Regulation of the Muscarinic M3 Receptor by Myocardin-Related Transcription Factors.
Myocardin-related transcription factors (MRTFs: myocardin/MYOCD, MRTF-A/MRTFA, and MRTF-B/MRTFB) are co-factors of serum response factor (SRF) that activate the smooth muscle cell (SMC) gene program and that play roles in cardiovascular development and mechanobiology. Gain and loss of function experiments have defined the SMC gene program under control of MRTFs, yet full understanding of their impact is lacking. In the present study, we tested the hypothesis that the muscarinic M3 receptor (CHRM3) is regulated by MRTFs together with SRF. Forced expression of MYOCD (8d) in human coronary artery (SMC) followed by RNA-sequencing showed increased levels of M2, M3, and M5 receptors (CHRM2: 2-fold, CHRM3: 16-fold, and CHRM5: 2-fold). The effect of MYOCD on M3 was confirmed by RT-qPCR using both coronary artery and urinary bladder SMCs, and correlation analyses using human transcriptomic datasets suggested that M3 may also be regulated by MRTF-B. Head-to-head comparisons of MYOCD, MRTF-A and MRTF-B, argued that while all MRTFs are effective, MRTF-B is the most powerful transactivator of CHRM3, causing a 600-fold increase at 120h. Accordingly, MRTF-B conferred responsiveness to the muscarinic agonist carbachol in Ca2+ imaging experiments. M3 was suppressed on treatment with the MRTF-SRF inhibitor CCG-1423 using SMCs transduced with either MRTF-A or MRTF-B and using intact mouse esophagus in culture (by 92±2%). Moreover, silencing of SRF with a short hairpin reduced CHRM3 (by >60%) in parallel with α-actin (ACTA2). Tamoxifen inducible knockout of Srf in smooth muscle reduced Srf (by 54±4%) and Chrm3 (by 41±6%) in the urinary bladder at 10days, but Srf was much less reduced or unchanged in aorta, ileum, colon, trachea, and esophagus. Longer induction (21d) further accentuated the reduction of Chrm3 in the bladder and ileum, but no change was seen in the aorta. Single cell RNA-sequencing revealed that Mrtfb dominates in ECs, while Myocd dominates in SMCs, raising the possibility that Chrm3 may be driven by Mrtfb-Srf in the endothelium and by Myocd-Srf in SMCs. These findings define a novel transcriptional control mechanism for muscarinic M3 receptors in human cells, and in mice, that could be targeted for therapy.


[Structural characteristics of tubal pregnancy].
Morphological and immunohistochemical analysis of fallopian pregnancy is performed. Structural features of cytotrophoblastic invasion in both types of pregnancy are without principal differences. Immunohistochemically low level of estrogen and progesteron receptors in the uterine tube as compared to the uterus is established. Decidual reaction in a tube pregnancy is not developed in the majority of cases this could be a reason of a limitless invasion of cytotrophoblast and hemosalpinx development.


Airway management of neonates with antenatally detected head and neck anomalies.
Five cases of prenatally detected neck masses that had a potential for airway obstruction at birth are described. The various options for management of the airway are discussed, including using maternal-fetal circulation until intubation, rigid bronchoscopy, tracheotomy, cyst aspiration, or extracorporeal membrane oxygen support. Congenital abnormalities involving the fetal face or neck are extremely rare. With technical advances in ultrasonography, these masses were first noted on prenatal ultrasound in the late 1970s. Before that period, they were detected at delivery. These masses are solid or cystic and may cause asphyxia because of airway obstruction at the time of delivery. The survivability of these neonates without immediate intervention at birth is 0% to 20%. If a neck mass is detected in the fetus by prenatal ultrasonography, then a strategic plan for these types of cases should be developed early in the prenatal period. The airway management plan should be tailored for each individual case. Coordination and the expertise of an obstetrician, neonatologist, anesthesiologist, and pediatric otolaryngologist are needed to manage these complex situations.


Synthesis of CdIn2S4 microsphere and its photocatalytic activity for azo dye degradation.
CdIn2S4 was prepared by ultrasonic spray pyrolysis. The prepared CdIn2S4 was characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FSEM), transmission electron microscopy (TEM), UV-visible diffuse reflectance spectroscopy (UV-Vis DRS), and N2-sorption techniques. Aqueous photocatalytic activity was evaluated by the decomposition of methyl orange under visible light irradiation. The results indicate that the prepared CdIn2S4 has spherical morphology with mesoporous structure which can efficiently degrade methyl orange in water. The sample prepared at 500°C exhibits the optimized photocatalytic activity.


Costs and benefits of the presence of leopards to the sport-hunting industry and local communities in Niassa National Reserve, Mozambique.
Sport hunting is often proposed as a tool to support the conservation of large carnivores. However, it is challenging to provide tangible economic benefits from this activity as an incentive for local people to conserve carnivores. We assessed economic gains from sport hunting and poaching of leopards (Panthera pardus), costs of leopard depredation of livestock, and attitudes of people toward leopards in Niassa National Reserve, Mozambique. We sent questionnaires to hunting concessionaires (n = 8) to investigate the economic value of and the relative importance of leopards relative to other key trophy-hunted species. We asked villagers (n = 158) the number of and prices for leopards poached in the reserve and the number of goats depredated by leopard. Leopards were the mainstay of the hunting industry; a single animal was worth approximately U.S.$24,000. Most safari revenues are retained at national and international levels, but poached leopard are illegally traded locally for small amounts ($83). Leopards depredated 11 goats over 2 years in 2 of 4 surveyed villages resulting in losses of $440 to 6 households. People in these households had negative attitudes toward leopards. Although leopard sport hunting generates larger gross revenues than poaching, illegal hunting provides higher economic benefits for households involved in the activity. Sport-hunting revenues did not compensate for the economic losses of livestock at the household level. On the basis of our results, we propose that poaching be reduced by increasing the costs of apprehension and that the economic benefits from leopard sport hunting be used to improve community livelihoods and provide incentives not to poach.


Effect of ketoconazole, itraconazole and fluconazole on the gastrointestinal colonization of mice by Candida albicans.
Crl:CD1 (ICR) BR mice were colonized in the gastrointestinal (GI) tract with Candida albicans. This strain was susceptible to ketoconazole (MIC=0.25 microg/ml), itraconazole (minimum inhibitory concentration, MIC=0.25 microg/ml), and fluconazole (MIC=4 microg/ml). Subsequently the animals received monotherapy with ketoconazole by mouth (equivalent to human dose of 2.9 mg/kg/day), or itraconazole by mouth (equivalent to human dose of 2.9 mg/kg/day), or fluconazole either subcutaneously (equivalent to human dose of 2.2 mg/kg/day), or by mouth (equivalent to human dose of 2.2 mg/kg/day), for 10 days. Quantitative stool cultures at the end and one week after the end of treatment revealed that all three azoles caused a small and statistically non significant reduction of C. albicans concentration in the stools. The different route of administration of fluconazole did not produce different results. In conclusion, these azoles, used at the present doses and schedules, have minimal effect on murine GI colonization by this strain of C. albicans which is susceptible but with rather increased MICs.


Changing P waves after mitral valve replacement.
A 55-year-old man is convalescing from mitral valve replacement five days earlier. He had severe calcific mitral stenosis and moderately severe hypertension, with repeated attacks of acute pulmonary edema. He had always been in normal sinus rhythm, except for a single episode of atrial fibrillation associated with one of his episodes of acute pulmonary edema. He had been taking digoxin (0.25 mg daily) but this was stopped the day before the operation. The cardiac rhythm has been mostly regular since the operation, but occasional irregularities have been noted. An ECG on the fifth postoperative day is shown.


Traditional Dietary Patterns and Risk of Mortality in a Longitudinal Cohort of the Salus in Apulia Study.
There is still room for further studies analyzing the long-term health impact of specific dietary patterns observable in regions belonging to the Mediterranean area. The aim of the study is to evaluate how much a diet practiced in southern Italy is associated to a risk of mortality. The study population included 2472 participants first investigated in 1985, inquiring about their frequencies of intake of 29 foods using a self-administered questionnaire covering the previous year. The population was followed up for mortality until 31 December 2017. Cox-based risk modeling referred to single foods, food groups, the results of principal component analysis (PCA), and a priori indexes. Single food analysis revealed eggs, fatty meat, and fatty/baked ham to be inversely associated with mortality. Furthermore, one of the 5 PCA derived dietary patterns, the "Farmhouse" pattern, showed a higher hazard ratio (HR), mostly driven by dairy products. In subsequent analyses, the increased risk of mortality for fresh cheese and decreased risk for fatty ham and eggs were confirmed. The a priori diet indexes (Italian Meddiet, Meddietscore, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay diet (MIND) indexes) showed borderline inverse relationships. In a Mediterranean population with an overall healthy diet, foods such as eggs and fatty meat, reflecting dietary energy and wealth, played a role in prolonging the life of individuals. Our study confirms that some dairy products might have a detrimental role in mortality in the Mediterranean setting.


[Endolymphatic sac tumor: a rare tumor of internal ear. Report of two cases].
Papillary tumors of the temporal bone are rare and aggressive neoplasms. Recently described, these tumors had initially a presumed middle-ear origin. Only recently, convincing anatomic, morphological and immunohistochemical arguments exist for an endolymphatic sac origin (inner-ear origin). We report two cases of endolymphatic sac tumor. These tumors can be encountered sporadically or in Von Hippel-Lindau disease. They classically grow very slowly, resulting in late clinical manifestations with expansive mass invading temporal bone and extending in posterior fossa. Radiologically, these endolymphatic sac tumors can mimic metastatic carcinoma, paraganglioma, or cerebellar haemangioblastoma specially in von Hippel-Lindau disease. Histology shows a papillary epithelial tumor with hypervascular stroma, without atypia. The treatment for these tumors is surgical and curative when early diagnosed. In apparently sporadic cases, genetic analysis for Von Hippel-Lindau disease should be considered.


Lower extremity physical performance and hip bone mineral density in elderly black and white men and women: cross-sectional associations in the Health ABC Study.
Aging is characterized by declines in physical capacity and bone mineral density (BMD), both of which contribute to increased risk for fracture. However, it is unclear if these factors coexist or are independent in elderly people, and if a relationship does exist, whether it varies by sex and/or race. Data are from 847 white women, 723 black women, 927 white men, and 544 black men aged 70-79 years participating in the Health Aging and Body Composition (ABC) Study, a cohort of well-functioning community-dwelling elders. BMD (g/cm(2)) of the hip (femoral neck and trochanter) was determined by dual X-ray absorptiometry. Physical capacity measures included knee extensor strength, repeated chair-stands, gait speed (6 m), walking endurance (400 m), and standing balance. In analyses of BMD as a continuous measure, BMD and physical performance were most consistently related at the trochanter in black women, even after adjusting for body size and several covariates including physical activity. For each performance measure, black women in the bottom quartile(s) had lower BMD than those in the top quartile(s). For the femoral neck, there was a significant association with performance tasks, except for the 400-m walk. In comparison, only chair-rise performance was related to BMD at the femoral neck, and knee extensor strength, chair-rise performance, and balance with the trochanter in white women. For white and black men, trends existed only for lower BMD in those with poorer knee extensor strength. In this cohort of well-functioning young-old seniors, physical capacity is only modestly related to BMD at the hip. The association was strongest in black women, who as a group exhibited the poorest functional capacity in the cohort. Our data show that, although both poorer physical performance and low BMD are risk factors for fracture, they remain largely independent in the well-functioning young-old, except in black women. This independence suggests that interventions to reduce fracture incidence should be targeted at improving both physical performance and bone density.


Potential Role of GLP-1 Based Therapeutics in Coronary Artery Disease.
Glucagon-like peptide-1 (GLP-1), an incretin hormone primarily secreted by intestinal L cells, regulates glucose metabolism by increasing insulin synthesis and secretion, decreasing plasma glucagon levels, reducing food intake, and slowing gastric emptying. This has led to the development of GLP-1 receptor (GLP-1R) agonists as a treatment for diabetes and obesity. In addition to being present in beta cells, GLP-1R has also been identified in blood vessels and the heart, suggesting that GLP-1R agonists may have an impact on cardiovascular health. There is now substantial evidence supporting GLP-1's protective effects on the cardiovascular system. This review summarizes the current research on GLP-1-based therapy for coronary artery disease (CAD) by examining its protective effects against inflammation and ischemia/reperfusion injury and analyzing clinical trials on GLP-1-based therapies for CAD. Although results from various studies were inconsistent, the challenge of transitioning GLP-1-based therapies from the laboratory to the clinical setting remains. Further well-designed and high-quality studies are necessary to determine the efficacy and safety of GLP-1 for patients with CAD.


Pectoral girdle and forelimb musculoskeletal function in the echidna (Tachyglossus aculeatus): insights into mammalian locomotor evolution.
Although evolutionary transformation of the pectoral girdle and forelimb appears to have had a profound impact on mammalian locomotor and ecological diversity, both the sequence of anatomical changes and the functional implications remain unclear. Monotremes can provide insight into an important stage of this evolutionary transformation, due to their phylogenetic position as the sister-group to therian mammals and their mosaic of plesiomorphic and derived features. Here we build a musculoskeletal computer model of the echidna pectoral girdle and forelimb to estimate joint ranges of motion (ROM) and muscle moment arms (MMA)-two fundamental descriptors of biomechanical function. We find that the echidna's skeletal morphology restricts scapulocoracoid mobility and glenohumeral flexion-extension compared with therians. Estimated shoulder ROMs and MMAs for muscles crossing the shoulder indicate that morphology of the echidna pectoral girdle and forelimb is optimized for humeral adduction and internal rotation, consistent with limited in vivo data. Further, more muscles act to produce humeral long-axis rotation in the echidna compared to therians, as a consequence of differences in muscle geometry. Our musculoskeletal model allows correlation of anatomy and function, and can guide hypotheses regarding function in extinct taxa and the morphological and locomotor transformation leading to therian mammals.


Lineage-specific loss and divergence of functionally linked genes in eukaryotes.
By comparing 4,344 protein sequences from fission yeast Schizosaccharomyces pombe with all available eukaryotic sequences, we identified those genes that are conserved in S. pombe and nonfungal eukaryotes but are missing or highly diverged in the baker's yeast Saccharomyces cerevisiae. Since the radiation from the common ancestor with S. pombe, S. cerevisiae appears to have lost about 300 genes, and about 300 more genes have diverged by far beyond expectation. The most notable feature of the set of genes lost in S. cerevisiae is the coelimination of functionally connected groups of proteins, such as the signalosome and the spliceosome components. We predict similar coelimination of the components of the posttranscriptional gene-silencing system that includes the recently identified RNA-dependent RNA polymerase. Because one of the functions of posttranscriptional silencing appears to be "taming" of retrotransposons, the loss of this system in yeast could have triggered massive retrotransposition, resulting in elimination of introns and subsequent loss of spliceosome components that become dispensable. As the genome database grows, systematic analysis of coordinated gene loss may become a general approach for predicting new components of functional systems or even defining previously unknown functional complexes.


Efficacy and Safety of Sea Salt-Derived Physiological Saline Nasal Spray as Add-On Therapy in Patients with Acute Upper Respiratory Infection: A Multicenter Retrospective Cohort Study.
BACKGROUND The purpose of this study was to assess the effects of seawater on nasal congestion and runny nose symptoms in adults with an acute upper respiratory infection (URI). MATERIAL AND METHODS This was a multicenter retrospective cohort trial of patients with acute URI and symptoms of nasal congestion and runny nose. The patients were assigned to 2 groups and were administered regular non-drug supportive treatment or supportive treatment with nasal irrigation with sea salt-derived physiological saline. The primary efficacy endpoint was the effective rate (percentage of patients with ≥30% symptom score reduction from baseline for nasal congestion and runny nose). RESULTS In total, 144 patients were enrolled, including 72 in each group, and 143 patients completed the study. Both groups had similar demographics and vital signs. The effective rates for nasal congestion and runny nose were significantly increased in the seawater group compared with patients in the control group (87.3% vs 59.7% for nasal congestion; 85.9% vs 61.1% for runny nose; both P<0.001). In addition, the 2 groups showed markedly different degrees of patient symptom score improvement in sleep quality and appetite (both P<0.01), but not in cough and fatigue (both P>0.05). There were no adverse events in either group. CONCLUSIONS The sea salt-derived physiological saline nasal spray device satisfactorily improved nasal congestion, runny nose, sleep quality, and appetite in adults with URI, with no adverse effects.


Intraspecific Trait Variation and Coordination: Root and Leaf Economics Spectra in Coffee across Environmental Gradients.
Hypotheses on the existence of a universal "Root Economics Spectrum" (RES) have received arguably the least attention of all trait spectra, despite the key role root trait variation plays in resource acquisition potential. There is growing interest in quantifying intraspecific trait variation (ITV) in plants, but there are few studies evaluating (i) the existence of an intraspecific RES within a plant species, or (ii) how a RES may be coordinated with other trait spectra within species, such as a leaf economics spectrum (LES). Using Coffea arabica (Rubiaceae) as a model species, we measured seven morphological and chemical traits of intact lateral roots, which were paired with information on four key LES traits. Field collections were completed across four nested levels of biological organization. The intraspecific trait coefficient of variation (cv) ranged from 25 to 87% with root diameter and specific root tip density showing the lowest and highest cv, respectively. Between 27 and 68% of root ITV was explained by site identity alone for five of the seven traits measured. A single principal component explained 56.2% of root trait covariation, with plants falling along a RES from resource acquiring to conserving traits. Multiple factor analysis revealed significant orthogonal relationships between root and leaf spectra. RES traits were strongly orthogonal with respect to LES traits, suggesting these traits vary independently from one another in response to environmental cues. This study provides among the first evidence that plants from the same species differentiate from one another along an intraspecific RES. We find that in one of the world's most widely cultivated crops, an intraspecific RES is orthogonal to an intraspecific LES, indicating that above and belowground responses of plants to managed (or natural) environmental gradients are likely to occur independently from one another.


Magnetic resonance imaging of the sacroiliac joints in patients with suspected spondyloarthritis--comparison of turbo spin-echo and gradient-echo sequences for the detection of structural alterations.
Magnetic resonance imaging (MRI) is the method of choice for the evaluation of spondyloarthritis (SpA). According to the guidelines of the Assessment of Spondyloarthritis International Society (ASAS) and Outcome Measures in Rheumatology (OMERACT), MRI findings in SpA of the spine and the sacroiliac joints (SIJ) are classified as inflammatory and structural alterations. Modern gradient-echo sequences (GRE) are recommended for optimized detection of structural alterations of the SIJ. We assess the benefit of GRE in the detection of structural alterations of the SIJ in comparison to conventional turbo spin-echo sequences (TSE). Retrospective study of 114 patients who received MRI of the SIJ for the evaluation of SpA. Structural alterations of the SIJ were assessed by two blinded readers separately for T1 TSE and T2* GRE. The findings were classified according to a previously published chronicity score separately for both sides and sequences. Interobserver reliability was calculated with Cohen's Kappa, and the significance of findings was assessed with the Wilcoxon test. P-values <0.05 were required for statistical significance. 68 of 114 (60%) patients showed SpA-typical findings of the SIJ. The average chronicity score for GRE (score 3.3) was significantly higher than for TSE (score 2.6), p=0.001. The Kappa-values for the interobserver reliability were 0.86-0.90 without any statistically significant differences between both sides and sequences. Both T1 TSE and T2* GRE showed a high interobserver reliability in the detection of structural alterations in patients with SpA. However, T2* GRE detected significantly more structural alterations than T1 TSE and should be an integral part of a modern MRI protocol for the diagnostic workup of patients with suspected SpA. T2* gradient-echo sequences are superior to T1 turbo spin-echo sequences in the detection of structural SI-joint alterations.


11beta-hydroxysteroid dehydrogenases, cell proliferation and malignancy.
The enzymes 11beta-hydroxysteroid dehydrogenase type 1 and 2 (11beta-HSD1 and 2) have well-defined roles in the tissue-specific metabolism of glucocorticoids which underpin key endocrine mechanisms such as adipocyte differentiation (11beta-HSD1) and mineralocorticoid action (11beta-HSD2). However, in recent studies we have shown that the effects of 11beta-HSD1 and 2 are not restricted to distinct tissue-specific hormonal functions. Studies of normal fetal and adult tissues, as well as their tumor equivalents, have shown a further dichotomy in 11beta-HSD expression and activity. Specifically, most normal glucocorticoid receptor (GR)-rich tissues such as adipose tissue, bone, and pituitary cells express 11beta-HSD1, whereas their fetal equivalents and tumors express 11beta-HSD2. We have therefore postulated that the ability of 11beta-HSD1 to generate cortisol acts as an autocrine anti-proliferative, pro-differentiation stimulus in normal adult tissues. In contrast, the cortisol-inactivating properties of 11beta-HSD2 lead to pro-proliferative effects, particularly in tumors. This proposal is supported by experiments in vitro which have demonstrated divergent effects of 11beta-HSD1 and 2 on cell proliferation. Current studies are aimed at (1) characterizing the underlying mechanisms for a "switch" in 11beta-HSD isozyme expression in tumors; (2) defining the molecular targets for glucocorticoids as regulators of cell proliferation; (3) evaluating the potential for targeting glucocorticoid metabolism as therapy for some cancers. These and other issues are discussed in the present review.


Patient safety training simulations based on competency criteria of the Accreditation Council for Graduate Medical Education.
This report reviews and critically evaluates the development of 3 movements in healthcare that have had a profound impact on changes occurring at all levels of medical education: patient safety, healthcare simulation, and competency-based education (exemplified by the Accreditation Council for Graduate Medical Education). The authors performed a critical and selective review of the literature from 1999 to 2011 to identify uses of simulation to address patient-safety issues aligned according to the Accreditation Council for Graduate Medical Education 6 core competencies: (1) patient care; (2) medical knowledge; (3) interpersonal and communication skills; (4) professionalism; (5) practice-based learning; and (6) systems-based practice. The research synthesis is reported to inform and provide evidence about how simulation is used to train and evaluate learners on a range of patient-safety issues for each of the core competencies: There is emerging evidence that simulation can be used in training efforts to reduce medical errors related to medical knowledge and patient care (particular invasive procedures as well as improved communication and teamwork skills). There remains limited evidence on its impact to improve patient safety related to more complex competencies of practice-based learning and systems-based practice. Simulation-based learning can lead to positive patient outcomes and reduction of medical errors particularly when used for individual skills. However, particular attention needs to be placed on the organizational context in which it is implemented if improvements in practice-based learning and systems-based practice are to be realized.


Functionalization of protein-based nanocages for drug delivery applications.
Traditional drug delivery strategies involve drugs which are not targeted towards the desired tissue. This can lead to undesired side effects, as normal cells are affected by the drugs as well. Therefore, new systems are now being developed which combine targeting functionalities with encapsulation of drug cargo. Protein nanocages are highly promising drug delivery platforms due to their perfectly defined structures, biocompatibility, biodegradability and low toxicity. A variety of protein nanocages have been modified and functionalized for these types of applications. In this review, we aim to give an overview of different types of modifications of protein-based nanocontainers for drug delivery applications.


The effectiveness of imagery and sentence strategy instructions as a function of visual and auditory processing in young school-age children.
The relationship between auditory and visual processing modality and strategy instructions was examined in first- and second-grade children. A Pictograph Sentence Memory Test was used to determine dominant processing modality as well as to assess instructional effects. The pictograph task was given first followed by auditory or visual interference. Children who were disrupted more by visual interference were classed as visual processors and those more disrupted by auditory interference were classed as auditory processors. Auditory and visual processors were then assigned to one of three conditions: interactive imagery strategy, sentence strategy, or a control group. Children in the imagery and sentence strategy groups were briefly taught to integrate the pictographs in order to remember them better. The sentence strategy was found to be effective for both auditory and visual processors, whereas the interactive imagery strategy was effective only for auditory processors.


Non-inferiority of retrospective data collection for assessing perioperative morbidity.
Background. Postoperative morbidity has immediate and delayed consequences for surgical patients, including excess risk of premature death. Capturing these data objectively and routinely in large electronic databases using tools such as the Postoperative Morbidity Survey (POMS) would offer tremendous clinical and translational potential. However, POMS has thus far only utilised prospective data collection by research staff. We hypothesised that retrospective data collection from routinely collated hospital data from paper and electronic charts, medical and nursing notes was non-inferior to prospective data collection requiring research staff capturing POMS-defined morbidity in real-time. Methods. Morbidity was recorded by a trained investigator as defined by POMS prospectively on postoperative days 3 and 7. Separately, an independent investigator blinded to prospectively acquired data retrospectively assessed the same patients' morbidity as defined by POMS criteria, using medical charts, nursing summaries and electronic data. Equivalence was accepted when the confidence limits for both modes of data collection fell completely inside the equivalence bounds, with the maximum equivalence difference (i.e., the largest value of the difference in sensitivities deemed to reach a conclusion of equivalence) set a priori at 0.2. Differences for confidence limits between retrospective and prospective data collection were based on Nam's RMLE method. The relationship between morbidity on postoperative day 3 as recorded by each data collection method on time to become morbidity free and length of hospital stay was compared using the log-rank test. Results. POMS data from 85 patients undergoing elective or emergency surgery were analyzed. At postoperative day 3, POMS-defined morbidity was similar regardless of whether data were collected prospectively or retrospectively (95% CI [-0.13-0.013]; p < 0.001). Non-inferiority for sensitivity was observed for all other POMS domains and timepoints. Time to become morbidity free Kaplan-Meier plots were indistinguishable between POMS obtained prospectively or retrospectively (hazard ratio: 1.09 (95% CI [0.76-1.57]); p = 0.33, log rank test). Similarly, the mode of data collection did not alter the association between early postoperative morbidity on postoperative day 3 and delayed hospital discharge. Conclusions. Postoperative morbidity as defined by the Post Operative Morbidity Survey can be assessed retrospectively. These data may therefore be easily captured using electronic patient record systems, thereby expanding the potential for bioinformatics approaches to generate new clinical and translational insights into recovery from surgery.


Zerumbone inhibits migration in ESCC via promoting Rac1 ubiquitination.
Zerumbone has been reported to maintain the anti-cancer effects in many malignant cells. However, the effect and mechanism of Zerumbone on esophageal squamous cell carcinomas (ESCC) is rarely investigated. Here we report the inhibitory effect of Zerumbone (hereinafter referred to as ZER) on ESCC migration and the underlying molecular mechanism. ZER could inhibit the migration of human esophageal squamous cancer KYSE-30 cells and KYSE-150 cells. ZER induced Rac1 protein down-regulation in a dose- and time-dependent manner. The reduction of Rac1 protein was crucial for ZER-induced inhibition of cell migration, as Rac1 knockdown could enhance ZER-induced inhibition of cell migration. We further demonstrated that the decrease of Rac1 after ZER treatment is via proteasome-dependent degradation pathway, and ZER treatment drastically enhanced ubiquitination of Rac1, which finally caused Rac1 degradation. Collectively, our results indicated that ZER inhibits cell migration by suppressing Rac1 expression. This suppresion is achieved through promoting Rac1 ubiquitination and degradation. Thus, the study raises the possibility of ZER as a potential drug for ESCC due to its ability to inhibit cell migration.


Metal ion release after hip resurfacing arthroplasty and knee arthroplasty: a retrospective study of one hundred ninety-five cases.
Hip arthroplasty with metal-on-metal bearings like hip resurfacing results in the release of metallic ions. In parallel, like every metallic implant, knee arthroplasty implants undergo passive corrosion. We analyzed blood levels of cobalt and chromium ions in patients who have a hip resurfacing arthroplasty and compared them to patients who have undergone knee arthroplasty at a minimum follow-up of one year. The hypothesis was that there is no difference in the ion release between hip resurfacing and knee arthroplasty. Sixty-three patients who underwent knee arthroplasty were compared to a cohort of 132 patients who underwent hip resurfacing. The blood levels of cobalt and chromium ions were determined preoperatively and at six and 12 months postoperatively and then compared between groups. We analyzed the relationship between ion release and the change in clinical outcome scores (Harris Hip score, Oxford Hip score, Merle D'Aubigné Postel score, Oxford Knee score, International Knee Society score), the BMI, sex, physical activity, implant size and inclination of the acetabular implant (hip resurfacing patients only). Mixed linear models were used to assess the changes in ion blood levels over time. The cobalt blood levels were higher in the first 6 months in the resurfacing group (0.87 ug/L vs 0.67 ug/L; p = 0.011), while it was higher in the knee arthroplasty group at 12 months (1.20 ug/L vs 1.41 ug/L; p = 0.0008). There were no significant differences in chromium levels during the follow-up period. The increase in metal ion release after knee arthroplasty is as high as after hip resurfacing at the one year follow-up. The monitoring of this parameter probably should not be recommended in case of good clinicals outcomes.


Improved model on fluorescence decay in singlet fission materials.
Singlet fission (SF) materials are a kind of promising material for breaking the solar cell efficiency limit. Here we rebuild the four-electron spin Hamiltonian under our coordinate system and present an improved model described by the population evolution equations on fluorescence decay (FD) dynamics that contain several detailed physical processes. The improved model for total random molecular orientation gives a more consistent fitting on the experimental data [G. B. Piland et al., J. Phys. Chem. C, 2013, 117, 1224] about time-resolved FD of amorphous rubrene thin films in the presence of a strong magnetic field. The fitting can reflect the relative rates of the real physical processes. Further on, our results show two kinds of magnetic field effect for the variety of two molecular relative orientations with respect to each other and the magnetic field by investigating the singlet projection and FD dynamics of the system.


Cloning, expression, and characterization of a novel Escherichia coli thioredoxin.
Thioredoxin (Trx) is a small ubiquitous protein that displays different functions mainly via redox-mediated processes. We here report the cloning of a gene (trxC) coding for a novel thioredoxin in Escherichia coli as well as the expression and characterization of its product. The gene encodes a protein of 139 amino acids (Trx2) with a calculated molecular mass of 15.5 kDa. Trx2 contains two distinct domains: an N-terminal domain of 32 amino acids including two CXXC motifs and a C-terminal domain, with the conserved active site, Trp-Cys-Gly-Pro-Cys, showing high homology to the prokaryotic thioredoxins. Trx2 together with thioredoxin reductase and NADPH is an efficient electron donor for the essential enzyme ribonucleotide reductase and is also able to reduce the interchain disulfide bridges of insulin. The apparent Km value of Trx2 for thioredoxin reductase is similar to that of the previously characterized E. coli thioredoxin (Trx1). The enzymatic activity of Trx2 as a protein-disulfide reductase is increased by preincubation with dithiothreitol, suggesting that oxidation of cysteine residues other than the ones in the active site might regulate its activity. A truncated form of the protein, lacking the N-terminal domain, is insensitive to the presence of dithiothreitol, further confirming the involvement of the additional cysteine residues in modulating Trx2 activity. In addition, the presence of the N-terminal domain appears to confer heat sensitivity to Trx2, unlike Trx1. Finally, Trx2 is present normally in growing E. coli cells as shown by Western blot analysis.


Anxiety as a risk factor for cardiovascular disease independent of depression: A narrative review of current status and conflicting findings.
The aim of this paper is to summarise and evaluate the empirical support for the association between anxiety and cardiovascular disease (CVD) and to address challenges related to method and study design. We review results from meta-analyses and more recent findings on the association of anxiety and the risk of CVD. Depression and anxiety are often listed as psychosocial risk markers of CVD, but the role of anxiety as a risk factor for CVD has not received the same evidential support as the effects of depression. Through a narrative review we identified six meta-analyses as well as 15 recent large studies of anxiety and CVD that we summarise. Some of the conflicting findings may be artefacts of study design or population the sample is drawn from. Researchers should take care to be population specific, measurement specific and outcome specific, and to control for comorbid depression.


Trends in Early Prenatal Care Among Women with Pre-Existing Diabetes: Have Income Disparities Changed?
Women with pre-existing diabetes are at high maternal risk for comorbidities and death, particularly when early prenatal care is not received. Low income is a known barrier to early prenatal care. It is unknown whether recent policies to expand access to prenatal care have reduced income disparities. We hypothesized that income disparities would be minimized and that the odds of receipt of first trimester prenatal care among women with pre-existing diabetes would become similar across income strata over time. Using the Colorado birth certificate registry from 2007 to 2014, receipt of prenatal care was assessed retrospectively in 2,497 women with pre-existing diabetes. Logistic regression was used to examine the association between high (>$50,000), medium ($25,000-50,000), and low (<$25,000) income strata and receipt of first trimester prenatal care by birth year, adjusted for demographics. High, medium, and low income represented 29.5%, 19.0%, and 51.5% of the cohort, respectively. Women with high income were more likely to receive first trimester care than women with low income from 2007 [adjusted odds ratio, 95% confidence interval: 2.16 (1.18, 3.96)] through 2013 [1.66 (1.01, 2.73)], but significant differences were no longer observed in 2014 [1.59 (0.89, 2.84)]. The likelihood of receiving first trimester prenatal care was not significantly different between medium- and low-income strata from 2007 [1.07 (0.66, 1.74)] through 2014 [0.77 (0.48, 1.23)]. From 2007 to 2013, women in Colorado with diabetes were more likely to receive early prenatal care if they were in the highest income stratum than in the lowest stratum. In 2014, receipt of first trimester care became equitable across all income strata. Future work should examine national patterns of income with receipt of prenatal care and outcomes among women with pre-existing diabetes.


Isolated tuberculous tenosynovitis of the flexor tendon of the fourth finger of the hand. Case report.
A 21-year-old woman presented with a painful swelling of her palm which prevented her from fully extending her fourth finger. Magnetic resonance imaging showed synovial thickening around the flexor tendon and fluid in the tendon sheath. The mass was excised and histopathological examination showed tuberculosis. She had a six-month course of antituberculous treatment and was perfectly well three years later.


High HIV-1 Genetic Diversity in Patients from Northern Brazil.
The HIV-1 epidemic in Brazil is driven by subtypes B, F1, and C and recombinants forms among those subtypes. The distribution of HIV-1 subtypes, however, may vary across different Brazilian regions and the molecular epidemiologic profile in Northern Brazil remains poorly explored. HIV-1 pol sequences were obtained from 305 patients failing antiretroviral therapy followed at outpatient clinics from five Northern Brazilian states. The most prevalent HIV-1 clade observed in the Northern Brazilian region was subtype B (81%), followed by BF1 recombinants (10%), subtype F1 (4%), subtype C (3%), BC recombinants (2%), and BU recombinants (1%). Although HIV-1 subtype B was the predominant HIV-1 clade in Northern Brazil, its prevalence greatly varies among different states, ranging from 63% in Rondônia to 92% in Acre. Among the 37 HIV-1 recombinant sequences detected in the Northern Brazilian region, nine (24%) displayed a unique recombinant form structure, five (14%) a CRF28/29_BF-like structure, and four (11%) a CRF31_BC-like structure. Two other BF1 recombinant patterns were identified in 16 (43%) and three (8%) samples that may correspond to two potentially new CRFs_BF characteristic of the Northern region. This study reveals that despite the low spatial connectivity with other Brazilian regions, the genetic complexity of the HIV-1 epidemic in Northern Brazil is very high and that the molecular epidemiologic pattern may vary across different northern states, reflecting a complex epidemic with multiple independent viral introductions into this Brazilian region.


Public's and police officers' interpretation and handling of domestic violence cases: divergent realities.
The public's and police officers'interpretation and handling of realistic hypothetical domestic violence cases and their stereotypic views about domestic violence are discussed. A sample of 131 experienced officers, 127 novice officers, and 157 adult laypersons were randomly assigned to read a domestic violence case. Experienced officers were more likely to arrest only the husband than were laypersons or rookie officers even when respondents inferred that the husband was primarily responsible or had used violence before. Experienced officers considered their stereotypic beliefs about battered women's propensity to use self-defense in arriving at their arrest decision whereas laypersons and rookie officers did not. These findings indicate that the public and police officers have not adopted the feminists' message that arrest is the best response to handle all domestic violence cases. Policy implications are discussed.


Is insomnia a perpetuating factor for late-life depression in the IMPACT cohort?
Insomnia and depressive disorders are significant health problems in the elderly. Persistent insomnia is a risk factor for the development of new-onset and recurrent major depressive disorder (MDD). Less clear is whether persistent insomnia may perpetuate MDD andlor dysthymia. The present longitudinal study examines the relationship of insomnia to the continuation of depression in the context of an intervention study in elderly subjects. Data were drawn from Project IMPACT, a multisite intervention study, which enrolled 1801 elderly patients with MDD and/or dysthymia. In the current study, subjects were assigned to an insomnia-status group (Persistent, Intermediate, and No Insomnia) based on insomnia scores at both baseline and 3-month time points. Logistic regressions were conducted to determine whether Persistent Insomnia was prospectively associated with increased risk of remaining depressed and/or achieving a less than 50% clinical improvement at 6 and at 12 months compared with the No Insomnia reference group. The Intermediate Insomnia group was compared with the other 2 groups to determine whether a dose-response relationship existed between insomnia type and subsequent depression. Eighteen primary clinics in 5 states. Older adults (60+) with depression. Overall, patients with persistent insomnia were 1.8 to 3.5 times more likely to remain depressed, compared with patients with no insomnia. The findings were more robust in patients receiving usual care for depression than in patients receiving enhanced care. Findings were also more robust in subjects who had MDD as opposed to those with dysthymia alone. These findings suggest that, in addition to being a risk factor for a depressive episode, persistent insomnia may serve to perpetuate the illness in some elderly patients and especially in those receiving standard care for depression in primary care settings. Enhanced depression care may partially mitigate the perpetuating effects of insomnia on depression.


[Carnosine protects against diabetic nephropathy in rats by activating the AKT/mTOR pathway and restoring autophagy in the renal tissue].
To explore the mechanisms mediating the protective effect of carnosine against nephropathy in rats with diabetes mellitus (DM). Rat models of DM established by high-fat diet feeding and streptozotocin injection were randomized into DM group and 3 treatment groups with daily carnosine treatment at 100, 300, and 900 mg/kg. Body weight and blood glucose level changes of the rats were measured regularly. After the treatment, 24-h urine, serum samples and kidneys of the rats were collected to measure urine volume, urine protein content, blood creatinine, and kidney mass; renal pathology was observed using HE staining, and MDA content and SOD activity in the kidney tissues were detected. Western blotting was performed to detect the protein expressions of p-AKT, AKT, p-mTOR, mTOR, LC3 and p62 in the kidney tissues. Compared with normal control rats, the diabetic rats exhibited dull and wet hair and showed decreased body weight, increased blood glucose, urinary protein content, 24-h urine volume, blood creatinine, and kidney mass with obvious swelling and deformation of the glomeruli, narrowing of the renal tubules, decreased SOD activity and increased MDA content, lowered p-mTOR/mTOR and p-AKT/AKT ratios and increased LC3 Ⅱ/Ⅰ ratio and p62 protein expression in the kidney tissue. The diabetic rats receiving carnosine treatments had dry hair with normal luster and showed increased body weight and slightly decreased blood glucose, urinary protein content, 24-h urine volume, blood creatinine, and kidney mass. The treatment also improved renal pathology, increased SOD activity, decreased MDA content, increased p-mTOR/mTOR and p-AKT/AKT ratios and lowered LC3 Ⅱ/Ⅰ ratio and p62 protein expression in renal tissue of the diabetic rats. Carnosine offers protection against nephropathy in rats with DM possibly by inhibiting oxidative stress, activating the AKT/mTOR pathway, and restoring autophagy in the kidneys.


Light and electron microscopic observations of the life cycle of Sarcocystis orientalis sp. n. in the rat (Rattus norvegicus) and the Malaysian reticulated python (Python reticulatus).
A light and electron microscopic study of Sarcocystis orientalis sp. n. was made. The life cycle of this parasite is in two hosts. Gametogony is in the intestinal epithelial cells of a predator, Python reticulatus. Isospora-like oocysts developed. Sporocysts average 9.1 by 7.7 mum. Rats (Rattus norvegicus) were infected with sporocysts and asexual stages developed. Ten days after infection large zoites (average 7.85 by 2.48 mum) were observed free in peripheral blood and within white blood cells. Small schizonts producing merozoites 2-3 mum long were seen in lung tissue. Tissue cysts developed in skeletal muscle and produced numerous cystozoites (average 5.53 by 1.38 mum). Fine structure was similar to previously described Sarcocystis spp.


Hand contamination of anesthesia providers is an important risk factor for intraoperative bacterial transmission.
We have recently shown that intraoperative bacterial transmission to patient IV stopcock sets is associated with increased patient mortality. In this study, we hypothesized that bacterial contamination of anesthesia provider hands before patient contact is a risk factor for direct intraoperative bacterial transmission. Dartmouth-Hitchcock Medical Center is a tertiary care and level 1 trauma center with 400 inpatient beds and 28 operating suites. The first and second operative cases in each of 92 operating rooms were randomly selected for analysis. Eighty-two paired samples were analyzed. Ten pairs of cases were excluded because of broken or missing sampling protocol and lost samples. We identified cases of intraoperative bacterial transmission to the patient IV stopcock set and the anesthesia environment (adjustable pressure-limiting valve and agent dial) in each operating room pair by using a previously validated protocol. We then used biotype analysis to compare these transmitted organisms to those organisms isolated from the hands of anesthesia providers obtained before the start of each case. Provider-origin transmission was defined as potential pathogens isolated in the patient stopcock set or environment that had an identical biotype to the same organism isolated from hands of providers. We also assessed the efficacy of the current intraoperative cleaning protocol by evaluating isolated potential pathogens identified at the start of case 2. Poor intraoperative cleaning was defined as 1 or more potential pathogens found in the anesthesia environment at the start of case 2 that were not there at the beginning of case 1. We collected clinical and epidemiological data on all the cases to identify risk factors for contamination. One hundred sixty-four cases (82 case pairs) were studied. We identified intraoperative bacterial transmission to the IV stopcock set in 11.5 % (19/164) of cases, 47% (9/19) of which were of provider origin. We identified intraoperative bacterial transmission to the anesthesia environment in 89% (146/164) of cases, 12% (17/146) of which were of provider origin. The number of rooms that an attending anesthesiologist supervised simultaneously, the age of the patient, and patient discharge from the operating room to an intensive care unit were independent predictors of bacterial transmission events not directly linked to providers. The contaminated hands of anesthesia providers serve as a significant source of patient environmental and stopcock set contamination in the operating room. Additional sources of intraoperative bacterial transmission, including postoperative environmental cleaning practices, should be further studied.


Surface curvature as a measure of image texture.
Methods from the theory of surfaces in differential geometry are applied to the gray tone intensity and absorbance surfaces defined by a digital image. In particular, the first fundamental form, the second fundamental form, the two principal curvatures, the Gaussian curvature, and mean curvature from classical differential geometry are presented. New curvatures are introduced which appear to be more appropriate for the purposes of image texture. For each curvature, a texture feature is generated. These features are applied to biological cell nuclei and it is found that they are useful for purposes of discrimination.


Making natural products from renewable feedstocks: back to the roots?
Covering: up to mid-2019 This review highlights the utilization of biomass-derived building blocks in the total synthesis of natural products. An overview over several renewable feedstock classes, namely wood/lignin, cellulose, chitin and chitosan, fats and oils, as well as terpenes, is given, covering the time span from the initial beginning of natural product synthesis until today. The focus is put on the origin of the employed carbon atoms and on the nature of the complex structures that were assembled therefrom. The emerging trend of turning away from petrochemically derived starting materials back to bio-based resources, just as seen in the early days of total synthesis, shall be demonstrated.


A study of the cross-reacting antigens on the intact foot-and-mouth disease virus and its 12S Subunits with antisera against the structural proteins.
Cross-reactions between two strains of foot-and-mouth disease virus (FMDV) belonging to different serotypes (A and O) were studied with intact virus and virus subunits and antisera produced against the isolated structural proteins. Anti-VP1 type O serum showed cross-reactive neutralizing activity, in contrast to the sera raised against intact virus type O, whereas anti-VP1 type A serum only neutralized homologous virus. Anti-VP2, VP3 and VP4 did not show neutralizing activity. In the enzyme-linked immunosorbent assay and radio-immunoassay anti-VP1, -VP2, and -VP3 sera reacted with the 12S virus subunits of both serotypes. No activity was obtained against VP4. Competition experiments with virus subunits of virus type A and O show that anti-VP1 serum is the most type-specific. Anti-VP2 serum is completely cross-reactive, while anti-VP3 serum reacted in an intermediate way. The identical reactions obtained with anti-VP2 sera and the homologous and heterologous virus subunits suggest that the exposed VP2 antigens are identical.


Longitudinal Soft Tissue Changes During Periodontal Ligament-Mediated Immediate Implant Placement with the Root-Membrane Technique.
To assess longitudinal volumetric changes during immediate implant placement with simultaneous intentional retention of the buccal aspect of the root. This study assessed 10 cases drawn from a previously reported cohort that had study casts available pretreatment and at least 2 years after periodontal ligament (PDL)-mediated immediate implant placement. Gypsum casts were scanned using a laser scanner and converted into digital three-dimensional rendered files. The digital casts were superimposed, and semi-automated subtractive assessment was performed via specialized software. Data from 10 patients with a minimum of 3 years follow-up (median follow-up time: 42 months) were analyzed. Each person contributed one implant site in this study. All implants successfully maintained osseointegration during the follow-up period and demonstrated optimal soft tissue stability. Changes during the observation period ranged from 0.19 mm (95% confidence interval [95% CI]: 0.10 to 0.28) in the midfacial region 6 mm apical to the mucosal zenith to -0.06 mm (95% CI: -0.14 to 0.02) at 5 mm apical to the base of the distal papilla. All changes were noninferior to pre-extraction baseline measurements based on a 0.5-mm noninferiority margin. The intentional retention of the buccal aspect of the root with its periodontal apparatus during immediate implant placement led to optimal soft tissue dimensional stability in the esthetic zone. This technique holds promise for clinical application, and further controlled clinical studies are warranted to determine the comparative clinical benefit from the use of this procedure.


Comparative interactomics.
The behavior, morphology and response to stimuli in biological systems are dictated by the interactions between their components. These interactions, as we observe them now, are therefore shaped by genetic variations and selective pressure. Similar to what has been achieved by comparing genome structures and protein sequences, we hope to obtain valuable information about systems' evolution by comparing the organization of interaction networks and by analyzing their variation and conservation. Equally, significantly we can learn whether and how to extend the network information obtained experimentally in well-characterized model systems to different organisms. We conclude from our analysis that, despite the recent completion of several high throughput experiments aimed at the description of complete interactomes, the available interaction information is not yet of sufficient coverage and quality to draw any biologically meaningful conclusion from the comparison of different interactomes. Thus, the transfer of network information obtained from simple organism to evolutionary distant species should be carried out and considered with caution. By using smaller higher-confidence datasets, a larger fraction of interactions is shown to be conserved; this suggests that with the development of more accurate experimental and informatic approaches, we will soon be in the position to study the network evolution.


18F-Fluoroestradiol Tumor Uptake Is Heterogeneous and Influenced by Site of Metastasis in Breast Cancer Patients.
Heterogeneity of estrogen receptor (ER) expression in breast cancer is recognized. However, knowledge about varying expression across metastases and surrounding normal tissue in patients is scarce. We therefore analyzed 16α-18F-fluoro-17β-estradiol (18F-FES) PET to assess ER expression heterogeneity. Methods:18F-FES PET on accredited PET/CT camera systems performed in patients with ER-positive metastatic breast cancer November 2009-December 2014 was analyzed. Lesions with an SUVmax 1.5 or more were considered ER-positive, but liver lesions were excluded given high background liver signal. CT lesions with a diameter 10 mm or more were included. We used multilevel linear-mixed models to evaluate determinants of 18F-FES uptake. Cluster analysis was performed with different imaging features per patient as input variables. Results: In 91 patients, 1,617 metastases in bone (78%), lymph node (15%), lung (4%), or liver (2%) were identified by CT (11.2%), PET (56.6%), or both (32.2%). Median tumor uptake varied greatly between patients (SUVmax, 0.54-14.21). 18F-FES uptake in bone metastases was higher than in lymph node and lung metastases (geometric mean SUVmax, 2.61 [95% confidence interval (CI), 2.31-2.94] vs. 2.29 [95% CI, 2.00-2.61; P < 0.001] vs. 2.23 [95% CI, 1.88-2.61; P = 0.021]), respectively. Cluster analysis identified 3 subgroups of patients characterized by particular metastatic sites and 18F-FES PET/CT features. SUVmax in surrounding normal tissue, highest in the bones, varied per patient (range, 0.7-3.3). Conclusion:18F-FES uptake is heterogeneous in tumor and normal tissue and influenced by anatomic site. Different patterns can be distinguished, possibly identifying biologically relevant ER-positive metastatic breast cancer patient subgroups.


Perspectives on the Current State of Bioprinted Skin Substitutes for Wound Healing.
Human skin is particularly vulnerable to external damaging influences such as irradiation, extreme temperatures, chemical trauma, and certain systemic diseases, which reduce the skin's capacity for regeneration and restoration and can possibly lead to large-scale skin defects. To restore skin continuity in severe cases, surgical interventions such as the transplantation of autologous tissue are needed. Nevertheless, the coverage of larger skin defects caused by severe third-grade burns or extensive irradiation therapy is limited due to the depletion of uninjured autologous tissue. In such cases, many of the patient's epidermal cells can become available using biofabricated skin grafts, thereby restoring the skin's vital functions. Given the limited availability of autologous skin grafts for restoring integrity in large-scale defects, using bioprinted constructs as skin graft substitutes could offer an encouraging therapeutic alternative to conventional therapies for large-scale wounds, such as the transplantation of autologous tissue. Using layer-by-layer aggregation or volumetric bioprinting, inkjet bioprinting, laser-assisted bioprinting, or extrusion-based bioprinting, skin cells are deposited in a desired pattern. The resulting constructs may be used as skin graft substitutes to accelerate wound healing and reconstitute the physiological functions of the skin. In this review, we aimed to elucidate the current state of bioprinting within the context of skin tissue engineering and introduce and discuss different bioprinting techniques, possible approaches and materials, commonly used cell types, and strategies for graft vascularization for the production of bioprinted constructs for use as skin graft substitutes.


[Use of phenomenon of adsorption decrease in solid cohesion for remote lithotripsy (experimental study)].
The possibility of using the phenomenon of adsorption decrease in solid cohesion well known in the colloid chemistry as Rebinder effect for nephrolith remote destruction was studied. Sorption properties of urine components in healthy persons and those suffering from urolithiasis were compared. The number of synthetic surfactants were studied according to the values of bordering moistening angle and efficiency of remote destruction of firm nephrolithes in vitro. The bordering moistening angle measurements have shown that the urine of healthy persons demonstrates higher surface activity compared with the urine of those suffering from urolithiasis. The correlation between the value of bordering moistening angle for the liquid into which the urolithiasis was immersed and the destruction efficiency in vitro in that media was established. The efficiency of nephrolith destruction was found to increase in the water solution of chlorhexidine bigluconate.


Activation of human neutrophils by mastoparan. Reorganization of the cytoskeleton, formation of phosphatidylinositol 3,4,5-trisphosphate, secretion up-regulation of complement receptor type 3 and superoxide anion production are stimulated by mastoparan.
In human neutrophils, mastoparan induced rapid F-actin polymerization which was followed by a slow and sustained depolymerization to below the initial F-actin content. Incubation of neutrophils with pertussis toxin inhibited mastoparan-stimulated actin polymerization; however it did not prevent sustained depolymerization of F-actin. Analyses of phospholipids performed in parallel revealed that mastoparan stimulated rapid formation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) and consumption of phosphatidylinositol 4,5-bisphosphate (PIP2). Pertussis toxin treatment blocked mastoparan-induced formation of PIP3. Furthermore, mastoparan stimulated the release of N-acetylglucosaminidase from primary granules. Cytochalasin B enhanced mastoparan-stimulated secretion. Mastoparan triggered superoxide radical production in a cytochalasin B-sensitive manner and induced complement type 3 receptor (CR3) up-regulation.


Striatal expression of GDNF and differential vulnerability of midbrain dopaminergic cells.
Glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-beta superfamily that when exogenously administrated exerts a potent trophic action on dopaminergic (DA) cells. Although we know a lot about its signalling mechanisms and pharmacological effects, physiological actions of GDNF on the adult brain remain unclear. Here, we have used morphological and molecular techniques, and an experimental model of Parkinson's disease in rats, to investigate whether GDNF constitutively expressed in the adult mesostriatal system plays a neuroprotective role on midbrain DA cells. We found that although all midbrain DA cells express both receptor components of GDNF (GFRalpha1 and Ret), those in the ventral tegmental area (VTA) and rostromedial substantia nigra (SNrm) also contain GDNF but not GDNFmRNA. The levels of GDNFmRNA are significantly higher in the ventral striatum (vSt), the target region of VTA and SNrm cells, than in the dorsal striatum (dSt), the target region of DA cells in the caudoventral substantia nigra (SNcv). After fluoro-gold injection in striatum, VTA and SNrm DA cells show triple labelling for tyrosine hydroxylase, GDNF and fluoro-gold, and after colchicine injection in the lateral ventricle, they become GDNF-immunonegative, suggesting that GDNF in DA somata comes from their striatal target. As DA cells in VTA and SNrm are more resistant than those in SNcv to intracerebroventricular injection of 6-OHDA, as occurs in Parkinson's disease, we can suggest that the fact that they project to vSt, where GDNF expression is significantly higher than in the dSt, is a neuroprotective factor involved in the differential vulnerability of midbrain DA neurons.


Controlled synthesis of organic nanophotonic materials with specific structures and compositions.
Organic nanomaterials have drawn great interest for their potential applications in high-speed miniaturized photonic integration due to their high photoluminescence quantum efficiency, structural processability, ultrafast photoresponse, and excellent property engineering. Based on the rational design on morphological and componential levels, a series of organic nanomaterials have been controllably synthesized in recent years, and their excitonic/photonic behaviors has been fine-tuned to steer the light flow for specific optical applications. This review presents a comprehensive summary of recent breakthroughs in the controlled synthesis of organic nanomaterials with specific structures and compositions, whose tunable photonic properties would provide a novel platform for multifunctional applications. First, we give a general overview of the tailored construction of novel nanostructures with various photonic properties. Then, we summarize the design and controllable synthesis of composite materials for the modulation of their functionalities. Subsequently, special emphasis is put on the fabrication of complex nanostructures towards wide applications in isolated photonic devices. We conclude with our personal viewpoints on the development directions in the novel design and controllable construction of organic nanomaterials for future applications in highly integrated photonic devices and chips.


Computer-based identification of a novel LIMK1/2 inhibitor that synergizes with salirasib to destabilize the actin cytoskeleton.
Neurofibromin regulates cell motility via three distinct GTPase pathways acting through two different domains, the Ras GTPase-activating protein-related domain (GRD) and the pre-GRD domain. First, the GRD domain inhibits Ras-dependent changes in cell motility through the mitogen activated protein cascade. Second, it also regulates Rho-dependent (Ras-independent) changes by activating LIM kinase 2 (LIMK2), an enzyme that phosphorylates and inactivates cofilin (an actin-depolymerizing factor). Third, the pre-GRD domain acts through the Rac1 GTPase, that activate the P21 activated kinase 1 (PAK1)-LIMK1-cofilin pathway. We employed molecular modeling to identify a novel inhibitor of LIMK1/2. The active sites of an ephrin-A receptor (EphA3) and LIMK2 showed marked similarity (60%). On testing a known inhibitor of EphA3, we found that it fits to the LIMK1/2-ATP binding site and to the latter's substrate-binding pockets. We identified a similar compound, T56-LIMKi, and found that it inhibits LIMK1/2 kinase activities. It blocked the phosphorylation of cofilin which led to actin severance and inhibition of tumor cell migration, tumor cell growth, and anchorage-independent colony formation in soft agar. Because modulation of LIMK by neurofibromin is not affected by the Ras inhibitor Salirasib, we examined the combined effect of Salirasib and T56-LIMKi each of which can affect cell motility by a distinct pathway. We found that their combined action on cell proliferation and stress-fiber formation in neurofibromin-deficient cells was synergistic. We suggest that this drug combination may be developed for treatment of neurofibromatosis and cancer.


The effect of magnetic fields on wound healing: experimental study and review of the literature.
Magnets are purported to aid wound healing despite a paucity of scientific evidence. The purpose of this study was to evaluate the effect of static magnetic fields on cutaneous wound healing in an animal model. The literature was reviewed to explore the historical and scientific basis of magnet therapy and to define its current role in the evidence-based practice of plastic surgery. Standardized wounds were created on the backs of 33 Sprague-Dawley rats, which were divided into 3 groups with either a 23 gauss magnet (group 1), a sham magnet (group 2), or nothing (group 3) positioned over the wound. The rate of wound closure by secondary intention was compared between the groups. Literature review was conducted through searches of PubMed and Ovid databases for articles pertinent to magnets and wound healing. Wounds in the magnet group healed in an average of 15.3 days, significantly faster than those in either the sham group (20.9 days, P = .006) or control group (20.3 days, P < .0001). There was no statistically significant difference between the sham and control groups (P = .45). An externally applied, low-power, static magnetic field increases the rate of secondary healing. Review of the literature reveals conflicting evidence regarding the use of magnetic energy to aid the healing of bone, tendon, and skin. Level I studies are lacking and difficult to execute but are needed to define conclusively the role of magnets in clinical practice.


Rectification of protein translocation in truncated pyramidal nanopores.
Solid-state nanopore technology presents an emerging single-molecule-based analytical tool for the separation and analysis of nanoparticles. Different approaches have been pursued to attain the anticipated detection performance. Here, we report the rectification behaviour of protein translocation through silicon-based truncated pyramidal nanopores. When the size of translocating proteins is comparable to the smallest physical constriction of the nanopore, the frequency of translocation events observed is lower for proteins that travel from the larger to the small opening of the nanopore than for those that travel in the reverse direction. When the proteins are appreciably smaller than the nanopore, an opposite rectification in the frequency of translocation events is evident. The maximum rectification factor achieved is around ten. Numerical simulations reveal the formation of an electro-osmotic vortex in such asymmetric nanopores. The vortex-protein interaction is found to play a decisive role in rectifying the translocation in terms of polarity and amplitude. The reported phenomenon can be potentially exploitable for the discrimination of various nanoparticles.


Elastic network models for RNA: a comparative assessment with molecular dynamics and SHAPE experiments.
Elastic network models (ENMs) are valuable and efficient tools for characterizing the collective internal dynamics of proteins based on the knowledge of their native structures. The increasing evidence that the biological functionality of RNAs is often linked to their innate internal motions poses the question of whether ENM approaches can be successfully extended to this class of biomolecules. This issue is tackled here by considering various families of elastic networks of increasing complexity applied to a representative set of RNAs. The fluctuations predicted by the alternative ENMs are stringently validated by comparison against extensive molecular dynamics simulations and SHAPE experiments. We find that simulations and experimental data are systematically best reproduced by either an all-atom or a three-beads-per-nucleotide representation (sugar-base-phosphate), with the latter arguably providing the best balance of accuracy and computational complexity.


Development of a Web-Based Health Care Intervention for Patients With Heart Disease: Lessons Learned From a Participatory Design Study.
The use of telemedicine technologies in health care has increased substantially, together with a growing interest in participatory design methods when developing telemedicine approaches. We present lessons learned from a case study involving patients with heart disease and health care professionals in the development of a personalized Web-based health care intervention. We used a participatory design approach inspired by the method for feasibility studies in software development. We collected qualitative data using multiple methods in 3 workshops and analyzed the data using thematic analysis. Participants were 7 patients with diagnosis of heart disease, 2 nurses, 1 physician, 2 systems architects, 3 moderators, and 3 observers. We present findings in 2 parts. (1) Outcomes of the participatory design process: users gave valuable feedback on ease of use of the platforms' tracking tools, platform design, terminology, and insights into patients' monitoring needs, information and communication technologies skills, and preferences for self-management tools. (2) Experiences from the participatory design process: patients and health care professionals contributed different perspectives, with the patients using an experience-based approach and the health care professionals using a more attitude-based approach. The essential lessons learned concern planning and organization of workshops, including the finding that patients engaged actively and willingly in a participatory design process, whereas it was more challenging to include and engage health care professionals.


Adiabatic Solid Effect.
The solid effect (SE) is a two spin dynamic nuclear polarization (DNP) mechanism that enhances the sensitivity in NMR experiments by irradiation of the electron-nuclear spin transitions with continuous wave (CW) microwaves at ω0S ± ω0I, where ω0S and ω0I are electron and nuclear Larmor frequencies, respectively. Using trityl (OX063), dispersed in a 60/40 glycerol/water mixture at 80 K, as a polarizing agent, we show here that application of a chirped microwave pulse, with a bandwidth comparable to the EPR line width applied at the SE matching condition, improves the enhancement by a factor of 2.4 over the CW method. Furthermore, the chirped pulse yields an enhancement that is ∼20% larger than obtained with the ramped-amplitude NOVEL (RA-NOVEL), which to date has achieved the largest enhancements in time domain DNP experiments. Numerical simulations suggest that the spins follow an adiabatic trajectory during the polarization transfer; hence, we denote this sequence as an adiabatic solid effect (ASE). We foresee that ASE will be a practical pulsed DNP experiment to be implemented at higher static magnetic fields due to the moderate power requirement. In particular, the ASE uses only 13% of the maximum microwave power required for RA-NOVEL.


Wall correction factors for calibration of plane-parallel ionization chambers with high-energy photon beams.
Most dosimetry protocols recommend that calibration of plane-parallel ionization chambers be performed in an electron beam of sufficiently high energy by comparison with cylindrical chambers. For various plane-parallel chambers, the 1997 IAEA TRS-381 protocol includes an overall perturbation factor pQ for electron beams, a wall correction factor p(wall) for a 60Co beam and the product of two wall corrections k(att)k(m) for 60Co in-air calibration. The recommended values of p(wall) for plane-parallel chambers, however, are limited to certain phantom materials and a 60Co beam, and are not given for other phantom materials and x-ray beams. In this work, the p(wall) values of the commercially available NACP, PTW/Markus and PTW/Roos plane-parallel chambers in a solid water phantom have been determined with 60Co and 4 and 10 MV photon beams. The k(att)k(m) values for the NACP and PTW/Markus chambers have also been obtained. The wall correction factors p(wall) and k(att)k(m) have been determined by intercomparison with a calibrated Farmer chamber. The average value of p(wall) for these plane-parallel chambers was 1.005 +/- 0.1% (1 SD) for 60Co beams and 1.007 +/- 0.2% (1 SD) for both 4 MV and 10 MV photons. The k(att)k(m) values for the NACP and PTW/Markus chambers were about 1.5% lower than other published data.


Early coagulopathy in children with isolated blunt head injury is associated with mortality and poor neurological outcomes.
Traumatic brain injury (TBI) is the leading cause of long-term disability and death in children and adolescents globally. Long-term adverse outcomes, including physical, cognitive, and behavioral sequelae, have been reported after TBI in a significant number of pediatric patients. In this study the authors sought to investigate the epidemiology of TBI-associated coagulopathy and its association with mortality and poor neurological outcome in a pediatric population with isolated moderate to severe blunt head injury treated at the authors' institution. This retrospective study was conducted in the children's emergency department between January 2010 and December 2016. Children < 18 years old who presented with isolated moderate to severe blunt head injury were included in the study. The authors collected data on patient demographics, clinical presentation, and TBI management. Outcomes studied were death and poor neurological outcome defined by a score of < 7 (death, moderate to severe neurological disability) at 6 months postinjury on the pediatric version of the Glasgow Outcome Scale-Extended (GOS-E Peds). In 155 pediatric patients who presented with isolated moderate to severe blunt head injury, early coagulopathy was observed in 33 (21.3%) patients during the initial blood investigations done in the emergency department. The mean (SD) age of the study group was 7.03 (5.08) years and the predominant mechanism of injury was fall from height (65.2%). The median Abbreviated Injury Scale of the head (AIS head) score was 4 and the median GCS score was 13 (IQR 12-15). TBI-associated coagulopathy was independently associated with GOS-E Peds score < 7 (p = 0.02, adjusted OR 6.07, 95% CI 1.32-27.83). The overall mortality rate was 5.8%. After adjusting for confounders, only AIS head score and hypotension at triage remained significantly associated with TBI-associated coagulopathy. TBI-associated coagulopathy was independently associated with GOS-E Peds score < 7 at 6 months postinjury. Larger prospective studies are needed to investigate the use of TBI-associated coagulopathy to prognosticate these critical clinical outcomes.


Modulation of collagen production by fibroblasts. Effects of chronic exposure to agonists that increase intracellular cyclic AMP.
Cultured human lung fibroblasts were evaluated for their responsiveness to isoprenaline (isoproterenol) or prostaglandin E2 before and after chronic incubation with the agonist. Cells incubated for 6 h with either agonist were suppressed in terms of collagen production and exhibited increased intracellular cyclic AMP. Cells incubated for 72 h with the agonist and then re-challenged for 6 h with the same agonist did not demonstrate suppressed collagen production or increased cyclic AMP. Cells incubated for 72 h with isoprenaline still responded to prostaglandin E2 when challenged for 6 h; however, when the order of agonist exposure was reversed, cells incubated with prostaglandin E2 did not respond to a challenge by isoprenaline. If cells were allowed to recover for 48 h without the agonist after a 72 h chronic incubation, they recovered their responsiveness to the agonist. The results indicate that, although cultured fibroblasts may become desensitized to one agonist, they may retain their sensitivity to a second agonist and chronic suppression of collagen production may be achieved by alternate exposure to isoprenaline and prostaglandin E2.


A new 2-alkylhydroquinone glucoside from Phagnalon saxatile (L.) Cass.
A new 2-alkylhydroquinone glucoside, 1-O-β-d-glucopyranosyl-1,4-dihydroxy-2-((E) 2-oxo-3-butenyl)benzene (1), in addition to nine known compounds were isolated from the aerial parts of Phagnalon saxatile (L.) Cass. (Asteraceae). Their structures were identified based on spectroscopic methods including 1D and 2D NMR, mass spectrometry (HR-ESI-MS), UV spectral analyses and by comparison with literature data. The cytotoxic activity of three isolated compounds (1-3) was evaluated against fibrosarcoma (HT1080), human lung cancer (A549) and breast cancer (MCF7) cell lines.


The multideterminant model of renal disease in a remote Australian Aboriginal population in the context of early life risk factors: lower birth weight, childhood post-streptococcal glomerulonephritis, and current body mass index influence levels of albuminuria in young Aboriginal adults.
Australian Aborigines in remote areas have very high rates of kidney disease, which is marked by albuminuria. We describe a "multihit" model of albuminuria in young adults in one remote Aboriginal community. Urinary albumin/creatinine ratios (ACR) were measured in all subjects who volunteered to participate in a community-wide health screen. Subjects for this study were young adults who had birth weights recorded and whose medical records were inspected for a history of post-streptococcal glomerulonephritis (PSGN). Urine ACR levels were evaluated in the context of birth weights, PSGN history and current BMI. 580 subjects (335 males and 245 females) who were aged 18 - 39 years at time of screening and qualified for inclusion. 26% of subjects had birth weights of < 2.5 kg, and the median birth weight was 2.8 kg. 23% of subjects had a remote history of PSGN, all 3 or more years earlier. Median BMI for the group was 21 kg/m2. Urine ACR levels exceeded the microalbuminuria threshold of 3.4 g/mol in 35.5% of subjects. Birth weight (inversely), remote PSGN, and current BMI were all independent predictors of ACR levels. Median levels of ACR were lowest in those with birth weights ≥ 2.5 kg, and no history of PSGN, intermediate in those with either birth weights < 2.5 kg or a history of PSGN, and highest in those with both low birth weights and a PSGN history. ACR levels were higher in those with BMIs above the median values, most notably in those with lower birth weights or a PSGN history or both. Much of the great excess of disease in this population is explained by high rates of the early life risk factors, low birth weight and PSGN. Their effects are expressed through amplification of ACR in the context of increasing age, and are further moderated by levels of current body size. Both early life risk factors are potentially modifiable.


The Epidemiology of Violent Deaths in Chile between 2001 and 2018: Prevalence, Trends, and Correlates.
Despite its enormous health and social burden, there are limited published studies describing the epidemiology of violent deaths in Chile. We described violent mortality rate trends in Chile between 2001 and 2018, its current spatial distribution and ecological level correlates. A population-based study using publicly accessible data. We calculated age-adjusted mortality rates per 100,000 persons for sex, age, intention, and mechanism of death. Next, we used linear regression to estimate time trends for sex and intention. We then employed hierarchical Poisson analyses to model the spatial distribution across 345 municipalities and the influence of six ecological level variables. The average rate of violent death in Chile between 2001 and 2018 was 15.9 per 100,000 people, with the majority (70.3%) of these attributed to suicide. Suffocation was the most common mechanism of death for suicide (82.3%) and cut/pierce for homicide (43.1%), followed by firearm (33.2%). Violent deaths are trending downward in Chile across all categories except suicides by women, which have remained stable. Poverty rates and urban population were positively associated with violent mortality rates. Although violence-related deaths seem to be decreasing, disparities across gender, age group, and geographic location may have continuing effects on mortality rates.


[Bone mass measurement in pediatrics].
The methodology of the bone mineral measurement from childhood through adolescence contains a few problems. Continuously growing child shows continuous enlargement of the bone and the difference in bone size exerts ineligible effects on the DXA value. Therefore, we should be careful to evaluate the value from the point of this view. This manuscript overviewed normal bone growth and problems in bone mineral assessment during childhood and adolescence.


Human lymphocyte surface immunoglobulin capping. Normal characteristics and anomalous behavior of chronic lymphocytic leukemic lymphocytes.
The phenomenon of redistribution of surface membrane immunoglobulin (Ig) components (capping) has been well described in mouse lymphoid cells. The characteristics of this process in human lymphocytes are less clear. This study characterizes the phenomenon of surface membrane Ig redistribution of normal and chronic lymphocytic leukemia (CLL) lymphocytes with the use of fluoroscein-labeled anti-Ig sera. Normal lymphocytes underwent rapid cap formation after incubation with anti-Ig serum in the cold and subsequent rewarming. The morphology was characteristic with aggregation over the pole of the cell opposite the nucleus and over the uropod when present. The process was energy dependent but independent of protein synthesis, and could be inhibited by vincristine, vinblastine, and colchicine but not by cytochalasin B. CLL cells, on the other hand, though showing fluorescent complex aggregation on the surface, rarely demonstrated unidirectional movement of these aggregates to form a cap. Cap formation in these cells could not be stimulated by supplementing the energy source or protein concentration of the medium nor by adding glutamic acid which could partially reverse the vincristine and vinblastine inhibition of normal capping. The failure of agents which inhibit motility to inhibit capping of the normal lymphocytes suggests that active locomotion is not a direct prerequisite for capping. The results also suggest the involvement of microtubules in normal capping and the possibility that abnormal membrane structure or microtubular function could explain the failure of CLL cells to behave normally in this regard. The role of this cellular defect in the immune deficiencies exhibited by many patients with CLL, however, is not established.


The feasibility of an innovative GP-physiotherapist partnership to identify and manage chronic obstructive pulmonary disease (INTEGRATED): study protocol.
Chronic obstructive pulmonary disease (COPD) contributes significantly to mortality, hospitalisations and health care costs worldwide. There is evidence that the detection, accurate diagnosis and management of COPD are currently suboptimal in primary care. Physiotherapists are well-trained in cardiorespiratory management and chronic care but are currently underutilised in primary care. A cardiorespiratory physiotherapist working in partnership with general practitioners (GPs) has the potential to improve quality of care for people with COPD. A prospective pilot study will test the feasibility of an integrated model of care between GPs and physiotherapists to improve the diagnosis and management of people with COPD in primary care. Four general practices will be selected to work in partnership with four physiotherapists from their local health district. Patients at risk of developing COPD or those with a current diagnosis of COPD will be invited to attend a baseline assessment with the physiotherapist, including pre- and post-bronchodilator spirometry to identify new cases of COPD or confirm a current diagnosis and stage of COPD. The intervention for those with COPD will involve the physiotherapist and GP working in partnership to develop and implement a care plan involving the following tailored to patient need: referral to pulmonary rehabilitation (PR), physical activity counselling, medication review, smoking cessation, review of inhaler technique and education. Process outcomes will include the number of people invited and reviewed at the practice, the proportion with a new diagnosis of COPD, the number of patients eligible and referred to PR and the number who attended PR. Patient outcomes will include changes in symptoms, physical activity levels, smoking status and self-reported exacerbations. If feasible, we will test the integration of physiotherapists within the primary care setting in a cluster randomised controlled trial. If the model improves health outcomes for the growing numbers of people with COPD, then it may provide a GP-physiotherapist model of care that could be tested for other chronic conditions. ANZCTR, ACTRN12619001127190. Registered on 12 August 2019-retrospectively registered.


Extracellular matrix domain formation as an indicator of chondrocyte dedifferentiation and hypertrophy.
Cartilage injury represents one of the most significant clinical conditions. Implantation of expanded autologous chondrocytes from noninjured compartments of the joint is a typical strategy for repairing cartilage. However, two-dimensional culture causes dedifferentiation of chondrocytes, making them functionally inferior for cartilage repair. We hypothesized that functional exclusion of dedifferentiated chondrocytes can be achieved by the selective mapping of collagen molecules deposited by chondrogenic cells in a three-dimensional environment. Freshly isolated and in vitro expanded human fetal or adult articular chondrocytes were cultured in a thermoreversible hydrogel at density of 1 × 10(7) cells/mL for 24 h. Chondrocytes were released from the gel, stained with antibodies against collagen type 2 (COL II) or COL I or COL X and sorted by fluorescence activated cell sorting. Imaging flow cytometry, immunohistochemistry, quantitative polymerase chain reaction, and glycosaminoglycan (GAG) assays were performed to evaluate the differences between COL II domain forming and COL II domain-negative cells. Freshly dissected periarticular chondrocytes robustly formed domains that consisted of the extracellular matrix surrounding cells in the hydrogel as a capsule clearly detectable by imaging flow cytometry (ImageStream) and confocal microscopy. These domains were almost exclusively formed by COL II. In contrast to that, a significant percentage of freshly isolated growth plate pre-hypertrophic and hyperdrophic chondrocytes deposited matrix domains positive for COL II, COL I, and COL X. The proportion of the cells producing COL II domains decreased with the increased passage of in vitro expanded periarticular fetal or adult articular chondrocytes. Sorted COL II domain forming cells deposited much higher levels of COL II and GAGs in pellet assays than COL II domain-negative cells. COL II domain forming cells expressed chondrogenic genes at higher levels than negative cells. We report a novel method that allows separation of functionally active chondrogenic cells, which deposit high levels of COL II from functionally inferior dedifferentiated cells or hypertrophic chondrocytes producing COL X. This approach may significantly improve current strategies used for cartilage repair.


Treatment and detection of ALK-rearranged NSCLC.
The recent approval of crizotinib for the treatment of anaplastic lymphoma kinase (ALK)-rearranged advanced non-small cell lung cancer (NSCLC) in the US and other countries has provoked intense interest in ALK rearrangements as oncogenic drivers, and promises to revolutionise the way in which NSCLC is diagnosed and treated. Here, we review clinical data to date for the use of crizotinib to treat patients with advanced, ALK-positive NSCLC and consider issues surrounding the detection of ALK-positivity including the use of fluorescence in situ hybridisation and the other potential techniques available, and their suitability for ALK screening. We also discuss the emergence of resistance to crizotinib therapy and the range of other ALK inhibitors currently in development.


Conductance studies on complex formation between c-methylcalix[4]resorcinarene and titanium (III) in acetonitrile-H₂O binary solutions.
Calixresorcinarenes have proved to be unique molecules for molecular recognition via hydrogen bonding, hydrophobic and ionic interactions with suitable substrates such as cations. The study of the interactions involved in the complexation of different cations with calixresorcinarenes in solvent mixtures is important for a better understanding of the mechanism of biological transport, molecular recognition, and other analytical applications. This article summarizes different aspects of the complexes of the Ti(3+) metal cation with c-methylcalix[4]resorcinarene (CMCR) as studied by conductometry in acetonitrile (AN)-water (H₂O) binary mixtures at different temperatures. Conductance data show that the metal cation/ligand (ML) stoichiometry of the complexes in solution is 1:1 in all cases. Non-linear behaviour was observed for the variation of logKf of the complexes vs. the composition of the binary solvent mixtures. Selectivity of CMCR for the Ti(3+) cation is sensitive to solvent composition; in some cases and at certain compositions of the mixed solvent systems, the selectivity order is changed. Values of thermodynamic parameters (ΔH(c)(0), ΔS(c)(0)) for formation of the CMCR-Ti(3+) complexes in AN-H₂O binary systems were obtained from the temperature dependence of stability constants, and the results show that the thermodynamics of complexation reactions are affected by the nature and composition of the mixed solvents.


Comparative analysis of the pivotal studies of extended half-life recombinant FVIII products for treatment of haemophilia A.
The need to reduce the burden of injections, and improve adherence and clinical outcomes in haemophilia A led to the development of recombinant FVIII products endowed with an extended plasma half-life (EHL-rFVIII) in comparison with standard half-life products (SHL-rFVIII). Lack of head-to-head studies makes difficult to grasp the relative value of each treatment option. We conducted a combined evaluation of the individual pivotal trials in order to assess between-product differences regarding the reported efficacy results and FVIII consumption. We evaluated 4 EHL-rFVIII products available to treat patients with haemophilia A without inhibitors and also a SHL-rFVIII as a comparator. In the frame of these clinical studies, all the EHL-rFVIII products showed a decrease in the injection burden coupled with good clinical efficacy, even though there were between-product differences in terms of reduction in injection frequencies. Further, between-product differences in terms of weekly/yearly consumption of rFVIII expressed in IU/Kg were identified, suggesting a different economic impact for the different EHL-rFVIII products in the context of comparable clinical efficacy. The present findings based upon the review of pivotal studies done in the frame of a highly selected clinical scenario should be integrated with real-life data.


Visual acuity in premature infants.
To measure grating visual acuity in premature infants and compare it with that in full-term infants. The visual acuity of 73 premature and 73 full-term infants was tested at 6 months of age by the Teller Acuity Card procedure. All premature infants had undergone indirect funduscopy for the detection of retinopathy of prematurity (ROP). Seven infants had developed ROP. The mean gestational age of the premature infants was 33 +/- 1.4 weeks as compared with 39.9 +/- 0.9 weeks in the full-term infants. The mean birth weights of the 2 groups were 1,906 +/- 412 and 3,244 +/- 420 g, respectively. Impaired binocular visual acuity was found in 53.4% of the premature infants, but in only 11% of the full-term infants (p < 0.0001). Impaired monocular visual acuity was found in 13.7% of the premature infants as compared with 2.7% of the full-term infants. Within the premature infant group, monocular visual acuity was impaired in 42.9% of those with ROP and in 10.6% of those without ROP (p = 0.0497). Pathological refraction was found in 33.3% of the prematures without ROP and in 14.3% of the prematures with ROP. This difference was not statistically significant. Visual acuity of preterm infants was not different from full-term infants when examined at 6 months of postconceptual age. Both monocular and binocular visual acuities as measured by the Teller Acuity Cards are worse in premature infants than in full-term infants at the same chronological age. Poor visual acuity in premature infants can be attributed mainly to immaturity of the visual system.


Comparison between platelet rich fibrin as space filling material versus xenograft and alloplastic bone grafting materials in immediate implant placement: a randomized clinical trial.
This study aimed to compare the efficacy of different gap filling materials in immediate implant in anterior and premolar regions of maxilla. Thirty-six implants were inserted in patients seeking for replacement of non-restorable maxillary anterior and premolar teeth (esthetic zone) by immediate implant. Patients were randomly distributed into three equal groups, twelve implants in each group. Group 1 received Platelet Rich Fibrin (PRF) into the jumping distance, Group 2 received Xenograft into the jumping distance and Group 3 received Alloplastic bone grafting material into the jumping distance. Implant stability by measuring the changes in Resonance Frequency Analysis (RFA), peri-implant pocket depth, marginal bone loss and changes in buccal bone thickness were evaluated during follow up periods. All the clinical and radiographic data were subjected to statistical analysis by One Way ANOVA test and the Post Hoc Tukey test. This study involved 19 female patients and 17 male patients who received 36 dental implants. There was no significant difference between the study groups regarding implant stability, peri-implant pocket depth and palatal bone loss, while there was a significant difference between PRF Group (Group 1) and the other Groups regarding buccal bone loss and changes in buccal bone thickness. PRF can be used as a gap filling material in conjunction with immediate implant placement, but other bone grafting materials give superior result regarding buccal bone loss and changes in buccal bone thickness. The study was listed on www. gov with registration number (NCT05878392) on 26/05/2023. The Institutional Review Board (IRB) of the Faculty of Dentistry, Mansoura University, Mansoura, Egypt, approved the current study in compliance with the seventh revision of the Helsinki Declaration in 2013 (A0103023OS).