Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis.
Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that Krüppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPARα-signaling. Mice with either hepatocyte-specific depletion of KLF6 ('ΔHepKlf6') or global KLF6 heterozygosity (Klf6+/-) were fed a high fat diet (HFD) or chow for 8 or 16 weeks. Glucose and insulin tolerance tests were performed to assess insulin sensitivity. Overexpression and knockdown of KLF6 in cultured cells enabled the elucidation of underlying mechanisms. In liver samples from a cohort of 28 NAFLD patients, the expression of KLF6-related target genes was quantified. Mice with global- or hepatocyte-depletion of KLF6 have reduced body fat content and improved glucose and insulin tolerance, and are protected from HFD-induced steatosis. In hepatocytes, KLF6 deficiency reduces PPARα-regulated genes (Trb3, Pepck) with diminished PPARα protein but no change in Pparα mRNA, which is explained by the discovery that KLF6 represses miRNA 10b, which leads to induction of PPARα. In NAFLD patients with advanced disease and inflammation, the expression of miRNA 10b is significantly downregulated, while PEPCK mRNA is upregulated; KLF6 mRNA expression also correlates with TRB3 as well as PEPCK gene expression. KLF6 increases PPARα activity, whereas KLF6 loss leads to PPARα repression and attenuation of lipid and glucose abnormalities associated with a high fat diet. The findings establish KLF6 as a novel regulator of hepatic glucose and lipid metabolism in fatty liver.


Second-hand Smoke Exposure Among Home Care Workers (HCWs) in Scotland.
Second-hand tobacco smoke (SHS) is a serious cause of ill-health, and concern around SHS exposure at work has driven legislation in public places. In Scotland, most workers are now protected from SHS at work. However, home care workers (HCWs) may still be exposed, as they enter private homes where smoking is unregulated. In this study, we aimed to understand the extent, duration and intensity of that exposure among HCWs in Lanarkshire, Scotland. We surveyed HCWs in four organisations involved in providing care at home: a public healthcare agency (NHS Lanarkshire), two local government entities and a private healthcare company. We also conducted personal exposure monitoring (PEM) of exposure to airborne nicotine and SHS-related fine particulate matter (PM2.5) with 32 HCWs. The vast majority of HCWs surveyed reported being exposed to SHS at work (395/537, 74%), and 50% of those who reported exposure in the home indicated daily exposure. We conducted PEM over 82 home visits, with 21% (17) demonstrating PM2.5 concentrations in excess of the WHO's 2010 air quality guideline limit for 24 h exposure. Duration of exposure to SHS tended to be short and as a result all nicotine samples were below the limit of quantification. Most HCWs are exposed to minimal levels of SHS at work. However, a minority may be exposed to concentrations which affect health. Policies to mitigate this exposure should be considered, such as the use of respiratory protective equipment, improved ventilation during visits, and interventions to reduce smoking in homes.


Resonant coupling of surface plasmons to radiation modes by use of dielectric gratings.
Efficient outcoupling of surface-plasma waves to radiation modes by use of dielectric diffraction gratings on a flat metallic surface is discussed. The dielectric gratings, which have a surface-relief structure with only several tens of nanometers in peak-to-trough height on a flat metal surface, can efficiently extract radiation modes propagating in free space from the surface-plasmon modes. An outcoupling efficiency of 50% is estimated with the rigorous coupled-wave diffraction theory, and it is confirmed by the experiment.


Impairment of the myocardial vasomotor response to cold pressor stress in collateral dependent myocardium.
To study the vasomotor response (cold pressor/basal flow) in myocardium perfused entirely by collaterals, using the reflex sympathetic stimulation of cold pressor stress. Regional myocardial blood flow was measured in collateral dependent and in remote myocardium using positron emission tomography with 15O water at basal and at cold pressor stress. Regional ischaemia was measured with 18F-fluorodeoxyglucose (FDG). Nine patients (mean (SD) age 53 (6) years) with an occluded coronary artery supplied entirely by collaterals from other angiographically normal arteries. In remote myocardium, basal and cold pressor flow were 0.99 (0.26) and 1.46 (0.60) ml/min/g (P < 0.05), respectively, a myocardial vasomotor response of 1.46 (0.45). In collateral dependent myocardium, basal and cold pressor flow were 0.91 (0.20) and 0.87 (0.35) ml/min/g, respectively (the latter value, P < 0.05 v remote region), a myocardial vasomotor response of 0.97 (0.43) (P < 0.05 v remote region). The myocardial vascular resistance (mean arterial pressure/flow) during cold pressor was higher in the collateral dependent than in remote myocardium, at 147.0 (61.1) and 85.6 (32.3) mm Hg.min.g/ml (P < 0.05), respectively, but with no relative increase in FDG uptake. In contrast to the decrease in myocardial resistance in remote myocardium with cold pressor, an increase was observed in collateral dependent myocardium suggesting a vasoconstrictor response in resistive vessels, without demonstrable myocardial ischaemia.


The effects of physics-based data augmentation on the generalizability of deep neural networks: Demonstration on nodule false-positive reduction.
An important challenge for deep learning models is generalizing to new datasets that may be acquired with acquisition protocols different from the training set. It is not always feasible to expand training data to the range encountered in clinical practice. We introduce a new technique, physics-based data augmentation (PBDA), that can emulate new computed tomography (CT) data acquisition protocols. We demonstrate two forms of PBDA, emulating increases in slice thickness and reductions of dose, on the specific problem of false-positive reduction in the automatic detection of lung nodules. We worked with CT images from the lung image database consortium (LIDC) collection. We employed a hybrid ensemble convolutional neural network (CNN), which consists of multiple CNN modules (VGG, DenseNet, ResNet), for a classification task of determining whether an image patch was a suspicious nodule or a false positive. To emulate a reduction in tube current, we injected noise by simulating forward projection, noise addition, and backprojection corresponding to 1.5 mAs (a "chest x-ray" dose). To simulate thick slice CT scans from thin slice CT scans, we grouped and averaged spatially contiguous CT within thin slice data. The neural network was trained with 10% of the LIDC dataset that was selected to have either the highest tube current or the thinnest slices. The network was tested on the remaining data. We compared PBDA to a baseline with standard geometric augmentations (such as shifts and rotations) and Gaussian noise addition. PBDA improved the performance of the networks when generalizing to the test dataset in a limited number of cases. We found that the best performance was obtained by applying augmentation at very low doses (1.5 mAs), about an order of magnitude less than most screening protocols. In the baseline augmentation, a comparable level of Gaussian noise was injected. For dose reduction PBDA, the average sensitivity of 0.931 for the hybrid ensemble network was not statistically different from the average sensitivity of 0.935 without PBDA. Similarly for slice thickness PBDA, the average sensitivity of 0.900 when augmenting with doubled simulated slice thicknesses was not statistically different from the average sensitivity of 0.895 without PBDA. While there were cases detailed in this paper in which we observed improvements, the overall picture was one that suggests PBDA may not be an effective data enrichment tool. PBDA is a newly proposed strategy for mitigating the performance loss of neural networks related to the variation of acquisition protocol between the training dataset and the data that is encountered in deployment or testing. We found that PBDA does not provide robust improvements with the four neural networks (three modules and the ensemble) tested and for the specific task of false-positive reduction in nodule detection.


Chapter 8: Invasive fungal rhinosinusitis.
Invasive fungal rhinosinusitis (IFRS) is a disease of the paranasal sinuses and nasal cavity that typically affects immunocompromised patients in the acute fulminant form. Early symptoms can often mimic rhinosinusitis, while late symptoms can cause significant morbidity and mortality. Swelling and mucosal thickening can quickly progress to pale or necrotic tissue in the nasal cavity and sinuses, and the disease can rapidly spread and invade the palate, orbit, cavernous sinus, cranial nerves, skull base, carotid artery, and brain. IFRS can be life threatening if left undiagnosed or untreated. While the acute fulminant form of IFRS is the most rapidly progressive and destructive, granulomatous and chronic forms also exist. Diagnosis of IFRS often mandates imaging studies in conjunction with clinical, endoscopic, and histopathological examination. Treatment of IFRS consists of reversing the underlying immunosuppression, antifungal therapy, and aggressive surgical debridement. With early diagnosis and treatment, IFRS can be treated and increase patient survival.


Quality and Safety in Health Care, Part XXIX: The Transcatheter Valve Therapy Registry.
The American College of Cardiology, the Society of Thoracic Surgeons, and other organizations cooperated to form the Transcatheter Valve Therapy Registry. This registry studies information on the outcome of valve therapy device placement with a transcatheter approach. The companies that manufacture these devices can use the registry to meet the post-product sale surveillance requirements of the US Food and Drug Administration. There will also be linkage to the registry information from the Society of Thoracic Surgeons Adult Cardiac Surgery Database, which has information on open cardiac valve surgery.


[Planning the nursing care for burned patients with a software: application in 4 patients].
In order to evaluate the applicability of a Software to the execution of a nursing process of care to burn patients, a case study method has been used. Four (4) subjects who had been admitted to a burn unit were evaluated. All the four cases were inserted into a computer program where the plan of nursing care was executed. The Software was adequate, enabling the planning of the nursing care in a reduced time.


A novel online method to monitor autonomic nervous activity based on arterial wall impedance and heart rate variability.
This paper proposes a new method of evaluating autonomic nervous activity using the mechanical impedance of arterial walls and heart rate variability. The cardiovascular system is indispensable to life maintenance functions, and homeostasis is maintained by the autonomic nervous system. Accordingly, it is very important to be able to make diagnosis based on autonomic nervous activity within the body's circulation. The proposed method was evaluated in surgical operations; the mechanical impedance of the arterial wall was estimated from arterial blood pressure and a photoplethysmogram, and heart rate variability was estimated using electrocardiogram R-R interval spectral analysis. In this paper, we monitored autonomic nervous system activity using the proposed system during endoscopic transthoracic sympathetic block surgery in eight patients with hyperhidrosis. The experimental results indicated that the proposed system can be used to estimate autonomic nervous activity in response to events during operations.


Monte Carlo simulation of a Knudsen effusion mass spectrometer sampling system.
Knudsen effusion mass spectrometry (KEMS) shows improved performance with the "restricted collimation" method of Chatillon and colleagues, which consists of two apertures between the Knudsen cell orifice and the ionizer. These apertures define the shape and position of the molecular beam independently of the sample and effusion orifice and as a result reduce background and improve sampling from the Knudsen cell. Modeling of the molecular beam in restricted collimation allows optimization of the apertures' diameters and spacing. Knudsen flow is easily simulated with a Monte Carlo method. In this study a Visual Basic for Excel (VBA) code is developed to simulate the molecular beam originating from a vaporizing condensed phase in a Knudsen cell and passing through the cell orifice and the two apertures. The code is able to calculate the transmission coefficient through the cell orifice, through the cell orifice and the first aperture, and through the cell orifice and first and second apertures. Also calculated are the angular distributions of the effusate density emerging from the cell and average number of collisions with the orifice walls. This code allows the geometry (aperture spacing and diameters) of the sampling system to be optimized for maximum transmission. The calculated effusate distributions and low average number of orifice wall collisions illustrated the advantages of restricted collimation. Calculated transmission factors are also compared to literature values calculated via the analytical method of Chatillon and colleagues. Published in 2017. This article is a U.S. Government work and is in the public domain in the USA.


[Treatment of postoperative sternal osteomyelitis (author's transl)].
Report on 5 cases of postoperative sternal osteomyelitis after cardiac valve replacement. In 3 cases evaluation of Pseudomonas aeruginosa in probes taken of sternal wounds. Treatment of the osteomyelitis with continuous irrigation and suction supported by excochleation of the fistulae and application of pure spongiosa chips to the bone defect of the sternum. Uncomplicated postoperative course in 4 patients. In 1 patient postoperative time too short for a final decision.


Improved outcomes with arthroscopic repair of partial-thickness rotator cuff tears: a systematic review.
The optimum treatment strategy for the surgical management of partial-thickness rotator cuff tears (PTRCT) is evolving. In this study, two research questions were sought to be answered: "Does the repair technique for PTRCTs involving >50% of the tendon thickness have an effect on structural and functional outcomes of arthroscopic repair?" and "Is there a difference in outcomes of arthroscopically treated articular- and bursal-sided PTRCTs?". A systematic review according to the PRISMA statement was conducted to identify all literature published reporting on outcomes of arthroscopic treatment of PTRCTs classified with the Ellman classification with minimum 2-year follow-up. Prospective randomized trials were eligible for quantitative synthesis. A total of 19 studies, published between 1999 and 2015, met the inclusion criteria of this systematic review. Two studies reporting outcomes of articular-sided PTRCTs with prospective randomized study design were included in quantitative synthesis calculations. Arthroscopic repair of PTRCTs >50% thickness results in significant pain relief and good to excellent functional outcomes. When in situ repair was compared with repair of the tendon after completion to full-thickness RCT, there were no significant differences in functional or structural outcomes or complication rates. The best treatment method for low-grade PTRCTs remains unclear. The repair technique (in situ repair versus repair of the tendon after completion to full-thickness RCT) did not significantly affect the outcomes for arthroscopic repair of PTRCTs >50% thickness. The current literature contains evidence for inferior outcomes and higher failure rates after arthroscopic debridement of bursal-sided compared to articular-sided PTRCTs, and some evidence suggests that repair of lower-grade bursal-sided tears may be beneficial over debridement. IV.


Effects of calcitonin gene-related peptide and lidocaine on mechanically-induced vasospasm in a rat island flap.
A neurovascular island flap based on the superficial epigastric vessels was raised in 59 rats. Blood flow in the flap was recorded continuously with a laser Doppler flowmeter. Complete vasospasm was induced mechanically in the artery by pinching it. Calcitonin gene-related peptide (10(-7) M), lidocaine 2 percent, lidocaine 20 percent, or sodium chloride 0.9 percent were applied topically to the vessels in order to relieve the vasospasm. In 18 arteries, spasm was induced a second time after the resolution of the first vasospasm. Calcitonin gene-related peptide significantly shortened the time to reach 50 percent of the original blood flow and increased the final blood-flow values 30 min after mechanically-induced vasospasm, in comparison with pre-spasm values, and significantly increased the number of flaps in which the blood-flow values were restored to pre-spasm levels. Lidocaine did not significantly change the time to reach 50 percent of the original blood-flow values and the number of flaps recovering to pre-spasm blood-flow levels, or the final levels after vasospasm, in comparison with saline. It was concluded that, in this model, calcitonin gene-related peptide, but not lidocaine, increased blood flow after mechanically-induced vasospasm.


From pathogen to a commensal: modification of the Microbacterium nematophilum-Caenorhabditis elegans interaction during chronic infection by the absence of host insulin signalling.
The nematode worm Caenorhabditis elegans depends on microbes in decaying vegetation as its food source. To survive in an environment rich in opportunistic pathogens, Celegans has evolved an epithelial defence system where surface-exposed tissues such as epidermis, pharynx, intestine, vulva and hindgut have the capacity of eliciting appropriate immune defences to acute gut infection. However, it is unclear how the worm responds to chronic intestinal infections. To this end, we have surveyed Celegans mutants that are involved in inflammation, immunity and longevity to find their phenotypes during chronic infection. Worms that grew in a monoculture of the natural pathogen Microbacterium nematophilum (CBX102 strain) had a reduced lifespan and vigour. This was independent of intestinal colonisation as both CBX102 and the derived avirulent strain UV336 were early persistent colonisers. In contrast, the long-lived daf-2 mutant was resistant to chronic infection, showing reduced colonisation and higher vigour. In fact, UV336 interaction with daf-2 resulted in a host lifespan extension beyond OP50, the Escherichia coli strain used for laboratory Celegans culture. Longevity and vigour of daf-2 mutants growing on CBX102 was dependent on the FOXO orthologue DAF-16. Our results indicate that the interaction between host genotype and strain-specific bacteria determines longevity and health for C. elegans.


Polyarylether-based COFs coordinated by Tb3+ for the fluorescent detection of anthrax-biomarker dipicolinic acid.
In this study, a rare-earth hybrid luminescent material (lanthanide@COF) was constructed for the detection of a biomarker for anthrax (dipicolinic acid, DPA). JCU-505-COOH was prepared by the hydrolysis of the cyano group in JCU-505 via a post-synthetic modification strategy, then the carboxyl groups in JCU-505-COOH coordinated with Tb3+ ions, similar to pincer vising nut. The prepared Tb3+@JCU-505-COOH exhibited a turn-on response toward DPA, which allowed the lanthanide@COF to serve as a fluorescence sensor with excellent selectivity and high sensitivity (binding constant Ka = 3.66 × 103). The fluorescent probe showed satisfactory performance for the determination of DPA in saliva and urine with a detection limit of 0.6 μM. Moreover, we established a facile point-of-care testing (POCT) using the Tb3+@JCU-505-COOH-based fluorescent test paper together with a smartphone for the initial diagnosis of anthrax. As expected, Tb3+@JCU-505-COOH showed great potential for the rapid screening of anthrax due to low cost, simple operation, and wide applicability.


Correlations between ultrasonography performed by the ENT specialist and pathologic findings in the management of three cases with thyroglossal duct cyst.
Thyroglossal duct cyst (TDC) has an increasing incidence. We present a series of three cases that benefited from the use of ultrasonography performed first hand by the ENT specialist. All cases underwent Sistrunk procedure and the diagnosis was confirmed by pathology results: one uncomplicated TDC, a thyroglossal duct carcinoma, and an infected TDC with the risk of becoming a diffuse cervical suppuration. Ultrasonography performed first hand by the ENT specialist enables a quick and thorough planning of the surgical procedure and management of the case.


Changes in morning salivary melatonin correlate with prefrontal responses during working memory performance.
Humans demonstrate a circadian rhythm of melatonin production that closely tracks the daily light/dark cycle, with profound increases in circulating levels during the night-time and nearly nonexistent levels during daylight hours. Although melatonin is known to play a role in preparing the brain and body for sleep, its effects on cognition and brain function are not well understood. We hypothesized that declines in morning melatonin would be associated with increased functional activation within cortical regions involved in alertness, attention, and executive function. We measured the change in salivary melatonin from mid-morning to late-morning in 26 healthy young adults who were also exposed to a 30-min period of blue or amber light followed by functional MRI during a working memory task (N-back). Brain activation was regressed on the change in melatonin scores from the mid-morning to late-morning saliva samples and the role of light exposure was also assessed. Although overall melatonin levels did not change significantly over the morning at the group level, individual declines in salivary melatonin were associated with significant increases in activation within the left dorsomedial and right inferior lateral prefrontal cortex during the 2-back condition (P<0.05, cluster corrected). Medial prefrontal activation also correlated modestly with better vigilance performance during the 0-back (P<0.05), but not the 1-back or 2-back conditions. The light condition did not affect the outcomes. These findings suggest declining melatonin levels in the morning are associated with increased prefrontal cortex functioning and may play a role in the increased frontal activation that occurs following awakening.


Microbial Invasion vs. Tick Immune Regulation.
Ticks transmit a greater variety of pathogenic agents that cause disease in humans and animals than any other haematophagous arthropod, including Lyme disease, Rocky Mountain spotted fever, human granulocytic anaplasmosis, babesiosis, tick-borne encephalitis, Crimean Congo haemorhagic fever, and many others (Gulia-Nuss et al., 2016). Although diverse explanations have been proposed to explain their remarkable vectorial capacity, among the most important are their blood feeding habit, their long term off-host survival, the diverse array of bioactive molecules that disrupt the host's natural hemostatic mechanisms, facilitate blood flow, pain inhibitors, and minimize inflammation to prevent immune rejection (Hajdušek et al., 2013). Moreover, the tick's unique intracellular digestive processes allow the midgut to provide a relatively permissive microenvironment for survival of invading microbes. Although tick-host-pathogen interactions have evolved over more than 300 million years (Barker and Murrell, 2008), few microbes have been able to overcome the tick's innate immune system, comprising both humoral and cellular processes that reject them. Similar to most eukaryotes, the signaling pathways that regulate the innate immune response, i.e., the Toll, IMD (Immunodeficiency) and JAK-STAT (Janus Kinase/ Signal Transducers and Activators of Transcription) also occur in ticks (Gulia-Nuss et al., 2016). Recognition of pathogen-associated molecular patterns (PAMPs) on the microbial surface triggers one or the other of these pathways. Consequently, ticks are able to mount an impressive array of humoral and cellular responses to microbial challenge, including anti-microbial peptides (AMPs), e.g., defensins, lysozymes, microplusins, etc., that directly kill, entrap or inhibit the invaders. Equally important are cellular processes, primarily phagocytosis, that capture, ingest, or encapsulate invading microbes, regulated by a primordial system of thioester-containing proteins, fibrinogen-related lectins and convertase factors (Hajdušek et al., 2013). Ticks also express reactive oxygen species (ROS) as well as glutathione-S-transferase, superoxide dismutase, heat shock proteins and even protease inhibitors that kill or inhibit microbes. Nevertheless, many tick-borne microorganisms are able to evade the tick's innate immune system and survive within the tick's body. The examples that follow describe some of the many different strategies that have evolved to enable ticks to transmit the agents of human and/or animal disease.


Too risky to settle: avian community structure changes in response to perceived predation risk on adults and offspring.
Predation risk is widely hypothesized as an important force structuring communities, but this potential force is rarely tested experimentally, particularly in terrestrial vertebrate communities. How animals respond to predation risk is generally considered predictable from species life-history and natural-history traits, but rigorous tests of these predictions remain scarce. We report on a large-scale playback experiment with a forest bird community that addresses two questions: (i) does perceived predation risk shape the richness and composition of a breeding bird community? And (ii) can species life-history and natural-history traits predict prey community responses to different types of predation risk? On 9 ha plots, we manipulated cues of three avian predators that preferentially prey on either adult birds or offspring, or both, throughout the breeding season. We found that increased perception of predation risk led to generally negative responses in the abundance, occurrence and/or detection probability of most prey species, which in turn reduced the species richness and shifted the composition of the breeding bird community. Species-level responses were largely predicted from the key natural-history trait of body size, but we did not find support for the life-history theory prediction of the relationship between species' slow/fast life-history strategy and their response to predation risk.


Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type.
In cultures of dissociated rat hippocampal neurons, persistent potentiation and depression of glutamatergic synapses were induced by correlated spiking of presynaptic and postsynaptic neurons. The relative timing between the presynaptic and postsynaptic spiking determined the direction and the extent of synaptic changes. Repetitive postsynaptic spiking within a time window of 20 msec after presynaptic activation resulted in long-term potentiation (LTP), whereas postsynaptic spiking within a window of 20 msec before the repetitive presynaptic activation led to long-term depression (LTD). Significant LTP occurred only at synapses with relatively low initial strength, whereas the extent of LTD did not show obvious dependence on the initial synaptic strength. Both LTP and LTD depended on the activation of NMDA receptors and were absent in cases in which the postsynaptic neurons were GABAergic in nature. Blockade of L-type calcium channels with nimodipine abolished the induction of LTD and reduced the extent of LTP. These results underscore the importance of precise spike timing, synaptic strength, and postsynaptic cell type in the activity-induced modification of central synapses and suggest that Hebb's rule may need to incorporate a quantitative consideration of spike timing that reflects the narrow and asymmetric window for the induction of synaptic modification.


Advanced magnetic resonance imaging with histopathological correlation in papillary tumor of pineal region: report of a case and review of literature.
Papillary tumors of the pineal region are recently described as rare mass lesions with limited literature available on their natural history and imaging features. Magnetic resonance imaging (MRI) including perfusion, diffusion, and spectroscopic features were described in an 18-year-old girl with papillary tumor of pineal region. A well-defined, T1 hyperintense and contrast-enhancing mass lesion was noted in pineal region with few cystic spaces within. Solid portion of lesion showed minimal diffusion restriction with average apparent diffusion coefficient of 0.812 Χ 10 -3 mm 2 /s; on MR spectroscopy elevated myo-inositol peak with reduced N-acetylaspartate and elevated choline in the tumor. On perfusion study there was significantly high relative cerebral blood volume (rCBV) (6-9 times) and relative cerebral blood flow (rCBF). Our findings agree with previous descriptions of cystic areas with T1 hyperintense appearance of this tumor but very high level of tumor perfusion, diffusion restriction, and presence of myo-inositol peak are important imaging findings and may correlate with the recent reports of high tumor recurrence in these cases.


Anthropometric measurements of the human knee: correlation to the sizing of current knee arthroplasty systems.
There is a paucity of data concerning the morphological dimensions of the distal part of the femur, the proximal part of the tibia, and the patella. The objective of this study was to analyze the exact anatomic data collected from a large group of patients undergoing total knee arthroplasty and to correlate the measurements to the dimensions of current prosthetic systems. Eight different centers collected morphologic data from the distal part of the femur, the proximal part of the tibia, and the patella from 337 knees during total knee arthroplasty. Microcaliper measurements from templates and measuring guides were used to decrease intraobserver variation. The study included 188 women (209 knees) and 107 men (128 knees) who had a mean age of sixty-nine years. A characterization of the aspect ratio (the medial-lateral to anterior-posterior dimensions) was made for the proximal aspect of the tibia and the distal part of the femur. Known dimensions from six prosthetic knee systems were compared with the morphologic data. A wide variation in the aspect ratio for the femoral component was seen among the six different prosthetic systems. For women, there was a significant association between the component size and the amount of medial-lateral overhang, with larger sizes having more overhang (p < 0.0001). Although the femoral aspect ratio for the morphologic data showed higher ratios for smaller knees and proportionally lower ratios for larger knees, the designs showed little change in the aspect ratio. The tibial aspect ratio from the morphologic data showed a higher ratio for smaller knees and a proportionally lower ratio for larger knees. The Duracon component tracked the decline in aspect ratio fairly well, whereas the other brands either did not change with anterior-posterior dimension or actually increased (NexGen). Gender differences in the morphologic data were shown by the variable tibial aspect ratios. A comparison of the bone dimensions from the study data and the dimensions of the implants indicated that the smaller sizes were too small while the larger sizes tended to be too large. The average overall unresected patellar thickness was 23.7 mm. The results of this study will allow manufacturers to make more appropriate determinations of the sizes and aspect ratios of components for use in total knee arthroplasty.


Using an animated patient avatar to improve perception of vital sign information by anaesthesia professionals.
Maintaining situation awareness of monitored patients can be challenging because care providers must continually read and integrate multiple waveforms and numerical vital sign values into a mental model of the patient's situation. We developed and evaluated a technology designed to improve perception of vital sign information by presenting patient status as an animated patient avatar. After step-wise improvement of the avatar, anaesthesia professionals from two hospitals participated in a comparative study of conventional monitoring. Participants observed identical monitoring scenarios via the two technologies for brief time intervals and afterwards recalled patient status. Overall, 150 anaesthesia professionals participated in the validation process and 32 participated in the comparative study, completing 128 scenarios, which allowed for 64 direct comparisons. The avatar's inter-rater reliability was high, with Fleiss' kappa of 0.98 (95% confidence interval 0.96-0.99, P<0.001). With the avatar, participants recalled almost twice as many vital signs correctly as with conventional monitoring (9 vs 5, P<0.001). Perceived confidence was improved (2=certain vs 1=uncertain, P<0.001) and perceived workload lowered (task load index 60 vs 76, P<0.001). Participants obtained these results only after watching an educational video explaining the avatar and suggesting quick learnability and potential for real-life usability. This study provides empirical evidence that an animated avatar offers the opportunity to transmit vital sign information significantly more quickly than conventional monitoring and with improved confidence and reduced cognitive effort. This could help care providers gain situation awareness more efficiently.


Detection of human papillomavirus DNA in genital lesions by using a modified commercially available in situ hybridization assay.
A modified, commercially available DNA-DNA in situ hybridization test that uses biotinylated probes for the identification of human papillomavirus (HPV) DNA types 6/11, 16/18, and 31/33/35 was evaluated. HPV DNA was detected in 314 of 787 (40%) histologically abnormal genital biopsy specimens by using the ViraType in situ assay (Life Technologies, Gaithersburg, Md.), in which the hybridization time was increased from 2 to 16 h. Ninety percent of positive condyloma acuminata specimens contained HPV type 6/11 DNA. The prevalences of HPV DNA for cervical intraepithelial neoplasia I, II, and III lesions by this in situ hybridization test were 42, 54, and 55%, respectively. The combined prevalence of HPV type 16/18 and 31/33/35 DNAs increased with the severity of the lesion, while the prevalence of type 6/11 DNA decreased. HPV type 6/11 DNA was found only in 1 of 16 (6%) positive cervical intraepithelial neoplasia III specimens. HPV type 16/18 and 31/33/35 DNA was detected in 11 of 16 (69%) and 4 of 16 (25%) in situ hybridization-positive cervical intraepithelial neoplasia III specimens, respectively. Thus, the observation that certain "higher-risk" HPV genotypes are associated with upper-grade cervical precancer lesions was confirmed by this commercial hybridization system. In general, the assay was found to be well suited for use in the clinical laboratory. The ViraType in situ procedure modified for a longer hybridization time may be helpful in identifying lesions containing higher-risk HPV strains.


EGR3 and estrone are involved in the tamoxifen resistance and progression of breast cancer.
Tamoxifen (Tam) is an effective treatment for estrogen receptor (ER) positive breast cancer. However, a significant proportion of patients develop resistance under treatment, presenting a therapeutic challenge. The study aims to determine the role of early growth response protein (EGR) 3 in tamoxifen resistance (TamR) and elucidate its molecular mechanism. TamR cell models were established and NGS was used to screening signaling alternation. Western blot and qRT-PCR were used to analysis the expression of ERα, EGR3, MCL1 and factors associated with apoptosis. CCK8, colony formation and apoptosis assay were used to analysis resistance to Tam. Immunofluorescence, chromatin immunoprecipitation, and dual luciferase assays were used to investigate mechanism of regulation. We observed that EGR3, a deeply rooted ERα response factor, showed increased upregulation in response to both estrone (E1) and Tam in TamR cells with elevated level of E1 and ERα expression, indicating a potential connection between EGR3 and TamR. Mechanically, manipulating EGR3 expression revealed that it imparted resistance to Tam through increased expression of the downstream molecule MCL1 (apoptosis suppressor gene) that it regulated. Mechanismly, EGR3 directly binds to the promoter of the anti-apoptotic factor MCL1 gene, facilitating its transcription. Furthermore, apoptosis assays revealed that E1 reduces Tam induced apoptosis by upregulating EGR3 expression. Importantly, clinical public database confirmed the high expression of EGR3 in breast cancer tissue and in Tam-treated patients. These findings shed light on the novel estrogen/EGR3/MCL1 axis and its role in inducing TamR in ER positive breast cancer. EGR3 emerges as a promising target to overcome TamR. The elucidation of this mechanism holds potential for the development of new therapeutic modalities to overcome endocrine therapy resistance in clinical settings.


Using Bi-Weekly Surveys to Portray Adolescent Partnership Dynamics: Lessons From a Mobile Diary Study.
Partnership formation is an important developmental task for adolescents, but cross-sectional and periodic longitudinal studies have lacked the measurement precision to portray partnership stability and flux and to capture the range of adolescent partnership experiences. This article assesses the promises and challenges of using bi-weekly mobile diaries administered over the course of a year to study adolescent partnership dynamics. Descriptive findings illustrate the potential of bi-weekly diaries for both capturing the longitudinal complexity and fluidity of adolescent partnerships as well as for reducing retrospection biases. Results also underscore several challenges, including those posed by missing data, and highlight several strategies for maximizing participant engagement and reliably tracing adolescent partnerships.


Inscribing an output coupler grating directly through the fiber coating with a 266 nm femtosecond laser.
We inscribe with 266 nm femtosecond pulses a ∼0.75% output coupler for a 1550 nm fiber laser directly through the coating of an SMF-28. The output coupler was inscribed with the phase-mask technique without H2 loading. This output coupler was spliced to an active Er/Yb fiber, and a fiber laser with an output power of ∼6.4 W and a slope efficiency of ∼30% was obtained. To the best of our knowledge, this is the first reported attempt to inscribe a fiber Bragg grating through the polymer jacket of an optical fiber with a UV femtosecond laser.


Functional and transmural modulation of M cell behavior in canine ventricular wall.
Previous studies have demonstrated a discrete population of midmyocardial (M) cells in the ventricular myocardium having excessive action potential duration (APD) prolongation during long activation cycle lengths (CL) and under the influence of APD-prolonging agents. However, M cells have not been found in other studies. Existing explanations for the discrepancies appear inadequate. We hypothesized that instead of being a discrete group, M cell behavior is functional and conditionally expressed. We mapped APDs on the cut-exposed transmural surfaces of arterially perfused ventricular wedges from 26 dogs during Na+ current modification with anemone toxin II (ATX-II). Compared with the endocardium, APDs were not statistically different in the parallel layer having the longest mean APD (APDL) and were significantly shorter in the epicardium in the 26 wedges before ATX-II. ATX-II (> or =5 nmol/l) prolonged APD heterogeneously (midmyocardium > endocardium > epicardium). The differences increased at longer CLs. ATX-II (20.0 nmol/l) shifted the APD(L) layer to 32 +/- 6.2% (6 wedges, CL: 4,000 ms) of the transmural thickness from the (sub)endocardium (8.6 +/- 7.2%, 26 wedges, ATX-II free). We detected the presence of M cell behavior (significantly longer APDs in the APDL layer than in the endocardium and epicardium, P < or = 0.04, CL: 4,000 ms) in the 18 wedges having > or =5 nmol/l ATX-II but not (P >0.36) in the other 18 wedges having < or =2.5 nmol/l ATX-II. Both the position of the APDL layer and presence of M cell-like behavior were modulated by ATX-II. The dynamic spatial modulation indicates that M cell behavior is functional and only becomes manifest under suitable conditions.


Evaluating amyloid-β oligomers in cerebrospinal fluid as a biomarker for Alzheimer's disease.
The current study evaluated amyloid-β oligomers (Aβo) in cerebrospinal fluid as a clinical biomarker for Alzheimer's disease (AD). We developed a highly sensitive Aβo ELISA using the same N-terminal monoclonal antibody (82E1) for capture and detection. CSF samples from patients with AD, mild cognitive impairment (MCI), and healthy controls were examined. The assay was specific for oligomerized Aβ with a lower limit of quantification of 200 fg/ml, and the assay signal showed a tight correlation with synthetic Aβo levels. Three clinical materials of well characterized AD patients (n = 199) and cognitively healthy controls (n = 148) from different clinical centers were included, together with a clinical material of patients with MCI (n = 165). Aβo levels were elevated in the all three AD-control comparisons although with a large overlap and a separation from controls that was far from complete. Patients with MCI who later converted to AD had increased Aβo levels on a group level but several samples had undetectable levels. These results indicate that presence of high or measurable Aβo levels in CSF is clearly associated with AD, but the overlap is too large for the test to have any diagnostic potential on its own.


Proteins and an inflammatory network expressed in colon tumors.
The adenomatous polyposis coli (APC) protein is crucial to homeostasis of normal intestinal epithelia because it suppresses the β-catenin/TCF pathway. Consequently, loss or mutation of the APC gene causes colorectal tumors in humans and mice. Here, we describe our use of multidimensional protein identification technology (MudPIT) to compare protein expression in colon tumors to that of adjacent healthy colon tissue from Apc(Min/+) mice. Twenty-seven proteins were found to be up-regulated in colon tumors and 25 were down-regulated. As an extension of the proteomic analysis, the differentially expressed proteins were used as "seeds" to search for coexpressed genes. This approach revealed a coexpression network of 45 genes that is up-regulated in colon tumors. Members of the network include the antibacterial peptide cathelicidin (CAMP), Toll-like receptors (TLRs), IL-8, and triggering receptor expressed on myeloid cells 1 (TREM1). The coexpression network is associated with innate immunity and inflammation, and there is significant concordance between its connectivity in humans versus mice (Friedman: p value = 0.0056). This study provides new insights into the proteins and networks that are likely to drive the onset and progression of colon cancer.


Non-HLA Antibodies to G Protein-coupled Receptors in Pediatric Kidney Transplant Recipients: Short- and Long-term Clinical Outcomes.
Angiotensin II type 1 receptor antibodies (AT1R-Abs) and endothelin-type A receptor antibodies (ETAR-Abs) are G protein-coupled receptor activating autoantibodies associated with antibody-mediated rejection, vascular pathology, increased cytokines, allograft dysfunction, and allograft loss in pediatric kidney transplant recipients in the first 2 y posttransplantation. The impact of AT1R-Ab and ETAR-Ab positivity on longer-term 5-y transplant outcomes is unknown. One hundred pediatric kidney transplant recipients were tested for ETAR-Ab and AT1R-Ab on serially collected blood samples in the first 2 y posttransplant. Biopsies were collected per protocol and 6, 12, and 24 mo posttransplant and at any time during the 5-y follow-up period for clinical indication. Clinical outcomes, including renal dysfunction, rejection, HLA donor-specific antibodies, and allograft loss, were assessed through 5 y posttransplantation. AT1R-Ab or ETAR-Ab were positive in 59% of patients. AT1R-Ab or ETAR-Ab positivity was associated with greater declines in estimated glomerular filtration rate, and de novo AT1R-Ab or ETAR-Ab was associated with allograft loss in the first 2 y posttransplant. There was no association between antibody positivity and rejection, antibody-mediated rejection, or allograft loss in the first 5 y posttransplant. In a model controlled for age, sex, immunosuppression, and HLA mismatch, AT1R-Ab or ETAR-Ab positivity was significantly associated with the development of HLA donor-specific antibodies at 5 y posttransplant (odds ratio 2.87, P = 0.034). Our findings suggest temporally distinct clinical complications associated with AT1R-Ab or ETAR-Ab positivity in pediatric patients; these injury patterns are of significant interest for developing effective treatment strategies.


Pharmacological management of male breast cancer.
Despite its rarity, male breast cancer shows a steadily rising incidence. Given the absence of ad hoc prospective randomized clinical trials, treatment strategies are based on extrapolation from female breast cancer recommendations or solely on population-based data. This review discusses the current treatment landscape for male breast cancer in the adjuvant and in the metastatic setting. The authors also discuss the biology and genomic landscape of male breast cancer. Original research and review articles, relative to the period 2010-2019, were included in the review of the literature. There is a major medical need to include male patients with breast cancer in prospective clinical trials. The call to equality in breast cancer care can be pursued via two divergent paths: (i) a gender-neutral delivery of breast cancer information and (ii) the creation of separate sections, for the more common female breast cancer and for the rare male ones. We propose to differentiate male breast cancer care, acknowledging unique onco-sexual and social needs that can be only partially shared.


A Mobile Clinical Decision Support System for High-Risk Pregnant Women in Rural India (SMARThealth Pregnancy): Pilot Cluster Randomized Controlled Trial.
Cardiovascular disease (CVD) is the leading cause of death in women in India. Early identification is crucial to reducing deaths. Hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM) carry independent risks for future CVD, and antenatal care is a window to screen and counsel high-risk women. In rural India, community health workers (CHWs) deliver antenatal and postnatal care. We developed a complex intervention (SMARThealth Pregnancy) involving mobile clinical decision support for CHWs and evaluated it in a pilot cluster randomized controlled trial (cRCT). The aim of the study is to co-design a theory-informed intervention for CHWs to screen, refer, and counsel pregnant women at high risk of future CVD in rural India and evaluate its feasibility and acceptability. In phase 1, we used qualitative methods to explore community priorities for high-risk pregnant women in rural areas of 2 diverse states in India. In phase 2, informed by behavior change theory and human-centered design, we used these qualitative data to develop the intervention components and implementation strategies for SMARThealth Pregnancy in an iterative process with end users. In phase 3, using mixed methods, we evaluated the intervention in a cRCT with an embedded qualitative substudy across 4 primary health centres: 2 in Jhajjar district, Haryana, and 2 in Guntur district, Andhra Pradesh. SMARThealth Pregnancy embedded a total of 15 behavior change techniques and included (1) community awareness programs; (2) targeted training, including point-of-care blood pressure and hemoglobin measurement; and (3) mobile clinical decision support for CHWs to screen women in their homes. The intervention focused on 3 priority conditions: anemia, HDP, and GDM. The evaluation involved a total of 200 pregnant women, equally randomized to intervention or enhanced standard care (control). Recruitment was completed within 5 months, with minimal loss to follow-up (4/200, 2%) at 6 weeks postpartum. A total of 4 primary care doctors and 54 CHWs in the intervention clusters took part in the study. Fidelity to intervention practices was 100% prepandemic. Over half the study population was affected by moderate to severe anemia at baseline. The prevalence of HDP (2.5%) and GDM (2%) was low in our study population. Results suggest a possible improvement in mean hemoglobin (anemia) in the intervention group, although an adequately powered trial is needed. The model of home-based care was feasible and acceptable for pregnant or postpartum women and CHWs, who perceived improvements in quality of care, self-efficacy, and professional recognition. SMARThealth Pregnancy is an innovative model of home-based care for high-risk pregnant women during the transitions between antenatal and postnatal care and adult health services. The use of theory and co-design during intervention development facilitated acceptability of the intervention and implementation strategies. Our experience has informed the decision to initiate a larger-scale cRCT. ClinicalTrials.gov NCT03968952; https://clinicaltrials.gov/ct2/show/NCT03968952. RR2-10.3389/fgwh.2021.620759.


Primate frontal eye fields. II. Physiological and anatomical correlates of electrically evoked eye movements.
We studied single neurons in the frontal eye fields of awake macaque monkeys and compared their activity with the saccadic eye movements elicited by microstimulation at the sites of these neurons. Saccades could be elicited from electrical stimulation in the cortical gray matter of the frontal eye fields with currents as small as 10 microA. Low thresholds for eliciting saccades were found at the sites of cells with presaccadic activity. Presaccadic neurons classified as visuomovement or movement were most associated with low (less than 50 microA) thresholds. High thresholds (greater than 100 microA) or no elicited saccades were associated with other classes of frontal eye field neurons, including neurons responding only after saccades and presaccadic neurons, classified as purely visual. Throughout the frontal eye fields, the optimal saccade for eliciting presaccadic neural activity at a given recording site predicted both the direction and amplitude of the saccades that were evoked by microstimulation at that site. In contrast, the movement fields of postsaccadic cells were usually different from the saccades evoked by stimulation at the sites of such cells. We defined the low-threshold frontal eye fields as cortex yielding saccades with stimulation currents less than or equal to 50 microA. It lies along the posterior portion of the arcuate sulcus and is largely contained in the anterior bank of that sulcus. It is smaller than Brodmann's area 8 but corresponds with the union of Walker's cytoarchitectonic areas 8A and 45. Saccade amplitude was topographically organized across the frontal eye fields. Amplitudes of elicited saccades ranged from less than 1 degree to greater than 30 degrees. Smaller saccades were evoked from the ventrolateral portion, and larger saccades were evoked from the dorsomedial portion. Within the arcuate sulcus, evoked saccades were usually larger near the lip and smaller near the fundus. Saccade direction had no global organization across the frontal eye fields; however, saccade direction changed in systematic progressions with small advances of the microelectrode, and all contralateral saccadic directions were often represented in a single electrode penetration down the bank of the arcuate sulcus. Furthermore, the direction of change in these progressions periodically reversed, allowing particular saccade directions to be multiply represented in nearby regions of cortex.(ABSTRACT TRUNCATED AT 400 WORDS)


Comparative analysis of secreted protein evolution using expressed sequence tags from four poplar leaf rusts (Melampsora spp.).
Obligate biotrophs such as rust fungi are believed to establish long-term relationships by modulating plant defenses through a plethora of effector proteins, whose most recognizable feature is the presence of a signal peptide for secretion. Since the phenotypes of these effectors extend to host cells, their genes are expected to be under accelerated evolution stimulated by host-pathogen coevolutionary arms races. Recently, whole genome sequence data has allowed the prediction of secretomes, facilitating the identification of putative effectors. We generated cDNA libraries from four poplar leaf rust pathogens (Melampsora spp.) and used computational approaches to identify and annotate putative secreted proteins with the aim of uncovering new knowledge about the nature and evolution of the rust secretome. While more than half of the predicted secretome members encoded lineage-specific proteins, similarities with experimentally characterized fungal effectors were also identified. A SAGE analysis indicated a strong stage-specific regulation of transcripts encoding secreted proteins. The average sequence identity of putative secreted proteins to their closest orthologs in the wheat stem rust Puccinia graminis f. sp. tritici was dramatically reduced compared with non-secreted ones. A comparative genomics approach based on homologous gene groups unravelled positive selection in putative members of the secretome. We uncovered robust evidence that different evolutionary constraints are acting on the rust secretome when compared to the rest of the genome. These results are consistent with the view that these genes are more likely to exhibit an effector activity and be involved in coevolutionary arms races with host factors.


Current role of endoscopic combined intrarenal surgery in the management of renal stones: A scoping review.
This study aims to review the current role of endoscopic combined intrarenal surgery (ECIRS) in the management of renal stones, with a focus on its efficacy and safety. The secondary outcome was to highlight the tips and tricks to improve the urologist's experience with ECIRS. A scoping review of the literature, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, was performed, using ECIRS and flexible ureteroscopy and percutaneous nephrolithotomy as the search terms. All original articles were screened and included. Thirty-three studies were included in the analysis. ECIRS showed a good efficacy and safety profile, with an excellent stone-free rate and a low rate of complications, mostly Clavien-Dindo I/II. With ECIRS, a reduction in the need for multiple access tracts was noted and direct visualization of the targeted calyx during the puncture increased the ability to attain transpapillary punctures, thereby reducing the amount of bleeding. ECIRS, as the first-line minimal access intervention, is safe and efficacious, particularly for achieving a stone-free status in patients with large complex stones in a single stage. The ability to gain access under direct vision and the reduction in the number of tracts, in both the supine and the prone positions, makes this procedure an attractive surgical choice.


Circular RNA Sequencing of Maternal Platelets: A Novel Tool for the Identification of Pregnancy-Specific Biomarkers.
In the first trimester of pregnancy, the maternal platelet is directly involved in a positive feedback mechanism that facilitates invasion of the extravillous trophoblast into the maternal spiral arteries. Dysfunctional trophoblast invasion with defective deep placentation is primordial in the etiology of the "great obstetrical syndromes." In this proof-of-concept study, using transcriptome analysis of circular RNA (circRNA) following RNA sequencing of maternal platelets, we tested whether pregnancy-specific circRNA markers could be identified in the first trimester of normal pregnancies. Differential transcript expression analysis of circRNAs, as predicted by Accurate CircRNA Finder Suite, CircRNA Identifier (version 2), and Known and Novel Isoform Explorer, was done using thromboSeq.R with variation of multiple settings. Test performance was checked for (a) de novo circRNA identification using the novel platelet-specific Plt-circR4 as a positive control, (b) complete segregation of groups (pregnant vs nonpregnant) after heat map-dendrogram clustering, (c) identification of pregnancy-specific circRNA markers at a false discovery rate (FDR) <0.05, and (d) confirmation of differentially expressed circRNA markers with an FDR <0.05 by an independent method, reverse transcription-quantitative PCR. Of the differentially expressed circRNAs with P values <0.05, 41 circRNAs were upregulated (logFC >2), and 52 circRNAs were downregulated (logFC less than -2) in first-trimester platelet RNA. Of these, nuclear receptor-interacting protein 1 circRNA covering exons 2 and 3 of the 5'-untranslated region was pregnancy specific with upregulation in first-trimester maternal platelets compared to nonpregnant controls. CircRNA sequencing of first-trimester maternal platelets permits the identification of novel pregnancy-specific RNA biomarkers. Future use could include the assessment of maternal and fetal well-being.


mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer.
Activating mutations of the PIK3CA gene occur frequently in breast cancer, and inhibitors that are specific for phosphatidylinositol 3-kinase (PI3K) p110α, such as BYL719, are being investigated in clinical trials. In a search for correlates of sensitivity to p110α inhibition among PIK3CA-mutant breast cancer cell lines, we observed that sensitivity to BYL719 (as assessed by cell proliferation) was associated with full inhibition of signaling through the TORC1 pathway. Conversely, cancer cells that were resistant to BYL719 had persistently active mTORC1 signaling, although Akt phosphorylation was inhibited. Similarly, in patients, pS6 (residues 240/4) expression (a marker of mTORC1 signaling) was associated with tumor response to BYL719, and mTORC1 was found to be reactivated in tumors from patients whose disease progressed after treatment. In PIK3CA-mutant cancer cell lines with persistent mTORC1 signaling despite PI3K p110α blockade (that is, resistance), the addition of the allosteric mTORC1 inhibitor RAD001 to the cells along with BYL719 resulted in reversal of resistance in vitro and in vivo. Finally, we found that growth factors such as insulin-like growth factor 1 and neuregulin 1 can activate mammalian target of rapamycin (mTOR) and mediate resistance to BYL719. Our findings suggest that simultaneous administration of mTORC1 inhibitors may enhance the clinical activity of p110α-targeted drugs and delay the appearance of resistance.


Symptoms of posttraumatic stress disorder in a clinical sample of refugees: a network analysis.
Background: Network analysis is an emerging methodology for investigating psychopathological symptoms. Given the unprecedented number of refugees and the increased prevalence of mental disorders such as posttraumatic stress disorder (PTSD) in this population, new methodologies that help us better to understand psychopathology in refugees are crucial. Objective: The objective of this study was to explore the network structure and centrality indices of DSM-5 PTSD symptoms in a cross-sectional clinical sample of 151 severely traumatized refugees with and without a formal PTSD diagnosis. Method: The R-packages qgraph and bootnet were used to estimate the structure of a PTSD symptom network and its centrality indices. In addition, robustness and significance analyses for the edges weights and the order of centrality were performed. Results: Three pairs of symptoms showed significantly stronger connections than at least half of the other connections: hypervigilance and exaggerated startle response, intrusion and difficulties falling asleep, and irritability or outbursts of anger and self-destructive or reckless behaviour. Emotional cue reactivity had the highest centrality and trauma-related amnesia the lowest. Conclusion: Although only 51.0% of participants fulfilled criteria for a probable PTSD diagnosis, emotional cue reactivity showed the highest centrality, emphasizing the importance of emotional trauma reminders in severely traumatized refugees attending an outpatient clinic. However, due to the small sample size, the results should be interpreted with care.


Microarray analysis of Akt1 activation in transgenic mouse hearts reveals transcript expression profiles associated with compensatory hypertrophy and failure.
To investigate molecular mechanisms involved in the development of cardiac hypertrophy and heart failure, we developed a tetracycline-regulated transgenic system to conditionally switch a constitutively active form of the Akt1 protein kinase on or off in the adult heart. Short-term activation (2 wk) of Akt1 resulted in completely reversible hypertrophy with maintained contractility. In contrast, chronic Akt1 activation (6 wk) induced extensive cardiac hypertrophy, severe contractile dysfunction, and massive interstitial fibrosis. The focus of this study was to create a transcript expression profile of the heart as it undergoes reversible Akt1-mediated hypertrophy and during the transition from compensated hypertrophy to heart failure. Heart tissue was analyzed before transgene induction, 2 wk after transgene induction, 2 wk of transgene induction followed by 2 days of repression, 6 wk after transgene induction, and 6 wk of transgene induction followed by 2 wk of repression. Acute overexpression of Akt1 (2 wk) leads to changes in the expression of 826 transcripts relative to noninduced hearts, whereas chronic induction (6 wk) led to changes in the expression of 1,611, of which 65% represented transcripts that were regulated during the pathological phase of heart growth. Another set of genes identified was uniquely regulated during heart regression but not growth, indicating that nonoverlapping transcription programs participate in the processes of cardiac hypertrophy and atrophy. These data define the gene regulatory programs downstream of Akt that control heart size and contribute to the transition from compensatory hypertrophy to heart failure.


Haplotypes vs single marker linkage disequilibrium tests: what do we gain?
The genetic dissection of complex diseases represents a formidable challenge for modern human genetics. Recently, it has been suggested that linkage disequilibrium (LD) based methods will be a powerful approach for delineating complex disease genes. Most proposed LD test statistics search for association between a single marker and a putative trait locus. However, the power of a single marker association test may suffer because LD information contained in flanking markers is ignored. Intuitively, haplotypes (which can be regarded as a collection of ordered markers) may be more powerful than individual, unorganised markers. In this study, we derive the analytical tools based on standard chi-square statistics to directly investigate and compare the power between multilocus haplotypes and single marker LD tests. More specifically, novel formulas are obtained in order to calculate expected haplotype frequencies of unlimited size. This study demonstrates that the use of haplotypes can significantly improve the power and robustness of mapping disease genes. Additionally, we detail how the power of haplotype based association tests are affected by important population genetic parameters such as the genetic distance between markers and disease locus, mode of disease inheritance, age of trait causing mutation, frequency of associated marker allele, and level of initial LD. Finally, published data from the Hereditary Hemochromatosis disease region is used to illustrate the utility of haplotypes.


Ion Transporters and Osmoregulation in the Kidney of Teleost Fishes as a Function of Salinity.
Euryhaline teleosts exhibit major changes in renal function as they move between freshwater (FW) and seawater (SW) environments, thus tolerating large fluctuations in salinity. In FW, the kidney excretes large volumes of water through high glomerular filtration rates (GFR) and low tubular reabsorption rates, while actively reabsorbing most ions at high rates. The excreted product has a high urine flow rate (UFR) with a dilute composition. In SW, GFR is greatly reduced, and the tubules reabsorb as much water as possible, while actively secreting divalent ions. The excreted product has a low UFR, and is almost isosmotic to the blood plasma, with Mg2+, SO4 2-, and Cl- as the major ionic components. Early studies at the organismal level have described these basic patterns, while in the last two decades, studies of regulation at the cell and molecular level have been implemented, though only in a few euryhaline groups (salmonids, eels, tilapias, and fugus). There have been few studies combining the two approaches. The aim of the review is to integrate known aspects of renal physiology (reabsorption and secretion) with more recent advances in molecular water and solute physiology (gene and protein function of transporters). The renal transporters addressed include the subunits of the Na+, K+- ATPase (NKA) enzyme, monovalent ion transporters for Na+, Cl-, and K+ (NKCC1, NKCC2, CLC-K, NCC, ROMK2), water transport pathways [aquaporins (AQP), claudins (CLDN)], and divalent ion transporters for SO4 2-, Mg2+, and Ca2+ (SLC26A6, SLC26A1, SLC13A1, SLC41A1, CNNM2, CNNM3, NCX1, NCX2, PMCA). For each transport category, we address the current understanding at the molecular level, try to synthesize it with classical knowledge of overall renal function, and highlight knowledge gaps. Future research on the kidney of euryhaline fishes should focus on integrating changes in kidney reabsorption and secretion of ions with changes in transporter function at the cellular and molecular level (gene and protein verification) in different regions of the nephrons. An increased focus on the kidney individually and its functional integration with the other osmoregulatory organs (gills, skin and intestine) in maintaining overall homeostasis will have applied relevance for aquaculture.


Nerve injury and grades II and III ankle sprains.
Nerve injuries associated with inversion sprains of the ankle have been mentioned in the literature on a case presentation basis only. Sixty-six consecutive patients with Grade II (30) and Grade III (36) ankle sprains were examined by electromyography 2 weeks after injury to determine the presence and distribution of nerve injuries. Ankle active range of motion (AROM) and the number of weeks postinjury when the patient could heel/toe walk and return to full activity were also noted. Five patients (17%) with Grade II sprains had mild peroneal nerve injury and three (10%) injured the tibial nerve. Clinical measurements were normal by the end of the second week. Thirty-one patients (86%) with Grade III sprains injured their peroneal nerve, while 30 (83%) incurred posterior tibial nerve injury. Ankle AROM was impaired, and heel/toe walking (5.1 weeks) and return to full activity (5.3 weeks) were markedly prolonged. The likely cause of this injury is considered to be a mild nerve traction or a hematoma in the epineural sheath at the bifurcation of the sciatic nerve into peroneal and posterior tibial branches. This report indicates that a consistently high percentage of patients with Grade III ankle sprains sustain a significant injury to both motor nerves in the leg and that rehabilitation time is markedly prolonged.


Reversible intramolecular hydrogen transfer: a completely new mechanism for low impact sensitivity of energetic materials.
The intramolecular H transfer of energetic NO2-compounds has been recognized as a possible primary step in triggering molecular decomposition for a long time. Nevertheless, studies on H transfer in different complex situations are limited, lacking a comprehensive understanding of its role in NO2-compounds. In this work, twenty intramolecular H transfer reactions are studied for eighteen nitro compounds and compared with the NO2 partition in thermodynamics and kinetics. Three factors, including the high planarity of molecules, the short transfer distance between the target H and O atoms and the high protonation of the H atom are identified to facilitate H transfer. If H transfer is more kinetically favorable than NO2 partition, and if a reverse H transfer occurs with a barrier less than 30 kcal mol-1, we define it as a reversible one. In our study, for those impact insensitive nitro compounds with H50 larger than that of 2,4,6-trinitrotoluene, all of them are found to be accompanied with reversible H transfer, while the impact sensitive compounds are not. Accordingly, we propose that the reversible H transfer can effectively buffer the external stimuli against the molecular decomposition through chemical energy absorption/release. Beyond the conventional understanding that H transfer triggers molecular decomposition, this work builds a new correlation between reversible H transfer and the low impact sensitivity of energetic nitro-compounds.


Mammalian BUB1 protein kinases: map positions and in vivo expression.
The spindle assembly checkpoint modulates the timing of anaphase initiation in mitotic cells containing improperly aligned chromosomes and increases the probability of successful delivery of a euploid chromosome set to each daughter cell. We have characterized cDNA sequences from several organisms with highly significant predicted protein sequence homologies to Saccharomyces cerevisiae Bub1p, a protein required for function of the spindle assembly checkpoint in budding yeast. The localization of mouse and human orthologs is in agreement with known conservation of synteny. Mouse backcross mapping data indicate that the murine gene resides on chromosome 2 near IL1A, 73 cM from the mouse centromere. Radiation hybrid mapping data indicate that the human locus exhibits linkage to microsatellite marker D2S176, which is located within 10 cM of human IL1A. Multiple-tissue Northern analysis indicates conservation of expression pattern in mouse and human with markedly high mRNA levels in testis. Northern analysis of two different spindle assembly checkpoint protein gene products from human, BUB1 and MAD2, reveals an expression pattern with common tissue distribution consistent with roles in a common pathway. In addition, we demonstrate that an mRNA found to accumulate in a rat fibroblast cell transformation system encodes rat BUB1, and we find that rat BUB1 mRNA accumulation correlates with the proliferation status of cells in culture.


Identification of leptospiral 3-hydroxyacyl-CoA dehydrogenase released in the urine of infected hamsters.
Leptospirosis is a global zoonosis caused by pathogenic Leptospira. The non-specific clinical signs and symptoms of leptospirosis lead to its misdiagnosis. To date, there is still no reliable rapid test kit that can accurately diagnose leptospirosis at bedside or in field. In this research, with the ultimate goal of formulating a rapid and accurate diagnostic tool for leptospirosis, we aimed to identify leptospiral proteins excreted in urine of infected hamsters, which are thought to mimic Weil's disease. Hamsters were subcutaneously infected with leptospires, and the general attributes of urine as well as the proteins excreted in it were examined. Some leptospiral proteins were found to be excreted in the urine from the early phase of infection. The most important finding of this study was the detection of the lipid-metabolizing enzyme, 3-hydroxyacyl-CoA dehydrogenase (HADH), before the onset of illness, when leptospires were not yet detected in the urine of infected hamsters. This is the first report on the detection of leptospiral HADH in the host urine, which may be a possible candidate leptospiral antigen that can be used in the early diagnosis of human and animal leptospirosis.


Venomics of Leiurus abdullahbayrami, the most lethal scorpion in the Levant region of the Middle East.
The scorpion Leiurus abdullahbayrami has been associated with severe/lethal envenomings throughout the Levant region of the Middle East, encompassing Turkey, Syria, and Lebanon, and only scarce information is available on its venom composition, activity, and antigenicity. We report on the composition of L. abdullahbayrami venom collected from Lebanese specimens using nESI-MS/MS, MALDI-TOF MS, SDS-PAGE and RP-HPLC. Venom lethality, through LD50 determination in mice (intraperitoneal), was also assessed (0.75 (0.16-1.09) mg/kg), confirming L.abdullahbayrami venom vertebrate toxicity. Fifty-four peaks were detected using RP-HPLC, half of which eluted in the gradient region between 20 and 40% acetonitrile. In reducing SDS-PAGE, most predominant components were <10 kDa, with minor components at higher molecular masses of 24.4, 43.1, and 48.9 kDa. Venom mass fingerprint by MALDI-TOF detected 21 components within the 1000-12,000 m/z range. Whole venom 'shotgun' bottom-up nLC-MS/MS approach, combined with in-gel tryptic digestion of SDS-PAGE bands, identified at least 113 different components belonging to 15 venom families and uncharacterized proteins, with ion channel-active components (K+ channel toxins (28); Na+ channel toxins (42); Cl- channel toxins (4); Ca+2 toxins (2)) being predominant. A single match for a L. adbullahbayrami NaTx was found in the UniProt database with other congeneric species, toxin h3.1 from Leiurus hebraeus, suggesting this might be an indication of venom divergence within Leiurus, eventhough this warrants further investigation involving venom proteomics and transcriptomics of relevant species. Considering such potential interspecific venom variation, future work should address whether preparation of a specific anti-L. abdullahbayrami antivenom is justified.


[Why do men use health services less than women? Explanations by men with low versus higher education].
The objective of this study was to analyze explanations in male discourse for men's relatively limited use of health services, using a qualitative methodology. Representation of caring as a female task, work-related issues, difficult access to services, and lack of services specifically targeting men's health were the main reasons for their limited use of health services. By way of conclusion, the social imagination by which men are viewed as invulnerable leads them to take less care of their own health and expose themselves to greater risk.


A technique for resolution of graft-tunnel length mismatch in central third bone-patellar tendon-bone anterior cruciate ligament reconstruction.
The existence of graft-tunnel length mismatch in correctly reconstructed anterior cruciate ligament (ACL)-deficient patients can occur due to both anatomic variation and compromised tunnel placement encountered during revision, despite attempts at prevention with accurate measurement techniques. This study reports a method for resolution of graft-tunnel length mismatch during central third bone-patellar tendon-bone ACL reconstruction. The technique involves rotation of the graft to shorten its length. Variation in graft shortening occurs depending on the direction of rotation, with external rotation achieving greater shortening. At 630 degrees of external rotation, approximately 25% shortening of the collagenous portion of the graft can be achieved, which allows for adequate bitunnel interference fixation in most instances. This technique can be used during difficult ACL reconstructions, both primary and revision, and may also have uses in routine reconstructions. Early clinical results are presented.


In vivo quantification of transvascular water exchange during the acute phase of permanent stroke.
Mechanisms that underlie early ischemic damages to the blood-brain-barrier (BBB) are not well understood. This study presents a novel magnetic resonance imaging (MRI) technique using a widely available pulse sequence and a long-circulating intravascular contrast agent to quantify water movements across the BBB at early stages of stroke progression. We characterized the integrity of the BBB by measuring the flip angle dependence of the water exchange-affected MRI signal intensity, to generate an efficient quantitative index of vascular permeability (WEI, or water exchange index). We performed in vivo MRI experiments to measure the transvascular WEI immediately after the permanent filament occlusion of the middle cerebral artery of mice (n = 5), in which we monitored changes in blood volume (V(b)), apparent diffusion coefficient (ADC), and intra-/extravascular WEI for 4 hours. Statistically significant elevations (P < 0.05) of WEI in the ischemic tissue were observed as early as 1 hour after ischemic onset. Initial reduction of the apparent blood volume (V(app)) in the infarct cortex was followed by a continuous increase of V(app) over time. Although the measured ADC in the ipsilesional cortex continuously decreased, the abnormally high intra-/extravascular WEI remained constant at a significantly elevated level, indicating apparent BBB injury at this early stage of stroke.


Occupational exposures and salivary gland cancer mortality among African American and white workers in the United States.
We conducted a large death certificate-based case-control study to assess occupational risks for salivary gland cancer. African American (168 cases, 672 controls) and white (2237 cases, 8748 controls) cases from 24 states (1984-1989) were matched to controls by age, sex, race, and region. Race- and sex-stratified multiple logistic regression models calculated adjusted odds ratios. The proportion of young cases (<50 years) was greatest among African Americans (20.8% vs. 8.8%). Higher socioeconomic status, ionizing radiation, formaldehyde, solvents, outdoor work, and animal contact were associated with elevated risk among white men. Physical activity reduced mortality risks among men, although significantly only among whites. Odds ratios for formaldehyde, solvents, benzene, and animal contact were 2.0 or greater among African American women, although not statistically significant. These findings suggest occupational and demographic factors needing further investigation.


Localization of CD9, an enhancer protein for proheparin-binding epidermal growth factor-like growth factor, in human atherosclerotic plaques: possible involvement of juxtacrine growth mechanism on smooth muscle cell proliferation.
Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), a member of the EGF family, has a potent mitogenic activity for vascular smooth muscle cells (SMCs). We previously reported that HB-EGF is involved in atherogenesis of human aorta and coronary arteries. ProHB-EGF (the membrane-anchored form of HB-EGF) has also been demonstrated to possess a mitogenic activity, which is approximately 30-fold increased when coexpressed with CD9 in mouse L cells. Thus, in the process of atherogenesis, CD9 may be involved in the proliferation of SMCs. We immunohistochemically investigated the localization of CD9 and proHB-EGF in the human aorta and coronary arteries. In normal aorta and coronary arteries, CD9 immunostaining was virtually negative, whereas proHB-EGF immunostaining was positive, especially in the arteries of babies. In contrast, in atherosclerotic lesions, some intimal SMCs were strongly positive for CD9 and proHB-EGF immunostaining. The juxtacrine growth activities of human aortic SMCs were inhibited in vitro by adding neutralization antibodies for CD9 or adding the specific inhibitor of HB-EGF. Besides, coexpressed CD9 and proHB-EGF cells markedly incorporated [(3)H]thymidine into the SMCs. CD9 is localized immunohistochemically in the SMCs of the atherosclerotic aorta and coronary arteries. CD9, when coexpressed with proHB-EGF, enhances proHB-EGF activities for SMC growth in a so-called juxtacrine manner in vitro and may be involved in atherogenesis.


Chemically induced DNA hypomethylation in breast carcinoma cells detected by the amplification of intermethylated sites.
Compromised patterns of gene expression result in genomic instability, altered patterns of gene expression and tumour formation. Specifically, aberrant DNA hypermethylation in gene promoter regions leads to gene silencing, whereas global hypomethylation events can result in chromosomal instability and oncogene activation. Potential links exist between environmental agents and DNA methylation, but the destabilizing effects of environmental exposures on the DNA methylation machinery are not understood within the context of breast cancer aetiology. We assessed genome-wide changes in methylation patterns using a unique methylation profiling technique called amplification of intermethylated sites (AIMS). This method generates easily readable fingerprints that represent the investigated cell line's methylation profile, based on the differential cleavage of DNA with methylation-specific isoschisomeric restriction endonucleases. We validated this approach by demonstrating both unique and reoccurring sites of genomic hypomethylation in four breast carcinoma cell lines treated with the cytosine analogue 5-azacytidine. Comparison of treated with control samples revealed individual bands that exhibited methylation changes, and these bands were excized and cloned, and the precise genomic location individually identified. In most cases, these regions of hypomethylation coincided with susceptible target regions previously associated with chromosome breakage, rearrangement and gene amplification. Similarly, we observed that acute benzopyrene exposure is associated with altered methylation patterns in these cell lines. These results reinforce the link between environmental exposures, DNA methylation and breast cancer, and support a role for AIMS as a rapid, affordable screening method to identify environmentally induced DNA methylation changes that occur in tumourigenesis.


From Athletes to Astrophysicists: Gender Differences in Patterns and Predictors of Career Aspirations in Pre-Adolescence.
This paper adds to research on girls' growing educational advantage by examining gender differences in career paths. Using baseline data from an intervention study (TRY-IT!) targeting 265 sixth-graders in Title I schools, our research traces adolescent career aspirations by gender, race and class. Additionally, we investigate whether girls and boys exhibit differential sensitivity to environmental risk and protective factors that shape career and educational aspirations. We find that the career choices of boys vary more widely by social context, including socioeconomic status, race, and academic resources. Specifically, among youth with fewer social and academic advantages, girls aspire to more practical careers and careers which require higher levels of educational attainment relative to boys. The findings reveal how sources of inequality such as race and class shape gendered aspirations and complicate gender inequality. We reason that boys' choices are more volatile and socially contingent because of the emphasis on high-status careers as a signifier of masculinity.


[Optical coherence tomography, an important new tool in the investigation of the retina].
Optical coherence tomography, an important new tool in the investigation ofthe retina Recently optical coherence tomography (OCT) has been introduced into the field of ophthalmology to enhance visualization ofthe various retinal layers. OCT uses interference of near infra-red, low-coherent light reflected from the retina and from a reference mirror, to create transverse sections of the retina. The strength of the signal is a measure of the reflection of the retinal layer which is situated at the same distance from the light source as the mirror. Accurate placement ofthe mirror gives a transverse view of the retina with an axial resolution of 10 microm, with which the resolution of a histological section can be approximated. OCT is used in ophthalmic diseases such as macular oedema, macular holes and other abnormalities on the retinal-vitreous border, following photodynamic therapy and in treating glaucoma. OCT has been used to detect early glaucoma by measuring the thickness of the retinal nerve fibre layer. OCT and fluorescence angiography complement one another as diagnostic methods but OCT is superior in the diagnosis of macular oedema and macular holes. OCT provides images of retinal pathology which can easily be interpreted by both ophthalmologists and patients.


Challenges facing professional nurses implementing the Integrated Management of Childhood Illness programme in rural primary health care clinics, Limpopo Province, South Africa.
Under-five mortality and morbidity could be reduced through increased implementation of the Integrated Management of Childhood Illness (IMCI) strategy. The aim of the study was to determine challenges facing IMCI-trained professional nurses on implementing this strategy when managing children less than 5 years of age. A quantitative descriptive survey method was used. The target populations were IMCI-trained professional nurses with the sample of 208 respondents. Data were collected through self-report questionnaires and analysed using statistical analysis system software. The implementation of the IMCI strategy by IMCI-trained professional nurses in Vhembe primary health care (PHC) clinics continues to face challenges, making it difficult for professional nurses to follow guidelines. These challenges range from staff barriers, management barriers, poor management process and poor infrastructure. All these challenges lead to poor-quality under-five patient care. Regardless of the IMCI strategy being implemented since its inception in 1999, the under-five mortality remains not reduced. This is related to the identified challenges facing the IMCI-trained professional nurses implementing the strategy.


Development curves of communication and social interaction in individuals with cerebral palsy.
To determine development curves of communication and social interaction from childhood into adulthood for individuals with cerebral palsy (CP). This Pediatric Rehabilitation Research in the Netherlands (PERRIN)-DECADE study longitudinally assessed 421 individuals with CP, aged from 1 to 20 years at baseline, after 13 years (n=121 at follow-up). Communication and social interactions were assessed using the Vineland Adaptive Behavior Scales. We estimated the average maximum performance limit (level) and age at which 90% of the limit was reached (age90 ) using nonlinear mixed-effects modeling. One-hundred individuals without intellectual disability were aged 21 to 34 years at follow-up (39 females, 61 males) (mean age [SD] 28y 5mo [3y 11mo]). Limits of individuals without intellectual disability, regardless of Gross Motor Function Classification System (GMFCS) level, approached the maximum score and were significantly higher than those of individuals with intellectual disability. Ages90 ranged between 3 and 4 years for receptive communication, 6 and 7 years for expressive communication and interrelationships, 12 and 16 years for written communication, 13 and 16 years for play and leisure, and 14 and 16 years for coping. Twenty-one individuals with intellectual disability were between 21 and 27 years at follow-up (8 females, 13 males) (mean age [SD] 24y 7mo [1y 8mo]). Individuals with intellectual disability in GMFCS level V showed the least favourable development, but variation between individuals with intellectual disability was large. Individuals with CP and without intellectual disability show developmental curves of communication and social interactions similar to typically developing individuals, regardless of their level of motor function. Those with intellectual disability reach lower performance levels and vary largely in individual development. Communication and social interactions in individuals with cerebral palsy without intellectual disability develop similarly to typically developing individuals. Communication and social interactions of individuals with intellectual disability develop less favourably and show large variation.


International reference study on the identification and scoring of human chromosome aberrations. Results of a WHO comparative study.
Chromosome aberrations in human peripheral blood are recognized parameters of cellular damage and are used as indicators of exposure to ionizing radiation and certain chemicals. However, significant interlaboratory variability exists in the results reported from different laboratories. The primary objective of the present study was to examine problems associated with the identification and analysis of chromosome aberrations. Significant interlaboratory variability was found to exist in the analysis of human chromosome spreads for induced interphase aberrations, apparently owing in part to differences in the selection and rejection of spreads for scoring and also in the recognition and classification of various types of aberrations. These differences are reflected in the dose-response relationships for aberrations as well as for damaged spreads. For damaged spreads the scoring variability appears to be relatively small. It is inferred that factors additional to differences in scoring may play a significant role in the large variation in the reported dose-response relationships both for ionizing radiation and for chemically induced aberrations.


Hemangiopericytoma of the skull base: A long-term complete response with trimodality treatment.
Hemangiopericytoma (HPC) is a rare tumor originating from Zimmerman pericytes. It constitutes less than 1% of all intracranial tumors. Because of the high recurrence rates, radiotherapy (RT) is a vital step in the treatment, but the timing and dose remain uncertain. We presented a 39-year-old patient with a high-grade hemangiopericytoma located at the skull base. The patient presented with a severe headache. Cranial magnetic resonance imaging (MRI) revealed a mass of size of 60 × 50 mm. A subtotal resection was performed that confirmed the diagnosis of HPC. The patient received 66 Gy postoperative RT. Adjuvant sunitinib treatment was initiated after RT. The complete regression was achieved in the third month after RT. The patient has a complete response for 25 months. To our knowledge, this case is one of the rare cases in the literature in which immediate RT and adjuvant chemotherapy were used in combination with surgery. Although HPC is a radio- and chemo-resistant disease, a trimodality treatment approach can provide the patients with a complete response. In particular, patients with high-grade and inoperable tumors and patients who undergo subtotal resection should be evaluated for trimodal therapy.


Persistent postoperative pain after cardiac surgery: a systematic review with meta-analysis regarding incidence and pain intensity.
Persistent postoperative pain (PPP) has been described as a complication of cardiac surgery (CS). We aimed to study PPP after CS (PPPCS) by conducting a systematic review of the literature regarding its incidence, intensity, location, and the presence of neuropathic pain, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The review comprised 3 phases: a methodological assessment of 6 different databases identifying potential articles and screening for inclusion criteria by 2 independent reviewers; data extraction; and study quality assessment. Meta-analysis was used to estimate the pooled incidence rates using a random effects model. We have identified 442 potentially relevant studies through database searching. A total of 23 studies (involving 11,057 patients) met our inclusion criteria. Persistent postoperative pain affects 37% patients in the first 6 months after CS, and it remains present more than 2 years after CS in 17%. The reported incidence of PPP during the first 6 months after CS increased in recent years. Globally, approximately half of the patients with PPPCS reported moderate to severe pain. Chest is the main location of PPPCS followed by the leg; neuropathic pain is present in the majority of the patients. This is the first systematic review and meta-analysis to provide estimates regarding incidence and intensity of PPPCS, which elucidates its relevance. There is an urgent need for adequate treatment and follow-up in patients with PPPCS.


Use of intravenous sodium bicarbonate in neonatal intensive care units in Italy: a nationwide survey.
Metabolic Acidosis (MA) is a disturbance of the acid-base balance that can occur in preterm and critically ill term neonates due to different etiologies. Intravenous sodium bicarbonate (SB) has been traditionally used to correct such unbalance, despite the lack of evidence about its safety and efficacy. In literature, reported undesirable effects of treatment with SB in neonates include worsening of intracellular acidosis, impairment of myocardial function, cerebral blood flow fluctuations and intracranial hemorrhage. A national survey was conducted by the Neonatal Pharmacotherapy Study Group of the Italian Society of Neonatology with the aim to assess and describe attitudes and practices concerning the use of SB, particularly for the treatment of MA in Italian NICUs. A questionnaire regarding treatment of MA and SB prescription habits was sent to the directors of 120 Italian NICUs from June 2017 to March 2018. The survey response rate was 97.5% (117/120 centers). Findings showed that in 55% of the surveyed NICUs (64/117 units) it is common practice to correct MA with intravenous SB. On the other hand, the remaining 45% of the units try to solve the metabolic disturbances adopting different approaches (improving perfusion, adjusting ventilation parameters or increasing blood volume). Moreover, to prevent the occurrence of MA, 37.6% of the NICUs (44/117) include buffer salts (lactate, acetate or both) in parenteral nutrition prescriptions. SB is also used as a treatment for other conditions, mainly pathologies with bicarbonate loss and tubular acidosis (respectively in 53.8 and 32.5% of the NICUs). This survey showed how SB is a commonly used treatment for MA in more than half of Italian NICUs, with indications and prescription criteria that significantly vary across centers. Based on current knowledge, it is reasonable to suggest that the management of neonatal MA should be firstly directed to identify the underlying disorders. Thus, the use of SB should be reserved only for selected cases, also considering the severity of SB adverse effects and the lack of evidence about its efficacy. Guidance for the management of MA is required to harmonize practices and reduce the use of potentially inappropriate and unsafe treatments.


Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5.
The ribonucleic acid (RNA) helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) recognize distinct viral and synthetic RNAs, leading to the production of interferons. Although 5'-triphosphate single-stranded RNA is a RIG-I ligand, the role of RIG-I and MDA5 in double-stranded (ds) RNA recognition remains to be characterized. In this study, we show that the length of dsRNA is important for differential recognition by RIG-I and MDA5. The MDA5 ligand, polyinosinic-polycytidylic acid, was converted to a RIG-I ligand after shortening of the dsRNA length. In addition, viral dsRNAs differentially activated RIG-I and MDA5, depending on their length. Vesicular stomatitis virus infection generated dsRNA, which is responsible for RIG-I-mediated recognition. Collectively, RIG-I detects dsRNAs without a 5'-triphosphate end, and RIG-I and MDA5 selectively recognize short and long dsRNAs, respectively.


Expression of p63 and Proliferating Cell Nuclear Antigen in Oral Submucous Fibrosis.
Oral squamous cell carcinoma (OSCC) may be preceded by potentially malignant disorders such as oral submucous fibrosis (OSMF). p63 can detect genetic changes in OSMF and it facilitates early detection of malignant transformation, whereas proliferating cell nuclear antigen (PCNA) is a marker of proliferation and may prove to be a useful objective indicator of the biological behavior of various tumors. The aim of this study was to investigate the expression and pattern of the intensity of p63 protein and PCNA in normal oral mucosa and OSMF using immunohistochemistry (IHC) and to correlate the expression of these biomarkers. A total of 15 archival paraffin-embedded blocks obtained from our department, which were histopathologically diagnosed early OSMF (n = 4), intermediate OSMF (n = 4), and advanced OSMF (n = 2) and normal mucosa (n = 5), were taken as the standard for comparison. p63 and PCNA positivity was analyzed using Kruskall-Wallis test followed by pairwise comparison using Mann-Whitney U test. The pattern of staining and intensity was compared using Chi-Square test for which Statistical Package for the Social Sciences (SPSS, v 22.0, IBM Corporation, Armonk, New York) was used. All samples showed positive staining for p63 and PCNA. A statistically significant difference (P < 0.05) was seen between the frequency of occurrence of p63 and the PCNA pattern of expression among all the groups. The intensity of staining was mild to intense in the basal layer, as there was a progression toward the severity of the disease. Almost 75.4% correlation existed between p63 and PCNA, with high correlation and marked relationship. The OSMF is considered a potentially malignant disorder that has the potential to get transformed into OSCC. The malignant transformation is often associated with changes at the genetic level, and these are reflected by the altered expression of proteins. Our results showed that biomarkers such as p63 and PCNA are significant in predicting the malignant transformation in OSMF, so in future they may serve as a prognostic tool in the early detection of malignancies.