Methylphenidate use and restorative treatment needs in young adults with attention deficit hyperactivity disorder.

OBJECTIVE: To assess the effect and dose-response of methylphenidate (MP) use on the restorative treatment needs in young adults with attention deficit hyperactivity disorder. PARTICIPANTS AND METHODS: This retrospective study comprises a cohort of military recruits aged 18-25 who served for 12 to 48 months between 2005 and 2017. The medical records of 213 604 participants were assessed of which: 6875 participants with ADHD who received treatment with MP, 6729 participants with ADHD who had no prescriptions for MP, and 200 000 healthy participants. The outcome was restorative treatment needs, which served as an indicator of caries: having at least one prescription for restorative treatment during the study period. RESULTS: Frequency of prescription for restorative treatment among the treated, the untreated and the control groups was 24%, 22%, and 17%, respectively (p < .0001). On multivariate analysis, the dose-response association between MP use and the odds of having at least one restorative treatment was confirmed (OR = 1.006 for each additional 1 gr of MP; 95% CI [1.004:1.009]) CONCLUSIONS: Participants with ADHD who receive chronic treatment with MP have higher restorative treatment needs than participants with untreated ADHD and healthy participants. Our results show that chronic MP medication among young adults leads to an elevated need for restorative treatment and implies a significant impact on oral health (OH).

Enzyme-Responsive Nanoparticles for Dexamethasone Targeted Delivery to Treat Inflammation in Diabetes.

Diabetes is a global epidemic accompanied by impaired wound healing and increased risk of persistent infections and resistance to standard treatments. Therefore, there is an immense need to develop novel methods to specifically target therapeutics to affected tissues and improve treatment efficacy. This study aims to use enzyme-responsive nanoparticles for the targeted delivery of an anti-inflammatory drug, dexamethasone, to treat inflammation in diabetes. These nanoparticles are assembled from fluorescently-labeled, dexamethasone-loaded peptide-polymer amphiphiles. The nanoparticles are injected in vivo, adjacent to labeled collagen membranes sub-periosteally implanted on the calvaria of diabetic rats. Following their implantation, collagen membrane resorption is linked to inflammation, especially in hyperglycemic individuals. The nanoparticles show strong and prolonged accumulation in inflamed tissue after undergoing a morphological switch into microscale aggregates. Significantly higher remaining collagen membrane area and less inflammatory cell infiltration are observed in responsive nanoparticles-treated rats, compared to control groups injected with free dexamethasone and non-responsive nanoparticles. These factors indicate improved therapeutic efficacy in inflammation reduction. These results demonstrate the potential use of enzyme-responsive nanoparticles as targeted delivery vehicles for the treatment of diabetic and other inflammatory wounds.

Addition of Resolvins D1 or E1 to Collagen Membranes Mitigates Their Resorption in Diabetic Rats.

Uncontrolled diabetes is characterized by aberrant inflammatory reactions and increased collagenolysis. We have reported that it accelerates the degradation of implanted collagen membranes (CM), thus compromising their function in regenerative procedures. In recent years, a group of physiological anti-inflammatory agents called specialized pro-resolving lipid mediators (SPMs) have been tested as a treatment for various inflammatory conditions, either systemically or locally, via medical devices. Yet, no study has tested their effect on the fate of the biodegradable material itself. Here, we measured the in vitro release over time of 100 or 800 ng resolvin D1 (RvD1) incorporated into CM discs. In vivo, diabetes was induced in rats with streptozotocin, while buffer-injected (normoglycemic) rats served as controls. Resolvins (100 or 800 ng of RvD1 or RvE1) were added to biotin-labeled CM discs, which were implanted sub-periosteally over the calvaria of rats. Membrane thickness, density, and uniformity were determined by quantitative histology after 3 weeks. In vitro, significant amounts of RvD1 were released over 1-8 days, depending on the amount loaded. In vivo, CMs from diabetic animals were thinner, more porous, and more variable in thickness and density. The addition of RvD1 or RvE1 improved their regularity, increased their density, and reduced their invasion by the host tissue significantly. We conclude that addition of resolvins to biodegradable medical devices can protect them from excessive degradation in systemic conditions characterized by high degree of collagenolysis.

The Cardiovascular Reserve Index-A Noninvasive Clinical Insight Into Heat Intolerance.

OBJECTIVE: To noninvasively explore the heat intolerance condition during exercise-heat stress by assessing cardiovascular (CV) performance. DESIGN: Prospective study of participants undergoing a standard heat-tolerance test (HTT). SETTING: Institutional study. PARTICIPANTS: Ninety-five young males: 16 heat-intolerant (HI) and 79 heat-tolerant (HT). INTERVENTIONS: Cardiovascular performance during an HTT was estimated by heart rate (HR) and blood pressure measurements. MAIN OUTCOME MEASURES: The sensitivity of the cardiovascular reserve index (CVRI) and the dynamic heart rate reserve (dHRR) index to predict heat intolerance was compared. RESULTS: A significant difference in the CV reserve during exercise-heat stress was exhibited between the HI and the HT groups. Starting at a similar level, the reduction in the CV reserve at HTT endpoint was much greater in the HI than the HT individuals (P < 0.0001), as depicted by both the CVRI and the dHRR. This result indicates a greater utilization of the CV reserve by HI individuals. The CVRI is likely to be better predictor of heat intolerance than the dHRR because the partial area under the curve in the high sensitivity (>90%) region of its receiver operating characteristic curve is higher (93.2 vs 76.8). CONCLUSIONS: More than being a predictor, the CVRI may provide a new clinical insight into heat intolerance because it noninvasively characterizes the efficiency of an individual's thermoregulatory mechanism and hints that an impaired CV reserve might underlie heat intolerance. The CVRI provides a noninvasive measurement of thermoregulation, which has been long awaited to enable on-field studies and dynamic monitoring of heat-exposed task forces.

Characterization and possible function of an enigmatic reflector in the eye of the shrimp Litopenaeus vannamei.

Reflective assemblies of high refractive index organic crystals are used to produce striking optical phenomena in organisms based on light reflection and scattering. In aquatic animals, organic crystal-based reflectors are used both for image-formation and to increase photon capture. Here we report the characterization of a poorly-documented reflector in the eye of the shrimp L. vannamei lying 150 µm below the retina, which we term the proximal reflective layer (PR-layer). The PR-layer is made from a dense but disordered array of polycrystalline isoxanthopterin nanoparticles, similar to those recently reported in the tapetum of the same animal. Each spherical nanoparticle is composed of numerous isoxanthopterin single crystal plates arranged in concentric lamellae around an aqueous core. The highly reflective plate faces of the crystals are all aligned tangentially to the particle surface with the optical axes projecting radially outwards, forming a birefringent spherulite which efficiently scatters light. The nanoparticle assemblies form a broadband reflective sheath around the screening pigments of the eye, resulting in pronounced eye-shine when the animal is viewed from a dorsal-posterior direction, rendering the eye pigments inconspicuous. We assess possible functions of the PR-layer and conclude that it likely functions as a camouflage device to conceal the dark eye pigments in an otherwise largely transparent animal.

A highly reflective biogenic photonic material from core-shell birefringent nanoparticles.

Spectacular natural optical phenomena are produced by highly reflective assemblies of organic crystals. Here we show how the tapetum reflector in a shrimp eye is constructed from arrays of spherical isoxanthopterin nanoparticles and relate the particle properties to their optical function. The nanoparticles are composed of single-crystal isoxanthopterin nanoplates arranged in concentric lamellae around a hollow core. The spherulitic birefringence of the nanoparticles, which originates from the radial alignment of the plates, results in a significant enhancement of the back-scattering. This enables the organism to maximize the reflectivity of the ultrathin tapetum, which functions to increase the eye's sensitivity and preserve visual acuity. The particle size, core/shell ratio and packing are also controlled to optimize the intensity and spectral properties of the tapetum back-scattering. This system offers inspiration for the design of photonic crystals constructed from spherically symmetric birefringent particles for use in ultrathin reflectors and as non-iridescent pigments.

VICKZ1 enhances tumor progression and metastasis in lung adenocarcinomas in mice.

The VICKZ (Igf2bp) family of RNA binding proteins regulate RNA function at many levels, including intracellular RNA localization, RNA stability, and translational control. One or more of the three VICKZ paralogs are upregulated in many different types of cancers. Here, we show how VICKZ1 enhances, and dominant negative VICKZ1 inhibits, cell migration, growth in soft agar, and wound healing in a mouse lung adenocarcinoma cell line containing a constitutively active, mutant Kras. Similarly, modulation of VICKZ1 activity promotes or inhibits metastases upon implantation of these cells into syngeneic mice. To test these effects in a genetic model system, we generated a mouse with an inducible VICKZ1 transgene and found that isolated overexpression of VICKZ1 in the lungs had no noticeable effect on morphology. Although directed overexpression of mutant Kras in the lungs led to the formation of small adenomas, concurrent overexpression of VICKZ1 remarkably accelerated tumor growth and formation of pulmonary adenocarcinomas. VICKZ1-containing ribonucleoprotein complexes are highly enriched in Kras mRNA in lung adenocarcinoma cells, and Kras signaling is enhanced in these cells by overexpression of VICKZ1. Analysis of lung carcinoma patients reveals that elevated VICKZ1 expression correlates with lower overall survival; this reduction is dramatically enhanced in those patients bearing a mutant Kras gene. Our study reveals that RNA binding proteins of the VICKZ family can synergize with Kras to influence signaling and oncogenic activity.

The validity of the heat tolerance test in prediction of recurrent exertional heat illness events.

OBJECTIVES: Heat-tolerance-testing (HTT) protocol is used as a screening test for secondary prevention of exertional heat illness (EHI) in the military. Subjects whose test results are positive (heat-intolerant, HI) are presumed to be at higher risk of repeated EHI events than heat-tolerant subjects (HT) and are therefore prevented from return to combat duty, but may return to unsupervised recreational activity. Our aim was to determine, whether HTT results predict the risk of repeated episodes of exertional heat illness (EHI). DESIGN: Retrospective cohort. METHODS: One-hundred-forty-five subjects (110 HT, 35 HI) who were diagnosed with an EHI event by a physician and underwent HTT during 2008-2015 were contacted and asked about recurrence of EHI. Incidence of recurrent events was reported as number of cases per 1000 person-years. Ratio of events among HI and HT individuals was presented as rate ratio (RR) and its 95% confidence interval. RESULTS: Of the 145 patients, six (4.1%) had experienced recurrent EHI events (10.63 per 1000PY): four HI subjects (11.4%, 26.6 per 1000PY) and two HT (1.8%, 4.8 per 1000PY) (RR=5.504, CI 95%=1.01-30, p=0.027). Only one of the six recurrent events was a heat stroke (HT individual), other five were heat exhaustions. Sensitivity, specificity and diagnostic accuracy of HTT were 66.7%, 77.7% and 77.2%, respectively. CONCLUSIONS: The risk of EHI recurrence is measurable and can be discussed with patients before they return to sports. A referral to HTT can be considered, as negative HTT result is associated with substantial and significant EHI risk reduction.

A pathway of targeted autophagy is induced by DNA damage in budding yeast.

Autophagy plays a central role in the DNA damage response (DDR) by controlling the levels of various DNA repair and checkpoint proteins; however, how the DDR communicates with the autophagy pathway remains unknown. Using budding yeast, we demonstrate that global genotoxic damage or even a single unrepaired double-strand break (DSB) initiates a previously undescribed and selective pathway of autophagy that we term genotoxin-induced targeted autophagy (GTA). GTA requires the action primarily of Mec1/ATR and Rad53/CHEK2 checkpoint kinases, in part via transcriptional up-regulation of central autophagy proteins. GTA is distinct from starvation-induced autophagy. GTA requires Atg11, a central component of the selective autophagy machinery, but is different from previously described autophagy pathways. By screening a collection of ∼6,000 yeast mutants, we identified genes that control GTA but do not significantly affect rapamycin-induced autophagy. Overall, our findings establish a pathway of autophagy specific to the DNA damage response.