Heat-induced unfolding facilitates plant protein digestibility during in vitro static infant digestion.
Soy protein is the main protein source for plant-based infant formula, whereas pea protein is considered as a potential alternative plant protein source. This study assessed the structural changes of soy and pea proteins after heating between 65 °C and 100 °C, and its effects on the in vitro digestibility in the context of infant digestion. We found that with increased heating intensity, both soy and pea proteins unfolded, manifested as the increased surface hydrophobicity, thereby potentially improving the accessibility to digestive enzymes. Their final in vitro digestibility increased from ∼ 30% of non-treated samples to ∼ 60% of 100 °C-heated samples for soy protein, and from ∼ 52% to ∼ 65% for pea protein. Surface hydrophobicity was strongly positively correlated to the overall digestibility. Therefore, the heating temperatures that enabled protein unfolding promoted the digestibility of soy and pea proteins under infant digestion conditions.


Choledochotomy for biliary lithiasis: T-tube drainage or primary closure. Effects on postoperative bacteremia and T-tube bile infection.
To compare the incidence of postoperative bacteremia in patients with biliary lithiasis after choledochotomy supplemented by either T-tube drainage or primary common bile duct closure, 117 patients who underwent surgery are presented in this clinical trial. It has been shown that primary common bile duct closure is associated with a lower incidence of postoperative bacteremia (3.3 percent), a lower mortality rate (0 percent), and a lower early morbidity rate (13.3 percent) than T-tube drainage (31.5, 3.5, and 36.1 percent, respectively). The above evidence supports the view that T-tube drainage might well provoke the exogenous acquisition of environmental microorganisms and thus promote further infection.


Evidence for a multi-compartmental histochemical organization of the nucleus accumbens in the rat.
In the present study, the compartmental organization of the nucleus accumbens was investigated by comparing the pattern of leu-enkephalin immunoreactivity with that of the opioid receptor ligand, naloxone, an established marker for the compartmental organization of the neostriatum. Both patterns have a nonhomogeneous, patch-like appearance throughout the rostrocaudal extent of the nucleus and show a good, mutual correspondence. In the core of the nucleus accumbens as well as in the border region between the nucleus accumbens and the caudate-putamen, leu-enkephalin-rich areas are in register with opioid receptor-dense areas. In the shell region the precise relationship between the enkephalin and the naloxone patterns could not be established. A comparison of the connectivity patterns and neurochemical characteristics of the opioid receptor-dense compartments in the nucleus accumbens with those in the caudate-putamen reveals major discrepancies between these two striatal subdivisions. We therefore conclude that, rather than a bicompartmental patch/striosome-matrix organization, the nucleus accumbens has a multicompartmental organization.


Induction and resetting of REM sleep rhythm in normal man by arecholine: blockade by scopolamine.
Arecholine, a cholinergic muscarinic agonist, was administered intravenously 35 min after sleep onset in eight normal volunteers who had been pretreated with either methscopolamine or scopolamine, muscarinic receptor blockers that do not and do cross the blood--brain barrier, respectively. Following pretreatment with methscopolamine, arecholine shortened the REM latency and increased the number of REM periods without altering the duration of individual REM periods or altering the REM--REM intervals. Pretreatment with scopolamine blocked the effects of arecholine. The results support the hypothesis that cholinergic muscarinic mechanisms are involved in the timing but not the duration of REM sleep.


The effect of tracheostomy on swallowing function in open partial horizontal laryngectomies: preliminary experience.
Tracheostomy is required to ensure a safe airway in open partial horizontal laryngectomies. The presence of the tracheostomy tube can contribute to post-operative dysphagia. This study aimed to evaluate the effects of a circumferential tracheostomy technique on swallowing. A retrospective study was conducted of patients who underwent open partial horizontal laryngectomies between April 2018 and June 2019. Patients were divided into two groups based on the tracheostomy technique: group 1 had two stitches from the inferior tracheal ring to the skin; group 2 had circumferential fixation of the trachea to the skin. Demographic information, surgical data, post-operative rehabilitation course and complication details were collected and analysed. Twenty-four patients were enrolled. Patients in group 2 had significant improvement in the initial phases of swallowing rehabilitation. Tracheostomy with anchorage of the trachea to the skin by circumferential stitches could allow early removal of the tracheal tube, with a better swallowing outcome.


Phosphate glass fibre scaffolds: Tailoring of the properties and enhancement of the bioactivity through mesoporous glass particles.
Novel bone glass fibre scaffolds were developed by thermally bonding phosphate glass fibres belonging to the P2O5-CaO-Na2O-SiO2-MgO-K2O-TiO2 system (TiPS2.5 glass). Scaffolds with fibres of 85 or 110μm diameter were fabricated, showing compressive strength in the range of 2-3.5MPa, comparable to that of the trabecular bone. The effect of different thermal treatments and fibre diameters and length on the final scaffold structure was investigated by means of micro-CT analysis. The change of the sintering time from 30 to 60min led to a decrease in the scaffold overall porosity from 58 to 21vol.% for the 85μm fibre scaffold and from 50 to 40vol.% when increasing the sintering temperature from 490 to 500°C for the 110μm fibre scaffold. The 85μm fibres resulted in an increase of the scaffold overall porosity, increased pore size and lower trabecular thickness; the use of different fibre diameters allowed the fabrication of a scaffold showing a porosity gradient. In order to impart bioactive properties to the scaffold, for the first time in the literature the introduction in these fibre scaffolds of a bioactive phase, a melt-derived bioactive glass (CEL2) powder or spray-dried mesoporous bioactive glass particles (SD-MBG) was investigated. The scaffold bioactivity was assessed through soaking in simulated body fluid. CEL2/glass fibre scaffold did not show promising results due to particle detachment from the fibres during soaking in simulated body fluid. Instead the use of mesoporous bioactive powders showed to be an effective way to impart bioactivity to the scaffold and could be further exploited in the future through the ability of mesoporous particles to act as systems for the controlled release of drugs.


Right hemisphere involvement in depression: toward a neuropsychological theory of negative affective experiences.
Several lines of inquiry provide converging evidence for a critical role for the right cerebral hemisphere in negative affective experiences. This research includes the assessment of affective consequences of both focal cerebral lesions and pharmacological inactivation of one or the other hemisphere, as well as experimental and physiological techniques assessing differential hemispheric activation. The specific nature of right hemispheric involvement is conceptualized as a tendency to become activated by aversive experiences, and once activated, to process stimuli in a manner consistent with the right hemisphere's more negative affective tone. A theory of right hemisphere involvement in depressive affect is presented in detail and its relevance to clinical phenomena, e.g., the co-occurrence of depression and pain, and sex differences in depression, is examined, as is congruence with cognitive theories of depression.


Regression and differentiation of neuroblastoma tumors in mice treated with differentiating agents--prostaglandin E1 and a phosphodiesterase inhibitor, RO 20-1724.
Prostaglandin E1 (PGE) and d, 1-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO 20-1724, an experimental cyclic nucleotide phosphodiesterase inhibitor) cause cell death and cyclic AMP-mediated differentiation of murine neuroblastoma (NB) (cell line C-1300) cells in vitro. We report, for the first time, that these agents can be used in vivo to cause regression of NBs in A/Jax mice. These drugs were also able to slow the growth of primary tumors, prevent metastases, and cause morphological differentiation of tumors. The similarity of the response of human and mouse NB cells to differentiating drugs indicate that these agents have the potential to replace or support conventional chemotherapy in treatment individualized to NB. The mouse model of NB provides an excellent means to study the effectiveness of alternative drug therapy in vivo.


Is there a genetic cause of appetite loss?-an explorative study in 1,853 cancer patients.
Appetite loss has a major impact on cancer patients. It is exceedingly prevalent, is a prognostic indicator and is associated with inferior quality of life. Cachexia is a multi-factorial syndrome defined by a negative protein and energy balance, driven by a variable combination of reduced food intake and abnormal metabolism. Not all cancer patients that experience weight loss have appetite loss, and the pathophysiology between cachexia and appetite loss may thus be different. Knowledge of pathophysiology of appetite loss in cancer patients is still limited. The primary object of this study was to explore the association with 93 predefined candidate single-nucleotide polymorphisms (SNPs) and appetite loss in cancer patients to possibly generate new theories of the pathophysiology of the condition. A total of 1,853 cancer patients were phenotyped according to appetite loss and then genotyped. After allowing for multiple testing, there was no statistically significant association between any of the SNPs analysed and appetite loss. The ten most significant SNPs in the co-dominant model had observed odds ratios varying from 0.72 to 1.28. This large exploratory study could not find any associations with loss of appetite and 93 SNPs with a potential to be involved in appetite loss in cancer patients. This does not however rule out genes putative role in the development of the symptom, but the observed odds ratios are close to one which makes it unlikely that any of the individual SNPs explored in the present study have great importance.


Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear.
Patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) requiring dialysis at diagnosis are at risk for developing end-stage renal disease (ESRD) or dying. Short-term results of a trial comparing plasma exchange (PLEX) to intravenous methylprednisolone (IV MeP) suggested PLEX improved renal recovery. Here we conducted long-term follow-up to see if this trend persisted. A total of 137 patients with newly diagnosed AAV and a serum creatinine over 500 μmol/l or requiring dialysis were randomized such that 69 received PLEX and 68 received IV MeP in addition to cyclophosphamide and oral glucocorticoids. The patients were followed for a median of 3.95 years. In each group there were 35 deaths, while 23 PLEX and 33 IV MeP patients developed ESRD. The hazard ratio for PLEX compared to IV MeP for the primary composite outcome of death or ESRD was 0.81 (95% confidence interval 0.53-1.23). The hazard ratio for all-cause death was 1.08 with a subhazard ratio for ESRD of 0.64 (95% confidence interval 0.40-1.05). Thus, although short-term results with PLEX are encouraging, the long-term benefits remain unclear. Further research is required to determine the role of PLEX in AAV. Given the poor outcomes of patients with severe AAV, improved treatment is urgently needed.


Normal motor development of Indian children on Peabody Developmental Motor Scales-2 (PDMS-2).
To compare normal motor development scores of children in Mangalore, India, on the Peabody Developmental Motor Scales-2 (PDMS-2) with the normative scores provided with the instrument. The PDMS-2 were administered to 300 children from Mangalore, India, between birth and 60 months of age. Participants' scores were compared with those of the normative sample given in the PDMS-2 manual. The Indian children's scores varied with some differing from the normative sample (p < 0.0001) whereas others did not differ across age groups and the different subtests of the PDMS-2. It is not possible to develop assessment tools that are culturally sensitive across different geographical regions and environments, but it is necessary to evaluate the cultural sensitivity of such tests for use in a particular region and ethnic group, especially when these assessment tools are being used to diagnose and plan treatment for a child.


Physiological demands and characteristics of the participants in a cycling sportive event.
Cycling sportives have become increasingly popular in the last years. With over 11,000 participants, the Quebrantahuesos (Qh), is one of the most prominent cycling events in Europe and its ever-growing competitive nature has increased the physiological demands required to obtain a great result. The objectives of the current study were to determine the relationship between the power profile and the result in the event as well as to describe the physiological differences among subgroups of participants according to their result. Ninety-one male cyclists took part in the study. Data regarding weight, height, experience and training volume were collected before the event. The raw data from the power meter used by the participants during the event's four climbs was sent to the researchers as an Excel file. Participants were then divided in three different groups according to their performance. One-way analysis of variance was performed to assess differences between groups. Pearson's product-moment correlation coefficient was used to assess for associations among performance and/or anthropometric data. Group differences were found in body weight (P<0.001), body mass index (P<0.001), training volume (P<0.001) and previous participations in the event (P<0.001). A very high negative correlation between relative power during the climbs and the final time was also observed (r>-0.92; P<0.001). Better performances were associated to lower body weight and body mass index and higher training volume, relative power and experience. The current study provides data that suggest that as long as the average relative power is sustained, the pacing strategy throughout the different climbs does not affect the race outcome. This information could be used by cyclists and coaches when preparing the pacing strategy for the event.


USE OF ANORECTAL MANOMETRY FOR OBJECTIVE ASSESSMENT OF ANORECTAL FUNCTION AFTER POUCH ILEOANAL ANASTOMOSIS.
Sixteen patients of ulcerative colitis and two of familial adenomatous polyposis were subjected to anorectal manometry, a minimal of three months after Pouch Ileo-Anal Anastomosis and closure of ileostomy. Using a perfusion catheter the parameters measured were resting anal pressure (RAP), maximum squeeze pressure (MSP), pouch volume and compliance at maximum tolerated volume. Subjective evaluation included anal continence and frequency of stools. The subjective functional results after surgery were then correlated with the objective findings of manometry. 4/18 patients (22%) had nocturnal incontinence only, while one patient (5%) had incontinence both by day and night. Frequency of stools was < 8/day in 10/18 patients (55%). Only 1/5 patients (20%) with incontinence had anal sphincter pressures greater than the controls while only 3/13 continent patients (22%) had anal sphincter pressures less than the controls. The study shows that low anal sphincter pressures are associated with post-operative incontinence and that there is a correlation between decreased frequency of stools and increased pouch volume as well as pouch compliance.


Thiamine-responsive acute cerebellar ataxia following febrile illness.
A case of post-pyrexial acute cerebellar ataxia in a 14 year old girl is presented and the available literature is reviewed. The therapeutic efficacy of thiamine hydrochloride observed in this patient lends some support to the view that acute thiamine depletion may be the pathogenetic mechanism for post-pyrexial acute cerebellar ataxia.


Concentration by centrifugation for gas exchange EPR oximetry measurements with loop-gap resonators.
Measurement of the bimolecular collision rate between a spin label and oxygen is conveniently carried out using a gas permeable plastic sample tube of small diameter that fits a loop-gap resonator. It is often desirable to concentrate the sample by centrifugation in order to improve the signal-to-noise ratio (SNR), but the deformable nature of small plastic sample tubes presents technical problems. Solutions to these problems are described. Two geometries were considered: (i) a methylpentene polymer, TPX, from Mitsui Chemicals, at X-band and (ii) Teflon tubing with 0.075 mm wall thickness at Q-band. Sample holders were fabricated from Delrin that fit the Eppendorf microcentrifuge tubes and support the sample capillaries. For TPX, pressure of the sealant at the end of the sample tube against the Delrin sample holder provided an adequate seal. For Teflon, the holder permitted introduction of water around the tube in order to equalize pressures across the sealant during centrifugation. Typically, the SNR was improved by a factor of five to eight. Oxygen accessibility applications in site-directed spin labeling studies are discussed.


A randomized trial of opinion leader endorsement in a survey of orthopaedic surgeons: effect on primary response rates.
Opinion leaders have been shown to have significant influence on the practice of health professionals and patient outcomes. Using focus groups, key informants, and sampling to redundancy techniques, we developed a questionnaire of surgeons' preferences in the treatment of tibial shaft fractures. Twenty-two well-respected and widely known orthopaedic traumatologists endorsed the questionnaire. We randomized 395 surgeon members of the Orthopaedic Trauma Association to receive either a questionnaire that included a letter informing them of the opinion leaders' endorsement, or a questionnaire without the endorsement. Surgeons who received the letter of endorsement had a significantly lower response rate at 2, 4, and 8 weeks. The absolute difference in response rates was 7.8% (4.6% versus 12.4%, P < 0.05) at 2 weeks, 13.1% at 4 weeks (28.6% versus 41.7% P < 0.02), and 12.3% at 8 weeks (47.5% versus 59.8% P = 0.02). The addition of a letter listing expert surgeons who endorse the survey lead to significantly lower primary response rates. Those interested in influencing physician responses cannot always assume a positive effect from endorsement by opinion leaders


Myelography as a stand-alone diagnostic procedure for degenerative spine disease in developing nations.
The use of "stand-alone" contrast myelography (i.e., without computed tomography) has a proven track record in developing nations where few patients have access to magnetic resonance imaging, whether on the basis of prohibitive cost or the absence of such a modality altogether. To substantiate the author's 12-year experience with more than 300 myelograms performed in 16 different countries (plus some 1500 studies during 30 years of practice in the United States), a prospective pilot study was undertaken over 1 month in a community-based neurosurgical setting in western Kenya. Forty patients underwent cervical or lumbar myelography at Tenwek Hospital under the auspices of the Neurosurgery Training Program for East, Central, and South Africa (NSTP-ECSA) following failure of conservative measures to treat spine-related pathology. Thirty-five of the forty patients (88%) came to definitive surgery on the basis of a positive study that correlated with their clinical history and physical examination. There were no significant complications from the procedures, and no false-positive studies, with virtually all patients returning to normal activity and/or gainful employment within 3 weeks of their surgery. Myelography as a stand-alone diagnostic procedure is a sensitive, specific, and cost-effective means of diagnosing symptomatic degenerative spine disorders. Accordingly, its use should be encouraged at every NSTP-ECSA training site to address such ubiquitous pathology.


Effects of gender and fatigue on strength and activity of gluteus medius muscle during a controlled cutting maneuver in preadolescent athletes.
The present study aimed to investigate the effects of gender on hip muscle strength and activity during a controlled cutting maneuver in preadolescent athletes. Fifty-six football and handball preadolescent players participated (35 females and 21 males). Normalized mean activity of the gluteus medius (GM) muscle was measured using surface electromyography during cutting maneuvers in pre-activation and eccentric phases. The stance duration and the strength of hip abductors and external rotators were recorded with a force plate and a handheld dynamometer, respectively. Descriptive statistics and mixed model analysis were used to assess statistical difference (α = 0.05). The results showed that boys activate the GM muscle significantly more than girls during the pre-activation phase (P = 0.022). Boys also demonstrated greater normalized strength of hip external rotation than girls (P = 0.038), but not for hip abduction or duration of stance (P > 0.05). When adjusted for abduction strength, however, boys had significantly shorter stance duration than girls (P = 0.006). It seems that sex-dependent differences are present in preadolescent athletes as observed in the strength of hip external rotator muscles and neuromuscular activity of the GM muscle during a cutting maneuver. Future studies are needed to investigate whether these changes influence risk of lower limb/ACL injury during sport activities.


In vivo quantification of T₂ anisotropy in white matter fibers in marmoset monkeys.
T₂-weighted MRI at high field is a promising approach for studying noninvasively the tissue structure and composition of the brain. However, the biophysical origin of T₂ contrast, especially in white matter, remains poorly understood. Recent work has shown that R₂ (=1/T₂) may depend on the tissue's orientation relative to the static magnetic field (B(0)) and suggested that this dependence could be attributed to local anisotropy in the magnetic properties of brain tissue. In the present work, we analyzed high-resolution, multi-gradient-echo images of in vivo marmoset brains at 7T, and compared them with ex vivo diffusion tensor images, to show that R₂ relaxation in white matter is highly sensitive to the fiber orientation relative to the main field. We directly demonstrate this orientation dependence by performing in vivo multi-gradient-echo experiments in two orthogonal brain positions, uncovering a nearly 50% change in the R₂ relaxation rate constant of the optic radiations. We attribute this substantial R₂ anisotropy to local subvoxel susceptibility effects arising from the highly ordered and anisotropic structure of the myelin sheath.


The roles of body mass and gravity in determining the energy requirements of homoiotherms.
Studies by Kleiber and by Brody in the 1930's established the 3/4 power of body weight as the unit for comparison of metabolic phenomena in homoiotherms. Later Kleiber conceived of the energy requirement as a composite function, with a thermoregulatory component, proportional to heat loss, and an antigravity component that is directly proportional to body weight. Maintenance feed requirements have been measured with groups of small animals chronically exposed to several acceleration fields. Analysis of the results leads to an arithmetic relationship between the maintenance requirement and acceleration field strength: Fg = Fo+k g Where: F is the maintenance feed requirement (Fg in field of g strength, and Fo where g=0); and, g is the ambient acceleration field strength. When the equations are compared for groups of different body size, Fo tends to vary between the 0.4 and 0.5 power of body mass--and k tends to be the same, irrespective of body mass (BM). These findings tend to confirm the Kleiber concept of a composite nature of homoiotherm maintenance requirements.


Comparison of modified montmorillonite adsorbents. Part II: The effects of the type of raw clays and modification conditions on the adsorption performance.
This paper builds on the preceding researches to study the effects of the type of clays (montmorillonites K10, KSF) and modifying conditions on the structure and adsorption behavior of resulting clay adsorbents. The raw clays were modified by polymeric Al/Fe species, hexadecyl-trimethylammonium (HDTMA) surfactant and a complex of polymeric Al/Fe-HDTMA. X-ray diffraction spectra was applied to analyze the structure of the raw and modified clays. After modification, the basal spacing of the clays varied, depending on the types of raw clay and modification conditions. Copper and phenol were selected as adsorbates for evaluating the adsorption performance of various clays, which was affected significantly by the types of raw clay and modification conditions. In general the inorganic contaminant (e.g., Cu) tend to be adsorbed by the polymeric Al/Fe modified clay and the organic impurities (e.g., phenol) will be preferably captured by the surfactant modified clay; both due to the specific surface properties resulting from introducing the modifiers. The complex modified clays possessed the ability of adsorbing both inorganic and organic contaminants. In addition, the d 0 0 1 spacing of modified KSF was greater than that of K10; the adsorption performance with modified KSF was thus greater than that with the modified K10. Finally, the ratio of modifiers to the clay (metal:surfactant:clay) has been observed to affect the adsorption performance; the optimal conditions have been defined.


Finding parametric representations of the cortical sulci using an active contour model.
The cortical sulci are brain structures resembling thin convoluted ribbons embedded in three dimensions. The importance of the sulci lies primarily in their relation to the cytoarchitectonic and functional organization of the underlying cortex and in their utilization as features in non-rigid registration methods. This paper presents a methodology for extracting parametric representations of the cerebral sulcus from magnetic resonance images. The proposed methodology is based on deformable models utilizing characteristics of the cortical shape. Specifically, a parametric representation of a sulcus is determined by the motion of an active contour along the medial surface of the corresponding cortical fold. The active contour is initialized along the outer boundary of the brain and deforms toward the deep root of a sulcus under the influence of an external force field, restricting it to lie along the medial surface of the particular cortical fold. A parametric representation of the medial surface of the sulcus is obtained as the active contour traverses the sulcus. Based on the first fundamental form of this representation, the location and degree of an interruption of a sulcus can be readily quantified; based on its second fundamental form, shape properties of the sulcus can be determined. This methodology is tested on magnetic resonance images and it is applied to three medical imaging problems: quantitative morphological analysis of the central sulcus; mapping of functional activation along the primary motor cortex and non-rigid registration of brain images.


Understanding patient perceptions following a psycho-educational intervention for psychogenic non-epileptic seizures.
This study formed part of an evaluation of a brief educational intervention for patients with psychogenic non-epileptic seizures (PNES). The sessions provide information, seizure control techniques and management planning. The qualitative component of the research reported here aimed to provide insight into the participants' perceptions following the intervention. Semi-structured interviews were conducted with twelve patients. Interviews were tape-recorded, transcribed and analyzed, using principles of thematic analysis. Six key themes were identified: getting answers; understanding the link with emotions; seeking a physiological explanation; doubting the diagnosis; the role of medication; and finding a way forward. The findings highlight considerable individual variation in response, with evidence of changed perceptions or enhanced understanding in some patients while others continued to seek answers or explanations about the cause of their seizures. There were no clear links between reported improved understanding or acceptance of the diagnosis and a perceived improvement in the condition.


Toward a general predictive QSAR model for gamma-secretase inhibitors.
Gamma secretase (GS) is an appealing drug target for Alzheimer disease and cancer because of its central role in the processing of amyloid precursor protein and the notch family of proteins. In the absence of three-dimensional structure of GS, there is an urgent need for new methods for the prediction and screening of GS inhibitors, for facilitating discovery of novel GS inhibitors. The present study reports QSAR studies on diverse chemical classes comprising 233 compounds collected from the ChEMBL database. Herein, continuous [PLS regression and neural-network (NN)] and categorical QSAR models (NN and linear discriminant analysis) were developed to obtain pertinent descriptors responsible for variation of GS inhibitor potency. Also, SAR within various chemical classes of compounds is analyzed with respect to important QSAR descriptors, which revealed the significance of electronegative substitutions on aryl rings (PEOE3) in determining variation of GS inhibitor potency. Furthermore, substitution of acyclic amines with N-substituted cyclic amines appears to be favorable for enhancing GS inhibitor potency by increasing the values of sssN_Cnt and number of aliphatic rings. The models developed are statistically significant and improve our understanding of compounds contributing toward GS inhibitor potency and aid in the rational design of novel potent GS inhibitors.


Spectroscopic and biological studies of spin-labeled tetracycline.
A new nitroxyl labeled tetracycline is synthesized. Proton NMR experiments of tetracycline, spin-labeled tetracycline, and the diamagnetic reduced form in DMSO-d6 are reported. The signals observed in the NMR spectra are all assigned. The NMR data revealed that the spin label is attached to the C-2 amide group on ring A of tetracycline. The spin-labeled tetracycline is also tested in vitro for antitumor activity and is found to be active against leukemia P338/ADR cell line and in melanoma LOX cell line.


Food liposomes: Structures, components, preparations, and applications.
This review explores liposomes, focusing on their structure, components, the characteristics influencing their stability and applicability in foods, and preparation methods. The role of phospholipids and liposome modulators in preparing liposomes of desired structure and size is emphasized. The potential of liposomes to enhance food value through liposomal encapsulation and delivery of functional substances is reviewed. Conventional and advanced liposome preparation methods are reviewed, underscoring their impact on the marketability of liposomes. The review highlights the need for research into lecithin properties and modulators that enhance liposome stability. The need to develop cost-effective and rapid liposome preparation methods is identified as a key factor in improving the marketability of food liposomes and promoting their use in foods.


The consequences of leaf damage for subsequent insect grazing on birch (Betula spp.) : A field experiment.
Low levels of artificial damage were imposed on the leaves of Betla pubescens and B. pendula in early summer 1985. Sixteen tress were used and the damage was distributed throughout the canopy in two ways. It was either randomly dispersed on the tree, or restricted to a localised region of the canopy. Up to 250 leaves/tree were damaged and the position of control leaves was marked as appropriate. At the end of the summer the experimental and control leaves were collected for analysis. Subsequent patterns of grazing by naturally-occurring herbivores were affected by the previous damage to the foliage. Fewer artificially-damaged leaves received subsequent insect grazing damage. The frequecy distribution of insect damage to previously-damaged leaves was significantly different from that of the control leaves, and less leaf tissue was removed from those experimental leaves which did receive subsequent insect attack. The evidence presented suggests that wound-induced changes in leaf palatability do occur in B. pubescens and B. pendula in the field and that a major role is to disperse the damage throughout the canopy.


Programmed intermittent epidural bolus for labour analgesia: a randomized controlled trial comparing bolus delivery speeds of 125 mL·hr-1 versus 250 mL·hr-1.
Programmed intermittent epidural bolus (PIEB) provides better analgesia for labour pain than continuous epidural infusion does. Nevertheless, commonly used PIEB regimens are associated with high sensory block. We hypothesized that a PIEB technique with slower bolus delivery speed would produce lower sensory levels. We recruited term nulliparous women with singleton pregnancies during the first stage of labour. All participants had an American Society of Anesthesiologists Physical Status score of II-III, had epidural catheters placed at L3/4, and had epidural analgesia maintained with PIEB 10 mL every 40 min using 0.0625% bupivacaine with fentanyl 2 µg·mL-1. Women were randomized to receive PIEB delivered at 250 mL·hr-1 (G250) or 125 mL·hr-1 (G125). The study was completed six hours after the loading dose or at full cervical dilatation, whichever occurred first. The primary outcome was the presence of sensory block to ice ≥ T6 in at least one assessment during the study period (maximum six hours). We analyzed data from 90 women. The proportion of women presenting sensory block ≥ T6 at any time was not different between G125 and G250 groups (60.0% vs 64.4%; difference, -4.4%; 95% confidence interval [CI], -24.5 to 15.6; P = 0.66). The median [interquartile range] highest sensory block level was also not different between G125 and G250 groups (T6 [T7-T5] vs T5 [T7-T5], P = 0.39). Women in the G125 group had a lower incidence of hypotension than women in the G250 group did (11.1% vs 33.3%; difference, -22.2%; 95% CI, -38.8 to -5.67; P = 0.01). Quality of analgesia and patient satisfaction were not different between groups. The maintenance of epidural analgesia with a PIEB delivery speed of 125 mL·hr-1 did not produce lower sensory block levels when compared with 250 mL·hr-1. The slower injection speed regimen was associated with lower incidence of hypotension, but this secondary finding warrants confirmation in a future trial. www.ClinicalTrials.gov (NCT03236298); registered 1 August 2017.


Negative symptoms in the course of first-episode affective psychosis.
To determine whether the prognostic implications of negative symptoms apply to functional psychotic disorders other than schizophrenia, we investigated the significance of negative symptoms in the 18-month course of individuals experiencing a first episode of affective psychosis. Although negative symptoms were found to occur during the acute phase of a major depression or a bipolar disorder with psychotic features, they did not endure and had limited prognostic value. Further, the findings suggest that enduring negative symptoms may be specific to schizophrenia.


Fatty acids are novel nutrient factors to regulate mTORC1 lysosomal localization and apoptosis in podocytes.
Podocyte apoptosis is a potent mechanism of proteinuria in diabetic nephropathy. More detailed mechanistic insight into podocyte apoptosis is needed to better understand the pathogenesis of diabetic nephropathy. An elevated level of serum free fatty acid (FFA), as well as hyperglycemia, is a clinical characteristic in diabetes, although its causal role in podocyte apoptosis remains unclear. This study examined the effect of three types of FFAs, saturated, monounsaturated and polyunsaturated FFAs, on podocyte apoptosis. Palmitate, a saturated FFA, induced endoplasmic reticulum (ER) stress-dependent apoptosis in podocytes. Oleate, a monounsaturated FFA, and eicosapentaenoic acid (EPA), an ω-3 polyunsaturated FFA did not induce apoptosis; rather, they antagonized palmitate-induced apoptosis. Palmitate activated mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a nutrient-sensing kinase regulating a wide range of cell biology. Furthermore, inhibition of mTORC1 activity by rapamycin or siRNA for Raptor, a component of mTORC1, ameliorated palmitate-induced ER stress and apoptosis in podocytes. Activity of mTORC1 is regulated by upstream kinases and Rag/Ragulator-dependent recruitment of mTOR onto lysosomal membranes. Palmitate activated mTORC1 by enhancing recruitment of mTOR onto lysosomal membranes, which was inhibited by co-incubation with oleate or EPA. Inhibition of mTOR translocation onto lysosomes by transfection with dominant-negative forms of Rag ameliorated palmitate-induced apoptosis. This study suggests that saturated and unsaturated FFAs have opposite effects on podocyte apoptosis by regulating mTORC1 activity via its translocation onto lysosomal membranes, and the results provide a better understanding of the pathogenesis in diabetic nephropathy and a novel role of mTORC1 in cell apoptosis.


Extracting a low-dimensional description of multiple gene expression datasets reveals a potential driver for tumor-associated stroma in ovarian cancer.
Patterns in expression data conserved across multiple independent disease studies are likely to represent important molecular events underlying the disease. We present the INSPIRE method to infer modules of co-expressed genes and the dependencies among the modules from multiple expression datasets that may contain different sets of genes. We show that INSPIRE infers more accurate models than existing methods to extract low-dimensional representation of expression data. We demonstrate that applying INSPIRE to nine ovarian cancer datasets leads to a new marker and potential driver of tumor-associated stroma, HOPX, followed by experimental validation. The implementation of INSPIRE is available at http://inspire.cs.washington.edu .


The profile of the key pro-inflammatory cytokines in the serum of patients with CD and their association with the disease severity and activity.
The epidemiology of Crohn's disease (CD) has changed over the past decades, demonstrating a trend toward increased prevalence in developing countries, while in developed countries, its incidence has stabilized. The study aimed to examine the profile of the key pro-inflammatory cytokines in the serum of patients with CD and establish their association with the severity and activity of the disease. A total of 61 patients (29 women (47.5%), 32 men (52.5%) aged from 18 to 40 years (mean age (30.42 ± 2.51) years) with the verified diagnosis of CD in the active phase were examined. The control group consisted of 30 healthy people of corresponding age. CD is characterized by a reliable increase of pro-inflammatory cytokines in blood compared to healthy people: tumor necrosis factor-α (TNF-α) - by 4.45 times (137.46 ± 9.72 vs. 30.88 ± 2.08 pg/ml in healthy people, p < 0,001), interleukin-1α (IL-1α) - by 5.08 times (51.55 ± 4.36 vs. 10.14 ± 0.93 pg/ml, p < 0.001), interleukin-6 (IL-6) - by 2.16 times (20.03 ± 1.81 vs. 9.27 ± 0.52 pg/ml, p < 0.001), interleukin-8 (IL-8) - by 2.04 times (25.74 ± 2.05 vs. 12.62 ± 1.16 pg/ml, p < 0.001), and interferon-γ (IFN-γ) - by 5.30 times (208.63 ± 14.29 vs. 39.35 ± 2.40 pg/ml, p < 0.001). The authors have established direct correlations between the Crohn's disease activity index and blood content of TNF-α (r = 0.84, p < 0.013), INF-γ (r = 0.61, p < 0.028); between TNF-α and INF-γ content (r = 0.67, p < 0.023), IL-1α (r = 0.49, p < 0.042), IL-6 (r = 0.40, p < 0.045), and IL-8 (r = 0.51, p < 0.033); INF-γ and IL-1α (r = 0.53, p < 0.040), IL-6 (r = 0.37, p < 0.039), IL-8 (r = 0.44, p < 0.040). Patients with CD were found to have multiple cytokines (TNF-α, IL-1α, IL-6, IL-8, and IFN-γ,). The content of cytokines correlated positively with the CD activity index.


Clinical evaluation of a paper chart for predicting ruthenium plaque placement in relation to choroidal melanoma.
PurposeTo determine the accuracy of estimated tumour location and required plaque position using fundus diagrams, and to evaluate their applicability in daily clinical practice.Patients and methodsBetween September 2013 and March 2016, all patients treated with ruthenium plaque brachytherapy for choroidal melanoma at the Department of Ophthalmology in Poznań underwent pretreatment planning with the use of printed or electronic fundus diagrams www.oculonco.comThe estimated distances were then verified intraoperatively.ResultsThere were 40 eyes of 40 patients: 15 men, 25 women, with a median age of 61 years (range: 21-88). The median longitudinal basal diameter (LBD) of the treated melanomas was 10.4 mm (range: 6.5-14.9) and the median thickness was 4.1 mm (range: 1.9-6). The final postition of the anterior tumour margin was within 1 mm of the estimated location in 39 cases (97 %), and within 2 mm in 1 case (3 %). Median follow-up was 15 months (range: 3-36). By the close of the study, there was one local tumour recurrence (3%) and one patient died of unrelated cause 1 year after treatment. No patient developed metastases by study close.ConclusionsThe plaque planning system using the paper fundus diagrams proved to be accurate, easily applicable and should aid plaque placement where computer modelling is not possible.


Photocurable hard and porous biomaterials from ROMP precursors cross-linked with diyl radicals.
A combination of (ROMP) ring-opening metathesis polymerization and diradical (diyl) cross-linking provides a new access to hard biomaterials and potential artificial bone replacements. ROMP was used to construct soft and pliable linear polymers bearing photolabile diazene functions. After treatment with light, a nitrogen aerosol is released throughout the polymer to create desirable porosity, cross-linking, and hardening in a single step. Nonpolymeric mechanistic work supporting these studies was also examined.


Ryanodine reveals multiple contractile and relaxant mechanisms in vascular smooth muscle: simultaneous measurements of mechanical activity and of cytoplasmic free Ca2+ level with fura-2.
1. The effects of ryanodine on changes in cytoplasmic Ca2+ level ([Ca2+]i) and muscle tension induced by maximum concentrations of phenylephrine (Phe; 1 microM), prostaglandin F2 alpha (PGF2 alpha, 10 microM), caffeine (Caf, 30 mM) and isoprenaline (Iso, 1 microM) were examined in rat aortic strips using fura-2. 2. In normal media, Phe and PGF2 alpha produced a phasic contraction, followed by a tonic one. Caf elicited only a transient contraction. When the preparation was treated with 10 microM ryanodine, an increase in [Ca2+]i was induced accompanied by a nicardipine (1 microM)-resistant contraction which was [Ca2+]o-dependent. 3. In Ca2(+)-free solution, the three stimulants elicited transient increases in [Ca2+]i. Transient contractions to Phe and Caf were accompanied by changes in [Ca2+]i. The transient increase in [Ca2+]i induced by PGF2 alpha was not accompanied by a corresponding contraction. 4. Sustained contractions were induced by Phe and PGF2 alpha in the absence of external Ca2+, while the increase in [Ca2+]i was reduced. A larger maximum contraction was induced by PGF alpha than by Phe. 5. Ryanodine abolished both the Caf- and Phe-induced [Ca2+]i transient increases and the corresponding contractions, but had no substantial effect on the PGF2 alpha-induced [Ca2+]i transient increase. Ryanodine had no influence on the sustained contractions induced by Phe and PGF2 alpha. 6. Iso relaxed both sustained contractions almost completely, without any detectable change in [Ca2+]i. Treatment of the preparation with ryanodine had no effect on the concentration-response curves for Iso in relaxing the 0.1 microM Phe- or 40 mM K(+)-induced precontraction. 7. It is suggested that Phe and Caf mobilize Ca2 + from a ryanodine-sensitive Ca2 + store and that PGF2 alpha. releases Ca2+ from a ryanodine-insensitive Ca2+ store. The former contributes to the transient contraction through a Ca2'-dependent process, while the latter seems not to be directly associated with the contraction. The sustained contraction under Ca2+-free conditions might involve a Ca2 '-independent process or a change in the sensitivity of the contractile filaments to Ca2 + 8. In addition to lowering cytoplasmic Ca2+ concentration, it is suggested that Iso counteracts the apparently Ca2 +-independent process. The ryanodine-sensitive Ca2+ store plays no substantial role in active relaxation by Iso, although it does play a major role in the maintenance of cytoplasmic Ca2+ in a quiescent muscle.


Tracking the time-dependent and tissue-specific processes of arsenic accumulation and stress responses in rice (Oryza sativa L.).
The present study analysed time (0.5 h to 24 h) and tissue [roots, old leaves (OL) and young leaves (YL)] dependent nature of arsenic (As) accumulation and ensuing responses in two contrasting varieties of rice (Oryza sativa L.); Pooja (tolerant) and CO-50 (moderately sensitive). Arsenic accumulation was 5.4-, 4.7- and 7.3-fold higher at 24 h in roots, OL and YL, respectively of var. CO-50 than that in var. Pooja. Arsenic accumulation in YL depicted a delayed accumulation; at 2 h onwards in var. Pooja (0.23 µg g-1 dw) while at 1 h onwards in var. CO50 (0.26 µg g-1 dw). The responses of oxidative stress parameters, antioxidant enzymes, metabolites and ions were also found to be tissue- and time-dependent and depicted differential pattern in the two varieties. Among hormone, salicylic acid and abscisic acid showed variable response in var. Pooja and var. CO-50. Metabolite analysis depicted an involvement of various metabolites in As stress responses of two varieties. In conclusion, an early sensing of the As stress, proper coordination of hormones, biochemical responses, ionic and metabolic profiles allowed var. Pooja to resist As stress and reduce As accumulation more effectively as compared to that of var. CO-50.


Rare case of adhesive large bowel obstruction in acute burn patient: management of open abdomen with ABTHERA ADVANCE™ Open Abdomen Dressing.
Large bowel obstructions (LBO) are rarely caused by adhesions. Surgical management of this condition may require an open approach but closure may not always be possible. There are many temporizing measures in clinical use; however, the ABTHERA ADVANCE™ Open Abdomen Dressing has demonstrated significantly improved outcomes compared to other negative pressure wound therapy dressings. There are few cases in the literature documenting adhesive LBO and none in an acutely unwell burn patient whose abdomen subsequently required the ABTHERA ADVANCE™ Open Abdomen Dressing. We emphasize the importance of considering adhesive LBO as a differential in bowel obstruction and highlight a novel but effective way of managing it in our unique case.


Disruption of a putative mitochondrial oxaloacetate shuttle protein in Aspergillus carbonarius results in secretion of malic acid at the expense of citric acid production.
In filamentous fungi, transport of organic acids across the mitochondrial membrane is facilitated by active transport via shuttle proteins. These transporters may transfer different organic acids across the membrane while taking others the opposite direction. In Aspergillus niger, accumulation of malate in the cytosol can trigger production of citric acid via the exchange of malate and citrate across the mitochondrial membrane. Several mitochondrial organic acid transporters were recently studied in A. niger showing their effects on organic acid production. In this work, we studied another citric acid producing fungus, Aspergillus carbonarius, and identified by genome-mining a putative mitochondrial transporter MtpA, which was not previously studied, that might be involved in production of citric acid. This gene named mtpA encoding a putative oxaloacetate transport protein was expressed constitutively in A. carbonarius based on transcription analysis. To study its role in organic acid production, we disrupted the gene and analyzed its effects on production of citric acid and other organic acids, such as malic acid. In total, 6 transformants with gene mtpA disrupted were obtained and they showed secretion of malic acid at the expense of citric acid production. A putative oxaloacetate transporter gene which is potentially involved in organic acid production by A. carbonarius was identified and further investigated on its effects on production of citric acid and malic acid. The mtpA knockout strains obtained produced less citric acid and more malic acid than the wild type, in agreement with our original hypothesis. More extensive studies should be conducted in order to further reveal the mechanism of organic acid transport as mediated by the MtpA transporter.


Buprenorphine + naloxone in the treatment of opioid dependence during pregnancy-initial patient care and outcome data.
Research has indicated that the buprenorphine-mono product yields maternal outcomes similar to methadone and a less severe neonatal abstinence syndrome. However, maternal and neonatal outcomes following buprenorphine + naloxone exposure during pregnancy have not been documented. Retrospective chart review identified 10 opioid-dependent pregnant women treated with the buprenorphine + naloxone film product between January, 2010-June, 2011. Seven maternal outcome measures - weight gain, fetal presentation at delivery, Cesarean delivery, analgesia during delivery, urine drug screening results at delivery, number of days of maternal hospital stay, and began breastfeeding following delivery-and eleven neonatal outcome measures-gestational age at delivery, 1- and 5-minute Apgar scores, head circumference, length, and weight at birth, treated for neonatal abstinence syndrome (NAS), total amount of morphine sulfate needed to treat NAS, length of hospital stay for NAS treatment, and length of hospital stay-were extracted from medical records. Maternal findings were unremarkable, and comparable with what might be found following treatment with the buprenorphine-mono product. Neonates were full-term with normal birth parameters. Four neonates were treated for NAS, and number of days treated for NAS and number of hospital days were in line with values reported for the buprenorphine-mono product. Findings suggest no obvious significant adverse maternal or neonatal outcomes related to the use of buprenorphine + naloxone for the treatment of opioid dependence during pregnancy. These initial findings underscore the need for future research to systematically examine the relative safety and effectiveness of buprenorphine + naloxone for mother, fetus, and child.


[Yersiniosis].
A survey was undertaken about bacteriologic, epidemiologic and clinical features of infections caused by Yersinia. Yersinia enterocolitica and Yersinia pseudotuberculosis are gram negative rods of the enterobacteriaceae family. The number of cases of these infections has increased considerably in the past few years. Erythema nodosum often occurs after an enteritic infection by Yersinia. Other skin manifestations are erythema exsudativum multiforme, erythema figuratum and "drug-eruption-like exanthema". Moreover, Yersinia-arthritis may occur. In one particular case a Reiter-syndrome was described. The mechanism whereby Yersinia induce skin lesions is unknown. Prognosis is good. Therapy of choice for infections caused by Yersinia are tetracyclines.


Aedes aegypti Totivirus identified in mosquitoes in the Brazilian Amazon region.
The totiviridae family contains viruses with double-stranded RNA genomes of 4.6-7.0 kpb, which encode a capsid protein (CP) and RNA-dependent RNA polymerase (RdRp), and they are approximately 40 nm in diameter with icosahedral symmetry. Totiviruses were first isolated from mosquitoes collected in Shaanxi Province (China). Here, we report a new Aedes aegypti Totivirus (AaTV) identified in mosquitoes from the Amazon rainforest. Mosquitoes (Diptera: Culicidae) were collected from a forest reserve belonging to the Amazon forest in the city of Macapá, Amapá state, Northern Brazil. A viral sequence with a 5748 nucleotide length that was nearly identical to Aedes aegypti Totivirus (AaTV), here named Aedes aegypti Totivirus BR59AP, was detected. A detailed molecular analysis was performed and shows that AaTV-BR59AP is highly related to the AaTV strain from the Caribbean region. We emphasize the importance of the characterization of new viruses in mosquitoes to deepen our understanding of viral diversity in insects and their potential role in disease.


[A predictive model on self care behavior for patients with type 2 diabetes: based on self-determination theory].
The study was conducted to develop and test a hypothetical model which explains self-care behavior in patients with type 2 diabetes was established based on the Self-Determination Theory. The participants were 218 patients with type 2 diabetes mellitus enrolled in an outpatient clinic of one endocrine center in Korea. The data were collected using questionnaires from April 5 through May 7, 2010. The descriptive and correlation statistics were analyzed using the SPSS/WIN 15.0 and the structural equation modeling procedure was performed using the AMOS 7.0 program. The results of this study showed that competence and autonomous motivation were the strong factors influencing self-care behavior in patients in this sample. Support from health provider for autonomy was a significant indirect factor on self-care behavior. These factors explained 64.9% of variance in the participants' self care behavior. The proposed model was concise and extensive in predicting self-care behavior of the participants. Findings may provide useful assistance in developing effective nursing interventions for maintaining and promoting self-care behavior in patients with type 2 diabetes.


The use of heat to deliver fentanyl via pulmonary drug delivery.
The golden standard to treat acute pain is by intravenous drug delivery of opioids such as fentanyl or morphine. Intravenous drug delivery requires the placement of an intravenous (IV) port, which can cause infections, dislodgments, and distress to the patients, and therefore a non-invasive method is desirable. Pulmonary drug delivery is a non-invasive method that has been shown to be a good alternative to intravenous administration. New devices have been investigated for treating acute pain by delivering fentanyl by heat. The pure drug, fentanyl, is applied onto a surface which is then heated up to 350 °C and inhaled, resulting in no formation of degradation products. Furthermore, forced degradation of fentanyl has been studied which showed that longer heating time and higher temperatures will result in the formation of degradation products. The evidence indicates that heat can be used to deliver drugs to the lungs where fast onset reaction can be obtained giving fast and non-invasive pain relief.


Bioconcentration, metabolism and alterations of thyroid hormones of Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) in Zebrafish.
Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is an organophosphate widely used as a flame retardant, and has frequently been detected in the environment and biota. The present study investigates the bioconcentration and metabolism of TDCPP in fish. Zebrafish embryos (from 2h post-fertilization) were exposed to TDCPP (0, 4, 20 and 100μg/L) for six months. Exposure to TDCPP significantly induced phase I metabolic enzymes 7-ethoxyresorufin O-deethylase (EROD) and 7-methoxyresorufin O-demethylase (MROD) in fish. The mRNA expression of genes related to Phase I and II metabolic enzymes, such as cyp1a1, cyp1b1, cyp1c1 and ugt1ab were also significantly upregulated. Exposure to TDCPP significantly reduced plasma thyroxine (T4) and 3,5,3'-triiodothyronine (T3) levels in females. Chemicals analysis indicated significant levels of TDCPP and its metabolite, bis (1,3-dichloro-2-propyl) phosphate (BDCPP), in the liver. The present study reveals that exposure to low concentrations of TDCPP can cause bioconcentration in fish, and TDCPP can be readily metabolized in liver.


Glycoprotein IIb/IIIa inhibition attenuates platelet-activating factor-induced platelet activation by reducing protein kinase C activity.
Glycoprotein (GP)IIb/IIIa inhibition may abolish activated leukocyte-induced platelet activation, in which leukocyte-released platelet-activating factor (PAF) is a major mediator. The present study thus investigated if and how GPIIb/IIIa inhibitors interfere with PAF-induced platelet activation. Platelet and leukocyte activation were monitored by flow cytometry and immunoblotting. GPIIb/IIIa inhibitors (c7E3, non-peptide SR121566, and MAb RFGP56) attenuated PAF-induced, but not adenosine diphosphate (ADP)- or thrombin receptor activating peptide (TRAP)-induced platelet P-selectin expression in whole blood. GPIIb/IIIa blockade enhanced ADP- or TRAP-induced leukocyte CD11b expression, but not the response to PAF. GPIIb/IIIa blockade attenuated PAF-induced, but enhanced ADP- or TRAP-induced platelet-leukocyte aggregation. Under the present experimental conditions, thromboxane A2 receptor antagonism did not significantly influence PAF-induced platelet activation, and GPIIb/IIIa inhibition did not interfere with calcium mobilization/influx in platelets. Protein kinase C (PKC) blockade inhibited PAF-induced platelet P-selectin expression, and PAF-induced PKC activity was reduced by GPIIb/IIIa inhibition. PAF (=1 micro m) did not induce MEK 1/2 or ERK 1/2 phosphorylation, whilst thrombin induced marked responses, which were enhanced by GPIIb/IIIa blockade. Thus, GPIIb/IIIa inhibition attenuates PAF-induced platelet activation via inhibiting PKC activity. GPIIb/IIIa blockade enhances thrombin-induced platelet MEK 1/2 and ERK 1/2 activation, and augments ADP- and TRAP-induced leukocyte activation by enhancing platelet-leukocyte aggregation.


Short-term Cardiovascular Complications of Multi-system Inflammatory Syndrome in Children (MIS-C) in Adolescents and Children.
We provide the readers with a review of cardiac complications in children with multi-system inflammatory syndrome in children (MIS-C) and its short-term outcomes. Recent reports described the acute cardiac manifestations of MIS-C in children and provided a glimpse of the short-term outcomes. Children with MIS-C have been reported to acutely have variable degrees of cardiac findings including abnormal cardiac enzymes, abnormal electrocardiographs, decreased systolic function, coronary artery abnormalities from coronary dilation to giant aneurysms, mitral valve regurgitation, tricuspid valve regurgitation, aortic valve insufficiency, pericardial effusion, diastolic dysfunction, abnormal cardiac strain, and abnormal cardiac MRI. The majority of these abnormalities resolved during short-term follow-up. Further studies are needed to assess if transient or persistent cardiac complications are associated with long-term adverse cardiac events in children with MIS-C. The online version contains supplementary material available at 10.1007/s40124-021-00258-5.


General ageing and ovarian ageing.
The age related decrease in female fertility is associated with a decrease in follicle numbers and oocyte quality. Meiotic division errors, mitochondrial DNA mutations and ageing itself have been suggested to play a part in the age associated reduction in oocyte quality. During the past decades several hypothesis have been proposed, trying to explain the underlying mechanisms. However, none of them is yet conclusive. This review will consider the main hypotheses regarding the age related reduction in oocyte quality. This will be reviewed together with recent results of studies analysing a possible relationship between ageing and ovarian ageing. On the basis of our own results and those presented in the literature, it is concluded that ovarian ageing may only be related to specific aspects of general ageing.


The implementation of social accountability in medical schools in Eastern Mediterranean region: A scoping review.
Social Accountability is a relatively new approach in medical education, Information about its implementation is scarce in the Eastern Mediterranean Region. The objective of this scoping review was to investigate the patterns and trends in reporting the social accountability (SA) of medical schools in the Eastern Mediterranean region (EMR). Using the Arksey and O'Malley approach, we conducted literature searches between 1995 and 2022 in the following databases: Scopus, Web of Sciences, CINAHL, PubMed, and Google Scholar using the search terms social accountability, medical school, faculty of medicine, Eastern Mediterranean Region, EMRO region. Using qualitative theme analysis, the extracted, coded, and analyzed data were reported. The screening of various databases revealed 164 articles, 26 articles were finally included in the review. The 26 included articles originated from only seven out of the 22 EMR countries: Iran, Sudan, Kingdom of Saudi Arabia (KSA), United Arab Emirates, Egypt, Morocco, and Pakistan. The articles included were categorized under six themes: defining the SA and compliance with SA values and concepts, accreditation, educational program, perceptions of faculty and students, admission of students, and measurement of social accountability. The publications related to SA from the EM regions countries revealed similarities with other parts of the world in that the SA concept is not effectively translated into real day-to-day activities in medical schools. More work is needed from leaders in education and health systems to examine SA enablers and improve the uptake of the concept.


A-412997 is a selective dopamine D4 receptor agonist in rats.
A-412997 (2-(3',4',5',6'-tetrahydro-2'H-[2,4'] bipyridinyl-1'-yl)-N-m-tolyl-acetamide) is a highly selective dopamine D4 receptor agonist that binds with high affinity to rat dopamine D4 and human dopamine D4.4 receptors (Ki=12.1 and 7.9 nM, respectively). In contrast to the dopamine D4 receptor agonists PD168077 and CP226269, A-412997 showed a better selectivity profile and no affinity <1000 nM for other dopamine receptors or any other proteins in a panel of seventy different receptors and channels. In functional assays using calcium flux, A-412997 was a potent full agonist at rat dopamine D4 receptors (28.4 nM, intrinsic activity=0.83) and did not activate rat dopamine D2L receptors, unlike CP226269. Dopamine D4 receptor selective agonists have been shown to induce penile erection in rats by central mechanisms. A-412997 induces penile erection in a conscious rat model (effective dose=0.1 micromol/kg, s.c.) with comparable efficacy as the nonselective D2-like agonist, apomorphine. When dosed systemically, A-412997 crossed the blood brain barrier rapidly and achieved significantly higher levels than PD168077. A-412997 is a highly selective dopamine D4 receptor agonist and a useful tool to understand the role of dopamine D4 receptors in rat models of central nervous system processes and disease.


Perspectives on recent reviews of aspartame cancer epidemiology.
Aspartame is a dipeptide non-sugar sweetener that was first marketed in the US in carbonated beverages in 1983, before gaining prominence globally. The Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) and the WHO International Agency for Research on Cancer (IARC) completed evaluations of aspartame and cancer in July 2023. JECFA reaffirmed the safety of aspartame, stating that epidemiology evidence is "not convincing," and that there are no consistent associations between aspartame and cancer (JECFA/IARC, 2023; JECFA, 2023). JECFA also noted "reverse causality, chance, bias and confounding by socioeconomic or lifestyle factors, or consumption of other dietary components, could not be completely ruled out" in relevant epidemiology studies (JECFA/IARC, 2023). In contrast, IARC stated that there are three "high quality" studies on liver cancer (Riboli, 2023), but that the evidence is limited because "chance, bias or confounding could not be ruled out as an explanation for the positive findings" (JECFA/IARC, 2023). IARC does not provide an explanation as to how these studies can be both high quality and have these weaknesses, most notably potential exposure misclassification, or how inconsistent associations from studies with these weaknesses constitute limited evidence. Further, when IARC concludes an agent has limited or inadequate human evidence (and no sufficient animal or strong mechanistic evidence), it classifies that agent as either Group 2B, a possible human carcinogen, or Group 3, not classifiable as to its carcinogenicity. Ultimately, the interpretations of Group 2B and Group 3 classifications are intended to be similar. However, a Group 2B designation may make it appear to scientists and non-scientists alike that the evidence is pointing in the direction of causality. This can lead to unnecessary confusion with respect to the evidence, as well as a perception of a disagreement within WHO regarding aspartame. This apparent contradiction could have been avoided by assigning the IARC classification most consistent with the conclusion that the human evidence for cancer is inadequate: Group 3.


Specific subsets of urothelial bladder carcinoma infiltrating T cells associated with poor prognosis.
Comprehensive investigation of tumor-infiltrating lymphocytes in cancer is crucial to explore the effective immunotherapies, but the composition of infiltrating T cells in urothelial bladder carcinoma (UBC) remains elusive. Here, single-cell RNA sequencing (scRNA-seq) were performed on total 30,905 T cells derived from peripheral blood, adjacent normal and tumor tissues from two UBC patients. We identified 18 distinct T cell subsets based on molecular profiles and functional properties. Specifically, exhausted T (TEx) cells, exhausted NKT (NKTEx) cells, Ki67+ T cells and B cell-like T (B-T) cells were exclusively enriched in UBC. Additionally, the gene signatures of TEx, NKTEx, Ki67+ T and B-T cells were significantly associated with poor survival in patients with BC and various tumor types. Finally, IKZF3 and TRGC2 are the potential biomarkers of TEx cells. Overall, our study demonstrated an exhausted context of T cells in UBC, which layed a theoretical foundation for the development of effective tumor immunotherapies.


[Ectopic ureter. Description of a clinical case with appearance of stress urinary incontinence].
A case of ectopic ureter in a 45 year old woman arising after the onset of stress incontinence is reported. The patient presented complete pyeloureteral duplication with an ectopic ureter whose orifice drained into the proximal urethra. The embryology, diagnostic and therapeutic problems of the case are discussed with emphasis on the tardive appearance of the symptoms.


NAD(P)+ analogues: tools for the investigation of the active site of oestradiol 17beta-dehydrogenase from human placenta.
Oestradiol-17beta:NAD+ 17-oxidoreductase from human placenta can accept coenzyme analogues of NAD+ and NADP+ where the amide group is replaced by methyl ketone, nitrile or thioamide. The inhibition with analogues of NAD+ has been studied. The presence of a substituent at C-3 of the pyridinium ring is necessary for the binding. The inhibition by C-4 methylated analogues is very poor, and the effect of a methyl group at C-5 depends on the substituent at C-3. The 1,4,5,6-tetrahydronicotinamide adenine dinucleotide is a competitive inhibitor. Nicotinamide 8-bromoadenine dinucleotide and nicotinamide 8-thioadenine dinucleotide are efficient hydrogen acceptors.


Small bowel obstruction due to adhesions following neonatal laparotomy.
The aim of this study was to assess the incidence of small bowel obstruction (SBO) due to adhesions following laparotomy in the neonatal period. This was a retrospective study of babies born between January 1998 and November 2003 who had a trans-abdominal procedure in the neonatal period in the John Radcliffe Hospital, Oxford, UK. Four hundred and fourteen patients had a trans-abdominal procedure during this period. The follow-up period ranged from 2 months to 6 years (median 39 months). Overall, twenty-three patients (6%) underwent subsequent laparotomy for SBO due to adhesions. Four patients (17%) who developed SBO due to adhesions had another adhesive obstruction requiring a further laparotomy. The majority of adhesions occurred within a year of the original procedure (87%). A single band caused the obstruction in eight patients (35%), multiple adhesions in six (26%), and dense adhesions in nine patients (39%). The incidence of SBO was highest following surgery for meconium ileus, followed by necrotizing enterocolitis (NEC), and malrotation. There were no deaths due to small bowel obstruction in this study.


Effects of vitamin D supplementation on the bone specific biomarkers in HIV infected individuals under treatment with efavirenz.
It was reported that antiretroviral drugs such as efavirenz can increase the catabolism of vitamin D in HIV infected individuals. We have not found any study that evaluated effects of vitamin D supplementation on the bone specific biomarkers in HIV positive patients under treatment with antiretroviral regimen containing efavirenz. Vitamin D deficiency was detected in 88.4 % of included patients. Baseline osteocalcin, but not collagen telopeptidase, serum levels were lower than normal range in all of these individuals. Both bone biomarkers' concentrations increased significantly (p < 0.001 for both of them) after supplementation of vitamin D and it was more predominant for osteocalcin. In the HIV-infected patients under treatment with efavirenz, vitamin D deficiency is prevalent. After supplementation with single dose of 300,000 IU vitamin D in this population, the activation of osteoblasts and osteoclasts stimulates bone formation and resorption respectively with favorable bone formation without any adverse event. Significant percent of HIV infected individuals are vitamin d deficient that could benefit from vitamin D supplementation.


Intertubercular sulcus of the humerus: biometry and morphology of 100 dry bones.
The dimensions and morphology of a critical zone of the intertubercular sulcus (ITS) of the humerus were specified for 100 dry bones. The upper part of the ITS was narrow and at an angle with the lower part. The tendon of the long head of the biceps brachii muscle (TLBB) was particularly worn down during its course through this critical zone. The critical zone extended from the first perceptible proximal depression to the distal extremity of the lesser tubercle. It showed a proximal part of 12.4 mm (standard deviation = 2.23) and a distal part of 15.1 mm (s.d. = 3.37). The two parts made an angle of 142 degrees (s.d. = 7.87). Its total length was 28.5 mm (s.d. = 4.74), depth 2.44 mm (s.d. = 0.49), width 6.33 mm (s.d. = 0.84). The supratubercular ridge was the only bony variation, found in 45% of the bones of this series. Bony abnormalities were of three types: (1) calcifications in 39% of the bones, (2) lateral spurs in 32% and medial spurs in 23%, (3) degenerative changes in 9% of the bones. Biometric considerations showed that the TLBB inside the ITS was unstable. The supratubercular ridge could increase this instability and thus favor disease of the tendon. Bony abnormalities which may be associated with TLBB lesions, can be seen in radiographs.


Spatio-temporal Distribution of Suicide Risk in Iran: A Bayesian Hierarchical Analysis of Repeated Cross-sectional Data.
We aimed to estimate the space-time distribution of the risk of suicide mortality in Iran from 2006 to 2016. In this repeated cross-sectional study, the age-standardized risk of suicide mortality from 2006 to 2016 was determined. To estimate the cumulative and temporal risk, the Besag, York, and Mollié and Bernardinelli models were used. The relative risk of suicide mortality was greater than 1 in 43.0% of Iran's provinces (posterior probability >0.8; range, 0.46 to 3.93). The spatio-temporal model indicated a high risk of suicide in 36.7% of Iran's provinces. In addition, significant upward temporal trends in suicide risk were observed in the provinces of Tehran, Fars, Kermanshah, and Gilan. A significantly decreasing pattern of risk was observed for men (β, -0.013; 95% credible interval [CrI], -0.010 to -0.007), and a stable pattern of risk was observed for women (β, -0.001; 95% CrI, -0.010 to 0.007). A decreasing pattern of suicide risk was observed for those aged 15-29 years (β, -0.006; 95% CrI, -0.010 to -0.0001) and 30-49 years (β, -0.001; 95% CrI, -0.018 to -0.002). The risk was stable for those aged >50 years. The highest risk of suicide mortality was observed in Iran's northwestern provinces and among Kurdish women. Although a low risk of suicide mortality was observed in the provinces of Tehran, Fars, and Gilan, the risk in these provinces is increasing rapidly compared to other regions.


Pathophysiology of cerebral palsy.
Cerebral palsy (CP), defined as a group of nonprogressive disorders of movement and posture, is the most common cause of severe neurodisability in children. Understanding its physiopathology is crucial to developing some protective strategies. Interruption of oxygen supply to the fetus or brain asphyxia was classically considered to be the main causal factor explaining later CP. However several ante-, peri-, and postnatal factors could be involved in the origins of CP syndromes. Congenital malformations are rarely identified. CP is most often the result of environmental factors, which might interact with genetic vulnerabilities, and could be severe enough to cause the destructive injuries visible with standard imaging (i.e., ultrasonographic study or MRI), predominantly in the white matter in preterm infants and in the gray matter and the brainstem nuclei in full-term newborns. Moreover they act on an immature brain and could alter the remarkable series of developmental events. Biochemical key factors originating in cell death or cell process loss, observed in hypoxic-ischemic as well as inflammatory conditions, are excessive production of proinflammatory cytokines, oxidative stress, maternal growth factor deprivation, extracellular matrix modifications, and excessive release of glutamate, triggering the excitotoxic cascade. Only two strategies have succeeded in decreasing CP in 2-year-old children: hypothermia in full-term newborns with moderate neonatal encephalopathy and administration of magnesium sulfate to mothers in preterm labor.


A Secondary Injury of the Anterolateral Structure Plays a Minor Role in Anterior and Anterolateral Instability of Anterior Cruciate Ligament-Deficient Knees in the Case of Functional Iliotibial Band.
To analyze the contribution of a secondary anterolateral structure (ALS) deficiency to knee instability based on anterior cruciate ligament (ACL) deficiency, in the condition of a functional iliotibial band (ITB). Nine freshly-frozen cadaveric knees were sectioned sequentially to create ACL deficiency and ACL-ALS deficiency, using intact knees before sectioning as controls. When ITB was tensioned with 30 N, 4 separate aspects of knee instability were tested as follows: anterior translation in 90 N anterior load, isolated internal rotation in 5 N·m internal rotational torque from 0° to 90° in 15° increments, and anterolateral translation and internal rotation during a simulated pivot-shift test at 0°, 15°, 30°, and 45°. The contribution of ACL deficiency alone and additional ALS deficiency to knee instability were evaluated. The addition of an ALS lesion produced no significant exacerbation of either anterior translational or pivot shift instability in ACL-deficient knees. Additional ALS deficiency in an ACL-deficient knee resulted in a significant increase in isolated internal rotation from 45° to 90° (P = .001 at 45° and P < .001 in other cases). After sequentially sectioning, the contribution to instability of additional ALS deficiency to the entire instability in ACL-ALS-deficient knees was significantly smaller than that of ACL deficiency alone during anterior load and pivot-shift test (P < .001 in all cases), but significantly contributed more to isolated internal rotational instability at 60° (P = .011) and 90° (P = .015). When ITB was tensioned, ALS played a minor role in controlling both anterior or pivot shift stability in ACL-deficient knees but a major role in restraining isolated internal rotation from 45° to 90°. In the condition of functional ITB, concomitant ALS injury might not exacerbate anterior and pivot-shift instability after ACL rupture, while affecting isolated internal rotation stability at higher flexion.


Metabolic activity assessment by 18 F-fluorodeoxyglucose positron emission tomography in patients with hepatocellular carcinoma undergoing Yttrium-90 transarterial radioembolization.
18 F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is a functional image technique that can inform clinical decisions related to prognosis. We investigated the predictive role of 18 F-fluorodeoxyglucose PET/CT in patients with hepatocellular carcinoma (HCC) undergoing Yttrium-90 (Y-90) transarterial radioembolization (TARE). Patients with HCC treated with TARE and pre-TARE PET/CT scan were recruited between 2009 and 2013. Maximum standardized uptake value and tumor-to-non-tumorous liver uptake ratio (TLR) were measured. Tumor response was evaluated in accordance with modified RECIST criteria at 3-month intervals after Y-90 TARE. Forty patients were included in the final analysis. The median age was 56.5 years and male predominant. Disease control in treated lesion was achieved in 82.5% (n = 33) of patients. During median 18.3-month follow-up, 27.5% (n = 11) of patients achieved progression-free survival. The cutoff of TLR, which was related to the median value, did not affect disease control rate, progression-free survival, and overall survival in patients with Y-90 TARE. The TLR-based stratification may be a simple method, but our study did not show the usefulness in predicting prognosis in HCC patients with Y-90 TARE. Further studies with large number of patients are needed.


Evaluation of skeletal muscle elasticity using color Doppler shear wave imaging.
This study aimed to (1) assess the precision and reproducibility of color Doppler shear wave imaging (CD SWI) by comparing it with shear wave elastography (SWE) via elasticity phantom measurements, and (2) investigate the potential clinical applications of CD SWI in the upper limb muscles by assessing the reproducibility of skeletal muscle elasticity evaluations. Four elastography phantoms of different stiffness (6.0-7.5 wt%) were used to assess the precision and reproducibility of CD SWI (compared with SWE) at depths. Typical upper limb muscles of 24 men were also assessed for this comparison. At superficial depths (0-2 cm), the phantom measurements obtained using CD SWI and SWE were similar at all levels of stiffness. Furthermore, both methods were highly reliable, with almost perfect intra- and inter-operator reliabilities. At greater depths (2-4 cm), measurements obtained using both methods were similar at all stiffness levels. Although standard deviations (SDs) of the phantom measurements obtained using both methods at lower stiffness were similar, those at higher stiffness were different. The SD of the CD SWI measurements was < 50% of that of the SWE measurements. However, both methods were highly reliable in the phantom test, with almost perfect intra- and inter-operator reliabilities. The intra- and inter-operator reliabilities of the shear wave velocity measurements for typical muscles of the upper limbs were also substantial in clinical settings. CD SWI is a valid method for measuring elasticity, with precision and reliability as high as those of SWE.


Data Integration for the Study of Outstanding Productivity in Biomedical Research.
Our goal is to analyze improvement of scientific performance in a multidimensional outcome space, with a focus on US-based biomedical research. With the growing diversity of research databases, limiting assessment of scientific productivity to bibliometric measures such as number of publications, impact factor of journals and number of citations, is increasingly challenged. Using a wider range of outcomes, from publications through practice improvements to entrepreneurial outcomes, overcomes many current limitations in the study of research growth. However, combining such heterogeneous datasets raise three challenges: 1. gathering in one common place a variety of data shared as csv, xml or xls files, 2. merging and linking this data, that sometimes overlap, 3. assessing the impact of research production and inclusive practices in a multidimensional space, that are often missing from the datasets. We would like to present our solution for the first of those challenges, and discuss our leads for the second and third challenges.


COVID-19-associated rhino-orbital-cerebral mucormycosis: A systematic review, meta-analysis, and meta-regression analysis.
Till now, no meta-analysis is available to address the clinical profile, risk factors, different interventions, and outcomes among COVID-19-associated rhino-orbito-cerebral mucormycosis (C-ROCM) cases. Eight literature databases were screened using appropriate keywords from November 1, 2019, to June 30, 2021. The objectives were to analyze the clinical and microbiological profile, risk factor/comorbidity, intervention, and outcome. "R-metafor package" was used for analysis. A total of 23 studies were included. The mean age of presentation of C-ROCM was 54.6 years. The most common presentation was ptosis (72.7%), lid edema (60.6%), proptosis (60.6%), ophthalmoplegia (57.3%), loss of vision (53.7%), facial edema (34.7%), and nasal-blockage (11.8%). Evidence of intracranial spread was seen in 42.8% of cases. Rhizopus was the most common fungus (57.1%) isolated in fungal culture. Among C-ROCM patients, diabetes was the commonest comorbid condition, and the use of corticosteroids related to COVID-19 treatment was the most common risk factor (85.75%). Compared to controlled diabetics, C-ROCM was significantly higher among uncontrolled diabetics (odds ratio [OR] 0.15, 95% confidence interval [C.I.] 0.041-0.544, P = 0.0010). However, no significant association was seen between C-ROCM and COVID-19 severity (OR 0.930, 95% C.I. 0.212-4.087, P = 0.923). For treatment, amphotericin-B was the most common antifungal drug used which was followed by surgical options. However, mortality was high (prevalence 0.344, 95% C.I. 0.205-0.403) despite treatment. Although local rhino-orbito symptoms were the first to appear, rapid intracranial extension was seen in a significant number of C-ROCM cases. Uncontrolled diabetes and excessive use of corticosteroid were the most common risk factors present among the C-ROCM cases. High index clinical suspicion is imperative (specifically among COVID-19 patients with diabetes), and routine screening may be helpful.


Using interviews and observations in clinical practice to enhance authenticity in virtual patients for interprofessional education.
Interprofessional collaboration is increasingly important in healthcare, but interprofessional education (IPE) faces challenges, such as different study programmes with varied schedules and campuses. These challenges can be met, in part, by using web-based virtual patients (VPs) as a tool in IPE. However, demands for relevant patient presentations and clinical practice increase when VPs are used by students from different programmes. The aim of this study was to improve the presentation of professional perspectives regarding nurses and physicians and their collaboration in order to increase the clinical authenticity of existing VPs. Clinical observations were conducted to gain familiarity with the context. Semi-structured interviews were performed with individual nurses and physicians with experience of patients with leg ulcers. The interviews were recorded, transcribed and analysed using thematic analysis. The clinical observations exposed a lack of interprofessional collaboration in practice with regard to patients with leg ulcers. The interview analysis resulted in two themes: Clinical care and Organizational structure. The theme Clinical care included nursing with a holistic approach to the patient and awareness of the patient's well-being, including nutrition and home situation. The theme Organizational structure revealed a lack of teamwork in primary care. The interviewees stressed learning together and sharing responsibility, and they emphasised the importance of implementing interprofessional learning in the education of nurses and physicians in order to stimulate future teamwork. The VP should offer a broad medical history so that healthcare students are made aware of how a disease can affect the patient's social situation, and thereby illustrate the importance of interprofessional collaboration. The information should also be comprehensive and clear, leading to a diagnosis, so the student can gain clinical knowledge and build a foundation for discussion of treatment. Interviews and observations in clinical practice can be used to enhance authenticity in VPs for interprofessional learning. A thorough look at authentic clinical environments can enrich and improve educational settings using VPs, and it can highlight the challenges students can encounter in clinical care of the patient and in an organisation with regard to interprofessional collaboration.


Impact of genetic relatedness on reproductive behavior in Pelvicachromis pulcher, a biparental cichlid fish with mutual mate choice and ornamentation.
Inbreeding can result in inbreeding depression. Therefore, many species seek to avoid inbreeding. However, theory predicts that inbreeding can be beneficial. Accordingly, some species tolerate inbreeding or even prefer mating with close relatives. Evidence for active inbreeding, i.e., kin-mating preference was reported in the biparental African cichlid fish Pelvicachromis taeniatus. Related mating partners revealed better parental cooperation due to kin selection, a potential benefit of inbreeding. In this study, we investigated kin-mating preference in a genetically diverse, outbred F2-lab population of Pelvicachromis pulcher, a closely related species to P. taeniatus. Like P. taeniatus, this species shows mutual ornamentation and mate choice as well as intense biparental brood care. The F1 P. pulcher generation had revealed signs of inbreeding depression but no inbreeding avoidance. We studied mating behavior and aggression in trios consisting of a male P. pulcher, an unfamiliar sister, and an unfamiliar, unrelated female. Because the study focused on kin-mating patterns, female pairs were matched for body size and coloration. The results provide no evidence for inbreeding avoidance but rather suggest inbreeding preference. We also found no significant impact of inbreeding on offspring survival. The results suggest no inbreeding avoidance in P. pulcher; however, the strength of inbreeding preference and inbreeding depression seems to be variable. We discuss possible causes for this variation like context-dependent inbreeding depression. The number of eggs positively correlated with female body size and coloration. Furthermore, the female aggressiveness was positively correlated with female coloration indicating that coloration signal female dominance and quality.


Interplay between plasmacytoid dendritic cells and tumor-specific T cells in peripheral blood influences long-term survival in non-small cell lung carcinoma.
Plasmacytoid dendritic cells (pDCs) represent a subset of antigen-presenting cells that play an ambivalent role in cancer immunity. Here, we investigated the clinical significance of circulating pDCs and their interaction with tumor-specific T cell responses in patients with non-small cell lung cancer (NSCLC, n = 126) . The relation between intratumoral pDC signature and immune checkpoint inhibitors efficacy was also evaluated. Patients with NSCLC had low level but activated phenotype pDC compared to healthy donors. In overall population, patients with high level of pDC (pDChigh) had improved overall survival (OS) compared to patients with pDClow, median OS 30.4 versus 20.7 months (P = 0.013). This clinical benefit was only observed in stage I to III patients, but not in metastatic disease. We showed that patients harboring pDChigh profile had high amount of Th1-diffentiation cytokine interleukin-12 (IL-12) in blood and had functional T cells directed against a broad range of tumor antigens. Furthermore, a high pDC signature in the tumor microenvironment was associated with improved clinical outcome in patients treated with anti-PD-(L)1 therapy. Overall, this study showed that circulating pDChigh is associated with long-term OS in NSCLC and highlighted the predictive value of intratumor pDC signature in the efficacy of immune checkpoint inhibitors.


Fibroblasts modulate cardiomyocyte excitability: implications for cardiac gene therapy.
In an earlier study exploring the potential of gene transfer to repair myocardial conduction defects, we observed that myotubes, generated by forced expression of MyoD, exhibit reduced excitability when also modified to express connexin43 (Cx43). We hypothesized that this effect was caused by gap junction-mediated coupling between myotubes and the underlying fibroblast feeder layer. This intriguing possibility has important implications for ongoing efforts to develop strategies for repairing myocardial conduction defects by gene transfer, and also provides novel insights into the electrophysiological function of naturally occurring heterologous cell coupling within the heart. Although a conductive function for fibroblasts through heterologous coupling has previously been reported, the current study provides novel evidence that fibroblasts can modulate cardiomyocyte excitability in a Cx43-dependent manner. In a co-culture study system, neonatal rat cardiomyocytes were grown on monolayers of mouse fibroblasts with genetically altered Cx43 expression and the effect on intrinsic beat frequency examined. Cardiomyocytes grown on wild-type (WT) fibroblasts expressing native levels of Cx43 beat significantly slower than cells grown on fibroblasts devoid of this molecule (germline knockout) or with dominant-negative functional suppression. Expression of Cx43 in fibroblasts from Cx43 knockout mice restored cardiomyocyte beat frequency, to rates comparable with those observed in co-culture with WT fibroblasts.


Stepwise tapering of remifentanil at the end of surgery decreased postoperative pain and the need of rescue analgesics after thyroidectomy.
This study was designed to investigate whether stepwise tapering of remifentanil at the end of surgery could decrease postoperative pain scores and requirements of rescue analgesics after remifentanil-desflurane anesthesia in patients with thyroidectomy. Sixty two patients undergoing thyroidectomy under general anesthesia were randomly allocated into two groups. All patients were anesthetised with desflurane and high-dose remifentanil. Remifentnail was infused at the rate of 0.3 μg/kg/min until the end of surgery in patients of the control group (group A) whereas remifentanil was tapered gradually from 0.3 to 0.1 μg/kg/min until the end of surgery for at least 30 minutes in patients with group B. Pain scores (0-100 numerical rating scale, NRS), rescue analgesic requirements and adverse events were assessed at 30 min, 2 h, 6 h, 12 h, and 24 h after operation. There was a significant decrease in pain scores at 30 min (20 [0-80] vs. 50 [0-100], P = 0.002) and 2 h (30 [10-60] vs. 40 [20-80], P = 0.018) after surgery in group B compared with group A. In addition, rescue analgesics are less required in group B than in group A postoperatively (2 [1-3] vs. 3 [2,3], P = 0.039). There were no significant differences in adverse events between the two groups. Tapering of remifentanil at the end of surgery decreased postoperative pain scores immediately after thyroidectomy with desflurane and high-dose remifentanil anesthesia. Clinical Research information Service (CRiS, registration number KCT0000589).


Effects of brief naps on mood and sleep in sleep-deprived depressed patients.
To determine the effects of brief naps on mood and electroencephalographic (EEG) sleep in sleep-deprived depressed patients, data from 19 hospitalized patients with depression were analyzed; all were kept awake from 0700h until the following day, when they were allowed 10-min naps at either 0830h or 1500h. Six of the patients showed a clinically significant improvement (greater than 40% change) on the Hamilton Rating Scale for Depression (HRSD) before the nap after all-night sleep deprivation, and the group as a whole showed a significant improvement on the HRSD, the Profile of Mood States, and the Brief Psychiatric Rating Scale subscale for depression. Naps did not alter mood in the responders, but did improve measured depression on the HRSD in the non-responders. Morning and afternoon naps did not differ significantly in their effects on mood or nap sleep. On the recovery sleep, patients who were classified as responders after the nap showed a significantly greater increase in delta (Stage 3 + 4) sleep compared with baseline than nonresponders.


Accuracy of genomic selection for reducing susceptibility to pendulous crop in turkey (Meleagris gallopavo).
Pendulous crop (PC) in the turkey occurs when the crop distends from its normal position, thereby preventing the movement of feed and water from the crop down into the digestive system. This condition negatively impacts the turkey industry at both production and welfare levels. In this study, we estimated the genetic parameters for PC incidence and its genetic correlation with 5 production traits. Additionally, we evaluated the prediction accuracy and bias of breeding values for the selection candidates using pedigree (BLUP) or pedigree-genomic (ssGBLUP) relationships among the animals. A total of 245,783 turkey records were made available by Hybrid Turkeys, Kitchener, Canada. Of these, 6,545 were affected with PC. In addition, the data included 9,634 records for breast meat yield (BMY); 5,592 records for feed conversion ratio (FCR) and residual feed intake (RFI) in males; 170,844 records for body weight (BW) and walking score (WS) between 18 and 20 wk of age for males (71,012) and females (99,832), respectively. Among this population, 36,830 were genotyped using a 65K SNP Illumina Inc. chip. While all animals passed the quality control criteria, only 53,455 SNP markers were retained for subsequent analysis. Heritability for PC was estimated at 0.16 ± 0.00 and 0.17 ± 0.00 using BLUP and ssGBLUP, respectively. The incidence of PC was not genetically correlated with WS or FCR. Low unfavourable genetic correlations with BW (0.12 and 0.14), BMY (0.24 and 0.24) and RFI (-0.33 and -0.28) were obtained using BLUP and ssGBLUP, respectively. Using ssGBLUP showed higher prediction accuracy (0.51) for the breeding values for the selection candidates than the pedigree-based model (0.35). Whereas the bias of the prediction was slightly reduced with ssGBLUP (0.33 ± 0.05) than BLUP (0.30 ± 0.08), both models showed a regression coefficient lower than one, indicating inflation in the predictions. The results of this study suggest that PC is a heritable trait and selection for lower PC incidence rates is feasible. Although further investigation is necessary, selection for BW, BMY, and RFI may increase PC incidence. Incorporating genomic information would lead to higher accuracy in predicting the genetic merit for selection candidates.


Long-term priors influence visual perception through recruitment of long-range feedback.
Perception results from the interplay of sensory input and prior knowledge. Despite behavioral evidence that long-term priors powerfully shape perception, the neural mechanisms underlying these interactions remain poorly understood. We obtained direct cortical recordings in neurosurgical patients as they viewed ambiguous images that elicit constant perceptual switching. We observe top-down influences from the temporal to occipital cortex, during the preferred percept that is congruent with the long-term prior. By contrast, stronger feedforward drive is observed during the non-preferred percept, consistent with a prediction error signal. A computational model based on hierarchical predictive coding and attractor networks reproduces all key experimental findings. These results suggest a pattern of large-scale information flow change underlying long-term priors' influence on perception and provide constraints on theories about long-term priors' influence on perception.


3D Computer aided treatment planning in endodontics.
Obliteration of the root canal system due to accelerated dentinogenesis and dystrophic calcification can challenge the achievement of root canal treatment goals. This paper describes the application of 3D digital mapping technology for predictable navigation of obliterated canal systems during root canal treatment to avoid iatrogenic damage of the root. Digital endodontic treatment planning for anterior teeth with severely obliterated root canal systems was accomplished with the aid of computer software, based on cone beam computer tomography (CBCT) scans and intra-oral scans of the dentition. On the basis of these scans, endodontic guides were created for the planned treatment through digital designing and rapid prototyping fabrication. The custom-made guides allowed for an uncomplicated and predictable canal location and management. The method of digital designing and rapid prototyping of endodontic guides allows for reliable and predictable location of root canals of teeth with calcifically metamorphosed root canal systems. The endodontic directional guide facilitates difficult endodontic treatments at little additional cost.