The impact of acute strenuous exercise on TLR2, TLR4 and HLA.DR expression on human blood monocytes induced by autologous serum.
Acute exercise alters the surface expression of toll-like receptors (TLRs) and HLA.DR on blood monocytes, which could transiently compromise immunity. As serum factors might be responsible, we examined the effects of autologous post-exercise serum exposure on TLR2, TLR4 and HLA.DR expression on resting blood monocytes and their subtypes. Eight trained cyclists completed an ergometer 60 km time trial. PBMCs and serum were obtained before, immediately after and 1 h after exercise. TLR2, TLR4 or HLA.DR expression (gMFI) was determined on blood monocyte subtypes expressing combinations of CD14 and CD16 by flow cytometry, and on resting monocytes exposed to 50% autologous serum (pre, immediately after or 1 h after exercise) for 18 h in culture. Immediately after exercise, total monocyte expression of TLR2 and TLR4 increased by 41 and 27%, respectively, while HLA.DR expression was 39% lower than baseline. TLR2 and TLR4 was 53 and 84% greater 1 h after exercise, respectively, while HLA.DR was 48% lower. Changes in TLR2 and TLR4 expression occurred on the CD14(++bright)/CD16(+dim) monocyte subtype only, while HLA.DR expression changed on the CD14(+dim)/CD16(++bright) subtype. Serum did not affect monocyte TLR2 or TLR4 expression but 1 h post serum increased expression of HLA.DR on total monocytes and the CD14(+dim)/CD16(++bright) subtype, which was in contrast to the change observed at this time after exercise. We conclude that a bout of strenuous aerobic exercise alters the surface expression of TLR2, TLR4 and HLA.DR on blood monocytes and some of their subtypes, but these changes appear to be unrelated to blood serum factors.


How do lesbian couples compare with heterosexual in vitro fertilization and spontaneously pregnant couples when it comes to parenting stress?
To study parenting stress in lesbian parents and to compare that stress with heterosexual parents following in vitro fertilisation (IVF) or spontaneous pregnancies. This survey took place during 2005-2008 and was part of the Swedish multicentre study on gamete donation. It comprised 131 lesbian parents, 83 heterosexual IVF parents, who used their own gametes, and 118 spontaneous pregnancy parents. The participants responded to the questionnaire when the child was between 12 and 36-months-old and parenting stress was measured by the Swedish Parenting Stress Questionnaire (SPSQ). Lesbian parents experienced less parenting stress than heterosexual IVF parents when it came to the General Parenting Stress measure (p = 0.001) and the subareas of Incompetence (p < 0.001), Social Isolation (p = 0.033) and Role Restriction (p = 0.004). They also experienced less parenting stress than heterosexual spontaneous pregnancy couples, according to the Social Isolation subarea (p = 0.003). Birth mothers experienced higher stress than co-mothers and fathers, according to the Role Restriction measure (p = 0.041). These are reassuring findings, considering the known challenges that lesbian families face in establishing their parental roles and, in particular, the challenges related to the lack of recognition of the co-mother.


Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2.
It was believed that Cdk2-cyclin E complexes are essential to drive cells through the G1-S phase transition. However, it was discovered recently that the mitotic kinase Cdk1 (Cdc2a) compensates for the loss of Cdk2. In the present study, we tested whether Cdk2 can compensate for the loss of Cdk1. We generated a knockin mouse in which the Cdk2 cDNA was knocked into the Cdk1 locus (Cdk1Cdk2KI). Substitution of both copies of Cdk1 by Cdk2 led to early embryonic lethality, even though Cdk2 was expressed from the Cdk1 locus. In addition, we generated Cdk2-/- Cdk1+/Cdk2KI mice in which one copy of Cdk2 and one copy of Cdk1 were expressed from the Cdk1 locus and the Cdk2 gene was deleted from the endogenous Cdk2 locus. We found that both male and female Cdk2-/- Cdk1+/Cdk2KI mice were sterile, similar to Cdk2-/- mice, even though they expressed the Cdk2 protein from the Cdk1 locus in testes. The translocational and cell cycle properties of knockin Cdk2 in Cdk2-/- Cdk1+/Cdk2KI cells were comparable to those of endogenous Cdk2, but we detected premature transcriptional activation of Cdk1 during liver regeneration in the absence of Cdk2. This study provides evidence of the molecular differences between Cdk2 and Cdk1 and highlights that the timing of transcriptional activation and the genetic locus play important roles in determining the function of Cdk proteins in vivo.


Review of controlled research on the transcendental meditation program and cardiovascular disease. Risk factors, morbidity, and mortality.
Because of growing evidence for stress as a major factor contributing to cardiovascular disease (CVD), techniques of meditation are being increasingly used. The Transcendental Meditation (TM) technique is distinct from other techniques of meditation not only in its origin and procedure, but also in the amount and breadth of research testing it. Evidence for its ability to reduce traditional and novel risk factors for CVD includes: 1) decreases in blood pressure, 2) reduced use of tobacco and alcohol, 3) lowering of high cholesterol and lipid oxidation, and 4) decreased psychosocial stress. Changes expected to result from reducing these risk factors, namely, reversal of atherosclerosis, reduction of myocardial ischemia and left ventricular hypertrophy, reduced health insurance claims for CVD, and reduced mortality, also have been found with TM practice. Research on mechanisms suggests that some of the CVD-related benefits as a result of this technique could arise from normalization of neuroendocrine systems whose function has been distorted by chronic stress. Further randomized clinical trials are in progress with a focus on underserved minority populations.


The Risk of Falls After Total Knee Arthroplasty with the Use of a Femoral Nerve Block Versus an Adductor Canal Block: A Double-Blinded Randomized Controlled Study.
Adductor canal block (ACB) has emerged as an appealing alternative to femoral nerve block (FNB) that produces a predominantly sensory nerve block by anesthetizing the saphenous nerve. Studies have shown greater quadriceps strength preservation with ACB compared with FNB, but no advantage has yet been shown in terms of fall risk. The Tinetti scale is used by physical therapists to assess gait and balance, and total score can estimate a patient's fall risk. We designed this study to test the primary hypothesis that FNB results in a greater proportion of "high fall risk" patients postoperatively using the Tinetti score compared with ACB. After institutional review board approval, informed written consent to participate in the study was obtained. Patients undergoing primary unilateral total knee arthroplasty were eligible for enrollment in this double-blind, randomized trial. Patients received either an ACB or FNB (20 mL of 0.5% ropivacaine) with catheter placement (8 mL/h of 0.2% ropivacaine) in the setting of multimodal analgesia. Continuous infusion was stopped in the morning of postoperative day (POD)1 before starting physical therapy (PT). On POD1, PT assessed the primary outcome using the Tinetti score for gait and balance. Patients were considered to be at high risk of falling if they scored <19. Secondary outcomes included manual muscle testing of the quadriceps muscle strength, Timed Up and Go (TUG) test, and ambulation distance on POD1 and POD2. The quality of postoperative analgesia and the quality of recovery were assessed with American Pain Society Patient Outcome Questionnaire Revised and Quality of Recovery-9 questionnaire, respectively. Sixty-two patients were enrolled in the study (31 ACB and 31 FNB). No difference was found in the proportion of "high fall risk" patients on POD1 (21/31 in the ACB group versus 24/31 in the FNB group [P = 0.7]; relative risk, 1.14 [95% confidence interval, 0.84-1.56]) or POD2 (7/31 in the ACB versus 14/31 in the FNB group [P = 0.06]; relative risk, 2.0 [95% confidence interval, 0.94-4.27]). The average distance of ambulation during PT and time to up and go were similar on POD1 and POD2. Manual muscle testing grades were significantly higher on POD1 in the ACB group when compared with that in the FNB (P = 0.001) (Wilcoxon-Mann-Whitney odds, 2.25 [95% confidence interval, 1.35-4.26]). There were no other differences in postoperative outcomes. ACB results in greater preservation of quadriceps muscle strength. Although we did not detect a significant reduction in fall risk when compared with FNB, based on the upper limit of the relative risk, it may very well be present. Further study is needed with a larger sample size.


How Can the Clinical Aptitude of AI Assistants Be Assayed?
Large language models (LLMs) are exhibiting remarkable performance in clinical contexts, with exemplar results ranging from expert-level attainment in medical examination questions to superior accuracy and relevance when responding to patient queries compared to real doctors replying to queries on social media. The deployment of LLMs in conventional health care settings is yet to be reported, and there remains an open question as to what evidence should be required before such deployment is warranted. Early validation studies use unvalidated surrogate variables to represent clinical aptitude, and it may be necessary to conduct prospective randomized controlled trials to justify the use of an LLM for clinical advice or assistance, as potential pitfalls and pain points cannot be exhaustively predicted. This viewpoint states that as LLMs continue to revolutionize the field, there is an opportunity to improve the rigor of artificial intelligence (AI) research to reward innovation, conferring real benefits to real patients.


Temporal uncertainty separates flashes from their background during saccades.
It is known that spatial localization of flashed objects fails around the time of rapid eye movements (saccades). This mislocalization is often interpreted in terms of a combination of shifts and deformations of the brain's representation of space to account for the eye movement. Such temporary remapping of positions in space should affect all elements in a scene, leaving ordinal relationships between positions intact. We performed an experiment in which we presented flashes on a background with red and green regions to human subjects. We found that flashes that were presented on the green part of the background around the time of a saccade were readily reported to have been presented on the red part of the background and vice versa. This is inconsistent with the notion of a temporary shift and deformation of perceived space. To explain our results, we present a model that illustrates how temporal uncertainty could give rise to the observed spatial mislocalization. The model combines uncertainty about the time of the flash with a bias to localize targets where one is looking. It reproduced the pattern of mislocalization very accurately, showing that perisaccadic mislocalization can best be explained in terms of temporal uncertainty about the moment of the flash.


Suppression of immunological functions in morphine addicted mice.
Lymphocytes isolated from morphine addicted mice show a number of impaired immunological functions. They include Con A stimulated mitogenesis, NK cell activity, plaque forming cell activity and delayed-type of hypersensitivity. In addition, the met-enkephalin and beta-endorphin level in the lymph nodes of addicted mice were also depressed.


A cultural neuropsychological approach to harmonization of cognitive data across culturally and linguistically diverse older adult populations.
To describe a cultural neuropsychological approach to prestatistical harmonization of cognitive data across the United States (U.S.) and Mexico with the Harmonized Cognitive Assessment Protocol (HCAP). We performed a comprehensive review of the administration, scoring, and coding procedures for each cognitive test item administered across the English and Spanish versions of the HCAP in the Health and Retirement Study (HRS) in the U.S. and the Ancillary Study on Cognitive Aging in Mexico (Mex-Cog). For items that were potentially equivalent across studies, we compared each cognitive test item for linguistic and cultural equivalence and classified items as confident or tentative linking items, based on the degree of confidence in their comparability across cohorts and language groups. We evaluated these classifications using differential item functioning techniques. We evaluated 132 test items among 21 cognitive instruments in the HCAP across the HRS and Mex-Cog. We identified 72 confident linking items, 46 tentative linking items, and 14 items that were not comparable across cohorts. Measurement invariance analysis revealed that 64% of the confident linking items and 83% of the tentative linking items showed statistical evidence of measurement differences across cohorts. Prestatistical harmonization of cognitive data, performed by a multidisciplinary and multilingual team including cultural neuropsychologists, can identify differences in cognitive construct measurement across languages and cultures that may not be identified by statistical procedures alone. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Global Transcriptomic Analysis of the Candida albicans Response to Treatment with a Novel Inhibitor of Filamentation.
The opportunistic pathogenic fungus Candida albicans can cause devastating infections in immunocompromised patients. Its ability to undergo a morphogenetic transition from yeast to filamentous forms allows it to penetrate tissues and damage tissues, and the expression of genes associated with a number of pathogenetic mechanisms is also coordinately regulated with the yeast-to-hypha conversion. Therefore, it is widely considered that filamentation represents one of the main virulence factors of C. albicans We have previously identified N-[3-(allyloxy)-phenyl]-4-methoxybenzamide (compound 9029936) as the lead compound in a series of small-molecule inhibitors of C. albicans filamentation and characterized its activity both in vitro and in vivo This compound appears to be a promising candidate for the development of alternative antivirulence strategies for the treatment of C. albicans infections. In this study, we performed RNA sequencing analysis of samples obtained from C. albicans cells grown under filament-inducing conditions in the presence or absence of this compound. Overall, treatment with compound 9029936 resulted in 618 upregulated and 702 downregulated genes. Not surprisingly, some of the most downregulated genes included well-characterized genes associated with filamentation and virulence such as SAP5, ECE1 (candidalysin), and ALS3, as well as genes that impact metal chelation and utilization. Gene ontology analysis revealed an overrepresentation of cell adhesion, iron transport, filamentation, biofilm formation, and pathogenesis processes among the genes downregulated during treatment with this leading compound. Interestingly, the top upregulated genes suggested an enhancement of vesicular transport pathways, particularly those involving SNARE interactions.IMPORTANCE These results from whole-genome transcriptional profiling provide further insights into the biological activity and mode of action of a small-molecule inhibitor of C. albicans filamentation. This information will assist in the development of novel antivirulence strategies against C. albicans infections.


Deletion of Runx2 in Articular Chondrocytes Decelerates the Progression of DMM-Induced Osteoarthritis in Adult Mice.
Runx2 may play an important role in development of osteoarthritis (OA). However, the specific role of Runx2 in articular chondrocyte function and in OA development in adult mice has not been fully defined. In this study, we performed the destabilization of the medial meniscus (DMM) surgery at 12-week-old mice to induce OA in adult Runx2 Agc1CreER mice, in which Runx2 was specifically deleted in Aggrecan-expressing chondrocytes by administering tamoxifen at 8-weeks of age. Knee joint samples were collected 8- and 12-weeks post-surgery and analyzed through histology, histomorphometry and micro-computed tomography (μCT). Our results showed that severe OA-like defects were observed after DMM surgery in Cre-negative control mice, including articular cartilage degradation and subchondral sclerosis, while the defects were significantly ameliorated in Runx2 Agc1CreER KO mice. Immunohistochemical (IHC) results showed significantly reduced expression of MMP13 in Runx2 Agc1CreER KO mice compared to that in Cre-negative control mice. Results of quantitative reverse-transcription PCR (qRT-PCR) demonstrated that expression of the genes encoding for matrix degradation enzymes was significantly decreased in Runx2 Agc1CreER KO mice. Thus, our findings suggest that inhibition of Runx2 in chondrocytes could at least partially rescue DMM-induced OA-like defects in adult mice.


Post-SSRI sexual dysfunction: Patient experiences of engagement with healthcare professionals.
A petition to the European Medicines Agency provided an opportunity to collect reports of a specific adverse event from patients and healthcare professionals, along with details of clinicians' attitudes when asked to endorse patient reports. We approached a cohort of patients reporting post-SSRI sexual dysfunction (PSSD) to an adverse event reporting website, RxISK.org. The responses of patients on their interactions with healthcare professionals were subject to a qualitative analysis. A total of 62 participants from 23 countries provided details of their experiences. While some had received support and validation of their condition, many described a number of difficulties including a lack of awareness or knowledge about PSSD, not being listened to, receiving unsympathetic or inappropriate responses, and a refusal to engage with the published medical literature. Healthcare professionals are nervous about or reluctant to engage with novel problems on a treatment. This is not widely appreciated and the reasons for this concern are not understood.


Downregulation of [3H]Ro5-4864 binding sites after exposure to peripheral-type benzodiazepines in vitro.
Peripheral-type benzodiazepine (BZD) binding sites undergo a rapid and pronounced downregulation after exposure to these compounds in vitro. Friend erythroleukemia cells were incubated with micromolar concentrations of BZD after which they were washed thoroughly and the binding of the specific peripheral-type BZD radioligand [3H]Ro5-4864 was determined. Exposure to the peripheral-type BZD Ro7-3351 decreased the number of [3H]Ro5-4864 binding sites from 324 to 41 fmol/10(6) cells with no change in affinity. Downregulation appears to require active cellular processes because it is blocked when exposure to BZD is at 4 degrees C rather than at 37 degrees C. Furthermore, whereas [3H]Ro5-4864 binding is decreased substantially in membrane preparations made from downregulated cells, it is not altered when membrane preparations from control cells are exposed to BZD. The time course of downregulation is quite rapid, as it occurs within minutes. In contrast, the return of sites requires days and there is a close relationship between return of sites and growth of new cells. The ability of BZDs to downregulate correlates more closely with affinity for the peripheral-type site than with biological activity. The ability to undergo downregulation is characteristic of receptors and its occurrence suggests that peripheral-type BZD binding sites are functional receptors.


Aortic arch replacement with frozen elephant trunk-when not to use it.
Current scientific evidence suggests the frozen elephant trunk (FET) technique plays an important role in modern aortic arch repair operations, both for aneurysmal disease and acute aortic dissection. Its use in extended aneurysm is generally therapeutic, aiming for complete exclusion of the diseased descending thoracic aorta. In acute aortic dissection type A, the application of FET is more prophylactic in nature, with the aim of preventing late dilatation of the proximal descending thoracic aorta. This review will present the journey of the elephant trunk from its conception to the current available technology. By tracing the historical evolution of the FET technique and prosthesis development, we explore the challenges and limitations of evidence-based surgical research. We present data from our growing experience in aortic arch reconstruction, the results from our latest 27 patients undergoing the 4-branch FET indicating substantially reduced morbidity and mortality (0%) in this complex patient cohort.


Phytochemical residue profiles in rice grains fumigated with essential oils for the control of rice weevil.
In the present study, we investigated the fumigant potential of five edible essential oils (EOs) against Sitophilus oryzae and their phytochemical residues in treated grains. Among the tested EOs, peppermint oil proved significantly effective (P ≤ 0.05) on S.oryzae at 400 μl/L air concentration, inducing 83 and 100% mortalities in with-food and without-food conditions respectively over 72 h exposure. In addition, it was also observed that the binary mixtures of peppermint + lemon oil (1:1 ratio) produced an equivalent effect to that of peppermint oil alone treatments. The phytochemical residue analysis by GC-MS revealed the presence of six compounds upon 72 h exposure to EOs. Further, the analysis of physico-chemical properties of the compounds indicated a positive correlation between polar surface area (PSA) and its residual nature. The residue levels of eugenol were significantly elevated corresponding to its high PSA value (29) in clove and cinnamon oils. On the other hand, the compounds with zero PSA value imparted very less or no (D-Limonene, caryophyllene, pinene and terpinolene) residues in treated grains. With respect to the most active peppermint oil, L-menthone, menthyl acetate and eucalyptol residues were at 67, 41 and 23% levels respectively. The outcome of the present study indicate the peppermint oil as a potent fumigant against S. oryzae, and although the residues of phytochemicals in treated grains is higher; they belong to the generally recognised as safe (GRAS) status leaving no harmful effect.


Quantitative variations in the pathology of 11 cases of variant Creutzfeldt-Jakob disease (vCJD).
Quantitative variations in the density and distribution of the vacuolation ('spongiform change'), surviving neurons, and prion protein (PrP) deposits were studied in eight brain regions from 11 cases of variant Creutzfeldt-Jakob disease (vCJD). Principal components analysis (PCA) was used to study the similarities and differences between cases and to identify the neuropathological variables which could best account for these variations. Two principal components (PC) were extracted from the data accounting in total for 93.4% of the variance; the majority of the variance (90%) being associated with PC1. Some clustering of the 11 cases in relation to PC1 and PC2 was evident. The densities of the vacuolation in the occipital cortex and the molecular layer of the cerebellum were positively and negatively correlated, respectively, with PC1. No significant variation between cases was associated with PrP deposition. These data suggest that vCJD cases have a consistent neuropathological profile characterised by the presence of vacuolation, neuronal loss and PrP deposition in the form of florid and non-florid deposits. However, there are quantitative variations between cases in the development of the vacuolation especially affecting the occipital cortex and cerebellum.


Video assisted thoracoscopic management of primary spontaneous pneumothorax.
Although Video-Assisted Thoracoscopic Surgery (VATS) is now accepted by many as the approach of choice in the management of primary spontaneous pneumothorax (PSP), the optimal procedure and the timing of surgical intervention remain areas of contention. The authors reviewed their combined experience with 518 consecutive VATS procedures for PSP in 483 patients. Mechanical pleurodesis was performed in every case and was the only procedure in 20 patients. We had experience with several means of eliminating subpleural bullae once identified: stapled bullectomy (196), endoloop (261), argon beam coagulation (6) and endoscopic suturing (35). There were no mortality or intraoperative complications. Median postoperative hospital stay was 3 days. So far, we have had 9 recurrences (1.74%), after a mean follow up of 20 months (range one to 36 months). Complications consisted of 18 persistent air leaks, 14 would infections and 1 chest wall bleeding. We conclude that (1) VATS is a safe and effective approach in the treatment of PSP; (2) Stapled-bullectomy is quick and reliable but costly; (3) Endoloop and suturing are viable alternative techniques that may prove to be more cost effective; (4) we do not recommend to use argon beam coagulation as the primary treatment modality.


Friction force measurements relevant to de-inking by means of atomic force microscope.
In the pulping step of the de-inking process, the ink detaches from the fibers due to shear and physical chemical interaction. In order to get a better understanding of the forces involved between cellulose and ink, the atomic force microscope and the colloidal probe technique have been used in the presence of a model chemical dispersant (hexa-ethyleneglycol mono n-dodecyl ether, C12E6). A cellulose bead was used as the colloidal probe and three different lower surfaces have been used, an alkyd resin, mica and a cellulose sphere. The normal and lateral forces have been measured at a range of nonionic concentrations. It was found that the lateral sliding friction forces deceased with increasing surfactant concentration for both the alkyd resin and mica while no differences were observed for the cellulose surface. In addition, only a very small change in normal force could be detected for the alkyd surface as the concentration changed.


Measurement of the Elastic Modulus of Cornea, Sclera and Limbus: The Importance of the Corneal-Limbus-Scleral Biomechanical Unit.
Energy storage, transmission and dissipation are important considerations of normal mechanical homeostasis. In this paper we present a new technique termed vibrational optical coherence tomography (VOCT) to study the anterior anatomic structures of the pig eye to better understand how energy applied to the cornea is dissipated without delamination occurring. VOCT uses infrared light and an applied sinusoidal audible sound wave to image and measure the resonant frequency and modulus of individual macromolecular components of tissue non-invasively. We have measured the resonant frequencies and calculated the moduli of tissues in the anterior portion of the pig eye using VOCT. While both pig and human eyes have similar resonant frequencies, they do differ in the peak amplitudes near the frequencies of 80, 120, 150 and 250 Hz. It is known that the stroma of pig cornea is much thicker than that of human corneas and these differences may explain the normalized peak height differences. The similarity of the resonant frequency peaks near 80, 120, 150 and 250 Hz of cornea, sclera and limbus suggest that the anatomically described layers in these tissues are connected into a single biomechanical unit that can store external mechanical energy and then transmit it for dissipation. Since the energy stored and dissipated is proportional to the modulus and the ability of the tissue to deform under stress, energy storage in these tissues is related to the stiffness. It is concluded that stored energy is transmitted to the posterior segment of the eye for dissipation through the attachment with the sclera. This mechanism of energy dissipation may protect the cornea from changes in shape, curvature, and refractive power. However, ultimately, energy dissipation through thinning of the sclera may cause globe elongation observed in subjects with myopia and glaucoma.


Musicians Show Improved Speech Segregation in Competitive, Multi-Talker Cocktail Party Scenarios.
Studies suggest that long-term music experience enhances the brain's ability to segregate speech from noise. Musicians' "speech-in-noise (SIN) benefit" is based largely on perception from simple figure-ground tasks rather than competitive, multi-talker scenarios that offer realistic spatial cues for segregation and engage binaural processing. We aimed to investigate whether musicians show perceptual advantages in cocktail party speech segregation in a competitive, multi-talker environment. We used the coordinate response measure (CRM) paradigm to measure speech recognition and localization performance in musicians vs. non-musicians in a simulated 3D cocktail party environment conducted in an anechoic chamber. Speech was delivered through a 16-channel speaker array distributed around the horizontal soundfield surrounding the listener. Participants recalled the color, number, and perceived location of target callsign sentences. We manipulated task difficulty by varying the number of additional maskers presented at other spatial locations in the horizontal soundfield (0-1-2-3-4-6-8 multi-talkers). Musicians obtained faster and better speech recognition amidst up to around eight simultaneous talkers and showed less noise-related decline in performance with increasing interferers than their non-musician peers. Correlations revealed associations between listeners' years of musical training and CRM recognition and working memory. However, better working memory correlated with better speech streaming. Basic (QuickSIN) but not more complex (speech streaming) SIN processing was still predicted by music training after controlling for working memory. Our findings confirm a relationship between musicianship and naturalistic cocktail party speech streaming but also suggest that cognitive factors at least partially drive musicians' SIN advantage.


Synthesis and high-throughput processing of polymeric hydrogels for 3D cell culture.
3D cell cultures have drawn a large amount of interest in the scientific community with their ability to closely mimic physiological conditions. Hydrogels have been used extensively in the development of extracellular matrix (ECM) mimics for 3D cell culture. Compounds such as collagen and fibrin are commonly used to synthesize natural ECM mimics; however they suffer from batch-to-batch variation. In this Review we explore the synthesis route of hydrogels; how they can be altered to give different chemical and physical properties; how different biomolecules such as arginylglycylaspartic acid (RGD) or vascular endothelial growth factor (VEGF) can be incorporated to give different biological cues; and how to create concentration gradients with UV light. There will also be emphasis on the types of techniques available in high-throughput processing such as nozzle and droplet-based biofabrication, photoenabled biofabrication, and microfluidics. The combination of these approaches and techniques allow the preparation of hydrogels which are capable of mimicking the ECM.


Characterization of opioid receptors on smooth muscle cells from guinea pig stomach.
On the basis of opioid-stimulated contraction of dispersed gastric smooth muscle cells it has been suggested that these cells possess opioid receptors of three subtypes: kappa (kappa), mu (mu), and delta (delta). We have used selective peptidase-resistant radioligands, agonists and antagonists, to examine receptor subtypes on dispersed gastric smooth muscle cells from guinea pigs prepared by collagenase digestion. The kappa-agonist U-50488H, the mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAGO), and the delta-agonist [D-Pen2,Pen5]enkephalin (DPDPE) each caused muscle contraction. The concentrations required to caused half-maximal contraction were U50488H (6 pM) greater than DAGO (13 pM) greater than DPDPE (6 nM). The abilities of these agonists to inhibit binding of [3H]U-69593 (kappa-preferring) by 50% were U50488H (43 nM) greater than DAGO (43 microM) greater than DPDPE (200 microM). Their abilities to inhibit binding of [3H]naloxone (mu-preferring) by 50% were DAGO (0.2 microM) greater than U50488H (10 microM) greater than DPDPE (greater than 100 microM). No binding could be detected with the delta-selective ligand [3H]DPDPE. The kappa-preferring antagonist Mr2266 (10 nM) preferentially inhibited contraction stimulated by the kappa-agonist U50488H, and naltrexone (10 nM) (mu-selective antagonist) preferentially inhibited contraction stimulated by the mu-agonist DAGO. ICI 174864 (200 microM; delta-selective antagonist) had no effect on contraction stimulated by mu-, kappa-, or delta-agonists. Contraction stimulated by the delta-agonist DPDPE was inhibited by both kappa- and mu-receptor antagonists. Studies on the effect of the antagonists on binding of [3H]naloxone and [3H]U69593 also provided evidence for kappa- and mu-sites but nor for delta-sites.(ABSTRACT TRUNCATED AT 250 WORDS)


On-chip density-based purification of liposomes.
Due to their cell membrane-mimicking properties, liposomes have served as a versatile research tool in science, from membrane biophysics and drug delivery systems to bottom-up synthetic cells. We recently reported a novel microfluidic method, Octanol-assisted Liposome Assembly (OLA), to form cell-sized, monodisperse, unilamellar liposomes with excellent encapsulation efficiency. Although OLA provides crucial advantages over alternative methods, it suffers from the presence of 1-octanol droplets, an inevitable by-product of the production process. These droplets can adversely affect the system regarding liposome stability, channel clogging, and imaging quality. In this paper, we report a density-based technique to separate the liposomes from droplets, integrated on the same chip. We show that this method can yield highly pure (>95%) liposome samples. We also present data showing that a variety of other separation techniques (based on size or relative permittivity) were unsuccessful. Our density-based separation approach favourably decouples the production and separation module, thus allowing freshly prepared liposomes to be used for downstream on-chip experimentation. This simple separation technique will make OLA a more versatile and widely applicable tool.


Helical Structure of Recombinant Melittin.
Melittin is an extensively studied, 26-residue toxic peptide from honey bee venom. Because of its versatility in adopting a variety of secondary (helix or coil) and quaternary (monomer or tetramer) structures in various environments, melittin has been the focus of numerous investigations as a model peptide in protein folding studies as well as in studies involving binding to proteins, lipids, and polysaccharides. A significant body of evidence supports the view that melittin binds to these macromolecules in a predominantly helical conformation, but detailed structural knowledge of this conformation is lacking. In this report, we present nuclear magnetic resonance (NMR)-based structural insights into the helix formation of recombinant melittin in the presence of trifluoroethanol (TFE): a known secondary structure inducer in peptides. These studies were performed at neutral pH, with micromolar amounts of the peptide. Using nuclear Overhauser effect (NOE)-derived distance restraints from three-dimensional NMR spectra, we determined the atomic resolution solution NMR structure of recombinant melittin bearing a TFE-stabilized helix. To circumvent the complications with structure determination of small peptides with high conformational flexibility, we developed a workflow for enhancing proton NOEs by increasing the viscosity of the medium. In the TFE-containing medium, recombinant monomeric melittin forms a long, continuous helical structure, which consists of the N- and C-terminal α-helices and the noncanonical 310-helix in the middle. The noncanonical 310-helix is missing in the previously solved X-ray structure of tetrameric melittin and the NMR structure of melittin in methanol. Melittin's structure in TFE-containing medium provides insights into melittin's conformational transitions, which are relevant to the peptide's interactions with its biological targets.


A Neutrophil Proteomic Signature in Surgical Trauma Wounds.
Non-healing wounds continue to be a clinical challenge for patients and medical staff. These wounds have a heterogeneous etiology, including diabetes and surgical trauma wounds. It is therefore important to decipher molecular signatures that reflect the macroscopic process of wound healing. To this end, we collected wound sponge dressings routinely used in vacuum assisted therapy after surgical trauma to generate wound-derived protein profiles via global mass spectrometry. We confidently identified 311 proteins in exudates. Among them were expected targets belonging to the immunoglobulin superfamily, complement, and skin-derived proteins, such as keratins. Next to several S100 proteins, chaperones, heat shock proteins, and immune modulators, the exudates presented a number of redox proteins as well as a discrete neutrophil proteomic signature, including for example cathepsin G, elastase, myeloperoxidase, CD66c, and lipocalin 2. We mapped over 200 post-translational modifications (PTMs; cysteine/methionine oxidation, tyrosine nitration, cysteine trioxidation) to the proteomic profile, for example, in peroxiredoxin 1. Investigating manually collected exudates, we confirmed presence of neutrophils and their products, such as microparticles and fragments containing myeloperoxidase and DNA. These data confirmed known and identified less known wound proteins and their PTMs, which may serve as resource for future studies on human wound healing.


Twitch and tetanic tension during culture of mature Xenopus laevis single muscle fibres.
Investigation of the mechanisms of muscle adaptation requires independent control of the regulating factors. The aim of the present study was to develop a serum-free medium to culture mature single muscle fibres of Xenopus laevis. As an example, we used the culture system to study adaptation of twitch and tetanic force characteristics, number of sarcomeres in series and fibre cross-section. Fibres dissected from m. iliofibularis (n = 10) were kept in culture at a fibre mean sarcomere length of 2.3 microm in a culture medium without serum. Twitch and tetanic tension were determined daily. Before and after culture the number of sarcomeres was determined by laser diffraction and fibre cross-sectional area (CSA) was determined by microscopy. For five fibres twitch tension increased during culture and tetanic tension was stable for periods varying from 8 to 14 days ('stable fibres'), after which fibres were removed from culture for analysis. Fibre CSA and the number of sarcomeres in series remained constant during culture. Five other fibres showed a substantial reduction in twitch and tetanic tension within the first five days of culture ('unstable fibres'). After 7-9 days of culture, three of these fibres died. For two of the unstable fibres, after the substantial force reduction, twitch and tetanic tension increased again. Finally at day 14 and 18 of culture, respectively, the tensions attained values higher than their original values. For stable fibres, twitch contraction time, twitch half-relaxation time and tetanus 10%-relaxation time increased during culture. For unstable fibres these parameters fluctuated. For all fibres the stimulus threshold fluctuated during the first two days, and then remained constant, even for the fibres that were cultured for at least two weeks. It is concluded that the present culture system for mature muscle fibres allows long-term studies within a well-defined medium. Unfortunately, initial tetanic and twitch force are poor predictors of the long-term behaviour of the fibres.


Diagnosis of cerebral ventriculomegaly in normal adult beagles using quantitative MRI.
The brain of 17 asymptomatic normal adult beagles was evaluated with magnetic resonance imaging. Lateral ventricular size was quantified using computer algorithms. In beagles with large ventricles, contrast medium was introduced into the cerebellomedullary cistern to determine whether obstructive hydrocephalus was present. Total lateral ventricular volume ranged from 77 mm3 to 11,726 mm3. Based on Gd-DTPA diffusion, the CSF flow pattern was considered normal and normal neural morphology was seen using electron microscopy. Results suggest a high incidence of clinically asymptomatic ventriculomegaly in normal adult beagles.


[Dental-craniofacial manifestation and treatment of rare diseases in China].
Rare diseases are genetic, chronic, and incurable disorders with relatively low prevalence. Thus, diagnosis and management strategies for such diseases are currently limited. This situation is exacerbated by insufficient medical sources for these diseases. The National Health and Health Committee of China recently first provided a clear definition of 121 rare diseases in the Chinese population. In this study, we summarize several dental-craniofacial manifestations associated with some rare diseases to provide a reference for dentists and oral maxillofacial surgeons aiming at fast-tracking diagnosis for the management of these rare diseases.


Lipid-rich enteral nutrition regulates mucosal mast cell activation via the vagal anti-inflammatory reflex.
Nutritional stimulation of the cholecystokinin-1 receptor (CCK-1R) and nicotinic acetylcholine receptor (nAChR)-mediated vagal reflex was shown to reduce inflammation and preserve intestinal integrity. Mast cells are important early effectors of the innate immune response; therefore modulation of mucosal mast cells is a potential therapeutic target to control the acute inflammatory response in the intestine. The present study investigates intestinal mast cell responsiveness upon nutritional activation of the vagal anti-inflammatory reflex during acute inflammation. Mucosal mast cell degranulation was induced in C57/Bl6 mice by administration of Salmonella enterica LPS. Lipid-rich enteral feeding prior to LPS significantly decreased circulatory levels of mouse mast cell protease at 30 min post-LPS compared with isocaloric low-lipid nutrition or fasting. CCK-1R blockage reversed the inhibitory effects of lipid-rich feeding, whereas stimulation of the peripheral CCK-1R mimicked nutritional mast cell inhibition. The effects of lipid-rich nutrition were negated by nAChR blockers chlorisondamine and α-bungarotoxin and vagal intestinal denervation. Accordingly, release of β-hexosaminidase by MC/9 mast cells following LPS or IgE-ovalbumin complexes was dose dependently inhibited by acetylcholine and nicotine. Application of GSK1345038A, a specific agonist of the nAChR α7, in bone marrow-derived mast cells from nAChR β2-/- and wild types indicated that cholinergic inhibition of mast cells is mediated by the nAChR α7 and is independent of the nAChR β2. Together, the present study reveals mucosal mast cells as a previously unknown target of the nutritional anti-inflammatory vagal reflex.


High compliance with newborn community-to-facility referral in eastern Uganda:.an opportunity to improve newborn survival.
Seventy-five percent of newborn deaths happen in the first-week of life, with the highest risk of death in the first 24-hours after birth.WHO and UNICEF recommend home-visits for babies in the first-week of life to assess for danger-signs and counsel caretakers for immediate referral of sick newborns. We assessed timely compliance with newborn referrals made by community-health workers (CHWs), and its determinants in Iganga and Mayuge Districts in rural eastern Uganda. A historical cohort study design was used to retrospectively follow up newborns referred to health facilities between September 2009 and August 2011. Timely compliance was defined as caretakers of newborns complying with CHWs' referral advice within 24-hours. A total of 724 newborns were referred by CHWs of whom 700 were successfully traced. Of the 700 newborns, 373 (53%) were referred for immunization and postnatal-care, and 327 (47%) because of a danger-sign. Overall, 439 (63%) complied, and of the 327 sick newborns, 243 (74%) caretakers complied with the referrals. Predictors of referral compliance were; the newborn being sick at the time of referral- Adjusted Odds Ratio (AOR) = 2.3, and 95% Confidence-Interval (CI) of [1.6 - 3.5]), the CHW making a reminder visit to the referred newborn shortly after referral (AOR =1.7; 95% CI: [1.2 -2.7]); and age of mother (25-29) and (30-34) years, (AOR =0.4; 95% CI: [0.2 - 0.8]) and (AOR = 0.4; 95% CI: [0.2 - 0.8]) respectively. Caretakers' newborn referral compliance was high in this setting. The newborn being sick, being born to a younger mother and a reminder visit by the CHW to a referred newborn were predictors of newborn referral compliance. Integration of CHWs into maternal and newborn care programs has the potential to increase care seeking for newborns, which may contribute to reduction of newborn mortality.


Postoperative complications after closure of a diverting ileostoma--differences according to closure technique.
The aim of this study was to compare three methods for closure of a diverting ileostoma according to development of postoperative small-bowel obstruction (SBO) and anastomotic leakage (AL). Complications arising within 30 days after closure of a defunctioning loop ileostomy in 351 patients during the period 1999-2006 were studied retrospectively by evaluation of case records. The techniques employed were: hand-sewn anastomosis without bowel resection, hand-sewn anastomosis with bowel resection and stapled anastomosis. Of the 351 patients, 149 had a hand-sewn anastomosis without bowel resection (HS), 70 had a hand-sewn anastomosis with bowel resection (HSR) and 132 patients had a stapled anastomosis (S). The total number of SBOs was 44 patients (12.5%). In the two hand-sewn groups, 15.5% (34 patients) suffered postoperative SBO compared to 7.6% (10 patients) in the stapled group (p = 0.029). No difference in AL could be found between the groups, where the overall frequency was 2.8% (10 patients). Median hospital stay was 6 days in the HS group, 5 days in the HSR group and 4 days in the S group (p = 0.001). In the present study, stapled anastomosis was associated with a lower frequency of postoperative SBO and a shorter hospital stay compared to sutured anastomosis (either with or without a short small-bowel resection) after closure of a diverting ileostoma.


Disease diagnosis in primary care in Uganda.
The overall burden of disease (BOD) especially for infectious diseases is higher in Sub-Saharan Africa than other regions of the world. Existing data collected through the Health Management Information System (HMIS) may not be optimal to measure BOD. The Infectious Diseases Capacity Building Evaluation (IDCAP) cooperated with the Ugandan Ministry of Health to improve the quality of HMIS data. We describe diagnoses with associated clinical assessments and laboratory investigations of outpatients attending primary care in Uganda. IDCAP supported HMIS data collection at 36 health center IVs in Uganda for five months (November 2009 to March 2010) prior to implementation of the IDCAP interventions. Descriptive analyses were performed on a cross-sectional dataset of 209,734 outpatient visits during this period. Over 500 illnesses were diagnosed. Infectious diseases accounted for 76.3% of these and over 30% of visits resulted in multiple diagnoses. Malaria (48.3%), cough/cold (19.4%), and intestinal worms (6.6%) were the most frequently diagnosed illnesses. Body weight was recorded for 36.8% of patients and less than 10% had other clinical assessments recorded. Malaria smears (64.2%) and HIV tests (12.2%) accounted for the majority of 84,638 laboratory tests ordered. Fewer than 30% of patients for whom a laboratory investigation was available to confirm the clinical impression had the specific test performed. We observed a broad range of diagnoses, a high percentage of multiple diagnoses including true co-morbidities, and underutilization of laboratory support. This emphasizes the complexity of illnesses to be addressed by primary healthcare workers. An improved HMIS collecting timely, quality data is needed. This would adequately describe the burden of disease and processes of care at primary care level, enable appropriate national guidelines, programs and policies and improve accountability for the quality of care.


First study of intra-arterial delivery of myogenic mononuclear cells to skeletal muscles in primates.
The main challenge of cell transplantation as a treatment of myopathies is the large amount of tissue to treat. Intravascular delivery of cells may be an ideal route if proven to be effective and safe. Given the importance of nonhuman primates for preclinical research in transplantation, we tested the intra-arterial injection of β-galactosidase (β-Gal)-labeled myoblasts in macaques. Cells were injected into one of the femoral arteries in seven monkeys. Some muscle sites were damaged concomitantly in three monkeys. Various organs and muscles were sampled 1 h, 1 day, 12 days, 3 weeks, and 5 weeks after transplantation. Samples were analyzed by histology. Most β-Gal(+) cells were observed in the capillaries and arterioles of muscles and other tissues of the leg homolateral to the cell injection. Groups of necrotic myofibers in the proximity of an arteriole plugged by a β-Gal(+) embolus were interpreted as microinfarcts. Scarce β-Gal(+) cells were observed in the lungs 1 h and 1 day posttransplantation. No β-Gal(+) cells were observed in other organs or muscles. β-Gal(+) myofibers were observed 12 days, 3 weeks, and 5 weeks after transplantation in muscles of the leg after the cell injection, in sites that were damaged at the time of cell injection. In conclusion, most intra-arterially injected myoblasts were retained in vessels of the leg homolateral to the cell injection site, and they fused with myofibers in regions in which there was a process of myofiber regeneration. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.


Effects of hypolipidemic agent nordihydroguaiaretic acid on lipid droplets and hepatitis C virus.
Hepatitis C virus (HCV) relies on host lipid metabolic pathways for its replication, assembly, secretion, and entry. HCV induces de novo lipogenesis, inhibits β-oxidation, and lipoprotein export resulting in a lipid-enriched cellular environment critical for its proliferation. We investigated the effects of a hypolipidemic agent, nordihydroguaiaretic acid (NDGA), on host lipid/fatty acid synthesis and HCV life cycle. NDGA negated the HCV-induced alteration of host lipid homeostasis. NDGA decreased sterol regulatory element binding protein (SREBP) activation and enhanced expression of genes involved in β-oxidation. NDGA inhibited very low-density lipoprotein (VLDL) secretion by affecting mediators of VLDL biosynthesis. Lipid droplets (LDs), the neutral lipid storage organelles, play a key role in HCV morphogenesis. HCV induces accumulation and perinuclear distribution of LDs, whereas NDGA most notably reduced the overall number and increased the average size of LDs. The antiviral effects of NDGA resulted in reduced HCV replication and secretion. NDGA-mediated alterations of host lipid metabolism, LD morphology, and VLDL transport appear to negatively influence HCV proliferation.


Milk Transmission of Mammalian Retroviruses.
The transmission of viruses from one host to another typically occurs through horizontal or vertical pathways. The horizontal pathways include transmission amongst individuals, usually through bodily fluids or excretions, while vertical transmission transpires from mother to their offspring, either during pregnancy, childbirth, or breastfeeding. While there are more than 200 human pathogenic viruses to date, only a small number of them are known to be transmitted via breast milk, including cytomegalovirus (CMV), human immunodeficiency virus type 1 (HIV-1), and human T cell lymphotropic virus type 1 (HTLV-1), the latter two belonging to the family Retroviridae. Breast milk transmission is a common characteristic among mammalian retroviruses, but there is a lack of reports summarizing our knowledge regarding this route of transmission of mammalian retroviruses. Here, we provide an overview of the transmission of mammalian exogenous retroviruses with a focus on Orthoretrovirinae, and we highlight whether they have been described or suspected to be transmitted through breast milk, covering various species. We also elaborate on the production and composition of breast milk and discuss potential entry sites of exogenous mammalian retroviruses during oral transmission.


Cerebral perfusion deficits in age-associated memory impairment. The role of tobacco smoking.
Several studies report a high prevalence of memory complaints in the elderly, non-demented population. Since the pathogenesis and diversity of memory impairment in healthy people is still an unresolved issue, we designed our study to ascertain the occurrence of brain abnormalities in Age-Associated Memory Impairment (AAMI) by measuring regional cerebral blood flow (rCBF). Fifty-three subjects were invited to the case-control study: 26 subjects who fulfilled the AAMI criteria, and 27 controls (age, mean+/-SD 65.8+/-7.3 vs 65.5+/-6.7). rCBF was determined using 99mTC-ECD SPECT by relative measurements made in the cortical and white matter regions and in the thalamus. The AAMI group vs controls had restricted rCBF in the temporal lobe of the left hemisphere (median; 85.8 vs 87.8, p=0.04), in the thalamus (median; 87.3 vs 89.8, p=0.036) and the frontal white matter (median; right hemisphere 80.0 vs 84.1, p=0.01; left hemisphere 77.7 vs 81.6, p=0.04). AAMI subjects who previously smoked had lower rCBF values in the temporal, parietal, occipital and frontal lobes bilaterally, and poorer memory test results than ex-smoker controls. By contrast, rCBF did not differ between non-smoking AAMI subjects and controls. Compared to controls, AAMI subjects had restricted rCBF, A history of previous smoking could partly contribute to the rCBF differences between these groups. Further studies on failing memory and rCBF in representative cohorts of smoking and non-smoking populations are now needed.


Novel inhibitors of Rad6 ubiquitin conjugating enzyme: design, synthesis, identification, and functional characterization.
Protein ubiquitination is important for cell signaling, DNA repair, and proteasomal degradation, and it is not surprising that alterations in ubiquitination occur frequently in cancer. Ubiquitin-conjugating enzymes (E2) mediate ubiquitination by selective interactions with ubiquitin-activating (E1) and ubiquitin ligase (E3) enzymes, and thus selective E2 small molecule inhibitor (SMI) will provide specificity unattainable with proteasome inhibitors. Here we describe synthesis and functional characterization of the first SMIs of human E2 Rad6B, a fundamental component of translesion synthesis DNA repair. A pharmacophore model for consensus E2 ubiquitin-binding sites was generated for virtual screening to identify E2 inhibitor candidates. Twelve triazine (TZ) analogs screened in silico by molecular docking to the Rad6B X-ray structure were verified by their effect on Rad6B ubiquitination of histone H2A. TZs #8 and 9 docked to the Rad6B catalytic site with highest complementarity. TZs #1, 2, 8, and 9 inhibited Rad6B-ubiquitin thioester formation and subsequent ubiquitin transfer to histone H2A. SMI #9 inhibition of Rad6 was selective as BCA2 ubiquitination by E2 UbcH5 was unaffected by SMI #9. SMI #9 more potently inhibited proliferation, colony formation, and migration than SMI #8, and induced MDA-MB-231 breast cancer cell G2-M arrest and apoptosis. Ubiquitination assays using Rad6 immunoprecipitated from SMI #8- or 9-treated cells confirmed inhibition of endogenous Rad6 activity. Consistent with our previous data showing Rad6B-mediated polyubiquitination stabilizes β-catenin, MDA-MB-231 treatment with SMIs #8 or 9 decreased β-catenin protein levels. Together these results describe identification of the first Rad6 SMIs.


Physical Activity in Immersive Virtual Reality: A Scoping Review.
Physical activity has benefits for health, but many adolescents are inactive. However, video games such as Immersive Virtual Reality (IVR) have grown in popularity as a leisure activity among young people, allowing them to manipulate objects in virtual environments increasing the practice of physical activity. The evidence indicates that the interest in physical activity through IVR is greater than in traditional methods, and different experiences have been reported. However, few studies indicate the sample evaluated, the effects found, or the IVR instruments used. Due to this, is the aim of this study is to identify the publications referring to IVR and physical activity, characterize them, and present the obtained main findings. For this, the guidelines described in the PRISMA-ScR for scoping reviews were applied. After the use of the inclusion and exclusion criteria, eight articles were included. Results show evidence regarding physiological outcomes, perceptual variables, interest and enjoyment, and psychological effects regarding physical activity through IVR. Additionally, the use of different devices and their prescriptions are explored. It is concluded that there is interest from the scientific community for the practice of physical activity through IVR, as well as for its application for the maintenance of active habits. This is important as it positions IVR as a method that can be a more experiential and effective way to develop and maintain a healthy lifestyle.


Genesis of cilia and microvilli of rat nasal epithelia during pre-natal development. II. Olfactory epithelium, a morphometric analysis.
Rat foetuses from intra-uterine days E14 through E22 (day before parturition) and adults were used for a quantitative scanning electron-microscopic examination of ciliogenesis in olfactory receptor cells and microvillogenesis in olfactory supporting cells. Four developmental stages in olfactory ciliogenesis can be discerned. Two of these are characterized by the presence of primary cilia only, the other two concern outgrowth in number and length of secondary cilia. (1) Primary cilia on undifferentiated cells; this stage occurs up to E14. (2) Primary cilia on differentiating olfactory receptor and also olfactory supporting cells. This stage begins at E14 and lasts, for the olfactory receptor cells, at least up to E22. On the supporting cells primary cilia are rarely observed after E18. Virtually all primary cilia are about 1 micron long. Up to E21 dendritic endings with primary cilia occur more frequently than those with any other number of cilia; all endings have a transitional stage in which they bear primary cilia only. (3) Secondary olfactory cilia increase in number. From E16 onwards the cells become multiciliated. Beginning at this stage and continuing up to E22 an average of one cilium per day is added to the endings. At E22 the average number of cilia observed per ending is about 70% of that in adults; more than 90% of the endings are multiciliated. From E15 to E22 the exchange rate between receptor cells with only primary cilia and multiciliated cells is about 0.5 X 10(6) cells/cm2 per day. When considered in the light of electrophysiological data on developing rats, our data suggest that when the cells have just primary cilia, they may respond indiscriminately to all odorants, whereas multiciliated cells display odorant specificity. (4) Secondary olfactory cilia increase in length. From E14 to E19 and over the whole population of receptor cells the cilia grow at an average rate of about 0.5 micron/day. Proximal parts of olfactory cilia are longer than primary cilia; olfactory cilia begin to taper in increasing numbers around E18. At E19 the receptive membrane surface, i.e. regions of the cells facing the nasal lumen, of individual cells is about 8%, and the increase in epithelial surface due to sprouting of cilia is 5% of such values in adult animals. Concomitant with the onset of tapering of olfactory cilia, i.e. around E18, microvilli of supporting cells show a spurt in growth from about 0.4 micron to about 1.3 micron. Unlike olfactory cilia they show no growth, on average, after E19.(ABSTRACT TRUNCATED AT 400 WORDS)


ERK1/2-mediated Cytoplasmic Accumulation of hnRNPK Antagonizes TRAIL-induced Apoptosis through Upregulation of XIAP in H1299 Cells.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance greatly limits the clinical therapeutic efficacy of TRAIL. Elucidating the molecular mechanism underlying TRAIL resistance will be fundamental to resolving this problem. Nuclear and cytoplasmic protein extraction and immuno?uorescence (IF) assay were used to detect changes in heterogeneous nuclear ribonucleoprotein K (hnRNPK) localization in H1299 cells. The evaluation of cell apoptosis in cells transfected with GFP-hnRNPK, GFP-hnRNPK S284/353A, or GFP-hnRNPK S284/353D mutant was performed using cleaved caspase-3 antibody. The gene expression of XIAP was tested by quantitative RT-PCR. Previously, we reported that hnRNPK antagonized TRAIL-induced apoptosis through inhibition of PKC-mediated GSK3β phosphorylation. In this study, we further demonstrate that TRAIL treatment induces cytoplasmic accumulation of hnRNPK in H1299 cells. The hnRNPK localized in the cytoplasm has a higher capacity to antagonize TRAIL-induced apoptosis. Both ERK1/2 signaling inhibitor U0126 and ERK-phosphoacceptor-site mutant (GFP-hnRNPK S284/353A) diminish cytoplasmic accumulation of hnRNPK induced by TRAIL. Moreover, we show that XIAP is involved in hnRNPK-mediated TRAIL resistance in H1299 cells. Taken together, these results give new insights into the understanding of the molecular mechanism associated with TRAIL resistance in lung adenocarcinoma.


Factored form descent: a practical algorithm for coherence retrieval.
We formulate coherence retrieval, the process of recovering via intensity measurements the two-point correlation function of a partially coherent field, as a convex weighted least-squares problem and show that it can be solved with a novel iterated descent algorithm using a coherent-modes factorization of the mutual intensity. This algorithm is more memory-efficient than the standard interior point methods used to solve convex problems, and we verify its feasibility by reconstructing the mutual intensity of a Schell-model source from both simulated data and experimental measurements.


Rapid diagnosis of intravascular catheter-related sepsis.
The use of Gram-stained "impression smears" of the external surface of intravascular catheters for rapid detection of catheter-associated infection was studied. Gram's stain results of 322 catheters were correlated with clinical episodes of systemic sepsis and semiquantitative cultures of the catheters. Organisms were seen on Gram's stain of 82 catheters, 37 of which were positive on semiquantitative cultures (greater than or equal to 15 colonies per plate). Catheter-related bacteremia occurred on three occasions. All three catheters showed numerous organisms on Gram's stain, although one was negative on semiquantitative culture. All five catheters, in place during bacteremic episodes that were unrelated to catheter infection, were negative on Gram's stain. If the presence of any organisms on Gram's stain was taken as a positive test result, the sensitivity of Gram's stain in predicting the result of semiquantitative culture was 83%, the specificity was 81%, and the predictive value of a positive and negative culture was 44% and 96%, respectively. Slides took two to five minutes to examine microscopically. Gram-stained impression smears of intravenous catheters can be made by a simple, inexpensive, and rapid technique that is accurate in diagnosing catheter-related infection. However, in this study in which a relatively low prevalence of catheter-related bacteremia occurred, the positive predictive value of the Gram's stain result in the diagnosis of catheter-related bacteremia, in contrast to catheter colonization, was low. Only in a patient group with a high prevalence of catheter-related bacteremia would the test be likely to have a high positive predictive value. Thus, selectivity should be exercised in the application of this method.


[Spontaneous contamination of primary green monkey kidney cell cultures by foamy virus].
Examinations of 1653 batches of green monkey kidney cell cultures revealed contamination with foamy virus (FV) in 243 (16%) batches. From some of these cultures 65 strains of virus belonging to two serotypes were isolated. Tests on sera from 1122 monkeys revealed antibody to FV in 985 (87.8%) animals. No correlation between the presence of antibody in the serum and virus recovery from monkey kidney cell cultures was observed, however. This might be due either to the lack of the virus in the kidneys or to the failure in its isolation from primary cultures. Passages of cell cultures were shown to facilitate additional recovery of FV. These experimental results may be used for screening and selection of FV-free cultures and for control purposes in the course of vaccine manufacture.


Tumour angiogenesis: vascular growth and survival.
Angiogenesis starts at the edge of a malignant epithelial tumour concurrently with tumour cell invasion and stromatogenesis, i.e. the formation of specific connective tissue stroma amenable to easy penetration by endothelial and tumour cells. However, as the tumour continues its growth, the edge becomes the inner tumour area, and a new invading tumour front is formed by the multiplying malignant cells which outflank the initial edge. This process, which repeats itself again and again, forms the "relay race" model of tumour vascular growth and regression. At the heart of the tumour unfavourable environmental conditions prevail -- hypoxia, acidity, lack of nutrients, failure of waste removal, and apoptosis rather than proliferation. Blood vessels and tumour cells are greatly decreased, but do not vanish, as tumour cells are shifting to anaerobic glycolysis, and blood vessels are turning into anti-apoptotic pathways -- vascular survival ability (VSA). Thus, assessing vascular density (VD) by simply counting "hot spots" at the edge of a tumour, where conditions are most favourable, is futile; it may reflect tumour angiogenic activity (TAA), but is not representative of genuine tumour vasculature. By combining vessel counts at the invading tumour front with those of the inner tumour areas a complete picture of tumour VD can be achieved. The thus formed four patterns of vascularization, designated as "edvin" (edge vsinner tumour area), are: edvin 1: low TAA/low VSA; edvin 4: high TAA/high VSA; edvin 2: low TAA/high VSA; and edvin 3: high TAA/low VSA. It is expected that this scheme will prove useful in the field of chemoradiotherapy and anti-angiogenic treatment.


DBS in the basolateral amygdala improves symptoms of autism and related self-injurious behavior: a case report and hypothesis on the pathogenesis of the disorder.
We treated a 13-year-old boy for life-threatening self-injurious behavior (SIB) and severe Kanner's autism with deep brain stimulation (DBS) in the amygdaloid complex as well as in the supra-amygdaloid projection system. Two DBS-electrodes were placed in both structures of each hemisphere. The stimulation contacts targeted the paralaminar, the basolateral (BL), the central amygdala as well as the supra-amygdaloid projection system. DBS was applied to each of these structures, but only stimulation of the BL part proved effective in improving SIB and core symptoms of the autism spectrum in the emotional, social, and even cognitive domains over a follow up of now 24 months. These results, which have been gained for the first time in a patient, support hypotheses, according to which the amygdala may be pivotal in the pathogeneses of autism and point to the special relevance of the BL part.


Longitudinal substance initiation outcomes for a universal preventive intervention combining family and school programs.
This study evaluated the substance initiation effects of an intervention combining family and school-based competency-training intervention components. Thirty-six rural schools were randomly assigned to 1 of 3 conditions: (a) the classroom-based Life Skills Training (LST) and the Strengthening Families Program: For Parents and Children 10-14, (b) LST only, or (c) a control condition. Outcomes were examined 1 year after the intervention posttest, using a substance initiation index (SII) measuring lifetime use of alcohol, cigarettes, and marijuana and by rates of each individual substance. Planned intervention-control contrasts showed significant effects for both the combined and LST-only interventions on the SII and on marijuana initiation. Relative reduction rates for alcohol initiation were 30.0% for the combined intervention and 4.1% for LST only.


Amino acid and phosphorus digestibility and concentration of digestible and metabolizable energy in hydrolyzed feather meal fed to growing pigs.
Two experiments were conducted to determine the standardized ileal digestibility (SID) of AA (Exp. 1), the standardized total tract digestibility (STTD) of P, and the concentration of DE and ME (Exp. 2) in hydrolyzed feather meal (FM) fed to growing pigs. Eight samples of FM were obtained from 4 different processing plants (FM1, FM2, FM3, and FM4). Each plant provided samples of FM without and with added blood. In Exp. 1, 10 barrows (initial BW: 24.0 ± 0.8 kg) were prepared with a T-cannula in the distal ileum and allotted to a 10 × 10 Latin square design with 10 diets and ten 7-d periods. A N-free diet, a diet based on soybean meal (SBM), and 8 diets based on a combination of SBM and each of the 8 sources of FM were formulated. Values for the SID of CP and AA in each source of FM were calculated using the difference procedure. The SID of CP and all AA was different (P < 0.001) among sources of FM. Among the indispensable AA, the overall effect of addition of blood was statistically significant (P < 0.05) for the SID of Ile, Leu, Lys, Phe, and Val, but for some sources, the SID of these AA was increased by addition of blood, whereas for other sources, the SID was reduced or not changed (interaction, P < 0.05). As an example, the SID of Lys in FM3 and FM4 with added blood were greater (P < 0.05) than in FM3 and FM4 without blood, but no difference in the SID of Lys was observed for FM1 and FM2 without and with blood (interaction, P < 0.01). In Exp. 2, 72 growing barrows (initial BW: 13.3 ± 1.5 kg) were used with 9 diets and 8 replicate pigs per diet. A corn-diet consisting of 98.4% corn was formulated and 8 additional diets were formulated by mixing corn with 25% FM. The STTD of P and the DE and ME of each source of FM were calculated using the difference procedure. The STTD of P tended (P = 0.09) to be different among FM sources and the STTD of P in FM with added blood was less than in FM without blood. On a DM basis, DE and ME values were affected (P < 0.05) by both source of FM and addition of blood. However, an interaction (P < 0.05) between source of FM and addition of blood for ME was observed because addition of blood to FM3 and FM4 reduced (P < 0.05) the ME, whereas addition of blood to FM1 and FM2 had no impact on ME. In summary, the SID of AA, STTD of P, and the energy concentration vary among sources of FM and the effects of adding blood to FM is not consistent among sources.


Cerebral hemodynamics changes during retrograde brain perfusion in dogs.
The objective of this study was to examine cerebral hemodynamics changes during hypothermic circulatory arrest (HCA) with and without retrograde cerebral perfusion (RCP). Thirteen colony-bred hound dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18 degrees C. Five dogs underwent 2 hours of HCA without RCP and 8 with RCP. The animals were then rewarmed on CPB until normothermic and weaned. Cerebral blood flow velocity (CBFV) and Gosling Pulsatility Index (PI) in the middle cerebral artery (MCA) were studied using trans-cranial Doppler ultrasound (TCD). At baseline and during pre- and postarrest CPB, there was anterograde direction of blood flow in the MCA. During HCA with RCP, there was retrograde direction of blood flow in the MCA. There was no difference in CBFV between pre-, during, and postarrest CPB in the group with RCP; however, there was significantly increased CBFV during postarrest CPB in the group without RCP compared to the dogs with RCP. Later, at 3 hours after postarrest CPB, there was decreased CBFV in all animals accompanied by increased PI (2.4 +/- 0.4 and 2.2 +/- 0.6 for animals with RCP and without RCP, respectively) and abnormal TCD waveform changes including decreased diastolic compartment and sharp systolic peak. During hypothermic circulatory arrest, RCP provides CBFV in the MCA comparable to MCA CBFV during CPB. HCA dogs without RCP showed immediate hyperemia on reperfusion. The decreased CBFV and increased PI at 1 hour after postarrest CPB could be an indicator of progressive ischemic injury due to the increased intracranial pressure despite the implementation of RCP.


[Physiology of the hydrophobic domain].
The role of the hydrophobic part in the functioning of some amphipathic enterocyte enzymes has been studied in various animal species (fish, mammals, insects). Kinetic (Km, Vmax, pHopt) and regulatory properties of membrane, detergent and protease forms of carbohydrases, alkaline phosphatase and alanine aminopeptidase were compared. All the species under study showed significant differences among these forms of enzymes. The data obtained demonstrate the important role of the hydrophobic anchor in forming both catalytic and regulatory properties of enzymes.


Autoantigen based vaccines for type 1 diabetes.
Type 1 diabetes is an organ-specific autoimmune disease caused by chronic inflammation (insulitis), which damages the insulin producing β-cells of the pancreatic Islets of Langerhans. Dendritic cells (DCs) are generally the first cells of the immune system to process β-cell autoantigens and, by promoting autoreactivity, play a major role in the onset of insulitis. Although no cure for diabetes presently exists, the onset of insulitis can be diminished in the non-obese diabetic (NOD) mouse type 1 diabetes model by inoculation with endogenous β-cell autoantigens. These include the single peptide vaccines insulin, GAD(65) (glutamic acid decarboxylase), and DiaPep277 (an immunogenic peptide from the 60-kDa heat shock protein). DiaPep277 is the only autoantigen so far to demonstrate positive results in human clinical trials. Diamyd (an alum adjuvant + recombinant GAD(65) protein formulation) has shown great promise for suppressing β-cell autoreactivity in phase I and II clinical trials. While Diamyd preserved residual insulin secretion in early-onset type 1 diabetes patients, it did not reduce the amounts of insulin required to maintain euglycemia. Recently, multi-component vaccines composed of the anti-inflammatory cytokine (IL-10) and insulin or GAD(55) linked to an immunostimulatory molecule, the cholera toxin B subunit, were shown to safely and completely inhibit diabetes onset in NOD mice. This result suggests that multi-component vaccine strategies are promising for prevention and reversal of diabetes autoimmunity in humans. Here we focus on the development of autoantigen vaccines for type 1 diabetes and demonstrate that multi-component vaccines are promising candidates for type 1 diabetes clinical studies.


Orbital dermoid cyst with intratumoral inflammatory hemorrhage: case report.
An 85-year-old female presented with a 3-month history of worsening hyperlacrimation and blurred vision following blunt head injury. Her past medical history was unremarkable. Her blood examination identified no abnormal findings. Neuroophthalmological inspection revealed extraocular movement disorder and mild exophthalmos on the affected side. Her visual acuity was not disturbed. Neuroimaging showed a cystic mass located extraconally in the superolateral compartment of the anterior orbit, without enhancement by contrast medium. Surgical exploration resulted in escape of chocolate-colored, liquefied hematoma during dissection. No vascular lesion was found. A grayish-white cyst wall was found adhering strongly to the lateral and superior rectus muscles. The lacrimal gland was not identified. The mass was totally resected. Histological examination indicated dermoid cyst with inflammatory interstitial hemorrhage. No component of vascular malformation or atypia was found. Hyperlacrimation and extraocular movement improved postoperatively. We thought that the previous blunt head injury might have induced intratumoral hemorrhage in the preexisting dermoid cyst and that the escaped contents caused inflammatory irritation, resulting in the hyperlacrimation. Dermoid cyst may show atypical presentation with intratumoral hemorrhage and should always be included in the differential diagnosis of orbital tumor.


Injury to the popliteal artery.
Popliteal artery injury is a common clinical problem which has been associated with a relatively high rate of limb loss. Proper management of popliteal artery injury, which includes attention to minimizing delay, repair of venous injury, careful technique and appropriate fasciotomy can result in substantial improvement in the rate of limb salvage following popliteal artery injury.


Population-based tuberculin skin testing and prevalence of tuberculosis infection in Afghanistan.
A tuberculin skin-test survey was conducted in eight provinces of Afghanistan to estimate the prevalence and annual risk of tuberculosis infection among the Afghan population. A cluster survey in eight Afghan provinces, chosen based on population density and geographic distribution, was carried out between October and February 2006. Interviews were conducted and tuberculin skin tests were administered and read. 11,413 individuals participated in the study. Using the international standard cut-off of >or= 10 mm, tuberculosis prevalence and annual risk of infection in the population were 15% (CI: 14.4-15.7) and 0.80 (CI: 0.76-0.84), respectively. Tuberculosis prevalence was higher in rural than in urban areas. Other risk factors included age, prior tuberculosis treatment or contact, productive cough or cough >3 weeks, no prior bacille Calmette Guérin (BCG) vaccination and a cooking fire in the sleeping room. The survey documented a lower prevalence and risk of tuberculosis infection than the 1978 national survey and a substantially lower estimate of incidence of new smear-positive tuberculosis cases than World Health Organization estimates. However, other findings suggest that active tuberculosis may remain widespread and undiagnosed, and indicate a need for both additional research and continued investment in tuberculosis treatment and prevention, and in health infrastructure.


Human Mesenchymal Stromal Cells Enhance Cartilage Healing in a Murine Joint Surface Injury Model.
Human umbilical cord (hUC)- or bone marrow (hBM)-derived mesenchymal stromal cells (MSCs) were evaluated as an allogeneic source of cells for cartilage repair. We aimed to determine if they could enhance healing of chondral defects with or without the recruitment of endogenous cells. hMSCs were applied into a focal joint surface injury in knees of adult mice expressing tdTomato fluorescent protein in cells descending from Gdf5-expressing embryonic joint interzone cells. Three experimental groups were used: (i) hUC-MSCs, (ii) hBM-MSCs and (iii) PBS (vehicle) without cells. Cartilage repair was assessed after 8 weeks and tdTomato-expressing cells were detected by immunostaining. Plasma levels of pro-inflammatory mediators and other markers were measured by electrochemiluminescence. Both hUC-MSC (n = 14, p = 0.009) and hBM-MSC (n = 13, p = 0.006) treatment groups had significantly improved cartilage repair compared to controls (n = 18). While hMSCs were not detectable in the repair tissue at 8 weeks post-implantation, increased endogenous Gdf5-lineage cells were detected in repair tissue of hUC-MSC-treated mice. This xenogeneic study indicates that hMSCs enhance intrinsic cartilage repair mechanisms in mice. Hence, hMSCs, particularly the more proliferative hUC-MSCs, could represent an attractive allogeneic cell population for treating patients with chondral defects and perhaps prevent the onset and progression of osteoarthritis.


Association between high-density lipoprotein cholesterol and renal function in elderly hypertension: a cross-sectional study in Chinese population.
Few studies have yet investigated the possible association between high-density lipoprotein cholesterol (HDL-C) and kidney function in elderly patients with primary hypertension. Accordingly, the aim of the present study was to evaluate the relationship between HDL-C and kidney function in elderly hypertension. A total of 14,644 elderly hypertensive subjects were enrolled in our cross-sectional study. The patients were categorized based on serum HDL-C level and glomerular filtration rate (GFR) value, respectively. One-way analysis of variance was used to compare the parameters among different groups. Bonferroni correction was performed for multiple comparisons. Analysis of covariance was used to control for confounding factors. The significance of difference between 3 groups and more was determined by chi-square test for categorical variables. Serum creatinine and uric acid were negatively related to HDL-C level, whereas GFR was positively related to HDL-C level in elderly hypertensive patients according to tertiles of HDL-C and tertiles of HDL-C/total cholesterol ratio (all P for trends <0.05). The male elderly hypertensive patients showed stronger relationship between HDL-C and renal function than the female elderly hypertensive subjects. Low HDL-C was associated with renal insufficiency and proteinuria in the hypertensive elderly (P < 0.05). The elderly "renal-hyperfiltrator" appeared to have lower HDL-C level, compared with the "normal renal-filtrator" (P < 0.05). There was an inverse "V" shape between HDL-C and GFR by GFR strata. Our results point out that there is an association of low HDL-C level with impaired kidney function in elderly hypertensive patients. Glomerular hyperfiltration may also affect HDL-C level and sex might be an influential factor for the association of HDL-C with kidney function in elderly hypertension.


Patellar Tendon Rupture During Postoperative Physiotherapy for Crouch Gait: A Case Report.
A 14-year-old adolescent girl with spastic diplegic cerebral palsy underwent bilateral distal femur extension osteotomy and patellar tendon plication. Two and a half months after surgery, during physiotherapy, she sustained mid-substance tear of the left patellar tendon. The girl was successfully managed with patellar tendon repair and augmentation with tensor fascia lata autograft. Patellar tendon rupture during rehabilitative physiotherapy after patellar tendon plication surgery is rare. Postoperative protocols in patients with cerebral palsy are crucial and should progress gradually to improve knee range of motion. This report highlights that patellar tendon repair with fascia lata augmentation yields good outcome.


Antibiotic Resistances and Molecular Characteristics of Clostridioides difficile in ICUs in a Teaching Hospital From Central South China.
Clostridioides (C.) difficile is a major healthcare-associated pathogen inducing infectious diarrhea. Approximately 25-33% of patients with antibiotic-associated diarrhea (AAD) and 90% of patients with pseudomembranous enteritis are caused by C. difficile infection (CDI). Stool samples were collected from hospitalized adults with presumptive AAD in four nonneonatal intensive care units (ICUs). Diagnosis of CDI was based on both clinical symptoms and laboratory results. The stool specimens were transferred onto CDIF (C. difficile agar), and C. difficile was finally confirmed by the latex agglutination test. Toxin-producing genes tcdA (A), tcdB (B), and cdt (CDT) were detected by PCR, and all isolates were performed multilocus sequence typing analysis. The antibiotic susceptibility of C. difficile isolates was assessed by the agar dilution method. A total of 184 C. difficile were isolated from 857 specimens in our study, the isolation rate of C. difficile was 21.5% (184/857). The 184 C. difficile were isolated from 179 patients, among these 115 patients were toxin-positive, giving the incidence of CDI being 58.0/10,000 patient days in the four ICUs. Among these 115 toxin-positive C. difficile isolates, 100 (87.0%) isolates produced two toxins (A+B+CDT-), three (2.6%) isolates were A+B+ with binary toxin-producing (A+B+CDT+), and 12 (10.4%) isolates only produced one toxin (A-B+CDT-). A total of 27 sequencing types (STs) were obtained. The most prevalent was ST3 (34 isolates), followed by ST39 (27 isolates), ST54 (19 isolates), ST26 (16 isolates), ST35 (15 isolates), and ST2 (13 isolates). All the ST26 isolates were nontoxigenic. Meanwhile, five STs were newly discovered. Although multidrug resistance was present in ≥50% of these C. difficile isolates, all of them were susceptible to tigecycline, fidaxomicin, metronidazole, and vancomycin. In conclusion, C. difficile isolates producing two toxins (A+B+CDT-) were dominant in our hospital. The most prevalent was ST3, and all ST26 isolates were NTCD. Although multidrug resistance was present in ≥50% of the C. difficile isolates, metronidazole, tigecycline, fidaxomicin, and vancomycin were still effective treatments for CDI in our hospital.


Modeling Outcomes: Modified Aortic Arch Advancement for Neonatal Hypoplastic Arch.
Numerous surgical approaches regarding aortic arch advancement for neonatal arch hypoplasia have been described. These repairs can be classified into two categories: those that incorporate a patch and those that do not. The decision between repairs remains largely experiential, rather than empirical, because of the limited number of reported outcomes. We report early outcomes from neonates undergoing modified aortic arch advancement with an anterior patch and our experience using computational fluid dynamic modeling to better understand the hemodynamic consequences associated with this repair. A retrospective review of neonates undergoing aortic arch advancement with anterior patch in 2014 at a single institution was performed. Anatomical, perioperative, and follow-up data were collected. Three-dimensional cardiac magnetic resonance images were used to generate computational fluid dynamic models of the modified anterior patch and direct end-to-side repairs. Cardiac waveform inputs were simulated and hemodynamic analyzed. Ten neonates underwent modified aortic arch advancement. No hemodynamically significant gradients were observed at a median follow-up of 0.77 (0.30-1.2) years. Asymmetrical flow was observed in the end-to-side repair, whereas more concentric laminar flow was observed throughout the modified model. Spatial variations in velocities immediately distal to the anastomosis were greater in the end-to-side model (0.35 vs 0.17 m/s, P < 0.001). Time-averaged variations in wall shear stress during systole were greater in the end-to-side model at the same location (3.44 vs 1.98 dynes/cm, P < 0.001). Early outcomes after the use of an anterior patch for neonatal hypoplastic aortic arch repair show favorable hemodynamic outcomes.


Inaction over retractions of identified fraudulent publications: ongoing weakness in the system of scientific self-correction.
Published articles may be retracted when their findings are no longer considered reliable due to honest error, publication misconduct, or research misconduct. This article focuses on the case of a single serial violator of research and publication ethics in anesthesiology and critical care, which is widely publicized. A chain of events led to detection of misconduct that had substantial impact on the evidence base for the safety of hydroxyethyl starch, an intravenous artificial colloid solution, which is reflected in current guidelines on fluid management and volume resuscitation. As citations to retracted works continue to be a cause for concern, this article reviews the retraction status of this author's published articles to determine whether sufficient action has been taken to retract his body of work. Results show that retraction practices are not uniform and that guidelines for retraction are still not being fully implemented, resulting in retractions of insufficient quantity and quality. As retractions continue to emerge for the author's publications, with ten more since 2011, and as they are generally increasing, these data on retractions not only provide findings of misconduct, but also allow us to make inferences about ongoing weaknesses in the system of scientific literature.


First direct evidence of adult European eels migrating to their breeding place in the Sargasso Sea.
The European eel (Anguilla anguilla) is critically endangered (according to the most recent IUCN assessment) and has suffered a 95% decline in recruitment since the 1980s, attributed in part to factors occurring during the marine phases of its life-cycle. As an adult, the European eel undertakes the longest spawning migration of all anguillid eels, a distance of 5000 to 10,000 km across the Atlantic Ocean to the Sargasso Sea. However, despite the passage of almost 100 years since Johannes Schmidt proposed the Sargasso Sea as the breeding place of European eels on the basis of larval surveys, no eggs or spawning adults have ever been sampled there to confirm this. Fundamental questions therefore remain about the oceanic migration of adult eels, including navigation mechanisms, the routes taken, timings of arrival, swimming speed and spawning locations. We attached satellite tags to 26 eels from rivers in the Azores archipelago and tracked them for periods between 40 and 366 days at speeds between 3 and 12 km day-1, and provide the first direct evidence of adult European eels reaching their presumed breeding place in the Sargasso Sea.


Low dose versus conventional dose of intravitreal bevacizumab injection for retinopathy of prematurity: a case series with paired-eye comparison.
To compare the clinical outcomes of intravitreal bevacizumab (IVB) injection, with different dosing (0.25 mg/0.01 ml versus 0.625 mg/0.025 ml) in each eye of the same patient with retinopathy of prematurity (ROP). Intravitreal bevacizumab (IVB) was injected into eight patients with stage 3+ in zone I or posterior zone II ROP (16 eyes). Bevacizumab, with different dosing (0.25 mg/0.01 ml and 0.625 mg/0.025 ml), was injected into the vitreous cavity of each eye. Among the 16 eyes treated with IVB, six eyes had zone I ROP and 10 eyes had zone II ROP. The mean birthweight was 800 ± 139 g (range, 533-955 g), and the mean gestational age was 25.9 ± 1.2 gestational weeks (range, 24.4-28.7 weeks). The postmenstrual age at initial treatment was 37.2 gestational weeks (range, 33.7-41 weeks). The mean follow-up was 312 ± 50 days (median, 305 days; range, 238-376 days). All eyes showed regression of plus sign after IVB injection within 1 week and revascularization to the ora serrata at the time of final visit. There was no difference in the time of anatomical achievement between the eyes with different doses. None of the patients received any additional IVB injection or laser photocoagulation. After the regression of ROP, tractional retinal detachment and macular ectopia were not observed in any patients during follow-up. There was no difference in the short-term clinical outcomes of stage 3+ ROP in zone I or II between the eyes with low dose and conventional dose of IVB.


Beat-to-beat P-wave morphological variability in patients with paroxysmal atrial fibrillation: an in silico study.
P-wave beat-to-beat morphological variability can identify patients prone to paroxysmal atrial fibrillation (AF). To date, no computational study has been carried out to mechanistically explain such finding. The aim of this study was to provide a pathophysiological explanation, by using a computer model of the human atria, of the correlation between P-wave beat-to-beat variability and the risk of AF. A physiological variability in the earliest activation site (EAS), on a beat-to-beat basis, was introduced into a computer model of the human atria by randomizing the EAS location. A methodology for generating multi-scale, spatially-correlated regions of heterogeneous conduction was developed. P-wave variability in the presence of such regions was compared with a control case. Simulations were performed with an eikonal model, for the activation map, and with the lead field approach, for P-wave computation. The methodology was eventually compared with a reference monodomain simulation. A total of 60 P-waves were simulated for each sinus node exit location (12 in total), and for each of the 15 patterns of heterogeneous conduction automatically generated by the model. A P-wave beat-to-beat variability was observed in all cases. Variability was significantly increased in presence of heterogeneous slow conducting regions, up to two-fold the variability in the control case. P-wave variability increased non-linearly with respect to the EAS variability and total area of slow conduction. Distribution of the heterogeneous conduction was more effective in increasing the variability when it surrounded the EAS locations and the fast conducting bundles. P-waves simulated by the eikonal approach compared excellently with the monodomain-based ones. P-wave variability in patients with paroxysmal AF could be explained by a variability in sinoatrial node exit location in combination with slow conducting regions.


Myocardial Contraction Fraction for Risk Stratification in Low-Gradient Aortic Stenosis With Preserved Ejection Fraction.
Myocardial contraction fraction (MCF) is a volumetric measure of myocardial shortening independent of left ventricular size and geometry. This multicenter study investigates the usefulness of MCF for risk stratification in low-gradient severe aortic stenosis with preserved ejection fraction. We included 643 consecutive patients with low-gradient severe aortic stenosis with preserved ejection fraction in whom MCF was computed at baseline and analyzed mortality during follow-up. Throughout follow-up with medical and surgical management (34.9 [16.1-65.3] months), lower MCF tertiles had higher mortality than the highest tertile. Eighty-month survival was 56±4% for MCF>41%, 41±4% for MCF 30% to 41%, and 40±4% for MCF<30% (P<0.001). After comprehensive adjustment, mortality risk remained high for MCF 30% to 41% (adjusted hazard ratio, 1.53 [1.08-2.18]) and for MCF<30% (adjusted hazard ratio, 1.82 [1.24-2.66]) versus MCF>41%. The optimal MCF cutoff point for mortality prediction was 41%. Age, body mass index, Charlson index, peak aortic velocity, and ejection fraction were independently associated with mortality. MCF (χ2 to improve 10.39; P=0.001), provided greater additional prognostic value over the baseline parameters than stroke volume (SV) index (χ2 to improve 5.41; P=0.042), left ventricular mass index (χ2 to improve 2.15; P=0.137), or global longitudinal strain (χ2 to improve 3.67; P=0.061). MCF outperformed ejection fraction for mortality prediction. When patients were classified by SV index and MCF, mortality risk was low when SV index was ≥30 mL/m2 and MCF>41%, higher for patients with SV index ≥30 mL/m2 and MCF≤41% (adjusted hazard ratio, 1.47 [1.05-2.07]) and extremely high for patients with SV index <30 mL/m2 (adjusted hazard ratio, 2.29 [1.45-3.62]). MCF is a valuable marker of risk in low-gradient severe aortic stenosis with preserved ejection fraction and could improve decision-making, especially in normal-flow low-gradient severe aortic stenosis with preserved ejection fraction.


The clinical problem of hepatitis transmission;.
Although blood banks in this country have been testing every unit of blood for hepatitis B surface antigen (HBSAg) by one of the highly sensitive "third generation" methods (radioimmunoassay or reversed passive hemagglutination) since September, 1975, post-transfusion hepatitis (PTH) still remains the major hazard to patients who require transfusion with blood and blood products. Since there may be an interval of many months between transfusion and onset of PTH and many cases are subclinical, the best data on the incidence of PTH have come from prospective studies with careful follow-up of transfused patients. Such studies first established the validity of HBSAg as a marker for the presence of hepatitis B virus (HBV), and they have shown a dramatic reduction in the incidence of post-transfusion type B hepatitis following the elemination of HBSAg positive blood from transfusion. Nevertheless, PTH cases not associated with HBV or HAV, which are termed non-A, non-B hepatitis, continue to occur commonly among transfused patients. Non-A, non-B hepatitis appears to be subclinical in many instances, but it can produce prolonged persistence of abnormal liver function tests, which may be associated with chronic liver disease. The outstanding risk factor responsible for the development of PTH has been shown to be blood from paid donors in every study which has evaluated this factor. HBSAg and anti-HBS prevalences were found to be much higher in paid donor groups than in voluntary donors. Accordingly, the Food and Drug Administration has proposed that all units of blood be labeled to indicate whether they were collected from voluntary or paid donors in order to inform consumers of the relative hepatitis risks of blood units from these different donor populations. In addition to HBSAg testing and reduced use of blood from paid donors, measures which may provide future reduction of the hepatitis hazard associated with blood transfusion include avoidance of unnecessary transfusions, identification of the agent(s) responsible for non-A non-B hepatitis and development of tests for these agents, idenfification and avoidance of blood from donors implicated in PTH cases, development of methods for immunizing transfused patients against the various agents responsible for PTH, and use of frozen-washed red blood cells for transfusion. Efforts to develop and/or evaluate these various approaches are currently being actively pursued in many laboratories.