL‐LAD converted to AL‐LAD as the most abundant metabolite consistent with the hypothesis that 1P‐AL‐LAD may act as a prodrug. Fourteen metabolites were detected in total; metabolic reactions included hydroxylation of the core lysergamide ring structure or the N 6‐allyl group, formation of dihydrodiol metabolites, N‐dealkylation, N 1‐deacylation, dehydrogenation, and combinations thereof. The in vivo behavioral activity of 1P‐AL‐LAD was evaluated using the mouse head twitch response (HTR), a 5‐HT2A‐mediated head movement that serves as a behavioral proxy in rodents for human hallucinogenic effects. 1P‐AL‐LAD induced a dose‐dependent increase in HTR counts with an inverted U‐shaped dose–response function, similar to lysergic acid diethylamide (LSD), psilocybin, and other psychedelics. Following intraperitoneal injection, the median effective dose (ED50) for 1P‐AL‐LAD was 491 nmol/kg, making it almost three times less potent than AL‐LAD (174.9 nmol/kg). Previous studies have shown that N 1‐substitution disrupts the ability of lysergamides to activate the 5‐HT2A receptor; based on the in vitro metabolism data, 1P‐AL‐LAD may induce the HTR because it acts as a prodrug and is metabolized to AL‐LAD after administration to mice.

Untargeted metabolomic analysis of urine samples for diagnosis of inherited metabolic disorders.

Metabolomics has become an important tool for clinical research, especially for analyzing inherited metabolic disorders (IMDs). The purpose of this study was to explore the performance of metabolomics in diagnosing IMDs using an untargeted metabolomic approach. A total of 40 urine samples were collected: 20 samples from healthy children and 20 from pediatric patients, of whom 13 had confirmed IMDs and seven had suspected IMDs. Samples were analyzed by Orbitrap mass spectrometry in positive and negative mode alternately, coupled with ultra-high liquid chromatography. Raw data were processed using Compound Discovery 2.0 ™ and then exported for partial least squares discriminant analysis (PLS-DA) by SIMCA-P 14.1. After comparing with m/zCloud and chemSpider libraries, compounds with similarity above 80% were selected and normalized for subsequent relative quantification analysis. The uncommon compounds discovered were analyzed based on the Kyoto Encyclopedia of Genes and Genomes to explore their possible metabolic pathways. All IMDs patients were successfully distinguished from controls in the PLS-DA. Untargeted metabolomics revealed a broader metabolic spectrum in patients than what is observed using routine chromatographic methods for detecting IMDs. Higher levels of certain compounds were found in all 13 confirmed IMD patients and 5 of 7 suspected IMD patients. Several potential novel markers emerged after relative quantification. Untargeted metabolomics may be able to diagnose IMDs from urine and may deepen insights into the disease by revealing changes in various compounds such as amino acids, acylcarnitines, organic acids, and nucleosides. Such analyses may identify biomarkers to improve the study and treatment of IMDs.

Abstract 1085: Serum miR-30e and miR-223 are promising non-invasive biomarkers for hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is the world's third most common cancer and causes 600,000 deaths annually. Early detection is the key for improving the survival of HCC patients. Current diagnostic markers, such as alpha fetoprotein or fibroscan have their own limitations. Investigating serum microRNA as biomarkers for early diagnosis of cancer has become an important tool in clinical research. In this study, we tested the hypothesis that serum microRNAs (miRNAs) can be used as a potential biomarker for HCC. We analyzed serum miRNA using reverse transcriptase-quantitative PCR (qRT-PCR) from serum samples. Our study revealed that two miRNAs, miR-30e and miR-223, were expressed at significantly lower levels (P < 0.003) in the sera of HCC patients as compared to healthy volunteers. Further, expression of these miRNA was compared between sera from chronic liver disease (CLD) and HCC patients. miR-30e and miR-223 expression was significantly lower in HCC sera as compared to sera from CLD patients. Both miRNA expression levels were lower in HCC liver biopsy specimens as compared to normal liver RNA. Taken together, our results indicated that serum miR-30e and miR-223 are useful biomarkers of HCC irrespective of etiology. Citation Format: Ratna B. Ray, Sourav Bhattacharya, Robert Steele, Adrian M. Di Bisceglie, Sounak chakraborty. Serum miR-30e and miR-223 are promising non-invasive biomarkers for hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1085.

Changes of serum amino acid profiles by an epidermal growth factor receptor mutation and benzo[a]pyrene in mouse lung tumorigenesis.

Studies suggest that gene mutation and carcinogen exposure contribute to lung tumorigenesis including a mutation of epidermal growth factor receptor (EGFR) and exposure to benzo[a]pyrene (BaP). However, the interaction between EGFR mutation and BaP exposure during lung tumorigenesis is unclear. Metabolomics has become an important tool in clinical research and has been utilized to help our understanding of mechanisms and to identify indicators of cancers. This study's aim was to identify the changes in metabolite profiles in mice associated with an EGFR exon 21 deletion and/or BaP treatment-induced lung tumorigenesis. While the EGFR mutation increased the incidence of lung adenoma in transgenic mice (EGFR mutant mice) at 32 weeks of age, exposure to BaP caused the onset of lung tumorigenesis in these mice as early as 16 weeks after exposure. Using a metabolomics strategy involving liquid chromatography-mass spectrometry in conjunction with principal component analysis and confirmation by liquid chromatography triple quadrupole tandem mass spectrometry, we demonstrated that the serum amino acid profiles of these mice were changed. A total of eight amino acid concentrations were lower in EGFR mutant mice than in wild-type mice at 32 weeks of age. Five amino acids were lower in tumor-bearing mice than in non-tumor-bearing EGFR mutant mice at 10th week post-treatment of BaP, namely phenylalanine, tyrosine, alanine, proline, and threonine. Our results suggest that gene mutation and carcinogen exposure-induced lung adenomas share some common mechanisms. Changes in serum amino acid profiles may be early indicators of lung tumorigenesis.

Abstract 222: North American Kawasaki Disease Registry - Advancing Clinical Research Through Collaboration

Background: Clinical research in children with Kawasaki disease (KD), particularly those with coronary artery aneurysms (CAA), is challenging due to the limited number of patients available at any single institution. This has resulted in imperfect evidence for optimal management and considerable practice variation. Methods: The North American Kawasaki Disease Registry (NAKDR) was started in July 2013 to determine the prevalence, patient-level and pharmacological risk factors for outcomes of CAA after KD. The NAKDR enrolls KD patients diagnosed from 1999-2013 with CAA (defined as any segment with a z-score >2.5). The NAKDR and its internet-based data entry portal are maintained at The Hospital for Sick Children in Toronto. Local ethics approvals and bilateral data sharing agreements are necessary for participation. Participation in the NAKDR is currently unfunded and voluntary. In September 2014, a survey on the future of the NAKDR was sent to all participating centers (response rate: 54%). Results: 45 sites have been invited, of which 37 (82%) agreed to participate. As of September 2014, 20 sites are actively submitting data; 17 are still being initiated; 706 cases have been submitted. The majority (90%) of members indicated that they wished to continue enrolling newly diagnosed patients and continue follow-up on patients already enrolled. Members were split (45% for, 55% against) as to whether the NAKDR should be expanded to include all KD patients, regardless of CAA status. Finally, while most NAKDR members (60%) indicated that site reimbursement was not an absolute condition for future participation, most members suggested that potential funding sources should be sought to expand/facilitate activities. At term, the NAKDR is expected to comprise ~1,400 patients and, if moving forward, add ~120 new KD patients with CAA per year. Conclusions: The NAKDR is an important tool for clinical research in children with CAAs after KD, and its success represents broad support from clinicians. The next step will be to formalize the NAKDR leadership structure, create standard operating procedures, and pursue prospective studies and funding.

Myocardium at risk quantified by contrast enhanced steady-state free precession does not differ in extent or severity when comparing patients with ST-elevation myocardial infarction treated with standard reperfusion or postconditioning

Background Accurate quantification of the ischemic myocardium at risk (MaR) in patients with STelevation myocardial infarction (STEMI) is paramount in studies of therapies seeking to reduce infarct size expressed as percent of MaR. Cardiac magnetic resonance (CMR) is an important clinical research tool for determination of MaR and infarct size in the same examination within one week after STEMI. Recent data suggest that cardioprotective interventions such as ischemic postconditioning or remote conditioning reduce infarct size, but may also reduce the extent and severity of edema detected with T2-weighted imaging. Such an effect might limit the value of determining MaR using T2-weighted sequences. Contrast enhanced steady-state free precession (CESSFP) imaging for quantifying MaR in STEMI has previously been validated compared to single photon emission computed tomography following radiotracer injection prior to reperfusion. The aim of the current study was to compare extent and severity of signal intensity changes in MaR determined from CE-SSFP in patients with STEMI randomized to postconditioning or standard percutaneous coronary intervention (PCI). Methods Patients (n=76, age 37-87 years) eligible for primary PCI due to STEMI were randomized to standard PCI (controls, n=38) or postconditioning (n=38) consisting of four cycles of 60 sec reperfusion and 60 sec of re-occlusion before permanent reperfusion. CMR (1.5T Signa Excite Twin Speed, General Electric Healthcare, Waukesha, Wisconsin, USA) was performed 7.8±1.2 days after myocardial infarction using a protocol in which the contrast agent (0.2 mmol/kg; Omniscan, GE Healthcare) was administered before acquisition of short-axis CE-SSFP images. MaR was determined by manual delineation, in end-diastole and end-systole, as the contrast-enhanced myocardial volume in relation to left ventricular mass (Figure 1). A subgroup of patients underwent quantification of the signal intensity ratio of the contrast enhanced MaR region divided by a remote region.

Metabolomics for Biomarker Discovery: Moving to the Clinic.

To improve the clinical course of diseases, more accurate diagnostic and assessment methods are required as early as possible. In order to achieve this, metabolomics offers new opportunities for biomarker discovery in complex diseases and may provide pathological understanding of diseases beyond traditional technologies. It is the systematic analysis of low-molecular-weight metabolites in biological samples and has become an important tool in clinical research and the diagnosis of human disease and has been applied to discovery and identification of the perturbed pathways. It provides a powerful approach to discover biomarkers in biological systems and offers a holistic approach with the promise to clinically enhance diagnostics. When carried out properly, it could provide insight into the understanding of the underlying mechanisms of diseases, help to identify patients at risk of disease, and predict the response to specific treatments. Currently, metabolomics has become an important tool in clinical research and the diagnosis of human disease and becomes a hot topic. This review will highlight the importance and benefit of metabolomics for identifying biomarkers that accurately screen potential biomarkers of diseases.

Age and Gender-Related Changes in Biogenic Amine Metabolites in Cerebrospinal Fluid in Children.

Metabolites of cerebrospinal biogenic amines (dopamine and serotonin)are an important tool in clinical research and diagnosis of children with neurotransmitter disorders. In this article we focused on finding relationships between the concentration of biogenic amine metabolites, age, and gender. We analyzed 148 samples from children with drug resistant seizures of unknown etiology and children with mild stable encephalopathy aged 0-18 years. A normal profile of biogenic amineswas found in 107 children and those children were enrolled to the study group. The CSF samples were analyzed by HPLC with an electrochemical detector. The concentrations of the dopamine and serotonin metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), respectively, were high at birth, gradually decreasing afterward until the 18 years of age. Nevertheless, the HVA/5-HIAA ratio did not vary with age, except in the children below 1 year of age. In the youngest group we observed a strong relationship between the HVA/5-HIAA ratio and age (r = 0.69, p < 0.001). There were no statistical differences in the level of both dopamine and serotonin metabolites between boys and girls, although a tread toward lower HVA and 5-HIAA in the boys was noticeable. Significant inter-gender differences in the level of HVA and 5-HIAA were noted only in the age-group of 1-4 years, with 5-HIAA being higher in the girls than boys (p = 0.004). In conclusion, the study revealed that the concentration of biogenic amine metabolites is age and sex dependent.

Untargeted metabolomic analysis of urine samples in the diagnosis of some inherited metabolic disorders.

Metabolomics is becoming an important tool in clinical research and the diagnosis of human diseases. It has been used in the diagnosis of inherited metabolic disorders with pronounced biochemical abnormalities. The aim of this study was to determine if it could be applied in the diagnosis of inherited metabolic disorders (IMDs) with less clear biochemical profiles from urine samples using an untargeted metabolomic approach. A total of 14 control urine samples and 21 samples from infants with cystinuria, maple syrup urine disease, adenylosuccinate lyase deficiency and galactosemia were tested. Samples were analyzed by liquid chromatography on aminopropyl column in aqueous normal phase separation system using gradient elution of acetonitrile/ammonium acetate. Detection was performed by time-of-flight mass spectrometer fitted with electrospray ionisation in positive mode. The data were statistically processed using principal component analysis (PCA), principal component discriminant function analysis (PCA-DFA) and partial least squares (PLS) regression. All patient samples were first distinguished from controls using unsupervised PCA. Discrimination of the patient samples was then unambiguously verified using supervised PCA-DFA. Known markers of the diseases in question were successfully confirmed and a potential new marker emerged from the PLS regression. This study showed that untargeted metabolomics can be applied in the diagnosis of mild IMDs with less clear biochemical profiles.

Metabolomic profiling of mice urine and serum associated with trans-trans 2, 4-decadienal induced lung lesions by liquid chromatography-mass spectrometry

Metabolomics has become an important tool in clinical research and the diagnosis of human disease. Intratracheal instillation of trans-trans 2,4-decadienal (tt-DDE), a major component in cooking oil fumes, has been demonstrated to cause lung lesions in mice at 8 weeks after treatment. The objective of this study was to identify any changes in metabolite profiles associated with the development of tt-DDE-induced lung lesions. Using a metabolomics strategy involving a liquid chromatography-mass spectrometry-based approach in conjunction with principal component analysis and confirmation by liquid chromatography triple quadrupole tandem mass spectrometry, we have demonstrated that the amino acid profiles of the urine and serum of tt-DDE-treated mice are changed. Ten amino acids were significantly reduced in serum of tt-DDE-treated mice at 8 weeks after treatment. Our results suggest that amino acid profiles may be useful as an early indicator of the presence of tt-DDE-induced lung lesions.

A Novel Approach to Solve the “Missing Marker Problem” in Marker-Based Motion Analysis That Exploits the Segment Coordination Patterns in Multi-Limb Motion Data

Marker-based human motion analysis is an important tool in clinical research and in many practical applications. Missing marker information caused by occlusions or a marker falling off is a common problem impairing data quality. The current paper proposes a conceptually new gap filling algorithm and presents results from a proof-of-principle analysis. The underlying idea of the proposed algorithm was that a multitude of internal and external constraints govern human motion and lead to a highly subject-specific movement pattern in which all motion variables are intercorrelated in a specific way. Two principal component analyses were used to determine how the coordinates of a marker with gaps correlated with the coordinates of the other, gap-free markers. Missing marker data could then be reconstructed through a series of coordinate transformations. The proposed algorithm was tested by reconstructing artificially created gaps in a 20-step walking trial and in an 18-s one-leg balance trial. The measurement accuracy’s dependence on the marker position, the length of the gap, and other parameters were evaluated. Even if only 2 steps of walking or 1.8 s of postural sway (10% of the whole marker data) were provided as input in the current study, the reconstructed marker trajectory differed on average no more than 11 mm from the originally measured trajectory. The reconstructed result improved further, on average, to distances below 5 mm if the marker trajectory was available more than 50% of the trial. The results of this proof-of-principle analysis supported the assumption that missing marker information can be reconstructed from the intercorrelations between marker coordinates, provided that sufficient data with complete marker information is available. Estimating missing information cannot be avoided entirely in many situations in human motion analysis. For some of these situations, the proposed reconstruction method may provide a better solution than what is currently available.

Integrating cancer patients' perspectives into treatment decisions and treatment evaluation using patient-reported outcomes - a concept paper

Patient-reported outcomes are an important tool in clinical research. In the setting of cancer treatments, benefit of therapy is essentially characterised by improvement of survival as well as quality of life (QoL). A standardised instrument to assess QoL is the standardised QoL questionnaire of the European Organisation for Research and Treatment (EORTC QLQ-C30 questionnaire). QoL instruments provide data on different aspects (domains) of the framework of QoL. Using these questionnaires in studies provides data on how a treatment affects QoL in a group of patients. The goal of our concept is to individualise QoL and to use validated instruments in order to integrate patients' perspectives and aims into treatment assessment, planning and control. We propose to use the domains of the EORTC QLQ-C30 and to ask the patient to determine which objectives besides survival are relevant for him and should be achieved by treatment. These individual goals can be used in a process of shared decision-making to choose and monitor treatment. In clinical studies, this approach would allow to recruit more patients who would most probably benefit from the therapy. In addition, supportive data could be gathered in correlation to treatment goals and actual benefits.

Anal Cancer Study Based on Korea Central Cancer Registry Data: One Step Forward in Clinical Research

See Article on Page 182-185 First of all, I would like to congratulate the authors of this work, which focused especially on rare tumors and anal cancer based on National Cancer Registry data. For colorectal surgeons, knowledge of oncologic outcomes for anal cancer is important for making a therapeutic decision. Furthermore, these outcomes should be based on Korean Cancer Registry data. Anal cancer constitutes a relatively small portion of gastrointestinal tract cancers [1]. However, anal cancers are probably underreported because some anal canal tumors are misclassified as rectal tumors. Wide geographical and racial variations in the incidence of cancers are observed around the world. The incidence and the survival rates are generally well publicized for the more common cancers, such as lung, breast, and colorectal tumors; however, little is written regarding the incidence and the survival rates for anal canal cancer. Although some authors have reported clinicopathologic features or prognostic factors for anal cancers [2, 3], the characteristics of and the survival rate for anal cancer in Korea are largely unknown because no population-based study has been performed to address these issues in Korea. For decades, in many countries and regions, registration of cancers has been mandatory. National cancer registration is rooted in public health, helps in the planning of health services, and can be an important tool in clinical research. However, sometimes clinicians are frustrated because the cancer registry cannot provide all the information they need. A limitation in this study based on Korea Central Cancer Registry data is that the database lacks information on interventions such as surgery, radiation, and chemotherapy, on time to any type of recurrence, or on aspects of quality of care for anal canal cancer. The authors compared the survival between males and females by Surveillance, Epidemiology and End Results (SEER) stage and found that survival rates showed a diffference according to sex and age which was related to the distinct features of Korean patients with anal cancer [4]. This study is the largest to date that reports population-based survival data for anal canal cancer in Korea, and it provides an updated picture of anal canal cancer during the past 17 years. Even though the results could be representative of the population in Korea and should be more meaningful than single-institution experiences, this study has some limitations. The study did not analyze oncologic oucomes according to TNM stage, therapeutic modality, or recurrence pattern. In the future, the detailed parameters must be checked before analyzing Korean Cancer Registry database. Additionally, current data needs to be compared with published single-institution anal cancer data. Finally, prospective multicenter studies based using clinical databases on rare cancers need to be done to improve the quality of the data.

An Improved Method for the Estimation and Visualization of Velocity Fields from Gastric High-Resolution Electrical Mapping

High-resolution (HR) electrical mapping is an important clinical research tool for understanding normal and abnormal gastric electrophysiology. Analyzing velocities of gastric electrical activity in a reliable and accurate manner can provide additional valuable information for quantitatively and qualitatively comparing features across and within subjects, particularly during gastric dysrhythmias. In this study, we compared three methods of estimating velocities from HR recordings to determine which method was the most reliable for use with gastric HR electrical mapping. The three methods were 1) simple finite difference (FD) 2) smoothed finite difference (FDSM), and 3) a polynomial-based method. With synthetic data, the accuracy of the simple FD method resulted in velocity errors almost twice that of the FDSM and the polynomial-based method, in the presence of activation time error up to 0.5 s. With three synthetic cases under various noise types and levels, the FDSM resulted in average speed error of 3.2% and an average angle error of 2.0° and the polynomial-based method had an average speed error of 3.3% and an average angle error of 1.7°. With experimental gastric slow wave recordings performed in pigs, the three methods estimated similar velocities (6.3-7.3 mm/s), but the FDSM method had a lower standard deviation in its velocity estimate than the simple FD and the polynomial-based method, leading it to be the method of choice for velocity estimation in gastric slow wave propagation. An improved method for visualizing velocity fields is also presented.

Targeted metabolomic analysis of plasma samples for the diagnosis of inherited metabolic disorders

Metabolomics has become an important tool in clinical research and diagnosis of human diseases. In this work we focused on the diagnosis of inherited metabolic disorders (IMDs) in plasma samples using a targeted metabolomic approach. The plasma samples were analyzed with the flow injection analysis method. All the experiments were performed on a QTRAP 5500 tandem mass spectrometer (AB SCIEX, USA) with electrospray ionization. The compounds were measured in a multiple reaction monitoring mode. We analyzed 50 control samples and 34 samples with defects in amino acid metabolism (phenylketonuria, maple syrup urine disease, tyrosinemia I, argininemia, homocystinuria, carbamoyl phosphate synthetase deficiency, ornithine transcarbamylase deficiency, nonketotic hyperglycinemia), organic acidurias (methylmalonic aciduria, propionic aciduria, glutaric aciduria I, 3-hydroxy-3-methylglutaric aciduria, isovaleric aciduria), and mitochondrial defects (medium-chain acyl-coenzyme A dehydrogenase deficiency, carnitine palmitoyltransferase II deficiency). The controls were distinguished from the patient samples by principal component analysis and hierarchical clustering. Approximately 80% of patients were clearly detected by absolute metabolite concentrations, the sum of variance for first two principle components was in the range of 44–55%. Other patient samples were assigned due to the characteristic ratio of metabolites (the sum of variance for first two principle components 77 and 83%). This study has revealed that targeted metabolomic tools with automated and unsupervised processing can be applied for the diagnosis of various IMDs.

Evaluation of vertebral fracture assessment by dual X-ray absorptiometry in a multicenter setting

The utility of vertebral fracture assessment (VFA) by DXA to detect prevalent vertebral fracture in a multicenter setting was investigated by comparison to conventional radiography. While limited by lower image quality, overall performance of VFA was good but had a tendency to miss mild prevalent fractures. In osteoporosis clinical trials standardized spine radiographs are used to detect vertebral fractures as a study endpoint. Lateral spine imaging with dual X-ray absorptiometry (DXA) scanners, known as vertebral fracture assessment (VFA) by DXA, presents a potential alternative to conventional radiography with lower radiation dose and greater patient convenience. We investigated in a multicenter setting the ability of VFA to detect fractures in comparison with conventional radiography. The study examined 203 postmenopausal women who had imaging of the spine by DXA and radiography. Three radiologists experienced in vertebral fracture assessment independently read the VFA scans and radiographs using the Genant semiquantitative method on two occasions. Analyzing the data from all readable vertebrae, the kappa statistic, sensitivity, and specificity ranged from 0.64-0.77, 0.65-0.84, and 0.97-0.98, respectively. Considering only moderate and severe fractures improved the kappa statistic (0.80-0.91) and sensitivity (0.70-0.86). While image quality of VFA is inferior to radiography, the detection of vertebral fractures using visual scoring is feasible. However, VFA underperformed due to unreadable vertebrae and reduced sensitivity for mild fractures. Nevertheless, VFA correctly identified most moderate and severe vertebral fractures. Despite this limitation, VFA by DXA provides an important tool for clinical research.

Systematic reviews and meta‐analyses in coloproctology: interpretation and potential pitfalls

A systematic review (SR) is the unbiased appraisal of systematically identified relevant studies. Implicit in its definition is a robust and scientifically valid process, and when performed as such, SR is an important clinical research tool and influence in health policy decision-making. This educational paper outlines that, from the original prototype based on randomized trials, there are now many other types of SRs including those based on: nonrandomized comparative studies, observational studies, prognostic studies, and studies of diagnostic and screening tools. While each of these has a similar 'anatomy' or format, at an individual class level, there are principles specific to each SR type. Several examples from the coloproctology literature are used as case-studies to illustrate potential pitfalls, and upon re-analysis, often reverse or attenuate the conclusions stated in the original publication. These examples serve to emphasize the need for health professionals to understand the process of SR and meta-analysis so that we all arrive at appropriate interpretations to the benefit of our patients.

A First Look at the Structured Clinical Interview for DSM-IV Personality Disorders Screening Questionnaire: More Than Just a Screener?

This study examined the psychometrics of the Structured Clinical Interview for DSM -1V Personality Disorders Personality Questionnaire (SC1D-IIP) self-report personality questionnaire. The responses to the instrument were found reliable and evidenced good self-other convergence. Correlations with external criteria showed the SCID-III’ to contain broad personological information. The scale s basis in DSM - IV nosology makes it a potentially important tool for clinical research.

Measuring ease of breathing in young patients with cystic fibrosis.

Our objective was to compare two new objective measures of ease of breathing with the visual analog scale (VAS). Twenty-eight patients with CF, 7-34 years old (FEV(1) 25-114% of predicted), enrolled. Ease of breathing was evaluated by a standard 10-cm VAS, maximum phonation (time, in seconds, to sustain the syllable "Ahh") using a single breath, and counting in a single breath at one number per second (Count) at rest, following 3 min of stepping exercise at 15 steps per minute (STEP15), and 3 min at 30 steps per minute (STEP30). Heart rate (HR) and oxyhemoglobin saturation (SaO(2)) were measured.HR and VAS increased significantly, and SaO(2), phonation, and Count decreased significantly from rest to STEP15 and STEP30. Phonation time correlated significantly (and inversely) with HR after exercise. Phonation time was positively correlated with SaO(2) at rest and after STEP30. Counts at rest and after STEP30 were significantly related to SaO(2). VAS showed no relationship to heart rate at rest or after exercise, but was related to SaO(2) at the end of STEP30. Test-retest reliability for three trials of phonation was 0.92, and for the five trials of counting was 0.93. Correlation coefficients for maximum phonation at rest, STEP15, and STEP30 on 2 separate days were 0.61, 0.94, and 0.91, respectively. Correlation coefficients for Count at rest, STEP15, and STEP30 on 2 separate days were 0.96, 0.94, and 0.94, respectively. Correlation coefficients for VAS at rest, STEP15, and STEP30 on 2 separate days were 0.25, 0.89, and 0.97, respectively. Thus both the maximum phonation and Count have good test-retest reliability within one session, and across 2 separate days, for both rest and exercise conditions. In conclusion, maximum phonation and Count are valid and reliable measures of ease of breathing; they reflect increasing work loads and show stronger correlations with heart rate and SaO(2) than does VAS. These measures could be an important tool for clinical research and patient care.

Theory and practice of microdialysis--prospect for future clinical use.

The application of microdialysis for neurochemical monitoring in neurosurgery and neurointensive care is rapidly expanding in a number of clinical centers around the world. In order for microdialysis to become a future routine method in these clinical settings a number of problems, outlined in this communication, must be solved by the clinical researchers and the commercial companies. Regardless of the future success as a routine method, it is already obvious that microdialysis will be an important clinical research tool for years to come, providing new important insights into the pathophysiology of acute human brain injury.