Gallbladder carcinoma is a highly malignant tumor and a public health problem in some parts of the world. It is characterized by a poor prognosis and its resistance to radio and chemotherapy. There is an urgent need to develop novel therapeutic alternatives for the treatment of gallbladder carcinoma. The mammalian target of the rapamycin (mTOR) signaling pathway is activated in about 50% of human malignancies, and its role in gallbladder carcinoma has previously been suggested. In the present study, we investigated the phosphorylation status of the mTOR substrate p70S6K in preneoplastic and neoplastic gallbladder tissues and evaluated the effect of three mTOR inhibitors on cell growth and migration in gallbladder carcinoma cell lines.
Immunohistochemical staining of phospho-p70S6K was analyzed in 181 gallbladder carcinoma cases, classified according to lesion type as dysplasia, early carcinoma, or advanced carcinoma. Protein expression of AKT/mTOR members was also evaluated in eight gallbladder carcinoma cell lines by Western blot analysis. We selected two gallbladder carcinoma cell lines (G415 and TGBC-2TKB) to evaluate the effect of rapamycin, RAD001, and AZD8055 on cell viability, cell migration, and protein expression.
Our results showed that phospho-p70S6K is highly expressed in dysplasia (66.7%, 12/18), early cancer (84.6%, 22/26), and advanced cancer (88.3%, 121/137). No statistical correlation was observed between phospho-p70S6K status and any clinical or pathological features, including age, gender, ethnicity, wall infiltration level, or histological differentiation (P < 0.05). In vitro treatment with rapamycin, RAD001, and AZD8055 reduced cell growth, cell migration, and phospho-p70S6K expression significantly in G-415 and TGBC-2TKB cancer cells (P < 0.001).
Our findings confirm the upregulation of this signaling pathway in gallbladder carcinoma and provide a rationale for the potential use of mTOR inhibitors as a therapeutic strategy for human gallbladder carcinoma.
gallbladder cancer; p70S6K; mTOR inhibitor; AKT; migration; cell line
Background. Using multinational collections of methicillin-susceptible Staphylococcus aureus (MSSA) isolates from infective endocarditis (IE) and soft tissue infections (STIs), we sought to (1) validate the finding that S. aureus in clonal complex (CC) 30 is associated with hematogenous complications and (2) test the hypothesis that specific genetic characteristics in S. aureus are associated with infection severity.
Methods. IE and STI isolates from 2 cohorts were frequency matched by geographic origin. Isolates underwent spa typing to infer CC and multiplex polymerase chain reaction for presence of virulence genes.
Results. 114 isolate pairs were genotyped. IE isolates were more likely to be CC30 (19.5% vs 6.2%; P = .005) and to contain 3 adhesins (clfB, cna, map/eap; P < .0001 for all) and 5 enterotoxins (tst, sea, sed, see, and sei; P ≤ .005 for all). CC30 isolates were more likely to contain cna, tst, sea, see, seg, and chp (P < .05 for all).
Conclusions. MSSA IE isolates were significantly more likely to be CC30 and to possess a distinct repertoire of virulence genes than MSSA STI isolates from the same region. The genetic basis of this association requires further study.
No association between the Human T-cell lymphotropic virus (HTLV), an oncogenic virus that alters host immunity, and the Human Papillomavirus (HPV) has previously been reported. Examining the association between these two viruses may permit the identification of a population at increased risk for developing cervical cancer.
Methods and Findings
Between July 2010 and February 2011, we conducted a cross-sectional study among indigenous Amazonian Peruvian women from the Shipibo-Konibo ethnic group, a group with endemic HTLV infection. We recruited women between 15 and 39 years of age who were living in the cities of Lima and Ucayali. Our objectives were to determine the association between HTLV and: (i) HPV infection of any type, and (ii) high-risk HPV type infection. Sexually active Shipibo-Konibo women were screened for HTLV-1 and HTLV-2 infections. All HTLV-1 or -2 positive women, along with two community-matched HTLV negative sexually active Shipibo-Konibo controls were later tested for the presence of HPV DNA, conventional cytology, and HIV. We screened 1,253 Shipibo-Konibo women, observing a prevalence of 5.9% (n = 74) for HTLV-1 and 3.8% (n = 47) for HTLV-2 infections. We enrolled 62 (60.8%) HTLV-1 positive women, 40 (39.2%) HTLV-2 positive women, and 205 community-matched HTLV negative controls. HTLV-1 infection was strongly associated with HPV infection of any type (43.6% vs. 29.3%; Prevalence Ratio (PR): 2.10, 95% CI: 1.53–2.87), and with high-risk HPV infection (32.3% vs. 22.4%; PR: 1.93, 95% CI: 1.04–3.59). HTLV-2 was not significantly associated with either of these HPV infections.
HTLV-1 infection was associated with HPV infection of any type and with high-risk HPV infection. Future longitudinal studies are needed to evaluate the incidence of high-risk HPV infection as well as the incidence of cervical neoplasia among HTLV-1 positive women.
Purpose. Application of anterior segment optical coherence (AS-OCT) in pediatric ophthalmology.
Methods. Retrospective clinical study case series of 26 eyes of 19 pediatric patients throughout a 21-month period, presenting anterior segment pathologies, were submitted to AS-OCT examination (OCT Visante, 1310 nm, Zeiss), noncontact technique, no sedation requirement. Results. AS-OCT images were obtained from 19 patients (range: 2 months to 12 years). Clinical diagnosis of anterior segment abnormalities included cornea disease (n = 7), congenital anterior segment conditions (n = 10), ocular trauma (n = 1), anterior segment surgeries (n = 2), iridocorneal angle abnormalities (n = 4), intermediate uveitis (n = 2). The most common OCT findings were corneal hyperreflectivity and thickening (n = 15), shallow anterior chamber with iris-lens diaphragm anterior displacement (n = 4), atypical corneal curvature (n = 4), corneal thinning (n = 4), peripheral synechiae with angle closure (n = 3), increased anterior chamber depth (n = 2), and proximal portion of glaucoma drainage tube (n = 2). Conclusion. In the present study, noncontact AS-OCT demonstrated to be a feasible technique to evaluate the anterior segment providing anatomic details and useful to clarify diagnosis in the pediatric population.
Rosanna Peeling and colleagues describe their experience of introducing point-of-care testing to screen for syphilis in pregnant women living in low- and middle-income countries.
A number of studies have demonstrated that receptor and co-receptor expression levels which may affect viral entry, promoting cervical HIV infection. The aim was to evaluate the expression levels of CCR5, CXCR4and DC-SIGN mRNA in a sample of heterosexually HIV infected Mexican women.
We enrolled twenty-six HIV heterosexual infected women attending a local infectious diseases medical unit.RNA was isolated from the cervix and gene expression analysis was performed using real-time PCR.
Expression rates for mRNA of CCR5 (median 1.82; range 0.003–2934) were higher than those observed for CXCR4 (0.79; 0.0061–3312) and DC-SIGN (0.33; 0.006–532) receptors (p < 0.05). A high correlation was found between the mRNA expression levels of these three receptors (rs = 0.52 to 0.85, p < 0.01).
Levels of expression of the tested chemokine receptors in the cervix are different from each other and alsovary from woman to woman, and seem to support the suggestion that chemokine receptor expression in genital tissues may be playing a role in the HIV transmission.
AIDS; HIV-1; Mucosae; CCR5; CXCR4; DC-SIGN.
To report the results of a needs assessment of research and training in Medical Informatics (MI) and Bioinformatics (BI) in Latin America.
Methods and results
This assessment was conducted by QUIPU: The Andean Global Health Informatics Research and Training Center. After sending email invitations to MI–BI related professionals from Latin America, 142 surveys were received from 11 Latin American countries. The following were the top four ranked MI-related courses that a training programme should include: introduction to biomedical informatics; data representation and databases; mobile health; and courses that address issues of security, confidentiality and privacy. Several new courses and topics for research were suggested by survey participants. The information collected is guiding the development of curricula and a research agenda for the MI and BI QUIPU multidisciplinary programme for the Andean Region and Latin America.
The objective of this paper is to report the results of the first needs assessment of research and training in Medical Informatics (MI) and Bioinformatics (BI) in Latin America.
Top ranked courses in biomedical informatics included: mobile health, issues on security, confidentiality and privacy, public and clinical informatics and electronic health records.
The information collected in this needs assessment is guiding the development of curricula and a research agenda for training and research in the Andean region through the Peruvian NIH funded centre QUIPU. ‘Quipu’ is a Quechua word that describes an ancient system used throughout the Andes by the Incas to record and distribute information.
Strengths and limitations of this study
The online survey included participants from 11 Latin American countries.
It is the first needs assessment in Latin America addressing issues of training and research in biomedical informatics.
The sample was, however, purposive.
Data on hepatitis B virus (HBV) prevalence are limited in developing countries. There is also limited information of consistent condom use efficacy for reducing HBV transmission at the population level. The study goal was to evaluate the prevalence and factors associated with HBV infection in Peru, and the relationship between anti-HBc positivity and consistent condom use.
Methods and Findings
Data from two different surveys performed in 28 mid-sized Peruvian cities were analyzed. Participants aged 18–29 years were selected using a multistage cluster sampling. Information was collected through a validated two-part questionnaire. The first part (face-to-face) concerned demographic data, while the second part (self-administered using handheld computers) concerned sexual behavior. Hepatitis B core antibody (anti-HBc) was tested in 7,000 blood samples. Prevalences and associations were adjusted for sample strata, primary sampling units and population weights. Anti-HBc prevalence was 5.0% (95%CI 4.1%–5.9%), with the highest prevalence among jungle cities: 16.3% (95%CI 13.8%–19.1%). In the multivariable analysis, Anti-HBc positivity was directly associated with geographic region (highlands OR = 2.05; 95%CI 1.28–3.27, and jungle OR = 4.86; 95%CI 3.05–7.74; compared to coastal region); and inversely associated with age at sexual debut (OR = 0.90; 95%CI 0.85–0.97). Consistent condom use, evaluated in about 40% of participants, was associated with reduced prevalence (OR = 0.34; 95%CI 0.15–0.79) after adjusting for gender, geographic region, education level, lifetime number of sex partners, age at sexual debut and year of survey.
Residence in highlands or jungle cities is associated with higher anti-HBc prevalences, whereas increasing age at sexual debut were associated with lower prevalences. Consistent condom use was associated with decreased risk of anti-HBc. Findings from this study emphasize the need of primary prevention programs (vaccination) especially in the jungle population, and imply that condom use promotion might be a potential strategy to prevent HBV infection.
Traumatic brain injury (TBI) is frequently complicated by alterations in mood and behaviour and changes in personality. We report mild personality changes post-TBI as a possible indicator of traumatic brain injury, but not of injury severity or psychiatric complications.
Well-trained people are urgently needed to tackle global health challenges through information and communication technologies. In this report, AMAUTA, a joint international collaborative training program between the Universidad Peruana Cayetano Heredia and the University of Washington, which has been training Peruvian health professionals in biomedical and health informatics since 1999, is described. Four short-term courses have been organized in Lima, offering training to more than 200 graduate-level students. Long-term training to masters or doctorate level has been undertaken by eight students at the University of Washington. A combination of short-term and long-term strategies was found to be effective for enhancing institutional research and training enterprise. The AMAUTA program promoted the development and institution of informatics research and training capacity in Peru, and has resulted in a group of trained people playing important roles at universities, non-government offices, and the Ministry of Health in Peru. At present, the hub is being extended into Latin American countries, promoting South-to-South collaborations.
Training; global health informatics; AMAUTA; Peru
This study preliminarily examined whether plasma ceramides were elevated in depression, and if the elevation was more pronounced in Alzheimer’s compared to controls. Results suggest plasma ceramides are elevated in persons with a major depression diagnosis regardless of dementia status.
ceramides; lipids; depression
Clinicians in developing countries have had limited access to continuing education (CE) outside major cities, and CE strategies have had limited impact on sustainable change in performance. New educational tools could improve CE accessibility and effectiveness.
The objective of this study was to evaluate an interactive Internet-based CE course on Sexually Transmitted Diseases (STDs) management for clinicians in Peru. Participants included physicians and midwives in private practice drawn from a census of 10 Peruvian cities. The CE included a three-hour workshop for improving Internet skills, followed by a 22-hour online course on STD-syndrome-management, with subsequent educational support. The course used case-based clinical vignettes tailored to local STD problems. Knowledge and reported practices on STD management were assessed before, immediately after and at four months after completion of the course. Statistical analysis included parametric tests-linear regression multivariate analysis, paired t-test and repeated measures ANOVA using SPSS 14.0. Of 1,071 eligible clinicians, 510 agreed to participate, as did an additional 132 public sector clinicians. Of these 642 participants, 619 (96.4%) completed the course, and 596 (96.3%) took the four-month follow-up evaluation. Physician and midwife scores improved from 64.2% correct answers on the pre-test to 77.9% correct on the four-month follow-up test (p<0.001). Most participants (95%) found the online course useful for their work needs. Self reported STD management practices did not change.
Among physicians and midwives in Peru, an Internet-based CE course was feasible, acceptable with high participation rates, and led to sustained improvement in knowledge at four months. Further studies are needed to test it as a model for improving the training of physicians, midwives, and other health care providers.
There are few published reports of research training needs assessments and research training programs. In an effort to expand this nascent field of study and to bridge the gap between research and practice, we sought to systematically assess the research training needs of health care professionals working at Peruvian governmental institutions leading HIV and tuberculosis (TB) control and among senior stakeholders in the field.
Six institutional workshops were conducted with the participation of 161 mid-level health professionals from agencies involved in national HIV and TB control. At each workshop informants completed a structured questionnaire and participated in small and large group discussions. Additional data and institutional commitment was obtained through in-depth interviews from 32 senior managers and researchers from the Ministry of Health, academia and NGOs.
Participants exhibited an overwhelming receptivity for additional research training, observing a gap between current levels of research training and their perceived importance. Specialized skills in obtaining funding, developing research protocols, particularly in operational, behavioral and prevention research were considered in greatest need. Beyond research training, participants identified broader social, economic and political factors as influential in infectious disease control.
The needs assessment suggests that future training should focus on operational research techniques, rather than on clinical skill building or program implementation only. Strengthening health systems not only requires additional research training, but also adequate financial resources to implement research findings.
The public sectors of developing countries require strengthened capacity in health informatics. In Peru, where formal university graduate degrees in biomedical and health informatics were lacking until recently, the AMAUTA Global Informatics Research and Training Program has provided research and training for health professionals in the region since 1999. The Fogarty International Center supports the program as a collaborative partnership between Universidad Peruana Cayetano Heredia in Peru and the University of Washington in the United States of America. The program aims to train core professionals in health informatics and to strengthen the health information resource capabilities and accessibility in Peru. The program has achieved considerable success in the development and institutionalization of informatics research and training programs in Peru. Projects supported by this program are leading to the development of sustainable training opportunities for informatics and eight of ten Peruvian fellows trained at the University of Washington are now developing informatics programs and an information infrastructure in Peru. In 2007, Universidad Peruana Cayetano Heredia started offering the first graduate diploma program in biomedical informatics in Peru.
Background Cervical cancer, although usually preventable by Pap smear screening, remains the leading cause of cancer-related deaths among women in Peru. The percentages and characteristics of women in Peru who have or have not had a Pap smear have not been defined.
Methods In an urban community randomized trial of sexually transmitted infection (STI)/HIV prevention in Peru, 6712 randomly selected women between the ages of 18 and 29 from 20 cities were interviewed regarding having had cervical Pap smears.
Results Among women sampled, only 30.9% had had a Pap smear. By multivariate analysis, the main predictors of having a Pap smear were having had sex, having had children, completion of secondary education and increasing age. Regional variations were also found: women from the highlands and rainforest were less likely to have had Pap smears than women from the coast.
Conclusion A norm of seeking and receiving Pap smears has not been established among sexually active young Peruvian women. To improve Pap smear coverage in Peru, promotion efforts should target underserved women and regions with less coverage.
Vaginal smear; Peru
The Schizosaccharomyces pombe exchange factor Rgf1p specifically regulates Rho1p during polarized growth. Rgf1p activates the β-glucan synthase (GS) complex containing the catalytic subunit Bgs4p and is involved in the activation of growth at the second end, a transition that requires actin reorganization. In this work, we investigated Rgf1p signaling and observed that Rgf1p acted upstream from the Pck2p-Pmk1p MAPK signaling pathway. We noted that Rgf1p and calcineurin play antagonistic roles in Cl− homeostasis; rgf1Δ cells showed the vic phenotype (viable in the presence of immunosuppressant and chlorine ion) and were unable to grow in the presence of high salt concentrations, both phenotypes being characteristic of knockouts of the MAPK components. In addition, mutations that perturb signaling through the MAPK pathway resulted in defective cell integrity (hypersensitivity to caspofungin and β-glucanase). Rgf1p acts by positively regulating a subset of stimuli toward the Pmk1p-cell integrity pathway. After osmotic shock and cell wall damage HA-tagged Pmk1p was phosphorylated in wild-type cells but not in rgf1Δ cells. Finally, we provide evidence to show that Rgf1p regulates Pmk1p activation in a process that involves the activation of Rho1p and Pck2p, and we demonstrate that Rgf1p is unique in this signaling process, because Pmk1p activation was largely independent of the other two Rho1p-specific GEFs, Rgf2p and Rgf3p.
Clandestine induced abortions are a public health problem in many developing countries where access to abortion services is legally restricted. We estimated the prevalence and incidence of, and risk factors for, clandestine induced abortions in a Latin American country.
We conducted a large population-based survey of women aged 18–29 years in 20 cities in Peru. We asked questions about their history of spontaneous and induced abortions, using techniques to encourage disclosure.
Of 8242 eligible women, 7992 (97.0%) agreed to participate. The prevalence of reported induced abortions was 11.6% (95% confidence interval [CI] 10.9%– 12.4%) among the 7962 women who participated in the survey. It was 13.6% (95% CI 12.8%– 14.5%) among the 6559 women who reported having been sexually active. The annual incidence of induced abortion was 3.1% (95% CI 2.9%– 3.3%) among the women who had ever been sexually active. In the multivariable analysis, risk factors for induced abortion were higher age at the time of the survey (odds ratio [OR] 1.11, 95% CI 1.07– 1.15), lower age at first sexual intercourse (OR 0.87, 95% CI 0.84– 0.91), geographic region (highlands: OR 1.56, 95% CI 1.23– 1.97; jungle: OR 1.81, 95% CI 1.41– 2.31 [v. coastal region]), having children (OR 0.82, 95% CI 0.68– 0.98), having more than 1 sexual partner in lifetime (2 partners: OR 1.61, 95% CI 1.23– 2.09; ≥ 3 partners: OR 2.79, 95% CI 2.12– 3.67), and having 1 or more sexual partners in the year before the survey (1 partner: OR 1.36, 95% CI 1.01– 1.72; ≥ 2 partners: OR 1.54, 95% CI 1.14– 2.02). Overall, 49.0% (95% CI 47.6%– 50.3%) of the women who reported being currently sexually active were not using contraception.
The incidence of clandestine, potentially unsafe induced abortion in Peru is as high as or higher than the rates in many countries where induced abortion is legal and safe. The provision of contraception and safer-sex education to those who require it needs to be greatly improved and could potentially reduce the rate of induced abortion.
The objective of this paper is to characterize effective patient care reminder strategies for people living with HIV/AIDS (PLWHA) to improve antiretroviral therapy (ART) adherence) using short message service (SMS) based on patient perspectives. We conducted a qualitative study with adult PLWHA in a community-based clinic in Lima, Peru using focus groups. 26 HIV-positive individuals participated in four focus groups (20 men, 6 women). The participants expressed positive perceptions towards receiving reminders via SMS, but specified certain characteristics they wanted them to have (such as being simple and concise). It was also important that the messages maintained confidentiality and privacy by using coded words or phrases (“Remember, it is the time of your life”) instead of “sensitive” words (HIV or antiretroviral). This study suggests that patients want healthcare SMS that appropriately notify them, deliver a careful crafted message, and assess the context in which they are received.
Low-cost handheld computers (PDA) potentially represent an efficient tool for collecting sensitive data in surveys. The goal of this study is to evaluate the quality of sexual behavior data collected with handheld computers in comparison with paper-based questionnaires.
A PDA-based program for data collection was developed using Open-Source tools. In two cross-sectional studies, we compared data concerning sexual behavior collected with paper forms to data collected with PDA-based forms in Ancon (Lima).
The first study enrolled 200 participants (18–29 years). General agreement between data collected with paper format and handheld computers was 86%. Categorical variables agreement was between 70.5% and 98.5% (Kappa: 0.43–0.86) while numeric variables agreement was between 57.1% and 79.8% (Spearman: 0.76–0.95). Agreement and correlation were higher in those who had completed at least high school than those with less education. The second study enrolled 198 participants. Rates of responses to sensitive questions were similar between both kinds of questionnaires. However, the number of inconsistencies (p = 0.0001) and missing values (p = 0.001) were significantly higher in paper questionnaires.
This study showed the value of the use of handheld computers for collecting sensitive data, since a high level of agreement between paper and PDA responses was reached. In addition, a lower number of inconsistencies and missing values were found with the PDA-based system. This study has demonstrated that it is feasible to develop a low-cost application for handheld computers, and that PDAs are feasible alternatives for collecting field data in a developing country.
New technologies that emerge at the interface of computational and biomedical science could drive new advances in global health, therefore more training in technology is needed among health care workers. To assess the potential for informatics training using an approach designed to foster interaction at this interface, the University of Washington and the Universidad Peruana Cayetano Heredia developed and assessed a one-week course that included a new Bioinformatics (BIO) track along with an established Medical/Public Health Informatics track (MI) for participants in Peru.
We assessed the background of the participants, and measured the knowledge gained by track-specific (MI or BIO) 30-minute pre- and post-tests. Participants' attitudes were evaluated both by daily evaluations and by an end-course evaluation.
Forty-three participants enrolled in the course – 20 in the MI track and 23 in the BIO track. Of 20 questions, the mean % score for the MI track increased from 49.7 pre-test (standard deviation or SD = 17.0) to 59.7 (SD = 15.2) for the post-test (P = 0.002, n = 18). The BIO track mean score increased from 33.6 pre-test to 51.2 post-test (P < 0.001, n = 21). Most comments (76%) about any aspect of the course were positive. The main perceived strength of the course was the quality of the speakers, and the main perceived weakness was the short duration of the course. Overall, the course acceptability was very good to excellent with a rating of 4.1 (scale 1–5), and the usefulness of the course was rated as very good. Most participants (62.9%) expressed a positive opinion about having had the BIO and MI tracks come together for some of the lectures.
Pre- and post-test results and the positive evaluations by the participants indicate that this first joint Bioinformatics and Medical/Public Health Informatics (MI and BIO) course was a success.
The pathogenesis of macular pucker and macular holes is poorly understood. Anomalous posterior vitreous detachment (PVD) and vitreoschisis have been proposed as possible mechanisms. This study used clinical imaging to seek vitreoschisis and study the topographic features of macular pucker and macular holes.
Combined optical coherence tomography and scanning laser ophthalmoscopy (OCT/SLO) was performed in 45 eyes with macular hole and 44 eyes with macular pucker. Longitudinal imaging was used to identify vitreoschisis and measure retinal thickness. The topographic features of eyes with macular hole with eccentric macular contraction were compared to 24 eyes with unifocal macular pucker using coronal plane imaging.
Vitreoschisis was detected in 24 of 45 eyes (53.3%) with macular hole and 19 of 44 (43.2%) with macular pucker. Retinal contraction was detected eccentrically in the macula of 18 of 45 eyes (40%) with macular hole. In eyes with macular hole with unifocal retinal contraction, the average surface area of contraction (23.12 ± 18.79 mm2) was significantly smaller than in eyes with macular pucker (63.20 ± 23.68 mm2; P = .006). The distance from the center of retinal contraction to the center of the macula was significantly greater in eyes with macular hole (8.64 ± 2.33 mm) than eyes with macular pucker (4.45 ± 1.90 mm; P = .0001).
Vitreoschisis was detected in about half of all eyes with macular hole and macular pucker. The topographic and structural features in eyes with macular hole with retinal contraction differed in comparison to eyes with macular pucker alone, suggesting that although each condition may begin with anomalous PVD, differences in subsequent cell migration and proliferation probably result in the different clinical appearances detected in this study.