3D-printed coaxial hydrogel patches with mussel-inspired elements for prolonged release of gemcitabine

With the aim of fabricating drug-loaded implantable patches, a 3D printing technique was employed to produce novel coaxial hydrogel patches. The core-section of these patches contained a dopamine-modified methacrylated alginate hydrogel loaded with a chemotherapeutic drug (Gemcitabine), while their shell section was solely comprised of a methacrylated alginate hydrogel. Subsequently, these patches were further modified with CaCO3 cross linker and a polylactic acid (PLA) coating to facilitate prolonged release of the drug. Consequently, the results showed that addition of CaCO3 to the formula enhanced the mechanical properties of the patches and significantly reduced their swelling ratio as compared to that for patches without CaCO3. Furthermore, addition of PLA coating to CaCO3-containing patches has further reduced their swelling ratio, which then significantly slowed down the release of Gemcitabine, to a point where 4-layered patches could release the drug over a period of 7 days in vitro. Remarkably, it was shown that 3-layered and 4-layered Gemcitabine loaded patches were successful in inhibiting pancreatic cancer cell growth for a period of 14 days when tested in vitro. Lastly, in vivo experiments showed that gemcitabine-loaded 4-layered patches were capable of reducing the tumor growth rate and caused no severe toxicity when tested in mice. Altogether, 3D printed hydrogel patches might be used as biocompatible implants for local delivery of drugs to diseased site, to either shrink the tumor or to prevent the tumor recurrence after resection

South African healthcare provider perspectives on transitioning adolescents into adult HIV care

Background. The first generation of South African (SA) children perinatally infected with HIV is entering adulthood, and there is now a pressing need for systematised transfer of these patients from paediatric to adult care.Objectives. Previous research has investigated the HIV healthcare transition in North America and Europe, yet none has been conducted in SA. Our study is the first to describe the perspectives of healthcare providers overseeing the transition in resource-limited settings.Methods. We approached healthcare providers working in government paediatric HIV clinics and hospitals in the Western Cape Province, SA. Seven physicians and counsellors in adolescent/paediatric care, representing five clinics, were  interviewed, and 43 completed a written survey. Interviews addressed the current state of the transition, barriers and facilitators, and model components. Interviews were assessed for major themes using framework analysis, while logistic regression was applied to survey responses to identify associations with measured covariates.Results. Analysis of interview transcripts revealed several overarching perspectives that were corroborated by survey responses. One barrier identified was the  healthcare providers’ difficulty in letting go of their relationships with the adolescent patients. Since healthcare providers regarded their patients as particularly  vulnerable, they felt a strong and protective attachment towards them. A second barrier identified was a lack of structure and effective communication between adult and paediatric providers; accordingly, healthcare providers feared that they were transferring their adolescents unprepared, to a judgemental, depersonalised and overburdened environment. All interviewees and a majority of survey respondents (>80%) agreed that the formation of adolescent support groups in adult care clinics as well as a later transition age would improve the transition process.Conclusion. This study highlights the need for a systematic healthcare transition for HIV-positive adolescents cared for in the Western Cape, while acknowledging the limitations of the current healthcare infrastructure. Several feasible   recommendations have been identified, including forming support groups and greater involvement of adolescent healthcare providers to facilitate the transition

A mixed methods approach to evaluating community drug distributor performance in the control of neglected tropical diseases

BACKGROUND: Trusted literate, or semi-literate, community drug distributors (CDDs) are the primary implementers in integrated preventive chemotherapy (IPC) programmes for Neglected Tropical Disease (NTD) control. The CDDs are responsible for safely distributing drugs and for galvanising communities to repeatedly, often over many years, receive annual treatment, create and update treatment registers, monitor for side-effects and compile treatment coverage reports. These individuals are 'volunteers' for the programmes and do not receive remuneration for their annual work commitment. METHODS: A mixed methods approach, which included pictorial diaries to prospectively record CDD use of time, structured interviews and focus group discussions, was used to triangulate data on how 58 CDDs allocated their time towards their routine family activities and to NTD Programme activities in Uganda. The opportunity costs of CDD time were valued, performance assessed by determining the relationship between time and programme coverage, and CDD motivation for participating in the programme was explored. RESULTS: Key findings showed approximately 2.5 working weeks (range 0.6-11.4 working weeks) were spent on NTD Programme activities per year. The amount of time on NTD control activities significantly increased between the one and three deliveries that were required within an IPC campaign. CDD time spent on NTD Programme activities significantly reduced time available for subsistence and income generating engagements. As CDDs took more time to complete NTD Programme activities, their treatment performance, in terms of validated coverage, significantly decreased. Motivation for the programme was reported as low and CDDs felt undervalued. CONCLUSIONS: CDDs contribute a considerable amount of opportunity cost to the overall economic cost of the NTD Programme in Uganda due to the commitment of their time. Nevertheless, programme coverage of at least 75 %, as required by the World Health Organisation, is not being achieved and vulnerable individuals may not have access to treatment as a consequence of sub-optimal performance by the CDDs due to workload and programmatic factors

TL1A/DR3 axis involvement in the inflammatory cytokine network during pulmonary sarcoidosis

BACKGROUND: TNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are now well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place. METHODS: In this study, by flow cytometry, real-time PCR, confocal microscopy and immunohistochemistry analyses, TL1A and DR3 were investigated in the pulmonary cells and the peripheral blood of 43 patients affected by sarcoidosis in different phases of the disease (29 patients with active sarcoidosis, 14 with the inactive form) and in 8 control subjects. RESULTS: Our results demonstrated a significant higher expression, both at protein and mRNA levels, of TL1A and DR3 in pulmonary T cells and alveolar macrophages of patients with active sarcoidosis as compared to patients with the inactive form of the disease and to controls. In patients with sarcoidosis TL1A was strongly more expressed in the lung than the blood, i.e., at the site of the involved organ. Additionally, zymography assays showed that TL1A is able to increase the production of matrix metalloproteinase 9 by sarcoid alveolar macrophages characterized, in patients with the active form of the disease, by reduced mRNA levels of the tissue inhibitor of metalloproteinase (TIMP)-1. CONCLUSIONS: These data suggest that TL1A/DR3 interactions are part of the extended and complex immune-inflammatory network that characterizes sarcoidosis during its active phase and may contribute to the pathogenesis and to the progression of the disease

Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema

Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al

Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms

<p>Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.</p> <p>Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.</p> <p>Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.</p&gt

Global distribution of two fungal pathogens threatening endangered sea turtles

This work was supported by grants of Ministerio de Ciencia e Innovación, Spain (CGL2009-10032, CGL2012-32934). J.M.S.R was supported by PhD fellowship of the CSIC (JAEPre 0901804). The Natural Environment Research Council and the Biotechnology and Biological Sciences Research Council supported P.V.W. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Thanks Machalilla National Park in Ecuador, Pacuare Nature Reserve in Costa Rica, Foundations Natura 2000 in Cape Verde and Equilibrio Azul in Ecuador, Dr. Jesus Muñoz, Dr. Ian Bell, Dr. Juan Patiño for help and technical support during samplingPeer reviewedPublisher PD

“Clinical features of women with gout arthritis.” A systematic review

Clinically, gout is generally considered as a preferential male disease. However, it definitely does not occur exclusively in males. Our aim was to assess differences in the clinical features of gout arthritis between female and male patients. Five electronic databases were searched to identify relevant original studies published between 1977 and 2007. The included studies had to focus on adult patients with primary gout arthritis and on sex differences in clinical features. Two reviewers independently assessed eligibility and quality of the studies. Out of 355 articles, 14 were selected. Nine fulfilled the quality and score criteria. We identified the following sex differences in the clinical features of gout in women compared to men: the onset of gout occurs at a higher age, more comorbidity with hypertension or renal insufficiency, more often use of diuretics, less likely to drink alcohol, less often podagra but more often involvement of other joints, less frequent recurrent attacks. We found interesting sex differences regarding the clinical features of patients with gout arthritis. To diagnose gout in women, knowledge of these differences is essential, and more research is needed to understand and explain the differences , especially in the general population