Demarcation laser therapy in the management of macular-sparing persistent subretinal fluid after scleral buckling procedures

Background: Persistent or recurrent macular-sparing subretinal fluid (SRF) can sometimes occur following scleral buckling procedures. Observation and reoperation have been used in the management of such cases. Demarcation laser therapy (DLT) has been used to treat macular-sparing retinal detachments in the context of cytomegalovirus retinitis and as primary treatment for selected rhegmatogenous retinal detachments. There are, however, scarce data in the literature regarding its use following primary scleral buckling procedures. The current study explores the use of DLT under the latter circumstances. Methods: The medical records of all consecutive patients with persistent SRF sparing the macula following primary rhegmatogenous retinal detachment repair using a scleral buckling procedure were retrospectively reviewed. Only those patients in whom the breaks were localised to the area of indentation and, thus, seemed to be well supported by the buckle were included. Demographics, clinical characteristics of the retinal detachment prior to scleral buckling, extension of the residual SRF observed postoperatively, details of the laser procedure, anatomical and functional outcomes and complications were evaluated. Results: Seven patients, all females, with a mean age of 47.9 years (range: 20-81) were included in the study. The retinal detachments were superior (n=3), inferior (n=3) and subtotal, affecting both superior and inferior retina (n=1). Scleral buckling procedures were used to treat the retinal detachments in all cases. Following demarcation laser therapy, the area of SRF remained stable in two patients, and flattened in four. In one patient, extension of SRF occurred requiring further surgery. Conclusions: Demarcation laser therapy appears to be a reasonable option in the management of patients with persistent or recurrent SRF sparing the macula following scleral buckling surgery. © Springer-Verlag 2006.

The Association of Skin-Intrinsic Fluorescence With Type 1 Diabetes Complications in the DCCT/EDIC Study

OBJECTIVESTo determine whether skin-intrinsic fluorescence (SIF) is associated with long-term complications of type 1 diabetes (T1D) and, if so, whether it is independent of chronic glycemic exposure and previous intensive therapy.RESEARCH DESIGN AND METHODSWe studied 1,185 (92%) of 1,289 active Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) participants from 2010 to 2011. SIF was determined using a fluorescence spectrometer and related cross-sectionally to recently determined measures of retinopathy (stereo fundus photography), cardiac autonomic neuropathy (CAN; R-R interval), confirmed clinical neuropathy, nephropathy (albumin excretion rate [AER]), and coronary artery calcification (CAC).RESULTSOverall, moderately strong associations were seen with all complications, before adjustment for mean HbA1c over time, which rendered these associations nonsignificant with the exception of sustained AER >30 mg/24 h and CAC, which were largely unaffected by adjustment. However, when examined within the former DCCT treatment group, associations were generally weaker in the intensive group and nonsignificant after adjustment, while in the conventional group, associations remained significant for CAN, sustained AER >30 mg/24 h, and CAC even after mean HbA1c adjustment.CONCLUSIONSSIF is associated with T1D complications in DCCT\EDIC. Much of this association appears to be related to historical glycemic exposure, particularly in the previously intensively treated participants, in whom adjustment for HbA1c eliminates statistical significance.

Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration:the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005)

Clinical treatment goals of type 1 diabetes mellitus (T1DM) have changed since the Diabetes Control and Complications Trial (DCCT) demonstrated reduced long-term complications with intensive diabetes therapy. There have been few longitudinal studies to describe the clinical course of T1DM in the age of intensive therapy. Our objective was to describe the current-day clinical course of T1DM.

Effect of intensive glycemic control on levels of markers of inflammation in type 1 diabetes mellitus in the diabetes control and complications trial

Type 1 diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD) that is not fully explained by conventional risk factors. The Diabetes Control and Complications Trial (DCCT) showed that intensive diabetes therapy reduced levels of LDL cholesterol and triglycerides but increased the risk of major weight gain, which might adversely affect CVD risk. The present study examined the effect of intensive therapy on levels of several markers of inflammation that have been linked to risk of CVD.

Triose phosphate isomerase from the blood fluke Schistosoma mansoni:Biochemical characterisation of a potential drug and vaccine target

The glycolytic enzyme triose phosphate isomerase from Schistosoma mansoni is a potential target for drugs and vaccines. Molecular modelling of the enzyme predicted that a Ser-Ala-Asp motif which is believed to be a helminth-specific epitope is exposed. The enzyme is dimeric (as judged by gel filtration and cross-linking), resistant to proteolysis and highly stable to thermal denaturation (melting temperature of 82.0°C). The steady-state kinetic parameters are high (Km for dihydroxyacetone phosphate is 0.51mM; Km for glyceraldehyde 3-phosphate is 1.1mM; kcat for dihydroxyacetone phosphate is 7800s(-1) and kcat for glyceraldehyde 3-phosphate is 6.9s(-1)).

Non-steroidal anti-inflammatory drug use and brain tumour risk:a case-control study within the Clinical Practice Research Datalink

Purpose: The aetiology of primary brain tumours is largely unknown; the role of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin use and glioma risk has been inconclusive, but few population-based studies with reliable prescribing data have been conducted, and the association with meningioma risk has yet to be assessed. Methods: The UK Clinical Practice Research Datalink was used to assess the association between aspirin and non-aspirin NSAID use and primary brain tumour risk using a nested case-control study design. Conditional logistic regression analysis was performed on 5,052 brain tumour patients aged 16 years and over, diagnosed between 1987 and 2009 and 42,678 controls matched on year of birth, gender and general practice, adjusting for history of allergy and hormone replacement therapy use in the glioma and meningioma models, respectively.

Results: In conditional logistic regression analysis, excluding drug use in the year preceding the index date, there was no association with non-aspirin NSAID use (OR 0.96, 95 % CI 0.81-1.13) or glioma risk comparing the highest category of daily defined dose to non-users; however, non-aspirin NSAID use was positively associated with meningioma risk (OR 1.35, 95 % CI 1.06-1.71). No association was seen with high- or low-dose aspirin use irrespective of histology.

Conclusions: This large nested case-control study finds no association between aspirin or non-aspirin NSAID use and risk of glioma but a slight increased risk with non-aspirin NSAIDs and meningioma. © 2013 Springer Science+Business Media Dordrecht.

Purple sweet potato colour - a potential therapy for galactosemia?

Galactosemia is an inherited metabolic disease in which galactose is not properly metabolised. There are various theories to explain the molecular pathology, and recent experimental evidence strongly suggests that oxidative stress plays a key role. High galactose diets are damaging to experimental animals and oxidative stress also plays a role in this toxicity which can be alleviated by purple sweet potato colour (PSPC). This plant extract is rich in acetylated anthocyanins which have been shown to quench free radical production. The objective of this Commentary is to advance the hypothesis that PSPC, or compounds therefrom, may be a viable basis for a novel therapy for galactosemia.

Investigation of the mechanism of repression of rRNA synthesis by an anticancer drug

Ribosome biogenesis is a fundamental cellular process which is tightly regulated in normal cells. A number of tumour suppressors and oncogenes could affect the production of ribosomes at different levels and an upregulation could lead to increased protein biosynthesis which is one of the characteristic features of all cancer cells. Ribosome biogenesis is a very complex process which requires coordinated transcription by all three nucleolar polymerases and the first event in this process is synthesis of ribosomal RNA (rRNA) by RNA Polymerase I (Pol I). Importantly, recent data has pictured rRNA transcription as a key regulator of whole ribosome biogenesis and therefore makes it a valid and very attractive target for anticancer therapy, as well as a perspective biomarker. However, at the moment there is only one known specific inhibitor of Pol I transcription (at stage one of clinical trials) and this makes it very difficult for the development of drugs which would target rRNA transcription and consequently ribosome biogenesis. We have recently discovered that antitumor alkaloid ellipticine (isolated in 1959 from the plant species Ochrosia) is a potent inhibitor of Pol I transcription (both in vitro and in vivo). Ellipticine and its derivatives are known as efficient topoisomerase II inhibitors and inhibitors of some kinases, however we have shown that these inhibitory activities and the ability of ellipticine to repress Pol I activity are unrelated. Moreover, our preliminary data suggests that ellipticine specifically targets Pol I transcription and it has no effect on transcription by Pol II and Pol III at the same time scale. The possible mechanisms of inhibition of Pol I transcription by ellipticines will be discussed.

Efficient Drug Delivery and Induction of Apoptosis in Colorectal Tumors Using a Death Receptor 5-Targeted Nanomedicine

Death Receptor 5 (DR5) is a pro-apoptotic cell-surface receptor that is a potential therapeutic target in cancer. Despite the potency of DR5-targeting agents in preclinical models, the translation of these effects into the clinic remains disappointing. Herein, we report an alternative approach to exploiting DR5 tumor expression using antibody-targeted, chemotherapy-loaded nanoparticles. We describe the development of an optimized polymer-based nanotherapeutic incorporating both a functionalized polyethylene glycol (PEG) layer and targeting antibodies to limit premature phagocytic clearance whilst enabling targeting of DR5-expressing tumor cells. Using the HCT116 colorectal cancer model, we show that following binding to DR5, the nanoparticles activate caspase 8, enhancing the anti-tumor activity of the camptothecin payload both in vitro and in vivo. Importantly, the combination of nanoparticle-induced DR5 clustering with camptothecin delivery overcomes resistance to DR5-induced apoptosis caused by loss of BAX or overexpression of anti-apoptotic FLIP. This novel approach may improve the clinical activity of DR5-targeted therapeutics while increasing tumor-specific delivery of systemically toxic chemotherapeutics.Molecular Therapy (2014); doi:10.1038/mt.2014.137.

The difficult-to-treat, therapy-resistant cough: Why are current cough treatments not working and what can we do?

Cough can persist despite exhaustive diagnostic and therapeutic effort and has been termed 'idiopathic' or 'unexplained' but perhaps 'difficult to treat' cough is a more appropriate description. In this article the reasons for poor treatment response are discussed. These include a lack of physician fidelity to management guidelines, patient non-adherence and the lack of effective medicines. A number of randomized controlled trials have been undertaken including low dose opiate therapy, the use of a speech pathology intervention, oral antibiotics and antidepressants. The success or otherwise of such interventions will be discussed. A number of approaches to deal with the problem of 'difficult to treat cough' will be considered.

Photosensitisers - the progression from photodynamic therapy to anti-infective surfaces

Introduction: The application of light as a stimulus in pharmaceutical systems and the associated ability to provide precise spatiotemporal control over location, wavelength and intensity, allowing ease of external control independent of environmental conditionals, has led to its increased use. Of particular note is the use of light with photosensitisers.

Areas covered: Photosensitisers are widely used in photodynamic therapy to cause a cidal effect towards cells on irradiation due to the generation of reactive oxygen species. These cidal effects have also been used to treat infectious diseases. The effects and benefits of photosensitisers in the treatment of such conditions are still being developed and further realised, with the design of novel delivery strategies. This review provides an overview of the realisation of the pharmaceutically relevant uses of photosensitisers, both in the context of current research and in terms of current clinical application, and looks to the future direction of research.

Expert opinion: Substantial advances have been and are being made in the use of photosensitisers. Of particular note are their antimicrobial applications, due to absence of resistance that is so frequently associated with conventional treatments. Their potency of action and the ability to immobilise to polymeric supports is opening a wide range of possibilities with great potential for use in healthcare infection prevention strategies.

Dietary habits of patients undergoing methadone therapy

OBJECTIVE: This study was designed to record the dietary habits of patients undergoing methadone therapy.

BACKGROUND: Numerous studies report that patients undergoing methadone treatment present with high levels of oral disease, especially dental caries. A number of factors have been described to account for this: sugared methadone preparations, prolonged oral retention, associated xerostomia and poor diet.

METHODS: A cross-sectional descriptive study using survey methodology was conducted of patients attending a non-resident drug rehabilitation clinic. A self-completion questionnaire and diet diary were developed and distributed to 66 patients over an 8 week period.

RESULTS: Of the 66 questionnaires distributed, 52 were successfully completed giving a response rate of 79%. 6 patients declined to complete the questionnaire. The surveyed patient pool consisted of 32 females (62%) and 20 males (38%) with a mean age of 32 years. All the participants were taking a prescribed daily dose of methadone when questioned. 68% of respondents consumed convience foods or sugary snacks every day. Of those patients who drank tea or coffee daily, 84% added sugar and 54% added 3 teaspoons or more. The majority of patients (71%) consumed at least one glass of a fizzy soft drink daily. In addition, the majority of respondents indicated that they snacked regularly between meals and 24% stated that they often woke up during the night for a snack. Patients recorded their last intake of food ranging from 5pm to 3am.

CONCLUSIONS: The patients surveyed had poor dietary habits. Respondents consumed a large amount of convience foods and sugars during mealtimes and through regular snacking. Dietary counselling should be considered as part of treatment for patients undergoing methadone therapy.

Methotrexate polyglutamates as a potential marker of adherence to long-term therapy in children with juvenile idiopathic arthritis and juvenile dermatomyositis: an observational, cross-sectional study

Introduction: Methotrexate (MTX) is a cornerstone of treatment in a wide variety of inflammatory conditions, including juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM). However, owing to its narrow therapeutic index and the considerable interpatient variability in clinical response, monitoring of adherence to MTX is important. The present study demonstrates the feasibility of using methotrexate polyglutamates (MTXPGs) as a biomarker to measure adherence to MTX treatment in children with JIA and JDM.
Methods: Data were collected prospectively from a cohort of 48 children (median age 11.5 years) who received oral or subcutaneous (SC) MTX therapy for JIA or JDM. Dried blood spot samples were obtained from children by finger pick at the clinic or via self- or parent-led sampling at home, and they were analysed to determine the variability in MTXPG concentrations and assess adherence to MTX therapy.
Results: Wide fluctuations in MTXPG total concentrations (>2.0-fold variations) were found in 17 patients receiving stable weekly doses of MTX, which is indicative of nonadherence or partial adherence to MTX therapy. Age (P = 0.026) and route of administration (P = 0.005) were the most important predictors of nonadherence to MTX treatment. In addition, the study showed that MTX dose and route of administration were significantly associated with variations in the distribution of MTXPG subtypes. Higher doses and SC administration of MTX produced higher levels of total MTXPGs and selective accumulation of longer-chain MTXPGs (P < 0.001 and P < 0.0001, respectively).
Conclusions: Nonadherence to MTX therapy is a significant problem in children with JIA and JDM. The present study suggests that patients with inadequate adherence and/or intolerance to oral MTX may benefit from SC administration of the drug. The clinical utility of MTXPG levels to monitor and optimise adherence to MTX in children has been demonstrated.Trial Registration: ISRCTN Registry identifier: ISRCTN93945409 . Registered 2 December 2011.

Pan-retinal photocoagulation and other forms of laser treatment and drug therapies for non-proliferative diabetic retinopathy: systematic review and economic evaluation

BACKGROUND: Diabetic retinopathy is an important cause of visual loss. Laser photocoagulation preserves vision in diabetic retinopathy but is currently used at the stage of proliferative diabetic retinopathy (PDR).

OBJECTIVES: The primary aim was to assess the clinical effectiveness and cost-effectiveness of pan-retinal photocoagulation (PRP) given at the non-proliferative stage of diabetic retinopathy (NPDR) compared with waiting until the high-risk PDR (HR-PDR) stage was reached. There have been recent advances in laser photocoagulation techniques, and in the use of laser treatments combined with anti-vascular endothelial growth factor (VEGF) drugs or injected steroids. Our secondary questions were: (1) If PRP were to be used in NPDR, which form of laser treatment should be used? and (2) Is adjuvant therapy with intravitreal drugs clinically effective and cost-effective in PRP?

ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) for efficacy but other designs also used.

REVIEW METHODS: Systematic review and economic modelling.

RESULTS: The Early Treatment Diabetic Retinopathy Study (ETDRS), published in 1991, was the only trial designed to determine the best time to initiate PRP. It randomised one eye of 3711 patients with mild-to-severe NPDR or early PDR to early photocoagulation, and the other to deferral of PRP until HR-PDR developed. The risk of severe visual loss after 5 years for eyes assigned to PRP for NPDR or early PDR compared with deferral of PRP was reduced by 23% (relative risk 0.77, 99% confidence interval 0.56 to 1.06). However, the ETDRS did not provide results separately for NPDR and early PDR. In economic modelling, the base case found that early PRP could be more effective and less costly than deferred PRP. Sensitivity analyses gave similar results, with early PRP continuing to dominate or having low incremental cost-effectiveness ratio. However, there are substantial uncertainties. For our secondary aims we found 12 trials of lasers in DR, with 982 patients in total, ranging from 40 to 150. Most were in PDR but five included some patients with severe NPDR. Three compared multi-spot pattern lasers against argon laser. RCTs comparing laser applied in a lighter manner (less-intensive burns) with conventional methods (more intense burns) reported little difference in efficacy but fewer adverse effects. One RCT suggested that selective laser treatment targeting only ischaemic areas was effective. Observational studies showed that the most important adverse effect of PRP was macular oedema (MO), which can cause visual impairment, usually temporary. Ten trials of laser and anti-VEGF or steroid drug combinations were consistent in reporting a reduction in risk of PRP-induced MO.

LIMITATION: The current evidence is insufficient to recommend PRP for severe NPDR.

CONCLUSIONS: There is, as yet, no convincing evidence that modern laser systems are more effective than the argon laser used in ETDRS, but they appear to have fewer adverse effects. We recommend a trial of PRP for severe NPDR and early PDR compared with deferring PRP till the HR-PDR stage. The trial would use modern laser technologies, and investigate the value adjuvant prophylactic anti-VEGF or steroid drugs.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005408.

FUNDING: The National Institute for Health Research Health Technology Assessment programme.