Spatio-temporal Models of Lymphangiogenesis in Wound Healing

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total

Computational modelling of wound healing insights to develop new treatments

About 1% of the population will suffer a severe wound during their life. Thus, it is really important to develop new techniques in order to properly treat these injuries due to the high socioeconomically impact they suppose. Skin substitutes and pressure based therapies are currently the most promising techniques to heal these injuries. Nevertheless, we are still far from finding a definitive skin substitute for the treatment of all chronic wounds. As a first step in developing new tissue engineering tools and treatment techniques for wound healing, in silico models could help in understanding the mechanisms and factors implicated in wound healing. Here, we review mathematical models of wound healing. These models include different tissue and cell types involved in healing, as well as biochemical and mechanical factors which determine this process. Special attention is paid to the contraction mechanism of cells as an answer to the tissue mechanical state. Other cell processes such as differentiation and proliferation are also included in the models together with extracellular matrix production. The results obtained show the dependency of the success of wound healing on tissue composition and the importance of the different biomechanical and biochemical factors. This could help to individuate the adequate concentration of growth factors to accelerate healing and also the best mechanical properties of the new skin substitute depending on the wound location in the body and its size and shape. Thus, the feedback loop of computational models, experimental works and tissue engineering could help to identify the key features in the design of new treatments to heal severe wounds

Efficacy of artesunate-amodiaquine and artemether-lumefantrine fixed-dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria among children aged six to 59 months in Nimba County, Liberia: an open-label randomized non-inferiority trial.

Prospective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development. The in vivo efficacy of artesunate-amodiaquine (ASAQ) fixed-dose combination (FDC) was compared to that of artemether-lumefantrine (AL) among children aged six to 59 months in Nimba County, Liberia, where Plasmodium falciparum malaria is endemic and efficacy data are scarce

GENERAL CHARACTERISTICS OF PATIENTS WITH SHOULDER PROBLEMS

Amaç: Omuz ekleminden ve özellikle de eklem çevresindeki yumuşak dokulardan kökenalan problemler üst ekstremite ağrılarının en önemli nedenini oluşturur. Çalışmamızın amacıomuz ağrısı yakınması ile başvuran hastaların klinik özelliklerinin değerlendirilmesidir.Gereç ve yöntem: Omuz ağrısı yakınması ile başvuran 709 hastanın 744 omuzuretrospektif olarak değerlendirildi.Bulgular: Hastaların yaş ortalaması 55,16  10,88 yıl idi ve 395 hastada sağ, 279 hastadasol ve 35 hastada her iki omuz etkilenmişti. Vakaların %35,4'ünde travma öyküsü mevcuttu.Klinik ve radyolojik olarak yapılan değerlendirmelerde hastaların %45'inde subakromiyalsıkışma sendromu, %39,4'ünde rotator kaf rüptürü, %1,5'inde bisipital tendinit, %6,5'indeakromioklavikuler eklem dejenerasyonu, %2,2'sinde kalsifik tendinit, %5'inde donuk omuzve %0,4'ünde glenohumeral eklem artrozu saptandı. Subakromiyal sıkışma sendromu olanhastalar ile rotator kaf rüptürü olan hastaların karşılaştırılmasında rüptürü olan hastalarınyaş ortalamalarının daha yüksek ve "American Shoulder Elbow Score" (ASES) skorlarınındaha düşük olduğu ancak "Constant" skorları arasında herhangi bir fark olmadığı görüldü.Bu iki grup etiolojideki travma açısından değerlendirildiğinde rotator kaf rüptürü olan gruptatravma öyküsünün subakromiyal sıkışma sendromlu hastalara göre anlamlı olarak dahafazla olduğu ve travma öyküsünün rotator kafta rüptür riskini 2,9 kat arttırdığı görüldü.Sonuç: Omuz ağrısı nedenleri arasında rotator kaf sorunları çok önemli bir yer tutmaktadır.Travma ve yaş rotator kafta rüptür insidansını arttırmaktadır.Objective: Problems originating from the shoulder joint and periarticular soft tissues arethe most important causes of upper limb pain. The aim of this study was to investigate theclinical charactersitic patients.Material and method: Seven hundred forty-four shoulders 709 patients wereretrospectively studied.Results: The mean age of the patients was 55.16  10.88 years. Right shoulder wasinvolved in 395 patients, left in 279, and both shoulders in 35 patients. Thirty-five percenthad a history of trauma. According to clinical and radiological assessments, 45 % of patientswere diagnosed as subacromial impingement syndrome, 39.4 % roator cuff tears, 1.5 %bicipital tendinitis, 6.5 % degeneration of the acromioclavicular joint, 2.2 % calcific tendinitis,5 % frozen shoulder, and 0.4 % osteoarthritis of the glenohumeral joint. When the patientswith subacromial impingement syndrome were compared with the patients with rotator cuff tears, the mean age of the patients with rotator cuff tears was significantly higher andAmerican Shoulder Elbow Scores (ASES) were lower than the patients with subacromialimpingement syndrome. There were no significant differences between the Constant scores.Significantly more patients with rotator cuff tears had a history of trauma than patients withsubacromial impingement syndrome, and trauma increased the risk of rotator cuff tears 2.9times.Conclusion: Rotator cuff problems is one of the most common causes of shoulder painand functional limitations. Trauma and age are risk factors for rotator cuff rupture

The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data

Background: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. Methods: We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. Findings: We included 61 studies done between January, 1998, and December, 2012, and included 14 327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose). Interpretation: The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. Funding: Bill and Melinda Gates Foundation

Molecular markers of anti-malarial drug resistance in Central, West and East African children with severe malaria.

BACKGROUND: The Plasmodium falciparum multidrug resistance 1 (PfMDR1), P. falciparum Ca(2+)-ATPase (PfATP6) and Kelch-13 propeller domain (PfK13) loci are molecular markers of parasite susceptibility to anti-malarial drugs. Their frequency distributions were determined in the isolates collected from children with severe malaria originating from three African countries. METHODS: Samples from 287 children with severe malaria [(Gabon: n = 114); (Ghana: n = 89); (Kenya: n = 84)] were genotyped for pfmdr1, pfatp6 and pfk13 loci by DNA sequencing and assessing pfmdr1 copy number variation (CNV) by real-time PCR. RESULTS: Pfmdr1-N86Y mutation was detected in 48, 10 and 10% in Lambaréné, Kumasi and Kisumu, respectively. At codon 184, the prevalence of the mutation was 73% in Lambaréné, 63% in Kumasi and 49% Kisumu. The S1034C and N1042D variants were absent at all three sites, while the frequency of the D1246Y mutation was 1, 3 and 13% in Lambaréné, Kumasi and Kisumu, respectively. Isolates with two pfmdr1 gene copy number predominantly harboured the N86Y wild-type allele and were mostly found in Kumasi (10%) (P < 0.0001). Among the main pfmdr1 haplotypes (NFD, NYD and YFD), NYD was associated with highest parasitaemia (P = 0.04). At the pfatp6 locus, H243Y and A623E mutations were observed at very low frequency at all three sites. The prevalence of the pfatp6 E431K variant was 6, 18 and 17% in Lambaréné, Kumasi and Kisumu, respectively. The L263E and S769N mutations were absent in all isolates. The pfk13 variants associated with artemisinin resistance in Southeast Asia were not observed. Eleven novel substitutions in the pfk13 locus occurring at low frequency were observed. CONCLUSIONS: Artemisinins are still highly efficacious in large malaria-endemic regions though declining efficacy has occurred in Southeast Asia. The return of chloroquine-sensitive strains following the removal of drug pressure is observed. However, selection of wild-type alleles in the multidrug-resistance gene and the increased gene copy number is associated with reduced lumefantrine sensitivity. This study indicates a need to constantly monitor drug resistance to artemisinin in field isolates from malaria-endemic countries