Programming DNA Nanoassembly for Enhanced Photodynamic Therapy.
Photodynamic therapy (PDT) has extraordinary promise for the treatment of many cancers. However, its clinical progress is impaired by the intrinsic hypoxic tumor microenvironment that limits PDT efficacy and the safety concern associated with biological specificity of photosensitizers or vehicles. Now it is demonstrated that rationally designed DNA nanosponges can load and delivery photosensitizer effectively, target tumor precisely, and relieve hypoxia-associated resistance remarkably to enhance the efficacy of PDT. Specifically, the approach exhibits a facile assembly process, provides programmable and versatile nanocarriers, and enables robust in vitro and in vivo anti-cancer efficacy with excellent biosafety. These findings represent a practical and safe approach by designer DNA nanoassemblies to combat cancer effectively and suggest a powerful strategy for broad biomedical application of PDT.


Combination of de novo assembly of massive sequencing reads with classical repeat prediction improves identification of repetitive sequences in Schistosoma mansoni.
The genome of the parasitic platyhelminth Schistosoma mansoni is composed of approximately 40% of repetitive sequences of which roughly 20% correspond to transposable elements. When the genome sequence became available, conventional repeat prediction programs were used to find these repeats, but only a fraction could be identified. To exhaustively characterize the repeats we applied a new massive sequencing based strategy: we re-sequenced the genome by next generation sequencing, aligned the sequencing reads to the genome and assembled all multiple-hit reads into contigs corresponding to the repetitive part of the genome. We present here, for the first time, this de novo repeat assembly strategy and we confirm that such assembly is feasible. We identified and annotated 4,143 new repeats in the S. mansoni genome. At least one third of the repeats are transcribed. This strategy allowed us also to identify 14 new microsatellite markers, which can be used for pedigree studies. Annotations and the combined (previously known and new) 5,420 repeat sequences (corresponding to 47% of the genome) are available for download (http://methdb.univ-perp.fr/downloads/).


[The antisteatosic activity of 2-MPG (Thiola). Study with the (BSF) dynamic test and with liver biopsy before and after the treatment].
The short-term therapeutic effect of 2-MPG has been studied in 12 patients suffering from chronic liver disease of prevalent steatosic type. The drug was administered in a dose of 2.5 g. for 20 days. Patients were submitted to hepatic needle biopsy and BSF load test, with compartmental analysis before and after treatment. A marked reduction in steatosis and a statistically significant fall in BSF retention at the 45th minute, with increase in conjugation and excretion of colorant, was observed in 11 patients.


Comparison of the transfer of 125I, 82Br, and 26Cl into the growing oocytes of the Japanese quail.
Laying Japanese quail were doubly-labeled with either 125I and 36Cl or 82Br and 36Cl. Eighteen-hour accumulations, expressed as percent of tracer doses, were: growing oocytes, 125I 48.2 vs. 36Cl 2.07, 82Br 4.01 vs. 36Cl 1.99; thyroids, 125I 10.6 vs. 36Cl .030, 82Br .027 vs. 36Cl .020. Concentrations (expressed as percent per gram) of the radionuclides in the growing oocytes and the thyroids as compared with concentrations in the plasma were: for oocytes, the mean 125I concentration was 199 times the mean plasma concentration, 82Br was .34 x and 36Cl was .13 x; for thyroids, 125I was 13,500 x, 82Br was .48 x, and 36Cl was .41 x the mean plasma concentration. Eight day totals for yolks of eggs laid were 125I 29% vs. 36Cl 3.7%.


Interspecies comparison of pharmacokinetic profile and bioavailability of (+/-)-gossypol in male Fischer-344 rats and male B6C3F mice.
Gossypol is a naturally occurring yellow substance in cotton plant that has male reproductive toxicity both in humans and some experimental animal species. Interspecies oral bioavailability and pharmacokinetic profile of (+/-)-gossypol were compared in male Fischer-344 rats and B6C3F mice after a 1) single intravenous dose, 2) single oral dose, and 3) 14 consecutive, daily, oral doses; all doses were 10 and 50 mg/kg rats and mice, respectively. In both species, the intravenous plasma (+/-)-gossypol concentrations showed a triexponential pattern, indicating a 3-compartment, open-model system. The apparent half-life of elimination of (+/-)-gossypol following intravenous injection was 9.1 h and 7.7 h in rats and mice, respectively. The total plasma clearance (Cl), volume of distribution (Vd), and AUCplasma after a single intravenous injection were 1.84 and 1.23 l/h per kg, 0.20 and 1.74 l/kg, and 36.0 and 115.8 mg.h/l, in rats and mice, respectively. The bioavailability of a single, oral dose of (+/-)-gossypol was 86% and 14.3% in rats and mice, respectively. In rats the change in plasma (+/-)-gossypol concentration after a single, dose was monophasic; multiple doses showed a biphasic pattern. In mice a single, dose of (+/-)-gossypol showed a biexponential plasma concentration pattern; daily dosing was monoexponential and was eliminated twice as fast as the single dose. Also, multiple doses of (+/-)-gossypol in the mouse were eliminated 7 times faster than in the rat. These findings are consistent with previous results that daily, oral dosing of (+/-)-gossypol, but not a single dose, produces infertility in the male rat, while the mouse is insensitive to (+/-)-gossypol action. The results of this study indicate that differential sensitivity of rats and mice to the contraceptive action of (+/-)-gossypol may be related, at least in part, to its pharmacokinetic profiles in both species.


Preparation of the renal function and imaging agent 99mTc-MAG3 starting from S-unprotected mercaptoacetyltriglycine.
A new approach that obviates inconvenient heating of the labelling solution when preparing the renal function and imaging agent 99mTc-MAG3 is described. The labelling procedure involves reduction of 99mTc-generator eluate with stannous chloride in alkaline solution in the presence of S-unprotected mercaptoacetyltriglycine (MAG3) and the co-ligand sodium tartrate, followed by neutralization with a phosphate buffer solution. After optimization of the kit preparation the radiochemical purity of the radiopharmaceutical amounts to greater than 98%. During the labelling process intermediate Tc-species occur.


Long-term exposure to polystyrene nanoparticles causes transgenerational toxicity by affecting the function and expression of MEV-1 and DAF-2 signals in Caenorhabditis elegans.
In this study, we determined the roles of oxidative stress and related signals in mediating transgenerational toxicity of 30 nm polystyrene nanoparticles (PS-NPs) in Caenorhabditis elegans. Using brood size and locomotion behavior as endpoints, exposure to 1-100 μg/L PS-NPs caused transgenerational toxicity. Meanwhile, the activation of reactive oxygen species (ROS) was also observed transgenerationally after exposure to 1-100 μg/L PS-NPs. After exposure to 1 μg/L PS-NPs, the transgenerational toxicity was monitored until F2 generation (F2-G) and recovered at F3-G. At the F1-G of 1 μg/L PS-NPs-exposed nematodes, RNAi knockdown of daf-2 with function to inhibit oxidative stress suppressed the transgenerational toxicity and increased the mitochondrial SOD-3 expression. In contrast, at F3-G of 1 μg/L PS-NPs-exposed nematodes, RNAi knockdown of mev-1 with function to induce oxidative stress promoted locomotion and brood size, and suppressed the SOD-3 expression. Moreover, we observed the dynamic expressions of mev-1, daf-2, and sod-2 transgenerationally after exposure to 1 μg/L PS-NPs at P0-G, which further suggested the involvement of MEV-1, DAF-2, and SOD-3 in affecting induction of transgenerational PS-NP toxicity. Therefore, we provided the evidence to suggest the roles of oxidative stress activation and related molecular signals in mediating induction of transgenerational PS-NP toxicity. Our data highlights the crucial function of oxidative stress-related signals during induction of transgenerational PS-NP toxicity.


Refined Sphenopalatine Ganglion Stimulator Placement and Intensity Setting to Augment Blood Flow and Neurologic Function.
Background and Purpose- Two large, randomized trials indicated that sphenopalatine ganglion (SPG) stimulation improves final disability outcome in acute anterior circulation patients with ischemic stroke with confirmed cortical involvement. This study evaluated 2 refinements in SPG stimulation treatment technique: (1) SPG electrode placement with real-time optical tracking guidance; and (2) stimulation intensity comfortable tolerance level selection using non-noxious facial physiological markers. Methods- This study was a single, active arm trial at 4 centers, enrolling patients with anterior circulation ischemic stroke, National Institutes of Health Stroke Scale 1 to 6 including arm weakness subitem score ≥1, not receiving recanalization therapies, and within 24 hours of onset. Stimulation level was set based on ipsilateral facial tingling sensation or lacrimation. SPG stimulation effects were assessed by measuring volumetric blood flow in the ipsilateral common carotid artery by ultrasound and grasp and pinch strength in the affected hand before and during stimulation, and by change in National Institutes of Health Stroke Scale from day 1 to 7. Results- Among 50 enrolled patients, age was median 66 years (interquartile range, 60-74), 44% were female, National Institutes of Health Stroke Scale median was 5 (interquartile range, 4-5), and median onset-to-screening time was 18 hours (interquartile range, 9-20). Median implantation skin-to-skin time was 4 minutes (interquartile range, 3-7), and all 50 implants were placed correctly. Comfortable tolerance level was found based on physiological biomarkers in 96% of patients, including 86% in the optimal, low-medium intensity range. SPG stimulation significantly increased common carotid artery peak systolic and end-diastolic blood flow (44%, P<0.0001; and 52%, P<0.0001) and improved pinch strength (42%, P<0.0001) and grasp strength (26%, P<0.0001). Degree of National Institutes of Health Stroke Scale recovery by day 7 was greater than in matched historic controls, median 75% versus 50%, P=0.0003. Conclusions- SPG stimulator placement with real-time optical tracking guidance was fast and accurate, and selection of stimulation intensity levels based on non-noxious facial tingling and lacrimation was feasible in nearly all patients. SPG stimulation led to cervico-cranial blood flow augmentation and improved hand motor function. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03551093.


Cellpose 2.0: how to train your own model.
Pretrained neural network models for biological segmentation can provide good out-of-the-box results for many image types. However, such models do not allow users to adapt the segmentation style to their specific needs and can perform suboptimally for test images that are very different from the training images. Here we introduce Cellpose 2.0, a new package that includes an ensemble of diverse pretrained models as well as a human-in-the-loop pipeline for rapid prototyping of new custom models. We show that models pretrained on the Cellpose dataset can be fine-tuned with only 500-1,000 user-annotated regions of interest (ROI) to perform nearly as well as models trained on entire datasets with up to 200,000 ROI. A human-in-the-loop approach further reduced the required user annotation to 100-200 ROI, while maintaining high-quality segmentations. We provide software tools such as an annotation graphical user interface, a model zoo and a human-in-the-loop pipeline to facilitate the adoption of Cellpose 2.0.


Analysis of epidermal growth factor receptor mRNA expression by polymerase chain reaction assay in 94 human breast adenocarcinoma tumors.
It is well known that breast cancer cells can synthesize and secrete various growth factors that are able to stimulate tumor growth through autocrine and/or paracrine mechanisms. EGF is one of these growth factors involved in normal breast epithelial development and tumor proliferation. EGF and TGF alpha (EGF-like peptide) are produced in variable amounts and both bind to the EGF receptor (EGF-R). Previous investigation in the laboratory measuring free and occupied EGF-R sites by differential ligand binding assays had demonstrated that non-occupied and total binding sites were present in 54 and 90% of 216 breast tumor biopsies respectively. EGF-R appeared to be totally masked by endogenous ligand in 40 and 21% of estrogen receptor positive and negative tumors respectively. The aim of the present study was to check by a molecular method the expression of the EGF-R gene. The PCR method was applied to 94 tumor samples of the previous series. Total RNA was treated with 0.5 units of Rnase-free Dnase/mg of RNA to remove any contaminating DNA. We simultaneously reverse transcribed and amplified another transcript (beta-actin) as an internal standard. Both signals were present in 88 of the 94 samples while the presence of EGF-R was detected in 74 of them when assessed by radioligand assay. The findings indicate that 93% of the tumors analysed in this series expressed EGF-R mRNA, in agreement with our previous data on occupied EGF-R sites, i.e. two-fold more than by using the standard binding assay. No significant correlation was observed between the expression of the EGF-R gene and the estrogen receptor content.


Glycerol restores heat-induced p53-dependent apoptosis of human glioblastoma cells bearing mutant p53.
We have previously reported that glycerol acts as a chemical chaperone to restore the expression of WAF1 in some human cancer cell lines bearing mutant p53. Since the expression of WAF1 is up-regulated by activated wildtype p53, glycerol appears to restore wtp53 function. The aim of the present study is to examine the restoration of heat-induced p53-dependent apoptosis by glycerol in human glioblastoma cells (A-172) transfected with a vector carrying a mutant p53 gene (A-172/mp53 cells) or neo control vector (A-172/neo cells). A-172/mp53 cells showed heat resistance compared with A-172/neo cells but A-172/mp53 cells in turn became heat sensitive when pre-treated with glycerol before heat treatment. The accumulation of Bax in the A-172/mp53 cells was induced by heating with glycerol pre-treatment, but not without it, whereas the accumulation in the A-172/neo cells was induced in both cases. Furthermore, mp53 extracted from heated cells came to bind to the sequence specific region after heating combined with glycerol pre-treatment. The phosphorylation of mp53 at serine15 was suppressed by an inhibitor of the phosphatidylinositol 3-kinase (PI3-K) family. These results suggest that glycerol is effective in inducing conformational change of phosphorylated p53 and restoring mp53 to wtp53 function, leading to enhanced heat sensitivity through the induction of apoptosis. This novel tool for enhancement of heat sensitivity in cancer cells bearing mp53 may be applicable for p53-targeted hyperthermia, because mutation or inactivation of p53 is observed in approximately 50% of human cancers.


Echocardiography of the mitral valve.
Mitral valve disease is the second most common valvular heart disease after the aortic valve worldwide. Mitral valve has historically been a structure of interest by pioneers in echocardiography. One of the earliest applications of echocardiography was in the diagnosis of valvular heart disease, particularly mitral stenosis. In this review we wish to take the reader through the structural and hemodynamic evaluation of the normal mitral valve.


Responses of stream zooplankton diversity metrics to eutrophication and temporal environmental variability in agricultural catchments.
Eutrophication of rivers and streams in agricultural lands is one of the main threats for biodiversity and ecosystem functions. This study was focused on seven subtropical streams where agriculture is the predominant land use. We tested the hypothesis that (i) eutrophication causes a decrease in taxonomic and functional diversity of zooplankton, leading to potential consequences for the ecosystem integrity. Furthermore, given that the temporal variability in the environmental conditions of each stream may influence the species sorting mechanisms, we also hypothesized that (ii) streams with higher temporal environmental variability have greater taxonomic and functional alpha (α) and temporal beta (βt) diversity measures regardless of the trophic state. Thus, we characterized the streams according to their trophic state and analyzed the zooplankton composition, α and βt by using taxonomic and functional perspectives. We found differences in the zooplankton composition between mesotrophic and eutrophic streams. However, eutrophic streams supported similar taxonomic and functional α diversity and similar taxonomic βt diversity to mesotrophic ones. These results were mainly explained by the occurrence of rare species occupying different temporal niches in eutrophic systems. On the contrary, functional βt diversity was lower in the eutrophic streams, being nestedness the ecological mechanisms underlying the variability in the zooplankton functional groups. Streams with higher temporal environmental variability supported greater α taxonomic diversity. However, the βt diversity metrics showed no correlation with the environmental variability, suggesting that the environmental filters of the studied systems were the overriding determinants of species turnover. Our study suggests that both taxonomic and functional perspectives should be considered to improve our knowledge on the biotic responses to environmental changes. Also, among all metrics analyzed on the zooplankton community, functional βt diversity was the most sensitive indicator of the eutrophication impact.


The Effect of Intermittent Vest Cooling on Thermoregulation and Cardiovascular Strain in Baseball Catchers.
Bishop, SH, Szymanski, DJ, Ryan, GA, Herron, RL, and Bishop, PA. The effect of intermittent vest cooling on thermoregulation and cardiovascular strain in baseball catchers. J Strength Cond Res 31(8): 2060-2065, 2017-Baseball catchers are exposed to multiple physiological challenges while playing outside during the spring and summer months, many of which deal with recovery and thermoregulation. The purpose of this study was to investigate the effect of intermittent cooling on core temperature, cardiovascular strain, exertion, and recovery during a simulated catching performance in the heat. Six trained college-aged baseball catchers performed in a controlled, hot (35° C), and humid (25% relative humidity) environment in a counter-balanced, cross-over design. Ice vest cooling (VC) was used as a cooling modality and was compared with a control of no cooling (NC). Rectal temperature (Tre), heart rate (HR), rating of perceived exertion (RPE), and perceived recovery scale (PRS) were recorded before and after each simulated inning. All activities took place in a heat chamber, and each inning consisted of catchers receiving 12 pitches in their position followed by 6 minutes of recovery. Nine total innings were performed, and 27 total innings were performed with each of the 2 treatments. A significantly smaller mean Tre change was seen in VC when compared with NC (0.58 ± 0.2° C, 0.98 ± 0.2° C, p ≤ 0.01, respectively). Rating of perceived exertion was significantly lower and PRS was significantly improved for VC compared with NC (both p ≤ 0.05). Mean recovery HR during VC was significantly lower than NC in the fifth (VC = 84 ± 8 b·min, NC = 90 ± 9 b·min, p = 0.04), seventh (VC = 84 ± 3 b·min, NC = 92 ± 7 b·min, p = 0.02), and ninth (VC = 85 ± 7 b·min, NC = 93 ± 5 b·min, p = 0.01) innings. Heart rate during catching was significantly lower at the end of the VC trials when compared with NC (108 ± 16 b·min vs. 120 ± 19 b·min, p = 0.02, respectively). Vest cooling decreased heat strain, cardiovascular strain, and RPE while it improved perceived recovery in catchers over a simulated 3-game series performed in hot conditions.


Delta thermal radiomics: An application in dairy cow teats.
We describe a novel approach for analyzing thermal images by way of radiomics (i.e., thermal radiomics) and how it can be used to monitor short-term temperature changes of dairy cow hind teats; that is, delta thermal radiomics. The heat generated from metabolic activities and blood-flow patterns can be visualized using thermal radiography of the skin surface. The hind teats from 25 dairy cows were imaged with a digital thermal camera and the images were converted to medical images (DICOM format) by mapping the multi-channel colorized thermal image to a monochromatic image whose intensities represent temperature. The 50 teats (left and right hind) were then manually segmented by 2 investigators. Radiomics analysis, which is a common method of extracting semantic and nonsemantic image biomarkers from medical images for machine learning, was performed. To evaluate whether this approach can detect pre- and postmilking differences, 18 cows were imaged before and after milking, the teats were manually segmented, and radiomic calculations were performed. Student's t-test was used to provide an estimate of the likelihood of whether postmilking thermal image biomarkers are the same as premilking thermal image biomarkers, and Cohen's d was used to evaluate the size of the effect (d > 1.2). To evaluate uncertainties from manual segmentation, the Dice similarity score (DS) between the 2 investigators' segments was computed. The average DS (95% confidence limit) was 0.952 (0.913-0.982) when comparing the 2 investigators' segmentations. There was no significant difference in DS when comparing the left and right segmented teats, suggesting that teats can be segmented consistently. No differences (d < 0.36) were observed when comparing image biomarkers from one investigator's segments with the other's, suggesting that image biomarkers computed from one investigator's segmentation of teats are not likely to differ from those computed from the other investigator. When comparing image biomarkers before and after milking, 109 image biomarkers were analyzed, and 17 image biomarkers were simultaneously significant and exhibited effect size. Thus, delta thermal radiomics offers a noninvasive and quantitative method of monitoring skin temperature changes in humans and animals after an intervention. The advantage of this approach is that it can reveal both perceptible and imperceptible surface temperature features that may be useful for detecting and managing dairy teat health.


A highly expressed odorant receptor from the yellow fever mosquito, AaegOR11, responds to (+)- and (-)-fenchone and a phenolic repellent.
The cornerstone of the reverse chemical ecology approach is the identification of odorant receptors (OR) sensitive to compounds in a large panel of odorants. In this approach, we de-orphanize ORs and, subsequently, measure behaviors elicited by these semiochemicals. After that, we evaluate behaviorally active compounds for applications in insect vector management. Intriguingly, multiple ORs encoded by genes highly expressed in mosquito antennae do not respond to any test odorant. One such case is CquiOR125 from the southern house mosquito, Culex quinquefasciatus Say. To better understand CquiOR125's role in Culex mosquito olfaction, we have cloned a CquiOR125 orthologue in the genome of the yellow fever mosquito, Aedes aegypti (L.), AaegOR11. Unlike the unresponsive nature of the orthologue in Cx. quinquefasciatus, oocytes co-expressing AaegOR11 and AaegOrco elicited robust responses when challenged with fenchone, 2,3-dimethylphenol, 3,4-dimethylphenol, 4-methycyclohexanol, and acetophenone. Interestingly, AaegOR11 responded strongly and equally to (+)- and (-)-fenchone, with no chiral discrimination. Contrary to reports in the literature, fenchone did not show any repellency activity against Ae. aegypti or Cx. quinquefasciatus. Laboratory and field tests did not show significant increases in egg captures in cups filled with fenchone solutions compared to control cups. The second most potent ligand, 2,3-dimethylphenol, showed repellency activity stronger than that elicited by DEET at the same dose. We, therefore, concluded that AaegOR11 is a mosquito repellent sensor. It is feasible that CquiOR125 responds to repellents that remain elusive.


Two examples of rapid and simple drug analysis in pharmaceutical formulations using capillary electrophoresis: naphazoline, dexamethasone and benzalkonium in nose drops and nystatin in an oily suspension.
Capillary electrophoresis is a versatile tool in pharmaceutical analysis. In the course of a revision of the "Standardrezepturen", a German formula of standard dispensings for preparation in pharmacies, this technique has been applied to drug analysis in pharmaceutical formulations. The present paper deals with two different examples. First, naphazoline, dexamethasone and the preservative benzalkonium are quantified in nose drops without any sample preparation. Second, the antifungal antibiotic nystatin is quantified using nonaqueous capillary electrophoresis in methanol after sample preparation from an oily suspension.


The efficacy and safety of PDE5 inhibitors.
Inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cyclic guanosine monophosphate, which allows erectile function to occur by relaxation of penile smooth muscle. Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) in a range of doses are available. PDE5 therapy, compared with placebo, significantly improves scores on the International Index of Erectile Function and has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. Sildenafil and vardenafil show some interaction with food intake. Time to onset of action is usually 30-120 minutes, but there are reports of shorter times to onset of action. The duration of action of sildenafil and vardenafil is about 4 hours, whereas that of tadalafil is about 36 hours. The overall safety of the treatments is good, even in patients with a history of cardiovascular disease. However, there is a risk of hypotension if nitrates are given concurrently. Increased QTc intervals have been reported, the longest with vardenafil, shortest with tadalafil, and intermediate with sildenafil. Priapism and prolonged erection are rare adverse events. Common side-effects include headache, facial flushing, nasal congestion, and dyspepsia. There may be interactions with other medications metabolized in a similar way, such as erythromycin and HIV protease inhibitors.


Stereotactic body radiation therapy for treatment of primary and metastatic pulmonary malignancies.
Stereotactic body radiation therapy (SBRT) has become the preferred treatment approach for patients with stage I non-small cell lung cancer who are medically inoperable or refuse surgery. SBRT consists of 3 to 5 radiation treatments delivered over a 10- to 14-day period. Local control is achieved in approximately 90% of patients, and the risk of toxicity is relatively low. Ongoing studies are examining whether SBRT can replace surgery for certain patients, the optimal dose-fractionation scheme, and how best to treat patients having central tumors near the primary tracheobronchial tree.


Peripheral Neural Interface.
Peripheral nervous system, widely spread in the whole body, is the important bridge for the transmission of neural signals. Signals from the central nervous system (brain and spinal cord) are transmitted to different parts of the body by the peripheral nerves, while along the way they also feedback all kinds of sensory information. Certain level of information integration and processing also occurs in the system. It has been shown that neural signals could be extracted from the distal end of the stump, indicating that the bridge is still effective after limb damage or amputation, which is the neurophysiological basis for the research and development of peripheral nerve interface for the prosthetic system.


Gender and Ethnic Diversity in Academic Facial Plastic Surgery.
Characterize academic facial plastic surgeons by demographics, time in practice, academic productivity, and faculty position. Cross-sectional study. Facial plastic surgery faculty in US otolaryngology residencies with a title of assistant professor, associate professor, or professor were identified. Demographics and academic data were obtained from public profiles and Scopus. One hundred sixty-eight surgeons were identified. Females comprised 25.6%. Most surgeons were White (69.6%), followed by Asian (25%), Hispanic (3.6%), and Black (1.8%). Mean h-index was similar between sexes when controlling for years in practice (1.13 vs. 1.14, p = 0.575). Female representation was greater among early-career surgeons (41%) than among mid- or late-career surgeons (24% and 13%, respectively) (p = 0.006). The correlation of years in practice with academic title was similar between sexes. There was no difference in h-index (p = 0.384) or distribution of academic positions (p = 0.658) between White and non-White surgeons. There was no statistical difference in full professorship (p = 1.0) or research productivity (p = 0.974) between late-career White and non-White academic facial plastic surgeons. There was no statistical difference in promotion from assistant professorship (p = 0.506) or research productivity (p = 0.857) between White and non-White surgeons in practice for over 5 years. Female representation in academic facial plastic surgery is low, though greater gender parity among younger surgeons suggests an improving trend. Hispanic and Black surgeons remain significantly underrepresented in the field. Although increased diversity is needed in academic facial plastic surgery, established minority surgeons have experienced similar research productivity and advancement through academic ranks as their majority counterparts. N/A Laryngoscope, 133:1869-1874, 2023.


The TEAD family transcription factor Scalloped regulates blood progenitor maintenance and proliferation in Drosophila through PDGF/VEGFR receptor (Pvr) signaling.
The Drosophila lymph gland is a well-characterized hematopoietic organ in which a population of multipotent stem-like progenitors is maintained by a combination of signals from different cellular populations within the organ. The lymph gland serves as an ideal model both for the interrogation of signaling mechanisms involved in progenitor maintenance as well as a tool for the identification of novel regulatory mechanisms in the highly conserved process of hematopoiesis. Here, we demonstrate a requirement for the TEAD transcription factor Scalloped in the maintenance and proliferation of hematopoietic progenitors. We have characterized a novel population of hemocytes in the early lymph gland identified by the expression of Hand, Scalloped, and the PVR ligand PVF2. In this unique population, we show that Scalloped maintains PVF2 expression, which is required for hemocyte proliferation and achievement of normal lymph gland size. We further demonstrate that STAT signaling marks actively proliferating hemocytes in the early lymph gland, and inhibition of this pathway causes decreased lymph gland growth similar to loss of Scalloped and PVF2, demonstrating a requirement for PVR/STAT signaling in the regulation of lymph gland size. Finally, we demonstrate that Scalloped regulates PVR expression and the maintenance of progenitors downstream of PVR/STAT/ADGF signaling. These findings further establish the role of the TEAD family transcription factors in the regulation of important signaling molecules, and expand our mechanistic insight into the balance between progenitor maintenance and proliferation required for the regulation of lymph gland homeostasis.


The reproductive regulation of LPXRFa and its receptor in the hypothalamo-pituitary-gonadal axis of the spotted scat (Scatophagus argus).
Gonadotropin-inhibitory hormone (GnIH) plays a critical role in regulating gonadotropin-releasing hormone (GnRH), gonadotropin hormone (GtH), and steroidogenesis. The Lpxrfa (the piscine ortholog of GnIH) system has been found to regulate fish reproduction. To gain insight into the role of Lpxrfa in the regulation of spotted scat (Scatophagus argus) reproduction, spotted scat Lpxrfa (ssLpxrfa), and its receptor (ssLpxrfa-r) were cloned and analyzed. Tissue distribution and expression patterns at the hypothalamo-pituitary-gonadal axis (HPG axis) of sslpxrfa and sslpxrfa-r mRNA were also investigated during gonadal development of spotted scat. The open reading frame (ORF) of the sslpxrfa was 606 bp encoding 201 amino acids and includes a putative signal peptide and two mature ssLpxrfa peptides with LPXRFamide motif at their C-terminus. The sslpxrfa-r ORF was 1449 bp encoding 482 amino acids and contracted a seven-hydrophobic transmembrane (TM) domain structure. The tissue distribution showe d that the sslpxrfa was highly expressed in hypothalami, gill, and the gonads. In addition, sslpxrfa-r was highly expressed in hypothalami, pituitaries, and the gonads. Quantitative real-time polymerase chain reaction (qPCR) revealed that sslpxrfa had the highest expression in the hypothalami and pituitaries, and the lowest expression in the gonads in stage V. During gonadal development, the expression of sslpxrfa-r was gradually increased in the hypothalami but reduced in the gonads. However, no obvious trend was observed in the pituitaries. The expression of sslpxrfa and sslpxrfa-r decreased significantly after injection with 17β-estradiol (E2). However, the expression of both sslpxrfa and sslpxrfa-r was not changed after injection with 17α-methyltestosterone(17α-MT) in the hypothalami. In addition, no changes were observed in the expression of fshβ and lhβ in the pituitaries after injecting ssLpxrfa-1. However, ssLpxrfa-2 could downregulate the expression of sbgnrh and fshβ in the hypothalami and pituitaries, respectively. Taken together, these findings suggested that ssLpxrfa may participate in E2 feedback in reproduction and regulate the reproductive axis of spotted scat.


Capillary supply of skeletal muscle fibers in untrained and endurance-trained women.
Muscle fiber diameters and number of capillaries per fiber, per mm2 and around each fiber were determined in needle biopsies from the lateral part of the quadriceps muscles of 11 young women. Six subjects were untrained (UT) and five were endurance-trained athletes (ET). Average values for maximal oxygen uptake were 43.9 (UT) and 62.1 ml/kg X min (ET). Mean fiber diameter was somewhat smaller in the UT than in the ET group (39.1 and 42.7 micrometer), but the difference was not statistically significant. Fibers with the highest content of mitochondria were on the average 9 micrometer thicker than those with the lowest content. The capillary per fiber ratios were 1.11 +/- 0.07 (mean +/- S.E.) and 1.69 +/- 0.13 in the UT and ET groups, respectively. The number of capillaries around each fiber was 3.04 +/- 0.17 (UT) and 4.42 +/- 0.31 (ET). After correction for shrinkage the number of capillaries per mm2 was 301 (UT) and 404 (ET). The capillary per fiber ratio increased with increasing fiber diameter and with the content content of mitochondria.


Diabetes insipidus.
Diabetes insipidus (DI) is a disorder characterized by a high hypotonic urinary output of more than 50ml per kg body weight per 24 hours, with associated polydipsia of more than 3 liters a day [1,2]. Central DI results from inadequate secretion and usually deficient synthesis of Arginine vasopressin (AVP) in the hypothalamus or pituitary gland. Besides central DI further underlying etiologies of DI can be due to other primary forms (renal origin) or secondary forms of polyuria (resulting from primary polydipsia). All these forms belong to the Polyuria Polydipsia Syndrom (PPS). In most cases central and nephrogenic DI are acquired, but there are also congenital forms caused by genetic mutations of the AVP gene (central DI) [3] or by mutations in the gene for the AVP V2R or the AQP2 water channel (nephrogenic DI) [4]. Primary polydipsia (PP) as secondary form of polyuria includes an excessive intake of large amounts of fluid leading to polyuria in the presence of intact AVP secretion and appropriate antidiuretic renal response. Differentiation between the three mentioned entities is difficult [5], especially in patients with Primary polydipsia or partial, mild forms of DI [1,6], but different tests for differential diagnosis, most recently based on measurement of copeptin, and a thorough medical history mostly lead to the correct diagnosis. This is important since treatment strategies vary and application of the wrong treatment can be dangerous [7]. Treatment of central DI consists of fluid management and drug therapy with the synthetic AVP analogue Desmopressin (DDAVP), that is used as nasal or oral preparation in most cases. Main side effect can be dilutional hyponatremia [8]. In this review we will focus on central diabetes insipidus and describe the prevalence, the clinical manifestations, the etiology as well as the differential diagnosis and management of central diabetes insipidus in the out- and inpatient setting.


Standardizing SPECT/CT dosimetry following radioembolization with yttrium-90 microspheres.
Multiple post-treatment dosimetry methods are currently under investigation for Yttrium-90 ([Formula: see text]) radioembolization. Within each methodology, a variety of dosimetric inputs exists that affect the final dose estimates. Understanding their effects is essential to facilitating proper dose analysis and crucial in the eventual standardization of radioembolization dosimetry. The purpose of this study is to investigate the dose differences due to different self-calibrations and mass density assignments in the non-compartmental and local deposition methods. A practical mean correction method was introduced that permits dosimetry in images where the quality is compromised by patient motion and partial volume effects. Twenty-one patients underwent [Formula: see text] radioembolization and were imaged with SPECT/CT. Five different self-calibrations (FOV, Body, OAR, Liverlung, and Liver) were implemented and dosimetrically compared. The non-compartmental and local deposition method were used to perform dosimetry based on either nominal- or CT calibration-based mass densities. A mean correction method was derived assuming homogeneous densities. Cumulative dose volume histograms, linear regressions, boxplots, and Bland Altman plots were utilized for analysis. Up to 270% weighted dose difference was found between self-calibrations with mean dose differences up to 50 Gy in the liver and 23 Gy in the lungs. Between the local deposition and non-compartmental methods, the liver and lung had dose differences within 0.71 Gy and 20 Gy, respectively. The local deposition method's nominal and CT calibration-based mass density implementations dosimetric metrics were within 1.4% in the liver and 24% in the lungs. The mean lung doses calculated with the CT method were shown to be inflated. The mean correction method demonstrated that the corrected mean doses were greater by up to [Formula: see text] Gy in the liver and lower by up to [Formula: see text] Gy in the lungs. The OAR calibration may be utilized as a potentially more accurate and precise self-calibration. The non-compartmental method was found more comparable to the local deposition method in organs that were more homogeneous in mass densities. Due to the potential for inflated lung mean doses, the non-compartmental and local deposition method implemented with nominal mass densities is recommended for more consistent dosimetric results. If patient motion and partial volume effects are present in the liver, our practical correction method will calculate more representative doses in images suboptimal for dosimetry.


Relaxation-compensated amide proton transfer (APT) MRI signal intensity is associated with survival and progression in high-grade glioma patients.
The purpose of this study was to investigate the association of relaxation-compensated chemical exchange saturation transfer (CEST) MRI with overall survival (OS) and progression-free survival (PFS) in newly diagnosed high-grade glioma (HGG) patients. Twenty-six patients with newly diagnosed high-grade glioma (WHO grades III-IV) were included in this prospective IRB-approved study. CEST MRI was performed on a 7.0-T whole-body scanner. Association of patient OS/PFS with relaxation-compensated CEST MRI (amide proton transfer (APT), relayed nuclear Overhauser effect (rNOE)/NOE, downfield-rNOE-suppressed APT (dns-APT)) and diffusion-weighted imaging (apparent diffusion coefficient) were assessed using the univariate Cox proportional hazards regression model. Hazard ratios (HRs) and corresponding 95% confidence intervals were calculated. Furthermore, OS/PFS association with clinical parameters (age, gender, O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status, and therapy: biopsy + radio-chemotherapy vs. debulking surgery + radio-chemotherapy) were tested accordingly. Relaxation-compensated APT MRI was significantly correlated with patient OS (HR = 3.15, p = 0.02) and PFS (HR = 1.83, p = 0.009). The strongest association with PFS was found for the dns-APT metric (HR = 2.61, p = 0.002). These results still stand for the relaxation-compensated APT contrasts in a homogenous subcohort of n = 22 glioblastoma patients with isocitrate dehydrogenase (IDH) wild-type status. Among the tested clinical parameters, patient age (HR = 1.1, p = 0.001) and therapy (HR = 3.68, p = 0.026) were significant for OS; age additionally for PFS (HR = 1.04, p = 0.048). Relaxation-compensated APT MRI signal intensity is associated with overall survival and progression-free survival in newly diagnosed, previously untreated glioma patients and may, therefore, help to customize treatment and response monitoring in the future. • Amide proton transfer (APT) MRI signal intensity is associated with overall survival and progression in glioma patients. • Relaxation compensation enhances the information value of APT MRI in tumors. • Chemical exchange saturation transfer (CEST) MRI may serve as a non-invasive biomarker to predict prognosis and customize treatment.


[Polymorphism study of small nuclear ribonucleoprotein polypeptide N gene rs220030 by DGGE].
To analyze the polymorphism of rs220030, a SNP which is located in the promoter region of small nuclear ribonucleoprotein polypeptide N (SNRPN) gene in the Chinese Han population and to obtain the data of population genetics. The denaturing gradient gel electrophoresis (DGGE) method was applied to detect the polymorphism of rs220030 in 100 unrelated and healthy individuals from the Shanghai Han population. The genotyping result of this SNP was confirmed by TaqMan assay in some typical samples. DGGE results showed 4 bands for CT heterozygote, and 1 band for CC or TT homozygote, and those results were confirmed by The TaqMan SNP genotyping assays. Genotyping results showed 34 individuals with CC, 41 with CT and 25 with TT of rs220030. The allele frequencies for C and T were 0.545 and 0.455, respectively. H was 0.500, PIC was 0.373, DP was 0.654, and PE was 0.186. The distribution of genotype frequencies were in Hardy-Weinberg equilibrium. DGGE is a quick and effective method in the analysis of SNP polymorphism in small population. Statistical parameters of rs220030 for forensic evaluation meet the requirements for forensic identification and paternity testing.


In Vitro Dosing Performance of the ELLIPTA® Dry Powder Inhaler Using Asthma and COPD Patient Inhalation Profiles Replicated with the Electronic Lung (eLung™).
To evaluate the in vitro dose delivery characteristics of approved asthma and chronic obstructive pulmonary disease (COPD) therapies delivered via the ELLIPTA(®) dry powder inhaler across inhalation endpoints representative of the target patient population, using the Electronic Lung (eLung™) to replicate inhaler-specific patient inhalation profiles that were previously recorded in vivo. Selected profiles, representative of the range of inhalation endpoints achieved by patients with all severities of asthma and COPD, were replicated using the eLung breathing simulator in conjunction with an oropharyngeal cast. A Next Generation Impactor was coupled to the eLung to determine the aerodynamic particle size distribution of the ex-throat dose (ETD) of asthma and COPD therapies delivered via the ELLIPTA inhaler. Delivered dose (DD), ETD, and fine particle dose (FPD; defined as a mass of active substance less than 5 μm) were determined for fluticasone furoate (FF)/vilanterol (VI) 100/25 μg and 200/25 μg (asthma and COPD), umeclidinium (UMEC)/VI 62.5/25 μg (COPD only), FF 100 μg and 200μg monotherapy (asthma only), and UMEC 62.5 μg monotherapy (COPD only). Inhalation profiles replicated by eLung covered a wide range of peak inspiratory flow rates (41.6-136.9 L/min), pressure drops (1.2-13.8 kPa), and inhaled volumes through the inhaler (0.7-4.2L). DD was consistent across the range of patient representative inhalation parameters for all components (FF, VI, and UMEC) of each therapy assessed; although ETD and FPD were also generally consistent, some small variation was observed. Dose delivery was consistent for each of the components, whether delivered as mono- or combination therapy. The in vitro performance of the ELLIPTA inhaler has been demonstrated for the delivery of FF/VI, UMEC/VI, FF monotherapy, and UMEC monotherapy. Across a range of inspiratory profiles, DD was consistent, while ETD and FPD showed little flow dependency.


The relationship between oxidized lipoprotein(a) and carotid atherosclerosis in asymptomatic subjects: a comparison with native lipoprotein(a).
Oxidized lipoprotein(a) (oxLp(a)) can be a more potent marker of atherogenesis than native Lp(a), although Lp(a) is considered to be a risk factor for atherosclerotic diseases. Limited clinical data are available regarding the significance of oxLp(a) in atherosclerotic manifestations. This study aimed to investigate the association between the serum oxLp(a) and carotid artery intima-media thickness (CIMT), in comparison to the serum Lp(a) levels, among asymptomatic subjects. The atheroscrerosis-related variables including Lp(a) and oxLp(a) were measured in 136 cardiovascular disease-free subjects (61 males and 75 females, mean age of 64 years). The serum oxLp(a) level was quantified using a sandwich ELISA system. The CIMT level was ultrasonographically measured on bilateral carotid arteries. The median level of Lp(a) was 120 μmol/L, oxLp(a) was 0.06 nmol/L, and CIMT was 0.7 mm, respectively. A simple correlation test showed that the CIMT was significantly and positively correlated with age, systolic blood pressure and oxLp(a) (r = 0.208, P < 0.05). A multiple linear regression analysis revealed that oxLp(a) continued to show a significant and positive correlation with the CIMT (β = 0.202, P = 0.01). Although the similar analyses were conducted for Lp(a), it showed only a weak correlation with the CIMT (r = 0.011, β = 0.041, both P < 0.05). These results suggest that oxLp(a) may be more closely associated with accelerated carotid atherosclerosis, in comparison to Lp(a), in this population. This finding can be important for obtaining a better understanding of the different atherogenic roles played by oxLp(a) in comparison to Lp(a).


Incidence and prognosis of N4 node involvement in gastric cancer.
We have undertaken a prospective study of the frequency and prognosis associated with N4 node metastases in gastric cancer in 136 patients referred for surgical treatment between 1976 and 1983. N4 node metastases (pre-aortic or hepatic hilar nodes) were present in 20 of 31 patients who had a laparotomy without resection (64 per cent), in 2 of 8 patients who had a 'palliative' resection in the presence of distant metastases (25 per cent) and, in 19 of 85 patients who had a 'curative' resection (22 per cent). The median survival in patients having a 'curative' resection with N4 nodes was 4.5 months which was only marginally longer than in patients having a 'palliative' resection (median survival 3 months). In view of these findings and since immediate imprint cytology can be used to detect nodal metastases at operation, involvement of N4 nodes might be a contra-indication to extensive gastric resection in non-obstructing gastric cancer.


Comparation of the phytotoxicity between chemically and green synthesized silver nanoparticles.
Green synthesis of silver nanoparticles (Ag NPs) by using plants extracts has provided an eco-friendly alternation for industry and agriculture application. Here, we prepared Ag NPs by using the cucumber leaves and rice husk extracts, and further assessed the antimicrobial activity and phytotoxicity of green synthesized Ag NPs (g-Ag NPs) comparing with chemically synthesized Ag NPs (chem-Ag NPs). The chem-Ag NPs had strong antibacterial activity on the growth of Escherichia coli, while g-Ag NPs by rice husks (gr-Ag NPs) exhibited long-term antibacterial effects. In terms of phytotoxicity, the chem-Ag NPs induced over-generation of ROS and activated plant antioxidant defense systems, thus resulting in the upregulation of MDA and Zn contents and downregulation of antioxidant capacity, carotenoid, globulin and Mo contents. However, g-Ag NPs significantly promoted cucumber photosynthesis by increasing chlorophyll contents. Besides, the green synthesized Ag NPs by cucumber extracts (gc-Ag NPs) increased protein contents and gr-Ag NPs stimulated the upregulation of Mn and the downregulation of Al, which were all positive effects. Overall, compared with chem-Ag NPs, g-Ag NPs exhibited long-tern antimicrobial properties and attenuated toxicity to plants, which could be used as potential nanopesticide or nanoscale growth regulator in agriculture.


Literacy and comprehension of Beck Depression Inventory response alternatives.
This study explored the relationship of literacy level to comprehension of response alternatives from the Beck Depression Inventory (BDI). Twenty-nine adult basic education students, 14 senior citizens, and 20 oncology patients were given a brief literacy assessment and a comprehension test of selected BDI response alternatives. Three raters with clinical experience assessed comprehension. Lower literacy was significantly associated with less comprehension, even when other factors were controlled, yet comprehension problems were still found among higher literacy groups. The percent of participants who correctly paraphrased the selected BDI response alternatives ranged from 0 to 60%. These preliminary results suggest that poor comprehension of mental health measures is not only prevalent, but also cannot be estimated from patients' education or assessed reading levels.


Community-associated methicillin-resistant Staphylococcus aureus (MRSA) in Australia.
A series of epidemics of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) have occurred in Australia, starting in Western Australia in the early 1990s, in the Northern Territory soon thereafter and in eastern states in the mid 1990s. The Western Australian epidemic has been due mainly to Panton-Valentine leukocidin (PVL)-negative clones, whilst PVL-positive clones have predominated in the east. More recently, the major epidemic clones have spread throughout the country, whilst multiple new minor clones have emerged, mainly in Western Australia. A total of 45 clones of CA-MRSA have been detected in Australia to date: 30 of these carry SCCmec IV, 6 carry SCCmec V and 9 carry novel SCCmec types. Overall, CA-MRSA clones have been associated predominantly with skin and soft-tissue infections. PVL-positive clones have been associated with furunculosis, necrotising pneumonia and osteomyelitis and have caused fatalities in otherwise healthy children and young adults. Initial treatment of these infections remains problematic, as it is frequently inappropriate. Of particular concern, healthcare-associated acquisition of CA-MRSA clones is now increasing, although major hospital outbreaks have not occurred yet.


Effects of intrasegmental electrical acupuncture on dental pain: evaluation by threshold estimation and sensory decision theory.
The effect of 80 min of low frequency (2 Hz) electric acupunctural stimulation at facial sites on the perception of induced dental pain was evaluated using both pain threshold and sensory decision theory (SDT) procedures. The demonstration of a 187% increase in threshold over a 20 min period of acupunctural stimulation replicated earlier work by Swedish investigators. SDT analyses indicated that the threshold increase reflected a relatively pure sensory change with no significant modification of response bias. However, subjects were able to perceive some of the stimuli presented below threshold level following acupuncture, thus indicating that the threshold concept has been an inadequate description of the phenomenon. This study demonstrated that intrasegmental analgesic stimulation is more efficacious than the extrasegmental meridian point stimulation used in our earlier studies. Possible mechanisms for the observed effect were discussed.


UPLC-QTOF-MS/MS assisted UPLC-TQ-MS/MS strategy to comparatively investigate the rat pharmacokinetics of N-acetyldopamine oligomers derived from Cicadae Periostracum.
Cicadae Periostracum (CP), the slough molted from the nymph of Cryptotympana pustulata, is a widely used medicinal material in traditional Chinese medicine (TCM). N-acetyldopamine oligomers (NAOs), the homologues of acetyldopamine, including N-acetyldopamine dimers/trimers/tetramers/pentamers (NADs/NATrs/NATes/NAPs), side-chain isomer of dimers/trimers (SCIDs/SCITrs), are major bioactive ingredients of CP. However, owing to commercially unavailable reference substances of all NAOs, simultaneous quantification of these NAOs in biological samples is difficult, and thus their pharmacokinetics are still unknown. In this study, a comprehensive strategy for simultaneous quantification/semi-quantification of NAOs in plasma with single N-acetyldopamine dimer A (NAD-A) as reference substance was established and comparatively investigated their pharmacokinetics after oral administration of pure NAD-A and two types of CP extracts, i.e., post-molting-washed slough (CP-WAT) and pre-molting-washed slough (CP-WBT). A UPLC-QTOF-MS/MS assisted UPLC-TQ-MS/MS strategy was developed to quantify NAOs in rat plasma. NAOs in CP extract were qualitatively characterized by UPLC-QTOF-MS/MS, then the quasi-molecular ions and characteristic fragment ions of the identified NAOs by UPLC-QTOF-MS/MS were transferred to UPLC-TQ-MS/MS as parent-daughter ion pairs for MRM mode quantification of the NAOs, and the method was validated with single NAD-A for quantifying NAD-A and semi-quantifying other NAOs in plasma. The established method was applied to compare the pharmacokinetics of NAOs after oral administration of NAD-A and the extracts of CP-WBT/CP-WAT respectively. Six quasi-molecular ions and characteristic fragment ion m/z 192.1 were characterized by UPLC-QTOF-MS/MS and transferred to be the parent-daughter ion pairs for UPLC-TQ-MS/MS analysis of six kinds of NAOs. For the pharmacokinetics, NAD-A showed double peaks absorption character when administered with single compound, but with higher relative bioavailability when administered with CP extracts with the similar dosage. Compared with CP-WAT, NAOs in CP-WBT reached the maximum plasma concentration in much shorter time.


Ten years' experience with the St. Jude Medical valve prosthesis.
Records of 1,298 consecutive patients who had received the St. Jude Medical prosthesis were reviewed (713 male and 585 female patients; mean age, 61.79 +/- 13.4 years). Early mortality was 5.7% (74 patients). Ninety-three percent complete follow-up was accomplished for the 1,224 patients who left the hospital (4,306.50 patient-years). One hundred ninety-two of these patients died, a late mortality of 16.9%. Sixty-four patients experienced thromboembolic episodes (17 major and 35 permanent). Twenty-four patients had anticoagulant-related bleeding, 4 had valve thrombosis, 7 had prosthetic valve endocarditis, 9 had paravalvular leak, and 10 underwent reoperation. There was no structural valve failure in this series. Twenty-two of the 118 patients who had valve-related complications died; another 15 patients died of sudden and unknown causes. Therefore, the total number of valve-related deaths was 37. Of those patients who survived, New York Heart Association functional class improved significantly (98% in classes II and III preoperatively and 96% in classes I and II postoperatively). Linearized rates for thromboembolism, valve thrombosis, and anticoagulant-related bleeding were 1.49% +/- 0.19%, 0.09% +/- 0.05%, and 0.56% +/- 0.11%/100 patient-years, respectively. The actuarial estimate of incidence free from all complications, operative death, and valve-related death was 66.9% +/- 8.2% at the end of 9 years. In spite of old age and advanced heart disease, the patients who received the St. Jude Medical prosthesis had very good results over a 10-year period.


The interaction between miR160 and miR165/166 in the control of leaf development and drought tolerance in Arabidopsis.
MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in plant development and abiotic stresses. To date, studies have mainly focused on the roles of individual miRNAs, however, a few have addressed the interactions among multiple miRNAs. In this study, we investigated the interplay and regulatory circuit between miR160 and miR165/166 and its effect on leaf development and drought tolerance in Arabidopsis using Short Tandem Target Mimic (STTM). By crossing STTM160 Arabidopsis with STTM165/166, we successfully generated a double mutant of miR160 and miR165/166. The double mutant plants exhibited a series of compromised phenotypes in leaf development and drought tolerance in comparison to phenotypic alterations in the single STTM lines. RNA-seq and qRT-PCR analyses suggested that the expression levels of auxin and ABA signaling genes in the STTM-directed double mutant were compromised compared to the two single mutants. Our results also suggested that miR160-directed regulation of auxin response factors (ARFs) contribute to leaf development via auxin signaling genes, whereas miR165/166- mediated HD-ZIP IIIs regulation confers drought tolerance through ABA signaling. Our studies further indicated that ARFs and HD-ZIP IIIs may play opposite roles in the regulation of leaf development and drought tolerance that can be further applied to other crops for agronomic traits improvement.


Latent infection of cattle with bovid herpesvirus 2.
In a series of experiments, 10 calves were infected by different routes with bovine mammillitis strain of bovid herpesvirus 2 (BHV2). Nine of the calves developed lesions and BHV2 was isolated from 8 calves. At intervals, after clinical recovery, the calves were given a course of corticosteroid by intravenous injection. Subsequently 7 calves developed lesions and from 3 calves BHV2 was reisolated. The shortest interval between initial infection and reisolation of virus was 10 weeks. In one calf virus was recovered on 3 occasions, at intervals of 20, 44 and 74 weeks post-infection. It is probable that BHV2 can occur as a latent infection in calves and that BHV2 should be included among the herpesviruses known to remain latent.


Locally administered ocular corticosteroids: benefits and risks.
Corticosteroids, used prudently, are one of the most potent and effective modalities available in the treatment of ocular inflammation. However, they can produce a plethora of adverse ocular and systemic events. In order to optimise and target drug delivery, whilst minimising systemic adverse effects, a diverse range of local ophthalmic preparations and delivery techniques have been developed. Topical drops and ointments remain the primary methods for administration of ocular corticosteroids. However, ocular penetration of topical corticosteroid drops depends upon drug concentration, chemical formulation of corticosteroid, and composition of the vehicle, therefore, apparently small modifications in preparations can produce a more than 20-fold difference in intraocular drug concentration. Periocular injections of corticosteroids continue to have a useful, but limited, therapeutic role and longer acting, intraocular delayed-release devices are in early clinical studies. Although newer corticosteroids with lesser pressure elevating characteristics have been developed, corticosteroid-induced ocular hypertension and glaucoma continue to be significant risks of local and systemic administration. Posterior subcapsular cataract, observed following as little as 4 months topical corticosteroids use, is thought to be due to covalent binding of corticosteroid to lens protein with subsequent oxidation. Inappropriate use of topical corticosteroid in the presence of corneal infections also continues to be a cause of ocular morbidity. Other risks of locally administered ophthalmic corticosteroids include: tear-film instability, epithelial toxicity, crystalline keratopathy, decreased wound strength, orbital fat atrophy, ptosis, limitation of ocular movement, inadvertent intraocular injection, and reduction in endogenous cortisol. This extensive review assesses the therapeutic benefits of locally administered ocular corticosteroids in the context of the risks of adverse effects.


Autotoxic inhibition of seed germination by Typha latifolia: an evaluation.
Seeds of Typha latifolia were exposed to leaf extracts, leaf pieces, and soil water from adult plants of T. latifolia. In liquid culture, only extracts of concentration greater than or equal to 3% (dry weight to volume) inhibited seed germination. Adding soil to the liquid cultures increased the inhibition of seed germination by extracts. The inhibitory effects of extracts were correlated with the development of water molds in the cultures; prior to the development of water molds, even 15% extracts were not inhibitory to germination. In contrast to results from extracts; neither 3% concentrations of senesced leaf pieces nor soil surface water from one year old pots of T. latifolia had any detrimental effects on germination. Seeds sown into pots containing established T. latifolia germinated as well as seeds sown into control pots. These results do not support the contention that T. latifolia inhibits the germination of its seeds by the release of allelopathic substances.


Evaluation of the Gam-COVID-Vac and vaccine-induced neutralizing response against SARS-CoV-2 lineage P.1 variant in an Argentinean cohort.
We evaluated humoral immune-response elicited by Sputnik-V by measuring anti-Spike (S) IgG antibodies (Abs) and neutralizing antibodies (NAb) prior to, 14 and 42 days after-vaccination. The safety and disease rates among vaccinated individuals were also evaluated. Since SARS-CoV-2 lineage P.1 is rapidly spreading in Argentina, virus-neutralizing activity of Sputnik-V-elicited and infection-elicited NAb faced to P.1 were also assessed. A total of 285 participants were recruited; all reported good tolerance, without any severe adverse event. Nine COVID-19 cases were confirmed in fully vaccinated individuals and viable P.1 variant was successfully isolated from one of them. At day 42, 99.65% of the individuals had anti-S IgG; however, 23.15% had not detectable NAbs. Significantly higher neutralization potency against WT compared to P.1 (p < 0·001) was observed. Some samples failed to neutralize P.1, mainly among vaccinated-naїve subjects; however, no significant differences were observed among previously infected-vaccinated individuals. Our results corroborated that Sputnik-V is safe and induces an efficient humoral immune response, although not all immunized subjects develop Nabs. Herein, we show for the first time, evidence of infectious SARS-CoV-2 shedding from Sputnik-V fully vaccinated individuals, by the isolation of viable virus from the nasopharyngeal swab of one participant of our study, 139 days after receiving the second dose. Thereby, we provide evidence indicating that the vaccine might avoid severe forms of COVID-19 but does not prevent infection nor prevents transmission from a fully vaccinated individual.


Nutrition: Prevention and management of nutritional failure in Cystic Fibrosis.
Close monitoring of nutritional status is critical to the overall health of a patient with CF. As part of routine CF care, measurement of weight and height (and calculation of weight/length or BMI as appropriate) should be performed and analyzed at each visit. Early recognition of nutritional risk is imperative and evaluation with a multidisciplinary team should be performed to assess for caloric intake, caloric malabsorption, and other causes of poor weight gain and growth. Many tools are available to use for intervention, including oral supplementation, behavioral interventions, medications, nutritional therapies, and enteral tube feeding.


The teaching of clinical pharmacology in Europe and North America.
A recent survey conducted under the auspices of the WHO shows that on average in European medical schools only 28 hours of teaching are devoted to clinical pharmacology, whereas over 100 hours are devoted to pharmacology. In many schools no clinical pharmacology is taught, and there is a lack of trained individuals and posts in clinical pharmacology. In North America there is a similar lack of clinical pharmacology teaching.


Analysis of the Lifestyle of Spanish Undergraduate Nursing Students and Comparison with Students of Other Degrees.
Nursing students are exposed to concepts of healthy lifestyles while they are attending university. The aim of this study was to analyze whether nursing students have a healthier lifestyle than non-nursing students and to determine whether their behaviour is consistent with their beliefs. A cross-sectional study, with 293 university students was performed by using a validated questionnaire to measure beliefs and behaviour regarding health. The lifestyle pattern of the nursing students evaluated was characterised by a high percentage of nurses with low levels of physical activity, poor balanced diet and smoking habits. The comparative analysis showed no significant differences between nursing students and students from other degrees. Students have a positive attitude and knowledge about healthy lifestyle, but do not transfer it to their own lives. Nurses' lifestyle can unintentionally affect the behaviour of other people through their own behaviour and beliefs because they serve as a model for a healthy lifestyle. These findings support that nurse educators have an active role as promoter of health by using lessons to modify the behaviour of their students.


Sensory neuroanatomy of a skin-penetrating nematode parasite: Strongyloides stercoralis. I. Amphidial neurons.
The Strongyloides stercoralis infective larva resumes feeding and development on receipt of signals, presumably chemical, from a host. Only two of the anterior sense organs of this larva are open to the external environment. These large, paired goblet-shaped sensilla, known as amphids, are presumably, therefore, the only chemoreceptors. Using three-dimensional reconstructions made from serial electron micrographs, amphidial structure was investigated. In each amphid, cilialike dendritic processes of 11 neurons extend nearly to the amphidial pore; a twelfth terminates at the base of the amphidial channel, behind an array of lateral projections on the other processes. A specialized dendritic process leaves the amphidial channel and forms a complex of lamellae that interdigitate with lamellae of the amphidial sheath cell. This "lamellar cell" is similar to one of the "wing cells" or possibly the "finger cell" of Caenorhabditis elegans. Each of the 13 amphidial neurons was traced to its cell body. Ten neurons, including the lamellar cell, connect to cell bodies in the lateral ganglion, posterior to the nerve ring. The positions of these cell bodies were similar to those of the amphidial cell bodies in C.elegans. Therefore, they were named by using C. elegans nomenclature. Three other amphidial processes connect to cell bodies anterior to the nerve ring; these have no homologs in C. elegans. A map allowing identification of the amphidial cell bodies in the living worm was prepared. Consequently, laser ablation studies can be conducted to determine which neurons are involved in the infective process.


Synchronous video-based communication and online learning: an exploration of instructors' perceptions and experiences.
Historically, online instructors have primarily, if not solely, used asynchronous text-based communication to interact and communicate with students in online courses. However, despite this use, online instructors and students have expressed concerns and limitations with asynchronous communication. Research suggests that synchronous communication technology may address some of the limitations of asynchronous communication. Further, advances in synchronous video-based communication technology make it easier than ever to incorporate synchronous communication technology into online courses. However, comparatively, little is known about online instructors' experiences and perceptions of using synchronous communication technologies in online courses and how they think they can help with community development. The purpose of this study was to explore instructors' experiences and perceptions of synchronous communication technology. Thematic analysis of semi-structured interviews with 18 online instructors resulted in the following themes: (a) instructors use synchronous communication technology in multiple and various ways in online courses; (b) the perceived benefits of real-time visual communication outweigh the drawbacks identified; (c) the benefits of nonverbal communication depend on situational factors and how synchronous features are used; (d) productive and meaningful interaction requires intentional yet flexible facilitation during synchronous sessions; (e) synchronous sessions can provide a place for community to build and grow but they are not required for community development. Altogether, findings suggest that real-time visual communication may aid in community building in online courses but that its effectiveness depends on several situational factors, and that synchronous lecturing may be less conducive to developing classroom community in online courses. Results and future research directions are discussed.


Biomarkers Derived from Alterations in Overlapping Community Structure of Resting-state Brain Functional Networks for Detecting Alzheimer's Disease.
Recent studies show that overlapping community structure is an important feature of the brain functional network. However, alterations in such overlapping community structure in Alzheimer's disease (AD) patients have not been examined yet. In this study, we investigate the overlapping community structure in AD by using resting-state functional magnetic resonance imaging (rs-fMRI) data. The collective sparse symmetric non-negative matrix factorization (cssNMF) is adopted to detect the overlapping community structure. Experimental results on 28 AD patients and 32 normal controls (NCs) from the ADNI2 dataset show that the two groups have remarkable differences in terms of the optimal number of communities, the hierarchy of communities detected at different scales, network functional segregation, and nodal functional diversity. In particular, the frontal-parietal and basal ganglia networks exhibit significant differences between the two groups. A machine learning framework proposed in this paper for AD detection achieved an accuracy of 76.7% when using the detected community strengths of the frontal-parietal and basal ganglia networks only as input features. These findings provide novel insights into the understanding of pathological changes in the brain functional network organization of AD and show the potential of the community structure-related features for AD detection.


Electronic colon-cleansing for CT colonography: diagnostic performance.
The purpose of this study was to evaluate whether an electronic-colonic-cleansing (ECC) algorithm is beneficial for the diagnostic performance compared to a CT colonography (CTC) evaluation without electronic cleansing in tagged datasets. Two blinded readers evaluated CTC datasets from 79 patients with 153 colorectal polyps confirmed by optical colonoscopy. Cases were read in a randomized order with and without the use of electronic colon-cleansing software. Per-polyp sensitivity, per-polyp/per-patient specificity and reading times (with and without ECC) have been calculated and reported. Per-polyp sensitivity for polyps >6 mm without using ECC was 60.4% (Reader 1: 59.7%, Reader 2: 61.1%), while polyps >10 mm were detected with a sensitivity of 58.3% (Reader 1: 66.7%, Reader 2: 50%). On electronically cleansed datasets, the sensitivity was 73.6% (Reader 1: 76.4%; Reader 2: 70.8%) for polyps >6 mm and 83.3% (Reader 1: 83.3%; Reader 2: 83.3%), respectively. Per-patient specificity was 75% without using cleansing (Reader 1: 68%, Reader 2: 82%) and 81.5% using ECC (Reader 1: 86%, Reader 2: 77%). Reading CTC cases using ECC software improves sensitivity in detecting clinically relevant colorectal polyps.


Regioselective synthesis and stereochemical structure of anti-tumor active dispiro[3H-indole-3,2'-pyrrolidine-3',3''-piperidine]-2(1H),4''-diones.
Reaction of 3,5-bis(arylmethylene)-1-methyl-4-piperidinones 1a-1g with azomethine ylides (generated in situ via decarboxylative condensation of isatins 2a,2b with sarcosine 3) in refluxing ethanol afforded 4'-aryl-5''-(arylmethylene)-dispiro[3H-indole-3,2'-pyrrolidine-3',3''-piperidine]-2(1H),4''-diones 4a-4m as the sole product in a high regioselective manner. Anti-tumor activity screening of 4e,4f,4k,4m, as representative examples of the synthesized compounds, at a dose of 10 microM utilizing 59 different human tumor cell lines representing leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate and kidney exhibited that, the tested compounds reflect mild activity against most of the used human tumor cells. Meanwhile, all the tested compounds reveal considerable anti-tumor properties against colon (HCT-116), breast (T-47D), leukemia [HL-60 (TB), MOLT-4, RPMI-8226] and prostate (PC-3) cancers. Anti-inflammatory properties of the prepared compounds (at a dose of 50 mg/kg body weight) using in vivo acute carrageenan-induced paw oedema in rats exhibited that all the tested compounds possess considerable anti-inflammatory activity especially 4a,4k,4l which reveal remarkable activities with potency 125.5, 139.3 and 126.4, respectively, relative to indomethacin which was used as a reference standard (at a dose of 10 mg/kg body weight).


COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study.
Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41-0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02-1.04; HR = 1.79, 95% CI:1.04-3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated.


Comprehensive analysis of biosecurity practices and antimicrobial use in broiler chicken production by integrated operations in Korea.
Integrated broiler operations that allow producers to combine various biosecurity and sanitation practices account for approximately 97.6% of chicken meat production in Korea, but it is not well known about the biosecurity level or compliance with regulations for each operation. Therefore, the objective this study was to analyze the current adoption of biosecurity practices and trends in antimicrobial use in 74 farms from 5 major integrated broiler chicken operations (A-E). The highest stock densities of more than 65 birds per 3.3 m2 (0.5 birds/ft2) showed in 66.7 and 33.3% of the farms in operations A and C, respectively. Also, the livability rate of 98% or less was observed in 73.3 and 93.4% of the farms, in operation A and C, respectively, which lower than other operations. Moreover, it was observed that 60.0 and 40.0% of farms in operations B and C reused litter 3 or more times. Among the 74 farms, the most common antimicrobials prescription frequency was 2 times (39.2%), and the prescription to β-lactams antibiotics (45.3%) showed the significantly highest (P < 0.05). The highest administration of antimicrobials was at 15 to 22-days old (42.7%), and most of them were recommended by veterinarian (80.7%). Footbath disinfectant and spraying outside the poultry house were performed in most of the farms (64.9 and 83.8%, respectively), but the use of quicklime (36.5%) and drinking water disinfectant (18.9%) was low in farms. Most of the farms washed vehicles for transportation of poultry (87.8%) and feed (100%) before arriving at the farms, however, 40.5% of the farms used little or no disinfectants when washing the transport vehicles. Moreover, wild birds, and cats and dogs were well controlled on most of the farms (each 94.6%), but only 74.3% of farms offered rodent control programs. Also, only 27.0% of the farms used farm-specific shoes and clothing as well as footbath disinfection for entrance. These findings can be useful in developing policies and guidelines for sustainable and responsible broiler chicken production and reduction of antimicrobial use in Korea.


A study of the effects of four concentrations of D-timolol, 0.25% L-timolol, and placebo on intraocular pressure on patients with raised intraocular pressure.
The intraocular pressure lowering effect in 30 patients with raised intraocular pressure and open angles following a single application in a randomised double-masked fashion of four concentrations of D-timolol (0.25%, 0.5%, 1.0%, and 2.0%), 0.25% L-timolol, and placebo are presented. The percentage reduction in intraocular pressure after four hours following single-drop instillation range from 20% to 25% in the D-timolol group, 32% in the L-timolol group, and only 8% in the placebo group of treated eyes.


κ-Opioid receptors in the medial amygdaloid nucleus modulate autonomic and neuroendocrine responses to acute stress.
The medial amygdaloid nucleus (MeA) is a key neural structure in triggering physiologic and behavioral control during aversive situations. However, MeA role during stress exposure has not yet been fully elucidated. Thus, in the present study, we investigated the involvement of the MeA opioid neurotransmission in the modulation of autonomic, neuroendocrine and behavioral responses evoked by acute restraint stress (RS). The bilateral microinjection of naloxone (non-selective opioid antagonist) into the MeA potentiated RS-evoked autonomic responses and increased plasma corticosterone levels, in a dose-dependent manner. However, no effects were observed in RS-evoked increases on plasma oxytocin levels and anxiogenic-like behavior. Similar to naloxone, MeA pretreatment with the selective κ-opioid antagonist (nor-BNI) also enhanced heart rate and corticosterone increases induced by RS, whereas treatment with selective µ- or δ-opioid antagonists did not affect the physiologic and behavioral responses caused by RS. The present results showed MeA κ-opioid receptors modulate heart rate and corticosterone increases evoked by acute RS, reinforcing the idea of an inhibitory role exerted by MeA during aversive situations .


Reconfiguration from veno-arterial to veno-arterio-venous extracorporeal membrane oxygenation for massive pulmonary embolism.
Differential hypoxia may occur after the initiation of femorofemoral veno-arterial extracorporeal membrane oxygenation (VA ECMO) if cardiac function improves while severe respiratory failure is still present, one of the most difficult problems encountered during VA ECMO. Reconfiguration to veno-arterio-venous ECMO (V-AV ECMO) is one of several methods of dealing with differential hypoxia. V-AV ECMO requires triple cannulation and careful management of the reinjection flow, but the risk of bleeding is lower than in a surgical procedure, such as central ECMO or a subclavian artery graft. Herein, we reported a patient with a massive pulmonary embolism who received VA ECMO, which was reconfigured to V-AV ECMO 3 days later when differential hypoxia occurred. A drainage cannula was newly inserted via the right internal jugular vein, and an existing drainage cannula was used for reinjection after repositioning it caudally. V-AV ECMO is an effective and feasible treatment for differential hypoxia despite the paucity of the procedure to date.


Trends of CT utilisation in an emergency department in Taiwan: a 5-year retrospective study.
To investigate the association between the trends of CT utilisation in an emergency department (ED) and changes in clinical imaging practice and patients' disposition. A hospital-based retrospective observational study of a public 1520-bed referral medical centre in Taiwan. Adult ED visits (aged ≥18 years) during 2009-2013, with or without receiving CT, were enrolled as the study participants. For all enrolled ED visits, we retrospectively analysed: (1) demographic characteristics, (2) triage categories, (3) whether CT was performed and the type of CT scan, (4) further ED disposition, (5) ED cost and (6) ED length of stay. In all, 269 239 adult ED visits (148 613 male patients and 120 626 female patients) were collected during the 5-year study period, comprising 38 609 CT scans. CT utilisation increased from 11.10% in 2009 to 17.70% in 2013 (trend test, p<0.001). Four in 5 types of CT scan (head, chest, abdomen and miscellaneous) were increasingly utilised during the study period. Also, CT was increasingly ordered annually in all age groups. Although ED CT utilisation rates increased markedly, the annual ED visits did not actually increase. Moreover, the subsequent admission rate, after receiving ED CT, declined (59.9% in 2009 to 48.2% in 2013). ED CT utilisation rates increased significantly during 2009-2013. Emergency physicians may be using CT for non-emergent studies in the ED. Further investigation is needed to determine whether increasing CT utilisation is efficient and cost-effective.


Pharmacogenomic Approach to Antimyopia Drug Development: Pathways Lead the Way.
Myopia is the most common eye disorder in the world which is caused by a mismatch between the optical power of the eye and its excessively long axial length. Recent studies revealed that the regulation of the axial length of the eye occurs via a complex signaling cascade, which originates in the retina and propagates across all ocular tissues to the sclera. The complexity of this regulatory cascade has made it particularly difficult to develop effective antimyopia drugs. The current pharmacological treatment options for myopia are limited to atropine and 7-methylxanthine, which have either significant adverse effects or low efficacy. In this review, we focus on the recent advances in genome-wide studies of the signaling pathways underlying myopia development and discuss the potential of systems genetics and pharmacogenomic approaches for the development of antimyopia drugs.


High intrapatient variability of tacrolimus exposure associated with poorer outcomes in liver transplantation.
Tacrolimus (TAC) is a dose-dependent immunosuppressor with considerable intrapatient variability (IPV) in its pharmacokinetics. The aim of this work is to ascertain the association between TAC IPV at 6 months after liver transplantation (LT) and patient outcome. This single-center cohort study retrospectively analyzed adult patients who underwent transplantation from 2015 to 2019 who survived the first 6 months with a functioning graft. The primary end point was the patient's probability of death and the secondary outcome was the loss of renal function between month 6 and the last follow-up. TAC IPV was estimated by calculating the coefficient of variation (CV) of the dose-corrected concentration (C0 /D) between the third and sixth months post-LT. Of the 140 patients who underwent LT included in the study, the low-variability group (C0 /D CV < 27%) comprised 105 patients and the high-variability group (C0 /D CV ≥ 27%) 35 patients. One-, 3-, and 5-year patient survival rates were 100%, 82%, and 72% in the high-variability group versus 100%, 97%, and 93% in the low-variability group, respectively (p = 0.005). Moreover, significant impaired renal function was observed in the high-variability group at 1 year (69 ± 16 ml/min/1.73 m2 vs. 78 ± 16 ml/min/1.73 m2 , p = 0.004) and at 2 years post-LT (69 ± 17 ml/min/1.73 m2 vs. 77 ± 15 ml/min/1.73 m2 , p = 0.03). High C0 /D CV 3-6 months remained independently associated with worse survival (hazard ratio = 3.57, 95% CI = 1.32-9.67, p = 0.012) and loss of renal function (odds ratio = 3.47, 95% CI = 1.30-9.20, p = 0.01). Therefore, high IPV between the third and sixth months appears to be an early and independent predictor of patients with poorer liver transplant outcomes.


Assessment of occupational exposure to leptospirosis in a sheep-only abattoir.
This study estimated the frequency of exposure of meat workers to carcasses infected with Leptospira serovars Hardjobovis or Pomona in a sheep-only abattoir in New Zealand. A stochastic spreadsheet model was developed to assess the daily risk of exposure of eviscerators, meat inspectors and offal handlers to live leptospires in sheep carcasses from May to November 2004 (high-risk period), and from December 2004 to June 2005 (low-risk period). The average sheep processed per day were 225 for an eviscerator, 374 for a meat inspector, and 1123 for an offal handler. The median daily exposures during high- and low-risk periods were 11 [95% distribution interval (DI) 5-19] and three (95% DI 1-8) infected carcasses/day for eviscerators, 18 (95% DI 9-29) and six (95% DI 2-12) for meat inspectors, and 54 (95% DI 32-83) and 18 (95% DI 8-31) for offal handlers, respectively. Stochastic risk modelling provided evidence that processing of sheep carcasses exposed meat workers regularly to live leptospires with substantial seasonal variation.


Channel based generating function approach to the stochastic Hodgkin-Huxley neuronal system.
Internal and external fluctuations, such as channel noise and synaptic noise, contribute to the generation of spontaneous action potentials in neurons. Many different Langevin approaches have been proposed to speed up the computation but with waning accuracy especially at small channel numbers. We apply a generating function approach to the master equation for the ion channel dynamics and further propose two accelerating algorithms, with an accuracy close to the Gillespie algorithm but with much higher efficiency, opening the door for expedited simulation of noisy action potential propagating along axons or other types of noisy signal transduction.


A subpopulation of arenavirus nucleoprotein localizes to mitochondria.
Viruses need cells for their replication and, therefore, ways to hijack cellular functions. Mitochondria play fundamental roles within the cell in metabolism, immunity and regulation of homeostasis due to which some viruses aim to alter mitochondrial functions. Herein we show that the nucleoprotein (NP) of arenaviruses enters the mitochondria of infected cells, affecting the mitochondrial morphology. Reptarenaviruses cause boid inclusion body disease (BIBD) that is characterized, especially in boas, by the formation of cytoplasmic inclusion bodies (IBs) comprising reptarenavirus NP within the infected cells. We initiated this study after observing electron-dense material reminiscent of IBs within the mitochondria of reptarenavirus infected boid cell cultures in an ultrastructural study. We employed immuno-electron microscopy to confirm that the mitochondrial inclusions indeed contain reptarenavirus NP. Mutations to a putative N-terminal mitochondrial targeting signal (MTS), identified via software predictions in both mamm- and reptarenavirus NPs, did not affect the mitochondrial localization of NP, suggesting that it occurs independently of MTS. In support of MTS-independent translocation, we did not detect cleavage of the putative MTSs of arenavirus NPs in reptilian or mammalian cells. Furthermore, in vitro translated NPs could not enter isolated mitochondria, suggesting that the translocation requires cellular factors or conditions. Our findings suggest that MTS-independent mitochondrial translocation of NP is a shared feature among arenaviruses. We speculate that by targeting the mitochondria arenaviruses aim to alter mitochondrial metabolism and homeostasis or affect the cellular defense.


Use of Millipore diffusion chambers to assay in vivo IL-2 activity.
Lymphokine-activated killer (LAK) cells were grown from C57BL/6 mouse spleen cells by culturing the cells with recombinant human IL-2 (r-IL-2). The unlabeled or [3H]uridine-labeled LAK cells were enclosed in a diffusion chamber, which was implanted into the peritoneal cavity of a syngeneic mouse, and the mouse was treated with an i.p. injection of r-IL-2 or saline (control). In order to detect the activity of administered r-IL-2, the diffusion chambers were taken out from the mice 20-40 h after the implantation, and the viability and cytotoxic activity of LAK cells in the chambers were determined by measuring the radioactivity of the cells and their cytotoxicity to EL 4 mouse leukemia cells respectively. When the mice were treated with saline, the radioactivity of LAK cells was greatly decreased. However, when the mice were treated with r-IL-2, the radioactivity of LAK cells was sustained. An i.p. administration of IL-2 also prevented any decrease in the cytotoxic activity of LAK cells.


Role of leukotriene B4 in the pathogenesis of hepatic ischemia-reperfusion injury in the rat.
A common feature to most models of ischemia-reperfusion injury is the accumulation of polymorphonuclear leukocytes (PMNs) into the post-ischemic tissue during the reperfusion period. Interventions that lead to decreased PMN infiltration protect against tissue injury and therefore a knowledge of the chemotactic mediators leading to PMN accumulation is essential to understanding the pathogenesis of the injury and to the development of successful therapeutic strategies. Leukotriene B4 (LTB4), a metabolite formed via the 5-lipoxygenase pathway from arachidonic acid, is one of the most potent chemotactic mediators known. We have investigated the formation of LTB4 in a well characterized model of hepatic ischemia-reperfusion injury in the rat and made use of a specific leukotriene biosynthesis inhibitor, L663,536, to determine the importance of LTB4 in the pathogenesis of the injury. LTB4 concentrations were measured with a specific and sensitive gas chromatographic-mass spectrometric method previously developed in our laboratory. In liver tissue LTB4 levels were below the detection limit of 20 pg/g before 45 min ischemia and did not increase during the first 6 h of reperfusion. However, at 15 h and 24 h reperfusion LTB4 concentrations had increased to levels 50-fold those in control liver (867 +/- 267 pg/g). The increase of plasma alanine aminotransferase (ALT) activities indicated two phases of injury, an initial phase during the first few hours of reperfusion, and a second more severe injury phase between 6 h and 24 h reperfusion. PMNs accumulated in tissue throughout the reflow period reaching 700 +/- 49 per 50 high power fields (HPF) at 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)


A Novel Frameshift Mutation of the IKBKG Gene Causing Typical Incontinentia Pigmenti.
Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis. Mutations of the IKBKG gene are responsible for IP. A deletion of exons 4-10 can be found in 80% of patients with IP. There are 69 different mutations of the IKBKG gene that have been reported. A proband, female patient from a family without previously diagnosed IP is reported. She had skin and dental changes typical of IP. The diagnosis was made according to updated IP criteria. Pathohistological and ultrastructural analysis of skin biopsy confirmed the diagnosis. However, the common deletion of exons 4-10 in the IKBKG gene could not be detected. Sequencing revealed the indel (deletion/insertion) mutation c.641_647delGCATGGAinsAT (p.Arg214HisfsX38) in exon 5 of the IKBKG gene. Because this mutation could not be detected in the unaffected mother of the proband, it seems to be a de novo mutation. The registered novel frameshift/KBKG mutation c.641_647delGCATGGAinsAT (p.Arg214HisfsX38) can be considered to be the cause of IP in this case.


Cancer in young adults with ischemic stroke.
Cancer is a risk factor for ischemic stroke. Little is known about cancer among young adults with ischemic stroke. We studied the frequency of cancer and its association with long-term risk of death among young patients with first-ever ischemic stroke. 1002 patients aged 15 to 49 years, registered in the Helsinki Young Stroke Registry, and with a median follow-up of 10.0 years (interquartile range 6.5-13.8) after stroke were included. Historical and follow-up data were derived from the Finnish Care Register and Statistics Finland. Survival between groups was compared with the Kaplan-Meier life-table method, and Cox proportional hazard models were used to identify factors associated with mortality. One or more cancer diagnosis was made in 77 (7.7%) patients, of whom 39 (3.9%) had cancer diagnosed prestroke. During the poststroke follow-up, 41 (53.2%) of the cancer patients died. Median time from prestroke cancer to stroke was 4.9 (1.0-9.5) years and from stroke to poststroke cancer was 6.7 (2.7-10.9) years. Poststroke cancer was associated with age>40 years, heavy drinking, and cigarette smoking. The cumulative mortality was significantly higher among the cancer patients (68.6%, 95% confidence interval 52.0%-85.3%) compared with patients without cancer (19.7%, 95% confidence interval 16.3%-23.2%). Active cancer at index stroke, melanoma, and lung/respiratory tract cancer had the strongest independent association with death during the follow-up when adjusted for known poststroke mortality prognosticators. Cancer, and especially active cancer and no other apparent cause for stroke, is associated with unfavorable survival among young stroke patients.


BIS-guided deep anesthesia decreases short-term postoperative cognitive dysfunction and peripheral inflammation in elderly patients undergoing abdominal surgery.
Postoperative cognitive dysfunction (POCD) is a common clinical complication, with an underlying pathophysiology linked to heightened levels of neuroinflammation. However, it requires clarification as to whether the depth of anesthesia modulates postoperative cognitive dysfunction. This study investigated the association between depth of anesthesia and POCD in elderly patients undergoing abdominal surgery. A total of 120 patients aged 60 years or older who were planned for abdominal surgery under total intravenous anesthesia were included in this study. The depth of anesthesia was guided by monitoring Bispectral Index (BIS) data. All study participants completed a battery of nine neuropsychological tests before surgery and at 7 days and 3 months after surgery. POCD was calculated by using the reliable change index. Plasma concentration of C-reactive protein (CRP), interleukin (IL)-1β, IL-10, S-100β, and norepinephrine (NE) were measured. The incidence of POCD at 7 days after surgery in the deep anesthesia group was 19.2% (10/52), which was significantly lower (p = 0.032) than the light anesthesia group 39.6% (21/53). The depth of anesthesia had no effect on POCD at 3 months after surgery (10.3% vs 14.6%, respectively, p = 0.558). Similarly, plasma levels of CRP and IL-1β in deep anesthesia group were lower than that in light anesthesia group at 7 days after surgery (p < 0.05), but not at 3 months after surgery (p > 0.05). There were no significant differences in the plasma concentration of IL-10, S-100β, and NE between the groups (p > 0.05). Deep anesthesia under total intravenous anesthesia could decrease the occurrence of short-term POCD and inhibit postoperative peripheral inflammation in elderly patients undergoing abdominal surgery, compared with light anesthesia.