Lysophosphatidic acid (LPA) acts on LPA2 receptor to mediate multiple pathological effects that are associated with tumorigenesis. The absence of LPA2 attenuates tumor progression in rodent models of colorectal cancer, but whether overexpression of LPA2 alone can lead to malignant transformation in the intestinal tract has not been studied. In this study, we expressed human LPA2 in intestinal epithelial cells (IECs) under control of the villin promoter. Less than 4% of F1-generation mice had germline transmission of transgenic (TG) human LPA2; as such only 3 F1 mice out of 72 genotyped had TG expression. These TG mice appeared anemic with hematochezia and died shortly after birth. TG mice were smaller in size compared with the wild type mouse of the same age and sex. Morphological analysis showed that TG LPA2 colon had hyper-proliferation of IECs resulting in increased colonic crypt depth. Surprisingly, TG small intestine had villus blunting and decreased IEC proliferation and dysplasia. In both intestine and colon, TG expression of LPA2 compromised the terminal epithelial differentiation, consistent with epithelial dysplasia. Furthermore, we showed that epithelial dysplasia was observed in founder mouse intestine, correlating LPA2 overexpression with epithelial dysplasia. The current study demonstrates that overexpression of LPA2 alone can lead to intestinal dysplasia.
Lysophosphatidic acid (LPA) acts on LPA2 receptor to mediate multiple pathological effects that are associated with tumorigenesis. The absence of LPA2 attenuates tumor progression in rodent models of colorectal cancer, but whether overexpression of LPA2 alone can lead to malignant transformation in the intestinal tract has not been studied. In this study, we expressed human LPA2 in intestinal epithelial cells (IECs) under control of the villin promoter. Less than 4% of F1-generation mice had germline transmission of transgenic (TG) human LPA2; as such only 3 F1 mice out of 72 genotyped had TG expression. These TG mice appeared anemic with hematochezia and died shortly after birth. TG mice were smaller in size compared with the wild type mouse of the same age and sex. Morphological analysis showed that TG LPA2 colon had hyper-proliferation of IECs resulting in increased colonic crypt depth. Surprisingly, TG small intestine had villus blunting and decreased IEC proliferation and dysplasia. In both intestine and colon, TG expression of LPA2 compromised the terminal epithelial differentiation, consistent with epithelial dysplasia. Furthermore, we showed that epithelial dysplasia was observed in founder mouse intestine, correlating LPA2 overexpression with epithelial dysplasia. The current study demonstrates that overexpression of LPA2 alone can lead to intestinal dysplasia.
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Alicia Smith;
Anna Knight;
H Park;
DB Hausman;
JM Fleming;
VL Bland;
G Rosa;
EM Kennedy;
MA Caudill;
O Malysheva;
GPA Kauwell;
A Sokolow;
S Fisher;
LB Bailey
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Marta C. Nunes;
Zachary Kuschner;
Zelda Rabede;
Richard Madimabe;
Nadia Van Niekerk;
Jackie Moloi;
Locadiah Kuwanda;
John W. Rossen;
Keith Klugman;
Peter V. Adrian;
Shabir A. Madhi
Background: Advances in molecular diagnostics have implicated newly-discovered respiratory viruses in the pathogenesis of pneumonia. We aimed to determine the prevalence and clinical characteristics of human bocavirus (hBoV), human rhinovirus (hRV), polyomavirus-WU (WUPyV) and -KI (KIPyV) and human coronaviruses (CoV)-OC43, -NL63, -HKU1 and -229E among children hospitalized with lower respiratory tract infections (LRTI). Methods: Multiplex real-time reverse-transcriptase polymerase chain reaction was undertaken on archived nasopharyngeal aspirates from HIV-infected and -uninfected children ( < 2 years age) hospitalized for LRTI, who had been previously investigated for respiratory syncytial virus, human metapneumovirus, parainfluenza I-III, adenovirus and influenza A/B. Results: At least one of these viruses were identified in 274 (53.0%) of 517 and in 509 (54.0%) of 943 LRTI-episodes in HIV-infected and -uninfected children, respectively. Human rhinovirus was the most prevalent in HIV-infected (31.7%) and - uninfected children (32.0%), followed by CoV-OC43 (12.2%) and hBoV (9.5%) in HIV-infected; and by hBoV (13.3%) and WUPyV (11.9%) in HIV-uninfected children. Polyomavirus-KI (8.9% vs. 4.8%; p = 0.002) and CoV-OC43 (12.2% vs. 3.6%; p < 0.001) were more prevalent in HIV-infected than -uninfected children. Combined with previously-tested viruses, respiratory viruses were identified in 60.9% of HIV-infected and 78.3% of HIV-uninfected children. The newly tested viruses were detected at high frequency in association with other respiratory viruses, including previously-investigated viruses (22.8% in HIV-infected and 28.5% in HIV-uninfected children). Conclusions: We established that combined with previously-investigated viruses, at least one respiratory virus was identified in the majority of HIV-infected and HIV-uninfected children hospitalized for LRTI. The high frequency of viral coinfections illustrates the complexities in attributing causality to specific viruses in the aetiology of LRTI and may indicate a synergetic role of viral co-infections in the pathogenesis of childhood LRTI.
There has been growing recognition of menstrual hygiene management (MHM) as a significant public health issue. However, research has predominately focused on the experiences of adolescent girls in school settings. The purpose of this research is to examine detailed accounts of menstruation for women in rural Odisha, India at various life stages with a view toward improving international monitoring of MHM. Focus group discussions and in-depth interviews were conducted to understand women’s experiences of menstruation across four life stages (unmarried women, recently married women, married women, and older women). Thematic analysis was used to identify menstruation-related challenges and needs. We found women voiced needs that aligned with those captured by the WHO/UNICEF Joint Monitoring Programme for Water Supply, Sanitation and Hygiene (JMP) definition for MHM: access to clean materials, privacy for changing materials, soap and water for bathing, and disposal facilities for materials. However, we also found women require materials that are not only clean but comfortable and reliable; soap and water for more than bathing; privacy for the full spectrum of menstruation-related practices, not just when changing; and disposal facilities that are private and safe, not just accessible. Additionally, we identified needs that extend beyond the existing definition: pain management, social support, and an enabling sociocultural environment. Overall, women representing all life stages discussed menstruation challenges, including bathing, pain, and washing, drying, and storing cloth materials. Cloth management challenges were most acute for unmarried and recently married women, who were concerned that practices could reveal their menstrual status and harm their reputations, thus informing their preference for disposable materials, if attainable. We propose a revised definition of adequate MHM for this population that more comprehensively captures their needs. This definition may also prove useful for other populations, future research, creating measures of assessment, and guiding interventions and program priorities.
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Anatoli Kamali;
Matt A. Price;
Shabir Lakhi;
Etienne Karita;
Mubiana Inambao;
Eduard J. Sanders;
Omu Anzala;
Mary H. Latka;
Linda-Gail Bekker;
Pontiano Kaleebu;
Gershim Asiki;
Ali Ssetaala;
Eugene Ruzagira;
Susan Allen;
Paul Farmer;
Eric Hunter;
Gaudensia Mutua;
Heeran Makkan;
Amanda Tichacek;
Ilene K. Brill;
Pat Fast;
Gwynn Stevens;
Paramesh Chetty;
Pauli N. Amornkul;
Jill Gilmour
HIV epidemiology informs prevention trial design and program planning. Nine clinical research centers (CRC) in sub-Saharan Africa conducted HIV observational epidemiology studies in populations at risk for HIV infection as part of an HIV prevention and vaccine trial network. Annual HIV incidence ranged from below 2% to above 10% and varied by CRC and risk group, with rates above 5% observed in Zambian men in an HIV-discordant relationship, Ugandan men from Lake Victoria fishing communities, men who have sex with men, and several cohorts of women. HIV incidence tended to fall after the first three months in the study and over calendar time. Among suspected transmission pairs, 28% of HIV infections were not from the reported partner. Volunteers with high incidence were successfully identified and enrolled into large scale cohort studies. Over a quarter of new cases in couples acquired infection from persons other than the suspected transmitting partner.
Background Using a cross-sectional design, we assessed the relationship between the time schools provide for physical activity and the proportion of students achieving a healthy aerobic capacity or body mass index. Methods In 2013–2014, physical education and grade-level teachers from 905 of 1,244 Georgia elementary schools provided survey data about the frequency and duration of physical activity opportunities offered before, during, and after school. Log-binomial models related the weekly physical activity minutes provided by schools to the proportion of children in the FitnessGram healthy fitness zone for aerobic capacity or body mass index while adjusting for school characteristics and demographics. Results During-school physical activity time was not associated with student fitness, but schools with before-school physical activity programs had a moderately higher prevalence of healthy aerobic capacity (prevalence ratio among girls: 1.06; 99% confidence interval: 1.00–1.13; prevalence ratio among boys: 1.03; 99% confidence interval: 0.99–1.08). Each additional 30 minutes of recess per week was associated with no more than a 3%-higher proportion of students with healthy body mass indexes (prevalence ratio among girls: 1.01; 99% confidence interval: 1.00–1.03; prevalence ratio among boys: 1.01; 99% confidence interval: 0.99–1.03). Conclusions The amount of physical activity time provided by schools is not strongly associated with school-aggregated student fitness. Future studies should be designed to assess the importance of school-based physical activity time on student fitness, relative to physical activity type and quality.
The need for annual revaccination against influenza is a burden on the healthcare system, leads to low vaccination rates and makes timely vaccination difficult against pandemic strains, such as during the 2009 H1N1 influenza pandemic. In an effort toward achieving a broadly protective vaccine that provides cross-protection against multiple strains of influenza, this study developed a microneedle patch to co-immunize with A/PR8 influenza hemagglutinin DNA and A/PR8 inactivated virus vaccine. We hypothesize that this dual component vaccination strategy administered to the skin using microneedles will provide cross-protection against other strains of influenza. To test this hypothesis, we developed a novel coating formulation that did not require additional excipients to increase coating solution viscosity by using the DNA vaccine itself to increase viscosity and thereby enable thick coatings of DNA vaccine and inactivated virus vaccine on metal microneedles. Co-immunization in this way not only generated robust antibody responses against A/PR8 influenza but also generated robust heterologous antibody responses against pandemic 2009 H1N1 influenza in mice. Challenge studies showed complete cross-protection against lethal challenge with live pandemic 2009 H1N1 virus. Control experiments using A/PR8 inactivated influenza virus vaccine with placebo DNA coated onto microneedles produced lower antibody titers and provided incomplete protection against challenge. Overall, this is the first study showing DNA solution as a microneedle coating agent and demonstrating cross-protection by co-immunization with inactivated virus and DNA vaccine using coated microneedles.
Influenza vaccines with broad cross-protection are urgently needed to prevent an emerging influenza pandemic. A fusion protein of the Toll-like receptor (TLR) 5-agonist domains from flagellin and multiple repeats of the conserved extracellular domain of the influenza matrix protein 2 (M2e) was constructed, purified and evaluated as such a vaccine. A painless vaccination method suitable for possible self-administration using coated microneedle arrays was investigated for skin-targeted delivery of the fusion protein in a mouse model. The results demonstrate that microneedle immunization induced strong humoral as well as mucosal antibody responses and conferred complete protection against homo- and heterosubtypic lethal virus challenges. Protective efficacy with microneedles was found to be significantly better than that seen with conventional intramuscular injection, and comparable to that observed with intranasal immunization. Because of its advantages for administration, safety and storage, microneedle delivery of M2e-flagellin fusion protein is a promising approach for an easy-to-administer universal influenza vaccine.