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In utero hematopoietic cell transplantation (IUHCT) is a potential therapy for the treatment of numerous genetic diseases such as hemoglobinopathies, immunodeficiencies, and inborn errors of metabolism.1 In utero therapy offers the benefit of avoiding host myeloablation and immunosuppression and has been shown to be successful in multiple animal models, including mice,2-5 dogs,6,7 pigs,8,9 and sheep.10-12 The timing of IUHCT exposes the transplanted human cells to the normal fetal migratory and developmental cues that facilitate proper stem cell distribution and differentiation.11,12 Clinically, IUHCT has been successful for fetuses with severe combined immunodeficiency (SCID),13,14 but therapeutic uses for other diseases, including hemoglobinopathies, have seen limited success.15 Further investigations identified multiple barriers to successful engraftment, including lack of space within the hematopoietic niche16,17 and the maternal immune system.2,18 Among available animal models of IUHCT, the fetal mouse remains an efficient and reproducible model to study the differentiation of stem cells in a nonirradiated host. NSG (NOD-SCID IL2Rg-null) mice, which are developed with SCID and IL-2Rg-null chain mutations, are a robust platform for the engraftment of human hematopoietic cells because they have no endogenous T, B, or natural killer cells.19-22 In this study, we used IUHCT of human CD341 cells in NSG mice to create a reproducible mouse model to study stem cell engraftment, differentiation, and systemic repopulation after IUHCT.

Fatigue and pain are disabling symptoms in patients with neuromyelitis optica spectrum disorder (NMOSD). The Modified Fatigue Impact Scale (MFIS) has not yet been validated in patients with NMOSD, and anti-interleukin-6 (IL-6) receptor antibody was reported to decrease pain and fatigue in patients with NMOSD. The aim of this study was to validate MFIS and to investigate the relationships among fatigue, pain and serum IL-6 levels in patients with NMOSD. MFIS and the Multidimensional Fatigue Inventory (MFI), an established scale for fatigue, were administered to patients with NMOSD and age- and sex-matched healthy controls (HCs). The Pain Effects Scale score and serum IL-6 levels were also measured in patients with NMOSD. Correlations among clinical characteristics, laboratory data and each score were investigated. To validate MFIS in patients with NMOSD, MFIS was administered twice within 4days from the first administration. Fifty-one patients answered the first MFIS, and 26 patients answered the second MFIS. There was no difference between the first and second MFIS scores. Patients with NMOSD had higher MFIS and MFI scores than HCs. No correlations were observed between serum IL-6 levels and either score. MFIS was validated in patients with NMOSD. Serum IL-6 levels may not be involved in the pathogenesis of fatigue and pain in patients with NMOSD.

Around 40% of systemic juvenile idiopathic arthritis (SJIA) in Thailand is steroid dependent or fails to respond to conventional therapy; therefore, tocilizumab (TCZ), a humanized anti-IL-6 receptor antibody, was indicated in these patients. Due to financial problems, some patients cannot receive TCZ treatment immediately following failure of the conventional treatment occurs, leading to disability and poor quality of life. Therefore, this study focused on the outcomes between early and late TCZ treatment in SJIA patients. This was an observational study. Baseline characteristics and disease severity were collected. Patients were divided into the early TCZ treatment group and the late TCZ treatment group. The outcomes of this study were the remission rates by the end of the study and treatment response using the American College of Rheumatology Pediatric (ACR Pedi) 30, 50, 70 criteria at 3, 6, 9, and 12 months after TCZ initiation. Descriptive analyses were conducted to determine the outcomes. Twenty-three SJIA patients were included in this study. At the end of this study, patients in the early TCZ treatment had a remission rate of 54.5%, whereas none in the late TCZ treatment achieved remission. At the 12-month follow-up, 10 patients (91%) in the early TCZ treatment group and 6 patients (50%) in the late TCZ achieved ACR Pedi 70. The outcomes of TCZ treatment in SJIA patients depend on the time to start TCZ treatment. In the early TCZ treatment, SJIA patients had a higher remission rate and better treatment response than patients who received TCZ treatment late.

A major advance in the treatment of rheumatoid arthritis has occurred following the introduction of tocilizumab (TCZ), an anti-IL-6 receptor antibody, into the therapeutic armory. Improvements in multiple aspects of the disorder including signs and symptoms, radiographic damage, disability and quality of life have been seen following its use. Extensive trial data revealed both the efficacy and safety of TCZ. Although methotrexate remains the foundation drug for rheumatoid arthritis, up to 30% of patients do not tolerate this disease-modifying antirheumatic drug. The following article will therefore focus on the current knowledge regarding TCZ as monotherapy, which to date, appears to be the most effective biologic agent administered in this way.

Purpose Patients with Ewing sarcoma (ES) with metastases and those who relapse fare poorly and receive therapies that carry significant toxicity. This phase 1/2 study was conducted to evaluate the efficacy of figitumumab in advanced ES. Patients and Methods Patients with sarcoma 10 to 18 years old were enrolled in two dose escalation cohorts (20 and 30 mg/Kg intravenously every 4 weeks) in the phase 1 portion of the study. Patients with ES 10 years old or older were enrolled in the phase 2 portion of the study. The primary phase 2 objective was objective response rate (ORR). Results Thirty-one patients with ES (n = 16), osteosarcoma (n = 11), or other sarcomas (n = 4) were enrolled in the phase 1 portion of the study. Dose escalation proceeded to 30 mg/kg every 4 weeks with no dose-limiting toxicity identified. In the phase 2 portion of the study, 107 patients with ES received figitumumab at 30 mg/kg every 4 weeks for a median of 2 cycles (range, 1 to 16). Sixty three percent of phase 2 patients had received at least three prior treatment regimens. Of 106 evaluable patients, 15 had a partial response (ORR, 14.2%) and 25 had stable disease. Median overall survival was 8.9 months. Importantly, patients with a pretreatment circulating free insulin-like growth factor (IGF) -1 lower than 0.65 ng/mL (n = 14) had a median OS of 3.6 months, whereas those with a baseline free IGF-1 ≥ 0.65 ng/mL (n = 84) had a median OS of 10.4 months (P < .001). Conclusion Figitumumab had modest activity as single agent in advanced ES. A strong association between pretreatment serum IGF-1 and survival benefit was identified.

A number of clinical trials have been done to investigate the role of interleukin-6 (IL-6) as a potential therapeutic target in rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Most of the data testing this comes from trials of the humanized anti Il-6 receptor antibody tocilizumab. Results from clinical trials worldwide have been promising so far. Additional study will define the ultimate role of tocilizumab and Il6 inhibitors in the treatment paradigms for RA and JIA.

Aim Heart transplant (HTX) candidates with pre-formed anti-HLA antibody (HLA-Ab) have lower transplantation rates and increased waiting time due to positive crossmatches. Anti-angiotensin II type 1 receptor antibody (AT1R-Ab) has recently been associated with allograft loss and antibody-mediated rejection. The aim of the present study was to evaluate: 1) the prevalence of anti-angiotensin receptor 1 antibody (AT1R-Ab) in HTX candidates and 2) the impact of AT1R-Ab on flow cytometry crossmatch (FXM). Methods 115 HTX candidates were tested by ELISA for the presence of AT1R-Ab (U/mL after 1:50 dilution, positive cut-off = 10 U/mL, strong-positive cut-off = 20 U/mL. 43/115 cases were identified with either positive (N = 15) or negative (N = 28) flow crossmatches in the absence of any donor-specific anti-HLA alloantibody (virtual negative crossmatches for HLA antibody). Mean channel shift (MCS) for flow cytometry crossmatches was measured on a 1024 scale. Finally, two index HTX cases with pre-formed AT1R-Ab and positive flow crossmatches are discussed. Results A high proportion of HTX candidates with HLA-Ab exhibited AT1R-Ab (Strongly reactive AT1R-Ab 46/115, 40%; weakly reactive AT1R-Ab 25/115, 21.7%; no AT1R-Ab 44/115, 38.2%). Furthermore, AT1R-Ab levels were significantly higher in patients with a positive versus a negative flow crossmatch (54.81 ± 54.92 versus 9.04 ± 7.36, p = 0.00001, Fig. 1). In addition, MCS was significantly higher in patients with AT1R-Ab versus patients without antibodies (73.95 ± 94.21 versus −51.45 ± 52.07, p = 000003, Fig. 2). In the 15 cases with positive flow crossmatch without HLA-specific antibody, all 15 patients exhibited AT1R-Ab, 11/15 had strong AT1R-Ab, while only 5/25 patients with negative FXM exhibited AT1R-Ab, Chi-square = 24, p = 0.00001). Conclusions More than half of HTX candidates exhibit AT1R-Ab, which can interfere with flow crossmatch interpretation even in the absence of HLA-specific antibodies.

Wai H Lim, Steve J Chadban, Scott Campbell, Hannah Dent, Graeme R Russ And Stephen P Mcdonald

Background. Insulin directly changes the sheep pleural electrophysiology. The aim of this study was to investigate whether insulin induces similar effects in human pleura, to clarify insulin receptor's involvement, and to demonstrate if glibenclamide (hypoglycemic agent) reverses this effect.Methods. Human parietal pleural specimens were mounted in Ussing chambers. Solutions containing insulin or glibenclamide and insulin with anti-insulin antibody, anti-insulin receptor antibody, and glibenclamide were used. The transmesothelial resistance (RTM) was determined. Immunohistochemistry for the presence of Insulin Receptors (IRa, IRb) was also performed.Results. Insulin increasedRTMwithin 1st min (P=.016), when added mesothelially which was inhibited by the anti-insulin and anti-insulin receptor antibodies. Glibenclamide also eliminated the insulin-induced changes. Immunohistochemistry verified the presence of IRa and IRb.Conclusion. Insulin induces electrochemical changes in humans as in sheep via interaction with its receptor. This effect is abolished by glibenclamide.

Hyaluronic acid (HA) hydrogel was modified with poly(L-lysine) (PLL) and Nogo-66 Receptor antibody (antiNgR) to enhance the repair of central nervous system (CNS) injuries. The immobilization of PLL was characterized by X-ray photoelectron spectroscopy (XPS) and the immobilization of antiNgR was studied by immunofluorescence. The cytocompatibility of this modified hydrogel was analyzed by culturing primary hippocampal neurons. The quantity and morphology of the neurons were influenced by different modifications; the primary hippocampal neurons cultured with modified HA hydrogel exhibited multipolar and bipolar morphology were compared with unmodified hydrogel cultures. The number of neurons obtained by culturing with HA hydrogel modified with both PLL and antiNgR was almost twice the number of neurons cultured with HA modified with only PLL or antiNgR. This phenomenon was attributed to the collaborative effect of PLL and antiNgR on the neurons. The characteristics of this new hydrogel system, including pore structure, water absorption, hydrolysis degradation did not change much when compared with the hydrogel modified with PLL or antiNgR, respectively. It is expected that this modified HA hydrogel has potential as a CNS tissue engineering material.

Interleukin-6 (IL-6) is a pleiotropic cytokine that acts in the development of B-lymphocytes; the proliferation of megakaryocytes, mesangial cells, and keratinocytes; and the production of acute-phase proteins such as C-reactive protein (CRP). Many reports suggest that IL-6 plays a partial role in the pathogenesis of systemic sclerosis (SSc). Here, I describe its functions, signal transduction pathways, and involvement in SSc and then introduce an anti-IL-6 therapy for SSc using an anti-IL-6 receptor antibody, tocilizumab. To evaluate the effect of such an anti-cytokine therapy, a large-scale study is needed. And a worldwide-scale study may require a new evaluation method to suppress inter-institute variability.

Aims: This paper investigates the action of M3 muscarinic acetylcholine receptor antibody present in serum from patients with Sjögren syndrome (SS). Methods: Enzyme-linked immunoabsorbent assay (ELISA) was performed in the presence or absence of different enzymatic and specific receptors?antagonist drugs. The levels and the generation of PGE2, 6-keto-PGF1α and cyclic AMP (cAMP) in rat submandibular gland acini?s preparations and in serum from pSS patients were measured in the presence of pSS IgG anti M3 peptide. COX-2 mRNA gene?s expression at Real Time PCR was done in acini?s preparations from rat submandibular gland in the presence of the autoantibodies alone or once previously incubated with different inhibitors.Results: In this study, we show that the activation of M3 mAChR of rat submandibular gland acini?s preparation triggers an increment both in the production of COX-2 mRNA gene?s expression and in the production of PGE2 and 6-keto-PGF1α. These phenomena are accompanied by an increment in the production of cAMP in the acini?s preparation and do not affect COX-1 mRNA?s levels. Both prostanoids are augmented in the sera of pSS patients as compared with healthy individuals.Conclusions: The present study suggests a complex interplay between different factors involved in adaptativa autoimmunity in pSS patients at the level of exocrine glands. The presence of pSS IgG anti M3 peptide, the enhancement of COX-2 mRNA gene?s expression and the increment in the generation of PGE2 and 6-keto-PGF1α abolished by M3 specific cholinergic antagonist, could provide evidence of a link between autoimmunity and the submandibular gland parasympathetic system in the course of Sjögren?s syndrome. This evidence is further supported by an increment in the production of AMP cyclic nucleotide (cAMP), and the subsequent induction of desensitization, internalization and/or intracellular degradation of the glandular M3 mAChR displayed by the cholinergic autoantibody. All of these statements cited above, are responsible for xerostomy, xerophthalmia and other parasympathetic symptoms observed in SS patients. Fil: Reina, Silvia Lorena. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pisoni, Cecilia. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; Argentina Fil: Eimon, Alicia. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; Argentina Fil: Carrizo, Carolina. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; Argentina Fil: Ganzinelli, Sabrina Belen. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Arana, Roberto. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; Argentina Fil: Borda, Enri Santiago. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Background: Anti-phospholipase A2 receptor antibody (PLA2R-Ab) is useful in diagnosing idiopathic membranous nephropathy (IMN). We investigated the clinical relevance of PLA2R-Ab enzyme-linked immunosorbent assay (ELISA) in patients with IMN. Methods: We measured PLA2R-Ab with an ELISA kit from the serum of 160 patients with IMN (n = 93), secondary MN (n = 14) and other glomerulonephritis (n = 41) as well as healthy controls (n = 12) at the time of renal biopsy and investigated the correlation of titers of PLA2R-Ab with clinical parameters. Results: PLA2R-Ab was positive in 41 of 93 patients (44.1%) with IMN. No samples from the patients with secondary MN and other glomerulonephritis or healthy controls were positive with the ELISA test. The PLA2R-Ab-positive patients showed severe disease activity and a low remission rate. The PLA2R-Ab titer positively correlated with proteinuria and was negatively associated with renal function and serum albumin. The patients with a high titer of PLA2R-Ab had significantly decreased remission rates. The cumulative probabilities of remission was significantly lower in patients with PLA2R-Ab (p = 0.01) and even so in patients with a high titer of PLA2R-Ab (p = 0.04). When we compared the ELISA titers with Western blot (WB) data of 43 patients who had been enrolled in our previous study, 18 and 30 patients were positive on ELISA (41.9%) and WB (69.8%), respectively. WB and ELISA had a concordance rate of 72.1% and were positively correlated (r = 0.590, p < 0.001). Conclusion: The presence, as well as a high titer, of PLA2R-Ab on ELISA was associated with poor prognosis of IMN. Assessment of PLA2R-Ab with ELISA is an easy and reliable tool for the diagnosis and guidance of therapeutic plans.

Background The relationship between the potential brain injury biomarker N-methyl-D-aspartate receptor antibody and quality of life has never been assessed. Methods We measured serum N-methyl-D-aspartate receptor antibody levels preoperatively in patients undergoing aortic valve replacement. Quality of life was scored using the Short Form-36 and European Quality of Life 5-Dimensions questionnaires pre- and postoperatively. We analyzed the antibody levels as a continuous variable and as a dichotomous variable with 1.8 ng mL−1 as the cutoff. Results Fifty-two patients (15 females) with a mean age of 71 ± 8.4 years were recruited for this study. Forty-eight (92%) patients attended the follow-up visit (405 ± 161 days). No mortality or severe neurological event was recorded. In both quality-of-life instruments, the low antibody level group ( n = 35) had significantly better scores than the high antibody level group ( n = 17) preoperatively. Postoperatively, the scores for both groups improved; however, the low antibody level group continued to score significantly better in most of the physical and mental health domains ( p = 0.04 to −1 cutoff were independently related to quality of life (pre- and postoperatively). Conclusions Higher N-methyl-D-aspartate receptor antibody levels in aortic valve replacement patients are independently related to poorer quality of life pre- and postoperatively.

A male patient developed ocular myasthenia gravis (MG) at the age of 33. He was anti-acetylcholine receptor antibody (anti-AChR Ab) negative. He received cholinesterase blocker for 5 months and went into a complete clinical remission that lasted untreated for 17 years. He relapsed recently with ocular symptoms only. He is now anti-AChR Ab positive and SFEMG is abnormal in a facial muscle. The patient is controlled with steroids. He had one of the longest spontaneous remissions reported in the natural history of MG, particularly unusual for an adult with the disease.

Thymoma screening is recommended at the onset of myasthenia gravis (MG) or when patients with MG present with clinical deterioration or a progressive increase of anti-acetylcholine receptor antibody. However, it is unknown if it is necessary to repeat the screening of thymoma at fixed intervals, even in the absence of MG deterioration, when the initial screening is negative. We analyzed the recurrence rate and incidence of new thymoma in a series of patients with well-controlled MG. The sample consisted of 53 patients, aged 17 to 72 years, and the follow-up varied between 75 and 472 months. The chest computerized tomography detected thymus abnormalities in eight patients at the initial screening and no abnormalities in all patients at a second screening after five years. The findings of this study support the classical opinion that screening for thymoma should be recommended only if there is clinical deterioration due to the disease. A investigação de timoma é recomendada em pacientes com miastenia gravis (MG) no início da doença, em caso de haver piora clínica ou aumento dos níveis do anticorpo antirreceptor de acetilcolina. Contudo, não foi estabelecido se é necessário repetir a investigação de timoma em intervalos fixos, na ausência de piora clínica, quando a investigação inicial foi negativa. A taxa de recorrência e a incidência de novo timoma foram analisadas em uma série de pacientes com MG bem controlada. A amostra consiste de 53 pacientes, idade entre 17 e 72 anos, com tempo de acompanhamento variando entre 75 e 472 meses. A primeira tomografia computadorizada de tórax detectou anormalidades no timo em oito pacientes durante a investigação inicial da doença e nenhuma anormalidade no segundo exame, após cinco anos de doença, em todos os pacientes. Os achados desse estudo corroboram a clássica opinião de que a investigação de timoma deveria ser recomendada somente se houver piora clínica da doença.

PURPOSE OF REVIEW Children with rheumatic diseases frequently require therapy with disease-modifying antirheumatic drugs and/or biologic agents. Therapies that have been prospectively tested in adults are often used in children before full evaluation of their safety and efficacy. Published experience that may report "off-label" usage can be helpful in decision making, although such reports do not reduce the need for prospective clinical trials in children. The purpose of this review is to summarize the recent published evidence regarding efficacy (and safety, when available) of standard and novel agents used in pediatric rheumatic disease. RECENT FINDINGS Etanercept, one of three currently available tumor necrosis factor-alpha inhibitors has a juvenile idiopathic arthritis indication. Novel "off-label" uses in children for interleukin-1 receptor agonist (Anakinra), antiinterleukin-6 receptor antibody (MRA), and rituximab (anti-CD20 monoclonal antibody) are discussed. SUMMARY This review summarizes the published evidence that supports the use of selected disease-modifying antirheumatic drugs and novel biologic agents in children with rheumatic diseases.

Aims Renal transplant (RTX) candidates with pre-formed anti-HLA antibody (HLA-Ab) have lower transplantation rates and increased mortality. Anti-angiotensin II type 1 receptor antibody (AT1R-Ab) has recently been associated with allograft loss and antibody-mediated rejection. The aim of the present study was to evaluate: (1) the prevalence of anti-angiotensin receptor 1 antibody (AT1R-Ab) in RTX candidates with circulating HLA-Ab and (2) AT1R-Ab response to VDS. Methods Thirty-nine patients receiving desensitization therapy had HLA-Ab levels determined by single-antigen bead array (Luminex). Mean fluorescence intensity (MFI) of the strongest HLA-Ab (immunodominant antibody -iDSA) was measured before and after therapy. A successful response was considered when iDSA decreased >50% at nadir versus pre-desensitization. Serum samples were also tested by ELISA for the presence of AT1R-Ab (U/mL after 1:50 dilution), before and after desensitization. Results A high proportion of candidates with HLA-Ab exhibited AT1R-Ab (20/39, 51%). A good response of AT1R-Ab to therapy was observed in 18/20 patients [Figure 1]: 17.4 ± 12.3 pre versus 10.9 ± 13.1 U/mL post therapy, p = 0.0009). iDSA reduction with desensitization was observed in 13/20 patients – 7996 ± 2580 pre versus 4410 ± 2695 MFI post therapy, p = 0.0001). 12/20 patients had both iDSA and AT1R-Ab reduction by therapy, 6/20 responded to AT1R-Ab only, 1/20 responded to iDSA only, and 1/20 was a non-responder. AT1R-Ab levels were more elevated in Caucasians then in African-Americans both before (20.7 ± 14.9 versus 12.3 ± 3.7 U/mL, p = 0.1), and after desensitization (14.7 ± 15.9 versus 5.2 ± 2.9 U/mL, p = 0.1). Conclusions More than half of HLA-sensitized candidates exhibit AT1R-Ab. This initial desensitization experience consistently provided substantial reductions both in HLA-Ab and AT1R-Ab levels in an unselected, highly sensitized kidney transplant candidate population. Download : Download high-res image (380KB) Download : Download full-size image

Die „activated clotting time“ (ACT) ist der Standard zur patientennahen Kontrolle der Gerinnungssituation wahrend der perkutanen transluminalen koronaren Ballonangioplastie (PTCA). Die Auswirkungen einer kombinierten Gabe von Heparin und dem Glykoprotein-IIb/IIIa-Antagonisten Abciximab auf die ACT ist jedoch nur unzureichend untersucht. 30 Patienten, bei denen eine PTCA durchgefuhrt wurde, erhielten 100 IU Heparin/kg Korpergewicht als Bolus. Weitere 30 Patienten erhielten einen initialen Bolus von 70 IU Heparin/kg + Abciximab. Wir bestimmten die ACT im Katheterlabor, die aktivierte partielle Thromboplastinzeit (APTT) im Labor und als „point-of-care“-Messung sowie die Plasmaheparinspiegel. Trotz der unterschiedlichen prainterventionellen Heparindosen war die maximale ACT statistisch nicht unterschiedlich zwischen den Gruppen. Nach der PTCA war die mediane ACT beider Gruppen fast identisch (267 vs. 272 Sekunden; p = 0,79). Der mediane ACT-verlangernde Effekt von Abciximab entsprach etwa 0,68 IU/ml Heparin. Beide APTT-Assays waren auf Grund ihrer hohen Sensitivitat nicht geeignet die Gerinnungseffekte der Medikamente wahrend der PTCA zu messen. Im Gegensatz dazu gelang dies mit der Bestimmung der Plasmaheparinspiegel sehr gut. Die schwache Korrelation (r=0.23) zwischen der ACT und dem Heparinspiegel bei Patienten, die eine Kombination von Heparin und Abciximab erhielten, konnte auf exzessiv verlangerte ACT-Werte (540–1245 s) bei sechs Patienten zuruckgefuhrt werden, was durch ein ungewohnlich starkes Ansprechen auf Abciximab zuruckzufuhren war. Im Gegensatz dazu korrelierte die ACT bei den nur mit Heparin behandelten Patienten gut mit den Heparinspiegeln. Wahrend die ACT sowohl die Heparin- als auch die Abciximab-Therapie widerspiegelt, zeigen die Heparinspiegel lediglich den Heparineffekt an. Die APTT-Assays sind nicht geeignet, die Gerinnungssituation von Patienten wahrend einer PTCA zu kontrollieren.

Medical therapy of refractory ulcerative colitis (UC) is associated with long-term side effects of cyclosporine and steroids. Because cyclosporine acts by inhibiting interleukin-2 (IL-2) production, we studied the efficacy and safety of humanized anti-IL2 receptor (CD25) antibodies daclizumab for refractory UC in an open label pilot study.Ten patients with chronically active UC received daclizumab, 1 mg/kg i.v. twice with a 4-wk interval. Clinical, endoscopic, and histological evaluation was scored at regular intervals. CD25 immunohistochemistry was followed in mucosal biopsies. The primary study endpoint was clinical improvement at wk 8.Nine of 10 patients completed the study. The median clinical activity score decreased from a median of 8 (95% CI = 7.2-9.2) at baseline to 3.5 (95% CI = 1.4-4.9) at wk 8 (p0.005). Endoscopic scores were significantly decreased at wk 8 (wk 0: 8, 95% CI = 6.3-8.5; wk 8: 5.0, 95% CI = 2.6-6.3; p0.01). Mucosal biopsies showed a significant decrease in CD25+ cells, and there was a trend toward lower histology scores at wk 8. Quality of life as assessed by the Inflammatory Bowel Disease Questionnaire increased after therapy (baseline: 131, 95% CI = 119-178; wk 8: 169; 95% CI = 124-216, p0.05). Nausea was most frequently reported as an adverse event, but always in patients that were concomitantly started on azathioprine.The anti-IL-2R antibody daclizumab was safe and well tolerated in acute UC. Patients experienced clinical benefit along with signs of endoscopic improvement, but further controlled trials are needed to determine the therapeutic benefit of this compound.

Secretory phospholipase A2 receptor (PLA2R) is the target antigen of the auto-antibodies produced in most (∼ 70%) patients with primary membranous nephropathy (pMN). The applicability of anti-PLA2R1 antibody monitoring for the prediction of MN recurrence in kidney transplant recipients still is a matter of debate.We sought to characterize the presence and concentration of anti-PLA2R antibodies by enzyme-linked immunosorbent assay (ELISA) in a cohort of 21 patients with pMN before and after transplantation to evaluate whether anti-PLA2R concentrations could predict pMN recurrence.The presence of pMN recurrence was significantly correlated with the existence of a positive ELISA assay at graft biopsy or with high level of anti-PLA2R1 activity before transplantation (P = 0.03). In the receiver operating characteristic analysis, anti-PLA2R levels (cut-off of 45 U/mL) during the pretransplantation period accurately predicted pMN recurrence, with a sensitivity of 85.3%, specificity of 85.1%, negative predictive value of 92%, and an area under the curve of 90.8%. This finding supports the hypothesis that anti-PLA2R cause pMN recurrence in humans and indicates the need to prove in an experimental model. Furthermore, 6 of 7 patients with recurrence were carriers of HLA DQA1* 05:01/05 and DQB1* 02:01, confirming these DQ alleles as those associated with higher anti-PLA2R levels.This study is the first to demonstrate pretransplantation circulating anti-PLA2R antibodies in a cohort of renal transplant recipients who prospectively developed recurrent disease. Currently, anti-PLA2R levels measured by ELISA may be a rational tool to establish the risk of MN recurrence in renal allograft recipients.

Background. Previous reports describe ethnicity based differences in clinical and laboratory features between Caucasians and African Americans with myasthenia gravis. However, it is not known whether these findings apply to other ethnicities.Methods. Retrospective analysis of all patients treated for myasthenia gravis during a three-year period at a community based medical center.Results. A total of 44 patients were included, including 19 of Hispanic, 16 of African American, 6 of Caucasian, and 3 of Asian ethnicities. Female gender was more common among those with Hispanic, Asian, and African American ethnicities compared to Caucasian ethnicity (p=0.029). Anti-acetylcholine receptor antibody subtypes demonstrated no significant ethnicity based differences in either generalized or ocular myasthenia gravis. A trend was noted towards greater frequency of blocking antibodies among Hispanics (52.6%) compared to African American (37.5%) and Caucasian (33.3%) patients (p=0.059). Generalized but not ocular myasthenia patients showed greater frequency of anti-muscle specific kinase antibodies in Asians and Hispanics compared to African Americans and Caucasians (p=0.041).Conclusions. The results of this study support the existence of ethnicity based differences in clinical and laboratory features of myasthenia gravis. Further study of genetic factors influencing clinical features of myasthenia gravis is indicated.

N-Methyl-D-Aspartate receptor antibody (NMDAR-ab) encephalitis is the most common antibody-mediated encephalitis. We compared four NMDAR-Ab assay methods: 1) live (a, L-CBA) or fixed (b, F-CBA) cell-based assays (CBA); 2) immunohistochemistry (IHC); 3) a commercially available CBA (C-CBA, Euroimmun AG). 180 sera and 48 CSFs were tested. Sera previously positive by the Oxford L-CBA but with unlikely phenotypes were intentionally over-represented. The results of the four assays agreed in only 55.6% of sera and 82% of CSFs. C-CBA was least likely to agree with other methods (37.7% in serum). Diagnosis was available, so far, for 54 patients (NMDAR ab-encephalitis ‘definite’ in 34, ‘unlikely’ in 20). In serum, L-CBA detected NMDAR-abs in 88% of ‘definite’ patients, but had a high false-positive rate (consistent with the biased selection). IHC was negative in all unlikely patients, but positive in only 73.5% ‘definite’ patients. F-CBA and C-CBA had intermediate performances. There was a worrying lack of concordance between tests. Assay results should be interpreted in the light of clinical information and a combination of L-CBA and IHC may give the most useful results. Further clinical information is being made available in order to increase the serum numbers and determine assay performance using CSF alone.

Aim We have previously reported that more than half of HLA-sensitized renal transplant candidates also exhibit anti-angiotensin II type 1 receptor antibody (AT1R-Ab). AT1R-Ab has been associated with antibody-mediated rejection and worse allograft survival. The aim of the present study was to prospectively compare the natural evolution of AT1R-Ab levels with response to desensitization therapy. Methods Ninety-three patients receiving desensitization therapy (VDS group, N = 23) or without desensitization therapy (non-VDS group, N = 70) had AT1R-Ab levels determined ELISA (U/mL after 1:50 dilution), before and after desensitization (VDS group) or before and after transplantation (non-VDS group). Results Initial AT1R-Ab levels were higher in VDS (17.64 ± 10.62 U/mL) then in non-VDS group (13.01 ± 9.14 U/mL, p Conclusions More than half of HLA-sensitized candidates exhibit AT1R-Ab. This initial desensitization experience consistently provided substantial reductions of AT1R-Ab levels in an unselected, highly sensitized kidney transplant candidate population, reduction that is more pronounced that post-transplant natural antibody dynamics. Download : Download high-res image (104KB) Download : Download full-size image

Background Previous studies have demonstrated that dysfunctional regulatory T cells (Tregs) may be associated with Graves’ disease (GD). In this study, we evaluated four serum Treg-associated miRNAs (miR-210, miR-182, miR-155, and miR-146a) expressions and assessed the potential of serum miRNAs as biomarkers of GD. Methods Foxp3 and serum miRNAs expressions both in GD patients and healthy controls were measured by RT-PCR. Results Serum miR-210 in GD patients was significantly higher than that of healthy controls (2.64-fold, P

Objectives Neurological disorders linked to antibodies against the glycine receptor were first comprehensibly described in Carvajal-Gonzalez et al’s 2014 case series of 42 patients. 1 Of the 42 patients the majority of cases (33) displayed features of Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM). Epilepsy or seizures were present in 4 cases, 2 of which were also associated with PERM. This report aims to broaden the clinical understanding of anti-glycine receptor antibody associated neurological disease by presenting data showing a much stronger association with seizures and epilepsy than previously reported. Methods Literature review and retrospective analysis of 11 cases of anti-glycine receptor associated neurological disease across multiple neurology centres in Queensland, Australia. Results Eleven cases were identified, with all cases known to the authors. Of the 11 cases, five had seizures/epilepsy as a prominent part of the presentation whereas two cases displayed features of PERM. A review of the literature revealed 103 cases of anti-glycine receptor antibody positive subjects. Of these 55 had clinical findings consistent with PERM, 36 had seizures/epilepsy and 20 had other neurological conditions. Some patients had more than one of these categories in their presentation. Conclusions Anti-glycine receptor antibody related neurological disease encompasses a broader clinical spectrum than originally reported with a greater association with epileptic seizures demonstrated both in the case series presented and in a review of the literature.

It has been suggested that interleukin-17 (IL-17) plays a crucial role in the development of several autoimmune diseases. However, there are no data about the relationship between myasthenia gravis and IL-17. The aim of this study was to measure the concentration of IL-17 and determine whether levels depend on the severity of MG. Serum IL-17 concentrations were measured in 25 patients. IL-17 concentrations were higher in generalized MG compared with controls and correlated with anti-acetylcholinesterase receptor antibody titers.

SUMMARY What is known and Objective: There is a growing body of experimental and clinical evidence for the atherogenic and pro-thrombotic potential of Lipoprotein(a) [Lp(a)], as well as for its causative role in coronary heart disease and stroke. We comment on novel strategies for reducing Lp(a) levels. Comment: Irrespective of the underlying biological mechanisms explaining the athero-thrombotic potential of this lipoprotein, most work has focused on the identification of suitable therapies for hyperlipoproteinemia(a). These include apheresis techniques, nicotinic acid and statins. None of these strategies have been shown to be definitely effective or convenient for the patient and new strategies are being attempted. Promising results are emerging with therapeutic interventions targeting the ‘inflammatory pathways’ by inhibition of Interleukin-6 (IL-6) signalling with natural compounds (e.g., Ginko biloba) or the IL-6 receptor antibody Tocilizumab. These may both lower Lp(a) and cardiovascular risk of the patients. Besides inhibiting platelet function, antiplatelet therapy with aspirin may also decrease the plasma concentration of Lp(a) and modulate its influence on platelets. What is new and Conclusion: We highlight the inadequacy of current approaches for lowering Lp(a) and draw attention to novel insights that may lead to better treatment.

In recent years, various molecular target agents have been investigated for gastric cancer. VEGF is one of the most potent angiogenic factors and is a signaling molecule secreted by many solid tumors. High VEGF expression is one of the characteristic features of gastric carcinomas, thus targeting VEGF is considered a promising strategy for gastric cancer. Ramucirumab, an anti-VEGF receptor antibody, has proven to be effective for previously treated advanced gastric cancer. Details of ramucirumab, including two pivotal Phase III studies, will be discussed in this review. Ramucirumab, with or without chemotherapy, improved survival in gastric cancer after previous systemic chemotherapy, thus becoming the standard of care for this patient population. Optimal timing of ramucirumab use and adequate biomarkers for patient selection as well as mechanism of resistance should be explored in future research.

We report two patients with myasthenia gravis (MG) who showed dropped head as an early myasthenic manifestation. They had elevated anti-acetylcholine receptor antibody and showed improvement of the symptoms after intravenous injection of edorophonium chloride. One patient had thymoma and developed myasthenic crisis two weeks after thymectomy. The patient recovered from the crisis after a combination of immunoadsorption plasmapheresis (IAPP) and initiation of steroid and tacrolimus. The other patient without thymoma initiated treatment with steroid, tacrolimus and IAPP and showed complete recovery one month later. Dropped head in MG can recover well with immunosuppression therapy using steroid, and IAPP is helpful in getting a rapid improvement of dropped head as well as recovery from myasthenic crisis. When we consider treatment for MG with dropped head, we should take into account that MG of this type can develop myasthenic crisis and use the same treatment strategy as that for generalized MG.

Background and Purpose IL-31, which is described as a pruritogenic cytokine, is linked to the itching that is associated with allergic and non-allergic eczema, but the precise pruritogenic mechanism of IL-31 and its potential as a therapeutic target for atopic dermatitis (AD) have not been determined.

We previously introduced video-assisted thoracoscopic ET (VATS-ET) as a therapeutic option for MG with acceptable results. We have conducted further investigations to improve the procedure without deterioration of operative results, including myasthenia gravis (MG) remission rate and palliation rate. Here, we report the details of our current procedure, as well as surgical results and patient outcomes as compared with the original VATS-ET procedure. From January 2002 to September 2013, we performed a VATS-ET procedure with an anterior chest wall lifting method for 77 patients who had MG with or without a thymoma. During that period, we investigated the appropriate indications and improved the procedure. Our current indication for this procedure is MG with the anti-acetylcholine receptor antibody or sero-negative type, or MG with a thymoma

Objectives - The aims of this study were to investigate myopathic changes in myasthenia gravis (MG) by using turns-amplitude analysis (TAA) and quantitative motor unit potential duration analysis (MUPan), to correlate myopathic changes with severity and duration of the disease and the results of diagnostic tests including repetitive nerve stimulation test (RNS), single fiber electromyography (SFEMG), and anti-acetylcholine receptor antibody (AChR-ab), and to compare the sensitivities of these two methods in detecting myopathic changes in MG. Materials and methods - We studied both MUPan and TAA in 32 patients with MG. Results The MUPan study showed myopathic changes in 12 patients (37.5%); TAA revealed a myopathic pattern in 4 (12.5%) and a neurogenic pattern in 4 cases (12.5%). Two of the 4 patients with a myopathic change by TAA also had short-duration mean MUP on the MUPan. No statistically significant association was found between the myopathic changes either by MUPan or TAA, and the various clinical and laboratory features. Conclusion - We conclude that MUPan is a more sensitive method than TAA in showing myopathic changes in MG, and that TAA is of limited help in demonstrating them.

In type B insulin resistance and acanthosis nigricans, the insulin resistance is due to the presence of anti-insulin receptor antibody 1. Approximately one-third of patients with these antibodies have an associated illness such as systemic lupus erythematosus (SLE) or Sjogren's syndrome. This report describes a case wherein the patient had presented with uncontrolled diabetes and required > 3000 units of human insulin to control hyperglycemia. She also had features of SLE. There was complete recovery following treatment with steroids.

Coronary stenting in acute coronary syndromes probably increases the risk of acute stent thrombosis. Recently, use of platelet glycoprotein IIb/IIIa receptor antibody has been shown to improve percutaneous transluminal coronary angioplasty (PTCA) outcomes in high risk lesions. The purpose of this analysis was to determine safety and efficacy of platelet glycoprotein IIb/IIIa receptor antibody administration in patients receiving coronary stents in high-risk lesions. Between October 1995 and November 1996, 282 patients with acute ischemic syndromes received coronary stents at our center: 73 had thrombus containing lesions--40 presented with AMI and 33 with unstable angina and make up the study population. The mean age of these patients was 61+/-13 years, 56 were male, 35 had a history of myocardial infarctions (MI), 21 had prior coronary artery bypass graft (CABG), and 21 had prior PTCA. Coronary stenting was used for suboptimal result in 46 patients (63%), threatened closure in 25 patients (34%), and acute closure in 2 patients (3%). Platelet glycoprotein IIb/IIIa receptor antibody was administered during the procedure in 74% and after the procedure in 26%. A total of 115 stents were deployed (Gianturco-Roubin 80, Palmaz-Schatz 29, and Wallstent 6) in 24 LAD, 21 RCA, 15 LCX, and 13 saphenous vein graft (SVG) lesions. Procedural success was 100%. The mean diameter stenosis before and after intervention was 60%+/-31% and 4%+/-14%, respectively. In-hospital events included 1 Q-wave MI (1.4%), 13 non-Q-wave MI (18%), and 1 death (1.4%). There was no subacute stent thrombosis, emergency CABG, or repeat PTCA. Significant in-hospital bleeding complications were noted in seven (10%) patients, with five patients (6.8%) requiring blood transfusions. In this series of patients with acute ischemic syndromes associated with angiographic evidence of thrombus, combined use of platelet glycoprotein IIb/IIIa receptor antibody and stenting resulted in a very low incidence of subacute stent thrombosis and emergency target lesion revascularization. However, bleeding complications were higher than expected with conventional antiplatelet therapy following routine stenting.

The "Fab immunogene" is a novel gene transfer vehicle in which the Fab fragment of anti-human epidermal growth factor (EGF) receptor antibody B4G7 is conjugated with poly-L-lysine to form an affinity complex with DNA. It was developed to target delivery of therapeutic genes into EGF receptor-hyperproducing tumor cells. Various characteristic features of the immunogene have been documented (Chen et al., 1998). Here we add further evidence to prove that in vitro transfer of beta-galactosidase/Fab immunogene is exclusively to EGF receptor-positive cells and that the herpes simplex virus thymidine kinase (TK)/Fab immunogene induces substantial suicide effects on A431 tumor cells when treated together with ganciclovir. The in vivo specificity of the immunogene transfer was examined using A431 tumor-bearing nude mice. When these nude mice were injected intraperitoneally with the chloramphenicol acetyltransferase (CAT)/Fab immunogene, CAT DNA was detected in the tumors as well as in liver and kidney but not brain, whereas CAT mRNA and enzyme activity were detected only in the tumors. Local and intraperitoneal injection of the TK/Fab immunogene and subsequent administration of ganciclovir effectively suppressed the growth of A431 tumors transplanted on the backs of nude mice. These observations suggest a possible application of the Fab immunogene system in cancer gene therapy.