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Liquid-phase pKa values play a key role in food science. Chemical properties of molecules depend largely on whether they are ionized or not. Most organic molecules are capable of gaining and/or losing a proton in aqueous solutions. Proton transfer most. frequently occurs between water and any ionizable atom of the organic molecule. The molecule’s response to profanation or deprotonation depends significantly on the site that was disturbed by proton transfer. Partial charge distribution in the molecule also varies with protonation of the acidlbase active sites. Then it can he used to determine the pKa of a molecule. First, we use the COSMO-RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment fin- more Realistic Solvation (RS) simulations, for the direct prediction of pKa constants of about 50 molecules (amino-acids, dipeptides and tripeptides). Then, we compare our results with experimental data and the pKa values predicted using two other methods. We used respectively the ChemAxon method using a program based on the calculation of partial charge of atoms in the molecule and the ACD/Labs method that enables to calculate single pKa values. for all possible dissociation centers when the rest of the molecule is considered neutral, using an internal database containing chemical structures and their experimental pKa values. The averaged Root Mean Square Error (RMSE) of the predicted pKa values for each method compared to experimental results were respectively 0.596 for COSMO-RS, 0.445 for ChemAxon and 0.490 for ACD/Labs. While ACDILabs and ChemAxon are parameterized using a large set ofexperimental data (including several of the studied molecules), the COSMO- RS method was used in a fully predictive way. Regarding these results, COSMO-RS appears as a promising method to predict the pKa values of molecules of interest in food science with scarce available pKa values such as peptides. The final goal of this study is to use the pKa values in a predictive thermodynamics model for products of interest in food industry. For this purpose, the effects of several factors (like conformations set treatment in COSMO-RS calculations, ionic strength effect) that can affect the comparison between observed and predicted pKa data are discussed. Les valeurs de constantes d’acidité (pKa) jouent un rôle très important, en particulier dans l’industrie alimentaire. Les propriétés chimiques des molécules dépendent significativement de leurs états d’ionisation. La plupart des molécules sont capables de gagner et/ou perdre un proton dans les solutions aqueuses. Ce transfert de proton apparaît la plupart du temps entre l’eau et un atome ionisable de la molécule organique. La réponse de la molécule à la protonation ou à la déprotonation dépend significativement du site concerné par le transfert de proton. La distribution partielle des charges dans la molécule varie également en fonction des sites actifs pour la protonation du couple acide; base. Par conséquent on peut l’utiliser pour déterminer le pKa d’une molécule. Dans un premier temps, nous avons utilisé la méthode COSMO-RS, une combinaison du modèle de solvatation diélectrique (COSMO) et d’un traitement de thermodynamique statistique pour des solvants plus réels (RS), pour prédire les constantes de dissociation de 50 molécules environ (des acides aminés, des dipeptides et des tripeptides). Les résultats de pKa obtenus ont été comparés aux valeurs expérimentales, ainsi qu’aux valeurs de pKa prédites par deux autres méthodes. Nous avons utilisé respectivement la méthode ChemAxon, utilisant un programme basé sur le calcul des charges partielles des atomes d’une molécule, et la méthode ACD/Labs qui permet de déterminer des valeurs de pKa pour chaque centre de dissociation en considérant que le reste de la molécule est neutre, en utilisant une base de données internes contenant des structures chimiques ainsi que leurs valeurs expérimentales de pKa. L’écart-type moyen des valeurs prédites vaut respectivement 0,596 pour la méthode COSMO-RS, 0,445 pour la méthode ChemAxon et 0,490 pour la méthode ACD/Labs. Au vu de ces résultats, la méthode COSMO-RS apparaît comme une méthode prometteuse pour prédire les valeurs de pKa de molécules d’intérêt dans l’industrie alimentaire pour lesquelles peu de données de pKa sont disponibles comme les peptides, d’autant plus que les méthodes ACD/Labs et ChemAxon ont été paramétrées en utilisant un grand nombre de données expérimentales (incluant certaines des molécules étudiées dans cet article) alors que la méthode COSMO-RS a été utilisée d’un point de vue purement prédictif. L’objectif final de cette étude est d’utiliser ces valeurs de pKa dans un modèle thermodynamique prédictif pour des produits d’intérêt dans l’industrie alimentaire. Pour ce faire, les effets de certains facteurs (comme le traitement des conformations dans les calculs COSMO-RS,l’infuence de la force ionique) pouvant influencer la comparaison entre les données expérimentales et les données prédites, seront discutés.

Rationale: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal, dominantly inherited genodermatosis that predisposes to fibrofolliculomas, kidney neoplasms, lung cysts, and spontaneous pneumothorax.Objectives: We evaluated 198 patients from 89 families with BHDS to characterize the risk factors for pneumothorax and genotype-pulmonary associations.Methods: Helical computed tomography scans of the chest were used to screen for pulmonary abnormalities. BHD mutation data were used for genotype-pulmonary associations. We examined the relationship of pneumothorax with categorical parameters (sex, smoking history, and lung cysts) and continuous parameters (number of cysts, lung cyst volume, and largest cyst diameter and volume). Logistic regression analyses were used to identify the risk factors associated with pneumothorax.Measurements and Main Results: Twenty-four percent (48/198) of patients with BHDS had a history of pneumothorax. The presence of lung cysts was significantly associated with pneumothorax (p = 0.006). Total lung cyst volume, largest cyst diameter and volume, and every parameter related to the number of lung cysts were significantly associated (p < 0.0001) with pneumothorax. A logistic regression analysis showed that only the total number of cysts in the right parenchymal lower lobe and the total number of cysts located on the pleural surface in the right middle lobe were needed to classify a patient as to whether or not he or she was likely to have a pneumothorax. Exon location of the BHD mutation was associated with the numbers of cysts (p = 0.0002).Conclusions: This study indicates that patients with BHDS have a significant association between lung cysts and spontaneous pneumothorax. [ABSTRACT FROM AUTHOR]

During the 2018-2020 Ebola virus disease outbreak in Democratic Republic of the Congo, a phase 3 trial of the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine (DRC-EB-001) commenced in Goma, with participants being offered the two-dose regimen given 56 days apart. Suspension of trial activities in 2020 due to the COVID-19 pandemic led to some participants receiving a late dose 2 outside the planned interval. Blood samples were collected from adults, adolescents, and children prior to their delayed dose 2 vaccination and 21 days after, and tested for IgG binding antibodies against Ebola virus glycoprotein using the Filovirus Animal Nonclinical Group (FANG) ELISA. Results from 133 participants showed a median two-dose interval of 9.3 months. The pre-dose 2 antibody geometric mean concentration (GMC) was 217 ELISA Units (EU)/mL (95% CI 157; 301) in adults, 378 EU/mL (281; 510) in adolescents, and 558 EU/mL (471; 661) in children. At 21 days post-dose 2, the GMC increased to 22,194 EU/mL (16,726; 29,449) in adults, 37,896 EU/mL (29,985; 47,893) in adolescents, and 34,652 EU/mL (27,906; 43,028) in children. Participants receiving a delayed dose 2 had a higher GMC at 21 days post-dose 2 than those who received a standard 56-day regimen in other African trials, but similar to those who received the regimen with an extended interval.

During the 2018-2020 Ebola virus disease (EVD) outbreak, residents in Goma, Democratic Republic of the Congo, were offered a two-dose prophylactic EVD vaccine. This was the first study to evaluate the safety of this vaccine in pregnant women. Adults, including pregnant women, and children aged ≥1 year old were offered the Ad26.ZEBOV (day 0; dose 1), MVA-BN-Filo (day 56; dose 2) EVD vaccine through an open-label clinical trial. In total, 20,408 participants, including 6635 (32.5%) children, received dose 1. Fewer than 1% of non-pregnant participants experienced a serious adverse event (SAE) following dose 1; one SAE was possibly related to the Ad26.ZEBOV vaccine. Of the 1221 pregnant women, 371 (30.4%) experienced an SAE, with caesarean section being the most common event. No SAEs in pregnant women were considered related to vaccination. Of 1169 pregnancies with a known outcome, 55 (4.7%) ended in a miscarriage, and 30 (2.6%) in a stillbirth. Eleven (1.0%) live births ended in early neonatal death, and five (0.4%) had a congenital abnormality. Overall, 188/891 (21.1%) were preterm births and 79/1032 (7.6%) had low birth weight. The uptake of the two-dose regimen was high: 15,328/20,408 (75.1%). The vaccine regimen was well-tolerated among the study participants, including pregnant women, although further data, ideally from controlled trials, are needed in this crucial group.

Introduction: Using health facility types as a measure of service availability is a common approach in international standards for health system policy and planning. However, this proxy may not accurately reflect the actual availability of specific health services., Objective: This study aims to evaluate the reliability of health facility typology as an indicator of specific health service availability and explore whether certain facility types consistently provide particular services., Design: We analysed a comprehensive dataset containing information from 1725 health facilities in Mali. To uncover and visualise patterns within the dataset, we used two analytical techniques: Multiple Correspondence Analysis and Between-Class Analysis. These analyses allowed us to quantitatively measure the influence of health facility types on the variation in health service provisioning. Additionally, we developed and calculated a Consistency Index, which assesses the consistency of a health facility type in providing specific health services. By examining various health facilities and services, we sought to determine the accuracy of facility types as indicators of service availability., Setting: The study focused on the health system in Mali as a case study., Results: Our findings indicate that using health facility types as a proxy for service availability in Mali is not an accurate representation. We observed that most of the variation in service provision does not stem from differences between facility types but rather within facility types. This suggests that relying solely on health facility typology may lead to an incomplete understanding of health service availability., Conclusions: These results have significant implications for health policy and planning. The reliance on health facility types as indicators for health system policy and planning should be reconsidered. A more nuanced and evidence-based understanding of health service availability is crucial for effective health policy and planning, as well as for the assessment and monitoring of health systems., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Diarrhoeal disease remains a significant cause of morbidity and mortality among the under-fives in many low- and middle-income countries. Changes to food safety practices and feeding methods around the weaning period, alongside improved nutrition, may significantly reduce the risk of disease and improve development for infants. We describe a protocol for a cluster randomised trial to evaluate the effectiveness of a multi-faceted community-based educational intervention that aims to improve food safety and hygiene behaviours and enhance child nutrition., Methods: We describe a mixed-methods, parallel group, two-arm, superiority cluster randomised controlled trial with baseline measures. One hundred twenty clusters comprising small urban and rural communities will be recruited in equal numbers and randomly allocated in a 1:1 ratio to either treatment or control arms. The community intervention will be focussed around an ideal mother concept involving all community members during campaign days with dramatic arts and pledging, and follow-up home visits. Participants will be mother-child dyads (27 per cluster period) with children aged 6 to 36 months. Data collection will comprise a day of observation and interviews with each participating mother-child pair and will take place at baseline and 4 and 15 months post-intervention. The primary analysis will estimate the effectiveness of the intervention on changes to complementary-food safety and preparation behaviours, food and water contamination, and diarrhoea. Secondary outcomes include maternal autonomy, enteric infection, nutrition, child anthropometry, and development scores. A additional structural equation analysis will be conducted to examine the causal relationships between the different outcomes. Qualitative and health economic analyses including process evaluation will be done., Conclusions: The trial will provide evidence on the effectiveness of community-based behavioural change interventions designed to reduce the burden of diarrhoeal disease in the under-fives and how effectiveness varies across different contexts., Trial Registration: ISRCTN14390796. Registration date December 13, 2021., (© 2023. The Author(s).)

Background: Most malaria-endemic countries use artemisinin-based combination therapy (ACT) as their first-line treatment. ACTs are known to be highly effective on asexual stages of the malaria parasite. Malaria transmission and the spread of resistant parasites depend on the infectivity of gametocytes. The effect of the current ACT regimens on gametocyte infectivity is unclear., Objectives: This study aimed to determine the infectivity of gametocytes to Anopheles gambiae following ACT treatment in the field., Methods: During a randomised controlled trial in Bougoula-Hameau, Mali, conducted from July 2005 to July 2007, volunteers with uncomplicated malaria were randomised to receive artemether-lumefantrine, artesunate-amodiaquine, or artesunate-sulfadoxine/pyrimethamine. Volunteers were followed for 28 days, and gametocyte carriage was assessed. Direct skin feeding assays were performed on gametocyte carriers before and after ACT administration., Results: Following artemether-lumefantrine treatment, gametocyte carriage decreased steadily from Day 0 to Day 21 post-treatment initiation. In contrast, for the artesunate-amodiaquine and artesunate-sulfadoxine/pyrimethamine arms, gametocyte carriage increased on Day 3 and remained constant until Day 7 before decreasing afterward. Mosquito feeding assays showed that artemether-lumefantrine and artesunate-amodiaquine significantly increased gametocyte infectivity to Anopheles gambiae sensu lato (s.l.) ( p < 10 -4 ), whereas artesunate-sulfadoxine/pyrimethamine decreased gametocyte infectivity in this setting ( p = 0.03)., Conclusion: Different ACT regimens could lead to gametocyte populations with different capacity to infect the Anopheles vector. Frequent assessment of the effect of antimalarials on gametocytogenesis and gametocyte infectivity may be required for the full assessment of treatment efficacy, the potential for spread of drug resistance and malaria transmission in the field., Competing Interests: The authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations., Competing Interests: JF: Director of the Wellcome Trust, one of the three founding funders of eLife. The other authors declare that no competing interests exist.

Standard Gibbs energies of formation are of primary importance in the field of biothermodynamics. In the absence of any directly measured values, thermodynamic calculations are required to determine the missing data. For several biochemical species, this study shows that the knowledge of the standard Gibbs energy of formation of the pure compounds (in the gaseous, solid or liquid states) enables to determine the corresponding standard Gibbs energies of formation in aqueous solutions. To do so, using chemical engineering tools (thermodynamic tables and a model enabling to predict activity coefficients, solvation Gibbs energies and pKa data), it becomes possible to determine the partial chemical potential of neutral and charged components in real metabolic conditions, even in concentrated mixtures., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Since 2010, WHO has recommended oral cholera vaccines as an additional strategy for cholera control. During a cholera episode, pregnant women are at high risk of complications, and the risk of fetal death has been reported to be 2-36%. Due to a lack of safety data, pregnant women have been excluded from most cholera vaccination campaigns. In 2012, reactive campaigns using the bivalent killed whole-cell oral cholera vaccine (BivWC), included all people living in the targeted areas aged ≥ 1 year regardless of pregnancy status, were implemented in Guinea. We aimed to determine whether there was a difference in pregnancy outcomes between vaccinated and non-vaccinated pregnant women., Methods and Findings: From 11 November to 4 December 2013, we conducted a retrospective cohort study in Boffa prefecture among women who were pregnant in 2012 during or after the vaccination campaign. The primary outcome was pregnancy loss, as reported by the mother, and fetal malformations, after clinical examination. Primary exposure was the intake of the BivWC vaccine (Shanchol) during pregnancy, as determined by a vaccination card or oral history. We compared the risk of pregnancy loss between vaccinated and non-vaccinated women through binomial regression analysis. A total of 2,494 pregnancies were included in the analysis. The crude incidence of pregnancy loss was 3.7% (95%CI 2.7-4.8) for fetuses exposed to BivWC vaccine and 2.6% (0.7-4.5) for non-exposed fetuses. The incidence of malformation was 0.6% (0.1-1.0) and 1.2% (0.0-2.5) in BivWC-exposed and non-exposed fetuses, respectively. In both crude and adjusted analyses, fetal exposure to BivWC was not significantly associated with pregnancy loss (adjusted risk ratio (aRR = 1.09 [95%CI: 0.5-2.25], p = 0.818) or malformations (aRR = 0.50 [95%CI: 0.13-1.91], p = 0.314)., Conclusions: In this large retrospective cohort study, we found no association between fetal exposure to BivWC and risk of pregnancy loss or malformation. Despite the weaknesses of a retrospective design, we can conclude that if a risk exists, it is very low. Additional prospective studies are warranted to add to the evidence base on OCV use during pregnancy. Pregnant women are particularly vulnerable during cholera episodes and should be included in vaccination campaigns when the risk of cholera is high, such as during outbreaks.

Background: Plasmodium falciparum resistance to artemisinin has been reported in South-East Asia. Long half-life drugs are increasingly being used for malaria prevention. The potential spread of parasite resistance to these regimens is real and makes regular efficacy surveillance a priority., Methods: From August to December 2004 and July to December 2005, a randomized open label trial of sulphadoxine-pyrimethamine (SP) + artesunate (AS) versus SP + amodiaquine (AQ), and SP alone, was conducted in two villages of Mali. PCR was used to distinguish new infections from recrudescent P. falciparum infections. Patients were followed for 28 days to assess treatment efficacy., Results: Overall 912 children aged between six to 59 months, with uncomplicated P. falciparum malaria were recruited. Baseline characteristics were similar in the three treatment arms. Crude ACPRs were 94.9%; 98.6% and 93.5% for SP + AS; SP + AQ and SP alone arms respectively (SP + AS versus SP + AQ, p = 0.01; SP + AS versus SP, p = 0.5; SP + AQ versus SP, p = 0.001). After PCR adjustment, cACPRs were 99%; 100% and 97.2% for SP + AS; SP + AQ and SP alone arms, respectively (SP + AS versus SP + AQ, p = 0.25; SP + AS versus SP, p = 0.12; SP + AQ versus SP, p = 0.007)., Conclusion: Sulphadoxine-pyrimethamine + amodiaquine therapy was as efficacious as sulphadoxine-pyrimethamine + artesunate, but more efficacious than sulphadoxine-pyrimethamine alone in the treatment of uncomplicated P. falciparum malaria in Mali.

Escherichia coli (E. coli) contamination in foods and water resources represents a major threat for human health and the environment. This work exploits the strong affinity of mannose-containing oligosaccharides with the fimbrial lectin of E. coli to design novel biosensors. Modified carbohydrate ligands were synthesized by introducing phenyl residues and aliphatic chains to mannose via reductive amination in order to increase both the affinity and selectivity to E. coli compared to other pathogenic bacteria. The synthesized ligands include p-thiolphenyl aminomannose (PTAM), p-carboxyphenyl aminomannose (PCAM), 1-deoxy-1-aminomannopyranoside (DAMP), glucosamine and low molecular weight chitosan bonded to mercapto undecanoic acid. The structures of the ligands were confirmed using (1)H NMR and 1H, (13)C, COZY NMR, and ESI/MS. The ligands were immobilized onto gold electrodes and SPR surfaces using-mercaptoundecanoic acid with glycine as deactivating agent. Two detection mechanisms were tested: (i) metal-enhanced electrochemical detection (MED) and (ii) label-free surface plasmon resonance (SPR) detection. The introduction of phenyl residues and aliphatic side groups to the mannose-containing oligosaccharides produced extremely high affinity for E. coli with detection limit of 1 cfu/mL. The relative selectivity of these ligands for E. coli, Citrobacter freundii, Staphylococcus epidermidis were 100%, 2.6% and 8.6% respectively. The biosensors were validated using spinach leaves at 3.0 cfu/mL. The work provides a generic biosensor for other pathogenic bacteria by enabling multivalent binding, immediate recognition for pathogens as well as inhibition of bacterial growth., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Malaria is a major health burden in sub-Saharan African countries, including Mali. The disease is complex, with multiple genetic determinants influencing the observed variation in response to infection, progression, and severity. We assess the influence of sixty-four candidate loci, including the sickle cell polymorphism (HbS), on severe malaria in a case-control study consisting of over 900 individuals from Bamako, Mali. We confirm the known protective effects of the blood group O and the HbS AS genotype on life-threatening malaria. In addition, our analysis revealed a marginal susceptibility effect for the CD40 ligand (CD40L)+220C allele. The lack of statistical evidence for other candidates may demonstrate the need for large-scale genome-wide association studies in malaria to discover new polymorphisms. It also demonstrates the need for establishing the region-specific repertoire of functional variation in important genes, including the glucose-6-phosphatase deficiency gene, before embarking on focused genotyping.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare cornification diseases. Germline mutations in TGM1 are the most common cause of ARCI in the United States. TGM1 encodes for the TGase-1 enzyme that functions in the formation of the cornified cell envelope. Structurally defective or attenuated cornified cell envelop have been shown in epidermal scales and appendages of ARCI patients with TGM1 mutations. We review the clinical manifestations as well as the molecular genetics of ARCI. In addition, we characterized 115 TGM1 mutations reported in 234 patients from diverse racial and ethnic backgrounds (Caucasion Americans, Norwegians, Swedish, Finnish, German, Swiss, French, Italian, Dutch, Portuguese, Hispanics, Iranian, Tunisian, Moroccan, Egyptian, Afghani, Hungarian, African Americans, Korean, Japanese and South African). We report 23 novel mutations: 71 (62%) missense; 20 (17%) nonsense; 9 (8%) deletion; 8 (7%) splice-site, and 7 (6%) insertion. The c.877-2A>G was the most commonly reported TGM1 mutation accounting for 34% (147 of 435) of all TGM1 mutant alleles reported to date. It had been shown that this mutation is common among North American and Norwegian patients due to a founder effect. Thirty-one percent (36 of 115) of all mutations and 41% (29 of 71) of missense mutations occurred in arginine residues in TGase-1. Forty-nine percent (35 of 71) of missense mutations were within CpG dinucleotides, and 74% (26/35) of these mutations were C>T or G>A transitions. We constructed a model of human TGase-1 and showed that all mutated arginines that reside in the two beta-barrel domains and two (R142 and R143) in the beta-sandwich are located at domain interfaces. In conclusion, this study expands the TGM1 mutation spectrum and summarizes the current knowledge of TGM1 mutations. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of 5' methylated CpG dinucleotides., ((c) 2009 Wiley-Liss, Inc.)

Unlabelled: The goal of this work was to study the possible use of the food cubes in bovines' and the small ruminants' feeding in Bamako district and to evaluate its potential effects on these animals' libido., Material and Methods: To undertake this study, a transversal investigation among 384 emboucheurs and emboucheurs stockbreeders were carried out from 22 to 24 April, 2007 in 11 cattle markets in the District of Bamako. The study included 20 Moor rams aged 2 to 3 years old, divided into 4 batches of 5 heads each; 15 Moor ewes aged 2 to 3 years old were synchronized regularly and put in heat for measurements of the libido. The sheep were fed with food made up with fan of Niébé and cotton oil cake, with respectively 0 cubes jumbo for the 1st batch (control group), 2 cubes for the 2nd batch and 4 cubes for 3rd and 6 cubes for the 4th batch (the study groups)., Results: Finding showed that the principal ration used by the emboucheurs was the combination of straw of bush and cattle food provided by HUICOMA factories (ABH), 98,70%. The investigations revealed also that only 0,50% of the emboucheurs used the cubes Jumbo or Maggi chicken to accelerate the weight increase of their animals. Regarding the measurement of the libido, findings showed that the addition of food cubes in rams of batches II, III and IV feeding, reduced in a remarkable way time that these animals put before jumping in the presence of a ewe in heat. Regarding dimensions of the scrotum, testicles of the rams, the addition of the food cubes does have any influence., Conclusion: The study enabled us to affirm that the addition of food cubes in rams feeding improved considerably the libido of these animals and any impact on their health have been observed.

Chronic lymphocytic leukemia (CLL) is the most prevalent form of leukemia in adults in western countries. A genome scan of CLL-prone families revealed a lod score of one in band 13q22.1. To investigate this finding, we selected 6 CLL families consisting of 63 individuals (CLL affected, n=19; unaffected, n=44) for fine mapping of a 23-megabase region in 13q14.2-q22.2. Interphase fluorescence in situ hybridization (FISH) revealed 13q14 deletion in 85% (11/13) of CLL patients. Four CLL families shared a 3.68-Mb minimal region in 13q21.33-q22.2. Two asymptomatic siblings who shared the 13q21.33-q22.2 at-risk haplotype exhibited CD5+ monoclonal B-cell lymphocytosis (MBL) on flow cytometry. One of these individuals also had a 13q14 deletion by FISH. These 2 individuals with MBL shared the at-risk haplotype with their CLL-affected relatives, providing further evidence of the relationship between CLL and MBL, as well as of the biologic significance of this novel region. Using direct DNA sequencing analysis, we screened 13 genes for mutations, but no frameshift or nonsense mutations were detected. Our studies revealed that 11 of the 13 genes in the candidate region were expressed in immune tissues, supporting their functional relevance in investigations of familial CLL. In conclusion, we identified a novel candidate region that may predispose to familial CLL.

Background: Spatial and temporal heterogeneities in the risk of malaria have led the WHO to recommend fine-scale stratification of the epidemiological situation, making it possible to set up actions and clinical or basic researches targeting high-risk zones. Before initiating such studies it is necessary to define local patterns of malaria transmission and infection (in time and in space) in order to facilitate selection of the appropriate study population and the intervention allocation. The aim of this study was to identify, spatially and temporally, high-risk zones of malaria, at the household level (resolution of 1 to 3 m)., Methods: This study took place in a Malian village with hyperendemic seasonal transmission as part of Mali-Tulane Tropical Medicine Research Center (NIAID/NIH). The study design was a dynamic cohort (22 surveys, from June 1996 to June 2001) on about 1300 children (<12 years) distributed between 173 households localized by GPS. We used the computed parasitological data to analyzed levels of Plasmodium falciparum, P. malariae and P. ovale infection and P. falciparum gametocyte carriage by means of time series and Kulldorff's scan statistic for space-time cluster detection., Results: The time series analysis determined that malaria parasitemia (primarily P. falciparum) was persistently present throughout the population with the expected seasonal variability pattern and a downward temporal trend. We identified six high-risk clusters of P. falciparum infection, some of which persisted despite an overall tendency towards a decrease in risk. The first high-risk cluster of P. falciparum infection (rate ratio = 14.161) was detected from September 1996 to October 1996, in the north of the village., Conclusion: This study showed that, although infection proportions tended to decrease, high-risk zones persisted in the village particularly near temporal backwaters. Analysis of this heterogeneity at the household scale by GIS methods lead to target preventive actions more accurately on the high-risk zones identified. This mapping of malaria risk makes it possible to orient control programs, treating the high-risk zones identified as a matter of priority, and to improve the planning of intervention trials or research studies on malaria.

The genome of the nitrogen-fixing soil bacterium Sinorhizobium meliloti does not possess genes for bioremediation of aromatic pollutants. It has the well-known ability to interact specifically with the leguminous alfalfa plant, Medicago sativa. Our previous work has shown enhanced degradation of the nitroaromatic compound 2,4-dinitrotoluene (DNT) when a plasmid containing degradative genes was introduced in it. In this study we report molecular evidence of the transfer of a polychlorinated biphenyl (PCB)-biodegradative plasmid pE43 to S. meliloti strain USDA 1936. Several standard analytical tests and plant growth chamber studies were conducted to test the ability of S. meliloti to degrade 2',3,4-PCB congener. Alfalfa plant alone was able to degrade 30% of PCBs compared with control. No enhanced dechlorination was noted when alfalfa plant was grown with wild-type S. meliloti, and when alfalfa plant was grown with the S. meliloti electrotransformants (genetically modified) dechlorination of PCBs was more than twice that when alfalfa plant was grown with wild-type S. meliloti. When alfalfa plant was grown with uncharacterized mixed culture (containing nodule formers), almost equally significant PCB degradation was observed. The significance of this work is that the naturally occurring nitrogen-fixing soil bacterium S. meliloti (genetically modified) has the ability to enhance fertility of soil in association with the leguminous alfalfa plant while simultaneously enhancing bioremediation of PCB-contaminated soils. Enhanced bioremediation of PCB and robust alfalfa plant growth was also noted when uncharacterized mixed cultures containing alfalfa plant nodule formers were used.