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Overexpression of MYC increases DNA Most aggressive lymphomas with MYC alterations are related to replication buy discount voveran sr 100 mg, possibly resulting in DNA damage that in turn triggers a follicular lymphoid cells effective 100 mg voveran sr, but the role of MYC in GC formation and TP53-mediated response purchase voveran sr 100mg free shipping, leading to apoptosis order voveran sr discount. MYC expression maintenance has been elusive until recently. The sole explain in part the need of other cooperative mechanisms for cell expression of MYC in these selective subsets of B cells explains the transformation and tumor progression. In the early steps of GC formation, MYC is transiently The relevant oncogenic role of MYC has stimulated the search for up-regulated in few B cells before BCL6 is expressed (Figure 1). This expression seems to be induced by the initial interaction with MYC protein itself has generally been considered “undruggable” antigens and T cells and is essential for GC formation because its and the potential approaches have been directed at reducing its abrogation results in a complete absence of GCs. In subsequent expression, interfering with MAX dimerization or DNA binding, or steps, BCL6 is up-regulated and directly represses MYC by binding acting on downstream target genes. This switch between MYC and BCL6 is associated strategies have been difficult to apply in in vivo models. MYC is then reexpressed in a subset of function of BRD4 has offered new promising therapeutic opportuni- activated cells of the light zone that have up-regulated NF- B and ties. This MYC up- (BET) subfamily of proteins that bind to lysine acetylated histones regulation is again dependent on antigen and T-cell interactions. The and recruit elements required for transcription. Two small mol- light zone MYC-positive cells seem to correspond to a selected ecules, JQ1 and iBET, displace BRD4 from acetylated chromatin, subpopulation of B cells with high-affinity BCR that are prepared to resulting in a down-regulation of MYC and modulation of its reenter the dark zone for a subsequent round of proliferation and further transcriptional program, including the up-regulation of MYC- acquisition of IG somatic mutations, perpetuating the GC reaction repressed miRs, with a marked antiproliferative cell effect and (Figure 1). MYC-negative cells in the light zone will probably be the 576 American Society of Hematology Table 1. Aggressive lymphomas with MYC genetic and protein alterations MYC genetic alterations BL DLBCL BCLU PBL Transformed lymphoma (rare) MYC protein overexpression without evidence of genetic aberrations DLBCL ALK-positive LBCL TCF3 may contribute to the attenuation of the TCF3 program allowing the cell to move from the dark to the light zone (Figure 2A). The expression of MYC in light zone cells would sustain this effect by the induction of ID3. MYC dysregulation in aggressive B-cell lymphomas MYC gene alterations were initially identified in lymphoid neo- plasms by cytogenetic and molecular genetic studies that recognized 8q24 translocations and MYC gene rearrangements, amplifications, or mutations. The development of MYC FISH probes and, more recently, a monoclonal antibody that specifically recognizes MYC protein in routinely processed tissues has simplified the analysis of these alterations in routine prac- tice. Intriguingly, most of these tumors originate in cells that do not express MYC protein. Oncogenic mechanisms of MYC in aggressive mature leading to the up-regulation of MYC seem to overcome the B-cell lymphomas. Activation of the TCF3/ID3 pathway cells or BLIMP1 in terminally differentiated B cells (Table 2). In cooperates with MYC in BL, whereas BCL2 and/or BCL6 translocations addition, these aggressive lymphomas appear to have acquired are the cooperating mechanisms in DLBCL. In both tumors, MYC activation overcomes the suppressor effect of BLIMP1. The activation of the unfolded protein BL response may be a survival mechanism to counterbalance the BL is composed of highly proliferating mature B cells expressing a proapoptotic function of MYC. It frequently presents in extranodal sites in children green and red boxes indicate activating and suppressing mechanisms, and young adults. Epidemiological studies have recognized 3 respectively. The genetic hallmark of BL is the MYC translocation usually, with the IGH locus subset primed to exit the GC as memory cells or early plasmablasts. These translocations are usually the sole BLIMP1 induction in these latter cells will promote the plasma cell chromosomal aberration or are associated with few additional differentiation program and will repress MYC expression by binding to alterations. In addition to MYC translocations, BL harbors also MYC its promoter (Figure 1). Recent gene expression profiling studies functional domains that enhance the oncogenic potential of MYC by of isolated cells from the GC dark and light zones have identified different mechanisms, including increased protein stability and different transcriptional programs. TCF3 (E2A), a potent transcrip- transcriptional function, or by impairing the induction of the tion factor highly expressed in the dark zone,30 up-regulates genes proapoptotic element BIM. ID3 expression promoted by profile of germinal center B-cell-like and activated B-cell-like Hematology 2013 577 Table 2. MYC activation and cooperating mechanisms in aggressive B-cell lymphomas MYC inhibitory Normal cell physiological MYC oncogenic Lymphoma counterpart mechanism activation MYC cooperating mechanism* BL DZ GC cell BCL6 MYC translocation TCF3/ID3/CCND3 mutations GCB-DLBCL LZ GC cell BCL6 MYC translocation/? BCL2 translocation ABC-DLBCL LZ GC cell BCL6 BCR/MYD88 activation BCL2 overexpression (18q amplifications) PBL Plasmablast BLIMP1 MYC translocation ER stress response? ALK-positive large B-cell lymphoma Plasmablast BLIMP1 ALK-STAT3 activation? In larger series, 40% of patients these lymphomas originate in different GC compartments. Conversely, 60% to 80% of MYC rearrangements in supposedly “bona fide” de novo DLBCL are accompanied by either BCL2 or Recent genomic sequencing studies have identified novel recurrent BCL6 rearrangements, thus indicating that this “double-hit” (DH) somatic mutations in BL. The inactivation of ID3 likely impedes TCF3 in its inhibitory effect, resulting in a constitutive activation of this In contrast to BL, MYC rearrangements in DLBCL are usually seen pathway (Figure 2A). ID3 mutations (38%-68%) are more frequent in the context of complex karyotypic alterations,40,52 and MYC is than those of TCF3 (11%). They are detected in 70% of sporadic more frequently translocated to IGL or to non-IG genes such as and HIV-associated BL, but in only 40% of endemic tumors. The activation of TFC3 promotes the A MYC rearrangement predicted an inferior outcome in DLBCL in survival of BL cells (thus intensifying BCR signaling through the most studies, but it is not yet entirely clear if this is due to the MYC PI3K pathway) and their proliferation by up-regulating the expres- rearrangement itself or because 58% to 83% of MYC-translocated sion of CCND3 (Figure 2A). DLBCL with MYC translocations However, only one-third of DLBCL cases with substantial ( 30%- Approximately 5% to 14% of DLBCL cases have been reported to 40% cells) MYC protein expression do carry MYC gene altera- carry MYC translocations. This suggests that mechanisms other than gene systematically studied, has been reported in 2% of DLBCL cases in rearrangements are responsible for elevated protein expression in a a recent study. Protein overexpres- phenomenon named complicon, has been observed in some cases. In the latter case, the MYC gene rearrangement is B-cell lymphoma, unclassifiable, with features intermediate be- frequently accompanied by a t(14;18)(q32;q21) chromosome trans- tween DLBCL and BL (BCLU) is a provisional category in the 578 American Society of Hematology World Health Organization (WHO) 2008 lymphoma classifica- tion. Interestingly, MYC rearrangements can be detected in 30% to 50% of these tumors. The term “intermediate” lympho- mas was derived from gene expression profiling studies in which tumors were classified as “molecularly intermediate” if their gene expression profile was fully consistent with neither BL nor DL- BCL. In contrast to BL, BCLU generally harbors many more aberrations in addition to 8q24 (MYC) translocations. In the former, MYC-IGH translocations prevail, whereas MYC is more frequently translocated to IGL or to non-IG genes in the latter. These particular tumors are referred to as DH or “triple-hit” (TH) lymphomas. Gene expression profiling analyses have shown a profile intermediate between BL and DLBCL in some of the DH/TH lymphomas, whereas others display a BL gene expression pro- file. A satisfactory therapeutic approach is lacking and the average survival time is short, usually 1 year. It has also been observed in FL,66 and in B-cell lymphoblas- tic leukemia/lymphoma (TdT ). In Mitelman’s database of cytogenetic alterations in cancer, 62% of DH/TH cases harbor MYC/BCL2 translocations; a TH constellation involving MYC, BCL2, and BCL6 is encountered in 16%; and MYC/BCL6- rearranged cases account for only 8%. Note large blastic cells with broad cytoplasm and large nuclei, finely dispersed nuclear chromatin, and single Plasmablastic lymphoma and PCM prominent nucleoli (H&E stain; magnification, 400 ). In Plasmablastic lymphoma (PBL) is an aggressive neoplasm com- comparison with BL, the tumor cells are slightly larger and harbor more posed of a diffuse proliferation of large B cells, usually with irregular nuclei, sometimes with single nucleoli. Some histiocytes are immunoblastic morphology and the phenotype of a terminally interspersed, but there is no clearcut starry sky pattern (H&E stain; differentiated B cell characterized by the loss of mature B-cell magnification, 400 ). The cells are small to markers and expression of plasma cell–related antigens (Figure 3C). Giemsa stain highlights the plasmablastic features of the tumor cells. CD20 was negative in this tumor (magnification, all cases. These tumors usually present in extranodal sites and 1000 ). Morphological, immunological, and genetic features differentiating BL, BCLU, and DLBCL with MYC rearrangements Feature BL BCLU DLBCL Architecture Cohesive Often cohesive Variable Starry sky pattern As a rule Very often Sometimes Cell size Medium Medium/large Large Chromatin distribution Coarse Variable Fine Proliferation (Ki67) 95% Variable, often 95% Variable, more often 95% CD10 Almost always Frequent 30% BCL2 protein expression Negative/weak Variable Variable MYC translocation 90% (IGH) 35%-50% (IGL and non-IG) 5%-14% (IGL und non-IG) BCL2/BCL6 translocation in addition to MYC No Frequent 50%-70% Complex karyotype No Yes Yes virtually all of them with an IG gene as a partner and usually in the plasmablastic phenotype and expression of ALK protein due to context of multiple chromosomal aberrations, and seem to confer an activating gene rearrangements with different partner chromo- inferior prognosis. Contrary to other PBL types, these tumors do MYC activation also seems to play a role in the progression of not carry MYC translocations, but express high levels of MYC plasma cell neoplasms, particularly from monoclonal gammopathy protein.

Tmprss6 is a genetic Hematology 2013 7 modifier of the Hfe-hemochromatosis phenotype in mice purchase voveran sr australia. Hepcidin and the iron-infection anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 axis buy voveran sr once a day. Minihepcidins are complex and is required for efficient erythropoiesis purchase voveran sr in united states online. Hashizume M order cheapest voveran sr and voveran sr, Uchiyama Y, Horai N, Tomosugi N, Mihara M. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, 30. Minihepcidins mouse model of inflammation-induced anemia. An RNAi of bone morphogenetic protein signaling attenuates anemia therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) associated with inflammation. Reducing TMPRSS6 inhibition of hepcidin expression reverses anemia of chronic ameliorates hemochromatosis and beta-thalassemia in mice. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Transferrin therapy Modulation of bone morphogenetic protein signaling in vivo ameliorates disease in beta-thalassemic mice. Heparin: a potent therapeutic tool to limit iron overload and improve anemia in inhibitor of hepcidin expression in vitro and in vivo. Kaplan1 1University of California, San Francisco, San Francisco, CA Human herpesvirus 8 (HHV8) is a gamma herpesvirus associated with Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma, lymphoproliferative diseases that are most commonly observed in immunocompromised individuals. The viral genome expresses genes responsible for inhibition of apoptosis, cell cycle entry, and angiogenesis. Viral homologs of human regulatory genes are expressed, providing stimuli for angiogenesis, B-cell proliferation, and immune evasion. Variations in expression of these factors give rise to the 3 known HHV8-associated malignancies. Identification of these pathogenetic mechanisms has led to exploration of targeted treatment approaches for all 3 of these disorders with success in Kaposi sarcoma and multicentric Castleman disease; primary effusion lymphoma remains a clinical challenge. Introduction binding of LANA-1 to p53, blocking its ability to act as a Since human herpesvirus 8 (HHV8; also known as Kaposi Sarcoma transcriptional activator and promoting survival. LANA-1 is also Herpesvirus [KSHV]) DNA sequences were first identified in responsible for maintenance of the latent viral episome. V-FLIP is cutaneous Kaposi sarcoma (KS) tissue by Chang et al in 1994,1 the third of the LANA-promoter coding regions that prevents much has been learned about its role in the pathogenesis of KS and Fas-induced programmed cell death by interfering with the Fas/ other lymphoproliferative disorders, including multicentric Castle- TNFR pathway. Cell survival is also promoted through v-FLIP man disease (MCD) and primary effusion lymphoma (PEL). In cultured PEL cells, inhibition of v-FLIP rare neoplastic disorders that result from HHV8 infection are most expression results in cell death and v-FLIP expression in primary commonly associated with immunodeficiency states, including HIV endothelial cells results in the formation of KS-like spindle cells, a infection, iatrogenic immunodeficiency, and aging. This review process that can be reversed with inhibitors of NF- B. In KS, focuses on the unique pathogenetic role the virus plays in each of NF- B may also play a role in up-regulation of host cytokine these neoplasms and discusses clinical management strategies with transcription. Kaposin B may play a role in stabilization of cytokine a focus on the lymphoproliferative disorders. Cytokines are respon- sible for the angiogenesis and inflammatory infiltrates that form a part of the histologic pattern observed in KS. Pathogenesis of HHV8-associated disease HHV8 is a gamma herpesvirus and, like other viruses in its class, Lytic gene expression has both latent and lytic cycles. Figure 1 illustrates the differences in HHV8 lytic genes include v-IL6, v-BCL2, v-MIP, viral G-protein viral gene transcripts identified in HHV8-associated disease and coupled receptor (v-GPCR), and viral IFN regulatory factor (v-IRF- will be referred to in the text. One of the unique characteristics of 1), all of which are homologs of human regulatory genes. Lytic this virus is its expression of viral homologs of human regulatory 2 virus expression is most common in MCD, less so in KS, and proteins such as cyclin D, IL-6, bcl-2, and others. Although the expression of lytic cycle genes in largely latent in B cells, neoplastic KS spindle cells, and some the 3 diseases discussed here may differ, there are certainly atypical endothelial cells in KS. Lytic infection occurs in 3% KS 3 commonalities that can be related to the clinical characteristics of cells and is more frequent in MCD. The unique role of HHV8 in the pathogenesis of each of the 3 malignancies is discussed below (Figure 2). Latent gene expression HHV8 latent genes expressed include latency associated nuclear KS. HHV8 is required for the development of KS and the virus is antigen (LANA-1), v-FLIP (a viral analog of the FLICE inhibitory found in all subtypes of the disease, including classical, endemic, protein), and v-cyclin, all expressed off of the LANA promoter; and epidemic (HIV-associated), and posttransplantation KS. KS lesions Kaposin B (for review, see Schulz4 and Fukumoto5). Latent gene are characterized by the presence of neoangiogenesis. Cultured cells expression is present in all 3 disorders and centers around the ability transfected with v-GPCR up-regulate VEGF and bFGF,6 factors that of these proteins to promote cell cycle progression and inhibit play key roles in the pathogenesis of KS. Expression of v-GPCR in apoptosis, whether in KS spindle cells or B cells associated with transgenic mice produces angioproliferative lesions that resemble MCD or PEL. Furthermore, HHV8 infection in- LANA-1, which binds the tumor suppressor Rb, leading to en- duces c-kit gene expression in dermal microvascular endothelial hanced expression of E2F, and by expression of v-cyclin, which cells, transforming them from a cobblestone-like monolayer to binds to and activates cdk6 (Figure 2). Genome diagram of KSHV and viral transcripts expressed in KS, PEL, and MCD. There are more than 90 genes in the viral genome, but this diagram only shows those mentioned in this review. The arrows underneath the genome indicate the transcripts expressed in virus-infected cells in the 3 pathologies associated with KSHV. As discussed in the text, the majority of cells are latently infected in KS, PEL, and MCD, whereas there is a higher rate of lytically infected cells in MCD than in KS or PEL. Also known as “angiofollicular hyperplasia,” MCD is most HHV8 infection also up-regulates mRNA expression of multiple commonly observed in HIV patients and transplantation recipients, matrix metalloproteinases. PEL is characterized as an aggressive lymphoma presenting sion is broad in MCD, indicating a much stronger component of with malignant pleural, pericardial, or peritoneal effusions in the lytic infection than in either PEL or KS. V-IL6 is expressed in many absence of a discrete tumor mass. The cells are of B-cell origin, of the LANA-positive cells, is frequently detected in blood, and is although they rarely express CD20. Expression of CD38 and 138 believed to be a key factor responsible for B-cell proliferation. The pattern of gene expression is role in enhancing cytokine expression, with VEGF again playing an predominantly latent. Most cells express LANA, v-cyclin, v-FLIP, important role in the “angioproliferative” component, as is the case and kaposin. In addition, the classic form of KS occurring in Figure 2. Pathogenesis of the HHV8-associated diseases KS, PEL, and MCD. Shown is the pathogenesis of the HHV8-associated diseases KS, PEL, and MCD demonstrating viral effects on apoptosis, cell cycle progression, angiogenesis, cytokine production, and B-cell proliferation as described in the text. Targeted therapies in KS Drug Population Target N ORR Reference IFN- HIV with cART Angiogenesis immune modulation 13 38% 15 COL-3 HIV MMP inhibitor 37 41% 16 Imatinib HIV c-kit PDGF 10 50% 17 Imatinib HIV c-kit PDGF 30 33% 18 Lenalidomide HIV VEGF, immune modulation 3 100% 19 Sirolimus Posttransplantation Akt/mTOR 15 100% 20 IL-12 HIV Angiogenesis 24 71% 21 MMP,matrixmetalloprotein;andORR,overallresponserate. The lesions typically have a violaceous appearance and involve KS is present in up to 70% of individuals with MCD at diagnosis. The disease can be cosmetically disfigur- Laboratory abnormalities include anemia in most patients, poly- ing and, with extensive spread of the disease in the skin, may be clonal hypergammaglobulinemia, hypoalbuminemia, cytopenias, associated with lymphedema, pain, and secondary infection. Vis- respiratory symptoms, elevated C-reactive protein, and weight loss. Death due to KS and a polyneuropathy may occur with or without POEMS syn- is rare and can be associated with pulmonary involvement. The disease may take on a pattern of exacerbations with subsequent spontaneous remissions, whereas in others, a severe Localized, cosmetically unsightly lesions are most commonly acute illness may occur with a rapid downhill course. Localized radiotherapy is also an option for The diagnosis of MCD is based upon tissue biopsy, usually from a larger lesions, but doses should be kept low to avoid late complica- lymph node. The plasmacytic variant is most commonly observed in tions of therapy, such as sclerotic skin changes and chronic HIV patients and consists of hyperplastic follicles with indistinct lymphedema.

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HIV Indicator diseases across Europe Study (HIDES I): Results from the Pilot Phase discount voveran sr 100mg without prescription. Syphilis (Lues) Syphilis is caused by Treponema pallidum generic voveran sr 100mg free shipping, a bacterium belonging to the Spirochaetaceae family cheap voveran sr 100 mg visa. The bacteria are mainly transmitted by direct sexual contact with infected persons best voveran sr 100 mg, and penetrate into the organism through microlesions in the mucosa or the skin. In the case of unprotected sexual contact, the risk of transmission ranges from 30 to 60%. Hematogenous or congenital trans- missions very seldomly occur in western countries. Clinical course The incubation period is usually 14 to 24 days. Approximately 40 to 50% of infec- tions show no symptoms or are self-limiting. Persistent infections may affect various organ systems, going through stages of the course of the disease. The highest risk of transmission is during the clin- ical symptomatic stages of early syphilis (primary and secondary syphilis), especially in case of a primary lesion in stage I. During the late latency period (>1–2 years after infection) and the clinically symptomatic late stages (tertiary syphilis: 2–50 years post infection) syphilis is considered to be non-infectious. Primary syphilis: 2–3 weeks after infection the primary lesion with ulcus durum (hard chancre, erosive chancre) appears at the site of inoculation. This indolent, sturdy ulcer with infiltrated borders usually yields a clear treponema-rich exudate when compressed or squeezed. The chancre is accompanied by a usually strong one- sided lymphadenitis, swelling of the lymph nodes. This primary complex will spon- taneously resolve after 4 to 6 weeks without treatment. Even an ocular involvement manifesting as episcleritis or iritis can be seen in secondary syphilis. The clinical variety of the frequent syphilids on the skin or the mucous membranes varies from exanthema (usually with palmoplantar participation) to roseola, alopecia syphilitica, moist papule, angina specifica, to condylomata lata (genital and perianal) as well as pigment changes (leukoderma specificum) and lues maligna. Headaches at night are a sign of an early syphilitic meningitis cerebrospinalis. Latent syphilis: When the infection is brought under control by the immune system the clinical features usually disappear entirely. However, during this latency period, syphilis remains serologically detectable and a relapse or progression is possible. During the early latency period (<1–2 years after infection) the syphilis can still be transmitted by blood. Tertiary syphilis: Years after primary infection, the so-called gummata may appear. These can affect any organ, showing tuberous or granulomatous changes with a ten- dency to ulceration and cicatricial healing. Major cardiovascular features of tertiary syphilis are asymptomatic aortitis, aortic insufficiency, coronary ostial stenosis and aortic aneurysm. Tertiary syphilis of the central nervous system (CNS) has many manifestations, involving the meninges and the arteries and parenchyma of the cere- bral cortex. Meningovascular syphilis is characterized by an obliterative endarteritis of the meningeal vessels with subsequent arterial thrombosis and ischemic necrosis in the brain and spinal cord. Strokes are observed even in young patients with per- sistent untreated syphilis infection. Quarternary syphilis: In untreated patients, a late neurosyphilis occurs in various forms after some years. In case of tabes dorsalis, a shooting and burning pain, sensory ataxia, reflective pupilloplegia (signs of Argyll Robertson syndrome) and optic atrophy are observed. Regarding syphilitic meningitis, cranial nerve paresis, an increase of intracranial pressure and other neurological symptoms are seen. In case of progressive paralysis symptoms like headache and a change in personality prevail followed by dysplasia (a speech disorder), cramps, dementia and apoplectic attacks. An untreated progressive paralysis will lead to death in 4 to 5 years. Connatal/Congenital Syphilis: Diaplacental transmission usually happens in the 4th to 5th month of pregnancy. Depending on the stage of syphilis in a pregnant woman, it will lead to an abortion or a lues connata of the infant, progressing in the following ways: Lues connata praecox, rhinitis syphilitica, interstitial hepatitis, encephalomeniningitis with hydrocephalus communicans hypersecretorius as well as Parrot’s pseudoparalysis. The typical stigmata of lues connata tarda (from the age of 3) are saddle nose, Parrot’s ulcer and Hutchinson’s triad: Hutchinson’s teeth, ker- atitis parenchymatosa and labyrinthine deafness. In HIV+ patients, unusual manifestations and fulminant progress of syphilis are often observed (Gregory 1990). Reactivation of earlier infections as well as shorter latency periods and faster progression to the later stages including neurosyphilis occur in addition to symptoms of the coexistent stages. Neurosyphilis can be diagnosed in about 20% of syphilis/HIV-coinfected patients during the early syphilis stages (Esser 2011). Syphilis can lead to a temporary increase in HIV viral load and to an addi- tional deterioration of the immune status even in patients on effective ART. HIV and Sexually Transmitted Diseases 477 Diagnosis The diagnosis of syphilis in HIV+ patients can be complicated because of a nonspe- cific clinical course and also due to unreliable screening tests and atypical syphilis serologies like a late IgM descent after treatment and fluctuating VDRL titers (Venereal Disease Research Laboratory test, detection of phosphatide antibodies). Silvery-shining, spiral treponema are noticeable due to their typical rotating and bending movements when applying large-scale dark-field microscopy obtained from the stimulus secretion from the ulcus durum. A direct microscopic viral detection should be done when a primary syphilis lesion is suspected, particularly in the case of an initially prevailing seronegativity. As a first reaction, IgM antibodies will appear (diagnostic test and lipoid antibody detection will still be negative). Due to a possible overlap of disease stages, each serologically syphilis-positive patient should be neurologically examined. As the risk for neurosyphilis is markedly increased in HIV+ patients, a lumbar puncture to collect cerebrospinal fluid (CSF) is recommended when the patient has low CD4 cells (<350 cells/µl) or high viral loads (HIV RNA >100,000 copies/ml) or is not on antiretroviral treatment or shows neu- rological symptoms or ocular involvement or the time of infection is not certain (DSTIG 2014, Ghanem 2008, Marra 2004). Diagnostic findings in the CSF and neurological symptoms may have therapeutic consequences (see below). Interpretation of CSF results in HIV+ patients should be done by experts on the basis of the ITPA index (intrathecal-produced Treponema pallidum antibodies), parameters of a cerebrovascular barrier disorder and the detec- tion of lymphomonocytic pleocytosis. Interpretation of syphilis serology in HIV-infected patients Syphilis serology is based in principle on treponema-specific diagnostic tests. These are TPHA (Treponema pallidum hemagglutination assay), TPPA (Treponema pallidum particle agglutination test), or ELISA (enzyme-linked immunosorbent assay). If pos- itive, treponema-specific tests to confirm will follow, like IgM ELISA, IgM and IgG Western Blot or 19-S-IgM-FTA-ABS (treponemal antibody-absorption test). In the case of a reactive 19-s-IgM-FTA-ABS test in untreated patients or a reactivation of the test in treated patients (Lues non satis curate), there is always need for treatment. False-negative test results can be explained by inadequate production of antibodies or by suppression of IgM production due to high IgG levels. When in doubt, spe- cific tests such as FTA-ABS or cardiolipin tests should be carried out, even though false-negative results may occur again. Should a syphilis infection be serologically confirmed, a quantitative evaluation of the non-treponema specific activity param- eters (lipoid antibodies, e. The prozone phenome- non refers to a false-negative response resulting from disproportionately high anti- body titers that interfere with the formation of antigen-antibody lattice necessary to visualize a positive flocculation test. This effect can be expected during second- ary syphilis and in syphilis/HIV-coinfected patients (Smith 2004). HIV-associated unspecific activation of B lymphocytes can also cause false positive VDRL tests. Possibly quantitative Treponema pallidum PCR may facilitate the diagnosis and mon- itoring of the course in syphilis patients. The longer a patient has untreated syphilis the longer the normalisation of the syphilis activity parameters will take even after a successful syphilis therapy in HIV+ patients. A successful therapy during this IgM-reactive period is indicated by a clear titer decrease of the non-treponema-spe- cific activity parameters (reduction of VDRL by at least 2 titer levels within 3 months).

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