73 research outputs found
AIDS and endemic Kaposi's sarcoma development : comparison by histopathology, virology (HHV8/KSHV) and cytogenetics
No full textKaposi’s sarcoma (KS) is a highly and abnormally vascularized tumor-like lesion with spindle cells (SC) affecting the skin, lymphnodes and viscera which is found in four different clinico-epidemiological forms as Classic KS (CKS), Iatrogenic KS (IKS), Endemic KS (EKS) and AIDS-associated KS (AKS). All KS forms develop from early stages of patch/plaque to late, nodular tumors and are associated with Kaposi's sarcomaassociated herpesvirus or human herpesvirus-8 (KSHV/ HHV-8). HHV-8 is also associated with primary effusion lymphoma (PEL) and multicentric castleman's disease (MCD). Various studies favour an endothelial origin (CD34+) of the KS SC but whether of vascular (VEC) or lymphatic endothelial cell (LEC) origin has not been settled. The HHV-8 latency-associated nuclear antigen type 1 (LANA-1) protein is the most frequently expressed viral antigen in infected cells. KS is promoted by HIV infection mainly by the angiogenic and proinflammatory effects of HIV-Tat. Whether KS represents a predominantly monoclonal neoplastic cell proliferation or a hyperplastic, reactive polyclonal process is still controversial. Reports on cytogenetic and molecular genetic changes in KS are few indicating that initially KS may develop as a reactive polyclonal cell proliferation associated with chromosome instability, followed by clonal chromosome changes in later stages.In the present KS histopathological studies (paper I & V) by triple antibody immunofluorescence we observed that: (a) the frequency of LANA+/CD34+ cells increased from early patch to late KS nodular lesions; (b) 30- 40% of the CD34+ SC were LANA- in both early and late KS, suggesting a continuous recruitment of noninfected endothelial cell into the KS lesion; (c) LANA+/CD34- cells were more frequent in early as compared to late KS and most of them expressed LEC markers such as LYVE-1 and D2-40, suggesting that the resident LECs represent an early target of primary HHV-8 infection; (d) LANA+/CD34-/LYVE-1+ cells decreased from early (25%) to late (4%) KS suggesting a phenotype switch from LEC to VEC; (e) the frequency of proliferating cells (Ki67+) was higher in early as compared to late KS stages and no significant difference in cell proliferation was observed between nodular AKS and EKS, suggesting that the growth of the usually more aggressive AKS tumors may reflect a higher rate of SC progenitor recruitment as compared to the slower growing EKS lesions, consistent with the observed increase in non-proliferative SC during KS (AKS) evolution to nodular stage; (f) infiltrating lymphocytes were LANA negative, whereas some CD68+ monocyte-macrophase appeared to be LANA+.To validate our results from LANA immunostaining, we established and optimized a semi-quantitative PCR assay for HHV-8 detection in formalin-fixed paraffin-embedded KS biopsies (paper III) and two different protocols for DNA extraction were compared namely the Chelex 100 and Qia-gene kit method. Our result indicate a better performance for Chelex-extracted DNA in paraffin embedded archival biopsies. In late, nodular stage of both AKS and EKS the virus load per unit tissue actin (HHV-8/actin) is higher than in early stages (patch/plaque), which corroborates our findings from double immunostaining for LANA and CD34 of the same cases. Thus these PCR results by serial dilutions of HHV-8 DNA show a correlation between virus load and progressive stages of KS development i.e. the increase in LANA+ SC and does not indicate an increase in viral content of individual tumor cells.With quantitative real time PCR on sera (paper II), we found higher HHV8 DNA load in AKS compared to EKS, patch compared to nodular KS and males compared to females as well as a significantly higher serum viral DNA load in KS compared to non-KS patients’ sera.AKS patient sera studied by ELISA for HIV-Tat antibodies showed that patients with high HHV8-DNA level had no or low levels of anti-Tat antibodies while patients with very low HHV8-DNA levels had several fold higher anti-Tat IgG titers. Analysis of these KS sera for epitope specificity showed reactivity to various Tat epitopes but not to the transcriptional (functional) epitopes 46-60 (TAR-binding region). To determine cytogenetic changes during the development of KS as well as possible differences between AKS and EKS we studied 27 KS (10 nodular AKS, 8 patch AKS, 8 nodular EKS and 1 patch EKS) cases by laser microdissection, global amplification of DNA and comparative genomic hybridization (paper IV). Deletion of Chromosome Y was detected in 20 of 23 male KS and was the only chromosomal deletion observed in early (patch) KS biopsies. Late AKS and EKS apart from random aberrations also showed recurrent chromosomal deletions of chromosome 16, 17, Y and a gain of chromosome 21. The deletion of chromosome 16 and Y was confirmed by interphase FISH on paraffin embedded sections. EKS had higher number of chromosomal abnormalities than AKS.In summary KS SC apparently represents a mixed pool endothelial cells including cells from both VEC and LEC the later being a possible early target for HHV-8 infection. Non-infected CD34+ progenitor cells appears to be continuously recruited to the developing KS lesion and locally infected during the development of KS. Serum HHV-8 DNA load is higher in AKS compared to EKS and HIV-Tat titers were inversely correlated to HHV-8 DNA load in AKS patients. Increased number of recurrent and sporadic chromosomal abnormalities found mostly in a subset of late nodular KS cases may indicate the onset of a clonal cell population (sarcoma).List of scientific papersI. Pyakurel P, Massambu C, Castanos-Velez E, Ericsson S, Kaaya E, Biberfeld P, Heiden T (2004). Human herpesvirus 8/Kaposi sarcoma herpesvirus cell association during evolution of Kaposi sarcoma. J Acquir Immune Defic Syndr. 36(2): 678-83. https://doi.org/10.1097/00126334-200406010-00004 II. Massambu C, Pyakurel P, Kaaya E, Enbom M, Urassa W, Demirhan I, Loewer J, Linde A, Chandra A, Heiden T, Doerr HW, Chandra P, Biberfeld P (2003). Serum HHV8 DNA and Tat antibodies in Kaposis sarcoma patients with and without HIV-1 infection. Anticancer Res. 23(3B): 2389-95. https://pubmed.ncbi.nlm.nih.gov/12894519 III. Pak F, Pyakural P, Kokhaei P, Kaaya E, Akbar Pourfathollah A, Selinova G, Biberfeld P (2005). HHV-8/KSHV during development of Kaposis sarcoma: evaluation by PCR and immunohistochemistry. J Cutan Pathol. 32(1): 21-7. https://doi.org/10.1111/j.0303-6987.2005.00256.x IV. Pyakurel P, Montag U, Castanos-Velez E, Kaaya E, Christensson B, Biberfeld P, Schrock E, Heiden T (2005). Kaposis sarcoma: CGH ctogenetic analysis of microdissected early and late stage biopsies. [Manuscript]V. Pyakurel P, Pak F, Mwakigonja AR, Kaaya E, Heiden T, Biberfeld P (2005). Recruitment of Kaposis sarcoma spindle cells during tumor development. [Manuscript]</p
Cervical Cytological Changes in HIV-Infected Patients Attending Care and Treatment Clinic at Muhimbili National Hospital, Dar es Salaam, Tanzania.
No full text\ud
Tanzania is among Sub-Saharan countries mostly affected by the HIV and AIDS pandemic, females being more vulnerable than males. HIV infected women appear to have a higher rate of persistent infection by high risk types of human papillomavirus (HPV) strongly associated with high-grade squamous intraepithelial lesions (HSIL) and invasive cervical carcinoma. Furthermore, although HIV infection and cervical cancer are major public health problems, the frequency and HIV/HPV association of cervical cancer and HSIL is not well documented in Tanzania, thus limiting the development of preventive and therapeutic strategies. A prospective unmatched, case-control study of HIV-seropositive, ≥ 18 years of age and consenting non-pregnant patients attending the care and treatment center (CTC) at Muhimbili National Hoospital (MNH) as cases was done between 2005 and 2006. HIV seronegative, non-pregnant and consenting women recruited from the Cervical Cancer Screening unit (CCSU) at ORCI were used as controls while those who did not consent to study participation and/or individuals under < 18 years were excluded. Pap smears were collected for routine cytodiagnosis and P53 immunohistochemistry (IHC). Cervical lesions were classified according to the Modified Bethesda System. A total of 170 participants from the two centers were recruited including 50 HIV-seronegative controls were from the CCSU. Ages ranged from 20-66 years (mean 40.5 years) for cases and 20-69 years (mean 41.6 years) for controls. The age group 36-45 years was the most affected by HIV (39.2%, n = 47). Cervicitis, squamous intraepithelial lesions (SIL) and carcinoma constituted 28.3% (n = 34), 38.3% (n = 46) and 5.8% (n = 7) respectively among cases, and 28% (n = 14), 34% (n = 17) and 2% (n = 1) for controls, although this was not statistically significant (P-value = 0.61). IHC showed that p53 was not detectable in HPV + Pap smears and cell blocks indicating possible degradation. The frequency of SIL and carcinoma appeared to be higher among HIV-infected women on HAART compared to seronegative controls and as expected increased with age. HIV seropositive patients appeared to present earlier with SIL compared to those HIV seronegative suggesting a role of HIV in altering the natural history of HPV infection and cervical lesions. The absence of p53 immunoreactivity in HPV + lesions is indicative of the ability of HPV E6 proteins to interact with the tumor suppressor gene and pave way for viral-induced oncogenesis in the studied Tanzanian women.\u
PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice
No full textOur laboratory established a role for poly(ADP-ribose)polymerase (PARP) in asthma. To increase the clinical significance of our studies, it is imperative to demonstrate that PARP is actually activated in human asthma, to examine whether a PARP inhibitor approved for human testing such as olaparib blocks already-established chronic asthma traits in response to house dust mite (HDM), a true human allergen, in mice and to examine whether the drug modulates human cluster of differentiation type 4 (CD4(+)) T-cell function. To conduct the study, human lung specimens and peripheral blood mononuclear cells (PBMCs) and a HDM-based mouse asthma model were used. Our results show that PARP is activated in PBMCs and lung tissues of asthmatics. PARP inhibition by olaparib or gene knockout blocked established asthma-like traits in mice chronically exposed to HDM including airway eosinophilia and hyper-responsiveness. These effects were linked to a marked reduction in T helper 2 (Th2) cytokine production without a prominent effect on interferon (IFN)-γ or interleukin (IL)-10. PARP inhibition prevented HDM-induced increase in overall cellularity, weight and CD4(+) T-cell population in spleens of treated mice whereas it increased the T-regulatory cell population. In CD3/CD28-stimulated human CD4 (+)T-cells, olaparib treatment reduced Th2 cytokine production potentially by modulating GATA binding protein-3 (gata-3)/IL-4 expression while moderately affecting T-cell proliferation. PARP inhibition inconsistently increased IL-17 in HDM-exposed mice and CD3/CD28-stimulated CD4(+) T cells without a concomitant increase in factors that can be influenced by IL-17. In the present study, we provide evidence for the first time that PARP-1 is activated in human asthma and that its inhibition is effective in blocking established asthma in mice
Energy Dissipation in Electron-only Reconnection
No full textMagnetic reconnection is a fundamental process in space and astrophysical plasmas that converts magnetic energy to particle energy. Recently, a novel kind of reconnection, called electron-only reconnection, has been observed in Earth's magnetosheath plasma. A defining characteristic of electron-only reconnection is that electron jets are observed but ion jets are absent. This is in contrast with traditional ion-coupled reconnection, where both ions and electrons exhibit outflowing velocity jets. Findings from the Magnetospheric Multiscale mission observations and particle-in-cell simulations show clear signatures of electron heating in electron-only reconnection events, while ions are not heated or cooled in these events. This result is unlike ion-coupled reconnection, where both ions and electrons are heated to varying degrees. The ratio of electron to ion dissipation increases with the local magnetic curvature, indicating that the partition of heat into ions and electrons is dependent on the current-sheet thickness
A study on microvascular density in breast carcinoma
No full textBackground: Breast Cancer is the most frequent neoplasm causing death in women between 35-55 years of age. Of the Prognostic indicators existing for breast cancer, axillary lymph node status has been regarded as the most important one. Twenty to thirty percent of all lymph node negative patients will still develop a recurrence of the disease within 10 years of initial treatment. Therefore, a new prognostic marker that could identify patients at high risk of tumor recurrence more accurately than existing indicators would be of great value, one potential indicator is tumor-induced angiogenesis. Materials and Methods: This is a six months prospective (January 2010-June 2010) and 1 year retrospective (Jan2009-Dec2009) study which included thirty five breast cancer cases visiting the Surgical OPD. Angiogenesis was estimated by determining micro vessel counting after immune staining the paraffin embedded tissue sections using anti-CD34 antibody. Results: Age of the patients ranged from 25 to 80 years with a mean age of 45.48 years. Most of the cases were infiltrating ductal carcinoma comprising of 33 cases (94.28%). Three cases (9.10%) showed vascular invasion by the tumor. Majority showed (63.64%) vessel count of less than 200 per 10 high power fields. Conclusion: Micro vascular density positively correlated with size of the tumor, lymph nodes involved by the tumor and Nottingham prognostic index. In the future, Antibodies specific to proliferating endothelium, together with the development of automated image analysis, may improve the accuracy and value of measuring angiogenesis-induced microvessel density. DOI: http://dx.doi.org/10.3126/jpn.v4i7.10315 Journal of Pathology of Nepal (2014) Vol. 4, 570-575 </p
Production from both wild harvest and cultivation:The cross-border <i>Swertia chirayita</i> (Gentianaceae) trade
No full textEthnopharmacological relevance: Swertia chirayita is the most widely traded species in a genus of 150 species, many of which are used in traditional medicine. S. chirayita is used mainly in Ayurvedic and Tibetan systems of medicine and the homoeopathic system of medicine as well as in regional folk medicine. Primarily wild collected, with some cultivation. S. chirayita is traded as a medicinal substance and exported in the forms of dried whole plant or extract of whole plant individually and/or as active ingredients of Ayurvedic medicines. S. chirayita export valuations continue to make S. chirayita one of Nepal's highest foreign exchange earning medicinal plant species. Aims of the review: The aims of this review were first, to assess the scale of the global trade in S. chirayita, second, to review evidence from plant population biology and from studies on the impacts of wild harvest on S. chirayita populations and cultivation as an alternative source of supply. Methods: The taxonomy and trade names for S. chirayita were reviewed, followed by a synthesis of published information on Swertia population biology and studies on impacts of wild S. chirayita harvest from across the geographic range of this species. Data on the prices paid for S. chirayita were then compiled for the period 2001–2017, followed by an analysis of global trade data for S. chirayita. Results and conclusions: Based on India import data and assuming an estimate in an earlier study that 60% of Nepal's S. chirayita production goes to India and 35% to Tibet, then Nepal's 2013 annual production was about 711 metric tonnes (MT) of which about 675.6 MT would be exported (India + Tibet). Nepal's 2014 annual production would be an estimated 503.25 MT of which about 478 MT would be exported. Declines in S. chirayita populations have been widely noted across its range. In India, since 2004, a ban was placed on the export of wild harvested S. chirayita by the Government of India, where the Director General of Foreign Trade prohibited export of S. chirayita plants, plant portions and their derivatives and extracts obtained from the wild with the exception of ‘formulations’. Cultivation of S. chirayita to meet commercial demand has been an important part of a solution to over-exploitation of wild stocks in eastern Nepal for 25 years, producing significant quantities that enter the export trade to India and Tibet. In Sankhuwasabha district, for example, 53.1 MT of S. chirayita were produced in 2013/014, just over half of which (27 MT) were exported to India, with the remainder exported to Tibet. Based on value-chain analysis and cost-benefit assessments, S. chirayita cultivation has been shown to be profitable in Nepal. However, since the first cost-benefit assessment was done (2013), prices dropped from NRs750/kg in April 2013 to a low of 250 NRs/kg in December 2017). Taking inflation into account further highlights the steep decline in the profitability for local farmers, who have limited options for value-adding. Consequently, farmers prefer to grow more profitable alternative crops, such as Nepal cardamom (Amomum subulatum Roxb.).Ethnopharmacological relevance: Swertia chirayita is the most widely traded species in a genus of 150 species, many of which are used in traditional medicine. S. chirayita is used mainly in Ayurvedic and Tibetan systems of medicine and the homoeopathic system of medicine as well as in regional folk medicine. Primarily wild collected, with some cultivation. S. chirayita is traded as a medicinal substance and exported in the forms of dried whole plant or extract of whole plant individually and/or as active ingredients of Ayurvedic medicines. S. chirayita export valuations continue to make S. chirayita one of Nepal's highest foreign exchange earning medicinal plant species. Aims of the review: The aims of this review were first, to assess the scale of the global trade in S. chirayita, second, to review evidence from plant population biology and from studies on the impacts of wild harvest on S. chirayita populations and cultivation as an alternative source of supply. Methods: The taxonomy and trade names for S. chirayita were reviewed, followed by a synthesis of published information on Swertia population biology and studies on impacts of wild S. chirayita harvest from across the geographic range of this species. Data on the prices paid for S. chirayita were then compiled for the period 2001–2017, followed by an analysis of global trade data for S. chirayita. Results and conclusions: Based on India import data and assuming an estimate in an earlier study that 60% of Nepal's S. chirayita production goes to India and 35% to Tibet, then Nepal's 2013 annual production was about 711 metric tonnes (MT) of which about 675.6 MT would be exported (India + Tibet). Nepal's 2014 annual production would be an estimated 503.25 MT of which about 478 MT would be exported. Declines in S. chirayita populations have been widely noted across its range. In India, since 2004, a ban was placed on the export of wild harvested S. chirayita by the Government of India, where the Director General of Foreign Trade prohibited export of S. chirayita plants, plant portions and their derivatives and extracts obtained from the wild with the exception of ‘formulations’. Cultivation of S. chirayita to meet commercial demand has been an important part of a solution to over-exploitation of wild stocks in eastern Nepal for 25 years, producing significant quantities that enter the export trade to India and Tibet. In Sankhuwasabha district, for example, 53.1 MT of S. chirayita were produced in 2013/014, just over half of which (27 MT) were exported to India, with the remainder exported to Tibet. Based on value-chain analysis and cost-benefit assessments, S. chirayita cultivation has been shown to be profitable in Nepal. However, since the first cost-benefit assessment was done (2013), prices dropped from NRs750/kg in April 2013 to a low of 250 NRs/kg in December 2017). Taking inflation into account further highlights the steep decline in the profitability for local farmers, who have limited options for value-adding. Consequently, farmers prefer to grow more profitable alternative crops, such as Nepal cardamom (Amomum subulatum Roxb.).</p
Kaposi's sarcoma and malignant lymphomas in Tanzania during the AIDS epidemic
No full textKaposi s sarcoma (KS) studies Kaposi´s sarcoma (KS) is the most frequent AIDS tumor (AKS) and associated with HHV-8, but controversial whether a clonal tumor or mostly a reactive proliferation of endothelial spindle cells (SC). In the present studies AKS and endemic KS (EKS) biopsies were compared for expression of HHV-8-LANA, the lymphatic endothelial (LEC) markers LYVE-1 and Ki-67 (proliferation).The study material is archival, formalin-fixed and paraffin-embedded (FFPE) surgical KS biopsies and sera from the Muhimbili National Hospital (MNH, Dar es Salaam, Tanzania) at early and late tumor stages of African AKS and EKS cases with cutaneous and oral (OKS) lesions from male, female, adult and juvenile KS patients.KS histopathological and immunohistochemical (IHC) studies (papers I-III) by single, double and/or triple antibody immunofluorescence (IFA) showed that: a) LANA+/CD34- cells were more frequent in early as compared to late KS and most of them expressed LEC markers LYVE-1, D2-40 and VEGFR-3, suggesting that the resident LECs represent an early target of primary HHV-8 infection; b) LANA+/CD34-/LYVE-1+ cells decreased from early (25%) to late (4%) KS while LANA+/CD34+ SC increased suggesting a phenotype switch from LEC to VEC; c) LANA appeared better correlated to LYVE-1 (LEC) than to CD34 (VEC) expression suggesting heterogeneous SC permissiveness to HHV-8 (paper I); d) the number of HHV-8 infected (LANA+) SC (CD34+) cells as well as LANA+ granules per SC nucleus was significantly higher in male vs. female, juvenile vs. adult and oral AKS [OAKS] vs. cutaneous KS lesions; e) similarly, tumor cell proliferation (Ki-67 immunoreactivity) in adult OAKS was significantly higher for male vs. female, juvenile vs. adult and OAKS vs. cutaneous KS lesions respectively; f) a positive correlation was apparently found between LANA+ SC and Ki-67 immunoreactivity (paper II).Together these findings suggest that tumor proliferation correlates with increasing HHV-8 LANA expression supporting the notion of viral (LANA)-driven cell proliferation during KS oncogenesis (paper II); g) a significantly higher viral load was also seen by quantitative RT-PCR in late nodular OAKS compared with cutaneous AKS lesions corroborating IHC results and indicating that the oral cavity is important for entry and/or reservoir for HHV-8 infection (papers II & III); h) the frequency of LANA+ SC in the tumor increases during the evolution of both cutaneous and oral KS lesions, suggesting a correlation between tumor growth and viral replication in the lesions, however, by RT-PCR, we observed that serum viral loads appeared to decrease in the corresponding patients whereas (paper III) all sera from early stage (patch-plaque) KS were positive for anti-HHV-8 antibodies while all HHV-8 negative sera were from late-stage nodular KS patients (paper IV). This supports our novel notion of a stage-dependent tissue-serum discrepancy in viral loads and HHV-8 antigen expression probably due to virus tissue retention, immune-segregation and/or selective clearance.Thus serum HHV-8 viral loads may not be sufficient for clinical and therapeutic prognostication (papers III & IV); i) the frequency of HHV-8 infection was high among the studied MNH cases and as expected, HHV-8 and HIV infection was more associated with KS compared to non-KS tumors and non-neoplastic conditions; j) the findings by IFA and ELISA had a high HHV-8 diagnostic concordance although ELISA seemed to have higher positive predictive value (PPV), specificity as well as a high sensitivity allowing more affordable HHV-8 screening in a resource-constrained country like Tanzania (paper IV). These findings also indicate the importance of routine HHV-8 screening among blood/organ donors to prevent transmission as well as in prospective transplant recipients to predict and possibly prevent iatrogenic KS (IKS) development (paper IV).Malignant lymphoma (ML) studies ML are second to KS as AIDS-related malignancies and have been reported to increase steadily with the HIV pandemic particularly in sub-Saharan Africa including Tanzania. The WHO classification, HIV and EBV association as well as ploidy and heterogeneity of diffuse large B-cell lymphoma (DLBCL) in Tanzania is not well documented. Our current study (paper V) has established that the WHO classification of lymphoid neoplasms can apparently be applied for the diagnosis of Tanzanian ML. Extranodal presentation of ML was frequent particularly for T-cell lymphomas (TCL). Diffuse large B-cell lymphoma (DLBCL) phenotype heterogeneity and frequency at MNH (Tanzania) was similar to that observed in Western countries suggesting applicability of similar, diagnostic, prognostic and therapeutic approaches (paper V). The attended ML at MNH had frequent aneuploidy, EBV infection as well as high DNA indices and cell proliferation (Ki-67). HIV infection was apparently associated with increased ML cell proliferation (paper V).List of scientific papersI. Pyakurel P, Pak F, Mwakigonja AR, Kaaya E, Heiden T, Biberfeld P (2006). Lymphatic and vascular origin of Kaposis sarcoma spindle cells during tumor development. Int J Cancer. 119(6): 1262-7 https://pubmed.ncbi.nlm.nih.gov/16615115II. Mwakigonja AR, Pak F, Pyakurel P, Mosha IJ, Urassa WK, Kaaya EE, Biberfeld P (2007). Oral Kaposis sarcoma in Tanzania: presentation, immunopathology and human herpesvirus-8 association. Oncol Rep. 17(6): 1291-9 https://pubmed.ncbi.nlm.nih.gov/17487381III. Pak F, Mwakigonja AR, Kokhaei P, Hosseinzadeh N, Pyakurel P, Kaaya E, Bogdanovic G, Selivanova G, Biberfeld P (2007). Kaposis sarcoma herpesvirus load in biopsies of cutaneous and oral Kaposis sarcoma lesions. Eur J Cancer. 43(12): 1877-82. Epub 2007 Jul 12 https://pubmed.ncbi.nlm.nih.gov/17627810IV. Mwakigonja AR, Pyakurel P, Kokhaei P, Pak F, Lema LK, Kaaya EE, Biberfeld P (2008). Human herpesvirus-8 (HHV-8) sero-detection and HIV association in Kaposis sarcoma (KS), non-KS tumors and non-neoplastic conditions. Infect Agent Cancer. 3: 10 https://pubmed.ncbi.nlm.nih.gov/18590556V. Mwakigonja AR, Kaaya EE, Heiden T, Wannhoff G, Castro J, Porwit A, Biberfeld P (2009). Tanzanian malignant lymphomas: WHO classification, presentation, ploidy, proliferation, and HIV/EBV associations. [Submitted]</p
PARP inhibition by olaparib or gene knockout blocks asthma-like manifestation in mice by modulating CD4+ T cell function
No full textBackground: An important portion of asthmatics do not respond to current therapies. Thus, the need for new therapeutic drugs is urgent. We have demonstrated a critical role for PARP in experimental asthma. Olaparib, a PARP inhibitor, was recently introduced in clinical trials against cancer. The objective of the present study was to examine the efficacy of olaparib in blocking established allergic airway inflammation and hyperresponsiveness similar to those observed in human asthma in animal models of the disease. Methods: We used ovalbumin (OVA)-based mouse models of asthma and primary CD4+ T cells. C57BL/6J WT or PARP-1-/- mice were subjected to OVA sensitization followed by a single or multiple challenges to aerosolized OVA or left unchallenged. WT mice were administered, i.p., 1 mg/kg, 5 or 10 mg/kg of olaparib or saline 30 min after each OVA challenge. Results: Administration of olaparib in mice 30 min post-challenge promoted a robust reduction in airway eosinophilia, mucus production and hyperresponsiveness even after repeated challenges with ovalbumin. The protective effects of olaparib were linked to a suppression of Th2 cytokines eotaxin, IL-4, IL-5, IL-6, IL-13, and M-CSF, and ovalbumin-specific IgE with an increase in the Th1 cytokine IFN-γ. These traits were associated with a decrease in splenic CD4+ T cells and concomitant increase in T-regulatory cells. The aforementioned traits conferred by olaparib administration were consistent with those observed in OVA-challenged PARP-1-/- mice. Adoptive transfer of Th2-skewed OT-II-WT CD4+ T cells reversed the Th2 cytokines IL-4, IL-5, and IL-10, the chemokine GM-CSF, the Th1 cytokines IL-2 and IFN-γ, and ovalbumin-specific IgE production in ovalbumin-challenged PARP-1-/-mice suggesting a role for PARP-1 in CD4+ T but not B cells. In ex vivo studies, PARP inhibition by olaparib or PARP-1 gene knockout markedly reduced CD3/CD28-stimulated gata-3 and il4 expression in Th2-skewed CD4+ T cells while causing a moderate elevation in t-bet and ifn-γ expression in Th1-skewed CD4+ T cells. Conclusions: Our findings show the potential of PARP inhibition as a viable therapeutic strategy and olaparib as a likely candidate to be tested in human asthma clinical trials
The Trend of Utilization of Therapeutic Plasmapheresis among Select Rheumatologic Diseases
No full textBlood Lead Level among school children in an Industrial city of Nepal
No full textBackground: Widespread use of lead has caused extensive environmental contamination and health problems in many parts of the world. Children are particularly vulnerable and even relatively low levels of exposure can cause serious health conditions. Our objective was to determine the prevalence of blood lead level in children in industrial city of Nepal, Birgunj.Materials and Methods: The cross sectional study was done on 50 school going student in Birgunj city, Nepal from November 2016 to January 2017. Questionnaire was used to collect data. Capillary blood was drawn and Blood Lead Level was measured immediately. SPSS ver. 22 was used to analyze the data.Results: The mean age of children in study was 12.5 ± 1.11 years.Among 50 children, 54% were male and 46% were female. The mean blood lead level was 20.33±9.36 μg/dl (male 21.08±8.87μg/dl, female 19.46±10.92 μg/dl). All the children in the study have elevated blood lead level and 84% of them have >10 μg/dl. About 26% of children have blood lead level between 15-20 μg/dl, 12% have level 20-25 μg/dl and 4% of them have more than 35 μg/dl.Conclusion: The prevalence of blood lead level in children from the industrial city of Nepal is alarmingly high. Children exposed with chipped paints have high level of blood lead level. However, further study in large population is required to address the current situation regarding the lead exposure to children. </p
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