Hair follicle morphogenesis depends on Wnt, Shh, Notch, BMP and other signaling pathways interplay between epithelial and mesenchymal cells. The Wnt pathway plays an essential role during hair follicle induction, Shh is involved in morphogenesis and late stage differentiation, Notch signaling determines stem cell fate while BMP is involved in cellular differentiation. The Wnt pathway is considered to be the master regulator during hair follicle morphogenesis. Wnt signaling proceeds through EDA/EDAR/NF-κB signaling. NF-κB regulates the Wnt pathway and acts as a signal mediator by upregulating the expression of Shh ligand. Signal crosstalk between epithelial and mesenchymal cells takes place mainly through primary cilia. Primary cilia formation is initiated with epithelial laminin-511 interaction with dermal β-1 integrin, which also upregulates expression of downstream effectors of Shh pathway in dermal lineage. PDGF signal transduction essential for crosstalk is mediated through epithelial PDGF-A and PDGFRα expressed on the primary cilia. Dermal Shh and PDGF signaling up-regulates dermal noggin expression; noggin is a potent inhibitor of BMP signaling which helps in counteracting BMP mediated β-catenin inhibition. This interplay of signaling between the epithelial and dermal lineage helps in epithelial Shh signal amplification. The dermal Wnt pathway helps in upregulation of epithelial Notch expression. Dysregulation of these pathways leads to certain abnormalities and in some cases even tumor outgrowth. Edar-directed stabilization of β-catenin is important in determining the position of the follicle [The hair follicle (HF) is considered a mini-organ formed with neuroectodermal-mesodermal interaction . HF morpfollicle .HF undergoes characteristic cyclic phases known as the hair cycle. The cycle includes anagen (growth phase), catagen (regression phase) and telogen (resting phase); exogen (release of the telogen club or hair shredding) does not occur at every cycle . Anagen 2.The stem cell microenvironment “niche”  plays a + cells are located in hair placodes and prenatally they give rise to HFs, sebaceous glands and interfollicular epidermis. Postnatally, their contribution to hair lineages diminish; they renew epidermal cells and sebocytes and give rise to LGR5+ stem cells that are Wnt-dependent and contribute in HF lineages. Nevertheless, following wounding, LGR6+ cells contribute to the epidermis healing including formation of new HFs. Hierarchically lower epithelial stem cells are dependent on Wnt signaling due to the presence of LGR4 and LGR5, an orphan group of G protein coupled receptors. These receptors express high affinity toward R-spondins and their binding causes increased Wnt/β-catenin signaling by enhanced Wnt-induced LRP6 phosphorylation [In adult HFs , the mosrylation . HF morprylation . Dlx3 isrylation .There is strong genetic evidence showing that progenitor cells at the bottom of the intestinal crypt accumulate nuclear β-catenin, a hallmark of active Wnt signaling , therefode novo formation of HF and increased follicle density [During telogen bulge stem cells reside in a Wnt-restricted environment . During  density  as well  density ,31,32. I density .Wnt signaling is not the only signal transduction pathway that instructs stem cells. Notch signaling controls selective cell-fate determination in a variety of tissues . Notch sBMPs are secreted signaling molecules that belong to the TGF-β superfamily and exert their biological activity via interaction with specific BMP receptors –42. In tSox4 and Sonic hedgehog (Shh) genes are not expressed in the bulge but are co-expressed in the developing hair germ [in vivo, and in vitro, ligands specific for each pathway cause proliferating keratinocytes to transiently withdraw from the cell cycle [Noggin-null mutants, and is elevated in the presence of excessive Noggin or in the absence of BMPR1A [Although the mechanisms controlling the hair cycle are still unfolding, BMP signaling is likely to be involved. BMP signaling also plays a role in HF morphogenesis, postnatal regeneration and control of the HF cycle through regulation of hair matrix precursor cell proliferation and differentiation . Enhanceair germ ,53. HF sll cycle ,54–56. Tll cycle . Conversll cycle ,57. Sox9ll cycle ,30. Thisll cycle . The prof BMPR1A ,52.Sonic Hedgehog (Shh) signaling regulates proliferation and developmental patterning in many tissues, including the HF ,59. Shh 3.HF morphogenesis is classified into three main stages: induction, organogenesis and cytodifferentiation . Regulat3.1.HF development is an orchestrated interaction between mesenchymal and epithelial cells mediated through the secretion of signaling molecules . Wnt is Stabilized dermal β-catenin activity is essential for expression and relaying signals to the overlying epithelium; the nature of this signaling is still elusive. β-catenin expression is sequentially activated starting first in upper dermis followed by epithelium of hair placodes ,74 and aEpithelial Wnt/β-catenin and EDA/EDAR/NF-κB signaling pathways play role in HF initiation and primary hair placodes maintenance. Wnt/β-catenin regulates expression of Eda ,78 as wePlacode formation is followed by dermal fibroblasts condensation. Condensation is mediated by fibroblast growth factor (FGF) 20  which isHF initiation in placodes requires down regulation of keratinocyte growth factor (KGF) and epidermal growth factor (EGF) signaling. Receptors of these pathways are down regulated (EGFR and FGFR IIIb) while their ligands persist throughout the initiation. In the presence of their ligands HF formation is inhibited in a time and dose dependent manner. The main function of these pathways is to promote epidermal differentiation at the expense of HF fate ; however3.2.i.e., epithelium and dermal condensate. The initial role of Shh signaling in early HF is epithelial proliferation [Placode proliferation and dermal condensation occur concomitantly and massive keratinocyte proliferation marks the beginning of organogenesis. In order for HF induction to proceed, it is essential to antagonise the inhibitory effect of BMP. Dermal Noggin mediates inhibition of BMP and regulates HF epithelial induction through Lef1 ,51. Soniferation –93. Epitferation . In the feration . Shh actferation .HF morphogenesis stalls in the absence of TGF-β2 signaling and Snail expression (involved in expression of certain adhesion proteins) by blocking HF down growth. TGF-β2 signaling is essential for transient induction of transcription factor Snail and activation of Ras-mitogen-activated protein kinase (MAPK) pathway in the bud. Snail functions in regulating cell proliferation and cell adhesion. Therefore this pathway precisely governs epithelial proliferation, junctional remodeling and bud formation which helps in proper progression of hair morphogenesis .3.3.HF differentiation is characterized by development of all the compartments of the HF. Various signaling molecules elicit their role in closely refining this process. IRS differentiation is regulated by the Gata3 and Cutl transcription factors –98, whilFoxN1 gene. FoxN1 plays an important role not only in regulating HF keratinocyte differentiation [Wnt signaling induces a positive effect on the Notch pathway while recent evidence has shown an antagonistic effect of Notch on Wnt signaling ,106. In ntiation  but alsontiation . HF diffntiation .Notch gene family  comprises highly conserved transmembrane receptors. Notch participates in HF development in three possible ways: lateral inhibition, boundary formation and lineage decision. Cell fate is dependent on asymmetrical inheritance of Notch regulators and regulating differentiation and promoting boundary formation by altering adhesive properties of keratinocytes [i.e., it plays a role in control of cell fate, stem cell potential and differentiation [The inocytes , i.e., intiation ,112. Notntiation . Notch, ntiation . By moduntiation .Hair shaft progenitor differentiation is under direct control of DP through Sox2 expression. BMP6 and Sostdc1 are direct transcriptional targets of Sox2. Sox2 leads to concomitant upregulation and downregulation of BMP6 and Sostdc1, respectively. Sostdc1 is a potent BMP inhibitor. BMP6 inhibits cell migration. Thus, Sox2 regulates hair growth by controlling progenitor cell migration through BMP-mediated epithelial-mesenchymal crosstalk .BMP and BMPRIA have been implicated in HF differentiation . Along wOther factors controlling differentiation include the Dlx3 transcription factor that controls differentiation of IRS and hair shaft. Dlx3 is a direct target of Lef1 and upregulates expression of Hoxc13 and Gata3 transcription factors, potent regulators of hair shaft differentiation .4.The process of HF regeneration involves BMP antagonism and subsequent activation of Wnt and other underlying pathways. The initial steps of regeneration involve crosstalk between quiescent epithelial stem cells and mesenchymal dermal papilla forming a repressive environment for BMP signals.Tmeff1, a target gene of the TGF-β2/Smad2/3 pathway, lowers the threshold of BMP in the niche promoting stem cell transition from telogen to anagen [TGF-β2 is an important factor essential for regeneration as it activates the Smad2/3 pathway in HF stem cells, which is crucial for avoiding delayed regeneration. o anagen . Recent o anagen .RAS gives rise to genetic disorders termed RAS/MAPK syndromes. Mutations in this gene affect HF morphogenesis, differentiation and hair cycling. RAS signaling mediates these effects by repression of Shh, and is supposed to be a mediator of FGF signaling. RAS signaling regulates HF morphogenesis by fine-tuning Shh levels [Normally, the hair cycle undergoes three phases named anagen, telogen and catagen ,85,124. h levels . At the h levels  and fromh levels .Nuclear factor 1 C (NF1C) is a key regulator in the transition from telogen to anagen phase in the hair cycle by inducing the expression of Shh, Wnt5a and Lef1. It also increases keratinocyte proliferation and initiates the induction of anagen by upregulating TGFβ1 and the inhibition of p21. The function of this transcription factor is required for postnatal tissue regeneration and adult progenitor cell proliferation .p21, p27, p57, and p15 transcription. Out of these genes, p21 acts as cell cycle inhibitor. Runx1 and p21 synergistically rescue cell cycle arrest depending on the required conditions by directly down-regulating mRNA levels of other cyclin-dependent kinase inhibitors [During embryonic HF formation the RunX1 transcription factor regulates HF stem cells emergence and maintenance via modulation of bidirectional cross talk between nascent stem cells and their niche. Detailed analysis revealed embryonic mesenchymal RunX1 expression is essential for proper adult HF stem cell differentiation and long-term skin integrity. In its absence, HF stem cells differentiate into sebaceous glands . RunX1 fhibitors .Fgf10, sclerostin, and BMP and activin membrane-bound inhibitor homolog (BAMBI), Dlx3 and a few keratin genes. Out of these genes, sclerostin and BAMBI are components of Wnt signaling while Dlx3 is of BMP signaling. Out of these arrays of genes, Krt16, Krt17, Dlx3, and Fgf10 serve as direct miR-31 targets. Thus miR31 regulates HF growth by modulating growth-regulating molecules and cytoskeletal proteins [miR-31 plays a significant role during HF growth and hair fiber formation by targeting a number of growth regulatory molecules and cytoskeletal proteins. Its expression increases during anagen and subsides during catagen and telogen phases. miR31 negatively regulates expression of proteins .5.HF disorders can be classified mainly into three types: alopecia, hirsutism and hair shaft disorders. Alopecia is characterized by abnormal loss or thinning of hairs. A common disorder associated with HF includes androgenic alopecia caused due to hormonal imbalance. Alopecia, hirsutism (excessive hair growth in adult women) and hair shaft disorders are mainly caused not only by the malfunction of one or more signaling pathways but also by other factors such as autoimmune disorders, genetic predisposition, cancer and microbial infections.5.1.Adenomatosis polyposis down regulated 1 (APCDD1) gene encodes a membrane bound glycoprotein that acts as a potent inhibitor of the Wnt signaling pathway by interacting with Wnt3A and LRP5. This inhibitory function plays an important role during development of neurons from the progenitors; however, L9R mutations inhibit membrane localization and stability thus rendering it free to act within the Wnt signaling pathway, predisposing the patient to alopecia [Various forms of alopecia involve deviations from normal signaling pathways, for instance hypotrichosis simplex disease, which is an autosomal disorder characterized by miniaturization of HFs . Adenomaalopecia . Trichoralopecia .One key factor in non-androgenic male pattern baldness is Dickkopf1 (DKK-1), which promotes catagen. It is suggested that DKK-1 blocks Wnt signaling by preventing β-catenin activation and instead activating the pro-apoptotic protein Bax, inducing apoptosis in outer root sheath keratinocytes. Current research supports that DKK-1 causes anagen to catagen induction leading to pattern baldness, which is commonly shown by older male populations .The main cause of male pattern baldness in response to hormones or androgenic alopecia is due to dihydrotesterone, which is produced by balding dermal papillae. Presence of dihydrotesterone in HF occurs either through the DP capillaries, as it is normally circulated in the blood, or by conversion of testosterone in balding DP cells. Presence of dihydrotesterone causes upregulation of IL-6 that in turn promotes the expression of the IL-6 receptor along with glycoprotein 130 in keratinocytes and matrix cells. The outcome of this IL-6-upregulated expression is inhibition of the hair shaft elongation with simultaneous suppression of matrix cells proliferation. Studies in this regard have shown that IL-6 expression induces anagen-catagen progression .Shh pathway is known to play an important role in both embryonic hair development as well as in the normal cycling of adult HF, and implies in the induction of anagen phase accompanied by hair growth . CertainA few miRNAs have been implicated in male patterned baldness. Recent evidence has demonstrated upregulation of miR-221, miR-125b, miR-106a and miR-410 in balding papilla cells . miRNAs 5.2.etc.HF associated tumors are rare and often associated with hair germ, infundibulum, ORS and matrix or follicle mesenchyme. Generally HF tumors arise due to unrestrained signaling pathways. Examples of HF tumors include trichofolliculoma, trichoepithelioma, trichoblastoma, trichilemmoma, and trichomatricoma Notch and BMP pathways are proliferation antagonists and suppress epithelial growth. Loss or mutation of these factors can facilitate tumor formation as evidenced from inhibition of BMP signaling in hair progenitor cells that leads to trichofolliculoma in humans .The Wnt pathway, along with its downstream effector β-catenin, plays an important role in cell proliferation, epithelial architecture and cell polarity regulation. The stabilization of β-catenin is essential for HF development but its dysregulation leads to HF tumors, e.g., trichomatricoma . AdditioThe Wnt pathway effector β-catenin activates downstream target genes either independently or in synergy with other factors and response elements. One of these response elements, vitamin D, is essential for β-catenin induced hair differentiation without which β-catenin is unable to carry out its physiological effect. Recent evidence has shown that β-catenin and vitamin D response elements are highly upregulated in human trichofolliculomas .Basal cell carcinoma is also linked with Shh pathway dysregulation. Evidence has strongly suggested an association between Shh and the insulin like growth factor binding protein-2 (IGFBP-2) in the transformation of normal HF to basal cell carcinoma . The oriSome very intriguing mechanisms underlie tumor cell formation given that they are massively reprogrammed back to embryonic HF cell progenitors. The expression of β-catenin is highly upregulated followed by the expression of SmoM2 in adult epidermis; deletion of β-catenin prevents progenitor reprogramming and tumor formation . This prPten, Pdcd4, Timp3 and Tpm1 while the expression of differentiation genes Idl, Id2, Id3 and Msx2 are unaffected. BMP exerts its effect on keratinocytes through regulated expression of miRNAs. BMP4 dramatically inhibits miR-21 expression in keratinocytes [BMP plays an essential role in controlling various developmental processes and acts as a potent tumor suppressor. Recent evidence has revealed a role of miRNA in antagonizing BMP effects. miR-21 negatively regulates BMP dependent tumor suppressor genes such as inocytes .The question is, where do the signals driving the tumors come from? What type of mutations occurs in genes and when do they happen? Are all the cells in a tumor involved in its growth equally? How are basic mechanisms of HF regeneration involved in tumorigenesis? What is the role of niche signaling in regulation of tumor growth? Can certain tumors be suppressed by turning off particular signaling pathways? Should different tumors be treated in different ways? Although there are many questions left unanswered in tumor biology, recent progress has refined knowledge concerning the role of signaling pathways involved in tumorigenesis.6.The insight gained from the signaling pathways involved in hair follicle morphogenesis will prove helpful in the research of hair follicle abnormalities arising from signaling dysregulation. Currently, only a few attempts to modify these pathways have been performed in the treatment of abnormalities such as alopecia. Although some promising drugs have emerged with the ability to target pathway effectors, providing some success in the treatment of hair follicle abnormalities, treatment attempts remain restricted due to the potential risk of carcinogenesis. Further, more in depth research is necessary to implement the knowledge acquired from these signaling pathways in stem cell based therapy.


Antibody screening tests are critical tools to identify individuals infected with HTLV-1 and HTLV-2. However, the lack of reference panels hinders the ability to evaluate existing tests and new technologies that aid in the screening for these agents. For example, some HTLV-2 subtypes may escape detection by currently available technology. The World Health Organization, through the support of the WHO Expert Committee on Biological Standardization, is in the process of generating such a reference panel.This reference panel will best function as a tool for test assessment only if it consists of specimens representing the diversity of HTLV-1 and HTLV-2, especially those subtypes known to present challenges to detection using serological tests. A panel consisting of seven members  is being considered.The reference panel will be fully characterised and assessed in an international collaborative study. This first WHO HTLV antibody reference panel is expected to be used by blood screening and diagnostic test developers, blood banks, hospitals and other establishments performing HTLV serology testing.


Human T-cell leukemia virus type-1 (HTLV-1) is a replication-competent human retrovirus associated with two distinct types of disease only in a minority of infected individuals: the malignancy known as adult T-cell leukemia (ATL) and a chronic inflammatory central nervous system disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic progressive myelopathy characterized by spastic paraparesis, sphincter dysfunction, and mild sensory disturbance in the lower extremities. Although the factors that cause these different manifestations of HTLV-1 infection are not fully understood, accumulating evidence from host population genetics, viral genetics, DNA expression microarrays, and assays of lymphocyte function suggests that complex virus-host interactions and the host immune response play an important role in the pathogenesis of HAM/TSP. Especially, the efficiency of an individual's cytotoxic T-cell (CTL) response to HTLV-1 limits the HTLV-1 proviral load and the risk of HAM/TSP. This paper focuses on the recent advances in HAM/TSP research with the aim to identify the precise mechanisms of disease, in order to develop effective treatment and prevention. Human T-cell leukemia virus type-1 (HTLV-1) is a human retrovirus etiologically associated with adult T-cell leukemia (ATL)  and HTLVDeltaretrovirus of the subfamily Orthoretrovirinae and infects 10–20 million people worldwide [+ T cells by transgenic expression, indicating the possible involvement of HBZ expression in the development of ATL [HTLV-1 is classified as a complex retrovirus in the genus orldwide –15. HTLVorldwide , injectiorldwide , 18. Fororldwide . Howeverorldwide . The splorldwide  and HAM/orldwide  cases, aorldwide . Also, Ht of ATL , 24. Mort of ATL . These ft of ATL .HAM/TSP is a chronic progressive myelopathy characterized by spastic paraparesis, sphincter dysfunction, and mild sensory disturbance in the lower extremities . In addiα, interleukin (IL)-6 and interferon (IFN)-γ, and an increased intrathecal antibody (Ab) synthesis specific for HTLV-1 antigens have also been described [Pathological analysis of HAM/TSP autopsy materials indicates that the disease affects the spinal cord, predominantly at the thoracic level , 32, 33.escribed . Clinicaescribed . The cliex vivo [+ T cell response, that is, the fraction of autologous HTLV-1-expressing cells eliminated per CD8+ T cell per day, was inversely correlated with both PVL and the rate of spontaneous proviral expression [A previous population association study of 202 cases of HAM/TSP and 243 ACs in Kagoshima prefecture, HTLV-1 endemic Southern Japan, revealed that one of the major risk factors is the HTLV-1 PVL. The median PVL was more than ten times higher in HAM/TSP patients than in ACs, and a high PVL was also associated with an increased risk of progression to disease , 37. A hex vivo , granzympression . These fpression . α promoter-863 A allele [Analysis of non-HLA host genetic factors by candidate gene approaches revealed that non-HLA gene polymorphisms also affect the risk of developing HAM/TSP . For exaA allele  and the A allele  predispoA allele , stromalA allele  conferreA allele , 49. Howtax gene variation and the risk of HAM/TSP [tax subgroup A, which belongs to cosmopolitan subtype A, was more frequently observed in HAM/TSP patients, and this association was independent of the protective effect of the HLA allele HLA-A*02. HLA-A*02 appeared to give protection against only one of the two prevalent sequence variants of HTLV-1, tax subgroup B which belongs to cosmopolitan subtype B, but not against tax subgroup A in the Japanese population [Although most studies of HTLV-1 genotype have reported no association between variants of HTLV-1 and the risk of HAM/TSP, Furukawa et al. reported the association between HTLV-1  HAM/TSP . The taxpulation . Interespulation . Moreoveμg of PBMC genomic DNA. They calculated an oligoclonality index (OCI) to quantify the clonality of HTLV-1-infected cells in vivo and found that the OCI did not distinguish between ACs and patients with HAM/TSP and that there was no correlation between OCI and HTLV-1PVL in either ACs or HAM/TSP patients. These results indicate that the higher PVL observed in patients with HAM/TSP was attributable to a larger number of UISs but not, as previously thought, from a difference in clonality. They also obtained evidence that the abundance of established HTLV-1 clones is determined by genomic features of the host DNA flanking the provirus. Namely, HTLV-1 clonal expansion in vivo is favored by a proviral integration site near a region of host chromatin undergoing active transcription, or same-sense transcriptional orientation of the provirus. Negative selection of infected clones, probably by CTLs during chronic infection, favors establishment of proviruses integrated in transcriptionally silenced DNA, and this selection is more efficient in ACs than in HAM/TSP, indicating the selection of HTLV-1-infected T-cell clones with low pathogenic potential.Recently, to test whether the genomic integration site determines the abundance and the pathogenic potential of an HTLV-1-positive T-cell clone, Gillet et al. reported the results of high-throughput mapping and quantification of HTLV-1 proviral integration in the host genome . They ma+CD16+ subset) than ACs although the results were not normalized with respect to PVL [+ cells, whereas there was no significant difference in the frequency of HLA-E tetramer-binding CD3− cells between patients with HAM/TSP and ACs [Lactobacillus casei strain Shirota resulted in a significant increase in NK cell activity, with improvements in clinical symptoms [+ T-cell spontaneous proliferation [+ NK cells also spontaneously proliferated in vitro, and spontaneous NK cell proliferation positively correlated with HTLV-1 PVL but not with the presence of HAM/TSP [in vitro proliferation of PBMCs when cultured in the absence of exogenous antigen or mitogen, referred to as spontaneous lymphocyte proliferation (SLP), and in HAM/TSP patients, the levels of SLP reflect the severity of the disease [+ T cells in culture [Previous reports indicated that patients with HAM/TSP had both a lower frequency and a lower activity of NK cells  and IFN-α is also beneficial for overall survival in smoldering and chronic (i.e. indolent) ATL [α treatment and the functional role of ISGs as potential targets for therapy. In PBMCs of HTLV-1-infected individuals, the level of HTLV-1 mRNA is very low, and viral protein is not detectable, but these molecules are rapidly expressed after a short time in culture in vitro  [α/β receptor only partly abrogated this phenomenon, the results indicate that the innate immune system suppresses HTLV-1 expression in vitro and in vivo, at least through type I IFN.Type I interferon (IFN) is a key innate immune cytokine produced by cells in response to viral infection. The type I IFN response protects cells against invading viruses by inducing the expression of interferon-stimulated genes (ISGs), which execute the antiviral effects of IFN . The ISGd trials , 63. Howent) ATL  althoughn vitro  . Howevern vitro  . Namely,In 2002, it was reported that antibodies that recognize HTLV-1 Tax protein can cross-react with a heterogenous-nuclear-riboprotein (hnRNP-) A1, suggesting intriguing evidence for antigen mimicry in HTLV-1 infection . Howeverin vivo and the existence of an augmented humoral immune response to HTLV-1 in HAM/TSP patients. Although Ab responses to the immunodominant epitopes of the HTLV-1 envelope (Env) proteins were similar in all of three clinical groups , reactivity to four Tax immunodominant epitopes was higher in HAM/TSP patients (71%–93%) than in ATL patients (4%–31%) or ACs (27%–37%) [in vivo are still largely unknown. It will be interesting to examine whether HTLV-1 neutralizing Ab titres correlate with disease status and PVL in infected individuals. Since the mutation rate of HTLV-1 provirus is significantly lower than HIV-1, passive immunization with human monoclonal Ab may be beneficial and effective method to prevent HTLV-1 infection.In HTLV-1 infection, HAM/TSP patients generally have a higher anti-HTLV-1 Ab titer than ACs with a similar HTLV-1 proviral load –71. Thes27%–37%) . Among t27%–37%) , 74, vac27%–37%) , 76, imm27%–37%) , and pas27%–37%) , 79 were+ CTLs are typically abundant, chronically activated, and mainly targeted to the viral trans activator protein Tax [+ T cells efficiently kill autologous Tax-expressing lymphocytes in fresh PBMCs in HTLV-1-infected individuals [+ CTL response plays a critical part in limiting HTLV-1 replication in vivo and that genetically determined differences in the efficiency of the CTL response to HTLV-1 account for the risk for developing HAM/TSP. Indeed, as mentioned above  and detrimental (inflammatory) effects, such as lymphocytic choriomeningitis virus (LCMV) infection in the mouse [Since the frequency of HTLV-1-specific CD8than ACs , 83, andthan ACs , there i low PVL , suggest low PVL . Recentl low PVL , indicathe mouse . Second,+ T-cell responses are of central importance in driving B-cell and CD8+ T-cell responses in vivo. The most common HTLV-1 antigen recognized by CD4+ T-cells is the Env protein [+ T-cell response [+ T cells compared to ACs [+ T cells in both ACs and patients with HAM/TSP [γ, TNF-α, and IL-2 production by CD4+ T cells in patients with HAM/TSP compared to AC of a similar PVL [+ T cells in initiating and causing HAM/TSP is also consistent with the immunogenetic observations that the possession of HLA-DRB1*0101, which restricts the immunodominant epitope of HTLV-1 Env gp21, was associated with susceptibility to HAM/TSP in independent HTLV-1-infected populations in Southern Japan [+ T cells directly ex vivo [+CD4+ T cells was significantly higher in HAM/TSP patients than ACs with similar PVL. Furthermore, direct ex vivo analysis of tetramer+CD4+ T cells from two unrelated DRB1*0101-positive HAM/TSP patients indicated that certain T-cell receptors (TCRs) Vβs were utilized and antigen-specific amino acid motifs were identified in complementarity determining region (CDR) 3 from both patients. These results suggest that the observed increase in virus-specific CD4+ T cells in HAM/TSP patients, which may contribute to CD4+ T cell-mediated antiviral immune responses and to an increased risk of HAM/TSP, was not simply due to the rapidly growing HTLV-1-infected CD4+ T cells but was the result of in vivo selection by specific MHC-peptide complexes, as observed in freshly isolated HLA-A*0201/Tax11-19 tetramer+CD8+ T cells [Antiviral CD4 protein , 88, in response –91. At ad to ACs . The ant HAM/TSP , and theilar PVL , 94. A rrn Japan , 41 and rn Japan . Accordi ex vivo . The res T cells  and musc T cells .+CD25+ lymphocytes in vivo [+ Tregs [+ expression in CD4+CD25+ cells is lower than that in ACs and uninfected healthy controls [+ cells in the CD4+CD25+ population in HTLV-1-infected individuals, especially HAM/TSP patients. It is important to note that the CD4+CD25+ population contains a mixture of Tregs and activated non-Tregs. Therefore, it is inappropriate to use CD25 as a marker of Tregs in HTLV-1 infection: the best current working definition of Treg phenotype is CD4+Foxp3+. Reports from different geographic regions indicate that the percentage of CD4+Foxp3+ cells is higher in the HAM/TSP patients than in ACs [+Foxp3+T cells in HTLV-1-infected individuals is maintained by CCL22 produced by HTLV-1-infected PBMCs [+Foxp3+ cells was positively correlated with the HTLV-1 proviral load [+Foxp3+ cells [+Foxp3+ Tregs may impair the CTL surveillance of HTLV-1. If this is the case, activity of CD4+Foxp3+ cells may also determine the risk of developing HAM/TSP via increasing the HTLV-1 PVL.Regulatory T cells (Tregs) are important mediators of peripheral immune tolerance and also play an important role in chronic viral infections. In HTLV-1 infection, it has been reported that HTLV-1 preferentially and persistently infects CD4 in vivo , which c[+ Tregs . In HAM/controls , 99. Thicontrols , which mn in ACs –103. It ed PBMCs . The freral load , 105, an3+ cells , suggest+ T cells [+ T cells both in vitro and in vivo [+ DCs, and a chimeric HTLV-1 that carries the envelope gene from Moloney murine leukemia virus, Rahman et al. demonstrated the critical role of DCs in their ability to mount both innate and adaptive immune responses during early cell-free HTLV-1 infection [Dendritic cells are antigen-presenting cells which play a critical role in the regulation of the adaptive immune response. In HTLV-1 infection, it has been shown that the DCs from HAM/TSP patients were infected with HTLV-1 , and the T cells . In addi T cells , and DCs in vivo . Moreovenfection , 113. Sinfection , the intAs shown in


Cell & Bioscience [The TGF-β family of cytokines encompasses a large number of versatile poly-peptide growth factors regulating a multitude of cellular processes in almost every aspect of cellular function, including proliferation, differentiation, apoptosis, migration, and adhesion. Inappropriate signaling by these factors is closely linked to cancer and other diseases. Although much has been known about the TGF-β signaling pathway since the discovery of Smads 15 years ago, remarkable progress has been made during the past few years in revealing details of different regulatory mechanisms that afford a full range of control of the biological functions of the TGF-β. In this special review issue of oscience , Liu-Ya oscience , and Xueoscience .With the deep understanding of the signaling mechanism and the availability of various genetic models, specific physiological and pathological roles of TGF-β/Smad in different cellular context start to emerge. Gangwen Han and Xiao-Jing Wang summarize the differential role of signaling Smads, including Smad2, Smad3 and Smad4, in squamous cell carcinoma . Yan CheThis special issue covers a broad, albeit not all-inclusive, aspect of TGF-β signaling and biology. It is my sincere hope that this collection of review articles will bring our readers to the cutting-edge of current development and is helpful in appreciating new breakthroughs in this field.The opinions expressed in this Editorial are of the author's personal view and do not necessarily reflect the views of her employer, the National Institutes of Health, USA.


Estimates of age-specific fertility rates based on survey data are known to suffer down-bias associated with incomplete reporting. Previously, William Brass  proposed a series of adjustments of such data to reflect more appropriate levels of fertility through comparison with data on children-ever-born by age, a measure of cohort-specific cumulative fertility. His now widely-used Parity/Fertility or PF ratio method makes a number of strong assumptions, which have been the focus of an extended discussion in the literature on indirect estimation. However, while it is clear that the measures used in making adjusted age-specific fertility estimates with this method are captured with statistical uncertainty, little discussion of the nature of this uncertainty around PF-ratio based estimates of fertility has been entertained in the literature. Since both age-specific risk of childbearing and cumulative parity (children ever born) are measured with statistical uncertainty, an unknown credibility interval must surround every PF ratio-based estimate. Using the standard approach, this is unknown, limiting the ability to make statistical comparisons of fertility between groups or to understand stochasticity in population dynamics. This paper makes use of approaches applied to similar problems in engineering, the natural sciences, and decision analysis—often discussed under the title of uncertainty analysis or stochastic modeling—to characterize this uncertainty and to present a new method for making PF ratio-based fertility estimates with 95 percent uncertainty intervals. The implications for demographic analysis, between-group comparisons of fertility, and the field of statistical demography are explored. Population dynamics are driven by the often complex interplay of demographic components of change including births, deaths, immigration, and emigration level of fertility achieved by a specific age level of achieved fertility captured in the cohort measures As early as 1964, William Brass suggested the possibility that given an assumption that underreporting is equivalent across age groups, period measures of age-specific fertility could be adjusted by leveraging information on cohort parity such as the average number of children ever born to a woman of a given age While there is no set algorithm for determining which PF ratio to use The simplicity and ease with which the Brass PF ratio method is implemented, its apparent ability to produce much more reasonable estimates of age-specific fertility rate and total fertility rate than unadjusted ones, and its promotion by the leading demographic research units involved in training demographers around the world uncertainty analysis or stochastic modelinginputs formulated with uncertainty affect uncertainty in an output of interest This issue of statistical uncertainty in estimation of fertility using the PF ratio method has received little attention in the demographic literature. Given the data sources used in its construction, however, it seems an unavoidable fact that such statistical uncertainty is associated with the ratio. Estimates of age-specific fertility risk and children ever born by age are both measured through survey data in the case of variant B3, and sampling variability is contained in both. If we think of both estimates as inputs to the PF ratio estimate, then the adjusted age-specific fertility schedules represent an output into which the uncertainty associated with each input is propagated. This uncertainty has not received an adequate amount of attention within the demographic literature, perhaps because demographers remain unfamiliar with potential solutions to the challenge and often make little use of statistical theory in their work as well as an estimate of the 95% upper and lower confidence bounds for the estimate. The end result of the procedure is a stochastic estimate of age-specific fertility that both adjusts for under-reporting while incorporating statistical information on uncertainty into the estimates. It provides a statistical distribution of ASFR to assess quality as well as to incorporate into stochastic projection models if desired The conceptual application of uncertainty analysis to the estimation of PF ratios with uncertainty intervals is illustrated in www.measuredhs.com) and survey-based estimates of age-specific fertility from the Sample Registration System (SRS) of India (www.census.in). These data are utilized to illustrate the stochastic approach to the Brass method and provide point estimates and 95% upper and lower uncertainty bounds on these estimates using the exact process described in The purpose of this paper is to illustrate this novel approach for producing stochastic estimates of ASFR within the Brass PF ratio framework. The paper utilizes data from 5 randomly-selected Indian provinces and models age-specific fertility using data on children-ever-born from the Demographic and Health Surveys (http://censusindia.gov.in). Data on children ever-born was obtained for each province using microdata from the associated Demographic and Health Surveys (www.measuredhs.com) for 1998. The one year gap between these datasets was considered trivial and unlikely to be of sufficient temporal duration to introduce bias into these estimates. Average children ever born by age were computed from the DHS data by the authors, including estimation of variance associated with each these estimates. The uncertainty associated with the SRS estimates is not publicly-reported, presenting a challenge for evaluating the uncertainty in PF ratio estimates associated with these data. As a reasonable substitute, we estimated variances associated with the binomial proportion of births in the last twelve months captured in the Demographic and Health Surveys, using the normal approximation A random sample of five Indian provinces was taken to include Bihar, Uttar Pradesh, Tamil Nadu, Madhya Pradesh, and Goa . ReporteUsing these data, PF ratios were computed, first using the standard procedure , then thThe base results suggest that fertility underreporting is greater in younger age intervals and varies across provinces . A consieven higher estimates of the overall level of fertility than were observed in the traditional application of the Brass method. The 95 percent uncertainty intervals presented in The main contribution of this research has been to illustrate how the Brass PF ratio method may be extended to incorporate statistical uncertainty associated with data inputs using simple methods from stochastic modeling and uncertainty analysis. The results of the procedure provide point estimates and 95% uncertainty intervals for age-specific fertility that adjust survey-based estimates for underreporting of births. The approach represents a potentially significant improvement in stochastic demographic modeling, suitable for use in making between-group fertility comparisons as well as in demographic estimation or projection models for which a desire to incorporate statistical uncertainty exists. In the latter vein, there are natural links between this work and recent developments within the field of stochastic population forecasting From a practical point of view, it is clear that the results of the stochastic Brass PF ratio method differ in important ways from those found using the traditional procedure. First and foremost, the stochastic PF ratio-based estimates of age-specific fertility suggest much higher total fertility rates than those calculated using the deterministic procedure . On averNo gold-standard reference fertility levels exist against which we may benchmark the performance of the stochastic method—or the traditional application for that matter. A number of possibilities exist with respect to the accuracy of the proposed method. First, it is possible that the traditional PF ratio based estimates of age-specific and total fertility are accurate and that the stochastic variants do represent over-estimates of fertility levels. A closer correspondence between the DHS-reported parity of women 45–49 and the traditional Brass-based estimates is supportive of this proposition, but this is likely a mechanistic artifact because it is the DHS data itself which drives the P3/F3 ratio used in the deterministic version of Brass' model. It seems more likely that some aspect of the error propagation associated with the simulation of the distribution of the P3/F3 ratio is responsible for the increased values. Along these lines, inflated values of the P3/F3 ratio could occur if the distributions associated with ASFR estimate are mis-specified. One way this could have occurred in the current analysis is associated with an assumption that the DHS distributions of fertility during the past 12 months would be reflective of the variation associated with the SRS-based estimates—introduced by a lack of available data from the Indian Census on standard deviations of these measurements. In this case, wider than estimated margins of error associated with mis-specified standard deviations could produce the higher than expected stochastic Brass PF ratio-based estimates reported here.While possible, this shortcoming does not invalidate the thrust of this paper. The focus of here has been illustrative: it provides a clear example with readily-available data of the proposed application. In practical application, any appropriate distribution might be applied to estimating the first-step inputs driving the procedure. Moreover, direct estimates of standard deviations with appropriate sample sizes—rather than surrogate inputs to approximate them—should produce less-inflated estimates of age-specific and total fertility rates. It remains possible that incomplete reporting in the DHS could result in mis-estimation of the surrogate standard deviations utilized in this study—just as easily as the case with the SRS-based estimates. In that case, the inflation could result from the same systematic incompleteness associated with this dataset. Systematic underreporting of fertility can lead to mis-estimation of variance just as easily as the proportion, suggesting that this inflation could as easily be real as artifactual. Without a gold-standard for comparison, this issue will remain unresolved in the current research.It is clear that the potential inflation of these estimates, however, is not a basic shortcoming related to the use of monte carlo simulation for fitting distributions, which has a long history in statistics, uncertainty analysis, and decision modeling. It is intimately associated with many forms of hypothesis testing in these disciplines The approach presented in this research appears to be a fruitful direction for further development of a stochastic methods for indirect estimation in demography. The paper presents a valid method for estimating the uncertainty associated with Brass PF ratio-based age-specific and total fertility rates. Future evaluations should explore the properties of this method across a larger variety of settings and attempt, where possible, to investigate further whether the method is prone to upward-biasing of these estimates or, in fact, produces more accurate ones. In either case, demographers in need of incorporation of statistical uncertainty into indirect estimation procedures may find the described method here to be a fruitful avenue for application.Figure S1Glossary of Terms.(DOCX)Click here for additional data file.Figure S2Annotated Sample R Code to Perform the Stochastic Brass PF Ratio Method(DOCX)Click here for additional data file.


Interestingly, three of our cases showed positive expression of Epstein-Barr-virus, (EBV-) encoded RNA within the tumor cells indicating a possible interaction between these two viruses. Furthermore, our three EBV-positive cases presented with similar clinical characteristics such as early clinical stage and low-risk indices. To the best of our knowledge, this is the first case series describing the characteristics of HTLV-1-positive DLBCL patients. The potential relationship between HTLV-1 and EBV should be further explored.We describe the clinical and pathological characteristics of seven patients who were human T-lymphotropic virus type 1 (HTLV-1) carriers and had a pathological diagnosis of  Diffuse large B-cell lymphoma (DLBCL) is the most common variant of non-Hodgkin lymphoma (NHL) accounting for approximately 30% of the NHL cases worldwide . PreviouThe human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus regarded as the pathogenic agent for adult T-cell lymphoma/leukemia (ATLL) . HTLV-1 As the association between HTLV-1 infection and DLBCL has not been previously evaluated, in this study, we aimed to describe the clinical and pathological characteristics of HTLV-1-positive patients with a pathological diagnosis of DLBCL.de novo DLBCL and concurrent positive serology for HTLV-1 were identified from the medical oncology consultation files at the Edgardo Rebagliati Martins and Jose Alcides Carrion Hospitals, both located in Lima, Peru, from January 2000 to December 2010. Patients with a diagnosis of HIV infection, transformed, primary cutaneous, or primary central nervous system (CNS) DLBCL were excluded. All cases had HTLV-1 detected in serum by ELISA and/or Western blot techniques. Clinical and laboratory information was obtained through medical chart review, after approval of this study by the Institutional Review Board at each center.Cases with a pathological diagnosis of in situ hybridization (CISH) technique to evaluate the presence of EBV-encoded RNA . Cases showing EBER nuclear expression in >10% of the tumor cells were considered positive. The presence of proviral HTLV-1 DNA was evaluated in the tissue blocks using a polymerase chain reaction (PCR) technique as previously described [Routine hematoxylin and eosin-stained sections were prepared from formalin-fixed, paraffin-embedded tissue blocks. Immunohistochemical analysis included a broad panel of antibodies against CD45 , CD20 , MUM1/IRF4 , bcl-6 , and CD10 . CD10, bcl-6, and MUM1/IRF4 were considered positive if expressed by >30% of the tumor cells. For the detection of EBV, we used a chromogenic escribed .de novo DLBCL and positive serology for HTLV-1 were identified. One case has been previously reported [Seven consecutive patients with a pathological diagnosis of reported . Completde novo DLBCL. A most salient point is that three of our cases (42%) demonstrated the presence of EBV genome in the tumor cells. Although this could suggest a high incidence of EBV positivity in HTLV-1 patients with DLBCL, if we consider that the incidence of EBV-positive DLBCL has been reported in the range of 3–15% [In this paper, we present a case series of 7 HTLV-1 carriers who have developed of 3–15% –12, giveof 3–15% –16.EBV is a recognized oncovirus with B-cell lymphotropism. EBV attaches to CD21 preparing the B-lymphocyte for EBV infection. EBV infection will promote an increased production of IL-6 and EBV-associated mRNAs promoting a blastic transformation. EBV is then inserted into the nucleus of the B cell where it acquires a circle-shaped configuration. EBV nuclear antigens are the first to be produced after infection, which are essential for immortalization of the cell and upregulation of the expression of other molecules and genes such as latent membrane proteins (LMPs) and C-MYC. LMPs increase expression of bcl-2 and drive the cell into a latent state, which is maintained by the production of EBV-encoded RNA. Hence, EBV-infected B cells enter an apparent resting phase; however, due to their activated phenotype, they are more prone to develop oncogenic changes . HTLV-1, on the other hand, is a retrovirus that infects a wide variety of cells  . An impoHowever, as we suggest in the present paper, there could be a potential lymphomagenetic interaction between EBV and HTLV-1. In a previous paper in patients with ATLL, Ueda et al. indicated that coinfection with HTLV-1 and EBV may induce a more extensive organ involvement through the enhanced expression of adhesion molecules via IL-4 signaling . Similarvia T-cell dysfunction and promote reactivation of EBV, which in turn will induce B-cell proliferation and lymphomagenesis. The identification of 3 HTLV-1 carriers with EBV-positive DLBCL in our study may suggest the immunosuppression induced by HTLV-1 could be implicated in the pathophysiology of this rare lymphoma. Additionally, our 3 EBV-positive DLBCL cases had similar clinical characteristics . Hence, we postulate an interesting hypothesis about a potential pathogenetic relationship between HTLV-1 and EBV. Theoretically, HTLV-1 infection can cause immunosuppression We understand the limitations of small retrospective case series such as ours, in terms of selection bias. However, these cases were identified from nonselected, consecutive patients with a diagnosis of DLBCL who were treated according to their diagnosis and stage with standard therapies. In order to investigate the potential relationship between HTLV-1 and EBV, large prospective cohort or population-based retrospective studies are needed.In this paper, we present 7 cases of DLBCL in HTLV-1 carriers from which 3 were EBV-positive DLBCL. Likely, the interaction between EBV and HTLV-1 could promote T-cell and B-cell dysfunction as well as antiapoptosis and cell proliferation, favoring lymphomagenesis. Further studies are needed to investigate this potential relationship.


Retroviral gene expression generally depends on a full-length transcript that initiates in the 5′ long terminal repeat (LTR), which is either unspliced or alternatively spliced. We and others have demonstrated the existence of an antisense transcript initiating in the 3′ LTR of the Human T-cell Leukemia Virus type 1 (HTLV-1) that is involved in the production of HBZ (HTLV-1 basic leucine zipper (bZIP) factor). HBZ is a Fos-like factor capable of inhibiting Tax-mediated activation of the HTLV-1 LTR by interacting with the cellular transcription factor cAMP-response element-binding protein (CREB) and the pleiotropic cellular coactivators p300/CBP. HBZ can also activate cellular transcription through its interaction with p300/CBP. Interestingly, HBZ has also been found to promote T-lymphocyte proliferation. By down-regulating viral expression and by stimulating T-cell proliferation, HBZ could be essential in the establishment of a chronic infection. Antisense transcription also occurs in the closely related HTLV-2 retrovirus as well as in the recently discovered HTLV-3 and HTLV-4. These antisense transcripts are also involved in the production of retroviral proteins that we have termed Antisense Protein of HTLVs (APH). Like HBZ, the APH proteins are localized in the nucleus of transfected cells and repress Tax-mediated viral transcription. HAM/TSP has a shorter incubation period than ATL and can show an accelerated development within one month to four years after transfusion of the infected blood sample. The main pathologic features of HAM/TSP are chronic inflammation in the spinal cord, characterized by perivascular lymphocytic cuffing and parenchymal lymphotropic infiltration including HTLV-1-infected CD4+ T cells . Di. Di46]. We have also recently tested whether the newly discovered human retroviruses HTLV-3 and HTLV-4 ,48 were 6.Tax and HBZ genes, whose expression is respectively controlled by the 5′ and 3′ LTR. In the first stage of the infection of T cells by HTLV-1, Tax expression is high and through a positive feedback stimulates protein viral synthesis, virus production, and viral infection. However, cells highly expressing HTLV-1 proteins are eliminated by the humoral response and CTL activity of the host. At this stage, HBZ can play a crucial role by down-regulating the 5′-LTR-dependent viral transcription and may allow infected cells to evade the immune response. In additionally, HBZ promotes the proliferation of infected T lymphocytes. This dual action probably confers a survival advantage on HBZ-expressing cells and is consistent with the observation that HBZ favors the establishment of persistent infection in HTLV-1-inoculated rabbits [Since the discovery of HBZ in 2002, accumulating evidence suggests that the development of HTLV-1 infection requires the  rabbits  and indu rabbits . Hencefo rabbits . Future


Human T-cell lymphotropic virus (HTLV) types 1 and 2 belong to the Oncorna group of retroviridae, a large family of viruses, grouped initially by pathogenic features, but later revised on the basis of genome structure and nucleotide sequence. HTLV-I was the first discovered human retrovirus to be associated with a malignancy in 1980. The malignancy, first described by Uchiyama and co-workers in southwestern Japan, was named Adult T-cell Leukemia/Lymphoma (ATL) and characterized with cutaneous and respiratory involvement, hepatosplenomegaly, lymphadenopathy and various metabolic abnormalities such as hypercalcemia. The HTLV-I has been known to be endemic to certain parts of Iran like the province of Khorasan in the northeast since 1990, with a 2.3% prevalence rate of infection. The main manifestations of HTLV-I infection are neurologic and hematologic (such as ATL) disorders, but it has also other manifestations such as uveitis, arthritis, dermatitis, vitiligo and lymphocytic alveolitis. Its main neurologic manifestation is a chronic progressive myelopathy that is referred to HTLV-I Associated Myelopathy (HAM) in Japan and Tropical Spastic Paraparesis (TSP) in Caribbean. But other disorders such as peripheral neuropathy, polyradiculoneuropathy, myopathy, peripheral facial paresis, and so on have been reported too. In this review we wish to give some brief information on the different aspects  of HTLV-I infection according to our twenty-year researches. The department of neurology of Mashhad University of Medical Sciences has been a pioneer in researches on HTLV-I in the last twenty years. It has been estimated that 10 to 20 million people around the world are infected with HTLV-I . Its prewas 2.3% . This wamong men . Howeveret al. studied the prevalence of IL2 receptor in HTLV-I carriers, HAM/TSP patients, and control group in 1997 and showed that IL2 receptor prevalence was significantly higher in HAM/TSP patients and HTLV-I carriers than in control group. However there was no significant difference between HAM/TSP patients and HTLV-I carriers. This study also showed that there was not any meaningful difference among receptor prevalence with relation to age, sex, and disease severity and duration  transmission . In Irannsfusion . This ra in 2010 . et al reported breast-feeding as the most important route of transmitting HTLV-Iinfection in Khorasan in 1993 , and maternal proviral load. Although transmission in utero is possible, it is very rare  is more suspected. Some cytokines such as interleukins, platelet activating factor (PAF), and tumor necrosis factor (TNF) have been found in serum of HAM/TSP patients. It seems that they have a role in demyelination in the nervous system. The relation of CD4-positive to CD8-positive T-cells is increased in these patients and the response of Natural Killer cells (NKs) is disrupted in ATL and HAM/TSP patients , 14-18. Osame has been suggested the immunological model that leads to HAM/TSP: 1- The activation of T-lymphocytes  and macrophages, and expression of cytokines , 2- The infiltration of CD8+ cytotoxic T-cells in the nervous system, 3- The localization of HTLV-I in the nervous system, mainly inside the T-lymphocytes, 4- The recruitment of T-lymphocytes due to the increased leukocyte adhesion molecules (such as VCAM-4) on the endothelial surface of the vessels and also disruption of blood-brain-barrier with secretion of matrix-metalo-proteinases (MMPs), and 5- The axonal degeneration in the spinal cord . These i,et al, investigated somatosensory evoked potentials (SSEP) changes in median nerve in HAM/TSP patients and found a meaningful correlation between disease severity and N20 latency. This study showed a significant involvement of posterior spinal column and medial lemniscuses tracts of brainstem and thalamocortical tracts even if there were no signs of upper limb involvement in HAM/TSP patients , sensory disturbances  and sensory ataxia, impotence, bladder dysfunction (spastic bladder) and less frequently bowel dysfunction, and generalized hyperreflexia except in cases of concomitant sensory neuropathy -24. Accoectively . In othemplaints . Accordiectively . The mos in 2005 . Moreoveactivity .et al in 1997, HTLV-I infection prevalence in spastic paraparetic or spastic tetraparetic patients was 20.6% , hereditary spastic paraplegia (HSP), and toxic-metabolic disorders such as vitamin B12 and niacin deficiency, tropical ataxic neuropathy (TAN), adrenoleukodystrophy, primary lateral sclerosis (PLS), lathyrism in India, cycad poisoning in Pacific Islands, or konzo in Central parts of Africa . Accordias 20.6% . This ra in 2000 .Neurologic findings other than myelopathyet al reported one case of brainstem involvement, one case of polymyositis, one case of neuropathy, and one case of muscular atrophy in 2000  or agglutination tests , 26. Pos protein . In 71%  glucose .et al in 2000 and another patient had a cervical plaque  and hyperintense signal abnormalities on T2-weighted images in periventricular or subcortical white matter in the brain. The lesions may show some enhancement in post-contrast images, usually with a diffuse or irregular pattern, in contrast to discrete or multifocal enhancement seen in MS , 7, 19. l plaque . In Eteml plaque . In a stthan 1cm .There is not any antiviral agents that can treat effectively HAM/TSP, but some immunomodulatory agents have some effects on the course of the disease , 31-33. et al studied methylprednisolone pulse therapy on HAM/TSP patients and concluded that more than 90% of the patients had a relative to absolute satisfaction of the treatment (et al showed that Danazol had a medium but statistically meaningful effect on the decrease of movement disability ( Various regimens for administrating corticosteroids have been experienced by different investigators, such as the initial IV pulse therapy with or without tapering, prolonged oral corticosteroid in a daily or every other day regimen, and even intrathecal corticosteroid. It has been effective in improving motor function to some extent. Patients who fail to respond to corticosteroid therapy or cannot tolerate it due to the side effects may have some improvements with PE or interferon alpha , 38-40. reatment . The mossability . The mossability . In this


Arabidopsis thaliana, revealed the identification of metabolites which are putatively acting as mediators of nuclear gene expression. Complimentary, the continuous technological developments in the field of metabolomics per se has further demonstrated its potential as a very suitable readout to unravel metabolite-mediated signaling processes. As foundation for these studies here we outline and discuss recent advances in elucidating retrograde signaling molecules and pathways with an emphasis on metabolomics and systems biology driven approaches.A tight coordination of biological processes between cellular compartments and organelles is crucial for the survival of any eukaryotic organism. According to cellular requirements, signals can be generated within organelles, such as chloroplasts and mitochondria, modulating the nuclear gene expression in a process called retrograde signaling. Whilst many research efforts have been focused on dissecting retrograde signaling pathways using biochemical and genetics approaches, metabolomics and systems biology driven studies have illustrated their great potential for hypotheses generation and for dissecting signaling networks in a rather unbiased or untargeted fashion. Recently, integrative genomics approaches, in which correlation analysis has been applied on transcript and metabolite profiling data of  Biological systems rely on complex interactions of heterogeneous small- and macro-molecules to execute cellular functions required for their growth, survival, and propagation . To mainIn contrast to bacteria, the eukaryotic cell comprises a large number of diverse subcellular compartments and organelles which are usually delineated by a lipid bilayer to maintain specific microenvironments . Along wWhile the different subcellular compartments are involved in storage, detoxification, and synthesis of a variety of specific and important compounds , plastidArabidopsis have resulted in identifying the genomes uncoupled (gun) mutants, which block Mg-proto mediated retrograde signaling by affecting its accumulation  components of tetrapyrrole biosynthetic pathway intermediates , (ii) remulation . Those emulation . Howevermulation . These fmulation . Innovatmulation . As the Whilst much research efforts have been focused on dissecting signaling pathways using biochemical and genetics approaches, the number of yet discovered mechanisms of retrograde signaling are likely not sufficient to explain the tight regulation and interdependence of organelle functions. For instance, the cellular metabolism is tightly correlated with processes occurring in chloroplasts and mitochondria. It is widely believed that changes in the concentration of metabolites triggered by the organelles are likely sensed in the cytosol and thus, might regulate nuclear gene expression . TherefoOver the past decades a number of analytical methods, such as gas chromatography (GC), liquid chromatography (LC), capillary electrophoresis (CE) coupled to mass spectrometry (MS) or nuclear magnetic resonance (NMR), have been developed and improved to accurately and sensitively analyze small molecules from complex sample mixtures . As thesceh1 mutant, which displayed changes in expression of stress-related genes associated to salicylic acid response and resistance to the pathogen Pseudomonas. Ceh1 is caused by a mutation in the HDS gene responsible for the conversion of MEcPP to hydroxymethylbutenyl diphosphate (HMBPP) in the methylerythritol phosphate (MEP) pathway. Metabolite profile analysis of MEP pathway intermediates by LC-MS revealed an accumulation of the intermediate metabolite MEcPP in ceh1. MEcPP is a specific and critical retrograde signaling metabolite that acts as a stress sensor by triggering the expression of specific stress-responsive nuclear encoded plastidial proteins  and confirm its role as a retrograde signal  nanosensor makes use of a recognition element (a protein that binds with the metabolite of interest) fused to a report element (a fluorophore pair). Changes in protein conformation triggered by ligand (metabolite)-recognition element binding leads to the emission of fluorescent light via the report element  and short-term chemical treatments  involved in plant mitochondrial dysfunction has been carried out to identify targets and pathways involved in mitochondrial retrograde signaling  which has been recently identified as a regulator of the sulfur status in Arabidopsis using computational analysis of time-series experiments and inducible transgenic plants revealing conditional increased OAS levels (Another important issue for the identification of signals is to distinguish between “true” primary targets from tertiary targets . SeveralS levels . HoweverThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The objective of this study was to discuss the influence of coinfection on mood states (depression and anxiety) in Human T Lymphotropic virus type 1 HTLV-1-infected patients. A cross-sectional study was performed with a sample obtained through a nonprobabilistic technique. A total of 130 patients in treatment at the HTLV Ambulatory of Instituto de Infectologia Emílio Ribas participated in the research, of whom 63 had HAM/TS and 67 were asymptomatic. A sociodemographic survey and the Beck Anxiety and Depression Inventories were used. The results indicated a prevalence of 7.2% for HTLV-1/HIV co-infection, 7.2% for HTLV-1/HCV, and 4.0% for HTLV-1/HIV/HCV. It is possible that the presence of a co-infection causes greater fear and concern about the future than asymptomatic HTLV-1 infection, increasing the observed degree of depression and anxiety. The HTLV virus is a retrovirus that was first isolated in 1980 from a patient with a rare type of T-cell leukemia. The disease has two subtypes: HTLV-1, which is associated with neurological disease  and adult T-cell leukemia (ATL), and HTLV-2, which has not been shown to cause disease .HTLV-1 infection is endemic in southwest Japan, the Caribbean Basin, Melanesia, and parts of Africa and Brazil. In some areas, the prevalence rate is as high as 15% of the general population. In the USA, the average rate of seroprevalence of HTLV-1 and HTLV-2 among volunteer blood donors is approximately 0.016% . It is eP = 0.0543) [The impact of HTLV-1 on patients' mood states has received attention from researchers; the effects have been examined in terms of the severity and chronicity of the symptoms and the prevalence of infections at the national and international levels. Preliminary results from an open cohort study of the prevalence of seropositive blood donors at a hemocenter in Minas Gerais, Brazil, suggested a higher rate of depression in HTLV-1-infected individuals compared to seronegative blood donors  .In a study by Souza  of 36 HTAnother study conducted in Salvador, Brazil, by de Carvalho et al. , examineGascón  studied HTLV can be transmitted sexually, parenterally, or vertically; the most effective route, when compared to HIV (Human Immunodeficiency Virus) and HVC (Hepatitis C Virus) transmission, is through breastfeeding . Both HICoinfection with other viruses, such as HIV and HVC, is a subject of public health interest due to effects on physical and emotional health. The data suggest that HIV patients who are co-infected with HTLV-1 have higher probabilities of developing neurological disease than do the monoinfected patients . Other sOne of the first reports of HIV/HTLV coinfection raised the possibility of faster disease progression among homosexual males in Trinidad and Tobago . In a stCoinfection thus contributes to physical damage and intense psychological suffering due to the increased possibility of death and the threat to the integrity of the ego , 17. TheA cross-sectional design was used for this study. The participant pool was composed of volunteers, and sampling was conducted using a non-probabilistic technique . The study was conducted at Instituto de Infectologia Emílio Ribas in São Paulo, Brazil, from May 2008 to July 2009. The sample group consisted of 130 adults with HTLV-1; 67 were asymptomatic, and 63 were co-infected with HAM/TSP.All of the patients were in clinical treatment for HTLV at Instituto de Infectologia Emília Ribas and were invited to participate in the research. A contact was established within the medical team responsible for the HTLV Clinic to identify patients fitting the research profile. According to the ethical precepts governing research with human subjects, the participants provided informed consent once they had been informed of the objectives of the research.A sociodemographic survey, the Beck Depression Inventory, and the Beck Anxiety Inventory were used to measure mood states in the participants. It is important to note that although the depression and anxiety inventories are self-report forms, the measures were read aloud by the researcher due to the low educational levels of most of the participants. The administration took, on average, 45 minutes. The sociodemographic questionnaire was created by the researchers. The questionnaire contained 17 items related to age, gender, relationship status, educational level, and family income.The Beck Depression Inventory  is probFor the evaluation of anxiety, the Beck Anxiety Inventory  was useAfter processing, the results were organized in tables and cross-tabulated when appropriate. The raw values and percentages were used in the analysis.rho of Spearmann. The variables considered were the presence of coinfection and the results of the Beck Depression and Anxiety Inventories, with a type-1 error probability  of 5%. This study observed the rules of Resolution no. 196 of October 10th, 1996, of Conselho Nacional de Saúde , approved by Comitê de Ética em Pesquisa do Instituto de Infectologia Emílio Ribas (Ethics Committee on Research of Emilio Ribas Institute of Infectology) in October 2007.The data were analyzed using descriptive statistics, including percentages, averages, frequencies, and the In total, 93 patients in the study sample were females (71.5%) and 37 were males (28.4%). The participants had a mean age of 49.8 years (SD = 11.6 years). Most of the participants were whites (39.2%), married (32.3%), had completed 0–4 years of education (34.6%), and hand manual occupations (30%). On Osame's scale, 21 patients had partial incapacity to walkwithout assistance, 31 needed hand support to walk, and 11 patients had complete walking incapacity.n = 9 (7.2%) for HTLV-1/HVC; n = 8 (6.4%) for HTLV-1/HIV; n = 6 (4.8%) for HTLV-1/HIV/HVC; n = 1 (0.8%) for HTLV-1/HBV; n = 1 (0.8%) for HTLV-1/HIV/HBV. Among the patients who were co-infected with HCV, eight presented with HAM/TSP, and one was asymptomatic; among those co-infected with HIV, most were asymptomatic carriers of HTLV-1 (n = 7), and only one presented with HAM/TSP. Among those co-infected with HTLV-1/HVC/HIV, four presented with HAM/TSP, and two were asymptomatic.The prevalences of various coinfections in the sample were n = 77; 59.2%) were unaware of their mode of infection. Based on the common sources of infection, we determined that sexual intercourse , blood transfusions , breastfeeding , use of endovenous drugs , and tattoos  were the main modes of infection. In the group of co-infected patients, 50% (n = 12) were unaware of their most likely source of infection; 33.3% reported sexual intercourse as the source (n = 8), while 8.3% named blood transfusions and use of injectable illicit drugs (n = 2).Most of those interviewed , in the HAM/TSP group and 13.5% and 8.9%, respectively , in the control group . The mosThe combined frequency of moderate (31.7%) and severe (23.8%) anxiety was 55.5% in the HAM/TSP group and 14.9%  in the control group . The mosThe analysis revealed impacts on mood state caused by the presence of a coinfection within the group of asymptomatic patients; both social and psychological vulnerabilities were observed to a greater extent in this group than among the mono-infected patients. These results are shown in The analysis demonstrated that the presence of a coinfection had significant effects on the severity of depression and anxiety in the asymptomatic group. Infection by HIV or HVC may make the individual more vulnerable, encouraging him or her to perseverate on topics such as death. In patients who show symptoms of the diseases caused by these viruses, the illusions of self-sufficiency and immortality are confronted by a real threat. It is important to understand these psychological effects because HIV and the liver diseases caused by HVC are worldwide epidemics that have already killed many people.The infections and threat of death caused by these viruses can increase patients' feelings of devaluation, fear, regret, and guilt, among other emotions; this experience causes the coinfection to be perceived as a threat that the individual cannot escape. Co-infected patients experience additional suffering due to social discrimination, multiple losses , and often the need to live a double life to avoid discrimination .In addition to the distress caused by the multiple losses that a patient incurs following the diagnosis of a coinfection, another type of distress is present in this context: the distress of castration. The real possibility of sickness and death is strongly linked to castration as it subtracts from the possibility of life and the fantasy of immortality. The distress of castration comes from the fear of separation from something extremely valuable, such as family and friends; therefore, the distress of castration can be defined as a reaction to situations involving danger and threat to the integrity of the subject. We can conclude that the co-infected patient's self remains absolutely vulnerable and helpless when facing possible death .The results within the group of asymptomatic patients can be translated as fear and apprehension among both patients that the severity of symptoms may worsen in the future.The results of the present study suggest that the presence of a coinfection in asymptomatic HTLV-1 patients is related to feelings of fear and apprehension about the future, in addition to depressive symptoms.The experimental portion of the research was exploratory and cross-sectional, allowing us to examine a rarely investigated theme: factors related to coinfections in the carriers of HTLV-1. We can conjecture that other factors influence the lives of these patients. This study can contribute to future research on the factors that were not studied, such as the psychosocial and organic factors related to coinfection and depression. Together with the findings of the present work, future research can guide the development of supportive interventions and protocols to promote the physical and mental health of patients infected with HTLV-1.In conclusion, the evidence provides important information for health professionals about the realities and vulnerabilities of HTLV-1 patients and about the possibility of their exposure to other viruses. Furthermore, it is the intention of this study to arouse the interest of authorities, professionals, and health researchers in systemic, multidisciplinary interventions providing clinical, epidemiological, psychological, and social support.


Demyelinating optic neuritis is the most common cause of unilateral painful visual loss in the United States. Although patients presenting with demyelinating optic neuritis have favorable long-term visual prognosis, optic neuritis is the initial clinical manifestation of multiple sclerosis in 20% of patients. The Optic Neuritis Treatment Trial (ONTT) has helped stratify the risk of developing multiple sclerosis after the first episode of optic neuritis based on abnormal findings on brain MRI. The ONTT also demonstrated that while initial treatment of optic neuritis with intravenous corticosteroids followed by an oral taper accelerates visual recovery, its use does not improve long-term visual outcomes. Long-term treatment with immunomodulating agents such as interferons has been shown to improve clinical outcomes and neuroimaging abnormalities in multiple sclerosis; furthermore interferon use has been associated with decreased risk of subsequent multiple sclerosis in patients with an acute neurologic syndrome. However, several questions regarding the presentation, management, and implications of acute demyelinating optic neuritis remain unanswered. A variety of conditions lead to inflammation of the optic nerve (optic neuritis), however, the form associated with demyelination due to multiple sclerosis is most common.The pathogenesis of optic neuritis, as with other demyelinating events associated with multiple sclerosis, is not entirely understood. It is believed that some inflammatory process leads to peripheral T-cell activation. These T-cells are thought to cross the blood-brain barrier and cause a delayed type IV hypersensitivity reaction causing destruction of myelin, the insulator and protector of nerves.3The typical patient who develops acute demyelinating optic neuritis is an otherwise healthy young adult, most often 20 to 45 years of age; women are affected three times more commonly than men.7A relative afferent pupillary defect is present in the affected eye unless there is symmetric involvement or history of optic neuropathy in the fellow eye.Several other findings have been described in optic neuritis, though they are not sensitive indicators of the condition. These include Uhthoff’s phenomenon which describes worsening of vision with increased body temperature, and the Pulfrich phenomenon, in which a simple pendulum swinging in one plane appears to trace an ellipse due to asymmetrical optic nerve conduction velocity.1Since the diagnosis of optic neuritis is clinical, it is useful for physicians to understand other processes which cause similar findings. The differential diagnosis for optic neuritis (defined as optic nerve inflammation) is very broad, including other auto-immune neuropathies , rheumatologic conditions, inflammatory conditions , compressive neuropathies , infections , and toxic  or nutritional neuropathies.Two conditions which are thought to be non-inflammatory and most closely resemble the clinical profile of optic neuritis are anterior ischemic optic neuropathy (AION) and Leber hereditary optic neuropathy (LHON). While sudden unilateral visual loss with optic disc swelling is present in AION, the patients are typically over 50 years of age  and less commonly have pain with eye movement.Because of the known association between optic neuritis and multiple sclerosis, patients without a known history of multiple sclerosis are typically offered a brain MRI. The Optic Neuritis Treatment Trial is one study that has helped stratify the risk of developing multiple sclerosis on the basis of abnormal findings on brain MRI . A patie8Other diagnostic tests do not have such clear support. Lumbar puncture for cerebrospinal fluid (CSF) analysis, for example, is recommended by some to look for the oligoclonal banding typical of multiple sclerosis.12Once a diagnosis of optic neuritis has been made and the risk of future development of multiple sclerosis has been estimated on the basis of a brain MRI, patients will likely ask about treatment options. The largest study to address this question is the Optic Neuritis Treatment Trial, a multicenter randomized clinical trial with fifteen years of follow up. Patients were assigned to three groups: one received oral prednisone, another received intravenous methylprednisolone followed by an oral prednisone taper, and the last received oral placebo.The trial showed that intravenous corticosteroids followed by an oral taper accelerated visual recovery, but did not improve the long-term visual outcome when compared to placebo. Patients who were treated with oral corticosteroids alone did not have improved visual outcomes and were actually shown to have an increased rate of recurrent optic neuritis in the same or fellow eye.The presentation of demyelinating optic neuritis often invites referral to a neurologist familiar with the diagnosis and treatment options. Data from the Optic Neuritis Treatment Trial have shown that patients who present with acute demyelinating optic neuritis have a favorable long-term visual prognosis, even if they develop multiple sclerosis.13Long-term treatments for optic neuritis include the interferons, often used in patients with multiple sclerosis. The neurologic literature has shown that patients treated with immunomodulating agents have improved clinical outcomes and neuroimaging abnormalities compared to those who are not treated.16Several unanswered questions remain regarding the presentation, treatment, and implications of optic neuritis. Studies have shown that the risk of developing clinically definite multiple sclerosis after presenting with a clinically isolated syndrome such as optic neuritis is increased in patients with an abnormal brain MRI, and evidence supports treatment of these patients with immunomodulating agents.Large clinical trials with long-term follow-up have provided invaluable insights on the clinical manifestations, management, prognosis, and implications of an initial bout of acute demyelinating optic neuritis, but the remaining uncertainties highlight the need for continued research.


A recent report has indicated that transgenic expression of HTLV-1 bZIP factor (HBZ) in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice. However, there is limited information on in vivo expression of HBZ in HTLV-1 infected individuals especially HAM/TSP.We have generated rat and human monoclonal antibodies against HBZ by hybridoma methodology and a phage display system, and developed the ELISA system for the detection of HBZ protein and anti-HBZ antibodies. Using these reagents, we analyzed the expression of HBZ protein in plasma and peripheral blood mononuclear cells (PBMCs) of HTLV-1 infected individuals as well as HTLV-1 infected cell lines. Then the results were compared with the real time PCR data.Although we successfully detected HBZ protein in an enforced overexpressed cells and HTLV-1 infected cell lines by flow cytometry, ELISA, immunofluorescence and immunoblotting, we could not detect HBZ protein or anti-HBZ antibodies in HAM/TSP patients and asymptomatic carrires (ACs) by our system. In contrast, HBZ mRNA was significantly elevated in HAM/TSP patients than ACs. Especially, rapidly progressive HAM/TSP patients showed extremely high expression of HBZ mRNA but not tax mRNA in their PBMCs.These findings suggest that although expression of HBZ protein was suppressed in vivo in HAM/TSP patients and ACs, high expression of HBZ mRNA is closely associated with the pathogenesis of HAM/TSP.


Human T-cell leukemia virus type I (HTLV-1) encodes a Tax oncoprotein that is critical for both viral replication and cellular transformation. HTLV-1 Tax possesses a PDZ domain binding motif (PBM) at its C-terminus that is essential for its transforming activity in a Rat-1 model and for IL-2. Tax has been shown to interact with several PDZ domain containing proteins including PSD-95, Beta1-syntrophin, the precursor of interleukin-16, the mammalian homolog of the Drosophila discs large tumor suppressor protein Dlg, PDLIM2, Lin7, hTid1, Tip1, hScrib and MAGI3. In the 15th International Conference on Human Retrovirology: HTLV and Related Retroviruses, we will present a specificity map for the Tax/PDZ domain interactions generated using the human ORFeome 5.1. and we will focus on some of the new Tax/PDZ interactions.


During craniofacial development, the Hedgehog (HH) signaling pathway is essential for mesodermal tissue patterning and differentiation. The HH family consists of three protein ligands: Sonic Hedgehog (SHH), Indian Hedgehog (IHH), and Desert Hedgehog (DHH), of which two are expressed in the craniofacial complex (IHH and SHH). Dysregulations in HH signaling are well documented to result in a wide range of craniofacial abnormalities, including holoprosencephaly (HPE), hypotelorism, and cleft lip/palate. Furthermore, mutations in HH effectors, co-receptors, and ciliary proteins result in skeletal and craniofacial deformities. Cranial suture morphogenesis is a delicate developmental process that requires control of cell commitment, proliferation and differentiation. This review focuses on both what is known and what remains unknown regarding HH signaling in cranial suture morphogenesis and intramembranous ossification. As demonstrated from murine studies, expression of both SHH and IHH is critical to the formation and fusion of the cranial sutures and calvarial ossification. SHH expression has been observed in the cranial suture mesenchyme and its precise function is not fully defined, although some postulate SHH to delay cranial suture fusion. IHH expression is mainly found on the osteogenic fronts of the calvarial bones, and functions to induce cell proliferation and differentiation. Unfortunately, neonatal lethality of IHH deficient mice precludes a detailed examination of their postnatal calvarial phenotype. In summary, a number of basic questions are yet to be answered regarding domains of expression, developmental role, and functional overlap of HH morphogens in the calvaria. Nevertheless, SHH and IHH ligands are integral to cranial suture development and regulation of calvarial ossification. When HH signaling goes awry, the resultant suite of morphologic abnormalities highlights the important roles of HH signaling in cranial development. Craniofacial morphogenesis, an intricate developmental process, begins with the synchronized development of head primordia, which involves several organizing centers located in the neural ectoderm, axial mesendoderm, and the cranial neural crest. The differentiation and spatial patterning of these tissues must occur before they can be successfully integrated  and completed within 2 days Slavkin, . In humaCharacterized as regions of fibrous tissue between cranial bones, sutures function as intramembranous osteogenic sites, permit cranium growth, inhibit bone separation, and absorb shock Baer, . CranialCranial suture fusion is a process whereby the cells in the middle of the suture complex mature into osteoblasts that eventually fuse into midline sutures , which join end-to-end. In humans all sutures close around the end of adolescence , Transforming Growth Factor (TGF-β), and Bone Morphogenetic Protein (BMP) signaling , a transcription factor mediating HH signaling found in Drosophila , CDO, and BOC  the precise function of SHH in cranial suture development, (2) whether IHH and SHH have different functions in the calvaria, and (3) improved understanding of the intersection of HH with other signaling pathways in craniofacial patterning, such as BMP signaling.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.