The role of micro-inflammation in the pathogenesis of uraemic pruritus in haemodialysis patients.

BACKGROUND: Uraemic pruritus (UP) is still one of the most vexing and disabling symptoms in chronic renal failure. The pathogenesis of UP is obscure and effective therapeutic strategies are elusive. Deduced from partial successful treatment modalities, there is evidence that an alteration of the immune system with a pro-inflammatory pattern along with a deranged T-helper-cell differentiation may be involved in the pathogenesis of UP. We, therefore, investigated whether UP is related to an augmented Th1-differentiation as measured by determination of intracytoplasmatic (i.c.) cytokines and expression of chemokine receptors. Additionally, pro-inflammatory cytokines were determined in serum. METHODS: In a multicentre study, 171 patients on haemodialysis (HD) were screened for UP. Finally, 13 HD patients with and 13 HD patients without UP, as well as 15 healthy controls were enrolled in the study. Peripheral blood mononuclear cells were isolated and the proportion of Th1- and Th2-cells was determined by flow cytometry. The expression of chemokine receptors on CD4 cells (CXCR3 preferentially on Th1 and CCR4 on Th2) and i.c. cytokines (IFNgamma for Th1 and IL4 for Th2) were measured after in vitro stimulation. Serum cytokine levels (IL6 and TNFalpha) and CRP were measured by ELISA. RESULTS: Compared to HD patients without UP, those complaining of UP showed a significantly enhanced proportion of Th1-cells as measured by both techniques. Additionally, serum CRP and IL6 levels were significantly higher in HD patients with UP, compared to HD patients without UP. CONCLUSIONS: These results point to a central role of inflammation in the pathogenesis of UP in HD patients.     

Complications of spinal cord arteriography: prospective assessment of risk for diagnostic procedures

A prospective study was done of complications associated with 134 consecutive diagnostic spinal cord arteriograms in 96 patients (63 men and 33 women aged 17-78 years). Patients were examined for either arteriovenous malformation (n = 88) or tumor (n = 8), as indicated by myelography. Among the complications, 11 (8.2%) were local, five (3.7%) were systemic nonneurologic, and three (2.2%) were neurologic (two were associated with full recovery in less than 24 hours, and one was associated with full recovery in less than 1 week). No specific clinical or technical factors were significantly associated with the development of neurologic complications. Details of the clinical profile, angiographic technique, and pathologic findings for each patient were recorded and analyzed with respect to the potential risk for arteriographic complications. Diagnostic spinal cord arteriography had an acceptable risk within the range of other neuroangiographic diagnostic procedures.     

Enhanced alveolar bone loss in a model of non-invasive periodontitis in rice rats

Oral Diseases (2012) 18 , 459–468 Objective: The rice rat (Oryzomys palustris) develops periodontitis‐like lesions when fed a diet rich in sucrose and casein (H‐SC). We aimed to establish whether this model can accurately mimic the development of human periodontitis. Materials and Methods: For this purpose, 28‐day‐old rice rats (15/group) were assigned to standard (STD) or H‐SC diets and sacrificed after 6, 12, and 18 weeks. Jaws were processed for morphometric, histometric, histologic, histomorphometric, and micro‐CT analyses. Results: We found a progressive increase in horizontal alveolar bone loss (ABL) with age in maxillae of rats fed the STD diet as determined by morphometry. The H‐SC diet exacerbated horizontal ABL at the palatal surface at 12 and 18 weeks. Furthermore, increased vertical ABL was detected in mandibles and maxillae of rats fed the H‐SC diet for 12 and/or 18 weeks by histometry and micro‐CT. Remarkably, the H‐SC diet significantly increased bone remodeling at the interproximal alveolar bone of mandibles from rats fed for 6 weeks, but not in those fed for longer periods. Conclusions: These findings indicate that the H‐SC diet induced a transient increase in alveolar bone remodeling, which is followed by ABL characteristic of moderate periodontitis.     

Targeted postoperative care improves discharge outcome after hip or knee arthroplasty

OBJECTIVE: To determine whether targeted postoperative care, based on preoperative risk assessment, can increase the number of patients who are discharged home directly from acute care after elective hip or knee arthroplasty. DESIGN: Quasiexperimental with historical control. SETTING: A public university teaching hospital. PARTICIPANTS: One hundred patients who had an elective hip or knee arthroplasty. INTERVENTIONS: Between January and July 2001, 50 patients had their risk of discharge to extended inpatient rehabilitation assessed preoperatively with a newly developed Risk Assessment and Prediction Tool (RAPT). Postoperative management was targeted on the basis of the identified level of risk. Results were compared with those of a similar group of 50 patients treated between January and July 2000. MAIN OUTCOME MEASURES: Discharge destination, length of stay (LOS), and readmission rates. RESULTS: The percentage of patients discharged directly home increased significantly, from 34% during 2000 to 64% in 2001 (P=.002), with no increase in readmission rates in the 12 months postdischarge. In addition, the mean acute hospital LOS decreased by 1.1 days to 7.5 days in 2001 (P=.02). CONCLUSIONS: Use of the RAPT and targeted postoperative care resulted in more patients being discharged directly home after hip or knee arthroplasty while hospital LOS further decreased.     

An endogenous glycosylphosphatidylinositol-specific phospholipase D releases basic fibroblast growth factor-heparan sulfate proteoglycan complexes from human bone marrow cultures

Basic fibroblast growth factor (bFGF) is a hematopoietic cytokine that stimulates stromal and stem cell growth. It binds to a glycosylphosphatidylinositol (GPI)-anchored heparan sulfate proteoglycan on human bone marrow (BM) stromal cells. The bFGF- proteoglycan complex is biologically active and is released by addition of exogenous phosphatidylinositol-specific phospholipase C. In this study, we show the presence of an endogenous GPI-specific phospholipase D (GPI-PLD) that releases the bFGF-binding heparan sulfate proteoglycan and the variant surface glycoprotein (a model GPI-anchored protein) from BM cultures. An involvement of proteases in this process is unlikely, because released proteoglycan contained the GPI anchor component, ethanol-amine, and protease inhibitors did not diminish the release. The mechanism of release is likely to involve a GPI-PLD and not a GPI-specific phospholipase C, because the release of variant surface glycoprotein did not reveal an epitope called the cross- reacting determinant that is exposed by phospholipase C-catalyzed GPI anchor cleavage. In addition, phosphatidic acid (which is specifically a product of GPI-PLD-catalyzed anchor cleavage) was generated during the spontaneous release of the GPI-anchored variant surface glycoprotein. We also detected GPI-PLD-specific enzyme activity and mRNA in BM cells. Therefore, we conclude that an endogenous GPI-PLD releases bFGF-heparan sulfate proteoglycan complexes from human BM cultures. This mechanism of GPI anchor cleavage could be relevant for mobilizing biologically active bFGF in BM. An endogenous GPI-PLD could also release other GPI-anchored proteins important for hematopoiesis and other physiologic processes.     

A G alpha-dependent pathway that antagonizes multiple chemoattractant responses that regulate directional cell movement

Chemotactic cells, including neutrophils and Dictyostelium discoideum, orient and move directionally in very shallow chemical gradients. As cells polarize, distinct structural and signaling components become spatially constrained to the leading edge or rear of the cell. It has been suggested that complex feedback loops that function downstream of receptor signaling integrate activating and inhibiting pathways to establish cell polarity within such gradients. Much effort has focused on defining activating pathways, whereas inhibitory networks have remained largely unexplored. We have identified a novel signaling function in Dictyostelium involving a Galpha subunit (Galpha9) that antagonizes broad chemotactic response. Mechanistically, Galpha9 functions rapidly following receptor stimulation to negatively regulate PI3K/PTEN, adenylyl cyclase, and guanylyl cyclase pathways. The coordinated activation of these pathways is required to establish the asymmetric mobilization of actin and myosin that typifies polarity and ultimately directs chemotaxis. Most dramatically, cells lacking Galpha9 have extended PI(3,4,5)P(3), cAMP, and cGMP responses and are hyperpolarized. In contrast, cells expressing constitutively activated Galpha9 exhibit a reciprocal phenotype. Their second message pathways are attenuated, and they have lost the ability to suppress lateral pseudopod formation. Potentially, functionally similar Galpha-mediated inhibitory signaling may exist in other eukaryotic cells to regulate chemoattractant response.