The artificial pancreas: two alternative approaches to achieve a fully closed-loop system with optimal glucose control.

INTRODUCTION: Diabetes mellitus type 1 is a chronic disease that implies mandatory external insulin delivery. The patients must monitor their blood glucose levels and administer appropriate insulin boluses to keep their blood glucose within the desired range. It requires a lot of time and endeavour, and many patients struggle with suboptimal glucose control despite all their efforts. MATERIALS AND METHODS: This narrative review combines existing knowledge with new discoveries from animal experiments. DISCUSSION: In the last decade, artificial pancreas (AP) devices have been developed to improve glucose control and relieve patients of the constant burden of managing their disease. However, a feasible and fully automated AP is yet to be developed. The main challenges preventing the development of a true, subcutaneous (SC) AP system are the slow dynamics of SC glucose sensing and particularly the delay in effect on glucose levels after SC insulin infusions. We have previously published studies on using the intraperitoneal space for an AP; however, we further propose a novel and potentially disruptive way to utilize the vasodilative properties of glucagon in SC AP systems. CONCLUSION: This narrative review presents two lesser-explored viable solutions for AP systems and discusses the potential for improvement toward a fully automated system: A) using the intraperitoneal approach for more rapid insulin absorption, and B) besides using glucagon to treat and prevent hypoglycemia, also administering micro-boluses of glucagon to increase the local SC blood flow, thereby accelerating SC insulin absorption and SC glucose sensor site dynamics.

In situ observations show vertical community structure of pelagic fauna in the eastern tropical North Atlantic off Cape Verde.

Distribution patterns of fragile gelatinous fauna in the open ocean remain scarcely documented. Using epi-and mesopelagic video transects in the eastern tropical North Atlantic, which features a mild but intensifying midwater oxygen minimum zone (OMZ), we established one of the first regional observations of diversity and abundance of large gelatinous zooplankton. We quantified the day and night vertical distribution of 46 taxa in relation to environmental conditions. While distribution may be driven by multiple factors, abundance peaks of individual taxa were observed in the OMZ core, both above and below the OMZ, only above, or only below the OMZ whereas some taxa did not have an obvious distribution pattern. In the eastern eropical North Atlantic, OMZ expansion in the course of global climate change may detrimentally impact taxa that avoid low oxygen concentrations (Beroe, doliolids), but favour taxa that occur in the OMZ (Lilyopsis, phaeodarians, Cydippida, Colobonema, Haliscera conica and Halitrephes) as their habitat volume might increase. While future efforts need to focus on physiology and taxonomy of pelagic fauna in the study region, our study presents biodiversity and distribution data for the regional epi- and mesopelagic zones of Cape Verde providing a regional baseline to monitor how climate change may impact the largest habitat on the planet, the deep pelagic realm.

[Hypothalamic intravascular B-cell lymphoma in an immunocompetent patient]. / Linfoma B intravascular hipotalamico en una paciente inmunocompetente.

TITLE: Linfoma B intravascular hipotalamico en una paciente inmunocompetente.

Complementary cathodoluminescence lifetime imaging configurations in a scanning electron microscope.

Cathodoluminescence (CL) spectroscopy provides a powerful way to characterize optical properties of materials with deep-subwavelength spatial resolution. While CL imaging to obtain optical spectra is a well-developed technology, imaging CL lifetimes with nanoscale resolution has only been explored in a few studies. In this paper we compare three different time-resolved CL techniques and compare their characteristics. Two configurations are based on the acquisition of CL decay traces using a pulsed electron beam that is generated either with an ultra-fast beam blanker, which is placed in the electron column, or by photoemission from a laser-driven electron cathode. The third configuration uses measurements of the autocorrelation function g(2) of the CL signal using either a continuous or a pulsed electron beam. The three techniques are compared in terms of complexity of implementation, spatial and temporal resolution, and measurement accuracy as a function of electron dose. A single sample of InGaN/GaN quantum wells is investigated to enable a direct comparison of lifetime measurement characteristics of the three techniques. The g(2)-based method provides decay measurements at the best spatial resolution, as it leaves the electron column configuration unaffected. The pulsed-beam methods provide better detail on the temporal excitation and decay dynamics. The ultra-fast blanker configuration delivers electron pulses as short as 30 ps at 5 keV and 250 ps at 30 keV. The repetition rate can be chosen arbitrarily up to 80 MHz and requires a conjugate plane geometry in the electron column that reduces the spatial resolution in our microscope. The photoemission configuration, pumped with 250 fs 257 nm pulses at a repetition rate from 10 kHz to 25 MHz, allows creation of electron pulses down to a few ps, with some loss in spatial resolution.

Disturbances of diurnal phase markers, behavior, and clock genes in a rat model of depression; modulatory effects of agomelatine treatment.

Major depressive disorder (MDD) is a growing problem worldwide. Though, the etiology remains unresolved, circadian rhythm disturbances are frequently observed in MDD and thus is speculated to play a key role herein. The present study focuses on circadian rhythm disturbances in the chronic mild stress (CMS) animal model of depression and examined whether the atypical antidepressant, agomelatine, which is mediating its action via melatonergic and serotonergic receptors, is capable of resynchronizing the perturbed rhythm. Melatonin is often used as a marker of the circadian phase, but the functional and behavioral output is dictated on a cellular level by the molecular clock, driven by the clock genes. We applied in situ hybridization histochemistry to measure the expression levels of the core clock genes, period (Per) 1 and 2 and bone and muscle ARNT-like protein 1 (Bmal1), in multiple brain regions believed to be implicated in depression. Agomelatine showed an antidepressant-like effect in the sucrose consumption test and an anxiolytic-like profile in the elevated zero maze. We found that CMS increased nighttime melatonin release in rats and that agomelatine attenuated this effect. Stress was shown to have a time and region-specific effect on clock gene expression in the brain. Treatment with agomelatine failed to normalize clock gene expression, and the observed modifying effect on gene expression did not associate with the antidepressant-like effect. This suggests that the antidepressant actions of agomelatine are mainly independent of circadian rhythm synchronization and, in this regard, not superior to traditional antidepressants tested in our model.

EDC IMPACT: Reduced sperm counts in rats exposed to human relevant mixtures of endocrine disrupters.

Human semen quality is declining in many parts of the world, but the causes are ill defined. In rodents, impaired sperm production can be seen with early life exposure to certain endocrine-disrupting chemicals, but the effects of combined exposures are not properly investigated. In this study, we examined the effects of early exposure to the painkiller paracetamol and mixtures of human relevant endocrine-disrupting chemicals in rats. One mixture contained four estrogenic compounds; another contained eight anti-androgenic environmental chemicals and a third mixture contained estrogens, anti-androgens and paracetamol. All exposures were administered by oral gavage to time-mated Wistar dams rats (n = 16-20) throughout gestation and lactation. In the postnatal period, testicular histology was affected by the total mixture, and at the end of weaning, male testis weights were significantly increased by paracetamol and the high doses of the total and the anti-androgenic mixture, compared to controls. In all dose groups, epididymal sperm counts were reduced several months after end of exposure, i.e. at 10 months of age. Interestingly, the same pattern of effects was seen for paracetamol as for mixtures with diverse modes of action. Reduced sperm count was seen at a dose level reflecting human therapeutic exposure to paracetamol. Environmental chemical mixtures affected sperm count at the lowest mixture dose indicating an insufficient margin of safety for the most exposed humans. This causes concern for exposure of pregnant women to paracetamol as well as environmental endocrine disrupters.

Understanding GaN/InGaN core-shell growth towards high quality factor whispering gallery modes from non-polar InGaN quantum wells on GaN rods.

GaN microrods are used as a basis for subsequent InGaN quantum well (QW) and quantum dot deposition by metal-organic vapor phase epitaxy. The coverage of the shell along the sidewall of rods is dependent on the rod growth time and a complete coverage is obtained for shorter rod growth times. Transmission electron microscopy measurements are performed to reveal the structural properties of the InGaN layer on the sidewall facet and on the top facet. The presence of layers in the microrod and on the microrod surface will be discussed with respect to GaN and InGaN growth. A detailed model will be presented explaining the formation of multiple SiN layers and the partial and full coverage of the shell around the core. Cathodoluminescence measurements are performed to analyze the InGaN emission properties along the microrod and to study the microresonator properties of such hexagonal core-shell structures. High quality factor whispering gallery modes with [Formula: see text] are reported for the first time in a GaN microrod/InGaN non-polar QW core-shell geometry. The GaN/InGaN core-shell microrods are expected to be promising building blocks for low-threshold laser diodes and ultra-sensitive optical sensors.

[Primary lymphoma of the anterior pituitary in an immunocompetent patient]. / Linfoma primario de adenohipofisis en una paciente inmunocompetente.

TITLE: Linfoma primario de adenohipofisis en una paciente inmunocompetente.

Altered levels of soluble CD18 may associate immune mechanisms with outcome in sepsis.

The pathogenesis of sepsis involves a dual inflammatory response, with a hyperinflammatory phase followed by, or in combination with, a hypoinflammatory phase. The adhesion molecules lymphocyte function-associated antigen (LFA-1) (CD11a/CD18) and macrophage-1 (Mac-1) (CD11b/CD18) support leucocyte adhesion to intercellular adhesion molecules and phagocytosis through complement opsonization, both processes relevant to the immune response during sepsis. Here, we investigate the role of soluble (s)CD18 in sepsis with emphasis on sCD18 as a mechanistic biomarker of immune reactions and outcome of sepsis. sCD18 levels were measured in 15 septic and 15 critically ill non-septic patients. Fifteen healthy volunteers served as controls. CD18 shedding from human mononuclear cells was increased in vitro by several proinflammatory mediators relevant in sepsis. sCD18 inhibited cell adhesion to the complement fragment iC3b, which is a ligand for CD11b/CD18, also known as Mac-1 or complement receptor 3. Serum sCD18 levels in sepsis non-survivors displayed two distinct peaks permitting a partitioning into two groups, namely sCD18 'high' and sCD18 'low', with median levels of sCD18 at 2158 mU/ml [interquartile range (IQR) 2093-2811 mU/ml] and 488 mU/ml (IQR 360-617 mU/ml), respectively, at the day of intensive care unit admission. Serum sCD18 levels partitioned sepsis non-survivors into one group of 'high' sCD18 and low CRP and another group with 'low' sCD18 and high C-reactive protein. Together with the mechanistic data generated in vitro, we suggest the partitioning in sCD18 to reflect a compensatory anti-inflammatory response syndrome and hyperinflammation, respectively, manifested as part of sepsis.

Significant performance enhancement of InGaN/GaN nanorod LEDs with multi-layer graphene transparent electrodes by alumina surface passivation.

Nanotextured surfaces provide an ideal platform for efficiently capturing and emitting light. However, the increased surface area in combination with surface defects induced by nanostructuring e.g. using reactive ion etching (RIE) negatively affects the device's active region and, thus, drastically decreases device performance. In this work, the influence of structural defects and surface states on the optical and electrical performance of InGaN/GaN nanorod (NR) light emitting diodes (LEDs) fabricated by top-down RIE of c-plane GaN with InGaN quantum wells was investigated. After proper surface treatment a significantly improved device performance could be shown. Therefore, wet chemical removal of damaged material in KOH solution followed by atomic layer deposition of only 10 [Formula: see text] alumina as wide bandgap oxide for passivation were successfully applied. Raman spectroscopy revealed that the initially compressively strained InGaN/GaN LED layer stack turned into a virtually completely relaxed GaN and partially relaxed InGaN combination after RIE etching of NRs. Time-correlated single photon counting provides evidence that both treatments-chemical etching and alumina deposition-reduce the number of pathways for non-radiative recombination. Steady-state photoluminescence revealed that the luminescent performance of the NR LEDs is increased by about 50% after KOH and 80% after additional alumina passivation. Finally, complete NR LED devices with a suspended graphene contact were fabricated, for which the effectiveness of the alumina passivation was successfully demonstrated by electroluminescence measurements.

Low-dose developmental exposure to bisphenol A alters the femoral bone geometry in wistar rats.

BACKGROUND: Bisphenol A (BPA) is a chemical produced in large volumes for use in manufacturing of consumer products and industrial applications, and an endocrine disruptor known to affect several hormonal systems. Bone produces hormones and is additionally a sensitive hormone target tissue, and is thus potentially sensitive to low doses of endocrine disruptors such as BPA, especially during development. METHODS: 110 pregnant Wistar rats were gavaged with 0; 25 µg; 250 µg; 5000 µg or 50,000 µg BPA/kg bodyweight (bw)/day from gestational day 7 until weaning at postnatal day 22. The three-month-old offspring were sacrificed and right femurs collected for length measurements, geometrical measurements by peripheral quantitative computed tomography (pQCT), as well as for analyses of biomechanical properties using the three-point-bending method. RESULTS: The femur was elongated in female offspring of dams exposed to 25 or 5000 µg BPA/kg bw/day (1.8% and 2.1%, respectively), and increased cortical thickness (4.7%) was observed in male offspring of dams exposed to 25 µg BPA/kg bw/day, compared to controls (p < 0.005). The biomechanical properties of the bone were not significantly altered. CONCLUSIONS: In utero and lactational exposure to the lowest BPA dose used in this study altered femoral geometry in both male and female offspring. This was observed at 25 µg BPA/kg bw/day, a dose lower than the Human Equivalent Dose (HED) applied by EFSA to set a temporary TDI (609 µg BPA/kg bw/day), and far lower than the No-Observed-Adverse-Effect-Level (NOAEL) (5000 µg BPA/kg bw/day) on which the US FDA TDI is based.

Altered Expression Pattern of Clock Genes in a Rat Model of Depression.

BACKGROUND: Abnormalities in circadian rhythms may be causal factors in development of major depressive disorder. The biology underlying a causal relationship between circadian rhythm disturbances and depression is slowly being unraveled. Although there is no direct evidence of dysregulation of clock gene expression in depressive patients, many studies have reported single-nucleotide polymorphisms in clock genes in these patients. METHODS: In the present study we investigated whether a depression-like state in rats is associated with alternations of the diurnal expression of clock genes. The validated chronic mild stress (CMS) animal model of depression was used to investigate rhythmic expression of three clock genes: period genes 1 and 2 (Per1 and Per2) and Bmal1. Brain and liver tissue was collected from 96 animals after 3.5 weeks of CMS (48 control and 48 depression-like rats) at a 4h sampling interval within 24h. We quantified expression of clock genes on brain sections in the prefrontal cortex, nucleus accumbens, pineal gland, suprachiasmatic nucleus, substantia nigra, amygdala, ventral tegmental area, subfields of the hippocampus, and the lateral habenula using in situ hybridization histochemistry. Expression of clock genes in the liver was monitored by real-time quantitative polymerase chain reaction (PCR). RESULTS: We found that the effect of CMS on clock gene expression was selective and region specific. Per1 exhibits a robust diurnal rhythm in most regions of interest, whereas Bmal1 and in particular Per2 were susceptible to CMS. CONCLUSION: The present results suggest that altered expression of investigated clock genes is likely associated with the induction of a depression-like state in the CMS model.

Self-Catalyzed Growth of Vertically Aligned InN Nanorods by Metal-Organic Vapor Phase Epitaxy.

Vertically aligned hexagonal InN nanorods were grown mask-free by conventional metal-organic vapor phase epitaxy without any foreign catalyst. The In droplets on top of the nanorods indicate a self-catalytic vapor-liquid-solid growth mode. A systematic study on important growth parameters has been carried out for the optimization of nanorod morphology. The nanorod N-polarity, induced by high temperature nitridation of the sapphire substrate, is necessary to achieve vertical growth. Hydrogen, usually inapplicable during InN growth due to formation of metallic indium, and silane are needed to enhance the aspect ratio and to reduce parasitic deposition beside the nanorods on the sapphire surface. The results reveal many similarities between InN and GaN nanorod growth showing that the process despite the large difference in growth temperature is similar. Transmission electron microscopy, spatially resolved energy-dispersive X-ray spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and Raman spectroscopy have been performed to analyze the structural properties. Spatially resolved cathodoluminescence investigations are carried out to verify the optical activity of the InN nanorods. The InN nanorods are expected to be the material of choice for high-efficiency hot carrier solar cells.

Low-dose effect of developmental bisphenol A exposure on sperm count and behaviour in rats.

Bisphenol A is widely used in food contact materials and other products and is detected in human urine and blood. Bisphenol A may affect reproductive and neurological development; however, opinion of the European Food Safety Authority (EFSA) on bisphenol A (EFSA J, 13, 2015 and 3978) concluded that none of the available studies were robust enough to provide a point of departure for setting a tolerable daily intake for bisphenol A. In the present study, pregnant Wistar rats (n = 17-21) were gavaged from gestation day 7 to pup day 22 with bisphenol A doses of 0, 25 µg, 250 µg, 5 mg or 50 mg/kg bw/day. In the offspring, growth, sexual maturation, weights and histopathology of reproductive organs, oestrus cyclicity and sperm counts were assessed. Neurobehavioural development was investigated using a behavioural testing battery including tests for motor activity, sweet preference, anxiety and spatial learning. Decreased sperm count was found at the lowest bisphenol A dose, that is 25 µg/kg/day, but not at the higher doses. Reproductive organ weight and histology were not affected and no behavioural effects were seen in male offspring. In the female offspring, exposure to 25 µg/kg bw/day bisphenol A dose resulted in increased body weight late in life and altered spatial learning in a Morris water maze, indicating masculinization of the brain. Decreased intake of sweetened water was seen in females from the highest bisphenol A dose group, also a possible sign of masculinization. The other investigated endpoints were not significantly affected. In conclusion, the present study using a robust experimental study design, has shown that developmental exposure to 25 µg/kg bw/day bisphenol A can cause adverse effects on fertility (decreased sperm count), neurodevelopment (masculinization of spatial learning in females) and lead to increased female body weight late in life. These results suggest that the new EFSA temporary tolerable daily intake of 4 µg/kg bw/day is not sufficiently protective with regard to endocrine disrupting effects of bisphenol A in humans.

Multiple Endocrine Disrupting Effects in Rats Perinatally Exposed to Butylparaben.

Parabens comprise a group of preservatives commonly added to cosmetics, lotions, and other consumer products. Butylparaben has estrogenic and antiandrogenic properties and is known to reduce sperm counts in rats following perinatal exposure. Whether butylparaben exposure can affect other endocrine sensitive endpoints, however, remains largely unknown. In this study, time-mated Wistar rats (n = 18) were orally exposed to 0, 10, 100, or 500 mg/kg bw/d of butylparaben from gestation day 7 to pup day 22. Several endocrine-sensitive endpoints were adversely affected. In the 2 highest dose groups, the anogenital distance of newborn male and female offspring was significantly reduced, and in prepubertal females, ovary weights were reduced and mammary gland outgrowth was increased. In male offspring, sperm count was significantly reduced at all doses from 10 mg/kg bw/d. Testicular CYP19a1 (aromatase) expression was reduced in prepubertal, but not adult animals exposed to butylparaben. In adult testes, Nr5a1 expression was reduced at all doses, indicating persistent disruption of steroidogenesis. Prostate histology was altered at prepuberty and adult prostate weights were reduced in the high dose group. Thus, butylparaben exerted endocrine disrupting effects on both male and female offspring. The observed adverse developmental effect on sperm count at the lowest dose is highly relevant to risk assessment, as this is the lowest observed adverse effect level in a study on perinatal exposure to butylparaben.

Low-dose effects of bisphenol A on mammary gland development in rats.

Bisphenol A (BPA) is widely used in food contact materials, toys, and other products. Several studies have indicated that effects observed at doses near human exposure levels may not be observed at higher doses. Many studies have shown effects on mammary glands at low doses of BPA, however, because of small number of animals or few doses investigated these data have not been used by EFSA as point of departure for the newly assessed tolerable daily intake (TDI). We performed a study with perinatal exposure to BPA (0, 0.025, 0.25, 5, and 50 mg/kg bw/day) in rats (n = 22 mated/group). One of the aims was to perform a study robust enough to contribute to the risk assessment of BPA and to elucidate possible biphasic dose-response relationships. We investigated mammary gland effects in the offspring at 22, 100, and 400 days of age. Male offspring showed increased mammary outgrowth on pup day (PD) 22 at 0.025 mg/kg BPA, indicating an increased mammary development at this low dose only. Increased prevalence of intraductal hyperplasia was observed in BPA females exposed to 0.25 mg/kg at PD 400, but not at PD 100, and not at higher or lower doses. The present findings support data from the published literature showing that perinatal exposure to BPA can induce increased mammary growth and proliferative lesions in rodents. Our results indicate that low-dose exposure to BPA can affect mammary gland development in male and female rats, although higher doses show a different pattern of effects. The observed intraductal hyperplasia in female rats could be associated with an increased risk for developing hyperplastic lesions, which are parallels to early signs of breast neoplasia in women. Collectively, current knowledge on effects of BPA on mammary gland at low doses indicates that highly exposed humans may not be sufficiently protected.

Disturbed diurnal rhythm of three classical phase markers in the chronic mild stress rat model of depression.

Disturbances of circadian rhythms have been suggested to be a causal factor in the development of major depressive disorder. However, the mechanisms underlying the association between circadian rhythm abnormalities and mood disorders are still unknown. In the current study the association between diurnal pattern of key phase markers (melatonin, corticosterone, and core body temperature) and anhedonic-like behavior was investigated using the highly validated rat chronic mild stress (CMS) model of depression. Phase marker measurements were done after 3.5 weeks of CMS in 48 control rats and 48 anhedonic-like rats at 6 time points within 24h. The results showed that anhedonic-like behavior associates with changes in all three phase markers: an increased dark phase melatonin secretion, an additional peak in corticosterone level in the beginning of the light phase, and hypothermia in the dark phase. The result adds to the validity of the CMS model in general and in particular to be adequate as a model for studying the chronobiology of depressive disorder.