Assessing psychosocial vulnerability and care needs of pretransplant patients by means of the INTERMED.

OBJECTIVE: We investigated whether the INTERMED, a generic instrument for assessing biopsychosocial case complexity and direct care, identifies organ transplant patients at risk of unfavourable post-transplant development by comparing it to the Transplant Evaluation Rating Scale (TERS), the established measure for pretransplant psychosocial evaluation. METHOD: One hundred nineteen kidney, liver, and heart transplant candidates were evaluated using the INTERMED, TERS, SF-36, EuroQol, Montgomery-Åsberg Depression Rating Scale (MADRS), and Hospital Anxiety & Depression Scale (HADS). RESULTS: We found significant relationships between the INTERMED and the TERS scores. The INTERMED highly correlated with the HADS,MADRS, and mental and physical health scores of the SF-36 Health Survey. CONCLUSIONS: The results demonstrate the validity and usefulness of the INTERMED instrument for pretransplant evaluation. Furthermore, our findings demonstrate the different qualities of INTERMED and TERS in clinical practice. The advantages of the psychiatric focus of the TERS and the biopsychosocial perspective of the INTERMED are discussed in the context of current literature on integrated care.

Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based Colaus study.

BACKGROUND: The relation of serum uric acid (SUA) with systemic inflammation has been little explored in humans and results have been inconsistent. We analyzed the association between SUA and circulating levels of interleukin-6 (IL-6), interleukin-1beta (IL-1beta), tumor necrosis factor- alpha (TNF-alpha) and C-reactive protein (CRP). METHODS AND FINDINGS: This cross-sectional population-based study conducted in Lausanne, Switzerland, included 6085 participants aged 35 to 75 years. SUA was measured using uricase-PAP method. Plasma TNF-alpha, IL-1beta and IL-6 were measured by a multiplexed particle-based flow cytometric assay and hs-CRP by an immunometric assay. The median levels of SUA, IL-6, TNF-alpha, CRP and IL-1beta were 355 micromol/L, 1.46 pg/mL, 3.04 pg/mL, 1.2 mg/L and 0.34 pg/mL in men and 262 micromol/L, 1.21 pg/mL, 2.74 pg/mL, 1.3 mg/L and 0.45 pg/mL in women, respectively. SUA correlated positively with IL-6, TNF-alpha and CRP and negatively with IL-1beta (Spearman r: 0.04, 0.07, 0.20 and 0.05 in men, and 0.09, 0.13, 0.30 and 0.07 in women, respectively, P<0.05). In multivariable analyses, SUA was associated positively with CRP (beta coefficient +/- SE = 0.35+/-0.02, P<0.001), TNF-alpha (0.08+/-0.02, P<0.001) and IL-6 (0.10+/-0.03, P<0.001), and negatively with IL-1beta (-0.07+/-0.03, P = 0.027). Upon further adjustment for body mass index, these associations were substantially attenuated. CONCLUSIONS: SUA was associated positively with IL-6, CRP and TNF-alpha and negatively with IL-1beta, particularly in women. These results suggest that uric acid contributes to systemic inflammation in humans and are in line with experimental data showing that uric acid triggers sterile inflammation.

Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma.

BACKGROUND & AIMS: Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC.¦METHODS: Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels.¦RESULTS: Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p<0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r(2)=0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6)×ULN for rs2858996 GG (n=148), GT (n=82), and TT (n=1 2) genotypes, respectively. All 12 TT patients had a maximum ALT>ULN, and 8 (67%) had ALT≥3×ULN. The odds ratio (95% CI) for ALT≥3×ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT≥3×ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure.¦CONCLUSIONS: The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC.

Clinical picture of the amyloid arthropathy in patients with chronic renal failure maintained on haemodialysis using cellulose membranes.

The clinical picture of 15 patients (10 male, five female) with amyloid arthropathy secondary to chronic renal failure treated with haemodialysis has been studied. The average period of haemodialysis was 10.8 years. Joint symptoms appeared between three and 13 years after starting haemodialysis. No patient had renal amyloidosis. Early symptoms were varied and often overlapped: knee swelling (seven patients), painful and stiff shoulders (seven), and carpal tunnel syndrome (six) were the most prominent. Follow up showed extension to other joints. Joint effusions were generally of the non-inflammatory type. Radiologically, geodes and erosions of variable sizes were seen in the affected joints, which can develop into a destructive arthropathy. Amyloid was found in abdominal fat in three of the 12 patients on whom a needle aspiration was performed. Four of 12 patients showed changes compatible with amyloid infiltration in the echocardiogram. One patient had amyloid in the gastric muscular layer, another in the colon mucus, and two of four in rectal biopsy specimens. Amyloid deposits showed the presence of beta 2 microglobulin in 10 patients. The clinical and radiological picture was similar to the amyloid arthropathy associated with multiple myeloma. These patients can develop systemic amyloidosis.

Fluorine-19 magnetic resonance angiography of the mouse.

PURPOSE: To implement and characterize a fluorine-19 ((19)F) magnetic resonance imaging (MRI) technique and to test the hypothesis that the (19)F MRI signal in steady state after intravenous injection of a perfluoro-15-crown-5 ether (PCE) emulsion may be exploited for angiography in a pre-clinical in vivo animal study. MATERIALS AND METHODS: In vitro at 9.4T, the detection limit of the PCE emulsion at a scan time of 10 min/slice was determined, after which the T(1) and T(2) of PCE in venous blood were measured. Permission from the local animal use committee was obtained for all animal experiments. 12 µl/g of PCE emulsion was intravenously injected in 11 mice. Gradient echo (1)H and (19)F images were obtained at identical anatomical levels. Signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were determined for 33 vessels in both the (19)F and (1)H images, which was followed by vessel tracking to determine the vessel conspicuity for both modalities. RESULTS: In vitro, the detection limit was ∼400 µM, while the (19)F T(1) and T(2) were 1350±40 and 25±2 ms. The (19)F MR angiograms selectively visualized the vasculature (and the liver parenchyma over time) while precisely coregistering with the (1)H images. Due to the lower SNR of (19)F compared to (1)H (17±8 vs. 83±49, p<0.001), the (19)F CNR was also lower at 15±8 vs. 52±35 (p<0.001). Vessel tracking demonstrated a significantly higher vessel sharpness in the (19)F images (66±11 vs. 56±12, p = 0.002). CONCLUSION: (19)F magnetic resonance angiography of intravenously administered perfluorocarbon emulsions is feasible for a selective and exclusive visualization of the vasculature in vivo.

Activation of the mouse TATA-less and human TATA-containing UDP-glucuronosyltransferase 1A1 promoters by hepatocyte nuclear factor 1.

UDP-glucuronosyltransferase (UGT) 1A1 (UGT1A1) catalyzes the glucuronidation of bilirubin in liver. Among all UGT isoforms identified to date, it is the only relevant bilirubin-glucuronidating enzyme in human. Because glucuronoconjugation is the major route of bilirubin elimination, any genetic alteration that affects bilirubin glucuronosyltransferase activity may result in a more or less severe hyperbilirubinemia. In this study, we report the cloning and characterization of the transcriptional regulation of the mouse UGT1A1 gene. Primary-structure analysis of the mouse Thymidine Adevice promoter revealed marked differences with its human homolog. First, the mouse promoter lacks the highly polymorphic thymidine/adenine repeat occurring in the human promoter, which has been associated with some forms of hyperbilirubinemia. Second, an L1 transposon element, which is absent in the human promoter, is found 480 bp upstream of the transcription start site in mouse. Using the electromobility shift and DNase I footprinting experiments, we have identified a hepatocyte nuclear factor 1-binding site in the mouse UGT1A1 promoter that confers responsiveness to both factors HNF1alpha and HNF1beta in HEK293 cells. Furthermore, we show that this element, which is conserved in the human promoter, also confers strong HNF1 responsiveness to the human UGT1A1 gene. Together, these results provide evidence for a major regulatory function of this liver-enriched transcription factor in UGT1A1 activity in both rodents and human.

The concept of the inflammasome and its rheumatologic implications.

The inflammasome is a proteolytic complex that regulates IL1β and IL-18 secretion in macrophages and dendritic cells. Its plays a vital role in the control of the inflammatory and cellular responses to infectious and danger signals and is an essential part of the innate immune system. Four different inflammasomes have been identified so far, and the NLRP3-inflammasome has been the best-studied in relation to human disease. Activation of the NLRP3-inflammasome by microcrystals, such as monosodium urate (MSU) and basic calcium phosphate (BCP) crystals, leads to IL1β release, which in turn triggers local inflammation. Dysfunction of the NLRP3-inflammasome due to mutations of the NLRP3 gene is the cause of the auto-inflammatory syndrome CAPS. The symptoms and signs of inflammation in both conditions respond to IL1 blockade. IL1 inhibitors have also been used successfully in other idiopathic inflammatory diseases, suggesting that dysregulated inflammasome activity contributes to the pathogenesis of multiple diseases, but the precise underlying mechanisms remain to be identified.

Infection of the central nervous system caused by varicella zoster virus reactivation: a retrospective case series study.

BACKGROUND: Recent data suggest that varicella zoster virus (VZV)-associated complications of the central nervous system (CNS) are more common and diverse than previously thought. The main purpose of this article is to describe the clinical characteristics and the outcome of patients suffering from meningitis and encephalitis caused by VZV reactivation. METHODS: A retrospective case study of adult patients (≥16 years old) diagnosed with a VZV reactivation in the CNS was performed. The cases were identified by a qualitative PCR DNA assay of the cerebrospinal fluid (CSF) at the Regional Hospital of Lugano between January 1, 2003 and July 31, 2010. RESULTS: Eleven out of 519 CSF samples (2.1%), submitted from patients with a clinical diagnosis of viral meningitis or encephalitis, were positive for VZV. A vesiculo-pustular skin eruption was observed in only five patients (45%). In six cases (55%), a systemic inflammatory syndrome was absent. The clinical outcome was favorable in eight patients (73%). Only one out of 11 patients (9%) died. The four patients with encephalitis had a less favorable prognosis: one patient recovered without residual neurological sequelae; two had a chronic neuropsychological handicap, speech difficulties, facial nerve palsy, and focal seizures; one patient died. We estimated an annual incidence rate of VZV infection of the CNS of 1.02/100 000 inhabitants for southern Switzerland. CONCLUSIONS: Screening of CSF for VZV by PCR is recommended for all patients with encephalitis and for those with viral meningitis of unclear origin in order to better target antiviral treatment.

Gp74 a membrane glycoprotein of the cis-Golgi network that cycles through the endoplasmic reticulum and intermediate compartment

A monoclonal antibody CC92 (IgM), raised against a fraction of rat liver enriched in Golgi membranes, recognizes a novel Endo H-resistant 74-kD membrane glycoprotein (gp74). The bulk of gp74 is confined to the cis-Golgi network (CGN). Outside the Golgi gp74 is found in tubulovesicular structures and ER foci. In cells incubated at 37 degrees C the majority of gp74 is segregated from the intermediate compartment (IC) marker p58. However, in cells treated with organelle perturbants such as low temperature, BFA, and [AIF4]- the patterns of the two proteins become indistinguishable. Both proteins are retained in the Golgi complex at 20 degrees C and in the IC at 15 degrees C. Incubation of cells with BFA results in relocation of gp74 to p58 positive IC elements. [AIF4]- induces the redistribution of gp74 from the Golgi to p58-positive vesicles and does not retard the translocation of gp74 to IC elements in cells treated with BFA. Disruption of microtubules by nocodazol results in the rapid disappearance of the Golgi elements stained by gp74 and redistribution of the protein into vesicle-like structures. The responses of gp74 to cell perturbants are in sharp contrast with those of cis/middle and trans-Golgi resident proteins whose location is not affected by low temperatures or [AIF4]-, are translocated to the ER upon addition of BFA, and stay in slow disintegrating Golgi elements in cells treated with nocodazol. The results suggest that gp74 is an itinerant protein that resides most of the time in the CGN and cycles through the ER/IC following the pathway used by p58.

Comparative socio-economic evaluation of IBD patients with and without infliximab maintenance therapy

Background: The anti-TNFα agent Infliximab (IFX) is used for the treatment of moderate to severe inflammatory bowel disease (IBD) with insufficient response to conventional immunomodulator therapy. IFX maintenance therapy is expensive and it is unknown if indirect costs (eg. by loss of work productivity) can be reduced by this therapy. Goal: to evaluate the direct and indirect costs of an IBD patient cohort under maintenance IFX compared to a cohort under "conventional" immunomodulator therapy. Methods: Direct and indirect costs of an IBD cohort under IFX and a reference cohort (similar disease activity and location) under conventional immunomodulator therapy (Azathioprine, or 6-MP, or MTX) were retrospectively evaluated over 12 months (January to December 2008). Results: 54 IFX-patients (24f/30m, 37 CD, 10 UC, 7 IC) and 71 non-IFX-patients (38f/33m, 56 CD, 12 UC, 3 IC) were included. IFX patients were younger than non-IFX patients (36 vs. 47 years, P = 0.0003). The mean duration of inpatient stay in hospital (23 in IFX vs. 21 days for non-IFX, P = 0.909) and the hospitalization costs (7,692 in IFX vs. 4,179 SFr for non-IFX, P = 0.4540) did not differ. IFX-patients had significantly more frequently specialist outpatient consultations (8 vs. 4, P < 0.001) and outpatient-related costs (3,633 vs. 2,186 SFr, P <0.001). Total costs for all diagnostic procedures (blood work, endoscopies, radiology) were higher in the IFXcohort (2,265 vs. 1,164 SFr, P < 0.001). Sixty-five percent of IFX-patients had a 100% job employment compared to 80% in the non-IFX cohort (P = 0.001). Conclusions: The direct and indirect costs of maintenance IFX-treated IBD patients are higher compared to IBD patients under conventional immunomodulators. Care should be taken not only to judge the costs as the IFX treated population may represent a cohort with more aggressive disease phenotype, furthermore, quality of life aspects were not assessed.

Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis

Background Multiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors of demyelination and neurodegeneration, by secreting cytokines and others neurotoxic agents. Previous studies have demonstrated that microglia expresses ATP-sensitive potassium (KATP) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of KATP channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Methods Anti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNy)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice were orally treated daily with diazoxide or vehicle for 15 days from the day of EAE symptom onset. Treatment starting at the same time as immunization was also assayed. Clinical signs of EAE were monitored and histological studies were performed to analyze tissue damage, demyelination, glial reactivity, axonal loss, neuronal preservation and lymphocyte infiltration. Results Diazoxide inhibited in vitro nitric oxide (NO), tumor necrosis factor alpha (TNF-¿) and interleukin-6 (IL-6) production and inducible nitric oxide synthase (iNOS) expression by activated microglia without affecting cyclooxygenase-2 (COX-2) expression and phagocytosis. Oral treatment of mice with diazoxide ameliorated EAE clinical signs but did not prevent disease. Histological analysis demonstrated that diazoxide elicited a significant reduction in myelin and axonal loss accompanied by a decrease in glial activation and neuronal damage. Diazoxide did not affect the number of infiltrating lymphocytes positive for CD3 and CD20 in the spinal cord. Conclusion Taken together, these results demonstrate novel actions of diazoxide as an anti-inflammatory agent, which might contribute to its beneficial effects on EAE through neuroprotection. Treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention in ameliorating MS disease.

Outcome and Prognostic Factors in Adenosquamous Carcinoma of the Head and Neck: A Multicenter Rare Cancer Network Study

Purpose/Objective(s): Adenosquamous carcinoma (AC) of the head and neck is a distinct entity first described in 1968. Its natural history is more aggressive than squamous cell carcinoma but this is based on very small series reported in the literature. The goal of this study was to assess the clinical profile, outcome, patterns of failure and prognostic factors in patients with AC of the head and neck treated by radiation therapy (RT) with or without chemotherapy (CT).Materials/Methods: Data from 18 patients with Stage I (n = 3), II (n = 1), III (n = 4), or IVa (n = 10) AC, treated between 1989 and 2009, were collected in a retrospective multicenter Rare Cancer Network study. Median age was 60 years (range, 48 - 73 years). Fourteen patients were male and 4 female. Risk factors, including perineural invasion, lymphangitis, vascular invasion, positive margins, were present in 83% of the patients. Tumor sites included oral cavity in 4, oropharynx in 4, hypopharynx in2, larynx in 2, salivary glands in 2, nasal vestibule in 2, nasopharynx in 1, and maxillary sinus in 1 patient. Surgery (S) was performed in all but 5 patients. S alone was performed in only 1 patient, and definitive RT alone in 3 patients. Fourteen patients received combined modality treatment (S+RT in 10, RT+CT in 2, and all of the three modalities in 2 patients). Median RT dose to the primary and to the nodes was 66 Gy (range, 50 - 72 Gy) and 53 Gy (range, 44 - 66 Gy), respectively (1.8 - 2.0 Gy/fr., 5 fr./ week). In 4 patients, the planning treatment volume included the primary tumor site only. Seven patients were treated with 2D RT, 7 with 3D conformal RT, and 2 with intensity-modulated RT.Results: After a median follow-up period of 38 months (range, 9 - 62 months), 8 patients developed distant metastases (lung, bone, mediastinum, and liver), 6 presented nodal recurrences, and only 4 had a local relapse at the primary site (all in-field recurrences). At last follow-up, 6 patients were alive without disease, 1 alive with disease, 9 died from progressive disease, and 2 died from intercurrent disease. The 3-year and median overall survival, disease-free survival (DFS) and locoregional control rates were 52% (95% confidence interval [CI]: 28 - 76%) and 39 months, 36% (95% CI: 13 - 49%) and 12 months, and 54% (95% CI: 26 - 82%) and 40 months, respectively. In multivariate analysis (Cox model), DFS was negatively influenced by the presence of extracapsular extension (p = 0.02) and advanced stage (IV versus I-III, p = 0.003).Conclusions: Overall prognosis of locoregionally advanced AC remains poor, and distant metastases and nodal relapse occur in almost half of the cases. However, local control is relatively good, and early stage AC patients had prolonged DFS when treated with combined modality treatment.

Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: Modulation in the spared nerve injury model of neuropathic pain.

Neuronal hyperexcitability following peripheral nerve lesions may stem from altered activity of voltage-gated sodium channels (VGSCs), which gives rise to allodynia or hyperalgesia. In vitro, the ubiquitin ligase Nedd4-2 is a negative regulator of VGSC α-subunits (Na(v)), in particular Na(v)1.7, a key actor in nociceptor excitability. We therefore studied Nedd4-2 in rat nociceptors, its co-expression with Na(v)1.7 and Na(v)1.8, and its regulation in pathology. Adult rats were submitted to the spared nerve injury (SNI) model of neuropathic pain or injected with complete Freund's adjuvant (CFA), a model of inflammatory pain. L4 dorsal root ganglia (DRG) were analyzed in sham-operated animals, seven days after SNI and 48h after CFA with immunofluorescence and Western blot. We observed Nedd4-2 expression in almost 50% of DRG neurons, mostly small and medium-sized. A preponderant localization is found in the non-peptidergic sub-population. Additionally, 55.7±2.7% and 55.0±3.6% of Nedd4-2-positive cells are co-labeled with Na(v)1.7 and Na(v)1.8 respectively. SNI significantly decreases the proportion of Nedd4-2-positive neurons from 45.9±1.9% to 33.5±0.7% (p<0.01) and the total Nedd4-2 protein to 44%±0.13% of its basal level (p<0.01, n=4 animals in each group, mean±SEM). In contrast, no change in Nedd4-2 was found after peripheral inflammation induced by CFA. These results indicate that Nedd4-2 is present in nociceptive neurons, is downregulated after peripheral nerve injury, and might therefore contribute to the dysregulation of Na(v)s involved in the hyperexcitability associated with peripheral nerve injuries.

Expression and function of the NALP3 inflammasome in rheumatoid synovium.

Summary The NACHT, LRR and PYD domains containing protein (NALP3) inflammasome is a key regulator of interleukin-1beta (IL-1beta) secretion. As there is strong evidence for a pro-inflammatory role of IL-1beta in rheumatoid arthritis (RA) and in murine models of arthritis, we explored the expression of the different components of the NALP3 inflammasome as well as other nucleotide oligomerization domain (NOD)-like receptors (NLRs) in synovium obtained from patients with RA. The expression of NLRs was also studied in fibroblast lines derived from joint tissue. By immunohistology, NALP3 and apoptosis-associated speck-like protein containing a CARD domain (ASC) were expressed in myeloid and endothelial cells and B cells. T cells expressed ASC but lacked NALP3. In synovial fibroblast lines, NALP3 expression was not detected at the RNA and protein levels and stimulation with known NALP3 agonists failed to induce IL-1beta secretion. Interestingly, we were unable to distinguish RA from osteoarthritis synovial samples on the basis of their basal level of RNA expression of known NLR proteins, though RA samples contained higher levels of caspase-1 assayed by enzyme-linked immunsorbent assay. These results indicate that myeloid and endothelial cells are the principal sources of inflammasome-mediated IL-1beta production in the synovium, and that synovial fibroblasts are unable to activate caspase-1 because they lack NALP3. The NALP3 inflammasome activity does not account for the difference in level of inflammation between RA and osteoarthritis.