Comorbidity of mitochondrial disease and dementia in patients with idiopathic polyneuropathy.

BACKGROUND AND PURPOSE: Studying the comorbidities of chronic idiopathic axonal polyneuropathy (CIAP) might help to better understand its etiopathogenesis. We aimed to assess the associations of mitochondrial disease (MD), Alzheimer's disease (AD) and vascular dementia (VD) with CIAP. METHODS: In this nested case-control study we included 2659 patients with CIAP identified from the Swedish Patient Register and 13 295 age- and sex-matched controls to assess the associations of MD, AD and VD with the subsequent risk of CIAP. We also conducted a follow-up study of the cases and controls to assess the risk of MD, AD or VD among patients with CIAP in comparison to individuals without CIAP. RESULTS: Individuals with MD had an increased risk of subsequent CIAP [odds ratio (OR), 4.17; 95% confidence intervals (CI), 1.27-13.65], whereas individuals with AD and VD had a decreased risk (OR, 0.18; 95% CI, 0.06-0.59 and OR, 0.17; 95% CI, 0.04-0.69). Patients with CIAP had a ninefold increased risk of subsequent MD [hazard ratio (HR), 9.37; 95% CI, 4.00-21.93], twofold increased risk of VD (HR, 1.97; 95% CI, 1.23-3.16), but no increased risk of AD (HR, 1.33; 95% CI, 0.89-1.98) compared with individuals without CIAP. CONCLUSIONS: We found a higher risk of MD among patients with CIAP, both before and after the diagnosis of CIAP. We found a higher risk of VD, but not AD, after the diagnosis of CIAP. The lower risks of AD and VD before CIAP might be due to a reduced surveillance of CIAP symptoms among patients with dementia.

Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale.

Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR(1)-MR(4)), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR(4.5) level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR(4.5) sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.

Steroids for chronic inflammatory demyelinating polyradiculoneuropathy: evidence base and clinical practice.

Evidence-based therapies for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) consist of corticosteroids, intravenous immunglobulins (IVIg), and plasma exchange. Steroids represent the oldest treatment used historically. In countries where readily available and affordable, IVIg tends to be favored as first-line treatment. The reason for this preference, despite substantially higher costs, is the perception that IVIg is more efficacious and safer than corticosteroids. However, the unselected use of IVIg as a first-line treatment option in all cases of CIDP raises issues of cost-effectiveness in the long-term. Furthermore, serious although rare, particularly thromboembolic side effects may result from their use. Recent data from randomized trials suggest pulsed corticosteroids to have a higher potential in achieving therapy-free remission or longer remission-free periods compared with IVIg, as well as relatively low rates of serious side effects when given as pulsed intravenous infusions during short periods of time. These specific advantages suggest that pulsed steroids could in many cases be used, as the first, rather than second choice of treatment when initiating immunomodulation in CIDP, primarily in hopes of achieving a remission after the short-term use. This article reviews the evidence base for the use of corticosteroids in its various forms in CIDP and factors that may influence clinicians' choice between IVIg and pulsed steroid treatment. The issue of efficacy, relapse rate and time, and side effect profile are analyzed, and some aspects from the authors' experience are discussed in relation to the possibility of using the steroid option as first-line therapy in a large proportion of patients with CIDP.

Autologous haematopoietic stem cell transplantation: a viable treatment option for CIDP.

OBJECTIVE: Only 70-80% of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) respond satisfactorily to the established first-line immunomodulatory treatments. Autologous haematopoietic stem cell transplantation (AHSCT) has been performed as a last treatment resort in a few therapy-refractory cases with CIDP. We describe the results of AHSCT in 11 consecutive Swedish patients with therapy-refractory CIDP with a median follow-up time of 28 months. METHOD: Case data were gathered retrospectively for AHSCT treatments in 11 patients with CIDP refractory to the first-line immunomodulatory treatments, intravenous high-dose immunoglobulin, corticosteroids and plasma exchange and to one or more second-line treatments used in 10 of the 11 patients. RESULTS: The median Inflammatory Neuropathy Cause and Treatment (INCAT) score within 1 month prior to AHSCT was 6 and the Rankin score 4. Total INCAT and Rankin scores improved significantly within 2-6 months after AHSCT and continued to do so at last follow-up. The motor action potential amplitudes (CMAP) improved already within 4 months (median) after AHSCT. Three of the 11 patients relapsed during the follow-up period, requiring retransplantation with AHSCT in one. Eight of the 11 patients maintained drug-free remission upon last follow-up. AHSCT was safe but on the short term associated with a risk of cytomegalovirus (CMV) and Epstein-Barr virus reactivation, CMV disease, haemorrhagic cystitis and pancreatitis. CONCLUSIONS: Our results though hampered by the limited number of patients and the lack of a control group suggest AHSCT to be efficacious in therapy-refractory CIDP, with a manageable complication profile. Confirmation of these results is necessary through randomised controlled trials.

Altered cerebrospinal fluid index of prealbumin, fibrinogen, and haptoglobin in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

OBJECTIVES: Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are autoimmune diseases of the peripheral nervous system. A clinical hallmark of GBS and CIDP is the albumino-cytologic dissociation in the cerebrospinal fluid (CSF). Changes in the CSF levels of proteins other than albumin in patients with GBS and CIDP are not as well studied. If altered, aberrant levels of CSF proteins may render it possible to establish useful biomarkers for GBS and CIDP. MATERIALS AND METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of prealbumin, fibrinogen, haptoglobin, apolipoprotein E, apolipoprotein A4 in both CSF and plasma samples from 19 patients with GBS and eight with CIDP, 24 controls with multiple sclerosis (MS) as well as 20 patients with other non-inflammatory neurological disorders (OND). RESULTS: The levels of prealbumin in both the plasma and the CSF were elevated in patients with GBS and MS compared with the controls. The higher levels of fibrinogen were seen in the CSF of patients with GBS and CIDP, but not in the plasma. The levels of CSF prealbumin and fibrinogen, measured by the CSF index of these proteins, were lower in patients with GBS and that of fibrinogen in patients with CIDP compared with controls with OND. Haptoglobin levels in the CSF rather than in the plasma were higher in patients with GBS and CIDP than in controls. The CSF haptoglobin index was higher in patients with CIDP and MS, but not in those with GBS. No correlation was found between levels of CSF proteins and clinical parameters in patients with GBS and CIDP. CONCLUSIONS: Our data provide preliminary evidence that GBS is associated with low CSF index levels of prealbumin and fibrinogen, but normal levels of haptoglobin, whereas CIDP is associated with normal CSF index levels of prealbumin, low fibrinogen, and high levels of haptoglobin. Further studies are needed to identify the underlying mechanisms behind these CSF protein alterations and to clarify whether prealbumin, fibrinogen, and haptoglobin can serve as useful biomarkers for GBS and CIDP.

Transcriptional characteristics of CD4+ T cells in multiple sclerosis: relative lack of suppressive populations in blood.

BACKGROUND: Multiple sclerosis (MS) is hypothetically caused by autoreactive Th1 and Th17 cells, whereas Th2 and regulatory T cells may confer protection. The development of Th subpopulations is dependant on the expression of lineage-specific transcription factors. OBJECTIVE: The aim of this study was to assess the balance of CD4(+)T cell populations in relapsing-remitting MS. METHODS: Blood mRNA expression of TBX21, GATA3, RORC, FOXP3 and EBI3 was assessed in 33 patients with relapsing-remitting MS and 20 healthy controls. In addition, flow cytometry was performed to assess T lymphocyte numbers. RESULTS: In relapsing-remitting MS, diminished expression of FOXP3 (Treg) was found (p < 0.05), despite normal numbers of CD4(+)CD25(hi)Treg. Immunoregulatory EBI3 and Th2-associated GATA3 ([a-z]+) was also decreased in MS (p < 0.005 and p < 0.05, respectively). Expression of TBX21 (Th1) and RORC (Th17) did not differ between patients and controls. Similar changes were observed when analysing beta-interferon treated (n = 12) or untreated (n = 21) patients. Analysis of transcription factor ratios, comparing TBX21/GATA3 and RORC/FOXP3, revealed an increase in the RORC/FOXP3 ratio in patients with relapsing-remitting MS (p < 0.005). CONCLUSION: Our findings indicate systemic defects at the mRNA level, involving downregulation of beneficial CD4(+)phenotypes. This might play a role in disease development by permitting activation of harmful T cell populations.

Individualizing calcineurin inhibitor therapy in renal transplantation--current limitations and perspectives.

Patient variability in clinical response to the calcineurin inhibitors (CNIs) cyclosporine A and tacrolimus partly results from differences in CNI exposure. For tacrolimus drug interactions and genetic variability relate to tacrolimus exposure. Patients carrying the CYP3A5*1 allele have an increased tacrolimus metabolism, hence lower drug exposure. Adjusting the tacrolimus dose to this genotype is a tool to optimize therapy from a pharmacokinetic perspective. In contrast, no genetic variants have been found to clearly relate to cyclosporine A exposure. Despite therapeutic drug monitoring aimed at individualizing CNI therapy, patients still suffer from acute or chronic rejection and CNI toxicity. To further optimize CNI therapy future research may incorporate genetic polymorphisms in proteins involved in CNI pharmacodynamics (i.e. drug target). Proteins potentially relevant for drug response are calcineurin and the CNI binding proteins immunophilins. Moreover, since the expression of the nuclear factor of activated T-cells (NFAT) is reduced after calcineurin inhibition, genetic polymorphisms in the genes encoding NFAT may also be interesting candidates for studying inter-patient differences in CNI efficacy and toxicity. In addition, the existence of isoforms and differences in tissue distribution of the calcineurin protein could potentially explain variable drug response. At present, the focus has been on the metabolism of CNIs and not on variability in the drug target. Therefore, future improvements in CNI therapy are likely to occur from a systems pharmacology approach taking into account genetic markers for both CNI pharmacokinetics and pharmacodynamics.

CsA exposure is associated with acute GVHD and relapse in children after SCT.

CsA is commonly used after haematological SCT (HSCT) as GVHD prophylaxis. In solid organ transplantation, area under the blood concentration vs time curve (AUC) correlates with clinical outcome. However, in HSCT, it has not been determined whether the AUC is superior to trough level monitoring to optimize clinical efficacy of CsA therapy. Therefore, the aim of this study was to investigate the relationships between CsA trough levels and/or AUC early after HSCT with clinical outcome. A total of 91 children (1.1-17.3 years) were treated consecutively with HSCT for a haematological malignancy. CsA trough levels were obtained and were used to estimate the AUC, retrospectively, with a NONMEM (Non-Linear Mixed Effects Modelling) method. Subsequently, these exposure parameters were correlated to the occurrence of acute GVHD, relapse risk (RR) and OS. Low CsA trough levels were found to correlate with the occurrence of acute GVHD. In addition, a CsA AUC over 3000 mcg h/l in AML patients was associated with a higher RR and a reduced OS. This was not the case for ALL patients. Thus, monitoring CsA exposure early after HSCT and adjusting the CsA dose to a predefined target trough level and AUC may provide a tool to influence GVHD/GVL balance.

Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia.

The BCR-ABL oncogenic tyrosine kinase causes chronic myeloid leukemia and is the target for imatinib therapy. During imatinib treatment, cells are selected in some patients with BCR-ABL kinase domain mutations that render decreased drug sensitivity. In addition, some patients express deletion mutants of BCR-ABL, apparently due to missplicing. Most commonly these deletion mutants lack a significant portion of the kinase domain that includes the P-loop. We describe a screen for such mutations in patients with CML and demonstrate that they are not oncogenic and are catalytically inactive. We hypothesized that coexpressing BCR-ABL deletion mutants has a dominant-negative effect on the native form through heterocomplex formation. However, upon coexpression of native and deletion mutant BCR-ABL in Ba/F3 cells, growth factor independence is maintained and signaling is activated normally. Despite this, these cells have increased imatinib sensitivity compared to cells expressing only native BCR-ABL. Thus, it will be important to investigate the prognostic impact of coexpression of deletion mutants in CML patients during imatinib treatment.

A genome-wide linkage scan for iron phenotype quantitative trait loci: the HEIRS Family Study.

Iron overload phenotypes in persons with and without hemochromatosis are variable. To investigate this further, probands with hemochromatosis or evidence of elevated iron stores and their family members were recruited for a genome-wide linkage scan to identify potential quantitative trait loci (QTL) that contribute to variation in transferrin saturation (TS), unsaturated iron-binding capacity (UIBC), and serum ferritin (SF). Genotyping utilized 402 microsatellite markers with average spacing of 9 cM. A total of 943 individuals, 64% Caucasian, were evaluated from 174 families. After adjusting for age, gender, and race/ethnicity, there was evidence for linkage of UIBC to chromosome 4q logarithm of the odds (LOD) = 2.08, p = 0.001) and of UIBC (LOD = 9.52), TS (LOD = 4.78), and SF (LOD = 2.75) to the chromosome 6p region containing HFE (each p < 0.0001). After adjustments for HFE genotype and other covariates, there was evidence of linkage of SF to chromosome 16p (LOD = 2.63, p = 0.0007) and of UIBC to chromosome 5q (LOD = 2.12, p = 0.002) and to chromosome 17q (LOD = 2.19, p = 0.002). We conclude that these regions should be considered for fine mapping studies to identify QTL that contribute to variation in SF and UIBC.

Mutations of the BCR-ABL-kinase domain occur in a minority of patients with stable complete cytogenetic response to imatinib.

Residual leukemia is demonstrable by reverse transcriptase-polymerase chain reaction in most patients with chronic myeloid leukemia who obtain a complete cytogenetic response (CCR) to imatinib. In patients who relapse during imatinib therapy, a high rate of mutations in the kinase domain of BCR-ABL have been identified, but the mechanisms underlying disease persistence in patients with a CCR are poorly characterized. To test whether kinase domain mutations are a common mechanism of disease persistence, we studied patients in stable CCR. Mutations were demonstrated in eight of 42 (19%) patients with successful amplification and sequencing of BCR-ABL. Mutation types were those commonly associated with acquired drug resistance. Four patients with mutations had a concomitant rise of BCR-ABL transcript levels, two of whom subsequently relapsed; the remaining four did not have an increase in transcript levels and follow-up samples, when amplifiable, were wild type. BCR-ABL-kinase domain mutations in patients with a stable CCR are infrequent, and their detection does not consistently predict relapse. Alternative mechanisms must be responsible for disease persistence in the majority of patients.

Increased soluble 4-1BB ligand (4-1BBL) levels in peripheral blood of patients with multiple sclerosis.

4-1BB ligand (4-1BBL; CD137L) is a member of the tumour necrosis factor superfamily expressed primarily on antigen presenting cells such as B cells, macrophages and dendritic cells. Its engagement with the receptor 4-1BB (CD137) has been shown to promote T-cell activation and regulate proliferation and survival of T cells. The role of the costimulatory molecule in multiple sclerosis (MS) remains unclear. In this study, the expression of 4-1BBL and soluble 4-1BBL (s4-1BBL) protein levels were analysed in peripheral blood of MS patients. Compared with healthy controls, MS patients had an increase in both plasma s4-1BBL protein levels and expression of 4-1BBL in CD14(+) monocytes. In contrast, myelin basic protein-reactive T-cell proliferation was not found to be inhibited by the use of an anti-4-1BBL antibody. The elevated s4-1BBL protein levels in the MS patients may function as a self-regulatory mechanism of 4-1BB/4-1BBL interaction and costimulation.

Dendritic cells in the cerebrospinal fluid and peripheral nerves in Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.

The role of antigen-presenting cells (APC) involved in induction of T and B cell mediated autoaggressive immunity in Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is poorly understood. We studied the numbers and phenotype of dendritic cells (DC) in blood and cerebrospinal fluid (CSF) over the course of GBS and CIDP before and after immunomodulatory treatment. Four out of seven GBS patients examined prior to treatment with high-dose intravenous immunoglobulins (IvIg) had elevated numbers of CD123(+) plasmacytoid DC in the CSF, while both GBS and CIDP patients examined prior to treatment had elevated numbers of CD11c(+) myeloid DC in the CSF, as compared to patients with noninflammatory neurological diseases (OND). The percentages of blood DC expressing the cell surface marker CD1a, co-stimulatory molecules CD80 and CD86, adhesion molecule CD54, and chemokine receptors CCR1, CCR2, CCR5, and CXCR4 were not affected in GBS or CIDP. The immunohistochemistry of sural nerve biopsies revealed CD11c(+)CD83(-)CD14(-)CD16(-) immature myeloid DC at low numbers, mostly in the perineurium, without difference between CIDP patients and controls. In contrast, the numbers of CD11c(+)CD14(+)/CD16(+) macrophages were higher within the endoneurium in CIDP patients compared with the controls. The recruitment of DC to CSF in GBS and CIDP may be important in capturing antigens released from inflamed spinal nerve roots into CSF and in transferring these antigens from CSF to local lymph nodes, where naive T and B cells may be activated.

Aberrated levels of cerebrospinal fluid chemokines in Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.

Infiltration of spinal nerve roots and peripheral nerves by macrophages and T cells are rather consistent immunopathologic findings in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Chemokines play a central role in recruitment of leukocytes to inflamed tissue. Chemokines have been implicated in the pathogenesis of the experimental autoimmune neuritis (EAN), which represents an animal model of GBS, but the role of chemokines in GBS and CIDP is not clear. Since chemokines may be released into CSF from inflamed spinal nerve roots, we studied the concentrations of the chemokines MCP-1, MIP-1beta, MIP-3beta, IP-10, SDF-1alpha, RANTES, and SLC in the CSF by sandwich ELISA in patients over the course of GBS and CIDP, before and after immunomodulatory treatment. Controls consisted of patients with noninflammatory neurological disorders. Patients examined in the acute phase of GBS prior to treatment with intravenous high dose immunoglobulins (IvIg) had elevated CSF levels of MCP-1 (a chemoattractant for blood monocytes and dendritic cells) and IP-10 (a chemoattractant for T cells). Patients with CIDP examined prior to immunomodulatory treatment had elevated CSF levels of MIP-3beta (a chemoattractant for mature dendritic cells, naïve and recently activated T cells) and IP-10. Levels of MIP-3beta tended to decreased during follow-up in those CIDP patients responding favorably to immunomodulatory treatment. CSF levels of MCP-1 and IP-10 correlated with the CSF:plasma albumin ratio in both GBS and CIDP patients. In CIDP patients, CSF levels of MIP-3beta also correlated with the CSF:plasma albumin ratio. These data implicate MCP-1 and IP-10 in the pathogenesis of GBS, and IP-10 and MIP-3beta in the pathogenesis of CIDP.

Temporal profile of anti-ganglioside antibodies and their relation to clinical parameters and treatment in Guillain-Barré syndrome.

Elevated anti-ganglioside antibody levels mainly of anti-GM1 and anti-GD1a specificities have been reported in THE serum of patients with Guillain-Barré syndrome (GBS). The relevance of anti-ganglioside antibodies other than anti-GM1 and anti-GD1a IgG antibodies and the temporal profile of anti-ganglioside antibodies in GBS is less clear. We studied serum antibodies to GM1, GD1a, GD1b, GQ1b, sulfatide and cardiolipin of the IgM, IgG and IgA classes over the course of GBS in patients who were untreated or treated with high dose intravenous immunoglobulin (IvIg). Antibodies to GD1b, GQ1b, sulfatide and cardiolipin were not detected in the sera of the GBS patients examined in this study. Anti-GM1 IgG titers peaked around 40 days and anti-GD1a IgM around 90 days after GBS onset. Titers of anti-GM1 IgG antibodies decreased following IvIg treatment. Patients with antibody peaks, defined as fivefold or higher increase in antibody titer compared to the lowest antibody titer over the course of GBS, had higher disability scores during the first two weeks of GBS and a worse clinical outcome (anti-GM1 IgG and anti-GD1a IgM antibody peaks) and axonal damage (anti-GD1a IgM antibody peaks), compared to patients without peak antibody titers. Anti-GM1 IgG and anti-GD1a IgM antibodies are thus strongly associated with more severe- and predominantly axonal cases of GBS. The appearance of anti-GM1 IgG and anti-GD1a antibody peaks in the serum after the termination of the acute phase of GBS suggests that these antibodies are produced secondary to nerve damage in GBS. The data does not exclude the possibility that secondarily secreted anti-GM1 IgG and anti-GD1a IgM antibodies may themselves be biologically active and play a role in disease propagation and/or recovery from disease in some patients with GBS.

Effect of surface treatment on fatigue life of postceramic soldered joints.

PURPOSE: This research investigated the effect of surface treatment on the fatigue life of metal-ceramic postsoldering. MATERIALS AND METHODS: Twenty cylindric specimens were cast in a metal-ceramic alloy. All specimens received appropriate heat treatment simulating ceramic application, although no porcelain was applied. Each specimen was cut in half to form two half specimens. The 40 half specimens were randomly assigned to one of the four treatment groups, which differed in the type of surface treatment performed on one end of each half specimen (joint surface) prior to soldering: (1) aluminous oxide pink stone; (2) 50-micron aluminum oxide sandblasting; (3) brown rubber point; and (4) gray silicone wheel followed by pink silicone wheel. All surface treatments were performed for 30 seconds. The half specimens were then steam cleaned, aligned, indexed, and oven soldered with #650 postceramic solder. The soldering of two half specimens formed a complete test specimen, and a total of 20 postceramic soldered specimens were prepared. Following soldering, a 241.1 MPa fatigue stress was applied to each solder joint during specimen testing. The test variable was the number of stress cycles required to fail each specimen. RESULTS: All specimens failed adhesively at the joint interface between the solder and parent metal. There were significant differences in the number of stress cycles to failure between groups 1 and 2, groups 1 and 4, and between groups 2 and 3. CONCLUSION: The load cycle to failure for postceramic soldered joints was affected by the metal surface treatment.

The use of fluoroquinolones as antiinfective transition-therapy agents in community-acquired pneumonia.

The newer quinolone antibiotics, including levofloxacin, moxifloxacin, and gatifloxacin, offer coverage of the likely pathogens in community-acquired pneumonia (CAP) and have been shown to be safe and effective treatments for CAP. Two of these agents, levofloxacin and gatifloxacin, have pharmacokinetic and antibacterial properties that are similar in both oral and intravenous formulations. As such, they may be excellent candidates for transition therapy involving early switch from intravenous to oral therapy followed by early hospital discharge for patients with CAP