Spontaneous Relapse Research Articles

Factors precipitating acute ulcerative colitis.

Ulcerative colitis is characterized by mucosal inflammation of a variable length of the colon starting from the rectum. The precise etiopathogenesis is unknown but it occurs in genetically susceptible individuals who manifest an abnormal immunological response against gut commensal bacteria. The disease course is-characterized by multiple spontaneous relapses and remissions. Two pathogens namely CMV and C. difficile have been associated with disease exacerbation in specific clinical situations. Whereas C. difficile may produce worsening of the disease in those exposed to broad spectrum antibiotics, CMV reactivation is seen only in patients with moderate to severe steroid refractory disease. The importance of these two super-infections can be gauged by the fact that both the ACG and the ECCO recommend testing for these two pathogens in appropriate clinical situations. The applicability of these guidelines in the Indian scenario has yet to be determined in view of the bacterial and parasitic infections endemic in tropical countries. The guidelines for diagnosis and management of these two super-infections in the presence of ulcerative colitis are discussed in this review.

Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer

Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible Kras(G12D)-driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras(G12D)-independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.

Association Study of Dopamine β-Hydroxylase Gene with Methamphetamine Psychosis

Dopamine is a key molecule in the pathophysiology of methamphetamine (METH) psychosis. We examined the association between METH psychosis and the dopamine β-hydroxylase (DBH) gene, which modulates dopaminergic cascades. Six polymorphisms, rs1989787, rs1611115, rs1108580, rs5320, rs1611125, and rs6271, of the DBH gene were genotyped. These polymorphisms were not associated with METH-seeking behaviors of patients with METH psychosis (N = 216) or healthy controls (N = 328), but rs1611125 affected one of the clinical phenotypes of METH psychosis. Individuals with the G/G homozygote of rs1611125 had a significant risk for spontaneous relapse of METH psychosis (P = .02, odds ratio = 2.2). In haplotype analyses, rs1108580-rs5320-rs1611125 was revealed to be associated with METH psychosis (P = .01). Having G-Ala-G was a significant risk factor, while A-Thr-A was a protective factor for METH psychosis (odds ratio were 9.9 and 0.16, resp.). Our present findings indicated that the DBH gene may play an important role in METH psychosis.

Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria.

Plasmodium vivax is an important cause of malaria in many parts of Asia and South America, and parasite resistance to the standard treatment (chloroquine) is now high in some parts of Oceania. This review aims to assess the current treatment options in the light of increasing chloroquine resistance. To compare artemisinin-based combination therapies (ACTs) with alternative antimalarial regimens for treating acute uncomplicated P. vivax malaria. We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; and the metaRegister of Controlled Trials (mRCT) up to 28 March 2013 using "vivax" and "arte* OR dihydroarte*" as search terms. Randomized controlled trials comparing ACTs versus standard therapy, or comparing alternative ACTs, in adults and children with uncomplicated P. vivax malaria. Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We used recurrent parasitaemia prior to day 28 as a proxy for effective treatment of the blood stage parasite, and compared drug treatments using risk ratios (RR) and 95% confidence intervals (CIs). We used trials following patients for longer than 28 days to assess the duration of the post-treatment prophylactic effect of ACTs. We assessed the quality of the evidence using the GRADE approach. We included 14 trials, that enrolled 2592 participants, and were all conducted in Asia and Oceania between 2002 and 2011. ACTs versus chloroquine: ACTs clear parasites from the peripheral blood quicker than chloroquine monotherapy (parasitaemia after 24 hours of treatment: RR 0.42, 95% CI 0.36 to 0.50, four trials, 1652 participants, high quality evidence).In settings where chloroquine remains effective, ACTs are as effective as chloroquine at preventing recurrent parasitaemias before day 28 (RR 0.58, 95% CI 0.18 to 1.90, five trials, 1622 participants, high quality evidence). In four of these trials, recurrent parasitaemias before day 28 were very low following treatment with both chloroquine and ACTs. The fifth trial, from Thailand in 2011, found increased recurrent parasitaemias following treatment with chloroquine (9%), while they remained low following ACT (2%) (RR 0.25, 95% CI 0.09 to 0.66, one trial, 437 participants).ACT combinations with long half-lives probably also provide a longer prophylactic effect after treatment, with significantly fewer recurrent parasitaemias between day 28 and day 42 or day 63 (RR 0.57, 95% CI 0.40 to 0.82, three trials, 1066 participants, moderate quality evidence). One trial, from Cambodia, Thailand, India and Indonesia, gave additional primaquine to both treatment groups to reduce the risk of spontaneous relapses. Recurrent parasitaemias after day 28 were lower than seen in the trials that did not give primaquine, but the ACT still appeared to have an advantage (RR 0.27, 95% CI 0.08 to 0.94, one trial, 376 participants, low quality evidence). ACTs versus alternative ACTs: In high transmission settings, dihydroartemisinin-piperaquine is probably superior to artemether-lumefantrine, artesunate plus sulphadoxine-pyrimethamine and artesunate plus amodiaquine at preventing recurrent parasitaemias before day 28 (RR 0.20, 95% CI 0.08 to 0.49, three trials, 334 participants, moderate quality evidence).Dihydroartemisinin-piperaquine may also have an improved post-treatment prophylactic effect lasting for up to six weeks, and this effect may be present even when primaquine is also given to achieve radical cure (RR 0.21, 95% CI 0.10 to 0.46, two trials, 179 participants, low quality evidence).The data available from low transmission settings is too limited to reliably assess the relative effectiveness of ACTs. ACTs appear at least equivalent to chloroquine at effectively treating the blood stage of P. vivax infection. Even in areas where chloroquine remains effective, this finding may allow for simplified protocols for treating all forms of malaria with ACTs. In areas where chloroquine no longer cures the infection, ACTs offer an effective alternative.Dihydroartemisinin-piperaquine is the most studied ACT. It may provide a longer period of post-treatment prophylaxis than artemether-lumefantrine or artesunate plus amodiaquine. This effect may be clinically important in high transmission settings whether primaquine is also given or not.

Collagenous Colitis and Inflammatory Bowel Disease: Is It a Complication or Spectrum of the Same Disease?

Purpose: Collagenous colitis is an inflammatory mucosal disorder that results in chronic watery diarrhea without bleeding. It is characterized by a thick subepithelial collagen band and increased lymphocytes in the lamina propria of an otherwise endoscopically normal-appearing colon. It is generally benign disease, with a course that is characterized by alternating spontaneous relapses and remissions. There have been cases reported in literature in which microscopic colitis preceded Crohn's disease and ulcerative colitis. It is unclear to date if these cases are only coincidental or represent progression of disease. We report one patient who was diagnosed with collagenous colitis 2 years ago. His prior treatment included budesonide and cholestyramine intermittently. The patient presented with severe abdominal pain, weight loss, anorexia, and bloody diarrhea. Colonoscopy showed mucosal changes suggestive of ulcerative colitis; diagnosis was confirmed with biopsy interpretation. Stool studies were negative. The patient was started on intravenous solu-medrol. His symptoms improved for a few days but then again progressed to severe bloody diarrhea with abdominal pain. A flexible sigmoidoscopy was performed revealing persistent inflammatory mucosal changes. Biopsies also showed cytomegalovirus in the background of ulcerative colitis. Intravenous gancyclovir therapy was added to the medical regimen. Patient's symptoms resolved within a week and the patient was discharged home on valgancyclovir and prednisone. We report an additional case report, added to the previous six, which augments the theory that collagenous colitis could be a part of the spectrum of inflammatory bowel disease (Table 1).Table 1: Reported cases of collagenous colitis evolving into ulcerative colitis

Spontaneous remission and relapse of primary central nervous system lymphoma: Case report and review

There are numerous reports of lesions affecting the central nervous system which disappear without treatment. They are called vanishing tumors. The most common of these is the primary central nervous system lymphoma, which accounts for 4% of all intracranial neoplasms. There are other factors that induce remission such as corticosteroid therapy, chemotherapy and radiotherapy. However,/INS; many of these vanishing tumors relapse. We present the case of a 58 year old, male patient who presented with partial third cranial nerve palsy. The brain MRI showed a periventricular mass and the biopsy was informed as diffuse large B-cell non-Hodgkin lymphoma. A control MRI was requested displaying complete disappearance of the mass. Patient was followed during 3 months with MRI, full body CT and lumbar puncture showing no evidence of the /INS;disease. One year after discharge patient presented with subtle memory alterations and progressive temporal–/INS;spatial disorientation. MRI showed a heterogeneous, hypointense, expansive process with left temporal periventricular epicenter. Spectroscopy was suggestive of lymphoma. Thoracic, abdominal, and pelvic CT scans evidenced an L1 lumbar fracture; MRI was suggestive of lymphoma metastasis. Daily methylprednisolone /INS;pulses were initiated and treatment with Methrotrexate, Cytarabine and Leucovorine was begun, with clinical improvement. /INS;Many reports present relapsing vanishing tumors, suggesting that full therapy should be initiated in spite of spontaneous remission. Clinical trials should be performed in order to prove the effectiveness of this proceeding.

AB0016 Association between the hla-b51 antigen and profiles of peripheral t cell subsets in tunisian patients with behcet’s disease

BackgroundBehçet’s disease (BD) is a multisystemic inflammatory disorder characterized by spontaneous remissions and relapses [1]. An association between Behçet’s disease and HLA-B51 has been regarded as the strongest evidence for...

Anti-ADAMTS13 Inhibitor Boosting During Plasma Exchange Therapy Often Causes an Intractable Acquired Idiopathic TTP

AbstractAbstract 1086 Introduction:Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder, characterized by classic “pentad”. Since 1998, it has been characterized by severe deficiency of ADAMTS13 activity (ADAMTS13:AC), due to genetic abnormalities or acquired autoantibodies (ADAMTS13:INH) to this enzyme. A drug-induced form of TTP, ticlopidine-associated (tc)- TTP, is also associated with severe deficiency of ADAMTS13:AC and ADAMTS13:INH, although unlike acquired idiopathic (ai)-TTP, spontaneous relapses do not occur. A first-line treatment of ai-and tc-TTP is plasma exchange (PE) that remarkably reduced the mortality. However, a certain population of the ai-TTP patients experiences a new drop in platelet count during the treatment. In 2011, we have reported that these ai-TTP patients were frequently associated with a tremendous increase of ADAMTS13:INH titers with PE, and termed “inhibitor boosting” (Isonishi et al. ISTH 2011). However, no systematic studies on this topic have been done. In this study, we analyzed ADAMTS13:INH boosting in Japan-Nara TMA registry. Patients and Methods:Between Jan 2004 and Dec 2011, 215 patients were diagnosed with ai-TTP (100 males/115 females) and 14 tc-TTP (7m/7f) in our registry. For analyzing of ADAMTS13:INH boosting, we evaluated patients in whom both ADAMTS13:AC and ADAMTS13:INH were analyzed more than 3 times within 14 hospital days after PE initiation (selected patients). The number of selected patients with ai-TTP was 56 (24m/32f) and tc-TTP was 5 (3m/2f). Assays for ADAMTS13:AC and ADAMTS13:INH were performed by chromogenic act-ELISA, and the ADMTS13:INH titers were expressed by the Bethesda units (BU). ADAMTS13:INH boosting was defined by fulfilling the followings: 1) patients must have ADAMTS13:INH titer of more than 1 BU/ml before PE; 2) ADAMTS13:INH levels increased more than those before PE, during PE or within 14 days after PE initiation. Autoantibody titers for anti-ADAMTS13 IgG, IgM, and IgA isotypes and IgG1-4 subclasses were determined as previously described (Ferrari et al, JTH 2009). Results:(1) Frequency of the boosting: In ai-TTP, 174 out of 215 (81%) patients showed severely decreased ADAMTS13:AC under 0.5% of the normal. All 56 selected ai-TTP patients had severe deficiency of ADAMTS13:AC, of which ADAMTS13:INH boosting was identified in 23 patients (23/56, 41%). The frequency of inhibitor boosting versus the inhibitor titers before PE was the followings: 4/17 (24%) with ADAMTS13:INH titers of 1-<2 BU/ml, 11/20 (55%) with ADAMTS13:INH titers of 2-<5 BU/ml, 4/10 (40%) with ADAMTS13:INH titers of 5-<10 BU/ml, and 4/7 (57%) with ADAMTS13:INH titers of · 10 BU/ml. In contrast, no patients had the boosting in the selected 5 tc-TTP patients. (2) Characterization of inhibitor autoantibodies:We analyzed the anti-ADAMTS13 immunoglobulin isotypes and IgG subtypes in 8 selected patients with ai-TTP (6 with the boosting, and 2 without) and 2 patients with tc-TTP. All 6 ai-TTP patients with boosting exhibited IgG antibodies, and 3 had additional IgA antibodies; none had IgM antibodies. As for the IgG subclasses, the following combinations were found: G1 alone (one patient), G1+G2 (one patient), G1+G2+G4 (three patients), and G1+G4 (one patient). On the other hand, among 2 ai-TTP patients without boosting, both had IgG antibodies, one had the additional IgA antibodies, and none had IgM antibodies. As for the IgG subclasses, the following combinations were found: G1 alone (one patient), and G1+G2+G4 (one patient). Thus, we did not identify any specific difference between patients with versus without the ADAMTS13:INH boosting. Further, in 2 tc-TTP patients, both had IgG+IgA antibodies. As for the IgG subclasses, one patient had G1+G2+G4, and the other had G1+G2+G3. (3) Effect of rituximab:Five ai-TTP patients with the boosting were treated with rituximab (375 mg/m2weekly 3–5 times), which remarkably suppressed high levels of ADAMTS13:INH and achieved clinical remission. Conclusion:In this study, we identified that ai-TTP patients with severe deficiency of ADAMTS13:AC with ADAMTS13:INH titers more than 2 BU/ml before PE are prone to develop the inhibitor boosting during PE, and that rituximab therapy is potentially very useful in this setting, due to suppression of IgG autoantibodies. Interestingly, the inhibitor boosting was not seen in tc-TTP patients with severe deficiency of ADAMTS13:AC with its autoantibodies. Disclosures:Matsumoto:Alexion Pharma: Membership on an entity's Board of Directors or advisory committees. Plaimauer:Baxter BioScience: Employment. Fujimura:Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees.

Cocaine-Levamisole Thrombovasculopathy: A Report From the Southern Network On Adverse Reactions (SONAR) Project

AbstractAbstract 3403 Introduction:In 2008, five emergency department patients with unexplained neutropenia and thrombovasculitis were reported from Vancouver, Canada. Similar reports have appeared from San Francisco, Denver, Providence, Chicago, New York, and Los Angeles. Methods:156 case reports of patients of unexplained thrombovasculopathy were identified from the published literature or by SONAR. Results:The average patient age was 44 years old (SD, 11 years); 65% were female. The earliest time to symptom onset was 12 hours following last cocaine use. Dermatologic findings included retiform purpura, purpuric rash, hemorrhagic bullae, or skin necrosis (59% of cases), and lesions on the ears (35% of cases), upper extremities (33% of cases), torso (22% of cases), and the nose (10% of cases). Of 79 patients with available data, 72% presented with severe neutropenia (<1500cells/μl). Among 80 persons who had serologic studies, 95% demonstrated anti-neutrophil cytoplasmic antibodies, 31% were positive for proteinase 3 antibodies, 40% were positive for myeloperoxidase antibodies, 32% were positive for IgM cardiolipin antibodies, and 20% were positive for lupus anti-coagulant. Biopsies (primarily skin) revealed thrombosis in 25%, vasculitis in 6%, and both vasculitis and thrombosis in 20%. Thirty cases tested positive for levamisole. All patients reported recent cocaine use. Treatment of 63 neutropenic patients included supportive care (6 patients; one death; 83% recovery; and 50% spontaneous relapse); G-CSF (15 patients; 100% response; 40% relapse), antibiotics (25 patients; 100% recovery; 28% relapse rate), and corticosteroids (14 patients; 100% recovery; 28% relapse rate). Among 30 persons with skin biopsies identifying thrombosis, treatments included conservative management (5 patients; 100% response rate; 33% relapse) and corticosteroids (13 patients; 100% recovery; 22% relapse rate); among 9 persons with vasculitis, treatments included conservative treatment (2 patients, both recovered no relapses) and corticosteroids (4 patients; 100% response; and 50% relapse). Among 27 persons with thrombosis and vasculitis, treatments included conservative treatment (6 patients; 100% recovery; 50% relapse) and corticosteroids (10 patients; 100% response rates; 40% relapse rate). Severe skin necrosis treatment included skin allografts (6%), above the knee amputation (1 case) and a nose amputation (1 case). One patient with agranulocytosis died of infectious complications. The DEA reports that since 2008, 93% of intercepted cocaine is contaminated with levamisole, a colorectal cancer and anti-helminthic agent. Conclusion:Cocaine-levamisole thrombovasculopathy is a new and increasingly seen syndrome seen among emergency department patients in major cities. A high index of suspicion is essential, as cocaine use may not be obvious and expensive testing and therapies initiated. Appropriate treatment would include withdrawal of cocaine, evaluation of urine samples for levamisole, and conservative management. Disclosures:Gilbert:Allergan: Consultancy; Merz Aesthetics: Consultancy; Johnson & Johnson: Consultancy.

Technique Offers Hope for Treatment-Resistant Depression

Technique Offers Hope for Treatment-Resistant Depression

Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Unipolar and Bipolar Depression

Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited. To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP). Open-label trial with a sham lead-in phase. Academic medical center. Patients Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened. Intervention Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single-blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation. Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation. A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n=17), 5 (36%) and 5 (36%) after 1 year (n=14), and 7 (58%) and 11 (92%) after 2 years (n=12) of active stimulation. No patient achieving remission experienced a spontaneous relapse. Efficacy was similar for patients with MDD and those with BP. Chronic DBS was safe and well tolerated, and no hypomanic or manic episodes occurred. A modest sham stimulation effect was found, likely due to a decrease in depression after the surgical intervention but prior to entering the sham phase. The findings of this study support the long-term safety and antidepressant efficacy of subcallosal cingulate DBS for TRD and suggest equivalent safety and efficacy for TRD in patients with BP. Trial Registration clinicaltrials.gov Identifier: NCT00367003.

The Natural History of Insomnia: What We Know, Don’t Know, and Need to Know

Over the last several decades the prevalence and incidence of insomnia has been described in great detail. These data, while essential to document the magnitude of this health problem, infrequently provide information related to the incidence of new-onset insomnia and even less frequently provide information on the incidence of spontaneous remission and relapse. Of the groundbreaking studies that document these phenomena, none have provided information about the factors that mediate/moderate the transitions between good sleep to acute insomnia and from acute insomnia to either recovery or chronic insomnia. In this review, what is known about the natural history of insomnia (in terms of prevalence, incidence, and clinical course) will be reviewed. In addition, the leading theoretical perspectives on insomnia will be reviewed (with an eye towards identifying the factors that may mediate/moderate the above noted transitions) and a research agenda provided.

Necrotizing vasculitis revealed in a case of multiple mononeuropathy after a 14-year course of spontaneous remissions and relapses

The involvement of the peripheral nervous system is a frequent linical feature of primary and secondary systemic vasculitides ften observed during the early phases of the disease. Some types f vasculitis, referred to as non-systemic vasculitic neuropathies NSVNs), are restricted to the peripheral nerves. However, whether SVNs represent a mild form of systemic vasculitis, involving redominantly the peripheral nervous system, or a unique type f organ-specific vasculitis is still under debate. This disorder s usually subacute in evolution, but some patients are sympomatic several years prior to diagnosis [1–3]. However, vasculitis s not usually considered to be a cause of migrant and sponaneously remitting neuritis. Moreover, nerve biopsies may be on-contributive because of the low sensitivity of sural and supercial peroneal nerve biopsies. We describe the case of a 43-year-old woman who suffered sevral episodes of burning pain and sensory loss in discrete areas ith spontaneous remissions and relapses over a period of foureen years. These episodes, which appeared to be compatible with n NSVN at the time, finally turned out to correspond to systemic asculitis.

Resolution of antibody in autoimmune urticaria

Chronic urticaria, defined as widespread daily or nearly daily wheals for at least 6 weeks, with or without angioedema, impacts on patients’ quality of life. Natural course is self-limited, with spontaneous remissions and occasional relapses. Antihistamines, leukotriene inhibitor, immunosuppressive agents are used. 60% are idiopathic and 40% are autoimmune due to presence of anti-IgE antibody or IgG autoantibodies against Fc∑R1. An association exists between chronic urticaria and autoimmune diseases. We report a case of a patient with autoimune urticaria, thyroid disease and vitiligo, who showed resolution of histamine releasing antibody (reflab) on remission. In February 2005, a 44 yr old healthy woman was referred to the Allergy outpatient clinic with two month history of daily hives, moderately controlled with antihistamines, with good response to oral steroid. Lesions were pruritic, raised, erythematous, lasting for < 24 hrs and resolved with purplish discoloration. Screening negative for malignancy, connective tissue disease. TSH normal. Histamine releasing antibody positive, maximum histamine release 27% (<16%). Skin biopsy confirmed chronic urticaria with neutrophils without vasculitis. Sulfasalazine was not tolerated, but control attained with antihistamines and leukotriene inhibitor. By one year, she failed trial of weaning medications. 6 months after presentation she developed vitiligo. 5 years later, she was hypothyroid. By 3 years, the urticaria was in complete remission without medications. Repeat histamine releasing antibody was negative. There is a known association of severe chronic urticaria with auto antibody etiology and other autoimmune disease. Does resolution of antibody correlate with achieving remission? Further prospective studies are required to establish this relationship.

273 ANDROGEN INDEPENDENT, TUMOR-REINITIATING CELLS ARE SELECTED BY ANDROGEN DEPRIVATION IN MODELS OF ANDROGEN DEPENDENT PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: Androgen deprivation (AD) therapy remains the standard treatment for non-organ confined prostate cancer (PCa). We previously demonstrated (GuzmanRamirez N et al 2009) radical prostatectomy samples and PCa xenograft models and cell lines contain stem/progenitor (S/P) and neuroendocrine (NE)cells. Although the normal prostate depends on androgens for its growth and secretory function, its acinar epithelium cells reinitiate growth when androgens are given indicating the presence of S/P and NE cells surviving AD. Here we investigated whether AD selects for S/Pand NE-like cells in androgen-dependent PCa models in vivo and in vitro. METHODS: The BM18 human xenograft model, which shows a nearly complete regression and no spontaneous relapse after AD, and the androgen dependent cell line LNCaP were used. AD was achieved in vivo by castration of tumor bearing mice and in vitro by bicalutamide treatment. Hormone replacement (HR) after AD was accomplished in vivo by administration of testosterone-pellets to tumor bearing mice and in vitro by androgen replenished medium. Gene expression was measured by realtime PCR and Immunostaining. Apoptosis and Proliferation was assessed by cell cycle analysis and Ki67 Immunostaining. RESULTS: BM18 tumors regress in average 96.5% in volume (SD: 2.1%) within 14 days of AD. Residual cells are positive for the luminal cytokeratin (CK) 18, but, compared to intact tumors, show a loss of luminal markers such as AR, Nkx3.1 and PSA. Further, expression of markers of S/P (Oct4, Sox2, Nanog, Bcl2, Bmi1, ƒN2-integrin, CD44) and NE (CgA, NSE, Synaptophysin) is strongly increased. In accordance, in LNCaP cells AD selects for CK18 positive cells with decreased Nkx3.1 and PSA expression and with increased NSE expression. After AD residual BM18 tumor cells are quiescent, while residual LNCaP cells maintain a subset of proliferative cells. In both models, HR reactivates proliferation and Nkx3.1 and PSA expression while reducing NSE expression. CONCLUSIONS: Our results suggest that AD therapy selects for S/Pand NE-like PCa cells in vitro and in vivo, which are able to reinitiate a tumor. Restoration of androgenic signaling in these cells induces the outgrowth of a more differentiated cellular phenotype. As AD resistant cells can even be proliferative without androgens, AD therapy may select for the outgrowth of a more malignant cellular phenotype leading to castration resistance.

P.1.021 Different influence of dopaminergic system genes on working memory in healthy subjects

D2-like receptors are key targets for methamphetamine in the CNS, and their activation is an initial and indispensable effect in the induction of dependence and psychosis. It is possible that genetic variants of D2-like receptors may affect individual susceptibility to methamphetamine dependence and psychosis. To test this hypothesis, 6 putatively functional polymorphisms of D2-like receptors, −141C Ins/Del, Ser311Cys and TaqIA of the DRD2 gene, Ser9Gly of the DRD3 gene, and −521C>T and a variable number of tandem repeats in exon 3 of the DRD4 gene, were analyzed in 202 patients with methamphetamine dependence and/or psychosis and 243 healthy controls in a Japanese population. No polymorphism examined showed significant association with methamphetamine dependence, but two polymorphisms of DRD2 were associated with the clinical course and prognosis of methamphetamine psychosis. The A1/A1 homozygote of DRD2 was a negative risk factor for a poorer prognosis of psychosis that continues for more than 1 month after the discontinuance of methamphetamine abuse and the beginning of treatment with neuroleptics (p = 0.04, odds ratio (OR) = 0.42, 95% CI; 0.27–0.65) and the complication of spontaneous relapse of methamphetamine psychosis after remission (p = 0.014, OR = 0.34, 95% CI; 0.22–0.54). The genotype of −141C Del positive (Del/Del and Del/Ins) was at risk for rapid onset of methamphetamine psychosis that develops into a psychotic state within 3 years after initiation of methamphetamine abuse (p = 0.00037, OR = 3.62, 95% CI 2.48–5.28). These findings revealed that genetic variants of DRD2, but not DRD3 or DRD4, confer individual risks for rapid onset, prolonged duration, and spontaneous relapse of methamphetamine psychosis.

Association Analysis of the Tryptophan Hydroxylase 2 Gene Polymorphisms in Patients with Methamphetamine Dependence/Psychosis

There is a growing evidence that serotoninergic systems modulate dopaminergic neurotransmission. We analyzed the association between the variations in the brain tryptophan hydroxylase 2 (TPH2) gene, a rate limiting enzyme for serotonin biosynthesis, and methamphetamine (METH) dependence/psychosis in a Japanese population. We found ten single nucleotide polymorphisms (SNPs) and two polynucleotide polymorphisms in TPH2 gene exons and exon-intron boundaries. A total of 162 patients and 243 controls were used for the association analysis between these polymorphisms and METH dependence/psychosis. No significant differences were observed in either genotypic or allelic frequencies between METH dependent/psychotic patients and controls. A global test of differentiation among samples based on haplotype frequencies showed no significant association. With respect to latency of psychosis, prognosis of psychosis, and spontaneous relapse, we found no significant association with these SNPs. These results suggest that the TPH2 gene variants may not be a factor in vulnerability to METH dependence/psychosis.

Association Analysis of the Adenosine A1 Receptor Gene Polymorphisms in Patients with Methamphetamine Dependence/Psychosis

Several lines of evidence suggest that the dopaminergic nervous system contributes to methamphetamine (METH) dependence, and there is increasing evidence of antagonistic interactions between dopamine and adenosine receptors in METH abusers. We therefore hypothesized that variations in the A1 adenosine receptor (ADORA1) gene modify genetic susceptibility to METH dependence/psychosis. In this study, we identified 7 single nucleotide polymorphisms (SNPs) in exons and exon-intron boundaries of the ADORA1 gene in a Japanese population. A total of 171 patients and 229 controls were used for an association analysis between these SNPs and METH dependence/psychosis. No significant differences were observed in either the genotypic or allelic frequencies between METH dependent/psychotic patients and controls. A global test of differentiation among samples based on haplotype frequencies showed no significant association. In the clinical feature analyses, no significant associations were observed among latency of psychosis, prognosis of psychosis, and spontaneous relapse. These results suggest that the ADORA1 gene variants may make little or no contribution to vulnerability to METH dependence/psychosis.

Association Between 5HT1b Receptor Gene and Methamphetamine Dependence

Several lines of evidence implicate serotonergic dysfunction in diverse psychiatric disorders including anxiety, depression, and drug abuse. Mice with a knock-out of the 5HT1b receptor gene (HTR1B) displayed increased locomotor response to cocaine and elevated motivation to self-administer cocaine and alcohol. Previous genetic studies showed significant associations of HTR1B with alcohol dependence and substance abuse, but were followed by inconsistent results. We examined a case-control genetic association study of HTR1B with methamphetamine-dependence patients in a Japanese population. The subjects were 231 patients with methamphetamine dependence, 214 of whom had a co-morbidity of methamphetamine psychosis, and 248 age- and sex-matched healthy controls. The three single nucleotide polymorphisms (SNPs), rs130058 (A-165T), rs1228814 (A-700C) and rs1228814 (A+1180G) of HTR1B were genotyped. There was no significant difference in allelic and genotypic distributions of the SNPs between methamphetamine dependence and the control. Genetic associations of HTR1B were tested with several clinical phenotypes of methamphetamine dependence and/or psychosis, such as age at first abuse, duration of latency from the first abuse to onset of psychosis, prognosis of psychosis after therapy, and complication of spontaneous relapse of psychotic state. There was, however, no asscocation between any SNP and the clinical phenotypes. Haplotype analyses showed the three SNPs examined were within linkage disequilibrium, which implied that the three SNPs covered the whole HTR1B, and distribution of estimated haplotype frequency was not different between the groups. The present findings may indicate that HTR1B does not play a major role in individual susceptibility to methamphetamine dependence or development of methamphetamine-induced psychosis.

Anti-Tumor Necrosis Factor-α Treatment with Infliximab for Disseminated Granuloma Annulare

Granuloma annulare (GA) is a chronic inflammatory disease of unknown etiology characterized by the development of plaques preferentially localized to the distal extremities. Spontaneous remission and relapses are quite common and the course of GA is not easy to predict. Moreover, most therapeutic regimens have been used anecdotally and with variable success. We report the case of a 62-year-old White female patient affected by disseminated GA unsuccessfully treated with psoralen plus UVA photochemotherapy, prednisone, and cyclosporine (ciclosporin) who responded to the anti-tumor necrosis factor-α monoclonal antibody infliximab administered intravenously at a dosage of 5 mg/kg at weeks 0, 2, and 6 and thereafter at monthly intervals for 10 additional months. Most of the GA lesions improved within 8 weeks and then slowly resolved within 10 months of treatment. We suggest that infliximab may be proposed as an additional therapeutic option in the treatment of recalcitrant forms of disseminated GA.