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Age-Related Tooth Wear Differs between Forest and Savanna Primates

  • Galbany i Casals, Jordi
  • Romero, Alejandro
  • Mayo-Alesón, M.
  • Itsoma, F.
  • Gamarra Rubio, Beatriz
  • Martínez Pérez-Pérez, Alejandro
  • Willaume, E.
  • Kappeler, P.M.
  • Charpentier, Marie J. E.
Tooth wear in primates is caused by aging and ecological factors. However, comparative data that would allow us to delineate the contribution of each of these factors are lacking. Here, we contrast age-dependent molar tooth wear by scoring percent of dentine exposure (PDE) in two wild African primate populations from Gabonese forest and Kenyan savanna habitats. We found that forest-dwelling mandrills exhibited significantly higher PDE with age than savanna yellow baboons. Mandrills mainly feed on large tough food items, such as hard-shell fruits, and inhabit an ecosystem with a high presence of mineral quartz. By contrast, baboons consume large amounts of exogenous grit that adheres to underground storage organs but the proportion of quartz in the soils where baboons live is low. Our results support the hypothesis that not only age but also physical food properties and soil composition, particularly quartz richness, are factors that significantly impact tooth wear. We further propose that the accelerated dental wear in mandrills resulting in flatter molars with old age may represent an adaptation to process hard food items present in their environment.
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The Burden of Cryptosporidium Diarrheal Disease among Children < 24 Months of Age in Moderate/High Mortality Regions of Sub-Saharan Africa and South Asia, Utilizing Data from the Global Enteric Multicenter Study (GEMS).

  • Sow, Samba O.
  • Muhsen, Khitam
  • Nasrin, Dilruba
  • Blackwelder, William C.
  • Wu, Yukun
  • Farag, Tamer H.
  • Panchalingam, Sandra
  • Sur, Dipika
  • Zaidi, Anita K. M.
  • Faruque, Abu S. G.
  • Saha, Debasish
  • Adegbola, Richard
  • Alonso, Pedro
  • Breiman, Robert F.
  • Bassat Orellana, Quique
  • Tamboura, Boubou
  • Sanogo, Doh
  • Onwuchekwa, Uma
  • Manna, Byomkesh
  • Ramamurthy, Thandavarayan
  • Kanungo, Suman
  • Ahmed, Shahnawaz
  • Qureshi, Shahida
  • Quadri, Farheen
  • Hossain, Anowar
  • Das, Sumon K.
  • Antonio, Martin
  • Hossain, M. Jahangir
  • Mandomando, Inácio
  • Nhampossa, Tacilta
  • Acácio, Sozinho
  • Omore, Richard
  • Oundo, Joseph O.
  • Ochieng, John B.
  • O’Reilly, Ciara E.
  • Berkeley, Lynette Y.
  • Livio, Sofie
  • Tennant, Sharon M.
  • Sommerfelt, Halvor
  • Nataro, James P.
  • Ziv-Baran, Tomer
  • Robins-Browne, Roy M.
  • Mishcherkin, Vladimir
  • Zhang, Jixian
  • Liu, Jie
  • Houpt, Eric R.
  • Kotloff, Karen L.
  • Levine, Myron M.
  • Mintz, Eric D.
Background: The importance of Cryptosporidium as a pediatric enteropathogen in developing countries is recognized. Methods: Data from the Global Enteric Multicenter Study (GEMS), a 3-year, 7-site, case-control study of moderate-to-severe diarrhea (MSD) and GEMS-1A (1-year study of MSD and less-severe diarrhea [LSD]) were analyzed. Stools from 12,110 MSD and 3,174 LSD cases among children aged <60 months and from 21,527 randomly-selected controls matched by age, sex and community were immunoassay-tested for Cryptosporidium. Species of a subset of Cryptosporidium-positive specimens were identified by PCR; GP60 sequencing identified anthroponotic C. parvum. Combined annual Cryptosporidium-attributable diarrhea incidences among children aged <24 months for African and Asian GEMS sites were extrapolated to sub-Saharan Africa and South Asian regions to estimate region-wide MSD and LSD burdens. Attributable and excess mortality due to Cryptosporidium diarrhea were estimated. Findings: Cryptosporidium was significantly associated with MSD and LSD below age 24 months. Among Cryptosporidium-positive MSD cases, C. hominis was detected in 77.8% (95% CI, 73.0%-81.9%) and C. parvum in 9.9% (95% CI, 7.1%-13.6%); 92% of C. parvum tested were anthroponotic genotypes. Annual Cryptosporidium-attributable MSD incidence was 3.48 (95% CI, 2.27–4.67) and 3.18 (95% CI, 1.85–4.52) per 100 child-years in African and Asian infants, respectively, and 1.41 (95% CI, 0.73–2.08) and 1.36 (95% CI, 0.66–2.05) per 100 child-years in toddlers. Corresponding Cryptosporidium-attributable LSD incidences per 100 child-years were 2.52 (95% CI, 0.33–5.01) and 4.88 (95% CI, 0.82–8.92) in infants and 4.04 (95% CI, 0.56–7.51) and 4.71 (95% CI, 0.24–9.18) in toddlers. We estimate 2.9 and 4.7 million Cryptosporidium-attributable cases annually in children aged <24 months in the sub-Saharan Africa and India/Pakistan/Bangladesh/Nepal/Afghanistan regions, respectively, and ~202,000 Cryptosporidium-attributable deaths (regions combined). ~59,000 excess deaths occurred among Cryptosporidium-attributable diarrhea cases over expected if cases had been Cryptosporidium-negative. Conclusions: The enormous African/Asian Cryptosporidium disease burden warrants investments to develop vaccines, diagnostics and therapies.
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Tailoring formulations to patients in need: Experience with the paediatric formulation of artemether-lumefantrine (Coartem(R) Dispersible) for the treatment of P. falciparum malaria

  • Bassat Orellana, Quique
  • Ogutu, Bernhards
  • Djimde, Abdoulaye A.
  • Stricker, Kirstin
  • Hamed, Kamal
Specially created paediatric formulations have the potential to improve the acceptability, effectiveness and accuracy of dosing of artemisinin-based combination therapy (ACT) in young children, a patient group that is inherently vulnerable to malaria. Artemether-lumefantrine (AL) Dispersible is a paediatric formulation of AL that is specifically tailored for the treatment of children with uncomplicated Plasmodium falciparum malaria, offering benefits relating to efficacy, convenience and acceptance, accuracy of dosing, safety, sterility and stability, and a similar pharmacokinetic profile and bioequivalence to crushed and intact AL tablets. However, despite being the first paediatric antimalarial to meet World Health Organization (WHO) specifications for use in infants and children >/=5 kg, and its inclusion in WHO Guidelines, there are very few publications that focus on AL Dispersible. Based on a systematic review of the recent literature, this paper provides a comprehensive overview of clinical experience with AL Dispersible to date. A randomised, phase 3 study that compared the efficacy and safety of AL Dispersible with crushed AL tablets in 899 African children reported high PCR-corrected cure rates at day 28 (97.8% and 98.5% for dispersible and crushed tablets, respectively), and several sub-analyses of these data indicate that this activity is observed regardless of patient weight, food intake, and maximum plasma concentrations of artemether or its active metabolite dihydroartemisinin. These and other clinical data support the continued use of paediatric antimalarial formulations in all children <5 years of age with uncomplicated malaria, while accompanied by continued monitoring for the emergence of resistance.
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An autopsy study of maternal mortality in Mozambique: the contribution of infectious diseases

  • Menéndez, Clara
  • Romagosa Pérez-Portabella, Cleofé
  • Ismail, Mamudo R.
  • Carrilho, Carla
  • Saute, Francisco
  • Osman, Nafissa
  • Machungo, Fernanda
  • Bardají, Azucena
  • Quintó, Llorenç
  • Mayor Aparicio, Alfredo Gabriel
  • Naniche, Denise
  • Dobaño, Carlota, 1969-
  • Alonso, Pedro
  • Ordi i Majà, Jaume
Background Maternal mortality is a major health problem concentrated in resource-poor regions. Accurate data on its causes using rigorous methods is lacking, but is essential to guide policy-makers and health professionals to reduce this intolerable burden. The aim of this study was to accurately describe the causes of maternal death in order to contribute to its reduction, in one of the regions of the world with the highest maternal mortality ratios. Methods and Findings We conducted a prospective study between October 2002 and December 2004 on the causes of maternal death in a tertiary-level referral hospital in Maputo, Mozambique, using complete autopsies with histological examination. HIV detection was done by virologic and serologic tests, and malaria was diagnosed by histological and parasitological examination. During 26 mo there were 179 maternal deaths, of which 139 (77.6%) had a complete autopsy and formed the basis of this analysis. Of those with test results, 65 women (52.8%) were HIV-positive. Obstetric complications accounted for 38.2% of deaths; haemorrhage was the most frequent cause (16.6%). Nonobstetric conditions accounted for 56.1% of deaths; HIV/AIDS, pyogenic bronchopneumonia, severe malaria, and pyogenic meningitis were the most common causes (12.9%, 12.2%, 10.1% and 7.2% respectively). Mycobacterial infection was found in 12 (8.6%) maternal deaths. Conclusions In this tertiary hospital in Mozambique, infectious diseases accounted for at least half of all maternal deaths, even though effective treatment is available for the four leading causes, HIV/AIDS, pyogenic bronchopneumonia, severe malaria, and pyogenic meningitis. These observations highlight the need to implement effective and available prevention tools, such as intermittent preventive treatment and insecticide-treated bed-nets for malaria, antiretroviral drugs for HIV/AIDS, or vaccines and effective antibiotics for pneumococcal and meningococcal diseases. Deaths due to obstetric causes represent a failure of health-care systems and require urgent improvement.
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Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine: further results from a phase IIb trial in Mozambican children

  • Guinovart, Caterina
  • Aponte, John J.
  • Sacarlal, Jahit
  • Aide, Pedro Carlos Paulino
  • Leach, Amanda
  • Bassat Orellana, Quique
  • Macete, Eusébio
  • Dobaño, Carlota, 1969-
  • Lievens, Marc
  • Loucq, Christian
  • Ballou, W. Ripley
  • Cohen, Joe
  • Alonso, Pedro
Background: The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S. Methodology/Principal Findings: The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1) and infection (cohort 2). Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase) and over the following 12 months (single-blind phase), and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5-56.3; p = 0.029) over the double-blind phase and of 9.0% (230.6-36.6; p = 0.609) during the single-blind phase. Conclusions/Significance: Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia.
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Characterisation of extended-spectrum b-lactamases among Klebsiella pneumoniae isolates causing bacteraemia and urinary tract infection in Mozambique

  • Pons, Maria J.
  • Vubil, Delfino
  • Guiral, Elisabet
  • Jaintilal, Dinis
  • Fraile, Oscar
  • Soto, Sara M. (Sara Maria)
  • Sigaúque, Betuel
  • Nhampossa, Tacilta
  • Aide, Pedro Carlos Paulino
  • Alonso, Pedro
  • Vila Estapé, Jordi
  • Mandomando, Inácio
  • Ruiz, Joaquim
The aim of this study was to determine the prevalence of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae isolated from urinary tract and bloodstream infections in a rural hospital in Manhiça, Mozambique. ESBLs were investigated among ceftriaxone-non-susceptible K. pneumoniae clinical isolates recovered between 2004 and 2009. Characterisation of blaCTX-M, blaSHV, blaOXA and blaTEM genes was performed by PCR and sequencing. Epidemiological relationships were established by phylogenetic analysis, repetitive extragenic palindromic PCR (REP-PCR), pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST), whilst plasmid transferability was evaluated by conjugation. In addition, the presence of class 1 and 2 integrons was studied. A total of 19 K. pneumoniae were analysed. The blaCTX-M-15 gene was found in all strains. Other ESBL genes were found concomitantly, including blaSHV-5, blaSHV-2, blaSHV-2A, blaSHV-12 and blaSHV-38. In addition, other β-lactamases such as blaTEM-1 and blaOXA-30 were also detected. REP-PCR identified 15 different epidemiological profiles. MLST analysis also showed great variability of sequence types. The blaCTX-M-15 gene showed a high transfer capacity. The presence of class 1 integrons was high. High levels of multidrug resistance were also found. In conclusion, these data show the dominance of the CTX-M-type ESBL, particularly CTX-M-15, supporting its worldwide dissemination, including in areas with limited access to third-generation cephalosporins. This finding is a matter of concern for clinical management as third-generation cephalosporins are an alternative for treating severe cases of multidrug-resistant infections in this community.
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Hypoxaemia in Mozambican children < 5 years of age admitted to hospital with clinical severe pneumonia: clinical features and performance of predictor models

  • Bassat Orellana, Quique
  • Lanaspa, Miguel
  • Machevo, Sonia
  • O'Callaghan Gordo, Cristina
  • Madrid, Lola
  • Nhampossa, Tacilta
  • Acácio, Sozinho
  • Roca, A.
  • Alonso, Pedro
OBJECTIVE: To determine the prevalence of hypoxaemia among under-five children admitted to hospital with clinical severe pneumonia, and to assess the performance to diagnose hypoxaemia of models based on clinical signs. METHODS: We conducted a hospital-based survey in a district hospital from Southern Mozambique. RESULTS: A total of 825 children were recruited after obtaining an informed consent. The prevalence of hypoxaemia on admission was 27.9%, and 19.8% of these children died (OR compared to non-hypoxaemic children 3.22, 95%CI 1.98 - 5.21, p<0.001). The model with larger area under the ROC curve (AUC-ROC) to predict hypoxaemia included cyanosis or thoracoabdominal breathing or respiratory rate >/= 70 breaths per minute. None of the models performed well when tested in different case scenarios of oxygen availability through mathematical modelling, with over 50% of hypoxaemic children not receiving oxygen even in favourable case scenarios. CONCLUSIONS: Clinical signs alone or in combination are not suitable to diagnose hypoxaemia. The use of pulse oximeters should be strongly encouraged. This article is protected by copyright. All rights reserved.
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A novel Plasmodium falciparum rhoptry associated adhesin mediates erythrocyte invasion through the sialic-acid dependent pathway

  • Anand, Gaurav
  • Reddy, K. Sony
  • Pandey, Alok Kumar
  • Mian, Syed Yusuf
  • Singh, Hina
  • Mittal, Shivani Arora
  • Amlabu, Emmanuel
  • Bassat Orellana, Quique
  • Mayor Aparicio, Alfredo Gabriel
  • Chauhan, Virander Singh
  • Gaur, Deepak
Erythrocyte invasion by Plasmodium falciparum merozoites is central to blood-stage infection and malaria pathogenesis. This intricate process is coordinated by multiple parasite adhesins that bind erythrocyte receptors and mediate invasion through several alternate pathways. P. falciparum expresses 2700 genes during the blood-stages, of which the identity and function of many remains unknown. Here, we have identified and characterized a novel P. falciparum rhoptry associated adhesin (PfRA) that mediates erythrocyte invasion through the sialic-acid dependent pathway. PfRA appears to play a significant functional role as it is conserved across different Plasmodium species. It is localized in the rhoptries and further translocated to the merozoite surface. Both native and recombinant PfRA specifically bound erythrocytes in a sialic-acid dependent, chymotrypsin and trypsin resistant manner, which was abrogated by PfRA antibodies confirming a role in erythrocyte invasion. PfRA antibodies inhibited erythrocyte invasion and in combination with antibodies against other parasite ligands produced an additive inhibitory effect, thus validating its important role in erythrocyte invasion. We have thus identified a novel P. falciparum adhesin that binds with a sialic acid containing erythrocyte receptor. Our observations substantiate the strategy to block P. falciparum erythrocyte invasion by simultaneously targeting multiple conserved merozoite antigens involved in alternate invasion pathways.
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Current Status of Whole-Slide Imaging in Education

  • Saco, Adela
  • Bombí, Josep Antoni
  • Garcia, Adriana
  • Ramírez, Josep
  • Ordi i Majà, Jaume
Conventional light microscopy (CLM) has classically been the basic tool to teach histology and pathology. In recent years, whole-slide imaging (WSI), which consists of generating a high-magnification digital image of an entire histological glass slide, has emerged as a useful alternative to CLM offering a myriad of opportunities for education. Navigation through the digitized slides closely simulates viewing glass slides with a microscope and is also referred to as virtual microscopy. WSI has many advantages for education. Students feel more comfortable with its use, and it can be used in any classroom as it only requires a computer with Internet access and it allows remote access from anywhere and from any device. WSI can be used simultaneously by a large number of people, stimulating cooperation between students and improving the interaction with the teachers. It allows making marks and annotations on specific fields, which enable specific directed questions to the teacher. Finally, WSI supports are cost-effective compared with CLM. Consequently, WSI has begun to replace CLM in many institutions. WSI has shown to be an extremely useful tool for undergraduate education (medical, dental and veterinary schools), for the training of residents of pathology, tele-education and in tumor boards.
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Differential expression of neurogenes among breast cancer subtypes identifies high risk patients.

  • Fernandez-Nogueira, Patricia
  • Bragado, Paloma
  • Almendro Navarro, Vanessa
  • Ametller, Elisabet
  • Rios, José
  • Choudhury, Sibgat
  • Mancino, Mario
  • Gascón, Pere
The nervous system is now recognized to be a relevant component of the tumor microenvironment. Receptors for neuropeptides and neurotransmitters have been identified in breast cancer. However, very little is known about the role of neurogenes in regulating breast cancer progression. Our purpose was to identify neurogenes associated with breast cancer tumorigenesis with a potential to be used as biomarker and/or targets for treatment. We used three databases of human genes: GeneGo, GeneCards and Eugenes to generate a list of 1266 relevant neurogenes. Then we used bioinformatics tools to interrogate two published breast cancer databases SAGE and MicMa (n=96) and generated a list of 7 neurogenes that are differentially express among breast cancer subtypes. The clinical potential was further investigated using the GOBO database (n=1881). We identified 6 neurogenes that are differentially expressed among breast cancer subtypes and whose expression correlates with prognosis. Histamine receptor1 (HRH1), neuropilin2 (NRP2), ephrin-B1 (EFNB1), neural growth factor receptor (NGFR) and amyloid precursor protein (APP) were differentially overexpressed in basal and HER2-enriched tumor samples and syntaxin 1A (STX1A) was overexpressed in HER2-enriched and luminal B tumors. Analysis of HRH1, NRP2, and STX1A expression using the GOBO database showed that their expression significantly correlated with a shorter overall survival (p < 0.0001) and distant metastasis-free survival (p < 0.0001). In contrast, elevated co-expression of NGFR, EFNB1 and APP was associated with longer overall (p < 0.0001) and metastasis-free survival (p < 0.0001). We propose that HRH1, NRP2, and STX1A can be used as prognostic biomarkers and therapeutic targets for basal and HER2-enriched breast cancer subtypes.
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