The rise of plasma ACTH induced by ether is mediated through neural pathways entering the medial basal hypothalamus

The effect of ether stress on the release of immunoreactive ACTH was studied in rats with an antero-lateral cut around the medial basal hypothalamus. Ether failed to raise the plasma ACTH level of rats in which an antero-lateral hypothalamic cut and adrenalectomy had been performed 7 to 8 days previously. Plasma ACTH was also unchanged in rats exposed to ether 2 h after an antero-lateral cut. These data suggest that intact neural pathways entering the medial basal hypothalamus from the antero-lateral direction are necessary for the ACTH releasing action of ether stress.     

Soluble polysaccharide and biomass of red microalga Porphyridium sp. alter intestinal morphology and reduce serum cholesterol in rats

The present study investigated the effects of the red microalga Porphyridium sp. on gastrointestinal physiology and lipid metabolism in male Sprague-Dawley rats. Diets containing dietary fibre from pelleted red microalgal cells (biomass) or their sulfated polysaccharide, pectin or cellulose (control) were fed to rats for a period of 30 d. All three fibre-supplemented diets increased the length of both the small intestine and colon, with a significantly greater effect in rats fed the algal polysaccharide. The polysaccharide also increased mucosa and muscularis cross-sectional area of the jejunum, and caused hypertrophy in the muscularis layer. The algal biomass significantly lowered gastrointestinal transit time by 44% in comparison with the control rats. Serum and mucosal cholecystokinin levels were lower in rats on the pectin and polysaccharide diets, while cholecystokinin levels in rats fed algal biomass were not different from those in the control animals. In comparison with the control diet, all the experimental diets significantly lowered serum cholesterol levels (22-29%). Feeding of non-fermentable algal polysaccharide or biomass significantly increased faecal weight and bile acid excretion compared with pectin-fed or control rats. The algal polysaccharide and biomass were thus shown to be potent hypocholesterolaemic agents active at low concentrations in the diet. Both metabolic and morphological changes were observed following consumption of algae, suggesting several possible mechanisms by which the alga affects lipid metabolism. The results presented in the present study encourage the use of red microalga as a functional food.     

Risk of congenital malformations associated with proximity to hazardous waste sites.

Concern about environmental pollutants has increased; however, it remains unclear whether chronic exposures to toxic chemicals in the environment occur at doses sufficient to produce adverse health effects in humans. To date, community studies have not adequately addressed this question. In this study, the authors linked two existing data bases of the New York State Department of Health to evaluate the relation between congenital malformations and residential proximity to hazardous waste sites in New York State. A total of 9,313 newborns with congenital malformations and 17,802 healthy controls living in proximity to 590 hazardous waste sites in 1983 and 1984 were evaluated. After the authors controlled for several possible confounding factors, results indicated that maternal proximity to hazardous waste sites may carry a small additional risk of bearing children with congenital malformations (odds ratio (OR) = 1.12, 95% confidence interval (Cl) 1.06-1.18). Higher malformation rates were associated with both a higher exposure risk (no exposure risk: OR = 1.00; low exposure risk: OR = 1.09, 95% Cl 1.04-1.15; high exposure risk: OR = 1.63, 95% Cl 1.34-1.99) and documentation of off-site chemical leaks (not exposed: OR = 1.00; exposed, but no leaks at site: OR = 1.08, 95% Cl 1.02-1.15; exposed, and leaks found at site: OR = 1.17, 95% Cl 1.08-1.27). The increased rates detected may be important in terms of their public health implications. Further research is necessary to strengthen causal inferences regarding the teratogenicity, of waste site exposure.     

Concentration gradients in evaporating binary droplets probed by spatially resolved Raman and NMR spectroscopy

Understanding the evaporation process of binary sessile droplets is essential for optimizing various technical processes, such as inkjet printing or heat transfer. Liquid mixtures whose evaporation and wetting properties may differ significantly from those of pure liquids are particularly interesting. Concentration gradients may occur in these binary droplets. The challenge is to measure concentration gradients without affecting the evaporation process. Here, spectroscopic methods with spatial resolution can discriminate between the components of a liquid mixture. We show that confocal Raman microscopy and spatially resolved NMR spectroscopy can be used as complementary methods to measure concentration gradients in evaporating 1-butanol/1-hexanol droplets on a hydrophobic surface. Deuterating one of the liquids allows analysis of the local composition through the comparison of the intensities of the C–H and C–D stretching bands in Raman spectra. Thus, a concentration gradient in the evaporating droplet was established. Spatially resolved NMR spectroscopy revealed the composition at different positions of a droplet evaporating in the NMR tube, an environment in which air exchange is less pronounced. While not being perfectly comparable, both methods—confocal Raman and spatially resolved NMR experiments—show the presence of a vertical concentration gradient as 1-butanol/1-hexanol droplets evaporate.

Evaporating droplets occur in various contexts such as inkjet printing (1, 2), heat transfer, or daily phenomena such as drying coffee stains (3, 4). In many applications, such as painting (5), cleaning, gluing, or printing (6), where liquid mixtures are used, the evaporation of a droplet is a complex process because the concentration profile within the droplet varies over time. To improve the controllability and predictability of the technical processes, it is essential to characterize the transport phenomena during the drying process. The measurement of the droplet composition is a crucial element and has to be carried out with sufficient spatial and temporal resolution. In particular, spectroscopic methods are promising tools for contactless concentration measurements of liquid mixtures.The evaporation of a droplet is governed by physical properties such as surface tension (7), density (8–10), vapor pressure (11), and boiling temperature. Additionally, concentration gradients can evolve in liquid mixtures (12). These gradients are driven by thermal gradients due to the enthalpy of evaporation (droplet cooling) or on heated surfaces, by surface tension gradients induced by preferential evaporation of one component or by density gradients for droplets composed of liquids with different densities like water and glycerol (13). The evaporation rates of the components can vary over the droplet surface. For sessile droplets with contact angles smaller than 90°, for example, the evaporation rates are higher at the three-phase contact line (14). These thermal or surface tension gradients can induce flow inside the droplet called Marangoni flow. This flow leads to concentration gradients across the droplet (7–10). The direction of the gradient depends on the density and surface tension. A direct application of this principle is, for instance, Marangoni cleaning in semiconductor technology (15).The investigation of the composition of sessile drops on the microliter scale, as they occur in inkjet printing or other technical processes, poses a challenge because the typical length scales of interest are smaller than the capillary length. In bulk samples, the composition can be examined in a straightforward manner with chromatographic methods such as gas chromatography and high-performance liquid chromatography or spectroscopic methods such as NMR spectroscopy, infrared spectroscopy, and Raman spectroscopy. However, for the investigation of sessile droplets, a high spatial and temporal resolution is required. For this purpose, confocal Raman spectroscopy and spatially resolved NMR spectroscopy are powerful tools. For both techniques, concentration determination is straightforward if at least two signals of the components of interest are baseline-separated. NMR is intrinsically calibration-free, whereas Raman spectroscopy requires calibration through reference experiments (16–18). Both approaches allow the quantification of concentration gradients in sessile droplets, as is shown here.In Raman microscopy, good spatial resolution can be achieved in a confocal setup. The components of mixtures can be distinguished via specific vibrations for different functional groups or through a careful analysis of the Raman signals in the fingerprint region (<1,500 cm⁻¹). For example, binary mixtures of ethanol and water can be characterized in a straightforward manner (17). If, however, both liquids have a similar chemical structure, the discrimination of the components might be hampered by signal overlap in the C–H stretching region (2,800 to 3,000 cm⁻¹); e.g., in such cases, Raman signals in the fingerprint region (<1,500 cm⁻¹) might be used for the identification of the species. However, these signals often provide a poor signal-to-noise ratio, which makes large integration times necessary. Thus, the image rate or resolution is so low that even slow diffusion processes are hardly resolved. Here, Raman stable isotope probing (SIP), which has been developed to monitor metabolic processes in microbiology, offers a solution (19). The basic idea of Raman SIP is to replace the proton in the C–H with deuterium in one of the mixture components such that the C–D stretching region occurs at roughly 1/2 times the C–H stretching and falls into a region with very weak or even without signals from the protonated liquid component. Thus, the concentration in a binary mixture can be calculated in a straightforward manner from the ratio of the integrated Raman intensities ICD/ICH of the respective stretching vibrations.Compared to Raman microscopy, where localization is achieved by scanning the focal point across the region of interest, in NMR experiments localization is achieved by using magnetic field gradients. Usually, one avoids phase boundaries (especially liquid–gas interfaces) in NMR experiments because they disturb the magnetic field homogeneity and reduce the spectral quality in terms of line shape and baseline separation of the resonances. Nevertheless, it has been shown that MRI can be used to characterize freezing water droplets (20), the infiltration of water into asphalts (21), and the evaporation of sessile droplets from porous surfaces (22–24). Additionally, NMR can be used to quantify the composition of binary droplets during evaporation (25).Thus, the use of both complementary approaches to characterize evaporating binary droplets may be beneficial. In this article, we discuss the capabilities of Raman SIP and NMR techniques to analyze the evolution of the composition of an evaporating sessile binary droplet. As a model system, a binary mixture of 1-butanol and 1-hexanol was used. This mixture shows a low volatility such that the evaporation process can be captured with both Raman and NMR spectroscopies. With Raman spectroscopy, it was possible to observe concentration gradients of 1-butan-d₉-ol over the height of the droplet during evaporation. NMR techniques were examined in terms of the capability to observe the evaporation of 1-butanol and yield time-dependent droplet composition with spatially resolved ¹H-NMR spectra. Furthermore, the contours of the evaporating droplets were tracked by optical measurements to characterize the time-dependent changes in the droplet dimensions. Flows induced by the concentration gradients were confirmed by astigmatic particle tracking velocimetry.     

Suramin induces and enhances apoptosis in a model of hyperoxia-induced oligodendrocyte injury

Recent evidence suggests oxygen as a powerful trigger for cell death in the immature white matter, leading to periventricular leukomalacia (PVL) as a cause of adverse neurological outcome in survivors of preterm birth. This oligodendrocyte (OL) death is associated with oxidative stress, upregulation of apoptotic signaling factors (i.e., Fas, caspase-3) and decreased amounts of neurotrophins. In search of neuroprotective strategies we investigated whether the polysulfonated urea derivative suramin, recently identified as a potent inhibitor of Fas signaling, affords neuroprotection in an in vitro model of hyperoxia-induced injury to immature oligodendrocytes. Immature OLs (OLN-93) were subjected to 80% hyperoxia (48 h) in the presence or absence of suramin (0, 30, 60, 120 microM). Cell death was assessed by flow cytometry (Annexin V, caspase-3 activity assay) and immunohistochemistry for activated caspase-3. Immunoblotting for the death receptor Fas, cleaved caspase-8 and the phosphorylated isoform of the serine-threonin kinase Akt (pAkt) was performed. Suramin lead to OL apoptosis and potentiated hyperoxia-induced injury in a dose-dependent manner. Immunoblotting revealed increased Fas and caspase-8 expression by suramin treatment. This effect was significantly enhanced when suramin was combined with hyperoxia. Furthermore, pAkt levels decreased following suramin exposure, indicating interference with neurotrophin-dependent growth factor signaling. These data indicate that suramin causes apoptotic cell death and aggravates hyperoxia-induced cell death in immature OLs. Its mechanism of action includes an increase of previously described hyperoxia-induced expression of pro-apoptotic factors and deprivation of growth factor dependent signaling components.     

Ankle fracture classification using deep learning: automating detailed AO Foundation/Orthopedic Trauma Association (AO/OTA) 2018 malleolar fracture identification reaches a high degree of correct classification

Background and purpose — Classification of ankle fractures is crucial for guiding treatment but advanced classifications such as the AO Foundation/Orthopedic Trauma Association (AO/OTA) are often too complex for human observers to learn and use. We have therefore investigated whether an automated algorithm that uses deep learning can learn to classify radiographs according to the new AO/OTA 2018 standards.Method — We trained a neural network based on the ResNet architecture on 4,941 radiographic ankle examinations. All images were classified according to the AO/OTA 2018 classification. A senior orthopedic surgeon (MG) then re-evaluated all images with fractures. We evaluated the network against a test set of 400 patients reviewed by 2 expert observers (MG, AS) independently.Results — In the training dataset, about half of the examinations contained fractures. The majority of the fractures were malleolar, of which the type B injuries represented almost 60% of the cases. Average area under the area under the receiver operating characteristic curve (AUC) was 0.90 (95% CI 0.82–0.94) for correctly classifying AO/OTA class where the most common major fractures, the malleolar type B fractures, reached an AUC of 0.93 (CI 0.90–0.95). The poorest performing type was malleolar A fractures, which included avulsions of the fibular tip.Interpretation — We found that a neural network could attain the required performance to aid with a detailed ankle fracture classification. This approach could be scaled up to other body parts. As the type of fracture is an important part of orthopedic decision-making, this is an important step toward computer-assisted decision-making.

Ankle fractures are recognized among the most common fractures, with peak incidence between 15 and 29 years (67 per 100,000 person-years) and elderly women ≥ 60 years (174 per 100,000 person-years) (Westerman and Porter 2007, Thur et al. 2012). Efforts to classify ankle fractures in clinically relevant entities have a long history, ending in 3 classic systems, i.e., the Lauge-Hansen (Hansen 1942), Danis–Weber, and the AO/OTA classifications (Association Committee for Coding and Classification 1996; Budny and Young 2008), where the Danis–Weber with its A, B, and C classes is probably the most used in everyday practice.The most recent update for the AO/OTA classification system was published in 2018 (Meinberg et al. 2018). The AO/OTA system contains classifications for the entire body. The ankle is divided into (1) malleolar, (2) distal tibia, and (3) fibular fractures. For malleolar fractures, the subcategories correspond to the Danis–Weber ABC classification (Hughes et al. 1979) with the addition of a suffix of 2 digits (range 1–3), e.g., the common intra-syndesmotic B-injury without widening of the mortise corresponds to the B1.1 class. The numbers correspond roughly to the severity of each fracture.The complexity of this classification makes it difficult to learn and apply, limiting inter-observer reliability and reproducibility (Fonseca et al. 2017). This has hindered its use in an everyday clinical setting, suggesting the need for better aid during the classification.During recent years, the resurgence of neural networks, a form of artificial intelligence (AI), has proven highly successful for image classification. In some medical image classification applications neural networks attain (Olczak et al. 2017, Kim and MacKinnon 2018, Gan et al. 2019), and surpass, human expert performance (Esteva et al. 2017, Lee et al. 2017, Chung et al. 2018, Urakawa et al. 2019). Machine learning and neural networks are also becoming more commonplace research tools in orthopedics. They hold great potential, as the diagnostic underpinning and intervention decision relies heavily on medical imaging (Cabitza et al. 2018). The strength of these learning algorithms is their ability to review a vast number of examinations and examples, and the speed and consistency with which they can review each examination and at the same time remember thousands of categories without issue.We therefore hypothesized that a neural network can learn to classify ankle fractures according to the AO/OTA 2018 classification from radiographs.     

Breaking News in Spinal Cord Injury Research FDA Approved Phase I Clinical Trial of Human, Autologous Schwann Cell Transplantation in Patients with Spinal Cord Injuries

##正##On July 31, 2012, The Miami Project to Cure Paralysis at the University of Miami Miller School of Medicine received permission from the Food and Drug Administration(FDA) to begin a Phase I clinical trial to evaluate the safety of transplanting human autologous Schwann cells to treat patients with spinal cord injuries. This is the only FDA-approved cell therapy-based clinical trial for sub-acute spinal cord injury in the United States.     

Safety and efficacy considerations due to misuse of extended-release formulations of stimulant medications

Amphetamine or methylphenidate are first-line options for treating attention-deficit/hyperactivity disorder (ADHD). Deviations from suggested routes of administration such as crushing, chewing, intravenous administration, or snorting stimulant medication may alter the release rate, absorption, and bioavailability of the active drug. Additionally, the pharmacokinetic (PK) profiles of extended-release formulations of certain medications (e.g., some opioids) are known to be dangerously altered when consumed with alcohol; specifically, there is an unintended, rapid release of a significant portion of the drug (dose dumping). In vitro data suggest some extended-release stimulants dose dump in the presence of alcohol, which is of concern because the ADHD patient population is at risk for alcohol abuse. This article reviews the available scientific literature concerning modifications to routes of administration that may alter PK properties of stimulant-based medication for treating ADHD. These modifications are of clinical interest because they may pose safety hazards and affect efficacy. Electronic databases were searched for appropriate studies using relevant search terms. The misuse and abuse potential for stimulants and the efforts to prevent misuse are also discussed. Future research should be focused on determining the PK ramifications of stimulant misuse, along with developing new formulations with abuse-deterrent properties.