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1.  Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Kassebaum, Nicholas J | Bertozzi-Villa, Amelia | Coggeshall, Megan S | Shackelford, Katya A | Steiner, Caitlyn | Heuton, Kyle R | Gonzalez-Medina, Diego | Barber, Ryan | Huynh, Chantal | Dicker, Daniel | Templin, Tara | Wolock, Timothy M | Ozgoren, Ayse Abbasoglu | Abd-Allah, Foad | Abera, Semaw Ferede | Abubakar, Ibrahim | Achoki, Tom | Adelekan, Ademola | Ademi, Zanfina | Adou, Arsène Kouablan | Adsuar, José C | Agardh, Emilie E | Akena, Dickens | Alasfoor, Deena | Alemu, Zewdie Aderaw | Alfonso-Cristancho, Rafael | Alhabib, Samia | Ali, Raghib | Al Kahbouri, Mazin J | Alla, François | Allen, Peter J | AlMazroa, Mohammad A | Alsharif, Ubai | Alvarez, Elena | Alvis-Guzmán, Nelson | Amankwaa, Adansi A | Amare, Azmeraw T | Amini, Hassan | Ammar, Walid | Antonio, Carl A T | Anwari, Palwasha | Ärnlöv, Johan | Arsenijevic, Valentina S Arsic | Artaman, Ali | Asad, Majed Masoud | Asghar, Rana J | Assadi, Reza | Atkins, Lydia S | Badawi, Alaa | Balakrishnan, Kalpana | Basu, Arindam | Basu, Sanjay | Beardsley, Justin | Bedi, Neeraj | Bekele, Tolesa | Bell, Michelle L | Bernabe, Eduardo | Beyene, Tariku J | Bhutta, Zulfiqar | Abdulhak, Aref Bin | Blore, Jed D | Basara, Berrak Bora | Bose, Dipan | Breitborde, Nicholas | Cárdenas, Rosario | Castañeda-Orjuela, Carlos A | Castro, Ruben Estanislao | Catalá-López, Ferrán | Cavlin, Alanur | Chang, Jung-Chen | Che, Xuan | Christophi, Costas A | Chugh, Sumeet S | Cirillo, Massimo | Colquhoun, Samantha M | Cooper, Leslie Trumbull | Cooper, Cyrus | da Costa Leite, Iuri | Dandona, Lalit | Dandona, Rakhi | Davis, Adrian | Dayama, Anand | Degenhardt, Louisa | De Leo, Diego | del Pozo-Cruz, Borja | Deribe, Kebede | Dessalegn, Muluken | deVeber, Gabrielle A | Dharmaratne, Samath D | Dilmen, Uğur | Ding, Eric L | Dorrington, Rob E | Driscoll, Tim R | Ermakov, Sergei Petrovich | Esteghamati, Alireza | Faraon, Emerito Jose A | Farzadfar, Farshad | Felicio, Manuela Mendonca | Fereshtehnejad, Seyed-Mohammad | de Lima, Graça Maria Ferreira | Forouzanfar, Mohammad H | França, Elisabeth B | Gaffikin, Lynne | Gambashidze, Ketevan | Gankpé, Fortuné Gbètoho | Garcia, Ana C | Geleijnse, Johanna M | Gibney, Katherine B | Giroud, Maurice | Glaser, Elizabeth L | Goginashvili, Ketevan | Gona, Philimon | González-Castell, Dinorah | Goto, Atsushi | Gouda, Hebe N | Gugnani, Harish Chander | Gupta, Rahul | Gupta, Rajeev | Hafezi-Nejad, Nima | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Hankey, Graeme J | Harb, Hilda L | Havmoeller, Rasmus | Hay, Simon I | Heredia Pi, Ileana B | Hoek, Hans W | Hosgood, H Dean | Hoy, Damian G | Husseini, Abdullatif | Idrisov, Bulat T | Innos, Kaire | Inoue, Manami | Jacobsen, Kathryn H | Jahangir, Eiman | Jee, Sun Ha | Jensen, Paul N | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kabagambe, Edmond Kato | Kan, Haidong | Karam, Nadim E | Karch, André | Karema, Corine Kakizi | Kaul, Anil | Kawakami, Norito | Kazanjan, Konstantin | Kazi, Dhruv S | Kemp, Andrew H | Kengne, Andre Pascal | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khan, Ejaz Ahmed | Khang, Young-Ho | Knibbs, Luke | Kokubo, Yoshihiro | Kosen, Soewarta | Defo, Barthelemy Kuate | Kulkarni, Chanda | Kulkarni, Veena S | Kumar, G Anil | Kumar, Kaushalendra | Kumar, Ravi B | Kwan, Gene | Lai, Taavi | Lalloo, Ratilal | Lam, Hilton | Lansingh, Van C | Larsson, Anders | Lee, Jong-Tae | Leigh, James | Leinsalu, Mall | Leung, Ricky | Li, Xiaohong | Li, Yichong | Li, Yongmei | Liang, Juan | Liang, Xiaofeng | Lim, Stephen S | Lin, Hsien-Ho | Lipshultz, Steven E | Liu, Shiwei | Liu, Yang | Lloyd, Belinda K | London, Stephanie J | Lotufo, Paulo A | Ma, Jixiang | Ma, Stefan | Machado, Vasco Manuel Pedro | Mainoo, Nana Kwaku | Majdan, Marek | Mapoma, Christopher Chabila | Marcenes, Wagner | Marzan, Melvin Barrientos | Mason-Jones, Amanda J | Mehndiratta, Man Mohan | Mejia-Rodriguez, Fabiola | Memish, Ziad A | Mendoza, Walter | Miller, Ted R | Mills, Edward J | Mokdad, Ali H | Mola, Glen Liddell | Monasta, Lorenzo | de la Cruz Monis, Jonathan | Hernandez, Julio Cesar Montañez | Moore, Ami R | Moradi-Lakeh, Maziar | Mori, Rintaro | Mueller, Ulrich O | Mukaigawara, Mitsuru | Naheed, Aliya | Naidoo, Kovin S | Nand, Devina | Nangia, Vinay | Nash, Denis | Nejjari, Chakib | Nelson, Robert G | Neupane, Sudan Prasad | Newton, Charles R | Ng, Marie | Nieuwenhuijsen, Mark J | Nisar, Muhammad Imran | Nolte, Sandra | Norheim, Ole F | Nyakarahuka, Luke | Oh, In-Hwan | Ohkubo, Takayoshi | Olusanya, Bolajoko O | Omer, Saad B | Opio, John Nelson | Orisakwe, Orish Ebere | Pandian, Jeyaraj D | Papachristou, Christina | Park, Jae-Hyun | Caicedo, Angel J Paternina | Patten, Scott B | Paul, Vinod K | Pavlin, Boris Igor | Pearce, Neil | Pereira, David M | Pesudovs, Konrad | Petzold, Max | Poenaru, Dan | Polanczyk, Guilherme V | Polinder, Suzanne | Pope, Dan | Pourmalek, Farshad | Qato, Dima | Quistberg, D Alex | Rafay, Anwar | Rahimi, Kazem | Rahimi-Movaghar, Vafa | Rahman, Sajjad ur | Raju, Murugesan | Rana, Saleem M | Refaat, Amany | Ronfani, Luca | Roy, Nobhojit | Sánchez Pimienta, Tania Georgina | Sahraian, Mohammad Ali | Salomon, Joshua A | Sampson, Uchechukwu | Santos, Itamar S | Sawhney, Monika | Sayinzoga, Felix | Schneider, Ione J C | Schumacher, Austin | Schwebel, David C | Seedat, Soraya | Sepanlou, Sadaf G | Servan-Mori, Edson E | Shakh-Nazarova, Marina | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shiue, Ivy | Sigfusdottir, Inga Dora | Silberberg, Donald H | Silva, Andrea P | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soshnikov, Sergey S | Sposato, Luciano A | Sreeramareddy, Chandrashekhar T | Stroumpoulis, Konstantinos | Sturua, Lela | Sykes, Bryan L | Tabb, Karen M | Talongwa, Roberto Tchio | Tan, Feng | Teixeira, Carolina Maria | Tenkorang, Eric Yeboah | Terkawi, Abdullah Sulieman | Thorne-Lyman, Andrew L | Tirschwell, David L | Towbin, Jeffrey A | Tran, Bach X | Tsilimbaris, Miltiadis | Uchendu, Uche S | Ukwaja, Kingsley N | Undurraga, Eduardo A | Uzun, Selen Begüm | Vallely, Andrew J | van Gool, Coen H | Vasankari, Tommi J | Vavilala, Monica S | Venketasubramanian, N | Villalpando, Salvador | Violante, Francesco S | Vlassov, Vasiliy Victorovich | Vos, Theo | Waller, Stephen | Wang, Haidong | Wang, Linhong | Wang, XiaoRong | Wang, Yanping | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | Wilkinson, James D | Woldeyohannes, Solomon Meseret | Wong, John Q | Wordofa, Muluemebet Abera | Xu, Gelin | Yang, Yang C | Yano, Yuichiro | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Yoon, Seok-Jun | Younis, Mustafa Z | Yu, Chuanhua | Jin, Kim Yun | El SayedZaki, Maysaa | Zhao, Yong | Zheng, Yingfeng | Zhou, Maigeng | Zhu, Jun | Zou, Xiao Nong | Lopez, Alan D | Naghavi, Mohsen | Murray, Christopher J L | Lozano, Rafael
Lancet  2014;384(9947):980-1004.
Summary
Background
The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100 000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.
Methods
We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990–2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.
Findings
292 982 (95% UI 261 017–327 792) maternal deaths occurred in 2013, compared with 376 034 (343 483–407 574) in 1990. The global annual rate of change in the MMR was −0·3% (−1·1 to 0·6) from 1990 to 2003, and −2·7% (−3·9 to −1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290–2866) maternal deaths were related to HIV in 2013, 0·4% (0·2–0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1–1262·8) in South Sudan to 2·4 (1·6–3·6) in Iceland.
Interpretation
Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(14)60696-6
PMCID: PMC4255481  PMID: 24797575
2.  Farnesoid X receptor directly regulates xenobiotic detoxification genes in the long-lived Little mice 
Mechanisms of ageing and development  2013;134(9):10.1016/j.mad.2013.08.003.
Activation of xenobiotic metabolism pathways has been linked to lifespan extension in different models of aging. However, the mechanisms underlying activation of xenobiotic genes remain largely unknown. Here we showed that although FXR mRNA levels do not change significantly, FXR (farnesoid X receptor, Nr1h4) protein levels are elevated in the livers of the long-lived Little mice, leading to increased DNA binding activity of FXR. Hepatic FXR expression is sex-dependent in wild-type mice but not in Little mice, implying that up-regulation of FXR might be dependent on the reduction of growth hormone in Little mice. Growth hormone treatment decreased hepatic expression of FXR and xenobiotic genes Abcb1a, Fmo3 and Gsta2 in both wild-type and Little mice, suggesting an association between FXR and xenobiotic gene expression. We found that Abcb1a is transactivated by FXR via direct binding of FXR/retinoid X receptor α (RXRα) heterodimer to a response element at the proximal promoter. FXR also positively controls Fmo3 and Gsta2 expression through direct interaction with the response elements in these genes. Our study demonstrates that xenobiotic genes are direct transcriptional targets of FXR and suggests that FXR signaling may play a critical role in the lifespan extension observed in Little mice.
doi:10.1016/j.mad.2013.08.003
PMCID: PMC3845407  PMID: 24007921
FXR; xenobiotic detoxification gene; Little mice; growth hormone
3.  CD24-Positive Cells from Normal Adult Mouse Liver Are Hepatocyte Progenitor Cells 
Stem Cells and Development  2011;20(12):2177-2188.
The identification of specific cell surface markers that can be used to isolate liver progenitor cells will greatly facilitate experimentation to determine the role of these cells in liver regeneration and their potential for therapeutic transplantation. Previously, the cell surface marker, CD24, was observed to be expressed on undifferentiated bipotential mouse embryonic liver stem cells and 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced oval cells. Here, we describe the isolation and characterization of a rare, primary, nonhematopoietic, CD24+ progenitor cell population from normal, untreated mouse liver. By immunohistochemistry, CD24-expressing cells in normal adult mouse liver were colocalized with CK19-positive cholangiocytes. This nonhematopoietic (CD45−, Ter119−) CD24+ cell population isolated by flow cytometry represented 0.04% of liver cells and expressed several markers of liver progenitor/oval cells. The immunophenotype of nonhematopoietic CD24+ cells was CD133, Dlk, and Sca-1 high, but c-Kit, Thy-1, and CD34 low. The CD24+ cells had increased expression of CK19, epithelial cell adhesion molecule, Sox 9, and FN14 compared with the unsorted cells. Upon transplantation of nonhematopoietic CD24+ cells under the sub-capsule of the livers of Fah knockout mice, cells differentiated into mature functional hepatocytes. Analysis of X and Y chromosome complements were used to determine whether or not fusion of the engrafted cells with the recipient hepatocytes occurred. No cells were found that contained XXXY or any other combination of donor and host sex chromosomes as would be expected if cell fusion had occurred. These results suggested that CD24 can be used as a cell surface marker for isolation of hepatocyte progenitor cells from normal adult liver that are able to differentiate into hepatocytes.
doi:10.1089/scd.2010.0352
PMCID: PMC3225069  PMID: 21361791
4.  Effect of vaccination with N-glycolyl GM3/VSSP vaccine by subcutaneous injection in patients with advanced cutaneous melanoma 
NeuGc-containing gangliosides have been described in melanoma cells and are an attractive target for cancer immunotherapy because they are minimally or not expressed in normal human tissues. Melanoma patients treated with a vaccine based on N-glycolyl gangliosides have shown benefit in progression free survival and overall survival. We conducted a multicenter Phase I/II clinical trial in patients with metastatic cutaneous melanoma treated with the N-gycolyl GM3/very-small-size proteoliposomes vaccine by the subcutaneous route. Selecting the optimal biological dose of the vaccine was the principal objective based on immunogenicity, efficacy, and safety results. Six dose levels were studied and the treatment schedule consisted of five doses administered every 2 weeks and then monthly until 15 doses had been given. Dose levels evaluated were 150, 300, 600, 900, 1200, and 1500 μg with five patients included in each dose level except the 900 μg dose (n = 10). Immunogenicity was determined by antibody titers generated in patients after vaccination. Antitumor effect was measured by response criteria of evaluation in solid tumors and safety was evaluated by common toxicity criteria of adverse events. The vaccine was safe and immunogenic at all doses levels. The most frequent adverse events related to vaccination were mild to moderate injection site reactions and flu-like symptoms. Vaccination induced specific anti-NeuGcGM3 immunoglobulin M and immunoglobulin G antibody responses in all patients. Disease control (objective response or stable disease) was obtained in 38.46% of patients. Global median overall survival was 20.20 months. Two patients achieved overall survival duration of about 4 and 5 years, respectively. The 900 μg dose resulted in overall survival duration of 19.40 months and was selected as the biological optimal dose.
doi:10.2147/CMAR.S22617
PMCID: PMC3468021  PMID: 23055778
melanoma; clinical trial; therapeutic vaccine; ganglioside; N-glycolyl GM3
5.  NGlycolylGM3/VSSP Vaccine in Metastatic Breast Cancer Patients: Results of Phase I/IIa Clinical Trial 
Patients treated with vaccines based on NGlycolil gangliosides have showed benefit in progression free survival and overall survival. These molecules, which have been observed in breast cancer cells, are minimally or not expressed in normal human tissue and have been considered as antigen tumor-specific. For this reason they are very attractive to immunotherapy. A phase I/II clinical trial was carried out in metastatic breast cancer patients with the NGlycolylGM3/VSSP vaccine administered by subcutaneous route. Selecting the optimal biological doses of the vaccine in these patients was the principal objective based on the immunogenicity, efficacy and safety results. Six levels of doses of vaccine were studied. Treatment schedule consisted of five doses every two weeks and then monthly until reaching a fifteenth doses. Doses levels studied were 150, 300, 600, 900, 1200 and 1500 μg. Five patients in each level were included except at the 900 μg dose, in which ten patients were included. Immunogenicity was determined by levels of antibodies generated in patients after vaccination. The response criteria of evaluation in solid tumors (RECIST) was used to evaluate antitumoral effect. Safety was evaluated by Common Toxicity Criteria of Adverse Event (CTCAE). The vaccine administration was safe and immunogenic in all does levels. Most frequent adverse events related to vaccination were mild or moderate and were related to injection site reactions and “flu-like” symptoms. Vaccination induced specific anti-NeuGcGM3 IgM and IgG antibodies responses in all patients. Disease control (objective response or stable disease) was obtained in 72.7% of evaluated patients. Median overall survival was 15.9 months. Two patients of two different dose levels achieved overall survival values of about six years. The dose of 900 μg was selected as biological optimal dose in which overall survival was 28.5 months.
doi:10.4137/BCBCR.S8488
PMCID: PMC3465086  PMID: 23055739
metastatic breast cancer; clinical trial; therapeutic vaccine; ganglioside; NGcGM3
6.  Secretion of biologically active interferon-gamma inducible protein-10 (IP-10) by Lactococcus lactis 
Background
Chemokines are a large group of chemotactic cytokines that regulate and direct migration of leukocytes, activate inflammatory responses, and are involved in many other functions including regulation of tumor development. Interferon-gamma inducible-protein-10 (IP-10) is a member of the C-X-C subfamily of the chemokine family of cytokines. IP-10 specifically chemoattracts activated T lymphocytes, monocytes, and NK cells. IP-10 has been described also as a modulator of other antitumor cytokines. These properties make IP-10 a novel therapeutic molecule for the treatment of chronic and infectious diseases. Currently there are no suitable live biological systems to produce and secrete IP-10. Lactococcus lactis has been well-characterized over the years as a safe microorganism to produce heterologous proteins and to be used as a safe, live vaccine to deliver antigens and cytokines of interest. Here we report a recombinant strain of L. lactis genetically modified to produce and secrete biologically active IP-10.
Results
The IP-10 coding region was isolated from human cDNA and cloned into an L. lactis expression plasmid under the regulation of the pNis promoter. By fusion to the usp45 secretion signal, IP-10 was addressed out of the cell. Western blot analysis demonstrated that recombinant strains of L. lactis secrete IP-10 into the culture medium. Neither degradation nor incomplete forms of IP-10 were detected in the cell or supernatant fractions of L. lactis. In addition, we demonstrated that the NICE (nisin-controlled gene expression) system was able to express IP-10 "de novo" even two hours after nisin removal. This human IP-10 protein secreted by L. lactis was biological active as demonstrated by Chemotaxis assay over human CD3+T lymphocytes.
Conclusion
Expression and secretion of mature IP-10 was efficiently achieved by L. lactis forming an effective system to produce IP-10. This recombinant IP-10 is biologically active as demonstrated by its ability to chemoattract human CD3+ T lymphocytes. This strain of recombinant L. lactis represents a potentially useful tool to be used as a live vaccine in vivo.
doi:10.1186/1475-2859-7-22
PMCID: PMC2503953  PMID: 18662403
7.  Substance P Is Responsible for Physiological Alterations Such as Increased Chloride Ion Secretion and Glucose Malabsorption in Cryptosporidiosis▿  
Infection and Immunity  2006;75(3):1137-1143.
Cryptosporidiosis, caused by the protozoan parasite Cryptosporidium, causes self-limited diarrhea in immunocompetent hosts and severe life-threatening diarrhea in AIDS patients. Highly active antiretroviral therapy has been used to effectively treat cryptosporiosis in some but not all AIDS patients. Therefore, there is an urgent need for innovative drugs to treat this disease. Cryptosporidium infection results in intestinal pathophysiological changes such as glucose malabsorption, increased chloride ion (Cl−) secretion, and epithelial barrier disruption, leading to disease pathogenesis. In order to develop tools to combat this opportunistic pathogen, it is vital to understand mediators involved in disease pathogenesis. Substance P (SP), a neuropeptide and pain transmitter, is located in the gastrointestinal tract. SP can cause Cl− secretion in human gastrointestinal explants. However, its role in cryptosporidiosis has not been fully studied. Jejunal samples from macaques before and after Cryptosporidium parvum infection were assayed for SP and SP receptor mRNA and protein levels by reverse transcription-PCR and by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. The role of SP in pathophysiological alterations, such as Cl− secretion and glucose malabsorption, was studied using tissues derived from macaques infected with C. parvum by the Ussing chamber technique. SP and SP receptor mRNA and protein expression levels were increased in jejunal samples following C. parvum infection and were accompanied by increased basal ion secretion and glucose malabsorption. In vitro treatment of samples obtained from infected macaques with the SP receptor antagonist aprepitant (Emend; Merck, Whitehouse Station, NJ) completely reversed the increase in basal ion secretion and corrected the glucose malabsorption. Our findings raise the possibility of using SP receptor antagonists for the treatment of symptoms associated with cryptosporidiosis.
doi:10.1128/IAI.01738-05
PMCID: PMC1828596  PMID: 17158891

Results 1-7 (7)