Stereolithography (SLA) 3D printing of a bladder device for intravesical drug delivery

Intravesical instillation therapy is an alternative approach to oral medications for the treatment of severe bladder diseases, offering high drug concentrations at the site of action while minimising systemic side effects. However, therapeutic efficacy is often limited because of the short residence time of the drug in the bladder and the need for repeated instillations. This study reports, for the first time, the use of stereolithography (SLA) 3D printing to manufacture novel indwelling bladder devices using an elastic polymer to achieve extended and localised delivery of lidocaine hydrochloride. The devices were designed to be inserted into and retrieved from the bladder using a urethral catheter. Two types of bladder devices (hollow and solid) were prepared with a resilient material (Elastic Resin) incorporating three drug loads of lidocaine hydrochloride (10% w/w, 30% w/w and 50% w/w); a drug frequently used to treat interstitial cystitis and bladder pain. All of the devices showed acceptable blood compatibility, good resistance to compressive and stretching forces and were able to recover their original shape immediately once external forces were removed. In vitro drug release studies showed that a complete release of lidocaine was achieved within 4 days from the hollow devices, whereas the solid devices enabled sustained drug release for up to 14 days. SLA 3D printing therefore provides a new manufacturing route to produce bladder-retentive drug delivery devices using elastic polymers, and offers a revolutionary and personalised approach for clinical intravesical drug delivery

3D Printed Punctal Plugs for Controlled Ocular Drug Delivery

Dry eye disease is a common ocular disorder that is characterised by tear deficiency or excessive tear evaporation. Current treatment involves the use of eye drops; however, therapeutic efficacy is limited because of poor ocular bioavailability of topically applied formulations. In this study, digital light processing (DLP) 3D printing was employed to develop dexamethasone-loaded punctal plugs. Punctal plugs with different drug loadings were fabricated using polyethylene glycol diacrylate (PEGDA) and polyethylene glycol 400 (PEG 400) to create a semi-interpenetrating network (semi-IPN). Drug-loaded punctal plugs were characterised in terms of physical characteristics (XRD and DSC), potential drug-photopolymer interactions (FTIR), drug release profile, and cytocompatibility. In vitro release kinetics of the punctal plugs were evaluated using an in-house flow rig model that mimics the subconjunctival space. The results showed sustained release of dexamethasone for up to 7 days from punctal plugs made with 20% w/w PEG 400 and 80% w/w PEGDA, while punctal plugs made with 100% PEGDA exhibited prolonged releases for more than 21 days. Herein, our study demonstrates that DLP 3D printing represents a potential manufacturing platform for fabricating personalised drug-loaded punctal plugs with extended release characteristics for ocular administration

Field and laboratory studies reveal interacting effects of stream oxygenation and warming on aquatic ectotherms

Aquatic ecological responses to climatic warming are complicated by interactions between thermal effects and other environmental stressors such as organic pollution and hypoxia. Laboratory experiments have demonstrated how oxygen limitation can set heat tolerance for some aquatic ectotherms, but only at unrealistic lethal temperatures and without field data to assess whether oxygen shortages might also underlie sublethal warming effects. Here, we test whether oxygen availability affects both lethal and nonlethal impacts of warming on two widespread Eurasian mayflies, Ephemera danica, Müller 1764 and Serratella ignita (Poda 1761). Mayfly nymphs are often a dominant component of the invertebrate assemblage in streams, and play a vital role in aquatic and riparian food webs. In the laboratory, lethal impacts of warming were assessed under three oxygen conditions. In the field, effects of oxygen availability on nonlethal impacts of warming were assessed from mayfly occurrence in 42 293 UK stream samples where water temperature and biochemical oxygen demand were measured. Oxygen limitation affected both lethal and sublethal impacts of warming in each species. Hypoxia lowered lethal limits by 5.5 °C (±2.13) and 8.2 °C (±0.62) for E. danica and S. ignita respectively. Field data confirmed the importance of oxygen limitation in warmer waters; poor oxygenation drastically reduced site occupancy, and reductions were especially pronounced under warm water conditions. Consequently, poor oxygenation lowered optimal stream temperatures for both species. The broad concordance shown here between laboratory results and extensive field data suggests that oxygen limitation not only impairs survival at thermal extremes but also restricts species abundance in the field at temperatures well below upper lethal limits. Stream oxygenation could thus control the vulnerability of aquatic ectotherms to global warming. Improving water oxygenation and reducing pollution can provide key facets of climate change adaptation for running waters

Impact of the Diamond Light Source on research in Earth and environmental sciences: current work and future perspectives.

Diamond Light Source Ltd celebrated its 10th anniversary as a company in December 2012 and has now accepted user experiments for over 5 years. This paper describes the current facilities available at Diamond and future developments that enhance its capacities with respect to the Earth and environmental sciences. A review of relevant research conducted at Diamond thus far is provided. This highlights how synchrotron-based studies have brought about important advances in our understanding of the fundamental parameters controlling highly complex mineral–fluid–microbe interface reactions in the natural environment. This new knowledge not only enhances our understanding of global biogeochemical processes, but also provides the opportunity for interventions to be designed for environmental remediation and beneficial use

BioLPG for Clean Cooking in Sub-Saharan Africa: Present and Future Feasibility of Technologies, Feedstocks, Enabling Conditions and Financing

Energy supply for clean cooking is a priority for Sub-Saharan Africa (SSA). Liquefied petroleum gas (LPG, i.e., propane or butane or a mixture of both) is an economically efficient, cooking energy solution used by over 2.5 billion people worldwide and scaled up in numerous low- and middle-income countries (LMICs). Investigation of the technical, policy, economic and physical requirements of producing LPG from renewable feedstocks (bioLPG) finds feasibility at scale in Africa. Biogas and syngas from the circular economic repurposing of municipal solid waste and agricultural waste can be used in two groundbreaking new chemical processes (Cool LPG or Integrated Hydropyrolysis and Hydroconversion (IH2)) to selectively produce bioLPG. Evidence about the nature and scale potential of bioLPG presented in this study justifies further investment in the development of bioLPG as a fuel that can make a major contribution toward enabling an SSA green economy and universal energy access. Techno-economic assessments of five potential projects from Ghana, Kenya and Rwanda illustrate what might be possible. BioLPG technology is in the early days of development, so normal technology piloting and de-risking need to be undertaken. However, fully developed bioLPG production could greatly reduce the public and private sector investment required to significantly increase SSA clean cooking capacity

Metabolic effects of diets differing in glycaemic index depend on age and endogenous GIP

Aims/hypothesis High- vs low-glycaemic index (GI) diets unfavourably affect body fat mass and metabolic markers in rodents. Different effects of these diets could be age-dependent, as well as mediated, in part, by carbohydrate-induced stimulation of glucose-dependent insulinotrophic polypeptide (GIP) signalling. Methods Young-adult (16 weeks) and aged (44 weeks) male wild-type (C57BL/6J) and GIP-receptor knockout (Gipr −/− ) mice were exposed to otherwise identical high-carbohydrate diets differing only in GI (20–26 weeks of intervention, n = 8–10 per group). Diet-induced changes in body fat distribution, liver fat, locomotor activity, markers of insulin sensitivity and substrate oxidation were investigated, as well as changes in the gene expression of anorexigenic and orexigenic hypothalamic factors related to food intake. Results Body weight significantly increased in young-adult high- vs low-GI fed mice (two-way ANOVA, p < 0.001), regardless of the Gipr genotype. The high-GI diet in young-adult mice also led to significantly increased fat mass and changes in metabolic markers that indicate reduced insulin sensitivity. Even though body fat mass also slightly increased in high- vs low-GI fed aged wild-type mice (p < 0.05), there were no significant changes in body weight and estimated insulin sensitivity in these animals. However, aged Gipr −/− vs wild-type mice on high-GI diet showed significantly lower cumulative net energy intake, increased locomotor activity and improved markers of insulin sensitivity. Conclusions/interpretation The metabolic benefits of a low-GI diet appear to be more pronounced in younger animals, regardless of the Gipr genotype. Inactivation of GIP signalling in aged animals on a high-GI diet, however, could be beneficial

Disentangling the genetic overlap and causal relationships between primary open-angle glaucoma, brain morphology and four major neurodegenerative disorders

BACKGROUND: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by progressive degeneration of the optic nerve that leads to irreversible visual impairment. Multiple epidemiological studies suggest an association between POAG and major neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease). However, the nature of the overlap between neurodegenerative disorders, brain morphology and glaucoma remains inconclusive. METHOD: In this study, we performed a comprehensive assessment of the genetic and causal relationship between POAG and neurodegenerative disorders, leveraging genome-wide association data from studies of magnetic resonance imaging of the brain, POAG, and four major neurodegenerative disorders. FINDINGS: This study found a genetic overlap and causal relationship between POAG and its related phenotypes (i.e., intraocular pressure and optic nerve morphology traits) and brain morphology in 19 regions. We also identified 11 loci with a significant local genetic correlation and a high probability of sharing the same causal variant between neurodegenerative disorders and POAG or its related phenotypes. Of interest, a region on chromosome 17 corresponding to MAPT, a well-known risk locus for Alzheimer's and Parkinson's disease, was shared between POAG, optic nerve degeneration traits, and Alzheimer's and Parkinson's diseases. Despite these local genetic overlaps, we did not identify strong evidence of a causal association between these neurodegenerative disorders and glaucoma. INTERPRETATION: Our findings indicate a distinctive and likely independent neurodegenerative process for POAG involving several brain regions although several POAG or optic nerve degeneration risk loci are shared with neurodegenerative disorders, consistent with a pleiotropic effect rather than a causal relationship between these traits. FUNDING: PG was supported by an NHMRC Investigator Grant (#1173390), SM by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (APP1150144), DM by an NHMRC Fellowship, LP is funded by the NEI EY015473 and EY032559 grants, SS is supported by an NIH-Oxford Cambridge Fellowship and NIH T32 grant (GM136577), APK is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award

CD98hc facilitates B cell proliferation and adaptive humoral immunity.

The proliferation of antigen-specific lymphocytes and resulting clonal expansion are essential for adaptive immunity. We report here that B cell-specific deletion of the heavy chain of CD98 (CD98hc) resulted in lower antibody responses due to total suppression of B cell proliferation and subsequent plasma cell formation. Deletion of CD98hc did not impair early B cell activation but did inhibit later activation of the mitogen-activated protein kinase Erk1/2 and downregulation of the cell cycle inhibitor p27. Reconstitution of CD98hc-deficient B cells with CD98hc mutants showed that the integrin-binding domain of CD98hc was required for B cell proliferation but that the amino acid-transport function of CD98hc was dispensable for this. Thus, CD98hc supports integrin-dependent rapid proliferation of B cells. We propose that the advantage of adaptive immunity favored the appearance of CD98hc in vertebrates

The Role of Atypical Protein Kinase C in CSF-1-Dependent Erk Activation and Proliferation in Myeloid Progenitors and Macrophages

Colony stimulating factor-1 (CSF-1 or M-CSF) is the major physiological regulator of the proliferation, differentiation and survival of cells of the mononuclear phagocyte lineage. CSF-1 binds to a receptor tyrosine kinase, the CSF-1 receptor (CSF-1R). Multiple pathways are activated downstream of the CSF-1R; however, it is not clear which pathways regulate proliferation and survival. Here, we investigated the role of atypical protein kinase Cs (PKCζ) in a myeloid progenitor cell line that expressed CSF-1R (32D.R) and in primary murine bone marrow derived macrophages (BMMs). In 32D.R cells, CSF-1 induced the phosphorylation of PKCζ and increased its kinase activity. PKC inhibitors and transfections with mutant PKCs showed that optimal CSF-1-dependent Erk activation and proliferation depended on the activity of PKCζ. We previously reported that CSF-1 activated the Erk pathway through an A-Raf-dependent and an A-Raf independent pathway (Lee and States, Mol. Cell. Biol. 18, 6779). PKC inhibitors did not affect CSF-1 induced Ras and A-Raf activity but markedly reduced MEK and Erk activity, implying that PKCζ regulated the CSF-1-Erk pathway at the level of MEK. PKCζ has been implicated in activating the NF-κB pathway. However, CSF-1 promoted proliferation in an NF-κB independent manner. We established stable 32D.R cell lines that overexpressed PKCζ. Overexpression of PKCζ increased the intensity and duration of CSF-1 induced Erk activity and rendered cells more responsive to CSF-1 mediated proliferation. In contrast to 32D.R cells, PKCζ inhibition in BMMs had only a modest effect on proliferation. Moreover, PKCζ -specific and pan-PKC inhibitors induced a paradoxical increase in MEK-Erk phosphorylation suggesting that PKCs targeted a common negative regulatory step upstream of MEK. Our results demonstrated that CSF-1 dependent Erk activation and proliferation are regulated differentially in progenitors and differentiated cells

Comparison of quality of life and causes of hospitalization between hemodialysis and peritoneal dialysis patients in China

<p>Abstract</p> <p>Background</p> <p>Hemodialysis (HD) and peritoneal dialysis (PD) are important renal replacement treatment in end stage renal disease (ESRD), but the comparison of quality of life (QOL) and causes of hospitalisation between the two modalities in China is lacking. In the present study, we compared the two modalities in a multi-center study.</p> <p>Subjects and methods</p> <p>Six hundred and fifty four HD and 408 PD patients were investigated from 10 hospitals in China from Sept, 2004 to Jan, 2005. Among the HD patients, there were 360 males and 294 females with a mean age of 57.22 ± 12.49 years (18–88 y). Among PD patients, there were 165 males and 243 females, with a mean age of 61.59 ± 12.65 years (22–89 y). Health related 36 items short form questionnaires (SF-36) were used to assess the quality of life. Hospitalisation data were collected and analyzed.</p> <p>Results</p> <p>SF-36 domains of Body Pain (BP), General Health (GH), Role-Emotional (RE), Social Functioning (SF), Vitality (VT) and Mental Health (MH) were all significantly higher in the PD patients as compared to the HD patients although there was no significant difference in Physical Functioning (PF) and Role-Physical (RP) between the two groups. The two most common causes of hospitalisation in HD patients were cardiovascular disease (39.8%) and pulmonary infection (21.3%), while they were infectious peritonitis (47.6%) and cardiovascular disease (31.9%) in PD patients. The ever hospitalised patients had lower SF-36 scores in the domains of PF, BP, GH, RE, SF, VT and MH as compared to those of non-hospitalised patients.</p> <p>Conclusion</p> <p>Our study indicated that with the current practice in China, PD patients may enjoy better quality of life than their HD counterparts. Our results also showed that the most common cause of hospitalisation was cardiovascular disease in HD patients and peritonitis in PD patients.</p