Prospective study evaluating the predictability of need for retreatment with intravitreal ranibizumab for age-related macular degeneration

Purpose

To investigate the rhythm and predictability of the need for retreatment with intravitreal injections of ranibizumab for neovascular age-related macular degeneration (nAMD).

Methods

This prospective study enrolled 39 patients with treatment-naïve nAMD. After three loading doses of intravitreal ranibizumab, patients underwent an intensified follow-up for 12 months (initially weekly, then with stepwise increases to every 2 weeks and to monthly after each injection). Patients were retreated on an as-needed basis if any fluid or increased central retinal thickness (CRT) (>50μm) was found on spectral domain optical coherence tomography (OCT). Statistical analysis included patients who received at least two retreatments (five injections).

Results

A mean of 7.5 injections (range 0–12) were given between months 3 and 15. The mean visual acuity increased by 13.1 and 12.6 ETDRS letters at months 12 and 15 respectively. Two or more injection–retreatment intervals were found in 31 patients. The variability of their intra-individual intervals up to 14 weeks was small (SD 0–2.13 weeks), revealing a high regularity of the retreatment rhythm. The SD was correlated with the mean interval duration (r?=?0.89, p?<?0.001). The first interval was a good predictor of the following intervals (regression coefficient =0.81). One retreatment criterion was stable in 97 % of patients (cysts or subretinal fluid).

Conclusion

The results of this study demonstrate a high intra-individual predictability of retreatment need with ranibizumab injections for nAMD. These findings may be helpful for developing individualized treatment plans for maintained suppression of disease activity with a minimum of injections and visits.     

Obstetrical and neonatal characteristics vary with birthweight in a cohort of 100 term newborns with symptomatic arterial ischemic stroke

ObjectivesMany questions remain regarding the mechanism of perinatal stroke.MethodsIn a series of 100 prospectively enrolled term neonates with symptomatic arterial ischemic stroke, we explored family antecedents, pregnancy and delivery conditions and clinical presenting features and distinguished features of the 50 larger infants with the remainder. Cardiac and cervical arterial imaging were performed in 70 and 51 cases.ResultsPrevious fetal loss, first pregnancy, primiparity, twin-gestation, cesarean and traumatic delivery, neonatal distress, male sex and premature rupture of membranes were statistically more common than in the general population. Normal pregnancy proportion and mean birthweight were in the normal range, arguing against a vasculo-placental origin in the majority. Furthermore, there was an excess of large babies. The larger infants were more subject to suffer from acute perinatal events, with a trend for an excess of neonatal distress (p = 0.065) and for more severe presenting features (p = 0.027), while the lighter were more likely to have experienced longstanding obstetrical risk factors such as complicated pregnancy (p = 0.047) and tobacco exposure (p = 0.028). Cervical MR angiography showed an internal carotid occlusion in two babies, whereas echo-Doppler was always normal; in one case the two methods were discordant. Echocardiography was non-informative.InterpretationThe data from this prospective cohort of neonates with stroke confirm that many obstetrical and perinatal factors are risk determinants. They also suggest that birthweight and gender may be biomarkers of two populations of neonates with different pathological mechanisms. MR angiography appears more sensitive than echo-Doppler for the exploration of the neonatal cervical vasculature.     

Gemcitabine in bladder cancer

Gemcitabine, a deoxycytidine analogue, is an inhibitor of DNA synthesis. With myelosupression being its most serious toxicity, gemcitabine has, however, a favourable toxicity profile. It was tested in urothelial bladder cancer at different stages of the disease. In superficial Bacillus Calmette-GuErin (BCG)-resistant bladder cancer as well as in BCG-intolerant patients, intravesical gemcitabine instillation has demonstrated a significant activity. In the adjuvant setting, the combination of gemcitabine and cisplatin (GC) has proved to be a feasible protocol. In locally advanced and metastatic disease, GC is admitted as a standard alternative first-line regimen. Gemcitabine is also an interesting choice for unfit patients when used as a single treatment or in combination with other chemotherapeutic agents as carboplatin or taxanes. This article reviews most of the studies performed in order to promote the usefulness of gemcitabine in bladder cancer.     

Spatial ensemble statistics are efficient codes that can be represented with reduced attention

There is a great deal of structural regularity in the natural environment, and such regularities confer an opportunity to form compressed, efficient representations. Although this concept has been extensively studied within the domain of low-level sensory coding, there has been limited focus on efficient coding in the field of visual attention. Here we show that spatial patterns of orientation information (“spatial ensemble statistics”) can be efficiently encoded under conditions of reduced attention. In our task, observers monitored for changes to the spatial pattern of background elements while they were attentively tracking moving objects in the foreground. By using stimuli that enable us to dissociate changes in local structure from changes in the ensemble structure, we found that observers were more sensitive to changes to the background that altered the ensemble structure than to changes that did not alter the ensemble structure. We propose that reducing attention to the background increases the amount of noise in local feature representations, but that spatial ensemble statistics capitalize on structural regularities to overcome this noise by pooling across local measurements, gaining precision in the representation of the ensemble.     

Intramuscular gene transfer of fibroblast growth factor-1 using improved pCOR plasmid design stimulates collateral formation in a rabbit ischemic hindlimb model

Fibroblast growth factor 1 (FGF1) is an angiogenic factor known to play a role in the growth of arteries. The purpose of this study was to evaluate the usefulness of direct intramuscular injection of an optimized expression plasmid encoding FGF1 to augment collateral formation and tissue perfusion in a rabbit ischemic hindlimb model. Truncated FGF1 fused to the human fibroblast interferon (FIN) signal peptide was expressed from a newly designed plasmid backbone with an improved safety profile for gene therapy applications. In vitro, optimization of plasmid design yielded in a dramatic increase in expression efficiency for FGF1, independent of the presence of a signal peptide, as analyzed by Western Blotting. In vivo, successful transgene expression could be demonstrated by FGF1 immunostaining after gene application. FGF1 plasmid containing FIN signal peptide (100, 500, and 1,000 μg), when injected into ischemic muscle areas of rabbits 10 days after ligation of the external iliac artery, exhibited a pronounced therapeutic effect on collateral formation to the ischemic hindlimb in a dose-depending manner, as assessed by physiological (blood pressure ratio, maximal intra-arterial Doppler flow) and anatomical (angiographic score, histologic evaluation of capillary density) measurements 30 days after therapy, compared to saline or lacZ control plasmid. FGF1 plasmid without a signal peptide sequence resulted in a comparable therapeutic effect on collateral formation at comparable doses (500 and 1,000 μg). Our results indicate that intramuscular FGF1 gene application could be useful to stimulate collateral formation in a situation of chronic peripheral ischemia. The presence of a signal peptide does not seem to be obligatory to achieve bioactivity of intramuscular transfected FGF1. An optimized vector design improved both biosafety of gene transfer and expression efficiency of the transgene, rendering this vector highly suitable for human gene therapy. Therefore, this new generation vector encoding FGF1 might be useful as an alternative treatment for patients with chronic ischemic disorders not amenable to conventional therapy.     

Induction of antigen-specific CD8+ cytotoxic T cells by dendritic cells co-electroporated with a dsRNA analogue and tumor antigen mRNA

The maturation state of dendritic cells (DCs) is an important determinant for the initiation and regulation of adaptive immune responses. In this study, we wanted to assess whether functional activation of human monocyte-derived DCs can be achieved by electroporation of an activation signal in the form of double-stranded (ds) RNA and whether simultaneous electroporation of the dsRNA with tumor antigen encoding mRNA can lead to the induction of a cytotoxic T-lymphocyte (CTL) response. Electroporation of immature DCs with poly(I:C(12)U), a dsRNA analogue, resulted in phenotypic as well as functional changes, indicative of DC maturation. Co-electroporation of DCs with both poly(I:C(12)U) and Melan-A/MART-1 encoding mRNA induced strong anti-Melan-A/MART-1 CD8(+) T-cell responses in vitro. Higher numbers of Melan-A/MART-1-specific CTLs were consistently obtained with poly(I:C(12)U)-activated DCs compared to DCs matured in the presence of an inflammatory cytokine cocktail. These results indicate that DC co-electroporation with both dsRNA and tumor antigen encoding mRNA induces fully activated and antigen-loaded DCs that promote antigen-specific CTL responses and may provide the basis for future immunotherapeutic strategies.     

Laboratory-observed behavioral disinhibition in the young offspring of parents with bipolar disorder: a high-risk pilot study

OBJECTIVE: This study tested whether behavioral disinhibition is more prevalent among offspring of parents with bipolar disorder than among offspring of parents without bipolar disorder. METHOD: The authors conducted a secondary analysis of data from a preexisting high-risk study of offspring at risk for panic disorder and depression (N=278) that had included some children with parents who had bipolar disorder (N=34). Children (ages 2-6) had been classified as behaviorally inhibited, disinhibited, or neither in laboratory assessments. RESULTS: Offspring of bipolar parents had significantly higher rates of behavioral disinhibition than offspring of parents without bipolar disorder. Behavioral inhibition did not differ between groups. Differences were not accounted for by parental panic disorder or major depression or by parental history of attention deficit hyperactivity disorder, conduct disorder, antisocial personality, or substance use disorders. CONCLUSIONS: Results suggest a familial link between bipolar disorder in parents and behavioral disinhibition in their offspring. Behavioral disinhibition may be a familially transmitted predisposing factor for dysregulatory distress later in life.     

NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer

Instability in the composition of gut bacterial communities (dysbiosis) has been linked to common human intestinal disorders, such as Crohn’s disease and colorectal cancer. Here, we show that dysbiosis caused by Nod2 deficiency gives rise to a reversible, communicable risk of colitis and colitis-associated carcinogenesis in mice. Loss of either Nod2 or RIP2 resulted in a proinflammatory microenvironment that enhanced epithelial dysplasia following chemically induced injury. The condition could be improved by treatment with antibiotics or an anti–interleukin-6 receptor–neutralizing antibody. Genotype-dependent disease risk was communicable via maternally transmitted microbiota in both Nod2-deficient and WT hosts. Furthermore, reciprocal microbiota transplantation reduced disease risk in Nod2-deficient mice and led to long-term changes in intestinal microbial communities. Conversely, disease risk was enhanced in WT hosts that were recolonized with dysbiotic fecal microbiota from Nod2-deficient mice. Thus, we demonstrated that licensing of dysbiotic microbiota is a critical component of disease risk. Our results demonstrate that NOD2 has an unexpected role in shaping a protective assembly of gut bacterial communities and suggest that manipulation of dysbiosis is a potential therapeutic approach in the treatment of human intestinal disorders.     

The Dragon’s Paralysing Spell: Evidence of Sodium and Calcium Ion Channel Binding Neurotoxins in Helodermatid and Varanid Lizard Venoms

Bites from helodermatid lizards can cause pain, paresthesia, paralysis, and tachycardia, as well as other symptoms consistent with neurotoxicity. Furthermore, in vitro studies have shown that Heloderma horridum venom inhibits ion flux and blocks the electrical stimulation of skeletal muscles. Helodermatids have long been considered the only venomous lizards, but a large body of robust evidence has demonstrated venom to be a basal trait of Anguimorpha. This clade includes varanid lizards, whose bites have been reported to cause anticoagulation, pain, and occasionally paralysis and tachycardia. Despite the evolutionary novelty of these lizard venoms, their neuromuscular targets have yet to be identified, even for the iconic helodermatid lizards. Therefore, to fill this knowledge gap, the venoms of three Heloderma species (H. exasperatum, H. horridum and H. suspectum) and two Varanus species (V. salvadorii and V. varius) were investigated using Gallus gallus chick biventer cervicis nerve–muscle preparations and biolayer interferometry assays for binding to mammalian ion channels. Incubation with Heloderma venoms caused the reduction in nerve-mediated muscle twitches post initial response of avian skeletal muscle tissue preparation assays suggesting voltage-gated sodium (Na_V) channel binding. Congruent with the flaccid paralysis inducing blockage of electrical stimulation in the skeletal muscle preparations, the biolayer interferometry tests with Heloderma suspectum venom revealed binding to the S3–S4 loop within voltage-sensing domain IV of the skeletal muscle channel subtype, Na_V1.4. Consistent with tachycardia reported in clinical cases, the venom also bound to voltage-sensing domain IV of the cardiac smooth muscle calcium channel, Ca_V1.2. While Varanus varius venom did not have discernable effects in the avian tissue preparation assay at the concentration tested, in the biointerferometry assay both V. varius and V. salvadorii bound to voltage-sensing domain IV of both Na_V1.4 and Ca_V1.2, similar to H. suspectum venom. The ability of varanid venoms to bind to mammalian ion channels but not to the avian tissue preparation suggests prey-selective actions, as did the differential potency within the Heloderma venoms for avian versus mammalian pathophysiological targets. This study thus presents the detailed characterization of Heloderma venom ion channel neurotoxicity and offers the first evidence of varanid lizard venom neurotoxicity. In addition, the data not only provide information useful to understanding the clinical effects produced by envenomations, but also reveal their utility as physiological probes, and underscore the potential utility of neglected venomous lineages in the drug design and development pipeline.     

High risk studies and developmental antecedents of anxiety disorders

The past two decades have witnessed significant growth in our understanding of the developmental antecedents of anxiety disorders. In this article, we review studies of offspring at risk for anxiety disorders, longitudinal studies of the course of anxiety disorders in clinical, epidemiologic, and at-risk samples, studies of hypothesized temperamental risk factors for anxiety, and give a brief overview of the literature on environmental risk factors. Clear developmental antecedents to anxiety disorders identified include (1) childhood anxiety disorders [in particular, separation anxiety and overanxious disorder/general anxiety disorder (GAD)], (2) behavioral inhibition which predicts later social phobia, (3) anxiety sensitivity which predicts later panic disorder, and (4) negative affectivity, which predicts a spectrum of psychopathology including anxiety disorders. Further prospective studies are needed to examine the roles of environmental factors such as parenting practices, peer influences, stressful life events, and perinatal stressors. Future studies could benefit from (1) beginning earlier in development and following individuals into adulthood, (2) assessing the overlap between multiple temperamental constructs, (3) greater use of observational measures of temperament and of parent-child and peer interactions, (4) greater attention to parental psychopathology which may confound associations noted, (5) exploration of other features of anxiety disorders (neurofunctional correlates, cognitive features, other aspects of emotional regulation) as potential precursors, and (6) intervention studies exploring whether modifying developmental antecedents can alter the course of anxiety disorders.