An immunohistochemical study of the diagnostic value of TREM-1 as marker for fatal sepsis cases

Triggering receptor expressed on myeloid cells-1 (TREM-1) is produced and up-regulated by exposure of myeloid cells to lipopolysaccharides or other components of either bacterial or fungal origin, which causes it to be strongly expressed on phagocytes that accumulate in inflamed areas. Because TREM-1 participates in septic shock and in amplifying the inflammatory response to bacterial and fungal infections, we believe it could be an immunohistochemical marker for postmortem diagnosis of sepsis. We tested the anti-TREM-1 antibody in 28 cases of death by septic shock and divided them into two groups. The diagnosis was made according to the criteria of the Surviving Sepsis Campaign. In all cases, blood cultures were positive. The first group was comprised subjects that presented high ante-mortem serum procalcitonin and the soluble form of TREM-1 (s-TREM-1) values. The second group comprised subjects in which s-TREM-1 was not measured ante-mortem. We used samples of brain, heart, lung, liver and kidney for each case to test the anti-TREM-1 antibody. A semiquantitative evaluation of the immunohistochemical findings was made. In lung samples, we found immunostaining in the cells of the monocyte line in 24 of 28 cases, which suggests that TREM-1 is produced principally by cells of the monocyte line. In liver tissue, we found low TREM-staining in the hepatocyte cytoplasm, duct epithelium, the portal-biliary space and blood vessel. In kidney tissue samples, we found the TREM-1 antibody immunostaining in glomeruli and renal tubules. We also found TREM-1 staining in the lumen of blood vessels. Immunohistochemical staining using the anti-TREM-1 antibody can be useful for postmortem diagnosis of sepsis

Prevalence of sexual and physical abuse in patients with obstructed defecation: impact on biofeedback treatment

Background: obstructed defecation is one of the most com mon subtypes of constipation, and it is frequently responsive to biofeedback treatment. Aims: since a history of sexual and physical abuse may be pre sent in patients with obstructed defecation, we assessed the inci dence of abuse history in patients with obstructed defecation re ferred to a general gastroenterology practice, and whether such a history may lead to a different outcome of biofeedback training in these patients. Patients and methods: one hundred and twenty-one pa tients (17 men, 104 women, age 53 ± 15 years) with obstructed defecation were studied by retrospective chart review. Their histo ry of sexual, physical and psychological abuse was obtained by a standard interview, and biofeedback training was carried out by means of a three-balloon technique. Results: a history of sexual/physical or psychological abuse was present in 12.4% patients. Biofeedback training yielded a successful improvement of obstructed defecation in 93% patients without abuse and in 100% of patients with abuse; this difference was not statistically different (p = 0.53). Conclusions: the prevalence of sexual/physical or psycholog ical abuse in a population of patients with obstructed defecation referred to a general gastroenterology practice is relatively low; such a history seems not to affect the outcome of biofeedback training in these patients

Vocal cord paralysis in Charcot–Marie–Tooth type 4b1 disease associated with a novel mutation in the myotubularin-related protein 2 gene : a case report and review of the literature

Charcot\u2013Marie\u2013Tooth type 4B1 (CMT4B1) is an autosomal recessive motor and sensory demyelinating neuropathy characterized by the association of early-onset neurological symptoms and typical histological findings. The natural history and the clinical variability of the disease are still poorly known, thus further clarification of the different phenotypes is needed. We report on the case of a Pakistani girl born to consanguineous parents harboring a novel mutation in the MTMR2 gene. When aged 18 months, reduced limb tone, muscle wasting associated with proximal and distal weakness prevalent in lower limbs, absence of tendon reflexes, hoarseness and inspiratory stridor were detected. Vocal cord palsy was diagnosed shortly after. We suggest that laryngeal involvement might be a relevant and initial feature of early-onset CMT4B1 neuropathy. Thus, affected patients should undergo early laryngological evaluation in order to prompt an appropriate management

Genetic Interaction between MTMR2 and FIG4 Phospholipid Phosphatases Involved in Charcot-Marie-Tooth Neuropathies

We previously reported that autosomal recessive demyelinating Charcot-Marie-Tooth (CMT) type 4B1 neuropathy with myelin outfoldings is caused by loss of MTMR2 (Myotubularin-related 2) in humans, and we created a faithful mouse model of the disease. MTMR2 dephosphorylates both PtdIns3P and PtdIns(3,5)P2, thereby regulating membrane trafficking. However, the function of MTMR2 and the role of the MTMR2 phospholipid phosphatase activity in vivo in the nerve still remain to be assessed. Mutations in FIG4 are associated with CMT4J neuropathy characterized by both axonal and myelin damage in peripheral nerve. Loss of Fig4 function in the plt (pale tremor) mouse produces spongiform degeneration of the brain and peripheral neuropathy. Since FIG4 has a role in generation of PtdIns(3,5)P2 and MTMR2 catalyzes its dephosphorylation, these two phosphatases might be expected to have opposite effects in the control of PtdIns(3,5)P2 homeostasis and their mutations might have compensatory effects in vivo. To explore the role of the MTMR2 phospholipid phosphatase activity in vivo, we generated and characterized the Mtmr2/Fig4 double null mutant mice. Here we provide strong evidence that Mtmr2 and Fig4 functionally interact in both Schwann cells and neurons, and we reveal for the first time a role of Mtmr2 in neurons in vivo. Our results also suggest that imbalance of PtdIns(3,5)P2 is at the basis of altered longitudinal myelin growth and of myelin outfolding formation. Reduction of Fig4 by null heterozygosity and downregulation of PIKfyve both rescue Mtmr2-null myelin outfoldings in vivo and in vitro

Using self-definition to predict the influence of procedural justice on organizational, interpersonal, and job/task-oriented citizenship behaviors

An integrative self-definition model is proposed to improve our understanding of how procedural justice affects different outcome modalities in organizational behavior. Specifically, it is examined whether the strength of different levels of self-definition (collective, relational, and individual) each uniquely interact with procedural justice to predict organizational, interpersonal, and job/task-oriented citizenship behaviors, respectively. Results from experimental and (both single and multisource) field data consistently revealed stronger procedural justice effects (1) on organizational-oriented citizenship behavior among those who define themselves strongly in terms of organizational characteristics, (2) on interpersonal-oriented citizenship behavior among those who define themselves strongly in terms of their interpersonal relationships, and (3) on job/task-oriented citizenship behavior among those who define themselves weakly in terms of their distinctiveness or uniqueness. We discuss the relevance of these results with respect to how employees can be motivated most effectively in organizational settings

Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J

Membrane-bound phosphoinositides are signalling molecules that have a key role in vesicle trafficking in eukaryotic cells(1). Proteins that bind specific phosphoinositides mediate interactions between membrane-bounded compartments whose identity is partially encoded by cytoplasmic phospholipid tags. Little is known about the localization and regulation of mammalian phosphatidylinositol-3,5-bisphosphate ( PtdIns( 3,5)P-2), a phospholipid present in small quantities that regulates membrane trafficking in the endosome - lysosome axis in yeast(2). Here we describe a multi-organ disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy and diluted pigmentation in the 'pale tremor' mouse. Positional cloning identified insertion of ETn2 beta ( early transposon 2 beta)(3) into intron 18 of Fig4 (A530089I17Rik), the homologue of a yeast SAC ( suppressor of actin) domain PtdIns(3,5) P-2 5-phosphatase located in the vacuolar membrane. The abnormal concentration of PtdIns( 3,5) P2 in cultured fibroblasts from pale tremor mice demonstrates the conserved biochemical function of mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice is filled with large vacuoles that are immunoreactive for LAMP-2 (lysosomal-associated membrane protein 2), consistent with dysfunction of the late endosome - lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia is followed by loss of neurons from layers four and five of the cortex, deep cerebellar nuclei and other localized brain regions. The sciatic nerve exhibits reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity and reduced amplitude of compound muscle action potentials. We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot - Marie - Tooth disorder is designated CMT4J.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62835/1/nature05876.pd

Phosphoinositide Regulation of Integrin Trafficking Required for Muscle Attachment and Maintenance

Muscles must maintain cell compartmentalization when remodeled during development and use. How spatially restricted adhesions are regulated with muscle remodeling is largely unexplored. We show that the myotubularin (mtm) phosphoinositide phosphatase is required for integrin-mediated myofiber attachments in Drosophila melanogaster, and that mtm-depleted myofibers exhibit hallmarks of human XLMTM myopathy. Depletion of mtm leads to increased integrin turnover at the sarcolemma and an accumulation of integrin with PI(3)P on endosomal-related membrane inclusions, indicating a role for Mtm phosphatase activity in endocytic trafficking. The depletion of Class II, but not Class III, PI3-kinase rescued mtm-dependent defects, identifying an important pathway that regulates integrin recycling. Importantly, similar integrin localization defects found in human XLMTM myofibers signify conserved MTM1 function in muscle membrane trafficking. Our results indicate that regulation of distinct phosphoinositide pools plays a central role in maintaining cell compartmentalization and attachments during muscle remodeling, and they suggest involvement of Class II PI3-kinase in MTM-related disease

The Rome III Criteria for the Diagnosis of Functional Dyspepsia in Secondary Care Are Not Superior to Previous Definitions

BACKGROUND & AIMS: Although the Rome III criteria for functional dyspepsia were defined 7 years ago, they have yet to be validated in a rigorous study. We addressed this issue in a secondary-care population. METHODS: We analyzed complete symptom, upper gastrointestinal (GI) endoscopy, and histology data from 1452 consecutive adult patients with GI symptoms at 2 hospitals in Hamilton, Ontario, Canada. Assessors were blinded to symptom status. Individuals with normal upper GI endoscopy and histopathology findings from analyses of biopsy specimens were classified as having no organic GI disease. The reference standard used to define the presence of true functional dyspepsia was epigastric pain, early satiety or postprandial fullness, and no organic GI disease. Sensitivity, specificity, and positive and negative likelihood ratios (LRs), with 95% confidence intervals (CIs), were calculated. RESULTS: Of the 1452 patients, 722 (49.7%) met the Rome III criteria for functional dyspepsia. Endoscopy showed organic GI disease in 170 patients (23.5%) who met the Rome III criteria. The Rome III criteria identified patients with functional dyspepsia with 60.7% sensitivity, 68.7% specificity, a positive LR of 1.94 (95% CI, 1.69-2.22), and a negative LR of 0.57 (95% CI, 0.52-0.63). In contrast, the Rome II criteria identified patients with functional dyspepsia with 71.4% sensitivity, 55.6% specificity, a positive LR of 1.61 (95% CI, 1.45-1.78), and a negative LR of 0.51 (95% CI, 0.45-0.58). The area under a receiver operating characteristics curves did not differ significantly for any of the diagnostic criteria for functional dyspepsia. CONCLUSIONS: In a validation study of 1452 patients with GI symptoms, the Rome III criteria performed only modestly in identifying those with functional dyspepsia, and were not significantly superior to previous definitions

Validation of the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care

BACKGROUND & AIMS: There are few validation studies of existing diagnostic criteria for irritable bowel syndrome (IBS). We conducted a validation study of the Rome and Manning criteria in secondary care. METHODS: We collected complete symptom, colonoscopy, and histology data from 1848 consecutive adult patients with gastrointestinal symptoms at 2 hospitals in Hamilton, Ontario; the subjects then underwent colonoscopy. Assessors were blinded to symptom status. Individuals with normal colonoscopy and histopathology results, and no evidence of celiac disease, were classified as having no organic gastrointestinal disease. The reference standard used to define the presence of true IBS was lower abdominal pain or discomfort in association with a change in bowel habit and no organic gastrointestinal disease. Sensitivity, specificity, and positive and negative likelihood ratios, with 95% confidence intervals, were calculated for each diagnostic criteria. RESULTS: In identifying patients with IBS, sensitivities of the criteria ranged from 61.9% (Manning) to 95.8% (Rome I), and specificities from 70.6% (Rome I) to 81.8% (Manning). Positive likelihood ratios ranged from 3.19 (Rome II) to 3.39 (Manning), and negative likelihood ratios from 0.06 (Rome I) to 0.47 (Manning). The level of agreement between diagnostic criteria was greatest for Rome I and Rome II (κ = 0.95), and lowest for Manning and Rome III (κ = 0.59). CONCLUSIONS: Existing diagnostic criteria perform modestly in distinguishing IBS from organic disease. There appears to be little difference in terms of accuracy. More accurate ways of diagnosing IBS, avoiding the need for investigation, are required

They are not all same: variations in Asian consumers' value perceptions of luxury brands

Asian markets are steadily becoming key growth regions for luxury brands. However, despite the growth, many luxury brand firms are unable to obtain the desired economic returns through their marketing strategies in Asia. Often these firms treat consumers across Asian markets as homogenous groups, which could lead to inaccurate luxury brand management strategy. Additionally, there is limited understanding of consumer value perceptions toward luxury brands across the Asian markets. Employing impression management theory and the horizontal/vertical collectivistic cultural distinctions, this study examines differences and similarities in constituent luxury value perceptions across three prominent Asian markets, namely China, India, and Indonesia. The results of a quantitative survey conducted with 626 real luxury consumers in these three countries identify variations in perceptions of symbolic, experiential, and functional value of luxury brands. The study contributes to knowledge on constituent luxury value perceptions, along with providing theoretical explanations for the differences between consumers across Asian markets. With the emerging novel insights on Asian consumers, luxury brand firms can align their marketing strategies to respective markets by leveraging the similarities and differences in consumer value perceptions. This approach, informed by empirical evidence, will enhance luxury brands’ competitiveness and profit opportunities in the high-growth Asian markets. The study identifies a number of future research directions