A broad definition of sensory gating refers to the ability of the brain to modulate its sensitivity to incoming sensory stimuli. This definition allows the concept of gating to include both the capacities to minimize or stop responding to incoming irrelevant stimuli (gating out) and to respond when a novel stimulus is presented or a change occurs in ongoing stimuli (gating in). In order to further characterize the function of sensory gating, we examined the attenuation (decreased responding) and augmentation (increased responding) of the P50 EP amplitudes in 22 normal volunteers. Three EP paradigms, each including a number of conditions, designed to examine both EP habituation (inhibition) and dishabituation (excitation) were administered to each subject. In conditions designed to examine habituation (identical pairs of clicks or trains of repetitive identical clicks), the P50 behaved, as expected, with decrease of the amplitude with repetition. In conditions designed to examine dishabituation the amplitude of the P50, EP did not decrease as much (and frequently increased) with stimulus change. The results suggest that the P50 EP is sensitive to the effects of stimulus repetition and stimulus change and can be used to study the different aspects of sensory gating.

OBJECTIVE

Long-term outcomes after endoscopic resection (ER) provide important information for the treatment of esophageal carcinoma. This study aimed to investigate the rates of survival and metastasis after ER of esophageal carcinoma.

METHODS

From 1995 to 2010, 570 patients with esophageal carcinoma were treated by ER. Of these, the 402 patients with squamous cell carcinoma (280 epithelial (EP) or lamina propria (LPM) cancer, 70 muscularis mucosa (MM) cancer, and 52 submucosal (SM) cancer) were included in our analysis. Seventeen patients had cancer invading into the submucosa up to 0.2 mm (SM1) and 35 patients had cancer invading into the submucosa more than 0.2 mm (SM2).

RESULTS

The mean (range) follow-up time was 50 (4-187) months. The 5-year overall survival rates of patients with EP/LPM, MM, and SM cancer were 90.5, 71.1, and 70.8%, respectively (P=0.007). Multivariate analysis identified depth of invasion and age as independent predictors of survival, with hazard ratios of 3.6 for MM cancer and 3.2 for SM cancer compared with EP/LPM cancer, and 1.07 per year of age. The cumulative 5-year metastasis rates in patients with EP/LPM, MM, SM1, and SM2 cancer were 0.4, 8.7, 7.7, and 36.2%, respectively (P<0.001). Multivariate analysis identified depth of invasion as an independent risk factor for metastasis, with hazard ratios of 13.1 for MM, 40.2 for SM1, and 196.3 for SM2 cancer compared with EP/LPM cancer. The cumulative 5-year metastasis rates in patients with mucosal cancer with and without lymphovascular involvement were 46.7 and 0.7%, respectively (P<0.0001).

CONCLUSIONS

The long-term risk of metastasis after ER was mainly associated with the depth of invasion. This risk should be taken into account when considering the indications for ER.

BACKGROUND

Whole blood serotonin (5-HT) and C-terminally directed beta-endorphin protein immunoreactivity (C-ter-beta-EP-ir) are known to be elevated in autistic subjects and might be possible markers of genetic liability to autism. This study thus investigates the familial aggregation of 5-HT and of C-ter-beta-EP-ir levels in first degree relatives of autistic probands.

METHODS

In a sample of 62 autistic subjects and 122 of their first-degree relatives, compared to age and sex-matched controls, we measured 5-HT by radioenzymology and C-ter-beta-EP-ir by radioimmunoassay.

RESULTS

We confirm the previously reported familiality of hyperserotoninemia in autism as mothers (51%), fathers (45%) and siblings (87%) have elevated levels of 5-HT, and we reveal presence of elevated levels of C-ter-beta-EP-ir in mothers (53%) of autistic subjects.

CONCLUSIONS

Familial aggregation of quantitative variables, such as concentration of neurotransmitters, within unaffected relative could serve as an intermediate phenotype and might thus help the search of genetic susceptibility factors in autism.

Extreme prematurity and pregnancy conditions leading to intrauterine growth restriction (IUGR) affect thousands of newborns every year and increase their risk for poor higher order cognitive and social skills at school age. However, little is known about the brain structural basis of these disabilities. To compare the structural integrity of neural circuits between prematurely born controls and children born extreme preterm (EP) or with IUGR at school age, long-ranging and short-ranging connections were noninvasively mapped across cortical hemispheres by connection matrices derived from diffusion tensor tractography. Brain connectivity was modeled along fiber bundles connecting 83 brain regions by a weighted characterization of structural connectivity (SC). EP and IUGR subjects, when compared with controls, had decreased fractional anisotropy-weighted SC (FAw-SC) of cortico-basal ganglia-thalamo-cortical loop connections while cortico-cortical association connections showed both decreased and increased FAw-SC. FAw-SC strength of these connections was associated with poorer socio-cognitive performance in both EP and IUGR children.

We reported that cyclo-oxygenase (COX)-2 expression in human breast cancer stimulated cancer cell migration and invasiveness, production of vascular endothelial growth factor (VEGF)-C and lymphangiogenesis in situ, largely from endogenous PGE2-mediated stimulation of prostaglandin E (<em>EP</em>)1 and <em>EP</em>4 receptors, presenting them as candidate therapeutic targets against lymphatic metastasis. As human breast cancer xenografts in immuno-compromised mice have limitations for preclinical testing, we developed a syngeneic murine breast cancer model of spontaneous lymphatic metastasis mimicking human and applied it for mechanistic and therapeutic studies. We tested the roles of COX-2 and <em>EP</em> receptors in VEGF-C and -D production by a highly metastatic COX-2 expressing murine breast cancer cell line C3L5. These cells expressed all <em>EP</em> receptors and produced VEGF-C and -D, both inhibited with COX-2 inhibitors or <em>EP</em>4 (but not <em>EP</em>1, <em>EP</em>2 or <em>EP</em>3) antagonists. C3H/HeJ mice, when implanted SC in both inguinal regions with C3L5 cells suspended in growth factor-reduced Matrigel, exhibited rapid tumor growth, tumor-associated angiogenesis and lymphangiogenesis (respectively measured with CD31 and LYVE-1 immunostaining), metastasis to the inguinal and axillary lymph nodes and the lungs. Chronic oral administration of COX-1/COX-2 inhibitor indomethacin, COX-2 inhibitor celecoxib and an <em>EP</em>4 antagonist ONO-AE3-208, but not an <em>EP</em>1 antagonist ONO-8713 at nontoxic doses markedly reduced tumor growth, lymphangiogenesis, angiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in responding mice revealed reduced VEGF-C and -D proteins, AkT phosphorylation and increased apoptotic/proliferative cell ratios consistent with blockade of <em>EP</em>4 signaling. We suggest that <em>EP</em>4 antagonists deserve clinical testing for chemo-intervention of lymphatic metastasis in human breast cancer.

METHODS

changes in cell density of endplate (EP), nucleus pulposus (NP), and anulus fibrosus (AF) during ageing were systematically investigated in defined regions of interest in complete human motion segments.

OBJECTIVE

to elucidate cell density and total cell number in distinct anatomic regions of the intervertebral disc; to test effects of gender, level and age on cell density; and to correlate changes in cell density with histologic signs of disc degeneration.

BACKGROUND

the available information on the cell density within intervertebral discs and its age-related changes is sparse. This knowledge, however, is a crucial prerequisite for cell-based tissue engineering approaches of the intervertebral disc.

METHODS

in 49 complete cross-sections from lumbar motion segments (newborn to 86 years) from 22 specimens, cell density was determined by the Abercrombie method in EP, NP, and AF, and total cell number was counted per region of interest.

RESULTS

cell density in EP, NP, and AF decreased significantly from 0 to 16 years with the main changes occuring from 0 to 3 years for NP and AF. No significant variations were observed thereafter. We found a significant correlation of cell density and histologic degeneration score between 0 and 1, but not for scores >1. Gender and disc level did not influence cell density.

CONCLUSIONS

This study provides data concerning the total number of cells in the various regions of the intervertebral disc for different age groups. This knowledge will be beneficial for cell-based treatment approaches, which may evolve in the future.

Pathology findings of encapsulating peritoneal sclerosis (EPS) are reviewed to establish histologic criteria for a diagnosis of EPS. The typical macroscopic finding is a cocoon-like encapsulation of the entire intestine. This encapsulation is frequently accompanied by fibrin deposition, focal bleeding on the peritoneum, and various quantities of bloody ascites. A thin membrane on the visceral peritoneum contributes to the formation of the intestinal encapsulation. Histologically, the membrane is composed mainly of organized fibrin, probably derived from plasma exudation from the peritoneal microvasculature. Peritoneal fibroblasts appear swollen and exhibit an increased level of cellularity, accompanied by expression of various activation and proliferation markers. According to the "two-hit" theory of EPS pathogenesis, deterioration of the peritoneum as a result of the peritoneal dialysis (PD) procedure (the first "hit") and superimposition of inflammatory stimuli such as infectious peritonitis (the second "hit") are thought to play key roles in the pathogenesis of EPS. Based on histologic examination of peritoneal biopsy specimens, the detection of fibrin deposition and fibroblast phenotypic alteration were proposed as important findings for early diagnosis of EPS. Persistent inflammatory changes are also predictive of the future onset of EPS. Careful histologic evaluation of peritoneal biopsy specimens, combined with Laparoscopic observations after withdrawal of PD, is required for the early diagnosis and treatment of EPS.

We present a critical review of the relationships among three microbial products: extracellular polymeric substances (EPS), soluble microbial products (SMP), and inert biomass. Up to now, two different "schools" of researchers have treated these products separately. The "EPS school" has considered active biomass and EPS, while the "SMP school" has considered active biomass, SMP, and inert biomass. Here, we provide a critical review of each of the microbial products. Then, we develop a unified theory that couples them and reconciles apparent contradictions. In our unified theory, cells use electrons from the electron-donor substrate to build active biomass, and they also produce bound EPS and utilization-associated products (UAP) at the same time and in proportion to substrate utilization. Bound EPS are hydrolyzed to biomass-associated products (BAP), while active biomass undergoes endogenous decay to form residual dead cells. Finally, UAP and BAP, being biodegradable, are utilized by active biomass as recycled electron-donors substrates. Our unified theory shows that the apparently distinct products from the SMP and EPS schools overlap each other. Soluble EPS is actually SMP, or the sum of UAP and BAP. Furthermore, active biomass, as defined by the SMP school, includes bound EPS, while inert biomass includes bound EPS and the residual dead cells.

The capacity of rabbit mononuclear cells to release an endogenous pyrogen (EP) in vitro has been studied. After incubation with tuberculin, preparations of predominantly monocytic cells, derived from the respiratory passages of the lungs of rabbits sensitized with BCG, were activated to release EP. Pyrogen production occurred more slowly with lung monocytes than with blood leukocytes of similarly sensitized rabbits and 9 to 10 hr incubation in a fully supportive medium was required to produce clear-cut results. As previously reported with blood leukocytes, mononuclear cells from the lungs of normal animals were also activated by tuberculin but to a lesser degree than were those from specifically sensitized rabbits. Under a variety of conditions, mononuclear cells from either spleen or lymph nodes of the same sensitized rabbits failed to release detectable amounts of pyrogen when incubated with tuberculin in vitro but were activated in a majority of instances when phagocytosis of heat-killed staphylococci was used as the stimulus. Release of pyrogen from lung monocytes appears to be an active process that is both temperature-dependent and requires protein synthesis. Neither serum antibody nor complement appears to play a role in this process. Evidence is presented that the granulocyte is the main source of pyrogen evolved by blood leukocytes incubated in vitro with OT or heat-killed staphylococci, whereas the lung macrophage and/or monocyte is responsible for most of the pyrogen released from the lung cell preparations. From these studies, it is concluded that mononuclear cells can be activated in vitro by several microbial stimuli and must be considered an additional cellular source of EP. The clinical implications of these findings for the pathogenesis of fever in granulomatous diseases where the monocyte is the predominant cell are discussed.

OBJECTIVE

The incidence of neuroleptic malignant syndrome (NMS) is not known, but the frequency of its occurrence with conventional antipsychotic agents has been reported to vary from 0.02% to 2.44%.

METHODS

MEDLINE search conducted in January 2003 and review of references within the retrieved articles.

RESULTS

Our MEDLINE research yielded 68 cases (21 females and 47 males) of NMS associated with atypical antipsychotic drugs (clozapine, N = 21; risperidone, N = 23; olanzapine, N = 19; and quetiapine, N = 5). The fact that 21 cases of NMS with clozapine were found indicates that low occurrence of extrapyramidal symptoms (EPS) and low EPS-inducing potential do not prevent the occurrence of NMS and D(2) dopamine receptor blocking potential does not have direct correlation with the occurrence of NMS. One of the cardinal features of NMS is an increasing manifestation of EPS, and the conventional antipsychotic drugs are known to produce EPS in 95% or more of NMS cases. With atypical antipsychotic drugs, the incidence of EPS during NMS is of a similar magnitude.

CONCLUSIONS

For NMS associated with atypical antipsychotic drugs, the mortality rate was lower than that with conventional antipsychotic drugs. However, the mortality rate may simply be a reflection of physicians' awareness and ensuing early treatment.

Spermatogonial stem cells (SSCs) are at the foundation of the highly productive spermatogenic process that continuously produces male gametes throughout postnatal life. However, experimental evaluation of SSCs in postnatal testes is complicated because these cells are extremely rare and few defining morphology or biochemical characteristics are known. In this study, we used the spermatogonial transplantation functional assay, combined with fluorescence-activated cell sorting (FACS) analysis to identify cellular, biochemical and surface antigenic characteristics of SSCs in rat testes during development. Our results demonstrated that forward scatter (FSc)(hi), side scatter (SSc)(hi), mitochondria membrane potential (DeltaPsim)(lo), Ep-CAM(+), Thy-1(+), beta3-integrin(+) stem cells in neonate rat testes become SSc(lo), DeltaPsim(hi), Ep-CAM(+), Thy-1(lo), beta3-integrin(-) stem cells in pup rat testes. Furthermore, prospective identification of rat testis cell populations (Ep-CAM(+)), highly enriched for SSCs (1 in 13 for neonate; 1 in 8.5 for pup) enabled us to predict the Thy-1 and beta3-integrin status of stem cells in neonate and pup testes, which was subsequently confirmed by transplantation analyses. Systematic characterization of SSCs enabled the production of testis cell populations highly enriched (up to 120-fold) for SSCs and will facilitate future investigations of functional and genomic characteristics.

The importance of the prostaglandin (PG) synthesis pathway, particularly the rate-limiting enzymatic step catalyzed by cyclooxygenase, to colorectal carcinogenesis and development of novel anticolorectal cancer therapy is well established. The predominant PG species in benign and malignant colorectal tumors is PGE2. PGE2 acts via four EP receptors termed EPEPEP receptors have been identified as potential targets for treatment and/or prevention of colorectal cancer. This review summarizes existing knowledge of the expression and function of the EP receptor subtypes in human and rodent intestine during tumorigenic progression and describes the current literature on targeting EP receptor signaling during intestinal tumorigenesis.

Prostanoids consisting of the prostaglandins (PGs) and the thromboxanes (TXs) are the cyclooxygenase metabolites of arachidonic acid. They exert a range of actions mediated by their respective receptors expressed in the target cells. The receptors include the DP, <em>EP</em>, FP, IP and TP receptors for PGD, PGE, PGF, PGI and TXA, respectively. Furthermore, <em>EP</em> is subdivided into four subtypes, <em>EP</em>1, <em>EP</em>2, <em>EP</em>3 and <em>EP</em>4, which are encoded by different genes and differ in their responses to various agonists and antagonists. Recent developments in the molecular biology of the prostanoid receptors have enabled the investigation of physiological roles of each receptor by disruption of the respective gene. At this point, all the eight types and subtypes of the prostanoid receptors have been individually knocked out in mice, and various phenotypes have been reported for each strain. Here, we review the findings obtained in these studies. The results from these knockout mice studies may be useful in the development of novel therapeutics that can selectively manipulate actions mediated by each receptor.

Cholera toxin secretion is dependent upon the extracellular protein secretion apparatus encoded by the eps gene locus of Vibrio cholerae. Although the eps gene locus encodes several type four prepilin-like proteins, the peptidase responsible for processing these proteins has not been identified. This report describes the identification of a prepilin peptidase from the V. cholerae genomic database by virtue of its homology with the PilD prepilin peptidase of Pseudomonas aeruginosa. Plasmid disruption or deletion of this peptidase gene in either EI Tor or classical V. cholerae O1 biotype strains results in a dramatic decrease in cholera toxin secretion. In the case of the EI Tor biotype mutants, surface expression of the type 4 pilus responsible for mannose-sensitive haemagglutination is abolished. The cloned V. cholerae peptidase processes either EpsI or MshA preproteins when co-expressed in E. coli. Mutation of the V. cholerae peptidase gene also results in a defect in virulence and decreased levels of OmpU. The V. cholerae peptidase gene sequence shows 80% homology with the Vibrio vulnificus VvpD type 4 prepilin peptidase required for pilus assembly and cytolysin secretion in V. vulnificus. Accordingly, the V. cholerae type 4 prepilin peptidase required for pilus assembly and cholera toxin secretion has been designated VcpD.

The pharmacokinetic analysis of dynamic-contrast-enhanced (DCE) MRI data yields K(trans) and k(ep), two parameters independently measuring the capillary wall contrast reagent transfer rate. The almost universally used standard model (SM) embeds the implicit assumption that equilibrium transcytolemmal water exchange is effectively infinitely fast. In analyses of routine DCE-MRI data from 22 patients with suspicious breast lesions initially ruled positive by institutional screening protocols, the SM K(trans) values for benign and malignant lesions exhibit considerable overlap. A form of the shutter-speed model (SSM), which allows for finite exchange kinetics, agrees with the SM K(trans) value for each of the 15 benign lesions. However, it reveals that the SM underestimates K(trans) for each of the seven malignant tumors in this population. The fact that this phenomenon is unique to malignant tumors allows their complete discrimination from the benign lesions, as validated by comparison with gold-standard pathology analyses of subsequent biopsy tissue samples. Likewise, the SM overestimates k(ep), particularly for the benign tumors. Thus, incorporation of the SSM into the screening protocols would have precluded all 68% of the biopsy/pathology procedures that yielded benign findings. The SM/SSM difference is well understood from molecular first principles.

Bacterial exopolysaccharide (EPS) is required for establishment of the nitrogen-fixing symbiosis between Rhizobium meliloti and its host plant, Medicago sativa (alfalfa), but the precise role of EPS in this interaction is not well defined. Bacterial mutants which fail to produce EPS induce nodules on the roots of the host plant, but fail to invade these root nodules. Research conducted in our lab and others suggests that EPS plays a specific role in the R. meliloti-M. sativa symbiosis. A common theme emerging from these studies is that small quantities of low-molecular-weight (LMW) EPS are sufficient to mediate successful invasion by R. meliloti mutants which fail to produce EPS, implying that LMW EPS may act as a signaling molecule during this process.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are antitumorigenic in humans as well as in animal models of intestinal neoplasia, such as the adenomatous polyposis coli (Min/+) (Apc(Min/+)) mouse. NSAIDs inhibit cyclooxygenase (COX) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which NSAIDs exert their antitumorigenic effects. However, mounting evidence suggests the existence of COX-independent mechanisms. In the present study, we attempted to clarify this issue by treating Apc(Min/+) mice bearing established tumors with NSAIDs (piroxicam and sulindac, 0.5 and 0.6 mg/mouse/day, respectively) for 6 days and concomitantly bypassing COX inhibition by treatment with the E prostaglandin (<em>EP</em>) receptor agonists 16,16-dimethyl-prostaglandin E(2) (PGE(2)) and 17-phenyl-trinor-PGE(2) (10 microg each, three times daily) administered via gavage and/or i.p. routes. Treatment with piroxicam and sulindac resulted in 95% and 52% fewer tumors, respectively, and a higher ratio of apoptosis:mitosis in tumors from sulindac-treated mice as compared with controls. These effects were attenuated by concomitant <em>EP</em> receptor agonist treatment, suggesting PGE(2) is important in the maintenance of tumor integrity. Immunological sequestration of PGE(2) with an anti-PGE(2) monoclonal antibody likewise resulted in 33% fewer tumors in Apc(Min/+) mice relative to untreated controls, additionally substantiating a role for PGE(2) in tumorigenesis. The <em>EP</em> receptor subtype <em>EP</em>1 mediates the effects of PGE(2) by increasing intracellular calcium levels ([Ca(2+)](i)), whereas antagonism of <em>EP</em>1 has been shown to attenuate tumorigenesis in Apc(Min/+) mice. We demonstrate that [Ca(2+)](i) is significantly elevated in tumors of Apc(Min/+) mice relative to the adjacent normal-appearing mucosa. Furthermore, treatment with piroxicam results in significantly lower [Ca(2+)](i) in tumors, and this effect is attenuated by concomitant treatment with the <em>EP</em>1/<em>EP</em>3 receptor agonist 17-phenyl-trinor-PGE(2). Overall, our results suggest that NSAIDs exert their antitumorigenic effects, in part, via interference with PGE(2) biosynthesis, and these effects may be mediated through changes in intracellular calcium levels.

Antipsychotic drugs were introduced in the early 50s on the basis of clinical observations in patients with schizophrenia. Experimental studies later revealed that antagonism at the D(2) dopamine receptor is a common characteristic of all antipsychotic drugs. In the 80s, the advent of brain imaging technologies such as positron emission tomography (PET) allowed for direct noninvasive studies of drug binding in treated patients. The concept receptor occupancy is defined as the fraction (%) of a receptor population that is occupied during treatment with an unlabelled drug. With regard to antipsychotic drugs, the radioligand [(11) C]-raclopride has been the most widely used for binding to the D(2) /D(3) -dopamine receptors. The present review discusses the contribution from molecular imaging to the current understanding of mechanism of action (MoA) of antipsychotic drugs. Consistent initial PET-findings of high D2-receptor occupancy in the striatum of patients responding to different antipsychotic drug treatments provided clinical support for the dopamine hypothesis of antipsychotic drug action. It has subsequently been demonstrated that patients with extrapyramidal syndromes (EPS) have higher occupancy (above 80%) than patients with good response but no EPS (65-80%). The PET-defined interval for optimal antipsychotic drug treatment has been implemented in the evolvement of dose recommendations for classical as well as more recently developed drugs. Another consistent finding is lower D(2) -occupancy during treatment with the prototype atypical antipsychotic clozapine. The MoA of clozapine remains to be fully understood and may include nondopaminergic mechanisms. A general limitation is that currently available PET-radioligands are not selective for any of the five dopamine receptor subtypes. Current attempts at developing such ligands may provide the tools required to refine further the MoA of antipsychotic drugs.

OBJECTIVE

To measure the degree of burnout among emergency physicians (EPs) and to identify and rank predictive factors.

METHODS

Using the Maslach Burnout Inventory as well as a 79-item questionnaire, a cross-sectional survey was conducted for physician registrants at the Annual Scientific Assemblies of the American College of Emergency Physicians from 1992 to 1995. Degrees of burnout were stratified into low, moderate, and high ranges. Univariate and stepwise multiple regression analyses were conducted to identify and rank correlates to burnout scores.

RESULTS

Of 1,272 registrants taking the inventory, 60% registered in the moderate to high burnout ranges. Twenty-one correlates were identified. These were classified broadly in terms of negative perceptions of self, negative practice habits and attitudes, and unhealthy lifestyles. The most highly ranked correlates were: self-recognition of burnout, lack of job involvement, negative self-assessment of productivity, dissatisfaction with career, sleep disturbances, increased number of shifts per month, dissatisfaction with specialty services, intent to leave the practice within 10 years, higher levels of alcohol consumption, and lower levels of exercise. Age and years of practice were not significant predictors of burnout. Projected attrition rates were 7.5% over 5 years and 25% over 10 years.

CONCLUSIONS

Elevated levels of burnout exist among a substantial percentage of surveyed EPs. However, there is evidence for a "survivor" category of practitioners for whom burnout either does not develop or is a reversible process. The projected attrition rate over 5 and 10 years appears to be no greater than that of the average medical specialty.

OBJECTIVE

The gold standard in assessing liver fibrosis is biopsy despite limitations like invasiveness and sampling error and complications including morbidity and mortality. Therefore, there is a major unmet medical need to quantify fibrosis non-invasively to facilitate early diagnosis of chronic liver disease and provide a means to monitor disease progression. The goal of this study was to evaluate the ability of several magnetic resonance imaging (MRI) techniques to stage liver fibrosis.

METHODS

A gadolinium (Gd)-based MRI probe targeted to type I collagen (termed EP-3533) was utilized to non-invasively stage liver fibrosis in a carbon tetrachloride (CCl4) mouse model and the results were compared to other MRI techniques including relaxation times, diffusion, and magnetization transfer measurements.

RESULTS

The most sensitive MR biomarker was the change in liver:muscle contrast to noise ratio (ΔCNR) after EP-3533 injection. We observed a strong positive linear correlation between ΔCNR and liver hydroxyproline (i.e. collagen) levels (r=0.89) as well as ΔCNR and conventional Ishak fibrosis scoring. In addition, the area under the receiver operating curve (AUR0C) for distinguishing early (Ishak ≤ 3) from late (Ishak ≥ 4) fibrosis was 0.942 ± 0.052 (p<0.001). By comparison, other MRI techniques were not as sensitive to changes in fibrosis in this model.

CONCLUSIONS

We have developed an MRI technique using a collagen-specific probe for diagnosing and staging liver fibrosis, and validated it in the CCl4 mouse model. This approach should provide a better means to monitor disease progression in patients.

OBJECTIVE

The aim of this study was to assess the outcome of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients treated with an implantable cardioverter-defibrillator (ICD).

BACKGROUND

Arrhythmogenic right ventricular dysplasia/cardiomyopathy is associated with tachyarrhythmia and an increased risk of sudden death.

METHODS

This study included 42 ARVD/C patients with ICDs (52% male, age 6 to 69 years, median 37 years) followed at our center.

RESULTS

Mean follow-up was 42 +/- 26 months (range 4 to 135 months). Complications associated with ICD implantation included need for lead repositioning (n = 3) and system infection (n = 2). During follow-up, one patient died of a brain malignancy and one had heart transplantation. Lead replacement was required in six patients as a result of lead fracture and insulation damage (n = 4) or change in thresholds (n = 2). During this period, 33 of 42 (78%) patients received a median of 4 (range 1 to 75) appropriate ICD interventions. The median period between ICD implantation and the first firing was 9 months (range 0.1 to 66 months). The ICD firing storms were observed in five patients. Inappropriate interventions were seen in 10 patients. Predictors of appropriate firing were induction of ventricular tachycardia (VT) during electrophysiologic study (EPS) (84% vs. 44%, p = 0.024), detection of spontaneous VT (70% vs. 15%, p = 0.001), male versus female gender (91% vs. 65%, p = 0.04), and severe right ventricular dilation (39% vs. 0%, p = 0.013). Using multivariate analysis, VT induction during EPS was associated with increased risk for firing in ARVD/C patients; odds ratio 11.2 (95% confidence interval 1.23 to 101.24, p = 0.031).

CONCLUSIONS

Patients with ARVD/C have a high arrhythmia rate requiring appropriate ICD interventions. The ICD therapy appears to be well tolerated and important in the management of patients with ARVD/C.

Erythroblasts isolated from the spleens of mice infected with the anemia-inducing strain of Friend virus (FVA cells)-are erythropoietin (EP)-sensitive cells at the late colony forming unit-erythroid (CFU-E) and cluster forming unit stages of differentiation (Koury et al., J. Cell. Physiol. 121:526-532, 1984). We investigate here the EP requirements of FVA cells in vitro for viability, proliferation, and maturation. By delaying the addition of EP to FVA cell cultures or by withdrawing EP at early times of culture, the subsequent viability, cell numbers, and maturation were diminished. The longer the delay in EP addition or the earlier the EP withdrawal, the more diminished these parameters were when compared to cultures which contained EP throughout the 48 h of differentiation. FVA cells had a period of EP requirement in vitro that lasted for only 24 h or less after the initiation of culture. During these crucial first 24 h, EP induced an increase in the synthesis of all size classes of RNA. Protein synthesis was maintained at a stable level in cells cultured with EP, but it declined in cells cultured without it. In contrast, the synthesis rate of DNA and the content of DNA per cell were not affected by the presence of EP in the culture. However, FVA cells cultured without EP had progressive accumulation of small sized DNA due to breakage of higher molecular weight DNA. The rate of DNA breakdown was sufficient to prevent DNA accumulation and thus it probably plays a role in the abortion of cell proliferation. No such breakage was found in cells cultured with EP. Our results indicate that EP exerts an effect on FVA cells in culture which is reflected in their viability, cell number, and maturation. This effect is not mediated by a stimulation of the rate of DNA synthesis, but is accompanied by stimulation of overall RNA synthesis and maintenance of protein synthesis.

OBJECTIVE

Research is required to monitor changes in the nature of neurobehavioral deficits in extremely preterm (EP) or extremely low birth weight (ELBW) survivors. This study examines cognitive, academic, and behavioral outcomes at age 8 years for a regional cohort of EP/ELBW children born in 1997.

METHODS

The EP/ELBW cohort comprised all live births with a gestational age <28 weeks (EP) or birth weight <1000 g (ELBW) born in the state of Victoria, Australia, in 1997. Of 317 live births, 201 (63.4%) survived to 2 years of age.A term/normal birth weight (T/NBW) cohort was recruited comprising 199 infants with birthweights ≥2500 g or gestational age ≥37 weeks [corrected]. Measures of intellectual ability, educational achievement, and behavior were administered at age 8.

RESULTS

Retention was 94% for the EP/ELBW group and 87% for the T/NBW group. The EP/ELBW group performed poorer than the T/NBW group on measures of IQ, educational achievement, and certain behavioral domains, even after adjustment for sociodemographic factors and exclusion of children with neurosensory impairment. The rate of any neurobehavioral impairment was elevated in the EP/ELBW group (71% vs 42%), and one-half of subjects had multiple impairments. The outcomes for those with <750 g birth weight or <26 weeks' gestational age were similar to those with a birth weight of 750 to 999 g or a gestational age of 26 to 27 weeks, respectively.

CONCLUSIONS

Despite ongoing improvements in the management of EP/ELBW infants, the rate of neurobehavioral impairment at school-age remains too high relative to controls.

BACKGROUND

The "Multidisciplinary Approach to the Study of Chronic Pelvic Pain" (MAPP) Research Network was established by the NIDDK to better understand the pathophysiology of urologic chronic pelvic pain syndromes (UCPPS), to inform future clinical trials and improve clinical care. The evolution, organization, and scientific scope of the MAPP Research Network, and the unique approach of the network's central study and common data elements are described.

METHODS

The primary scientific protocol for the Trans-MAPP Epidemiology/Phenotyping (EP) Study comprises a multi-site, longitudinal observational study, including bi-weekly internet-based symptom assessments, following a comprehensive in-clinic deep-phenotyping array of urological symptoms, non-urological symptoms and psychosocial factors to evaluate men and women with UCPPS. Healthy controls, matched on sex and age, as well as "positive" controls meeting the non-urologic associated syndromes (NUAS) criteria for one or more of the target conditions of Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS) or Irritable Bowel Syndrome (IBS), were also evaluated. Additional, complementary studies addressing diverse hypotheses are integrated into the Trans-MAPP EP Study to provide a systemic characterization of study participants, including biomarker discovery studies of infectious agents, quantitative sensory testing, and structural and resting state neuroimaging and functional neurobiology studies. A highly novel effort to develop and assess clinically relevant animal models of UCPPS was also undertaken to allow improved translation between clinical and mechanistic studies. Recruitment into the central study occurred at six Discovery Sites in the United States, resulting in a total of 1,039 enrolled participants, exceeding the original targets. The biospecimen collection rate at baseline visits reached nearly 100%, and 279 participants underwent common neuroimaging through a standardized protocol. An extended follow-up study for 161 of the UCPPS participants is ongoing.

CONCLUSIONS

The MAPP Research Network represents a novel, comprehensive approach to the study of UCPPS, as well as other concomitant NUAS. Findings are expected to provide significant advances in understanding UCPPS pathophysiology that will ultimately inform future clinical trials and lead to improvements in patient care. Furthermore, the structure and methodologies developed by the MAPP Network provide the foundation upon which future studies of other urologic or non-urologic disorders can be based.

BACKGROUND

ClinicalTrials.gov identifier: NCT01098279 "Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)". http://clinicaltrials.gov/show/NCT01098279.