Current Clinical Measures Research Articles

Effects of chronic pain and psychosocial stress on telomere length and telomerase activity

Osteoarthritis (OA), a leading cause of chronic pain and disability, is characterized by significant individual variability. Further complicating matters, current clinical measures offer limited utility in predicting disease progression and disability. Pain is recognized as a primary factor contributing to functional limitations in OA. Psychosocial stress can contribute to the onset and exacerbation of chronic pain and living with chronic pain can propel increased psychosocial stress. The relationship between acute pain and biological markers has been explored but the long-term consequences of chronic pain and associated psychosocial stressors on physiological functioning are poorly understood. High levels of chronic stress are associated with dysregulated stress response systems and pathophysiology. Identifying biological markers predictive of the onset of chronic pain or reflective of the consequences of chronic pain and psychosocial stress would have significant clinical and scientific value. Telomeres are DNA complexes protecting the ends of chromosomes. Although buffered by telomerase activity, leukocyte telomere length, a biomarker of cellular aging, decreases with replication and has been associated with persistent biological and psychosocial stress. Our exploratory findings in a study of cellular aging, chronic pain, and perceived stress in ethnically diverse older adults are encouraging. Specifically, individuals experiencing chronic knee OA-related pain and high stress had significantly shorter telomeres than individuals reporting no knee pain and low stress. Overall research aims are to: 1) better understand the interaction between biological processes, chronic pain, and psychosocial variables in older, ethnically diverse adults with and without symptomatic knee OA; 2) identify resilience and vulnerability factors; and 3) determine the clinical and predictive utility of telomere measures. Long-term objectives are to identify potential targets to decrease system burden, pain severity, and functional decline; evaluate the effectiveness and biological consequences of clinical interventions; and promote the development of efficacious prevention strategies. Osteoarthritis (OA), a leading cause of chronic pain and disability, is characterized by significant individual variability. Further complicating matters, current clinical measures offer limited utility in predicting disease progression and disability. Pain is recognized as a primary factor contributing to functional limitations in OA. Psychosocial stress can contribute to the onset and exacerbation of chronic pain and living with chronic pain can propel increased psychosocial stress. The relationship between acute pain and biological markers has been explored but the long-term consequences of chronic pain and associated psychosocial stressors on physiological functioning are poorly understood. High levels of chronic stress are associated with dysregulated stress response systems and pathophysiology. Identifying biological markers predictive of the onset of chronic pain or reflective of the consequences of chronic pain and psychosocial stress would have significant clinical and scientific value. Telomeres are DNA complexes protecting the ends of chromosomes. Although buffered by telomerase activity, leukocyte telomere length, a biomarker of cellular aging, decreases with replication and has been associated with persistent biological and psychosocial stress. Our exploratory findings in a study of cellular aging, chronic pain, and perceived stress in ethnically diverse older adults are encouraging. Specifically, individuals experiencing chronic knee OA-related pain and high stress had significantly shorter telomeres than individuals reporting no knee pain and low stress. Overall research aims are to: 1) better understand the interaction between biological processes, chronic pain, and psychosocial variables in older, ethnically diverse adults with and without symptomatic knee OA; 2) identify resilience and vulnerability factors; and 3) determine the clinical and predictive utility of telomere measures. Long-term objectives are to identify potential targets to decrease system burden, pain severity, and functional decline; evaluate the effectiveness and biological consequences of clinical interventions; and promote the development of efficacious prevention strategies.

Measurements for posterior shoulder tightness: reliability without validity

This article was the fi rst to describe the loss of glenohumeral internal rotation range of motion (ROM) in pitchers, and the authors report using glenohumeral horizontal adduction with the humerus in neutral internal/external rotation to assess posterior shoulder tightness. In the 26 years since this publication, posterior shoulder tightness has regularly been examined for its role in shoulder pathology, especially in overhead athletes. Whenever a clinical measurement is taken, two critical properties of that measurement should be known: validity and reliability. The current paper has compiled a summary of many previous studies that have examined these constructs as they relate to measuring posterior shoulder tightness. What becomes apparent through this summary is that the reliability of current clinical measurements is fairly strong, especially when the measurement method appears to be well-defined, tightly controlled, and repeated within a short time interval by experienced raters. What is also apparent in the summary is that the validity of measuring posterior shoulder tightness is not only considered modest at best, but arguably, has not been established.

Outcome measures for clinical trials assessing treatment of cystic fibrosis lung disease.

Cystic fibrosis (CF) is a complex genetic disease characterized by death from loss of lung function. Therapies target pathophysiologic changes associated with pulmonary disease progression. Although therapeutic mechanisms differ, efficacy demonstration is limited to a few accepted outcome measures, each with shortcomings that are becoming more pronounced as CF population health improves. Pulmonary function improvement (as forced expiratory volume in 1 s [FEV1]) and reduction of pulmonary exacerbation risk are commonly used outcomes. Changes in FEV1 decline rate, quality of life, linear growth and/or weight gain are less utilized outcomes. Validated outcomes tend to work best in subjects with more aggressive or advanced lung disease and less so in healthier subjects. Assays of effects on primary therapeutic targets have yet to be validated as surrogate measures of clinical efficacy. As CF population health improves, it will become increasingly difficult to employ current clinical outcome measures to demonstrate efficacy.

Olfactory function and dysfunction

Olfaction is phylogenetically the oldest sense, but receives scant attention in contrast to other special senses. Smell is often taken for granted, but it is central to our everyday life and helps to protect us from harmful substances, contributes to the livelihood of many professions as well as to the nutritional status and general quality of life. Olfactory disorders are common, yet remain the least understood. This paper gives an overview of the anatomy, physiology, and management of olfactory disorders with particular emphasis on current clinical measurements of olfactory dysfunction. Literature from relevant textbooks and selected journal articles has been reviewed in this article. Olfactory disorders can be classified as conductive, sensory, and neural. Localization of olfactory centers in the brain by electroencephalography has been described recently. However, quantitative evaluation by threshold measurements and qualitative testing with identification test formats continues to be the most popular type of olfactory test in use. While treatment of olfactory disorders remains disappointing, conductive disorders are amenable to treatment. Full understanding of the olfactory organ and its pathways is essential for the development of any reliable means of testing its function and managing dysfunction. With recent developments in olfactory mapping of the brain, it won't be long before a more robust test for olfaction akin to visual acuity and auditory thresholds is developed.

Individual variance of hearing-impaired consonant perception

Individuals with sensorineural hearing loss (SNHL) are prescribed hearing aids (HAs), based on the results of clinical measurements. Although the HAs do help these individuals communicate in quiet surroundings, many listeners have complained that their HAs do not provide enough benefit to facilitate understanding of normal speech. We argue that the current clinical measurements, which interpret the result as a mean score (e.g., pure-tone average, speech recognition threshold, AI-gram, etc.), do not deliver sufficient information about the characteristics of a SNHL listener's impairment when hearing speech, resulting in a poorly fitting HA. We confirm how reliably this consonant-vowel (CV) test could measure a SNHL listener's consonant loss using only zero-error utterances (in normal hearing listeners) and having a statistically suitable number of presentations in CVs, in order to characterize unique SNHL consonant loss. As noise increased, the percentage of error and confusions of target consonants increa...

Objective Visual Assessment of Antiangiogenic Treatment for Wet Age-Related Macular Degeneration

To assess cortical responses in patients undergoing antiangiogenic treatment for wet age-related macular degeneration (AMD) using functional magnetic resonance imaging (fMRI) as an objective, fixation-independent measure of topographic visual function. A patient with bilateral neovascular AMD was scanned using fMRI before and at regular intervals while undergoing treatment with intravitreal antiangiogenic injections (ranibizumab). Blood oxygenation level-dependent signals were measured in the brain while the patient viewed a stimulus consisting of a full-field flickering (6 Hz) white light alternating with a uniform gray background (18 s on and 18 s off). Topographic distribution and magnitude of activation in visual cortex were compared longitudinally throughout the treatment period (<1 year) and with control patients not currently undergoing treatment. Clinical behavioral tests were also administered, including visual acuity, microperimetry, and reading skills. The area of visual cortex activated increased significantly after the first treatment to include more posterior cortex that normally receives inputs from lesioned parts of the retina. Subsequent treatments yielded no significant further increase in activation area. Behavioral measures all generally showed an improvement with treatment but did not always parallel one another. The untreated control patient showed a consistent lack of significant response in the cortex representing retinal lesions. Retinal treatments may not only improve vision but also result in a concomitant improvement in fixation stability. Current clinical behavioral measures (e.g., acuity and perimetry) are largely dependent on fixation stability and therefore cannot separate improvements of visual function from fixation improvements. fMRI, which provides an objective and sensitive measure of visual function independent of fixation, reveals a significant increase in visual cortical responses in patients with wet AMD after treatment with antiangiogenic injections. Despite recent evidence that visual cortex degenerates subsequent to retinal lesions, our results indicate that it can remain responsive as its inputs are restored.

SU‐E‐T‐137: Evaluating How the Sample‐Volume Dependence of Well‐Type Chambers Affects the Current Clinical Determination of Y‐90 Microsphere Activity

Purpose: To evaluate how the sample‐volume dependence of well‐type chambers affects the current clinical determination of Y‐90 microsphere activity.Methods: A Y‐90 standard activity solution from the NIST SRM program was used for all measurements. Ionization current measurements were made in a Standard Imaging IVB1000 well chamber and a Capintec 12‐atm dose calibrator with Sirtex Medicalˈs glass shipping vial and plastic v‐vial for volume levels from 1mL to 5mL in 1mL increments. A calibration coefficient was calculated for each volume level and the percent difference from the 5mL calibration coefficient was calculated. To evaluate how the differences in calibration coefficients between the volume levels affect the delivered activity, a theoretical prescription level of 2.4GBq was assumed. Using the appropriate calibration coefficients and the source measurement methods suggested by Sirtex Medical, the actual activity that would be delivered and percent difference from 2.4GBq were calculated.Results: The largest variation in calibration coefficient for each chamber and vialconfiguration was between the 5mL and 1mL volume levels. The largest difference of 45% was seen in the IVB1000 well chamber with the shipping vial and the smallest difference of 1.3% was seen in the 12‐atm dose calibrator with the v‐vial. These differences translated into 11.3% and 0.3% differences, respectively, from the theoretical 2.4GBq prescription. A 2.6% difference from the 2.4GBq prescription was found for the Capintec 12‐atm with the shipping vial held in the dipper holder, which represents the current clinical measurement geometry Conclusions: Based on the results, the IVB1000 would not be recommended for the current activity determination methods as proposed by Sirtex Medical for microspheres. The 2.6% difference determined for the currently used measurement geometry may be resolved with calibration and measurement with the v‐vial.

Reliability of the Translation of Center of Force Using Pressure Mapping in the Older Adult

Testing for falls prevention in the older adult population is a critical element in preventative interventions. Testing is often laboratory based creating a barrier to screening for this population. Equipment that is inexpensive and portable would facilitate testing and diminish a barrier to preventative screening. PURPOSE: To determine the reliability of a measurement device, that utilizes pressure mapping, for measuring translation of center of force in older adults. METHODS: Nineteen (6 males; 13 females) physically active older adults (m = 65.3 + 7.2 yrs., m = 166.9 +10.6 cm, m = 69.4 + 12.9 kg) participated in balance testing across three days after signing an informed consent document. Five measures across six conditions were tested within 24 to 72 hrs of the previous test day. The variables of area, distance, variability (SD of distance), A-P and R-L excursion were computer generated under the six conditions of two-feet eyes open (2FEO), two feet eyes closed (2FEC), right foot eyes open (RFEO) and eyes closed (RFEC), left foot eyes open (LFEO) and eyes closed (LFEC). Subjects were asked to stand quietly for 30 seconds, for three trials, with arms crossed across the chest, viewing an eye level target on the wall. A tracing of foot position was taken to ensure similar stance positioning within each day across trials. RESULTS: ICCs (2,3) ranged from poor (0.24 for variability RFEC) to high (0.94 for area 2FEO). In general, reliability appears higher (around 0.80) in the EO condition compared to the EC condition where the ICCs are around 0.73. Variance being higher in general for the eyes closed data explains in part this difference. Furthermore, 12 out of the 15 eyes open ICCs are at 0.75 or better, while 10 of the 15 eyes closed ICCs are at or over 0.75. The worst ICCs (all below 0.56) are found for the variability-eyes closed condition. However, the ICCs in all the other measurements and conditions range from good (0.75) to very good (0.94), except for the ICC of left foot eyes open which is at 0.48. CONCLUSION: This portable pressure mapping device provides several stable measurements for postural balance in an older adult population across days. This successful first step provides encouragement for use of this devise for falls risk. Future study will be conducted for validation of the variables to current clinical measures for falls risk.

Mean transit time as an index of cerebral perfusion pressure in experimental systemic hypotension

Early diagnosis of cerebrovascular disease requires the accurate identification of brain regions with compromised cerebral perfusion pressure (CPP). Current clinical measures of CPP are invasive and lack regional information. Dynamic contrast-enhanced imaging provides a means of looking at regional cerebral hemodynamics. The purpose of this study was to determine if any of the parameters associated with dynamic contrast-enhanced imaging could be used as an index for CPP under graded systemic hypotension in a rabbit model. Cerebral blood flow (CBF), cerebral blood volume, mean transit time (MTT), and cerebrovascular reserve (CVR) were measured using Computed Tomography Perfusion in three groups: normotensive (n = 14), mild hypotensive (n = 9), and moderate hypotensive (n = 6). MTT demonstrated the strongest correlation with CPP (ρ = −0.642, P < 0.05). CBF was the only other parameter to demonstrate a statistically significant correlation (ρ = 0.575, P < 0.05). CVR is gaining momentum for diagnosing cerebrovascular disease; however, the technique requires patients to be given a hemodynamic challenge, which could aggravate symptoms and even trigger stroke. The results of this study suggest that the use of MTT, not requiring hemodynamic manipulation, is more sensitive to subtle changes in CPP, as would occur in the early stages of cerebrovascular disease.

Biomarkers in schizophrenia: we need to rebuild the Titanic

Lawrie et al have made a remarkable effort to take stock of the number of current clinical and neurobiological measures which may serve as potential objective diagnostic and prognostic markers, and may move future clinical, therapeutic and pathophysiological re- search in schizophrenia in a promising direction. They argue that replacing current diagnostic criteria for this illness by another set of subjective criteria would be comparable to rearranging deck chairs on the Titanic. We cannot agree more, and believe that we should look at salvaging the Titanic itself. The major challenge in developing biomarkers of diagnostic value lies in the limitations of the current diagnostic and classificatory approaches. While the current diagnostic approaches have clearly improved reliability of diagnoses with the recurrent revisions of the DSM, the validity of disorders such as schizophrenia remains in question. First, the content validity of the schizophrenia construct is seriously limited by the substantive heterogeneity of the disorder in cross-sectional presentations, neurobiological characteristics as well as the etiological factors implicated 1. It is commonplace in the schizophrenia literature for authors to invoke heterogeneity as an explanation for inconsistent findings. Heterogeneity must be viewed as a problem to be addressed rather than as an explanation or a solution, and is the strongest reason to revisit the long-entrenched and inadequate conceptualization of this disease entity 2. The predictive validity of schizophrenia as a construct is hampered by the fact that the longitudinal course of this illness is highly variable 3,4,5, as is the response to different treatments 6. Furthermore, the discriminate validity of schizophrenia is limited by its blurred boundary with other major disorders such as bipolar disorder. Overlap between these disorders is seen in neurobiology, genetics, symptomatology as well as treatment response, posing a central challenge to the century-old Kraepelinian view that these are distinct illnesses 7. At the heart of this debate is the core concept of schizoaffective disorder as an entity that combines the features of both illnesses. Psychiatric disorders generally do not meet the time-honored dictates that symptom constellations (syndromes) would have specific pathology which would lead to specific etiology. In this context, Robins and Guze 8 proposed four tenets of a valid psychiatric diagnosis. These include the need for a distinct signature in phenomenology, course, family history, and biology. Schizoaffective disorder fails to meet these criteria, being characterized by having overlaps with schizophrenia and bipolar disorder in each of these domains 6,9. The interface between schizophrenia and the continuum of “health” is also fuzzy, leading to the intermediate syndromes of schizotypal and brief psychotic disorders. An increasingly held view is that the pathophysiological heterogeneity of schizophrenia may be resolved by elu- cidating independent families of intermediate phenotypes that traverse across structural, functional, neurochemical and molecular domains, and map on to psychopathological dimensions, but are agnostic to diagnostic categorization 10. As progress is made toward these goals, it is possible that the current entity of schizophrenia will be deconstructed and rebuilt as phenotypically overlapping, but etiopathologically distinct component entities. Biomarkers of the kind Lawrie et al review may be of better value to identify and “diagnose” such entities, perhaps in the not too distant future. Lawrie et al suggest other key scena- rios beyond diagnosis where current clinical practice operates in the dark: early detection and predicting response to treatment. It is in these venues that the application of our understanding of the pathophysiology of schizophrenia may make an earlier impact in the clinical world. The ability to identify the cohort that is likely to develop these disorders may enable effective preventive interventions with non-pharmacologic means such as cognitive behavior therapy and cognitive remediation, and pharmacological interventions such as omega3 fatty acids and low-dose atypical antipsychotics. One can also envision in the relatively near future biomarker screens that may predict treatment response and side effects irrespective of diagnosis. In conclusion, the paper by Lawrie et al provides a useful, quantitative appraisal of the state of our understanding of schizophrenia as we now know it and how that understanding impacts clinical care. Some of the more prognostic issues outlined by the authors regarding early identification and prediction of outcome have the potential to be dramatically affected by our ability to understand this disease in biological terms. We are in agreement with their conclusion that diagnosis by biomarkers is not currently feasible and would add that, for various reasons mentioned above, this particular issue may not be where our biological understanding of schizophrenia makes the most immediate impact in the clinical world. That may change, however, as our current Titanic-like construct of schizophrenia gives way to component entities defined across phenomic, genomic, enviromic and endophenomic dimensions 11.

Verification of In Situ Thresholds and Integrated Real-Ear Measurements

Accurate prescriptive gain results in a more accurate fit, lower return rate in hearing aids, and increased patient satisfaction. In situ threshold measurements can be used to determine required gain. The Widex Corporation uses an in situ threshold measurement strategy, called the Sensogram. Real-ear measurements determine if prescriptive gain targets have been achieved. Starkey Laboratories introduced an integrated real-ear measurement system in their hearing aids. To determine whether the responses obtained using the Widex Sensogram were equivalent to those obtained using current clinical threshold measurement methods. To determine the accuracy of the Starkey IREMS™ (Integrated Real Ear Measurement System) in measuring RECD (real-ear to coupler difference) values compared to a dedicated real-ear measurement system. A verification design was employed by comparing participant data measured from standard, benchmark equipment and procedures against new techniques offered by hearing-aid manufacturers. A total of 20 participants participated in this study. Ten participants with sensorineural hearing loss were recruited from the Ohio University Hearing, Speech, and Language Clinic participated in the first experiment. Ten participants with normal hearing were recruited from the student population at Ohio University participated in both experiments. The normal-hearing group had thresholds of 15 dB HL or better at the octave frequencies of 250-8000 Hz. The hearing-impaired group had thresholds of varying degrees and configurations with thresholds equal to or poorer than 25 dB HL three-frequency pure-tone average. The order of measurement method for both experiments was counterbalanced. In Experiment 1, thresholds obtained via the Widex Sensogram were compared to thresholds obtained for each participant using a clinical audiometer and ER-3A insert ear phones. In Experiment 2, RECD values obtained via the Starkey IREMS were compared to RECD values obtained via the Audioscan Verifit™. A repeated-measures analysis of variance (ANOVA) was used for statistical analysis, and a Fisher's LSD (least significant difference) was used as a post hoc analysis tool. A significant difference between Sensogram thresholds and conventional audiometric thresholds was found with the Sensogram method resulting in better threshold values at 0.5, 1.0, and 2.0 kHz for both groups. In Experiment 2, a significant difference between RECD values obtained by the Starkey IREMS and the Audioscan Verifit system was found with significant differences in RECD values found at 0.25, 0.5, 0.75, 1.5, 2.0, and 6.0 kHz. The Sensogram data differ significantly from traditional audiometry at several frequencies important for speech intelligibility. Real-ear measures are still required for verification of prescribed gain, however, calling into question any claims of shortened fitting time. The Starkey IREMS does perform real-ear measurements that vary significantly from benchmark equipment. These technologies represent a positive direction in prescribing accurate gain during hearing-aid fittings, but a stand-alone system is still the preferred method for real-ear measurements in hearing-aid fittings.

Comparing self‐reported and measured high blood pressure and high cholesterol status using data from a large representative cohort study

To examine the relationship between self-reported and clinical measurements for high blood pressure (HBP) and high cholesterol (HC) in a random population sample. A representative population sample of adults aged 18 years and over living in the north-west region of Adelaide (n=1537) were recruited to the biomedical cohort study in 2002/03. In the initial cross-sectional component of the study, self-reported HBP status and HC status were collected over the telephone. Clinical measures of blood pressure were obtained and fasting blood taken to determine cholesterol levels. In addition, data from a continuous chronic disease and risk factor surveillance system were used to assess the consistency of self-reported measures over time. Self-report of current HBP and HC showed >98% specificity for both, but sensitivity was low for HC (27.8%) and moderate for HBP (49.0%). Agreement between current self-report and clinical measures was moderate (kappa 0.55) for HBP and low (kappa 0.30) for HC. Demographic differences were found with younger people more likely to have lower sensitivity rates. Self-reported estimates for the surveillance system had not varied significantly over time. Although self-reported measures are consistent over time there are major differences between the self-reported measures and the actual clinical measurements. Technical aspects associated with clinic measurements could explain some of the difference. Monitoring of these broad population measures requires knowledge of the differences and limitations in population settings.

Possible clinical outcome measures for clinical trials in patients with multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease with both clinical and pathological heterogeneity. The complexity of the MS population has offered challenges to the measurement of MS disease progression in therapeutic trials. The current standard clinical outcome measures are relapse rate, Expanded Disability Severity Scale (EDSS), and the MS Functional Composite (MSFC). These measures each have strengths and some weakness. Two additional measures, the six-minute walk and accelerometry, show promise in augmenting current measures. MS therapeutics is a quickly advancing field which requires sensitive clinical outcome measures that can detect small changes in disability that reliably reflect long-term changes in sustained disease progression in a complex population. A single clinical outcome measure of sustained disease progression may remain elusive. Rather, an integration of current and new outcome measures may be most appropriate and utilization of different measures depending on the MS population and stage of the disease may be preferred.

The value of positron emission tomography and proliferation index in predicting progression in low-grade astrocytomas of childhood

Astrocytomas are the most common brain tumors of childhood and adolescence. Low-grade astrocytomas (LGAs), in general, have favorable prognosis, but recurrence or progressive disease with dissemination, malignant transformation, and death occur in some cases. Current clinical and pathological measures including age, sex, imaging characteristics, location and size of the tumor, histopathology, and degree of resection cannot predict with certainty which tumors will demonstrate aggressive behavior. The objective of the study is to determine the predictive value of positron emission tomography (PET) and a proliferation index (PI) in identifying high risk LGAs. We reviewed 46 cases ages 5 months to 17 years with low-grade (WHO I-II) astrocytomas. All patients had PET scans utilizing [(18)F] fluorodeoxyglucose (FDG) and 24 cases had measurements with Ki-67/MIB-1 immunohistochemistry. Review of our data confirmed progressive disease (PD) in 18/46 (39%) of cases with 9/21 (42%) occurring after subtotal resection and 9/25 (36%) after gross total resection. The mortality rate was 5/46 (10.8%). Tumors with FDG hypermetabolism were significantly more likely to demonstrate aggressive behavior and PD. Increased PI values also suggested PD. Progression-free survival and time to progression were significantly longer for patients with hypometabolic scans. Time to progression was significantly longer with lower PI values. Results demonstrate that PET and PI are useful measures in the identification and stratification of high risk LGAs. The ability to identify a subset of progressive LGAs earlier may suggest the need for second-look neurosurgical procedures or more intensified adjuvant treatment that may ultimately improve outcome and survival.

Resolved

Resolved

Identification of Prognostic Biomarkers for Prostate Cancer

This paper describes a process for the identification of genes that can report on the aggressiveness of prostate tumors and thereby add to the information provided by current pathologic analysis. Expression profiling data from over 100 laser capture microdissection derived samples from nonneoplastic epithelium; Gleason patterns 3, 4, and 5 and node metastasis prostate cancer were used to identify genes at abnormally high levels in only some tumors. These variably overexpressed genes were stratified by their association with aggressive phenotypes and were subsequently filtered to exclude genes with redundant expression patterns. Selected genes were validated in a case-control study in which cases (systemic progression within 5 years) and controls (no systemic progression at 7 years of follow-up) were matched for all clinical and pathologic criteria from time of prostatectomy (n = 175). Both cases and controls, therefore, could have nodal invasion or seminal vesicle involvement at the time of initial treatment. A number of candidate variably overexpressed genes selected for their association with aggressive prostate cancer phenotype were evaluated in the case control study. The most prominent candidates were SSTR1 and genes related to proliferation, including TOP2A. The process described here identified genes that add information not available from current clinical measures and can improve the prognosis of prostate cancer.

Disorders in Amniotic Fluid

Abstract Disorders in amniotic fluid production occur frequently in pregnancy, and are associated with increased perinatal mortality and morbidity. This article will discuss amniotic fluid physiology, and will summarize noninvasive methods of measuring amniotic fluid. The definitions, common causes and possible therapeutic interventions available to treat oligohydramnios and polyhydramnios will be discussed. Learning objectives To have an understanding of the mechanisms underlying the regulation of amniotic fluid volumes To understand the limitations of current clinical measurements of amniotic fluid volumes To know the definitions, causes and potential treatments of disorders in amniotic fluid.

Volume Segmentation and Reconstruction from Freehand Three-Dimensional Ultrasound Data with Application to Ovarian Follicle Measurement

This article presents a semi-automatic method for segmentation and reconstruction of freehand three-dimensional (3D) ultrasound data. The method incorporates a number of interesting features within the level-set framework: First, segmentation is carried out using region competition, requiring multiple distinct and competing regions to be encoded within the framework. This region competition uses a simple dot-product based similarity measure to compare intensities within each region. In addition, segmentation and surface reconstruction is performed within the 3D domain to take advantage of the additional spatial information available. This means that the method must interpolate the surface where there are gaps in the data, a feature common to freehand 3D ultrasound reconstruction. Finally, although the level-set method is restricted to a voxel grid, no assumption is made that the data being segmented will conform to this grid and may be segmented in its world-reference position. The volume reconstruction method is demonstrated in vivo for the volume measurement of ovarian follicles. The 3D reconstructions produce a lower error variance than the current clinical measurement based on a mean diameter estimated from two-dimensional (2D) images. However, both the clinical measurement and the semi-automatic method appear to underestimate the true follicular volume. (E-mail: gooding@robots.ox.ac.uk)

Computer-assisted evaluation of kinematics of the two bundles of the anterior cruciate ligament / Computer-assistierte Evaluation der Kinematik der beiden Bündel des VKB

The aim of this cadaveric study was to describe the kinematics of the anterior cruciate ligament (ACL)-intact, posterolateral (PL) bundle-deficient and ACL-deficient knee by applying a protocol for computer-assisted evaluation of knee kinematics. The hypothesis that the PL bundle functions mainly at low knee flexion angles was tested. An optical tracking system was used to acquire knee joint motion on 10 knees during clinical evaluations by tracking markers rigidly attached to the bones. The protocol included acquisition of anterior-posterior (AP) translations and internal-external (IE) rotations, and evaluation of three clinical knee laxity tests (anterior drawer, manual and instrumented Lachman). The data demonstrated no significant contribution to AP translation and IE laxity from the PL bundle over the entire range of motion. The clinical knee laxity tests showed no significant differences between the ACL-intact and PL bundle-deficient states. The hypothesis could not be proven. Current clinical knee laxity measurements may not be suited for detecting subtle changes such as PL bundle deficiency in the ACL anatomy. The computation of knee laxity might be a step towards a more precise kinematic test of knee stability not only in the native and torn ACL state of the knee but also in the reconstructed knee.

Computer Evaluation of Kinematics of Anterior Cruciate Ligament Reconstructions

Current clinical and instrumented outcome measurements of knee instability lack accuracy, especially when multiplanar instability is considered. The aim of our cadaveric study was to describe the kinematics in the intact, double bundle, and anteromedial bundle reconstructed anterior cruciate ligament knee by applying a protocol for computer-assisted evaluation of knee kinematics. An optical navigation system was used to acquire knee motion (n = 5) during clinical evaluations by tracking markers rigidly attached to the bones. The protocol included acquisition of anteroposterior translations and internal-external rotations and evaluation of three clinical knee laxity tests (anterior drawer, manual, and instrumented Lachman). Our anteroposterior translation data showed the double-bundle technique and anteromedial bundle technique could restore anteroposterior stability comparable to the intact state. For internal-external laxity, the double-bundle technique demonstrated overcorrection at 15 degrees, 60 degrees, 75 degrees, and 90 degrees. The anterior drawer and manual Lachman knee laxity tests showed improved stability for the double-bundle compared to the anteromedial bundle technique. This pilot study suggests the computation of knee laxity with a high precision method might be a step toward a more precise kinematic test of knee stability for evaluating different reconstruction methods.