Influence of iterative reconstruction and dose levels on metallic artifact reduction: A phantom study within four CT systems

Purpose

To compare metallic artifact reduction (MAR) algorithms proposed by four vendors according to the delivered dose and iterative level using a phantom study.

Fatty acid alterations in liver and milk of cadmium exposed rats and in brain of their suckling offspring

Fatty acid composition was studied in milk at day 14 and in liver at day 24 after parturition of lactating rats exposed to 0 ppm, 5 ppm or 25 ppm cadmium (Cd) via drinking water for 17 days during lactation, and in the brain of their offspring at day 19 after birth. In the liver phospholipid fraction, 22:5(n-3) was significantly higher, while in the triacylglycerol fraction 22:6(n-3)/20:5(n-3) ratio was significantly lower in the 25 ppm group compared to the controls. Significantly higher proportions of 16:0 and lower proportions of medium-chain fatty acids, 8:0-14:0, were observed in milk of dams in the 25 ppm group, indicating decreased enzymatic activity of thiotransferase II in the mammary gland. Slightly increased levels of 20:3(n-6) were observed in brains of pups in the 25 ppm group compared to control. The results indicate that Cd exposure influences fatty acid metabolism in lactating rats.     

Bioavailability of cadmium from infant diets in newborn rats

Infants are exposed to higher levels of cadmium (Cd) from infant and follow-on formulas than from breast milk. We studied the bioavailability of 109CdCl2 from cows' milk formula, soy formula, wheat/oat/milk formula, wholemeal/milk formula and water in 11-day-old rat pups. The pups received a single oral dose of one diet labelled with 109Cd, 0.1 or 0.3 mg Cd/kg body weight. After 2 or 24 h or 4, 9 or 12 days the fractional retention of 109Cd in the whole body, in segments of rinsed small intestine and in tissue was measured in a gamma counter. Pups receiving 109Cd in water or cows' milk formula had the highest mean whole-body retention. It ranged from 67% of the dose in the water group to 52% in the wholemeal/milk formula group 4 days after dosing. The retention of 109Cd in the rinsed small intestine was significantly higher in the water group and the cows' milk formula group than in the cereal-based formula groups at 24 h and 4 days after dosing. It was still high in all groups on day 9, ranging from 26 to 11%. Initially most of the 109Cd was retained in the duodenum but by day 4 it had moved further down into the jejunum. In the liver, the highest and lowest retention on day 4 was 16%, and 3 per thousand of the dose in the water group and wholemeal/milk formula group, respectively. In the kidney, 109Cd was still increasing 12 days after exposure in all groups. Whole-body retention and tissue levels were higher than previously reported in adult animals. The lower bioavailability of 109Cd from the cereal-based formulas compared to water and cows milk formula on the longer survival times is most likely explained by Cd binding to dietary fibre and phytic acid in the cereal-based formulas reducing the intestinal binding and decreasing the bioavailability of Cd. The high retention of 109Cd in the small intestine, leading to a prolonged absorption period, emphasizes the importance of extending studies on neonatal Cd absorption over a long time period in order to detect for example, endpoints, accumulation of Cd in the kidney.     

Increased spontaneous motor activity in offspring after maternal cadmium exposure during lactation

Lactating rats were exposed to 0, 5 or 25ppm cadmium as cadmium chloride in the drinking water. A battery of neurobehavioural tests was applied to the male offspring after weaning at 5 weeks until 4 months of age. The mean cadmium levels in exposed pup kidneys ranged from 0.006 to 0.030mg/kg wet weight at weaning, with the corresponding maternal kidney cadmium levels ranging from 4 to 13mg/kg wet weight. Significantly increased activity during the initial 20min of the spontaneous motor activity test was observed in the highest-dose group compared to the control group. The activity outcome was significantly positively correlated with cadmium levels in the pup kidneys. No cadmium-related changes in performance were observed in the Morris water maze, the E-shaped maze or the elevated plus-maze. The results indicate that neurobehavioural effects during development may be a more sensitive parameter for Cd toxicity than renal dysfunction.     

Cadmium in milk and mammary gland in rats and mice

The purpose of the present investigation was to study the uptake of cadmium in mammary tissue, effects on milk secretion and composition, and lactational transport of cadmium to the sucklings. Cadmium exposure during lactation resulted in retention of cadmium in the mammary tissue in mice and rats. The uptake of cadmium in the mammary tissue was rapid, as shown in lactating mice by whole-body autoradiography 4 h after an intravenous injection of a tracer dose of (109)CdCl(2). Retention of cadmium in kidneys of suckling pups was observed in the autoradiograms at 7 days after exposure of the dams. Lactating rats were intravenously infused with (109)CdCl(2) in 0.9% saline via osmotic minipumps from day 3 to day 16 after parturition. The cadmium dose given was 0, 8.8, 62 and 300 microg Cd/kg body wt. per day. Plasma and milk were collected at day 10 and 16 after parturition. Plasma cadmium levels in dams increased from day 10 to day 16. Cadmium levels were higher in milk than in plasma, with milk/plasma ratios varying from 2 to 6. Zinc levels in milk were positively correlated to cadmium levels in milk (r(2)=0.26; P=0. 03). In milk, (109)Cd was distributed in fat (46-52%), casein fraction (40-46%), and whey fraction (6-8%). There was a high correlation between cadmium concentrations in pups' kidney and cadmium concentrations in dam's milk (r(2)=0.98; P < 0.001). Of the cadmium dose given to the dams <0.05% was retained in the litters on day 16 of lactation. No effects were observed due to cadmium exposure on body weight in pups or dams. Cadmium treatment did not cause any effect on the lactose or protein concentration in milk, the concentrations of DNA, RNA or the ratio RNA/DNA in the mammary gland. Histological evaluation of mammary tissue did not reveal any abnormalities at any dose level. (109)Cd was bound to metallothionein in mammary tissue. The fraction of radiolabelled cadmium bound to metallothionein increased in a dose-dependent manner in both the liver (88-98%) and mammary tissue (57-80%). The present results indicate a low transfer of cadmium to the suckling pup, which might be due to binding of cadmium to metallothionein in the mammary tissue. However, during the susceptible developmental period even a low cadmium exposure may be of concern.     

Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy

Brain damage can occasionally result in paradoxical functional benefit, which could help identify therapeutic targets for neuromodulation. However, these beneficial lesions are rare and lesions in multiple different brain locations can improve the same symptom. Using a technique called lesion network mapping, we show that heterogeneous lesion locations resulting in tremor relief are all connected to common nodes in the cerebellum and thalamus, the latter of which is a proven deep brain stimulation target for tremor. These results suggest that lesion network mapping can identify the common substrate underlying therapeutic lesions and effective therapeutic targets. Ann Neurol 2018;83:153–157     

Morphological Characterization of Polyanhydride Biodegradable Implant Gliadel® During in Vitro and in Vivo Erosion Using Scanning Electron Microscopy

Purpose. The objectives of the current study are to characterize the distribution of the chemotherapeutic agent carmustine (BCNU) in spray dried polyanhydride microspheres and to describe the morphological changes that occur during the in vitro and in vivo erosion of the polyanhydride implant-GLIADEL^®, which consists of BCNU distributed in the copolymer matrix of poly(carboxyphenoxy propane:sebacic acid) in a 20:80 molar ratio (p(CPP:SA, 20:80)). Methods. Scanning electron microscopy (SEM) was used to visualize the morphological changes of the polymer during the manufacturing process and in vitro and in vivo erosion. Results. This study revealed that BCNU was homogeneously distributed within spray dried polyanhydride microspheres with no phase separation. The porosity of the wafer fabricated from spray dried polyanhydride microspheres gradually increased during erosion. During the initial period following wafer implantation in the brains of rats, erosion was mainly confined to the surface layer of the wafer with the majority of the wafer remaining intact. The eroding front gradually advanced from the surface to the interior of the wafer in a layerwise fashion, creating pores and connecting channel. Eventually both the interior and exterior of the wafers were eroded and the same porous structure was seen throughout the whole wafer. Conclusions. This study provides the first visual observation of the morphological changes of the GLIADEL^® wafer during erosion of the polyanhydride matrix and release of the drug substance BCNU. The observations in this study support the conclusion that BCNU release from a polyanhydride wafer is controlled both by diffusion of the drug and erosion of the polymer matrix.     

Nonsurgical Repair of a Pseudoaneurysm in a Cynomolgus Macaque (Macaca fascicularis)

A cynomolgus macaque presented with an ecchymotic and edematous left leg approximately 1 wk after a blood sample had been collected from the left femoral vein. Ecchymosis was noted in the femoral triangle, prepuce, and scrotum. The animal was not febrile or exhibiting signs of pain or distress. Duplex Doppler ultrasound imaging was used to evaluate the area. An arteriovenous fistula between the femoral artery and vein, accompanied by a pseudoaneurysm arising from the femoral artery, was identified. Various invasive and noninvasive treatment options for the pseudoaneurysm, including surgical repair, thrombin injection, stent placement, and ultrasound-guided compression repair (UGCR), were considered. UGCR was chosen as the first option for treatment. After a total of 20 min of UGCR at the neck of the pseudoaneurysm, complete thrombosis was achieved. Subsequent imaging of the lesion revealed resolution of the pseudoaneurysm. Because of the risks involved with invasive management techniques for this vascular lesion, UGCR is a valuable noninvasive treatment option for the repair of pseudoaneurysms.Abbreviation: CDI, color Doppler imaging; UGCR, ultrasound-guided compression repairVascular malformations have been reported to occur in a wide variety of species.^{2,3,5-7,10,11,13,15-22,24,25,27-35} These abnormalities include arteriovenous fistulas, vascular shunts, hemangiomas, vascular atresias, aneurysms, pseudoaneurysms, telangectasia, and lymphangiomas, with the overwhelming majority of reports describing arteriovenous fistulas.^{2,3,5,6,11,15-19,25,27,30,33,35} Aneurysms have occurred in several primates including chimpanzees, gorillas, squirrel monkeys, howler monkeys, owl monkeys, African green monkeys, spider monkeys, patas monkeys, and capuchin monkeys.²⁴ Pseudoaneurysms are reported infrequently. Pseudoaneurysms (or false) aneurysms are the result of leakage of blood from an artery into a defined space. A pseudoaneurysm associated with the femoral artery in a black and white colobus monkey was detected 6 d after manual restraint for routine blood collection from the femoral artery.³² The pseudoaneurysm was excised, and the resulting vascular defect was closed with an autologous graft. Another report¹⁰ describes a pseudoaneurysm associated with the femoral artery in a rhesus monkey. The diagnosis was obtained interoperatively, and excision of the defect was successful. Because surgical treatment of pseudoaneurysm has inherent risks and requires considerable surgical skill for a successful outcome, a noninvasive approach would be a valuable and cost-effective treatment option. This report is the first to describe the clinical presentation, diagnosis, and nonsurgical treatment of a pseudoaneurysm in a cynomolgus macaque.     

Proteomics of HCV virions reveals an essential role for the nucleoporin Nup98 in virus morphogenesis

Hepatitis C virus (HCV) is a unique enveloped virus that assembles as a hybrid lipoviral particle by tightly interacting with host lipoproteins. As a result, HCV virions display a characteristic low buoyant density and a deceiving coat, with host-derived apolipoproteins masking viral epitopes. We previously described methods to produce high-titer preparations of HCV particles with tagged envelope glycoproteins that enabled ultrastructural analysis of affinity-purified virions. Here, we performed proteomics studies of HCV isolated from culture media of infected hepatoma cells to define viral and host-encoded proteins associated with mature virions. Using two different affinity purification protocols, we detected four viral and 46 human cellular proteins specifically copurifying with extracellular HCV virions. We determined the C terminus of the mature capsid protein and reproducibly detected low levels of the viral nonstructural protein, NS3. Functional characterization of virion-associated host factors by RNAi identified cellular proteins with either proviral or antiviral roles. In particular, we discovered a novel interaction between HCV capsid protein and the nucleoporin Nup98 at cytosolic lipid droplets that is important for HCV propagation. These results provide the first comprehensive view to our knowledge of the protein composition of HCV and new insights into the complex virus–host interactions underlying HCV infection.Compositional studies of virions provide powerful clues for understanding the functions of viral proteins; assembly and entry pathways; and, more broadly, mechanisms of virus–host interactions. Increasingly sensitive MS techniques have enabled the detection of viral and cellular proteins that are incorporated in virions even at very low levels (1).Hepatitis C virus (HCV) is a positive-sense ssRNA virus of the Flaviviridae family. This bloodborne pathogen causes chronic liver infection that develops into cirrhosis and hepatocellular carcinoma and is the leading indication for liver transplantation. Over 185 million people are chronically infected with HCV (2). Despite great advances in the ability to study this virus in vitro, significant gaps remain in our understanding of the infectious particle and the virus–host interactions required for HCV propagation.The protein composition of HCV is not known. Although the capsid protein, Core, and the E1 and E2 envelope glycoproteins are thought to be the major constituents of the virion, it remains to be determined if nonstructural viral proteins are packaged as well. A growing body of literature suggests that cellular proteins are important components of HCV. Indeed, this virus closely associates with LDL and very-LDL components, forming a chimeric lipoviral particle (LVP). Biochemical and ultrastructural studies demonstrated that infectious HCV particles are coated with endogenous apolipoproteins that play key roles in viral attachment and entry, explaining the higher infectivity of lipoprotein-associated HCV (2).The heterogeneous size and appearance of extracellular HCV, ranging from 40 to >100 nm in diameter, suggests that the set of associated proteins (both viral and cellular), as well as their stoichiometry, might vary across the virion population. Additionally, the specific infectivity of HCV changes according to the cell system/host that the virus is produced in, highlighting a strong contribution of the host to the makeup of the virus particles (2). Therefore, a proteomic analysis of HCV represents an attractive means of discovering novel virus–host interactions with possible implications for understanding exploitation/subversion strategies that this chronic virus uses to persist within the host.We recently described two methods for producing and affinity-purifying high titers of cell culture-derived HCV (HCVcc) that enabled ultrastructural analysis of HCV virions (3). The first was based on the construction of an infectious clone with tags fused at the N terminus of E2, whereas the second relied on the use of potent HCV-neutralizing Abs.In this study, we used both affinity purification approaches to perform proteomic analysis of extracellular HCV virions. We established that Core¹⁷⁷ (amino acids 1–177) is the form incorporated in mature HCV particles and detected a number of virion-associated viral and cellular proteins. Functional characterization of HCV-associated cellular proteins identified new host factors, including a nuclear pore complex (NPC) protein, that participate in HCV infection.