Glaucoma: Hot topics in Pharmacology

BACKGROUND: Glaucoma comprises a group of neurodegenerative diseases resulting in retinal ganglion cell death within the optic nerve head. It is projected to affect almost 80 million people worldwide by 2020. The condition's asymptomatic nature translates to over half of glaucoma sufferers being unaware of their condition. By the time of diagnosis, irreversible blindness is likely to have occurred. Prime areas of glaucoma research therefore include identification and optimization of risk factors for the disease, accurate and early diagnostic tools and novel therapeutic methods. METHODS: The goal of this review was to summarize main areas of latest glaucoma research into risk factors of glaucoma, diagnostic tools and treatments. PubMed was used to search for terms including glaucoma risk factors, glaucoma diagnostics, glaucoma treatment, glaucoma drug delivery and glaucoma IOP. RESULTS: The evidence for risk factors of low CSF pressure, IOP, smoking, vascular risk factors and light toxicity is described. Latest diagnostic and monitoring techniques for glaucoma include SD-OCT, DARC and IOP telemetry. Current and emerging medical and surgical treatments in glaucoma are discussed. Rho kinase inhibitors have the potential to both lower IOP and also provide neuroprotection, several of which are in clinical trials. Several other new medical treatments such as calcium channel blockers and neurotrophic agents also have the capacity to provide neuroprotection. Minimally Invasive Glaucoma Surgery (MIGS) devices provide an improved safety profile compared to traditional trabeculectomy; the latest ab interno and ab externo devices are described. Novel drug delivery methods, including punctual plugs and contact lenses, help overcome the challenges with patient adherence. CONCLUSION: The ultimate goals are to reduce the individual patient risk factors associated with glaucoma, diagnose the condition early and to find treatments that not only reduce IOP but also reverse neurodegeneration of RGCs. The usage of combinations of novel medical and surgical treatments may help maximize IOP reduction and neuroprotection

Importance of Magnetic Resonance Imaging With Diffusion-weighted Imaging in Guiding Biopsy of Nodular Ganglioneuroblastoma: A Case Report

BACKGROUND: Nodular ganglioneuroblastoma is a rare peripheral neuroblastic tumor of variable prognosis. Accurate diagnosis, staging, and risk categorization can be particularly challenging in patients with nodular ganglioneuroblastoma due to the inherent heterogeneity of these lesions. CASE PRESENTATION: We illustrate the use of diffusion-weighted magnetic resonance imaging to identify tumor nodules and guide tumor biopsy in an almost 5-year-old boy with a large abdominal tumor. CONCLUSIONS: Diffusion-weighted magnetic resonance imaging was successful in detecting and guiding biopsy of a poorly differentiated neuroblastoma nodule within the context of a well-differentiated ganglioneuroma, allowing the diagnosis and characterization of a ganglioneuroblastoma nodular, thus influencing the child's prognosis and treatment

Numerical Modeling of Fluid Flow in Solid Tumors

A mathematical model of interstitial fluid flow is developed, based on the application of the governing equations for fluid flow, i.e., the conservation laws for mass and momentum, to physiological systems containing solid tumors. The discretized form of the governing equations, with appropriate boundary conditions, is developed for a predefined tumor geometry. The interstitial fluid pressure and velocity are calculated using a numerical method, element based finite volume. Simulations of interstitial fluid transport in a homogeneous solid tumor demonstrate that, in a uniformly perfused tumor, i.e., one with no necrotic region, because of the interstitial pressure distribution, the distribution of drug particles is non-uniform. Pressure distribution for different values of necrotic radii is examined and two new parameters, the critical tumor radius and critical necrotic radius, are defined. Simulation results show that: 1) tumor radii have a critical size. Below this size, the maximum interstitial fluid pressure is less than what is generally considered to be effective pressure (a parameter determined by vascular pressure, plasma osmotic pressure, and interstitial osmotic pressure). Above this size, the maximum interstitial fluid pressure is equal to effective pressure. As a consequence, drugs transport to the center of smaller tumors is much easier than transport to the center of a tumor whose radius is greater than the critical tumor radius; 2) there is a critical necrotic radius, below which the interstitial fluid pressure at the tumor center is at its maximum value. If the tumor radius is greater than the critical tumor radius, this maximum pressure is equal to effective pressure. Above this critical necrotic radius, the interstitial fluid pressure at the tumor center is below effective pressure. In specific ranges of these critical sizes, drug amount and therefore therapeutic effects are higher because the opposing force, interstitial fluid pressure, is low in these ranges

Childhood Correlates of Blood Lead Levels in Mumbai and Delhi

BACKGROUND: Lead exposure has previously been associated with intellectual impairment in children in a number of international studies. In India, it has been reported that nearly half of the children have elevated blood lead levels (BLLs). However, little is known about risk factors for these elevated BLLs. METHODS: We conducted a retrospective cross-sectional analysis of data from the Indian National Family Health Survey, a population-based study conducted in 1998–1999. We assessed potential correlates of BLLs in 1,081 children who were < 3 years of age and living in Mumbai or Delhi, India. We examined factors such as age, sex, religion, caste, mother’s education, standard of living, breast-feeding, and weight/height percentile. RESULTS: Most children (76%) had BLLs between 5 and 20 μg/dL. Age, standard of living, weight/height percentile, and total number of children ever born to the mother were significantly associated with BLLs (log transformed) in multivariate regression models. Compared with children ≤3 months of age, children 4–11 and 12–23 month of age had 84 and 146% higher BLLs, respectively (p < 0.001). A low standard of living correlated with a 32.3% increase in BLLs (p = 0.02). Children greater than the 95th percentile for their weight/height had 31% (p = 0.03) higher BLLs compared with those who were below the 5th percentile for their weight/height. CONCLUSIONS: Our study found various factors correlated with elevated BLLs in children. The correlation between greater than the 95th percentile weight/height and higher BLL may reflect an impact of lead exposure on body habitus. Our study may help in targeting susceptible populations and identifying correctable factors for elevated BLLs in Mumbai and Delhi

Cross-polarized photon-pair generation and bi-chromatically pumped optical parametric oscillation on a chip

Nonlinear optical processes are one of the most important tools in modern optics with a broad spectrum of applications in, for example, frequency conversion, spectroscopy, signal processing and quantum optics. For practical and ultimately widespread implementation, on-chip devices compatible with electronic integrated circuit technology offer great advantages in terms of low cost, small footprint, high performance and low energy consumption. While many on-chip key components have been realized, to date polarization has not been fully exploited as a degree of freedom for integrated nonlinear devices. In particular, frequency conversion based on orthogonally polarized beams has not yet been demonstrated on chip. Here we show frequency mixing between orthogonal polarization modes in a compact integrated microring resonator and demonstrate a bi-chromatically pumped optical parametric oscillator. Operating the device above and below threshold, we directly generate orthogonally polarized beams, as well as photon pairs, respectively, that can find applications, for example, in optical communication and quantum optics

Predicting the safety and efficacy of butter therapy to raise tumour pHe: an integrative modelling study

Background: Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts.\ud \ud Methods: We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies.\ud \ud Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2.\ud \ud Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising

Spectroscopic investigation of quantum confinement effects in ion implanted silicon-on-sapphire films

Crystalline Silicon-on-Sapphire (SOS) films were implanted with boron (B$^+$) and phosphorous (P$^+$) ions. Different samples, prepared by varying the ion dose in the range $10^{14}$ to 5 x $10^{15}$ and ion energy in the range 150-350 keV, were investigated by the Raman spectroscopy, photoluminescence (PL) spectroscopy and glancing angle x-ray diffraction (GAXRD). The Raman results from dose dependent B$^+$ implanted samples show red-shifted and asymmetrically broadened Raman line-shape for B$^+$ dose greater than $10^{14}$ ions cm$^{-2}$. The asymmetry and red shift in the Raman line-shape is explained in terms of quantum confinement of phonons in silicon nanostructures formed as a result of ion implantation. PL spectra shows size dependent visible luminescence at $\sim$ 1.9 eV at room temperature, which confirms the presence of silicon nanostructures. Raman studies on P$^+$ implanted samples were also done as a function of ion energy. The Raman results show an amorphous top SOS surface for sample implanted with 150 keV P$^+$ ions of dose 5 x $10^{15}$ ions cm$^{-2}$. The nanostructures are formed when the P$^+$ energy is increased to 350 keV by keeping the ion dose fixed. The GAXRD results show consistency with the Raman results.Comment: 9 Pages, 6 Figures and 1 Table, \LaTex format To appear in SILICON(SPRINGER

Pseudo-aneurysm of the anterior tibial artery, a rare cause of ankle swelling following a sports injury

BACKGROUND: Ankle pain and swelling following sports injuries are common presenting complaints to the accident and emergency department. Frequently these are diagnosed as musculoskeletal injuries, even when no definitive cause is found. Vascular injuries following trauma are uncommon and are an extremely rare cause of ankle swelling and pain. These injuries may however be limb threatening and are important to diagnose early, in order that appropriate treatment can be delivered. We highlight the steps to diagnosis of these injuries, and methods of managing these injuries. It is important for clinicians to be aware of the potential for this injury in patients with seemingly innocuous trauma from sports injuries, who have significant ankle pain and swelling. CASE PRESENTATION: A young, professional sportsman presented with a swollen, painful ankle after an innocuous hyper-plantar flexion injury whilst playing football, which was initially diagnosed as a ligamentous injury after no bony injury was revealed on X-Ray. He returned 2 days later with a large ulcer at the lateral malleolus and further investigation by duplex ultrasound and transfemoral arteriogram revealed a Pseudo-Aneurysm of the Anterior Tibial Artery. This was initially managed with percutaneous injection of thrombin, and later open surgery to ligate the feeding vessel. The patient recovered fully and was able to return to recreational sport. CONCLUSION: Vascular injuries remain a rare cause of ankle pain and swelling following sports injuries, however it is important to consider these injuries when no definite musculo-skeletal cause is found. Ultrasound duplex and Transfemoral arteriogram are appropriate, sensitive modalities for investigation, and may allow novel treatment to be directed percutaneously. Early diagnosis and intervention are essential for the successful outcome in these patients

Adaptive Reference Vector Generation for Inverse Model Based Evolutionary Multiobjective Optimization with Degenerate and Disconnected Pareto Fronts

Inverse model based multiobjective evolutionary algorithm aims to sample candidate solutions directly in the objective space, which makes it easier to control the diversity of non-dominated solutions in multiobjective optimization. To facilitate the process of inverse modeling, the objective space is partitioned into several subregions by predefining a set of reference vectors. In the previous work, the reference vectors are uniformly distributed in the objective space. Uniformly distributed reference vectors, however, may not be efficient for problems that have nonuniform or disconnected Pareto fronts. To address this issue, an adaptive reference vector generation strategy is proposed in this work. The basic idea of the proposed strategy is to adaptively adjust the reference vectors according to the distribution of the candidate solutions in the objective space. The proposed strategy consists of two phases in the search procedure. In the first phase, the adaptive strategy promotes the population diversity for better exploration, while in the second phase, the strategy focused on convergence for better exploitation. To assess the performance of the proposed strategy, empirical simulations are carried out on two DTLZ benchmark problems, namely, DTLZ5 and DTLZ7, which have a degenerate and a disconnected Pareto front, respectively. Our results show that the proposed adaptive reference vector strategy is promising in tacking multiobjective optimization problems whose Pareto front is disconnected