Supraspinatus tendon overuse injuries lead to significant pain and disability in athletes and workers. Despite the prevalence and high social cost of these injuries, the early pathological events are not well known. We analyzed the potential relation between glycosaminoglycan (GAG) composition and phenotypic cellular alteration using a rat model of rotator cuff overuse. Total sulfated GAGs increased after 4 weeks of overuse and remained elevated up to 16 weeks. GAG accumulation was preceded by up-regulation of decorin, versican, and aggrecan proteoglycans (PGs) mRNAs and proteins and biglycan PG mRNA after 2 weeks. At 2 weeks, collagen 1 transcript decreased whereas mRNAs for collagen 2, collagen 3, collagen 6, and the transcription factor Sox9 were increased. Protein levels of heparin affine regulatory peptide (HARP)/pleiotrophin, a cytokine known to regulate developmental chondrocyte formation, were enhanced especially at 4 weeks, without up-regulation of HARP/pleiotrophin mRNA. Further results suggest that the increased GAGs present in early lesions may sequester HARP/pleiotrophin, which could contribute to a loss of tenocyte's phenotype. All these modifications are characteristic of a shift towards the chondrocyte phenotype. Identification of these early changes in the extra-cellular matrix may help to prevent the progression of the pathology to more disabling, degenerative alterations.

Health research systems can link knowledge generation with practical concerns to improve health and health equity. Interest in health research, and in how health research systems should best be organised, is moving up the agenda of bodies such as the World Health Organisation. Pioneering health research systems, for example those in Canada and the UK, show that progress is possible. However, radical steps are required to achieve this. Such steps should be based on evidence not anecdotes. Health Research Policy and Systems (HARPS) provides a vehicle for the publication of research, and informed opinion, on a range of topics related to the organisation of health research systems and the enormous benefits that can be achieved. Following the Mexico ministerial summit on health research, WHO has been identifying ways in which it could itself improve the use of research evidence. The results from this activity are soon to be published as a series of articles in HARPS. This editorial provides an account of some of these recent key developments in health research systems but places them in the context of a distinguished tradition of debate about the role of science in society. It also identifies some of the main issues on which 'research on health research' has already been conducted and published, in some cases in HARPS. Finding and retaining adequate financial and human resources to conduct health research is a major problem, especially in low and middle income countries where the need is often greatest. Research ethics and agenda-setting that responds to the demands of the public are issues of growing concern. Innovative and collaborative ways are being found to organise the conduct and utilisation of research so as to inform policy, and improve health and health equity. This is crucial, not least to achieve the health-related Millennium Development Goals. But much more progress is needed. The editorial ends by listing a wide range of topics related to the above priorities on which we hope to feature further articles in HARPS and thus contribute to an informed debate on how best to achieve such progress.

OBJECTIVE

To establish a screening instrument for identifying older hospitalised patients at risk for functional decline by comparing the predictive values of three screening instruments: identification of seniors at risk, care complexity prediction instrument and hospital admission risk profile.

BACKGROUND

After being hospitalised, 30-60% of older patients experience a decline in functioning, resulting in a decreased quality of life and autonomy.

METHODS

A prospective cohort study.

METHODS

Included were patients, aged 65 years and older, acutely admitted to a general internal ward of a university teaching hospital. Within 48 hours after hospital admission, baseline data were completed--demographic, cognitive, social and pre-admission functional status and the screening instruments. Three months after discharge, functional status was measured by telephone interview. The Katz index was used to measure functional status (six activities). Functional decline was defined as a decline of at least one point on the Katz index at three months after discharge compared to pre-admission state.

RESULTS

Included were 177 patients; mean age was 77.6 years and 51.7 % were male. Functional decline was found in 27.8% of all patients. Sensitivity, specificity and area under receiver operating curve for identification of seniors at risk (ISAR) were 93, 39% and 0.67, respectively. The corresponding results for the care complexity prediction instrument (COMPRI) were 70, 62% and 0.69 and for the hospital admission risk profile (HARP) 21, 89% and 0.56.

CONCLUSIONS

The discriminative values of both identification of seniors at risk and care complexity prediction instrument are fair. Hospital admission risk profile shows the poorest results. Identification of seniors at risk shows the best ability to predict those patients at risk for functional decline and seems to be the easiest instrument in clinical practice.

CONCLUSIONS

Identifying patients at risk for functional decline is a first step in prevention, followed by geriatric assessment and targeted interventions. Studying the validity of existing instruments is necessary before implementation in clinical practice.

OBJECTIVE

To extend the harmonic phase (HARP) tracking method in order to track the myocardial tissue that appears near the epicardial contour during systole and reappears near the endocardial contour during diastole, due to the longitudinal motion and conical shape of the heart.

METHODS

A mathematical model of myocardial deformation was used to quantify the accuracy of the extended HARP tracking and of the strain computation. For six healthy volunteers, the number of tracked points and the two-dimensional strain components were computed with the extended and with the original HARP tracking version.

RESULTS

High accuracy was obtained for the circumferential strain (maximum error is 0.5% relative to analytical strain). The extended version tracked 22 +/- 7%, 51 +/- 19%, and 67 +/- 20% more points than the original version on the basal, mid, and apical slices, respectively (P < or = 0.001 for each slice), and yielded a decreased circumferential shortening (relative decrease: 2 +/- 4%, 9 +/- 4%, and 12 +/- 5% for the three slices; P < 0.005 for mid and apex), at end systole. These differences in circumferential strain were related to the more complete coverage of the myocardial wall with tracked points.

CONCLUSIONS

The extended HARP tracking also provides strain values from myocardial regions that were not covered by the original HARP tracking.

OBJECTIVE

To develop a 3D MR tagging method that combines harmonic phase (HARP) and homogeneous strain analysis methods for quantification of regional myocardial wall motion in mice.

METHODS

3D tagged images were acquired from seven C57BL/6 mice. Intersecting tag points were reconstructed and 3D strains were quantified at apical, midventricular, and basal levels. Circumferential and radial strains quantified with 2D MR tagging were compared with those calculated from 3D tagged images.

RESULTS

Our data showed significant heterogeneity in radial, circumferential, and shear strains. Longitudinal strain was more homogeneous. The circumferential-longitudinal shear strain, a unitless measure of ventricular torsion, was positive throughout the left ventricle. There were strong correlations between 2D and 3D studies at the basal and midventricular levels.

CONCLUSIONS

This work demonstrates the feasibility of 3D characterization of cardiac function in mouse via the combination of HARP and homogeneous strain analysis.

OBJECTIVE

To examine effects of sedative music on cancer pain.

METHODS

A randomized controlled trial.

METHODS

Two large medical centers in Kaoshiung City, in southern Taiwan.

METHODS

126 hospitalized persons with cancer pain.

METHODS

Participants were randomly assigned to an experimental (n=62) or a control group (n=64), with computerized minimization, stratifying on gender, pain, and hospital unit. Music choices included folk songs, Buddhist hymns (Taiwanese music), plus harp, and piano (American). The experimental group listened to music for 30 min; the control group rested in bed. Sensation and distress of pain were rated on 100mm VAS before and after the 30-min test.

RESULTS

Using MANCOVA, there was significantly less posttest pain in the music versus the control group, p<.001. Effect sizes were large, Cohen's d=.64, sensation, d=.70, distress, indicating that music was very helpful for pain. Thirty minutes of music provided 50% relief in 42% of the music group compared to 8% of the controls. The number needed to treat (NNT) to find one with 50% sensation relief was three patients. More patients chose Taiwanese music (71%) than American music (29%), but both were liked and effective.

CONCLUSIONS

Offering a choice of familiar, culturally appropriate music was a key element of the intervention. Findings extend the Good and Moore theory (1996) to cancer pain. Soft music was safe, effective, and liked by participants. It provided greater relief of cancer pain than analgesics alone. Thus nurses should offer calming, familiar music to supplement analgesic medication for persons with cancer pain.

BACKGROUND

Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction, but its effects on kidney function and cardiac biomarkers in people with moderate to severe chronic kidney disease are unknown.

METHODS

The UK HARP-III trial (United Kingdom Heart and Renal Protection-III), a randomized double-blind trial, included 414 participants with an estimated glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. The primary outcome was measured GFR at 12 months using ANCOVA with adjustment for each individual's baseline measured GFR. All analyses were by intention to treat.

RESULTS

In total, 207 participants were assigned to sacubitril/valsartan and 207 to irbesartan. Baseline measured GFR was 34.0 (SE, 0.8) and 34.7 (SE, 0.8) mL/min/1.73 m2, respectively. At 12 months, there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 m2 among those assigned irbesartan; difference, -0.1 (0.7) mL/min/1.73 m2. Effects were similar in all prespecified subgroups. There was also no significant difference in estimated GFR at 3, 6, 9, or 12 months and no clear difference in urinary albumin:creatinine ratio between treatment arms (study average difference, -9%; 95% CI, -18 to 1). However, compared with irbesartan, allocation to sacubitril/valsartan reduced study average systolic and diastolic blood pressure by 5.4 (95% CI, 3.4-7.4) and 2.1 (95% CI, 1.0-3.3) mm Hg and levels of troponin I and N terminal of prohormone brain natriuretic peptide (tertiary end points) by 16% (95% CI, 8-23) and 18% (95% CI, 11-25), respectively. The incidence of serious adverse events (29.5% versus 28.5%; rate ratio, 1.07; 95% CI, 0.75-1.53), nonserious adverse reactions (36.7% versus 28.0%; rate ratio, 1.35; 95% CI, 0.96-1.90), and potassium ≥5.5 mmol/L (32% versus 24%, P=0.10) was not significantly different between randomized groups.

CONCLUSIONS

Over 12 months, sacubitril/valsartan has similar effects on kidney function and albuminuria to irbesartan, but it has the additional effect of lowering blood pressure and cardiac biomarkers in people with chronic kidney disease.

BACKGROUND

URL: http://www.isrctn.com . Unique identifier: ISRCTN11958993.

It has long been hypothesized that the visual systems of animals are evolutionarily adapted to their visual environment. The entrance many millions of years ago of mammals into the sea gave these new aquatic mammals completely novel visual surroundings with respect to light availability and predominant wavelengths. This study examines the cone opsins of marine mammals, hypothesizing, based on previous studies [Fasick et al. (1998) and Levenson & Dizon (2003)], that the deep-dwelling marine mammals would not have color vision because the pressure to maintain color vision in the dark monochromatic ocean environment has been relaxed. Short-wavelength-sensitive (SWS) and long-wavelength-sensitive (LWS) cone opsin genes from two orders (Cetacea and Sirenia) and an additional suborder (Pinnipedia) of aquatic mammals were amplified from genomic DNA (for SWS) and cDNA (for LWS) by PCR, cloned, and sequenced. All animals studied from the order Cetacea have SWS pseudogenes, whereas a representative from the order Sirenia has an intact SWS gene, for which the corresponding mRNA was found in the retina. One of the pinnipeds studied (harp seal) has an SWS pseudogene, while another species (harbor seal) appeared to have an intact SWS gene. However, no SWS cone opsin mRNA was found in the harbor seal retina, suggesting a promoter or splice site mutation preventing transcription of the gene. The LWS opsins from the different species were expressed in mammalian cells and reconstituted with the 11-cis-retinal chromophore in order to determine maximal absorption wavelengths (lambda(max)) for each. The deeper dwelling Cetacean species had blue shifted lambda(max) values compared to shallower-dwelling aquatic species. Taken together, these findings support the hypothesis that in the monochromatic oceanic habitat, the pressure to maintain color vision has been relaxed and mutations are retained in the SWS genes, resulting in pseudogenes. Additionally, LWS opsins are retained in the retina and, in deeper-dwelling animals, are blue shifted in lambda(max).

OBJECTIVE

To evaluate the relationship between delayed enhancement (DE) and regional left ventricular function in hypertrophic cardiomyopathy (HCM) using gadolinium enhancement MRI and myocardial tagging MRI.

METHODS

Cine imaging, delayed enhancement imaging, and tagging MRI were performed in 25 patients with HCM. The location, pattern, and extent of DE were evaluated. Circumferential shortening (Ecc) was obtained by analyzing MR tagging images with HARP software.

RESULTS

DE occurred in 21 (84%) patients with a high frequency of localization in the septum and the right ventricular attachment sites. Circumferential shortening was significantly decreased in the enhanced segments compared with nonenhanced segments (P < 0.0001). The myocardial wall was thicker in the enhanced segments than in the nonenhanced segments (P < 0.0001). However, circumferential shortening was significantly decreased in the enhanced segments of the same thickness (P < 0.0001). Circumferential shortening was more substantially impaired in the segments with focal nodular enhancement than those in the segments with ill-defined patchy enhancement (P = 0.0002).

CONCLUSIONS

In HCM, DE is commonly found and circumferential shortening is significantly impaired in the regions with DE, regardless of the degree of myocardial hypertrophy. Focal nodular enhancement is particularly related with regional dysfunction in patients with HCM.

Associative memory for auditory-cued events involves specific plasticity in the primary auditory cortex (A1) that facilitates responses to tones which gain behavioral significance, by modifying representational parameters of sensory coding. Learning strategy, rather than the amount or content of learning, can determine this learning-induced cortical (high order) associative representational plasticity (HARP). Thus, tone-contingent learning with signaled errors can be accomplished either by (1) responding only during tone duration ("tone-duration" strategy, T-Dur), or (2) responding from tone onset until receiving an error signal for responses made immediately after tone offset ("tone-onset-to-error", TOTE). While rats using both strategies achieve the same high level of performance, only those using the TOTE strategy develop HARP, viz., frequency-specific decreased threshold (increased sensitivity) and decreased bandwidth (increased selectivity) (Berlau & Weinberger, 2008). The present study challenged the generality of learning strategy by determining if high motivation dominates in the formation of HARP. Two groups of adult male rats were trained to bar-press during a 5.0kHz (10s, 70dB) tone for a water reward under either high (HiMot) or moderate (ModMot) levels of motivation. The HiMot group achieved a higher level of correct performance. However, terminal mapping of A1 showed that only the ModMot group developed HARP, i.e., increased sensitivity and selectivity in the signal-frequency band. Behavioral analysis revealed that the ModMot group used the TOTE strategy while HiMot subjects used the T-Dur strategy. Thus, type of learning strategy, not level of learning or motivation, is dominant for the formation of cortical plasticity.

A model-based method for calculating three-dimensional (3D) cardiac wall strain distributions in the mouse has been developed and tested in a genetically engineered mouse model of dilated cardiomyopathy. Data from MR tagging and harmonic phase (HARP) tracking were used to measure material point displacements, and 3D Lagrangian strains were calculated throughout the entire left ventricle (LV) with a deformable parametric model. A mouse model where cardiomyocytes are specifically made deficient in vinculin (VclKO) were compared to wild-type (WT) littermates. 3D strain analysis revealed differences in LV wall mechanics between WT and VclKO mice at 8 weeks of age when systolic function had just begun to decline. Most notably, end-systolic radial strain and torsional shear were reduced in VclKO hearts which contributed to regional mechanical dysfunction. This study demonstrates the feasibility of using MRI tagging methods to detect alterations in 3D myocardial strain distributions in genetically engineered mouse models of cardiovascular disease.

Mutations in HepA-related protein (HARP, or SMARCAL1) cause Schimke immunoosseous dysplasia (SIOD). HARP has ATP-dependent annealing helicase activity, which helps to stabilize stalled replication forks and facilitate DNA repair during replication. Here, we show that the conserved tandem HARP (2HP) domain dictates this annealing helicase activity. Furthermore, chimeric proteins generated by fusing the 2HP domain of HARP with the SNF2 domain of BRG1 or HELLS show annealing helicase activity in vitro and, when targeted to replication forks, mimic the functions of HARP in vivo. We propose that the HARP domain endows HARP with this ATP-driven annealing helicase activity.

Although many physiological adaptations of diving mammals have been reported, little is known about how their brains sustain the high demands for metabolic energy and thus O(2) when submerged. A recent study revealed in the deep-diving hooded seal (Cystophora cristata) a unique shift of the oxidative energy metabolism and neuroglobin, a respiratory protein that is involved in neuronal hypoxia tolerance, from neurons to astrocytes. Here we have investigated neuroglobin in another pinniped species, the harp seal (Pagophilus groenlandicus), and in two cetaceans, the harbor porpoise (Phocoena phocoena) and the minke whale (Balaenoptera acutorostrata). Neuroglobin sequences, expression levels and patterns were compared with those of terrestrial relatives, the ferret (Mustela putorius furo) and the cattle (Bos taurus), respectively. Neuroglobin sequences of whales and seals only differ in two or three amino acids from those of cattle and ferret, and are unlikely to confer functional differences, e.g. in O(2) affinity. Neuroglobin is expressed in the astrocytes also of P. groenlandicus, suggesting that the shift of neuroglobin and oxidative metabolism is a common adaptation in the brains of deep-diving phocid seals. In the cetacean brain neuroglobin resides in neurons, like in terrestrial mammals. However, neuroglobin mRNA expression levels were 4-15 times higher in the brains of harbor porpoises and minke whales than in terrestrial mammals or in seals. Thus neuroglobin appears to play a specific role in diving mammals, but seals and whales have evolved divergent strategies to cope with cerebral hypoxia. The specific function of neuroglobin that conveys hypoxia tolerance may either relate to oxygen supply or protection from reactive oxygen species. The different strategies in seals and whales resulted from a divergent evolution and an independent adaptation to diving.

OBJECTIVE

The purpose of this study was to examine the use of benzodiazepines (BZs) and selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors (SSRIs/SNRIs) over nine years of follow-up in middle-aged and older adults with diagnoses of panic disorder with or without agoraphobia, social phobia, or generalized anxiety disorder.

METHODS

Participants in this study were enrolled in the Harvard/Brown Anxiety Research Project (HARP). HARP is a naturalistic, longitudinal, multisite study of adults with anxiety disorders who are recruited from psychiatric settings. The analytic sample consisted of 51 participants with anxiety disorders who were 55 to 70 years old at baseline and a younger cohort of 211 participants added for comparative analysis.

METHODS

The authors examined patterns of medication use (BZs and SSRIs/SNRIs) in participants with anxiety disorders as they aged, by assessing the proportion of participants taking these medications using generalized estimating equation modeling.

METHODS

The present data were derived from the structured diagnostic interview administered at enrollment using a combination of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Third Edition-R Non-Affective Disorder, Patient Version, Research Diagnostic Criteria Schedule for Affective Disorders-Lifetime, and subsequent follow-up interviews over a nine-year period using the Longitudinal Interval Follow-up Evaluation-Pharmacia & Upjohn to assess the weekly course of disorders to indicate syndrome severity and document medication use by specific type and dose on a weekly basis.

RESULTS

Findings showed that rates of BZ use were high among both the older (53% at baseline) and the younger (57.4%) age groups and did not significantly decrease over time, after controlling for time in episode of their anxiety disorders. There was a statistically significant increase in SSRI/SNRI use over time in both groups. At the beginning of the study, 18% of the older group and 21% of the younger group were using SSRIs/SNRIs; however, at the end of the study, the rates increased to 35% and 43%, respectively.

CONCLUSIONS

Although there was an increase in SSRI/SNRI use in older participants with anxiety disorders over the course of study, at nine years of follow-up, only 35% of participants were utilizing SSRI/SNRI medication, while more than one-half of the same participants were continuing to use BZs. To the authors' knowledge, there are no randomized clinical trials that have addressed comparative efficacy and safety of BZs and SSRIs/SNRIs in this population. However, there is documented evidence of adverse effects of chronic BZ use and the risk of developing dependency in older populations.

OBJECTIVE

To determine whether imaging at 3 T could improve and prolong the tag contrast compared to images acquired at 1.5 T in normal volunteers, and whether such improvement would translate into the ability to perform strain measurements in diastole.

METHODS

Normal volunteers (N = 13) were scanned at 1.5 T (GE Signa CV/i) and 3.0 T (GE VH/i). An ECG-triggered, segmented k-space, spoiled-gradient-echo grid-tagged sequence was used during cine acquisition. Tag contrast was determined by the difference of the mean signal intensity (SI) of the tagline to the mean SI of the myocardium divided by the standard deviation (SD) of the noise (CNR(tag)). Matched short-axis (SA) slices were analyzed. Strain measurements were performed on images using a 2D strain analysis software program (harmonic phase (HARP)).

RESULTS

The average CNR(tag) over the cardiac cycle was superior at 3 T compared to 1.5 T for all slices (3 T: 23.4 +/- 12.1, 1.5 T: 9.8 +/- 8.4; P < 0.0001). This difference remained significant at cycle initiation, end-systole, and the end R-R interval (at cycle termination: 3 T = 14.0 +/- 11.0 vs. 1.5 T = 4.4 +/- 3.5; P < 0.01). Strain measures were obtainable only in early systole for 1.5 T images, but were robust throughout the entire R-R interval for 3 T images.

CONCLUSIONS

Imaging at 3 T had a significant benefit for myocardial tag persistence through the cardiac cycle. The improvement allowed strain analysis to be performed into diastole.

In the last ten to fifteen years there has been much research in using amorphous and polycrystalline semiconductors as x-ray photoconductors in various x-ray image sensor applications, most notably in flat panel x-ray imagers (FPXIs). We first outline the essential requirements for an ideal large area photoconductor for use in a FPXI, and discuss how some of the current amorphous and polycrystalline semiconductors fulfill these requirements. At present, only stabilized amorphous selenium (doped and alloyed a-Se) has been commercialized, and FPXIs based on a-Se are particularly suitable for mammography, operating at the ideal limit of high detective quantum efficiency (DQE). Further, these FPXIs can also be used in real-time, and have already been used in such applications as tomosynthesis. We discuss some of the important attributes of amorphous and polycrystalline x-ray photoconductors such as their large area deposition ability, charge collection efficiency, x-ray sensitivity, DQE, modulation transfer function (MTF) and the importance of the dark current. We show the importance of charge trapping in limiting not only the sensitivity but also the resolution of these detectors. Limitations on the maximum acceptable dark current and the corresponding charge collection efficiency jointly impose a practical constraint that many photoconductors fail to satisfy. We discuss the case of a-Se in which the dark current was brought down by three orders of magnitude by the use of special blocking layers to satisfy the dark current constraint. There are also a number of polycrystalline photoconductors, HgI(2) and PbO being good examples, that show potential for commercialization in the same way that multilayer stabilized a-Se x-ray photoconductors were developed for commercial applications. We highlight the unique nature of avalanche multiplication in a-Se and how it has led to the development of the commercial HARP video-tube. An all solid state version of the HARP has been recently demonstrated with excellent avalanche gains; the latter is expected to lead to a number of novel imaging device applications that would be quantum noise limited. While passive pixel sensors use one TFT (thin film transistor) as a switch at the pixel, active pixel sensors (APSs) have two or more transistors and provide gain at the pixel level. The advantages of APS based x-ray imagers are also discussed with examples.

Temporal stability has served as a conceptual basis for the distinction between the clinical syndromes of Axis I disorders and the Axis II personality disorders, the latter being viewed as lifelong enduring patterns. However, comparisons of the stability of Axis I and II disorders have been limited. The present review examines findings from three naturalistic longitudinal studies that utilize similar methodology: the Collaborative Longitudinal Personality Disorders Study (CLPS; Gunderson et al., 2000), the Collaborative Depression Study (CDS; Katz & Klerman, 1979), and the Harvard/Brown Anxiety Research Program (HARP; Keller et al., 1994). Using a definition of remission/recovery as having no or minimal symptoms for 8 consecutive weeks, the courses of personality, depressive, and anxiety disorders were compared. Though remission/recovery rate at the 2-year follow-up was highest for mood disorders, the probability of recurrence was also particularly high. Personality disorders, with remission rates higher than the anxiety disorders, appear to be less stable than conceptualized. The anxiety disorders had remarkably low recovery rates even beyond 5 years of prospective follow-up. Factors that may explain these findings, as well as implications for future conceptualization of DSM, are discussed.

Fibroblast growth factor 2 (FGF2) is a pleiotropic growth factor that has been implicated in prostate cancer formation and progression. In the present study we found that exogenous FGF2 significantly increased human prostate cancer LNCaP cell proliferation and migration. Heparin affin regulatory peptide (HARP) or pleiotrophin seems to be an important mediator of FGF2 stimulatory effects, since the latter had no effect on stably transfected LNCaP cells that did not express HARP. Moreover, FGF2, through FGF receptors (FGFRs), significantly induced HARP expression and secretion by LNCaP cells and increased luciferase activity of a reporter gene vector carrying the full-length promoter of HARP gene. Using a combination of Western blot analyses, as well as genetic and pharmacological inhibitors, we found that activation of FGFR by FGF2 in LNCaP cells leads to NAD(P)H oxidase-dependent hydrogen peroxide production, phosphorylation of ERK1/2 and p38, activation of AP-1, increased expression and secretion of HARP, and, finally, increased cell proliferation and migration. These results establish the role and the mode of activity of FGF2 in LNCaP cells and support an interventional role of HARP in FGF2 effects, providing new insights on the interplay among growth factor pathways within prostate cancer cells.

OBJECTIVE

To use magnetization tagged magnetic resonance imaging (MRI) (tag-MRI) to quantify cardiac induced liver strain and compare strain of cirrhotic and normal livers.

METHODS

Tag-MRI was performed at 1.5T on eight subjects with no history of liver disease and 10 patients with liver cirrhosis. A breath-hold peripheral pulse-gated (PPG) conventional tag-MRI cine sequence was performed with planes to include the left lobe of the liver and the inferior wall of the heart. Commercially available software HARP (Diagnosoft, Palo Alto, CA) was used for image analysis and strain calculation. Three regions-of-interest (ROIs) were selected: segment II of the liver near the heart (A), right liver lobe far from the heart (B), and the left ventricular wall (C). The average and maximal (max) strain were measured in A, B, and C. The maximum strains were used to generate a cardiac-corrected strain gradient: (maxA-maxB)/maxC. Results were compared with Student's t-test (SPSS, Chicago, IL).

RESULTS

In subjects with no history of liver disease vs. cirrhotic patients, the average strain was 22% ± 7% vs. 4% ± 3% (P < 0.001), the max strain was 63% ± 15% vs. 17% ± 5% (P < 0.001), and the corrected strain gradient was 0.52 ± 0.16 vs. 0.11% ± 0.08%.

CONCLUSIONS

There is a significant difference in liver strain measured with tag-MRI between subjects with no history of liver disease and patients with cirrhosis.

BACKGROUND

The European Alzheimer's Disease Consortium and Alzheimer's Disease Neuroimaging Initiative (ADNI) Harmonized Protocol (HarP) is a Delphi definition of manual hippocampal segmentation from magnetic resonance imaging (MRI) that can be used as the standard of truth to train new tracers, and to validate automated segmentation algorithms. Training requires large and representative data sets of segmented hippocampi. This work aims to produce a set of HarP labels for the proper training and certification of tracers and algorithms.

METHODS

Sixty-eight 1.5 T and 67 3 T volumetric structural ADNI scans from different subjects, balanced by age, medial temporal atrophy, and scanner manufacturer, were segmented by five qualified HarP tracers whose absolute interrater intraclass correlation coefficients were 0.953 and 0.975 (left and right). Labels were validated as HarP compliant through centralized quality check and correction.

RESULTS

Hippocampal volumes (mm(3)) were as follows: controls: left = 3060 (standard deviation [SD], 502), right = 3120 (SD, 897); mild cognitive impairment (MCI): left = 2596 (SD, 447), right = 2686 (SD, 473); and Alzheimer's disease (AD): left = 2301 (SD, 492), right = 2445 (SD, 525). Volumes significantly correlated with atrophy severity at Scheltens' scale (Spearman's ρ = <-0.468, P = <.0005). Cerebrospinal fluid spaces (mm(3)) were as follows: controls: left = 23 (32), right = 25 (25); MCI: left = 15 (13), right = 22 (16); and AD: left = 11 (13), right = 20 (25). Five subjects (3.7%) presented with unusual anatomy.

CONCLUSIONS

This work provides reference hippocampal labels for the training and certification of automated segmentation algorithms. The publicly released labels will allow the widespread implementation of the standard segmentation protocol.

Magnetic resonance tagging makes it possible to measure the motion of tissues such as muscles in the heart and tongue. The harmonic phase (HARP) method largely automates the process of tracking points within tagged MR images, permitting many motion properties to be computed. However, HARP tracking can yield erroneous motion estimates due to 1) large deformations between image frames, 2) through-plane motion, and 3) tissue boundaries. Methods that incorporate the spatial continuity of motion--so-called refinement or flood-filling methods--have previously been reported to reduce tracking errors. This paper presents a new refinement method based on shortest path computations. The method uses a graph representation of the image and seeks an optimal tracking order from a specified seed to each point in the image by solving a single source shortest path problem. This minimizes the potential errors for those path dependent solutions that are found in other refinement methods. In addition to this, tracking in the presence of through-plane motion is improved by introducing synthetic tags at the reference time (when the tissue is not deformed). Experimental results on both tongue and cardiac images show that the proposed method can track the whole tissue more robustly and is also computationally efficient.

The authors describe a patient with hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP) who has two compound heterozygote mutations of the PANK2 gene. IVS4-1 G>T segregates with the lipid and erythrocyte changes in the mother and sister. No other family members have the lipid, erythrocyte, or clinical abnormalities. The father and two brothers are heterozygous for Met327Thr. One other mutation has been found in this PANK2 region associated with the HARP phenotype, suggesting a local genotype effect.

HARP (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) is a rare syndrome with many clinical similarities to pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome). Despite these common features, lipoprotein abnormalities have not been reported in PKAN. After the recent discovery of the genetic defect in PKAN, we report a homozygous nonsense mutation in exon 5 of the PANK2 gene that creates a stop codon at amino acid 371 (R371X) in the original HARP patient. This finding establishes that HARP is part of the PKAN disease spectrum.

OBJECTIVE

To establish the reproducibility of complementary spatial modulation of magnetization (CSPAMM) tagged cardiovascular MR (CMR) data in normal volunteers.

METHODS

Twelve healthy volunteers underwent CMR studies on two separate occasions using an identical CSPAMM pulse sequence with images acquired in three short axis slices. Data were analyzed by two independent observers using harmonic phase analysis (HARP). Lagrangian circumferential and radial strain, rotation, and left ventricular twist were calculated.

RESULTS

The intraobserver reproducibility of circumferential strain (CoV [coefficient of variation] 1.5-4.3%) and LV twist (CoV 1.2-4.4%) was better than radial strain (CoV 10.6-14.8%). For interobserver reproducibility, circumferential strain (CoV 3.5-6.2%) and LV twist (CoV 3.5-7.2%) were more reproducible than radial strain (CoV 11.8-21.8%). Interstudy reproducibility of circumferential strain (CoV 3.7-5.5%) and LV twist (CoV 9.8-12.2%) were good but radial strain (CoV 13.8-23.4%) but showed poorer interstudy reproducibility. Sample size calculations suggested 20 or fewer subjects are needed to detect a 10% change in circumferential strain (power 90%; α error 0.05), whereas for twist, 66 subjects would be required.

CONCLUSIONS

In normal volunteers, the intraobserver, interobserver, and interstudy reproducibility of circumferential strain and LV twist measured from CSPAMM tagged CMR data are good, but are less so for radial strain.