Early selective neuroretinal disorder in prepubertal type 1 (insulin-dependent) diabetic children without microvascular abnormalities

The duration of diabetes before puberty is not considered relevant to the future development of complications. To evaluate the effects of diabetes on the neural retina, we analysed macular function by steady-state focal electroretinography in 20 prepubescent diabetic children without vascular retinopathy and in 39 sex- and age-matched normal children. The mean (±SD) response related to retinal cellular elements between the photoreceptors and ganglion cells was significantly lower in diabetic children than in the control group (0.38±0.12 vs. 0.51±0.13 V; unpairedt-test=3;P=0.005). Similarly, ganglion cell function showed a significant impairment in diabetic children with respect to the control group (0.4±0.13 vs. 0.53±0.09 V; unpairedt-test=5.4;P=0.0001), whereas the photoreceptors appeared unaffected. Metabolic control and disease duration were not correlated with functional deficits. Our results suggest that before puberty, early diabetes may have a selective effect on the neural retina prior to the appearance of microvascular changes. A focal electroretinogram could identify diabetic children with neurosensory disorders who may have a higher risk of developing microvascular retinopathy.     

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1–2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex‐influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre‐symptomatic diagnosis has the greatest clinical utility.     

A Monte Carlo approach for improving transient dopamine release detection sensitivity

Current methods using a single PET scan to detect voxel-level transient dopamine release—using F-test (significance) and cluster size thresholding—have limited detection sensitivity for clusters of release small in size and/or having low release levels. Specifically, simulations show that voxels with release near the peripheries of such clusters are often rejected—becoming false negatives and ultimately distorting the F-distribution of rejected voxels. We suggest a Monte Carlo method that incorporates these two observations into a cost function, allowing erroneously rejected voxels to be accepted under specified criteria. In simulations, the proposed method improves detection sensitivity by up to 50% while preserving the cluster size threshold, or up to 180% when optimizing for sensitivity. A further parametric-based voxelwise thresholding is then suggested to better estimate the release dynamics in detected clusters. We apply the Monte Carlo method to a pilot scan from a human gambling study, where additional parametrically unique clusters are detected as compared to the current best methods—results consistent with our simulations.     

p64 flow diverter: Results in 108 patients from a single center

Background and purposeFlow diverters are increasingly used to treat intracranial aneurysms. We report the safety and efficacy of the p64 flow diverter, a resheathable and detachable device for intracranial aneurysms.Materials and methodsWe retrospectively reviewed 108 patients with 109 aneurysms treated with the p64 between March 2014 and July 2019. There were 87 women and 21 men, mean age 57 years. Of 109 aneurysms, 74 were discovered incidentally, 12 were symptomatic, 18 were previously treated, and five were ruptured dissection aneurysms. A total of 10 aneurysms were located in the posterior circulation. The mean aneurysm or remnant size was 8.1 mm.ResultsHemorrhage by perforation with the distal guidewire occurred in two patients with permanent neurological deficits in one. In one patient, acute in-stent occlusion caused infarction with a permanent deficit. Permanent morbidity was 1.9% (2 of 108, 95%CI 0.1–6.9%); there was no mortality. During follow-up, three in-stent occlusions occurred, all asymptomatic. There were no delayed hemorrhagic complications. At six months, 77 of 96 aneurysms (80.2%) were completely occluded, and at last follow-up, this increased to 93 of 96 aneurysms (96.9%). In-stent stenosis at any degree occurred in 11 patients, progressing to asymptomatic complete occlusion in one. In the other patients, stenosis resolved or improved at further follow-up.ConclusionThe p64 offers an effective and safe treatment option. Aneurysm occlusion rate was 97% at last follow-up, mostly achieved with a single device. There were no delayed hemorrhagic complications. Delayed in-stent stenosis infrequently progresses to occlusion but remains a matter of concern.     

Activated natural killer cells and interleukin-2 promote granulocytic and megakaryocytic reconstitution after syngeneic bone marrow transplantation in mice

Purified populations of natural killer (NK) cells were obtained from mice with severe combined immune deficiency (SCID). SCID spleen cells were cultured and activated with recombinant human interleukin-2 (rhIL- 2) in vitro. The activated NK cells were then transferred with syngeneic BALB/c bone marrow cells (BMC) and rhIL-2 into lethally irradiated syngeneic recipients to determine their effect on long-term hematopoietic reconstitution. On analysis, the transfer of rhIL-2- activated NK cells along with BMC resulted in significant increases in splenic and BM hematopoietic progenitor cells when compared with those for mice not receiving NK cells. Histologic and flow cytometric analysis showed a marked increase in granulocytic and megakaryocytic lineage cells present in the spleens of the mice receiving activated NK cells. Analysis of the peripheral blood indicated that the transfer of activated NK cells with BMC also significantly improved platelet and total white blood cell counts, with increases in segmented neutrophils. Erythroid recovery was not affected. Finally, lethally irradiated mice receiving activated NK cells and rhIL-2 along with limiting numbers of syngeneic BMC showed a marked increase in survival rate. These results show that the use of populations enriched for activated NK cells after syngeneic BM transplantation (BMT) has a profound enhancing effect on engraftment primarily affecting megakaryocytic and granulocytic cell reconstitution. Therefore, the transfer of activated NK cells and rhIL- 2 may be of clinical use to promote hematopoietic reconstitution after BMT.     

8-chloro-cAMP inhibits smooth muscle cell proliferation in vitro and neointima formation induced by balloon injury in vivo

OBJECTIVES: The aims of the present study were to assess 1) the effect of 8-C1-cAMP (cyclic-3'-5'-adenosine monophosphate) on vascular smooth muscle cell (VSMC) proliferation in vitro and 2) the efficacy of systemic administration of 8-C1-cAMP on neointimal formation after balloon injury in vivo. BACKGROUND: Neointimal formation after vascular injury is responsible for restenosis after arterial stenting. Recently, 8-C1-cAMP, a cAMP analogue that induces growth arrest, has been safely administered in phase I studies in humans. METHODS: The effect of 8-C1-cAMP on cell proliferation was first assessed on SMCs in vitro. To study the effects of cAMP in vivo, balloon injury was performed in 67 rats using a 2F Fogarty balloon catheter. RESULTS: The 8-C1-cAMP markedly inhibited VSMC proliferation in vitro, reduced protein kinase A (PKA) RIalpha subunit expression, and induced PKA RIIbeta subunit expression. In addition, 8-C1-cAMP reduced, in a dose-dependent manner, neointimal area and neointima/media ratio after balloon injury. The proliferative activity, assessed by proliferating nuclear cell antigen immunostaining, revealed a reduction of proliferative activity of VSMCs in vivo in the 8-C1-cAMP group. Moreover, the systemic administration of 8-C1-cAMP did not affect renal function, blood pressure and heart rate. CONCLUSIONS: We conclude that 8-C1-cAMP potently inhibits VSMC proliferation in vitro and reduces neointima formation by balloon injury in vivo after systemic administration. These data may have a clinical relevance in designing future strategies to prevent restenosis after arterial stenting and perhaps after percutaneous transluminal coronary angioplasty.     

A comprehensive optical analysis of nanoscale structures: from thin films to asymmetric nanocavities

A simple and robust method able to evaluate and predict, with high accuracy, the optical properties of single and multi-layer nanostructures is presented. The method was implemented using a COMSOL Multiphysics simulation platform and it has been validated by four case studies with increasing numerical complexities: (i) a single thin layer (20 nm) of Ag deposited on a glass substrate; (ii) a metamaterial composed of five bi-layers of Ag/ITO (indium tin oxide), with a thickness of 20 nm each; (iii) a system based on a three-material unit cell (AZO/ITO/Ag), but without any thickness periodicity (AZO stands for Al₂O₃/zinc oxide); (iv) an asymmetric nanocavity (thin-ITO/Ag/thick-ITO/Ag). A thorough study of this latter configuration reveals peculiar metamaterial effects that can widen the actual scenario in nanophotonic applications. Numerical results have been compared with experimental data provided by real ellipsometric measurements performed on the above mentioned ad hoc fabricated nanostructures. The obtained agreement is excellent, suggesting this research as a valid design approach to realize multi-band metamaterials able to work in a broad spectral range.

Hyper transmission of asymmetric nanocavity metamaterials; a comprehensive optical analysis of multi-layered nanostructures.