Cell and tissue therapy regulation: worldwide status and harmonization.
Rapid developments in scientific and technological aspects in stem cell biology and tissue engineering have led to the increased use of human cells and tissues for the treatment of various diseases and injuries. The regulatory environment for CTT products is rapidly evolving and drug regulatory agencies are working towards establishment of a risk-based system with some common features. Various drug regulatory agencies in many countries/regions have implemented regulatory controls in the last few years. This article will highlight some of works done till date to regulate CTT products in Australia, Canada, Europe, Japan, Korea, Singapore and United States of America.


Molecular characterization of the Candida albicans LYS5 gene and site-directed mutational analysis of the PPTase (Lys5p) domains for lysine biosynthesis.
The LYS2 and LYS5 genes of the pathogenic yeast Candida albicans are required for the alpha-aminoadipate reductase (AAR) reaction in the lysine biosynthetic pathway. The LYS2 encodes an apo-AAR (Lys2p) and the LYS5 encodes a phosphopantetheinyl transferase (PPTase) for the post-translational activation of AAR. Our cloned C. albicans LYS5 gene encodes a 38.4 kDa PPTase which is 27% identical and 43% similar to the Saccharomyces cerevisiae Lys5p. Sequence alignment of Lys5p with other PPTases reveals highly conserved putative PPTase domains including the Core 3, WXXKESXXK (residues 194-202). Recombinant Lys5p expressed in Escherichia coli activates C. albicans Lys2p for the AAR activity and also activates AARs from S. cerevisiae and to a lesser extent Schizosaccharomyces pombe. Site-directed mutational analyses reveal glutamic acid 198 in the Lys5p Core 3 as essential for the activation of recombinant Lys2p AAR activity. Other conserved amino acids were also analyzed for their influence on Lys5p PPTase activity. Our results demonstrate cloning of the LYS5 gene, expression of Lys5p, in vitro Lys2p activation model and characterization of the functional motifs of the C. albicans PPTase.


Protein-predominant meals inhibit the development of gastric tachyarrhythmia, nausea and the symptoms of motion sickness.
Meal ingestion has been suggested to reduce susceptibility to the development of gastric tachyarrhythmia, the abnormal activity of the stomach that frequently accompanies nausea. To determine the types of meal that are most effective in preventing the development of gastric tachyarrhythmia, nausea and the symptoms of motion sickness provoked by a rotating optokinetic drum. Participants received a carbohydrate beverage, a protein-predominant beverage or nothing immediately before exposure to the rotating drum. Subjective symptoms of motion sickness and electrogastrograms were collected during a 6-min baseline period and a subsequent 16-min drum rotation period. Subjective symptoms of motion sickness scores were significantly more severe during the no-meal condition than during either the protein or carbohydrate condition. Central, peripheral and, to some extent, gastrointestinal symptoms were more severe during the carbohydrate condition than during the protein condition. Gastric tachyarrhythmia increased significantly less from baseline to drum rotation during both the protein and carbohydrate conditions than during the no-meal condition. Liquid protein-predominant meals were most effective in suppressing both the development of gastric tachyarrhythmia and the entire spectrum of motion sickness symptoms, including nausea.


Unusual 5/5 fused bicyclosesquiterpenoids from Eupatorium adenophorum.
The chemical analysis on the aerial sections of Eupatorium adenophorum Spreng. resulted in the identification of four unprecedented 5/5 fused bicyclosesquiterpenoids, eupatorid A (1), and its analogues named eupatorester A-C (2-4) using various chromatographic techniques. Their structures were unambiguously confirmed by detailed spectroscopic investigations (including 1D, 2D-NMR and HRMS), and single crystal X-ray diffraction. The anti-inflammatory activities, in vitro tumor growth inhibitory activities and antibacterial activities of these compounds were evaluated.


Effects of ramp shortening during linear phase of relaxation on [Ca2+]i in intact skeletal muscle fibers.
The effects of shortening distance at Vu, the unloaded shortening speed, and filament overlap on the amount of extra Ca2+ released during relaxation in muscle, as indicated by the bump area, were studied. Single, intact frog skeletal muscle fibers at 3 degreesC were used. The myoplasmic free Ca2+ concentration ([Ca2+]i) was estimated by using fura 2 salt injected into the myoplasm. Ramps were applied, either at full overlap with different sizes or at varying overlaps with a fixed size, in the linear phase of relaxation. At full overlap, a plot of bump area vs. ramp size was fit by using a sigmoidal curve with one-half of the bump area equal to 25.9 nm. With a fixed ramp size of 100 nm/half-sarcomere, the plot of bump area vs. mean sarcomere length (SLm) was fit by a straight line intersecting the SLm axis at approximately 3.5 micrometers, close to just no overlap. The results suggest that the transition in the distribution of attached cross bridges from the isometric case to one appropriate for unloaded shortening at Vu is completed within 50 nm/half-sarcomere and support the view that attached cross bridges in the overlap zone influence the affinity of Ca2+ for troponin C in the thin filament.


β-HPV 8E6 combined with TERT expression promotes long-term proliferation and genome instability after cytokinesis failure.
Human papillomavirus (HPV) is a family of viruses divided into five genera: alpha, beta, gamma, mu, and nu. There is an ongoing discussion about whether beta genus HPVs (β-HPVs) contribute to cutaneous squamous cell carcinoma (cSCC). The data presented here add to this conversation by determining how a β-HPV E6 protein (β-HPV 8E6) alters the cellular response to cytokinesis failure. Specifically, cells were observed after cytokinesis failure was induced by dihydrocytochalasin B (H2CB). β-HPV 8E6 attenuated the immediate toxicity associated with H2CB but did not promote long-term proliferation after H2CB. Immortalization by telomerase reverse transcriptase (TERT) activation also rarely allowed cells to sustain proliferation after H2CB exposure. In contrast, TERT expression combined with β-HPV 8E6 expression allowed cells to proliferate for months following cytokinesis failure. However, this continued proliferation comes with genome destabilizing consequences. Cells that survived H2CB-induced cytokinesis failure suffered from changes in ploidy.


Satellite heterophagosomes.
An incidental observation made during a recent ultrastructural study shows that after ingestion of an erythrocyte by a Kupffer cell surface budding occurred from the heterophagosome leading to the formation of smaller satellite or daughter heterophagosomes. It is suggested that an entire erythrocyte may be too large to digest in a single heterolysosome and that fragmentation into smaller units facilitates digestion by bringing about better contact between the enzymes and substrates.


Peroxisome proliferator activated receptor-γ in osteoblasts controls bone formation and fat mass by regulating sclerostin expression.
The nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) is a key contributor to metabolic function via its adipogenic and insulin-sensitizing functions, but it has negative effects on skeletal homeostasis. Here, we questioned whether the skeletal and metabolic actions of PPARγ are linked. Ablating Pparg expression in osteoblasts and osteocytes produced a high bone mass phenotype, secondary to increased osteoblast activity, and a reduction in subcutaneous fat mass because of reduced fatty acid synthesis and increased fat oxidation. The skeletal and metabolic phenotypes in Pparg mutants proceed from the regulation of sclerostin production by PPARγ. Mutants exhibited reductions in skeletal Sost expression and serum sclerostin levels while increasing production normalized both phenotypes. Importantly, disrupting the production of sclerostin synergized with the insulin-sensitizing actions of a PPARγ agonist while preventing bone loss. These data suggest that modulating sclerostin action may prevent bone loss associated with anti-diabetic therapies and augment their metabolic actions.


Practical synthesis of androgen: the efficient transformation of 17-oxo group to 17 alpha-hydroxy group.
The present report describes the improved transformation of the 17-oxo group in 3 beta-acetoxy-5 alpha-androstan-17-one to a 17 alpha-hydroxy group. A mixture of 17 alpha-acetoxy and 16-ene compounds, which are usually produced by the standard synthetic route, were treated with peracetic acid (epoxidation of the 16-ene compound) and then sodium borohydride-sodium hydroxide (reduction-hydrolysis) to give the desired 17 alpha-hydroxy compound in much better yield than that in previous reports. Recrystallization of the crude product with cyclohexane-methanol gave the pure compound in 54% yield (total yield from starting ketone).


Mechanisms for binocular depth sensitivity along the vertical meridian of the visual field.
By removing the visual cortex unilaterally, and recording along the intact 17/18 border, we have investigated the influence of the corpus callosum on the tuning curves for stimulus disparity of cat cortical neurons. Responses to binocular stimulation were examined to movement in the same (in-phase) and in the opposite direction (antiphase) across the two retinae. In lesioned cats, as in normal cats, units were encountered which showed high sensitivity and narrow tuning for stimulus disparity. In contrast to normal cats, however, lesioned cats showed a reduced proportion of units displaying moderate binocular interactions, as well as a substantial increase in disparity-insensitive cells. The loss of disparity sensitivity after decortication was associated with a reduced incidence of both selectivity for the direction of stimulus motion and binocular activation. No large differences between the preparations were seen, however, in the ocular dominance of the total populations of cells. Differences between the normal and lesioned cats were found in binocular responses to in-phase but not to antiphase stimulation motion. Tuning curves in lesioned cats showed reduced binocular inhibition but no changes in binocular facilitation. Our findings indicate that callosal input contributes to unit disparity sensitivity by enhancing direction-selective binocular inhibition. The corpus callosum generates disparity sensitivity in a population of units in the superficial cortical layers which may play a particular role in the perception of stereoscopic depth.


Precise control of maxillary multidirectional movement in Le Fort I osteotomy using a surgical guiding device.
We introduced a surgical protocol to achieve accurate maxillary multidirectional movement in Le Fort I osteotomies. This comprised a way of controlling precision and a guiding device together with prebent titanium plates. We evaluated the protocol using a semiautomated 3-dimensional assessment in 22 patients with maxillary multidirectional movement (movement in three or more of six directions). Operations were all done between October 2015 and April 2017 by the same surgeon, who followed the protocol strictly. To evaluate the accuracy, we measured the deviation of the orientation of landmarks and of the upper dentition. All cases were followed up for at least a year. They all involved maxillary movement in at least three directions, and nine involved movement in six. The guiding device was used intraoperatively in all cases. Vertical deviation of the segments of bone was often detected during removal of bone, and sagittal deviation in three cases, but we found no transverse deviations. The assessment of accuracy showed that the mediolateral, anteroposterior, and superoinferior translations of landmarks were all less than 1mm, with mean values of 0.29, 0.43, and 0.39mm, respectively. The pitch, roll, and yaw of the upper dentition were also less than 1°, with mean values of 0.60°, 0.35°, 0.36°, respectively. The proposed protocol allowed accurate reposition of the maxilla with multidirectional movement during Le Fort I osteotomy.


Studies in fetal wound healing: III. Early deposition of fibronectin distinguishes fetal from adult wound healing.
Wound healing in the fetus proceeds through a series of steps that differ in the fetus and the adult. At each phase of this complex process, there is signaling between the tissue cells and the wound microenvironment, signals that are mediated by and through the extracellular matrix. We postulate that these signals occur earlier in fetal wounds, resulting in more rapid repair. To investigate this, we compared the first 24 hours of wound healing in the rabbit fetus and adult, using antibodies against key extracellular matrix macromolecular components: laminin, fibronectin, and type-specific collagens I, III, IV, and V. Fibronectin was the first matrix component to be deposited, and was visualized as early as four hours after fetal wounding and 12 hours after adult wounding. There was no evidence of new laminin or collagen deposition in either the fetal or adult wounds at any time point examined. The early deposition of fibronectin, a matrix adhesion molecule that provides a scaffolding for epithelial migration, may underlie the rapid reepithelialization observed in fetal wounds.


Correlation of ultrasound imaging of oral swallow with ventilatory alterations in cerebral palsied and normal children: preliminary observations.
Preliminary results of an investigation that synchronizes the videotaped output of ultrasound camera and the analog data from physiological measurements of swallowing and ventilation in normal and cerebral palsied (CP) children are presented. Four cerebral palsied children and three control children undertook a single sip-swallow of 5 ml of liquid and a solid mastication-swallow sequence on three occasions according to a defined protocol. The CP children exhibited much more variability and less control of the liquid bolus than did the controls. The ultrasound image clearly demonstrates the lack of control of the posterior of the tongue in many CP children. Some parts of the sequence of oral swallow and the time to achieve maximum anterior displacement of the hyoid bone appear to be slowed. The sequential events of swallowing show less variability as the sip-swallow proceeds from the oral voluntary to pharyngeal and lower involuntary phases. This study also identified a short-latency apnea that appears to accompany a saliva (protective) swallow and a long-latency apnea that accompanies semi-solid or liquid bolus (alimentary) swallows. Further investigations of normal and CP children utilizing a combined diagnostic imaging-physiological measurement approach will follow this initial study.


Overview of the nutritional status of selected micronutrients in Mexican children in 2006.
To present an overview of micronutrient status of Mexican children in 2006. Data on iron, zinc, folate and vitamin B12 deficiencies and low serum copper and magnesium were gathered and critically analyzed from the 2006 National Health and Nutrition Survey. Iron deficiency is still the main nutritional deficiency in children (13%-26%). Zinc deficiency was high in all age groups (≈25%) but reduced 5.6 PP in children <5 y from 1999 to 2006. Folate deficiency was 3.2% and vitamin B12 deficiency 7.7% in children. Low serum magnesium and copper were high (22.6% and 30.6%, respectively). The prevalence of iron deficiency seems to be lowering, and zinc deficiency has reduced in Mexican children. A high prevalence of copper and magnesium deficiencies warrants further research on their public health implications.


Scientific education early in the curriculum using a constructivist approach on learning.
Physicians need to stay up-to-date with new developments in their field of expertise. This expectation has been made explicit by competency-based educational outcomes in the domain of scholar in the Dutch blueprint. There is a great diversity in teaching methods that aim to achieve a better understanding of scientific knowledge. Applying a constructivist approach to learning in acquiring research competencies we wonder how a research-intensive course is evaluated early in the curriculum and what learning gain students perceive. In a collaborative research-intensive course, the class of 300s-year students rated the quality of 150 preselected randomized controlled trials (RCT) using JAMA Users' Guides, and the pharmaceutical advertisements in which they were referenced. Each student rated two RCTs. Data were analyzed to answer a relevant research question. After the course students completed an evaluation survey. We did this in five consecutive years to capture student experience in relation to fostering a scientific mindset (n = 1,500). In addition we studied outcome of this scientific mindset as scientific output (publications) in journals. Survey data indicate that it is feasible to successfully implement a research-intensive course based on a large cohort using a constructivist paradigm early in the curriculum. Students consider it challenging and report high learning gain in several domains. Aggregated data have even led to four publications in journals. Implementing an active learning research experience early in the curriculum can foster student attitudes, provided the level of difficulty correctly matches the learners' prior knowledge. Further research is required to determine how to improve these active research curricula to maximize impact on learners.


Complex acetabular reconstruction for metastatic tumor.
Twenty-six hips were reconstructed in 25 patients with periacetabular metastatic lesions. Twelve hip reconstructions were performed using a modified Harrington technique with polymethyl methacrylate, cancellous screws, and reinforcement rings (type I). Fourteen hip reconstructions were performed using bulk bone-graft and reinforcement rings (type II). According to the Musculoskeletal Tumor Society functional rating score, there was no appreciable difference between the two types of reconstructions. Either technique can give satisfactory results depending on the anatomic location and extent of bone loss. Careful patient selection is the prime determinant of a successful outcome.


SIMToolbox: a MATLAB toolbox for structured illumination fluorescence microscopy.
SIMToolbox is an open-source, modular set of functions for MATLAB equipped with a user-friendly graphical interface and designed for processing two-dimensional and three-dimensional data acquired by structured illumination microscopy (SIM). Both optical sectioning and super-resolution applications are supported. The software is also capable of maximum a posteriori probability image estimation (MAP-SIM), an alternative method for reconstruction of structured illumination images. MAP-SIM can potentially reduce reconstruction artifacts, which commonly occur due to refractive index mismatch within the sample and to imperfections in the illumination. SIMToolbox, example data and the online documentation are freely accessible at http://mmtg.fel.cvut.cz/SIMToolbox. email@example.com Supplementary data are available at Bioinformatics online.


Multi-faceted substrate specificity of heparanase.
Heparan sulfate is a highly sulfated polysaccharide abundantly present in the extracellular matrix. Heparan sulfate consists of a disaccharide repeating unit of glucosamine and glucuronic and iduronic acid residues. The functions of heparan sulfate are largely dictated by its size as well as the sulfation patterns. Heparanase is an enzyme that cleaves heparan sulfate polysaccharide into smaller fragments, regulating the functions of heparan sulfate. Understanding the substrate specificity plays a critical role in dissecting the biological functions of heparanase and heparan sulfate. The prevailing view is that heparanase recognizes specific sulfation patterns in heparan sulfate. However, emerging evidence suggests that heparanase is capable of varying its substrate specificities depending on the saccharide structures around the cleavage site. The plastic substrate specificity suggests a complex role of heparanase in regulating the structures of heparan sulfate in matrix biology.


Menu Planning in Residential Aged Care-The Level of Choice and Quality of Planning of Meals Available to Residents.
Choice of food is an imperative aspect of quality of life for residents in Residential Aged Care Homes (RACHs), where overall choice and control is diminished upon entering a home to receive care. The purpose of this study was to examine the current strategies of menu planning in a range of RACHs in Australia, and whether this facilitated appropriate levels of choice for residents receiving texture modified and general diets. The study comprised a National Menu Survey using a new survey instrument collecting general information about the RACH and foodservice system, menu information and staffing information (n = 247); a national menu analysis (n = 161) and an observational case study of 36 meal environments. Choice was low for the entire sample, but particularly for those receiving pureed texture modified diets. Evidence of menu planning to facilitate the inclusion of choice and alternatives was limited. Regulation and monitoring of the Australian Aged Care Accreditation Standards needs to be strengthened to mandate improvement of the choice and variety offered to residents, particularly those on pureed texture modified diets. Further research on how menu choice and a lack of variety in meals affects the quality of life residents is needed in this context, but current evidence suggests the effect would be detrimental and undermine resident autonomy and nutritional status.


Hemoglobin C acquired via a blood transfusion. Detection by automated blood counter.
Hemoglobin C was acquired by a 52-year-old man via a blood transfusion. The presence of nonlysis of erythrocytes on the Technicon H6000 (Tarrytown, NY) scattergram after blood transfusions and the absence of this process in the admission peripheral blood count confirmed that this abnormal hemoglobin was acquired and not endogenous to the patient. Homozygous hemoglobin C disease was confirmed in one of the donors of blood received by the patient.


Selective removal of phenanthrene for the recovery of sodium dodecyl sulfate by UV-C and UV-C/PDS processes: Performance, mechanism and soil washing recycling.
Soil washing is commonly used to remediate PAHs contaminated sites. However, the effluent after washing containing PAHs and surfactant may cause secondary pollution and remediation cost is still high, unless PAHs are selectively removed from the effluent and the surfactant is recovered and recycled. Herein, ultraviolet irradiation (254 nm, UV-C) and its combination with peroxydisulfate (UV-C/PDS) were applied to selectively degrade PHE in the synthetic soil washing effluent. At natural pH of 8.6, 98.2 % of PHE was removed within 30 min under 6 W UV-C irradiation. After adding 2 mM PDS, the time was shortened to 8 min but still achieving 98.7 % PHE removal and less toxic treated effluent than UV-C alone. The 1O2 was the main oxidizing species in UV-C alone system, while 1O2 as well OH and SO4- were responsible for PHE removal in the UV-C/PDS system. The possible intermediates of PHE degradation were recognized using liquid chromatography-mass spectrometry technique and the degradation pathways in both systems were proposed. Soil washing recycling experiments verified the recovered SDS could be reused directly without surfactant supplement and the soil washing efficiency changed insignificantly during three cycles. It indicates UV-C/PDS coupled with soil washing is a promising remediation technology.


Rural pharmacy in New Zealand: effects of a compulsory externship on student perspectives and implications for workforce shortage.
To explore student perceptions of rural pharmacy practice, factors affecting interest in rural work and effects of an educational intervention designed to raise awareness of rural practice. Qualitative and quantitative survey questionnaire administered before and after a week-long rural externship. Undergraduate - rural pharmacy externship. Third-year Bachelor of Pharmacy undergraduate cohort (n = 123). Week-long exposure to rural pharmacy practice Rural/urban origin of students, interest in working in rural practice, views held of rural practice and towards externship. Rural-origin students were significantly more likely to report they would consider working in rural practice prior to the intervention than urban-origin students (77% rural origin versus 40% urban origin). The intervention significantly increased the overall proportion (48% pre-versus 73% post-externship), proportion of female students (48% pre versus 79% post-externship) and proportion of urban-origin students (38% pre-versus 67% post-externship) prepared to consider rural practice. Despite apprehension towards the externship, students reported overwhelmingly positive experiences of it. Negative aspects related mainly to travel and accommodation costs incurred. This targeted, experiential intervention affected perceptions of rural practice in a positive direction among urban-origin students by raising awareness and challenging their preconceptions of rural pharmacy practice. Further research is required to see whether this will affect recruitment and to investigate what appears to be a particular effect on female students.


The new fabrication method of standard surface sources.
We developed a new fabrication method for standard surface sources by using an inkjet printer with inks in which a radioactive material is mixed to print on a sheet of paper. Three printed test patterns have been prepared: (1) 100mm x 100mm uniformity-test patterns, (2) positional-resolution test patterns with different widths and intervals of straight lines, and (3) logarithmic intensity test patterns with different radioactive intensities. The results revealed that the fabricated standard surface sources had high uniformity, high positional resolution, arbitrary shapes and a broad intensity range.


Incidence and risk factors of major toxicity associated to first-line antituberculosis drugs for latent and active tuberculosis during a period of 10 years.
Adverse drug reactions (ADR) to first-line antituberculosis drugs are frequent and have important implications that may affect the effectiveness of treatment and course of tuberculosis (TB). Retrospective data analysis of clinical records and national registration forms from patients with ADR to first line antituberculosis that occurred between 2004 and 2013 at a Portuguese Pulmonology Diagnostic Centre, and from a case-control population matched by sex, age and year of initiation of treatment. Of the 764 patients treated with antituberculosis drugs, 55 (52.7% male, 92.7% European, mean age 50.8±19.5 years) had at least one severe ADR and six had a second ADR, for a total of 61 events. The most frequent ADR were hepatotoxicity (86.9%), rash (8.2%) and others, such as ocular toxicity, gastrointestinal intolerance and angioedema (4.9%). Isoniazid, alone or in combination, was the antituberculosis drug most associated to toxicity. Due to ADR, treatment time changed an average of 1.0±2.6 months (range -3.4 to 10.6). There was no correlation between age or gender and the overall incidence of ADR although we found a significant association between younger age and an increased risk of hepatotoxicity (P=0.035). There was also a statistically significant relationship between ADR and diabetes mellitus (P=0.042) but not for other comorbidities or multi-resistant TB risk factors. This study found a high frequency of ADR with strong impact on subsequent therapeutic orientation. What seems to be of particular interest is the relationship between ADR and diabetes mellitus and the increased frequency of hepatotoxicity in younger patients.


The effect of insularity on the diversity of land birds in the Fiji islands: implications for refuge design.
Ecologists have argued over rules of thumb that could be used to set priorities in configuring systems of reserves for preserving biological diversity. To evaluate these simple strategies, I assembled a particularly large and comprehensive data set on the land birds of the Fiji archipelago. I analyzed the species distribution on 220 islands to compare the running total of species preserved by differènt sequences of adding nature reserves to a hypothetical reserve system, treating each island as if it were a potential reserve. A strategy of maximizing the number of islands contributing to any given reserve area (maximum fragmentation) is much more effective at including species than a strategy of maximizing the size of the island components of a reserve (minimum fragmentation). Nevertheless the maximum fragmentation strategy is not a very good one. It is less effective than many random strategies, especially when about 2-10% of total area is to be set aside as reserve, and when only rare species are considered. A computer program was used to determine an "optimal" strategy by maximizing the number of additional species added for each unit of area added. This strategy is always substantially more effective at encompassing species diversity than either the maximum or minimum fragmentation strategies. It is suggested that the poor performance of the minimum fragmentation strategy is due principally to the presence of many smaller-island endemics within the Fiji archipelago. More generally, it is argued that the effect of fragmentation on species diversity depends on the geographic scale and isolation of the region under consideration. In these respects the Fiji Archipelago may be a particularly good model for continental reserve systems.


[Haemorrhagic complications following ibrutinib intake after dermatological surgery].
Ibrutinib is a selective oral inhibitor of Bruton's tyrosine kinase. It is used in haematology to treat lymphoid B disorders. Haemorrhagic complications in dermatological surgery are occasionally associated with the use of anti-platelet and/or anticoagulant medication. Herein, we report a case of haemorrhage under ibrutinib following skin surgery. A 70-year-old male patient began treatment with ibrutinib for chronic lymphocytic leukaemia had 2 basal cell carcinomas of the face. The next day he had a persistent haemorrhage lasting more than 48h, with no effects on the final scarring result. Ibrutinib is a tyrosine kinase inhibitor whose mechanism of action plays a role in platelet adhesion. It is known to cause haemorrhaging, either spontaneously or following invasive procedures, especially at the beginning of treatment. In the case of low-risk haemorrhagic procedures in which bleeding may be controlled by mechanical haemostasis, ibrutinib should be discontinued 3 days before and after surgery. In the event of recent initiation of ibrutinib and in the absence of urgent dermatological management, it is preferable to schedule any surgical procedures 3 months after the start of ibrutinib.


A model-based approach to assess reproducibility for large-scale high-throughput MRI-based studies.
Magnetic Resonance Imaging (MRI) technology has been increasingly used in neuroscience studies. Reproducibility of statistically significant findings generated by MRI-based studies, especially association studies (phenotype vs. MRI metric) and task-induced brain activation, has been recently heavily debated. However, most currently available reproducibility measures depend on thresholds for the test statistics and cannot be use to evaluate overall study reproducibility. It is also crucial to elucidate the relationship between overall study reproducibility and sample size in an experimental design. In this study, we proposed a model-based reproducibility index to quantify reproducibility which could be used in large-scale high-throughput MRI-based studies including both association studies and task-induced brain activation. We performed the model-based reproducibility assessments for a few association studies and task-induced brain activation by using several recent large sMRI/fMRI databases. For large sample size association studies between brain structure/function features and some basic physiological phenotypes (i.e. Sex, BMI), we demonstrated that the model-based reproducibility of these studies is more than 0.99. For MID task activation, similar results could be observed. Furthermore, we proposed a model-based analytical tool to evaluate minimal sample size for the purpose of achieving a desirable model-based reproducibility. Additionally, we evaluated the model-based reproducibility of gray matter volume (GMV) changes for UK Biobank (UKB) vs. Parkinson Progression Marker Initiative (PPMI) and UK Biobank (UKB) vs. Human Connectome Project (HCP). We demonstrated that both sample size and study-specific experimental factors play important roles in the model-based reproducibility assessments for different experiments. In summary, a systematic assessment of reproducibility is fundamental and important in the current large-scale high-throughput MRI-based studies.


Distribution of noradrenergic nerve fibers in canine nasal mucosa following selective neurectomies.
In this study, we have used noradrenergic histofluorescence and selective neurectomies of the vidian, ethmoid and caudal nasal nerves to evaluate the distribution of postganglionic sympathetic fibers in the canine nasal mucosa. In conjunction with the histochemical localization of the noradrenergic fibers in the nasal mucosa after vidian neurectomy, the norepinephrine content of the mucosa was also evaluated using high-performance liquid chromatography. Unilateral neurectomy of the superior cervical ganglion (SCG) resulted in the unilateral disappearance of all noradrenergic histofluorescence in the nasal mucosa, while no morphological changes in noradrenergic fibers could be identified after neurectomy of the cervical sympathetic trunk 1 cm below the SCG. Ethmoid neurectomy caused the disappearance of noradrenergic fibers of the upper third of the nasal mucosa, while vidian neurectomy resulted in a partial loss of noradrenergic fibers in the lower two-thirds of the nasal mucosa. The loss was chiefly in the area adjacent to venous sinusoids and was responsible for 50% of the norepinephrine content of this tissue. We concluded that all the postganglionic sympathetic fibers are from the ipsilateral SCG. Some of them travel via the ethmoid nerve and innervate the upper third of the nasal mucosa. The remaining fibers travel via the vidian nerve and perhaps the vessel walls of the supplying arteries and innervate the lower two-thirds of the nasal mucosa. The vidian nerve chiefly innervates the venous sinusoids of the lower two-thirds of the nasal mucosa.


B cells and their mediators as targets for therapy in solid tumors.
B cells have recently been appreciated as paracrine mediators of solid tumor development. Their ability to influence various hallmarks of cancer development, aside from antigen presentation, can be attributed to the diversity of soluble mediators they express, including cytokines and immunoglobulins, that can act directly and indirectly on the diversity of leukocyte subsets that infiltrate developing tumors, evolving neoplastic cells, as well as select T cell populations in secondary lymphoid organs and within tumor stroma. Herein, we review the literature supporting these interactions and discuss novel approaches to ameliorate protumoral B cell effects for anti-cancer therapy.


Ivermectin binds avidly to plasma proteins.
Human pharmacokinetic data on the new anti-parasitic agent, ivermectin, are scanty. For the evaluation of its disposition a specific HPLC assay with sensitive fluorescence detection was developed. Applying equilibrium dialysis, plasma protein binding of ivermectin was measured in five healthy individuals and it averaged 93.2 +/- 4.4% (SD). Such strong binding should be taken into consideration, especially in patients with malnutrition or with diseases in which a decrease in plasma proteins and consequently a higher free fraction of ivermectin could be expected.


Konjac glucomannan-based composite films fabricated in the presence of carnauba wax emulsion: hydrophobicity, mechanical and microstructural properties evaluation.
Despite the excellent characteristics of carnauba wax (CW), hydrophobicity in particular, its complementary effect on the enhancement of konjac glucomannan (KGM) films remains poorly documented. KGM is a promising food bio-packaging material with excellent film-forming abilities, which could be improved further through modification of its hydrophilic nature using CW. In this study, emulsified composite films (KW) of KGM incorporated with varied CW concentration levels (0%, 4%, 8%, 12%, 16% and 20% w/w) were successfully prepared by solvent casting method. Increasing CW in KW films significantly improved the hydrophobicity, barrier and mechanical properties. The recorded improvements in functional properties relative to KGM films include fivefold solubility reduction, twofold contact angle and strength increment, as well as significant increase in stretch (61%) and decrease in water vapour transmission rate (48%). Microstructure analyses using scanning electron microscopy demonstrated remarkable improvements in cohesiveness, smoothness and homogeneity in KW aggregates with higher CW concentrations. Generally, our findings reveal the potential use of KW films as food packaging material which could reduce the availability of unsafe and environmentally unfriendly food packages in the market.


Corrigendum: Positive Reciprocal Feedback of LncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer.
[This corrects the article DOI: 10.3389/fonc.2021.761979.].


Extent and utilisation of computerisation in Australian general practice.
To assess the availability of computers to general practitioners and individual GPs' use of computers for clinical functions. A secondary analysis of data from a random sample of 1319 Australian GPs who participated in the Bettering the Evaluation and Care of Health (BEACH) survey, a continuous cross-sectional survey of general practice activity, between November 2003 and March 2005. Participants reported the availability of computers at their major practice address and the clinical functions for which they used the computers. Proportion of practices with computers available; proportion of individual GPs who used computers for clinical purposes. The proportion of GPs not using a computer was 11.2% (6% did not have a computer at their major practice address and a further 5.2% chose not to use an available computer). The majority of GPs using a computer at work used it for electronic prescribing (94.7%), ordering tests (82.2%) and keeping some patient data in an electronic medical record (79.5%). Of those with clinical software available (n = 1114), 6.6% chose not to use it. A third of GPs (32.8%) kept all patient information in an electronic format. The proportion of GPs keeping all data electronically and using all clinical functions available in their computer was 21.7%. While the physical presence of computers has increased significantly over the past decade, GPs are still reluctant to fully embrace the technology.


Challenges facing case management in a changing social service environment.
Case management has been a difficult practice to track, particularly for the purposes of outcome measurements and accountability. As both policymakers and program administrators consider options for providing long-term care, the Data Analysis and Regulations Team of the California Department of Aging studied computerized client information for one of its case management programs to examine what we know about the people being served and the ability of the data collection system to meet the increasing demand for accountability. This article details the results of our study and discusses their implications within the dynamics of a changing social service environment.


Complexes With Biologically Active Ligands. Part 6 Ni(II) Coordination Compounds of Hydrazine and Heterocyclic Sulfonamides as Inhibitors of the Zinc Enzyme Carbonic Anhydrase.
Ternary Ni(II) complexes of hydrazine and eight heterocyclic sulfonamides possessing carbonic anhydrase (CA) inhibitory properties, were prepared and characterized by elemental analysis, spectroscopic, magnetic, thermogravimetric, and conductimetric measurements. The complexes behave as strong inhibitors for two isozymes (I and II) of carbonic anhydrase.


The effect of intrinsic muscular nonlinearities on the energetics of locomotion in a computational model of an anguilliform swimmer.
Animals move through their environments using muscles to produce force. When an animal׳s nervous system activates a muscle, the muscle produces different amounts of force depending on its length, its shortening velocity, and its time history of force production. These muscle forces interact with forces from passive tissue properties and forces from the external environment. Using an integrative computational model that couples an elastic, actuated model of an anguilliform, lamprey-like swimmer with a surrounding Navier-Stokes fluid, we study the effects of this coupling between the muscle force and the body motion. Swimmers with different forms of this coupling can achieve similar motions, but use different amounts of energy. The velocity dependence is the most important property of the ones we considered for reducing energy costs and helping us to stabilize oscillations. These effects are strongly influenced by how rapidly the muscle deactivates; if force decays too slowly, muscles on opposite sides of the body end up fighting each other, increasing energy cost. Work-dependent deactivation, an effect that causes a muscle to deactivate more rapidly if it has recently produced mechanical work, works together with the velocity dependence to reduce the energy cost of swimming.


Specific resonance mode enhancement and suppression using non-uniform polarization of piezoelectric wafers: Theory and experiments.
We present experimental demonstration of specific resonance mode enhancement and suppression in circular and rectangular piezoelectric wafers with engineered non-uniform polarization profiles. The polarization profiles are designed based on the electromechanical impedance response of non-uniformly polarized wafers as obtained from the theory. The circular wafers are fabricated with non-uniform polarization profiles that involve a central polarized region surrounded by an unpolarized region. The radius of the polarization zone is designed based on the condition for specific mode enhancement obtained from the electromechanical impedance response of non-uniformly polarized wafers. We actually show how the condition can not only be used to enhance but also to suppress electromechanical resonances. Two kinds of wafers are designed and fabricated to specifically suppress second and third radial modes respectively. Similarly, rectangular wafers are designed with two different kinds of non-uniform polarization profiles - the first of which enhances the second in-plane extensional mode in the impedance spectrum and the second polarization profile suppresses all the electromechanical resonances pertaining to the in-plane extensional modes and selectively excites only the in-plane bending modes. The proposed approach of using non-uniformly polarized wafers finds application in designing multi-frequency sensors/transducers, frequency-tuned receivers, acoustic beamforming, and other non-traditional applications such as information storage.


Improved glycemic control induces regression of left ventricular mass in patients with type 1 diabetes mellitus.
Diabetes mellitus has been associated with abnormalities of cardiac function and left ventricular hypertrophy. We sought to determine whether improved glycemic control in patients with type 1 diabetes mellitus will induce reversal of those abnormalities. We prospectively studied 19 patients (mean age 40+/-9 years) with longstanding type 1 diabetes mellitus (28+/-4 years), who participated in a program of stringent glycemic control. Glycemic control was monitored with hemoglobin A1c levels, and improvement was defined as >1% (absolute) decrease of hemoglobin A1c. Two-dimensional and Doppler echocardiograms and ambulatory 24-h blood pressures were obtained at baseline and after 1 year. Left ventricular mass was determined using the area-length method. In the patients with improved glycemic control (n=12), hemoglobin A1c decreased from 9.8% to 7.8% (p< or =0.0001), interventricular septal thickness decreased from 10.3 to 9.4 mm (p< or =0.05), and left ventricular mass regressed from 205 to 182 g (p< or =0.05). Septal thickness and left ventricular mass remained unchanged in the patients who did not achieve improvement of glycemic control. Left ventricular internal diameters, posterior wall thickness, fractional shortening, E/A ratio of mitral inflow, E-wave deceleration time (DT), and ambulatory 24-h blood pressures did not change significantly after 1 year in either group. Improved glycemic control in patients with type 1 diabetes mellitus is associated with regression of septal thickness and left ventricular mass without significant effect on systolic or diastolic function, in the absence of significant alterations in ambulatory 24-h blood pressures.


LPO-Antioxidant Defense System in Newborns and Women Drinking Small Amounts of Alcohol During Pregnancy.
We studied the effects of consumption of low-alcohol drinks (no more than 2 doses) during pregnancy on the state of LPO-antioxidant defense system and glutathione level in the blood serum and erythrocytes of pregnant women and newborns. It was found that even single alcohol intake was followed by the development of oxidative stress in women and newborns. In pregnant women, the decrease in reduced glutathione content and glutathione reductase activity associated with increased level of oxidized glutathione and glutathione transferase activity were typical changes. In newborns, the decrease in reduced glutathione concentration was accompanied by a decrease in glutathione reductase, glutathione transferase, and glutathione peroxidase activities. It should be emphasized that even small alcohol doses produce delayed negative effects on metabolism of the mother and newborns.


Comparison of bioimpedance spectroscopy and dual energy X-ray absorptiometry for assessing body composition changes in obese children during weight loss.
Obesity and age influence the reliability of dual energy X-ray absorptiometry scanning (DEXA) and bioimpedance spectroscopy (BIS). Both are used in clinical settings, but have not been compared for measurements in obese children. We compared DEXA and BIS for evaluating body composition and inherent changes in obese children before and after a 10-month weight loss programme. DEXA and BIS were used to evaluate 130 patients at baseline and 75 at follow-up. We tested agreement between the two techniques using Bland-Altman plots and proportional bias using Passing-Bablok regressions. The Bland-Altman plots showed wide agreement limits before and after weight loss and when monitoring longitudinal changes. At baseline, the Passing-Bablok regressions revealed a proportional bias for all body compartments. After significant weight loss no proportional bias was found for fat mass and percentage, although BIS systematically underestimated fat mass by 2.9 kg. Longitudinally, no proportional bias was found in the measured changes of absolute fat, fat-free mass and fat-free percentage between both methods, although BIS systematically underestimated fat and fat-free mass by 2.6 and 0.7 kg, respectively. While BIS and DEXA are not interchangeable at baseline, the agreement between the two improved after significant weight loss. Proportional changes in fat mass, fat-free mass and fat-free percentage were similar for both techniques. BIS is a viable alternative to DEXA for future paediatric obesity studies measuring treatment effect at group levels, but is not superior to DEXA and cannot be used for monitoring individual changes due to wide limits of agreement.


Human T-cell leukemia virus type 1 Tax attenuates gamma-irradiation-induced apoptosis through physical interaction with Chk2.
Checkpoint kinase 2 (Chk2) is known to mediate diverse cellular responses to genotoxic stress. The fundamental role of Chk2 is to regulate the network of genome-surveillance pathways that coordinate cell-cycle progression with DNA repair and cell survival or death. Defects in Chk2 contribute to the development of both hereditary and sporadic human cancers. We now present evidence that the human T-cell leukemia virus type-1 (HTLV-1) Tax protein directly interacts with Chk2 and the kinase activity of Chk2 is inhibited by Tax. The physical interaction of Chk2 and Tax was observed by co-immunoprecipitation assays in HTLV-1-infected T cells (C81) as well as GST pull-down assays using purified proteins. Binding and kinase activity inhibition studies with Tax deletion mutants indicated that at least two domains of Tax mediate the interaction with Chk2. We have analysed the functional consequence of de novo expression of Tax upon the cellular DNA-damage-induced apoptosis, which is mediated by Chk2. Using transient transfection and TUNEL assay, we found that gamma-irradiation-induced apoptosis was decreased in 293T and HCT-116 (p53(-/-)) cells expressing HTLV-1 Tax. Our studies demonstrate an important potential target of Tax in cellular transformation.


Generation and Analysis of Expressed Sequence Tags from Chimonanthus praecox (Wintersweet) Flowers for Discovering Stress-Responsive and Floral Development-Related Genes.
A complementary DNA library was constructed from the flowers of Chimonanthus praecox, an ornamental perennial shrub blossoming in winter in China. Eight hundred sixty-seven high-quality expressed sequence tag sequences with an average read length of 673.8 bp were acquired. A nonredundant set of 479 unigenes, including 94 contigs and 385 singletons, was identified after the expressed sequence tags were clustered and assembled. BLAST analysis against the nonredundant protein database and nonredundant nucleotide database revealed that 405 unigenes shared significant homology with known genes. The homologous unigenes were categorized according to Gene Ontology hierarchies (biological, cellular, and molecular). By BLAST analysis and Gene Ontology annotation, 95 unigenes involved in stress and defense and 19 unigenes related to floral development were identified based on existing knowledge. Twelve genes, of which 9 were annotated as "cold response," were examined by real-time RT-PCR to understand the changes in expression patterns under cold stress and to validate the findings. Fourteen genes, including 11 genes related to floral development, were also detected by real-time RT-PCR to validate the expression patterns in the blooming process and in different tissues. This study provides a useful basis for the genomic analysis of C. praecox.


Slowly conducting potentials in human sensory nerves.
In clinical practice, small myelinated sensory fibers, Aδ-fibers, conveying mainly pain and temperature sensations, cannot be examined with available nerve conduction study techniques. Currently, these fibers can only be examined with experimental or very specialized and not commonly available nerve conduction techniques, or only indirectly with cerebral evoked potentials. This study uses equipment and methods available in clinical neurophysiology laboratories to record from human sensory nerves ≥1000 averaged responses to focal, non-painful stimuli applied by a special electrode to epidermal nerves. The averaged responses to odd numbered stimuli are compared to the averaged responses to even numbered stimuli. An algorithm identifies potentials common in both averages. The 99th and 99.9th percentiles for this algorithm are obtained from control records without stimulation and applied to records with stimulation to identify potentials resulting from stimulation of intraepidermal nerves. The algorithm identifies numerous negative and positive potentials as being different from controls at the 99th and 99.9th percentile levels. The conduction velocities of the potentials range from of 1.3-29.9 m/s and are compatible with conduction velocities of Aδ-fibers. No existing methods. The stimulation, recording and data analysis methods used in this study can be applied in the clinical EMG laboratory to identify Aδ-fibers in human sensory nerves.


Germinal vesicle components are not required for the cell-cycle oscillator of the early starfish embryo.
We show that certain events of the cell cycle can still occur in starfish oocytes or fertilized eggs from which the germinal vesicle (the prominent nucleus of prophase-arrested oocytes) has been removed before the induction of meiotic maturation. Two meiotic asters develop following hormonal induction of meiotic maturation in these enucleated oocytes. The asters then divide to form a transient tetrapolar figure. When enucleated oocytes are fertilized, the sperm centrosome duplicates at the times corresponding to each cleavage in control nucleated embryos. Periodic changes in the organization of the asters and in the morphology of the cell surface also occur in synchrony with controls. Decondensation of the sperm nucleus, spindle formation, and cleavage do not occur when enucleated oocytes are fertilized. Ultimately the number of asters increases to approximately 520 (about 2(9] before the pseudo-embryo arrests and cytolyzes. Fertilized eggs from which both pronuclei but not the sperm aster have been removed undergo nine cleavages and then cease cell division. The cessation of division may be related to the events that cause the midblastula transition after seven cleavages in normal nucleated embryos.


Nonpharmacological approaches: diet and neurostimulation.
There are many children with intractable epilepsy who do not respond to anticonvulsant medications yet are not candidates for resective epilepsy surgery. For these children and more, nonpharmacologic therapies can be very helpful. The primary therapies include diet and neurostimulation. Dietary therapies available currently include the ketogenic diet, modified Atkins diet, medium chain triglyceride diet, and low glycemic index treatment. Neurostimulation, using electricity to abort seizures, includes vagus nerve stimulation only at this time. However, other treatments such as deep brain stimulation and cortical responsive stimulation (NeuroPace) are under active development.


Focus on phosphoaspartate and phosphoglutamate.
Protein phosphorylation is a common signalling mechanism in both prokaryotic and eukaryotic organisms. Whilst the focus of protein phosphorylation research has primarily been on protein serine/threonine or tyrosine phosphorylation, there are other phosphoamino acids that are also biologically important. Two of the phosphoamino acids that are functionally involved in the biochemistry of protein phosphorylation and signalling pathways are phosphoaspartate and phosphoglutamate, and this review focuses on their chemistry and biochemistry. In particular, we cover the biological aspects of phosphoaspartate and phosphoglutamate in signalling pathways and as phosphoenzyme intermediates. In addition, we examine the synthesis of both of these phosphoamino acids and the chemistry of the acyl phosphate group. Although phosphoaspartate is a major component of prokaryotic two-component signalling pathways, this review casts its net wider to include reports of phosphoaspartate in eukaryotic cells. Reports of phosphoglutamate, although limited, appear to be more common as free phosphoglutamate than those found in phosphoprotein form.


Pregnancy outcome in Swiss-Webster mice infected with Chlamydia trachomatis.
The objective of this study was to observe pregnancy outcomes in mice infected transvaginally with Chlamydia trachomatis. Pregnant mice were inoculated transvaginally with either C. trachomatis (CT) or sterile calf serum (CON) on pregnancy day 4. Pregnancy outcomes as well as genital tract histology and culture were compared. Statistical analysis was performed using Fisher's exact test and Student's t-test. Twenty-four of 26 CT mice had positive uterine cultures for C. trachomatis. Inflammation occurred in 9 (34.6%) (P = 0.002, 95% confidence interval = 1.7-3.5) and intrauterine fetal demise occurred in 5 (19.2%) (P = 0.05, 95% confidence interval = 1.6-2.9) of CT mice. No mice in the CON group (0/24) had positive uterine cultures, developed inflammation, or experienced intrauterine fetal demise. Lower genital tract chlamydial infection is associated with intrauterine fetal demise in Swiss-Webster mice.


[Echographic and x-ray computed tomographic aspects of pneumatosis cystoides of the colon in the adult. Apropos of a case].
A case of pneumatosis cystoides Coli located in the sigmoid in an adult is reported, with emphasis on US and CT aspects. CT patterns of pneumatosis cystoides Coli are highly significative; particularly attenuation values measured in the endoluminal polypoid images are characteristics and represent an interesting contribution to the diagnosis of this disease.


Typical patterns in atypical anorexia nervosa.
Only a few published accounts describe atypical anorexia nervosa. To provide more information about this eating-disorder subtype, 15 patients (12 females, 3 males) with atypical anorexia nervosa were studied. In general, the 12 female patients were characterized by 1) older age at onset and presentation, 2) recurring bouts of depression, 3) numerous somatic complaints, 4) unmet dependency needs, and 5) little evidence of distortion in body image. The three male patients were characterized by a younger age at onset compared to the females, and in many ways they resembled young female anorexics or bulimic anorexics.


Base-of-tongue carcinoma: treatment results using concomitant boost radiotherapy.
To evaluate the efficacy of accelerated fractionated radiotherapy using the concomitant boost schedule for patients with squamous cell carcinoma of the base of tongue. Between September 1984 and July 1992, 54 patients with squamous carcinoma of the base of tongue were treated at The University of Texas M. D. Anderson Cancer Center using the concomitant boost schedule. The distribution of T and N stages was T1-4, T2-27, T3-22, and T4-1; N0-9, N1-11, N2-24, N3-7, and NX-3. American Joint Committee on Cancer (AJCC) stage groupings were II-6, III-14, and IV-34. Before radiation, nodal excision and neck dissection were done in 5 and 10 patients, respectively; 5 patients had neck dissections after radiotherapy. Standard on and off spinal cord fields were irradiated with 1.8 Gy fractions to 54 Gy given over 6 weeks. The boost was given concomitantly during the large field treatment as a second daily (1.5 Gy) fraction, with an interfraction interval of 4-6 h. The median dose to the primary tumor was 72 Gy (range, 66-74 Gy). The median treatment duration was 42 days (range, 39-48 days). Only three patients had treatment interrupted for more than one scheduled treatment day. The 5-year actuarial overall survival and disease-specific survival rates were 59 and 65%, respectively, with a median follow-up of 41 months. The 5-year actuarial locoregional control rate was 76%. The actuarial local control rates achieved with radiotherapy at 5 years for T1, T2, and T3 primary tumors were 100%, 96%, and 67%, respectively; including surgical salvage, the local control rate of T3 primary tumors was 70%. Six patients had regional failures, which in three patients occurred in conjunction with primary tumor recurrence. Twenty-six patients with regional adenopathy were treated with radiation alone to full dose and had a complete clinical response in the neck; no planned neck dissections were performed in these patients. Only 2 of these 26 patients had subsequent regional failures. The 5-year actuarial risk of distant metastases in patients whose disease was controlled locoregionally was 21%. Grade 3 or 4 confluent acute mucositis occurred in 94% of patients. However, late complications were limited to two cases of transient mandibular exposure and three cases of self-limited mucosal ulcerations. The concomitant boost fractionation schedule is a very effective regimen for this disease when appropriately selected patients are treated with meticulous technique. The therapeutic ratio is favorable, with a high rate of disease control and no persistent severe late complications. Patients whose neck disease responds completely to treatment with this schedule do not appear to need a planned neck dissection.


Effects of BPA on right ventricular mechanical dysfunction in patients with inoperable CTEPH - A cardiac magnetic resonance study.
The aim of this study was to assess effects of balloon pulmonary angioplasty (BPA) on right ventricular (RV) mechanical dysfunction in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) via MRI. MRI at 1.5 Tesla and right heart catheterization were performed before and 6 months after BPA in 30 CTEPH patients (mean age 63.4 ± 10.6 years; 17 female). Feature-tracking strain analysis, including global longitudinal (GLS), circumferential (GCS), and radial (GRS) strain, was performed and compared with right ventricular function, myocardial remodelling (assessed by native T1 times), and pulmonary haemodynamics (mean pulmonary arterial pressure and pulmonary vascular resistance). RVEF (35.9% to 48.4%) increased and mPAP (42.1 mmHg to 33.1 mmHg) and PVR (551.8 to 377.7 dyn∙s/cm5) decreased after BPA (all p < 0.0001). Moreover, RV strain increased (GLS -19.9 to -24.0%, p = 0.0003; GCS -9.4 to -11.0%, p = 0.0022; GRS 38.2 to 50.7%, p = 0.001) and septal native area-adjusted T1 time (AA-T1) decreased (1019.4 to 988.7 ms, p < 0.0001). GLS revealed the best correlations with RVEF (before BPA r = -0.75; after BPA r = -0.54), mPAP (r = 0.36; r = 0.52), PVR (r = 0.49; r = 0.48), and AA-T1 (r = 0.44; 0.19). RV mechanical dysfunction, pulmonary haemodynamics, and myocardial remodelling are markedly improved by BPA. Moreover, RV strain values showed good correlations with RV function, pulmonary haemodynamics, and myocardial remodelling. Therefore, strain analysis might provide new insights regarding therapy outcome, monitoring, and prognosis.


Nucleotide and deduced amino acid sequences of rat myosin binding protein H (MyBP-H).
The complete nucleotide sequence of the cDNA clone encoding rat skeletal muscle myosin-binding protein H (MyBP-H) was determined and amino acid sequence was deduced from the nucleotide sequence (GenBank accession number AF077338). The full-length cDNA of 1782 base pairs(bp) contains a single open reading frame of 1454 bp encoding a rat MyBP-H protein of the predicted molecular mass 52.7 kDa and includes the common consensus 'CA__TG' protein binding motif. The cDNA sequence of rat MyBP-H show 92%, 84% and 41% homology with those of mouse, human and chicken, respectively. The protein contains tandem internal motifs array (-FN III-Ig C2-FN III-Ig C2-) in the C-terminal region which resembles to the immunoglobulin superfamily C2 and fibronectin type III motifs. The amino acid sequence of the C-terminal Ig C2 was highly conserved among MyBPs family and other thick filament binding proteins, suggesting that the C-terminal Ig C2 might play an important role in its function. All proteins belonging to MyBP-H member contains 'RKPS' sequence which is assumed to be cAMP- and cGMP-dependent protein kinase A phosphorylation site. Computer analysis of the primary sequence of rat MyBP-H predicted 11 protein kinase C (PKC) phosphorylation site, 7 casein kinase II (CK2) phosphorylation site and 4 N-myristoylation site.


Incidence and considerations of 90-day readmissions following posterior lumbar fusion.
Posterior lumbar fusion (PLF) is a commonly performed procedure. The evolution of bundled payment plans is beginning to require physicians to more closely consider patient outcomes up to 90 days after an operation. Current quality metrics and other databases often consider only 30 postoperative days. The relatively new Healthcare Cost and Utilization Project Nationwide Readmissions Database (HCUP-NRD) tracks patient-linked hospital admissions data for up to one calendar year. To identify readmission rates within 90 days of discharge following PLF and to put this in context of 30 day readmission and baseline readmission rates. Retrospective study of patients in the HCUP-NRD. Any patient undergoing PLF performed in the first 9 months of 2013 were identified in the HCUP-NRD. Readmission patterns up to a full calendar year after discharge. PLFs performed in the first 9 months of 2013 were identified in the HCUP-NRD. Patient demographics and readmissions were tracked for 90 days after discharge. To estimate the average admission rate in an untreated population, the average daily admission rate in the last quarter of the year was calculated for a subset of PLF patients who had their operation in the first quarter of the year. This study was deemed exempt by the institution's Human Investigation Committee. Of 26,727 PLFs, 1,580 patients (5.91%) were readmitted within 30 days of discharge and 2,603 patients (9.74%) were readmitted within 90 days of discharge. Of all readmissions within 90 days, 54.56% occurred in the first 30 days. However, if only counting readmissions above the baseline admission rate of a matched population from the 4th quarter of the year (0.08% of population/day), 89.78% of 90 day readmissions occurred within the first 30 days. The current study delineates readmission rates after PLF and puts this in the context of 30-day readmission rates and baseline readmission rates for those undergoing PLF. These results are important for patient counseling, planning, and preparing for potential bundled payments in spine surgery.


Single-cell RNA transcriptome reveals the intra-tumoral heterogeneity and regulators underlying tumor progression in metastatic pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is the most frequent and aggressive pancreatic tumor characterized by high metastatic risk and special tumor microenvironment. To comprehensively delineate the complex intra-tumoral heterogeneity and the underlying mechanism during metastatic lesions malignant progression, single-cell RNA sequencing (scRNA-seq) was employed. PCA and TSNE were used for dimensionality reduction analysis and cell clustering. Find All Markers function was used to calculate differential genes in each cluster, and Do Heatmap function was used to plot the distribution of differential genes in each cluster. GSVA was employed to assign pathway activity estimates to individual cells. Lineage trajectory progression was inferred by monocle. CNV status was inferred to compare the heterogeneity among patients and subtypes by infercnv. Ligand-receptor interactions were identified by CellPhoneDB, and regulons network of cells was analyzed by SCENIC. Through RNA-sequencing of 6236 individual cells from 5 liver metastatic PDAC lesions, 10 major cell clusters are identified by using unbiased clustering analysis of expression profiling and well-known cell markers. Cells with high CNV level were considered as malignant cells and pathway analyses were carried out to highlight intratumor heterogeneity in PDAC. Pseudotime trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. The complex cellular communication suggested potential immunotherapeutic targets in PDAC. Regulon network identified multiple candidates for promising cell-specific transcriptional factors. Finally, metastatic-related genes expression levels and signaling pathways were validated in bulk RNA Sequencing data. This study contributed a comprehensive single-cell transcriptome atlas and contributed into novel insight of intratumor heterogeneity and molecular mechanism in metastatic PDAC.


Diversity of axonal growth-promoting receptors and regulation of their function.
Growth-promoting receptors for substrate-bound molecules are usually found to belong to the integrin, immunoglobulin, or cadherin families of glycoproteins. New members of each of these families have been identified in the past year, and advances have been made in our understanding of their functional regulation.


Separation of plasma membrane markers by glycerol-induced blistering of muscle cells.
Glycerol (50%, w/w) was found to cause blistering of chick primary myoblast and fibroblast plasma membranes and extensive blistering of 5--6-day-old-myotube plasma plasma membranes in tissue culture. The tips of myoblasts and fibroblasts appeared to be the most sensitive portion of the plasma membrane to the blistering effect of glycerol. The glycerol-induced blistering of myotubes was reduced and delayed by brief EDTA pretreatment. Glycerol treatment (50, 15 and 8% sequentially) of myotubes was used to remove plasma membrane blisters and a plasma membrane-enriched fraction was isolated from these blisters using a modified Dextran T500-polyethylene-glycol 6000 aqueous two-phase polymer system. This fraction was found to be enriched 4.1-fold for 5'-nucleotidase activity, but not for other putative plasma membrane markers, (Na+ + K+)-ATPase activity or alpha-[125I]bungarotoxin binding material. Autoradiographs of alpha-[125I]bungarotoxin, glycerol-treated (50%, w/w) myotubes showed the plasma membrane blisters to be devoid of reduced silver grains. 5'-Nucleotidase was shown to be an ectoenzyme on myoblasts and 5-day-old myotubes and the total cellular activity was present on the cell surface. During the period of myoblast fusion and myotube formation, cell surface activity decreased to a low level while total cellular activity was elevated.


Hydrogen bonding involving the ornithine side chain of gramicidin S.
The side-chain and backbone hydrogen bonding pattern is identical in the computed minimum-energy conformation of gramicidin S and in the recently determined X-ray crystallographic structure of the hydrated urea complex of this peptide. The identity of hydrogen bonding (except where it is affected by intermolecular interactions in the crystal) and the close agreement of the overall backbone conformation attest to the validity of the conformational energy computations used to determine the unique low-energy conformation of this cyclic peptide.


Intraoperative Pathologic Consultation on Hysterectomy Specimens for Endometrial Cancer: An Assessment of the Accuracy of Frozen Sections, "Gross-Only" Evaluations, and Obtaining Random Sections of a Grossly "Normal" Endometrium.
Pathologic intraoperative consultation (IOC) is a common approach for segregating the subset of patients with endometrial cancer who likely require a lymphadenectomy. We evaluate factors related to the performance and value of IOC, including the accuracy of frozen sections, "gross-only examinations," and obtaining random sections when a gross lesion is not apparent. IOC was performed by gross examination only in 17 (8%) of 250 cases, the specificity and negative predictive value of which in diagnosing cancer were 100% and 85%, respectively. Among the 64 cases wherein a gross lesion was not apparent and random sections were examined, a final diagnosis of carcinoma was rendered in 20, of which only three (15%) had a diagnosable malignancy on the random section. The frozen-section/final diagnosis concordance was 80% for tumor grade. Determining the depth of myometrial invasion was problematic, with 36% underestimation and 2.6% overestimation. Obtaining random sections in the absence of a gross lesion has no significant benefit, and a negative result is likely to provide inaccurate data to the surgeon. Frozen-section analyses are a generally reliable tool to determine "low-risk" pathologic parameters that were evaluated herein when a gross lesion is present.


Study population and treatment titration in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT).
To ascertain the baseline characteristics of the high-risk hypertensive patients entering the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT). To determine the success of single and combination therapy in achieving target blood pressures in such a population. INSIGHT is a double-blind, prospective outcome trial comparing the efficacy of the calcium channel blocker, nifedipine GITS, and the thiazide, co-amilozide, in preventing myocardial infarction and stroke. We recruited 2996 men and 3454 women, aged 55-80 years, with blood pressure during placebo run-in >150/95 mmHg or isolated systolic blood pressure >160 mmHg from nine countries. Treatment allocation to nifedipine GITS 30 mg daily or co-amilozide (hydrochlorothiazide 25 mg/amiloride 5 mg) once daily was performed by minimization rather than randomization to balance additional risk factors. This was followed by four optional increases in treatment: dose-doubling of the primary drug, addition of atenolol 25/50 mg or enalapril 5/10 mg, and then any other hypotensive drug excluding calcium blockers or diuretics. Target blood pressure was 140/90 mmHg or a fall > or = 20/10 mmHg. Blood pressure at randomization was 172+/-15 / 99+/-9 mmHg. Thirteen per cent of the patients were previously untreated. The proportions of each additional risk factors were: smoking > 10/day, 29%; cholesterol > 6.43 mmol/l, 52%; family history of premature myocardial infarction or stroke, 21%; diabetes mellitus 20%; left ventricular hypertrophy, 10%; previous myocardial infarction, other presentations of coronary heart disease, and peripheral vascular disease, each 6%; proteinuria, 3%. Fifty-five per cent of patients had one additional risk factor, whereas 33%, 9% and 3% had two, three or more additional risk factors, respectively. The blood pressure (and falls in blood pressure) at the end of titration and at 1 year after minimization was 139+/-12 / 82+/-7 mmHg (33+/-15 / 17+/-9) in the 5226 patients still on randomized treatment The numbers requiring the four treatment increments were, respectively, 1591, 780, 597 and 294, meaning that almost 70% of patients on randomized treatment in INSIGHT are receiving only the primary drug. At one year, 69% of patients had a blood pressure < or = 140/90 mmHg. INSIGHT is one of the first double-blind comparisons of active antihypertensive treatments, requiring high-risk patients to achieve sufficient power. Despite this requirement, it is possible to achieve good blood pressure control in most patients without the addition of multiple additional treatments that may dilute any differences between the primary agents.


[New data on coat color gene frequencies in cats: 1. the Armavir population].
The population of domestic cats from the city of Armavir has been examined. A high frequency of gene O was revealed in the population. Differences among three subpopulations estimated using two genetic distances showed heterogeneity of the Armavir cat population. The extreme samples showed highly significant differences (P < 0.01; chi2[6] = 24.67), likely explained by the structural features of the synantropous population and human-driven frequency- dependent selection operating in it. The feline population of Armavir underwent significant changes during the past two decades. The d(ij) coefficient in it was 0.093; D(p) = 0.05. The frequencies of genes orange and Long-hair have increased in the general population. The frequency of gene dilution has decreased. These changes may have occurred because of genetic exchange with purebred domestic cats that have become more popular as pets in the recent years.


Multi-PGS enhances polygenic prediction by combining 937 polygenic scores.
The predictive performance of polygenic scores (PGS) is largely dependent on the number of samples available to train the PGS. Increasing the sample size for a specific phenotype is expensive and takes time, but this sample size can be effectively increased by using genetically correlated phenotypes. We propose a framework to generate multi-PGS from thousands of publicly available genome-wide association studies (GWAS) with no need to individually select the most relevant ones. In this study, the multi-PGS framework increases prediction accuracy over single PGS for all included psychiatric disorders and other available outcomes, with prediction R2 increases of up to 9-fold for attention-deficit/hyperactivity disorder compared to a single PGS. We also generate multi-PGS for phenotypes without an existing GWAS and for case-case predictions. We benchmark the multi-PGS framework against other methods and highlight its potential application to new emerging biobanks.


A Slam-dependent hemophore contributes to heme acquisition in the bacterial pathogen Acinetobacter baumannii.
Nutrient acquisition systems are often crucial for pathogen growth and survival during infection, and represent attractive therapeutic targets. Here, we study the protein machinery required for heme uptake in the opportunistic pathogen Acinetobacter baumannii. We show that the hemO locus, which includes a gene encoding the heme-degrading enzyme, is required for high-affinity heme acquisition from hemoglobin and serum albumin. The hemO locus includes a gene coding for a heme scavenger (HphA), which is secreted by a Slam protein. Furthermore, heme uptake is dependent on a TonB-dependent receptor (HphR), which is important for survival and/or dissemination into the vasculature in a mouse model of pulmonary infection. Our results indicate that A. baumannii uses a two-component receptor system for the acquisition of heme from host heme reservoirs.


Baicalin, silver titanate, Bletilla striata polysaccharide and carboxymethyl chitosan in a porous sponge dressing for burn wound healing.
This study tests the efficacy of Bletilla striata polysaccharide (BSP), carboxymethyl chitosan (CMC), baicalin (BA) and silver titanate (ST) in a wound dressings to fight infection, promote healing and provide superior biocompatibility. The antibacterial activity of BA and ST was evaluated in vitro using the inhibition zone method. BA/ST/BSP/CMC porous sponge dressings were prepared and characterized. The biocompatibility of BA/ST/BSP/CMC was assessed using the cell counting kit-8 assay. The therapeutic effect of BA/ST/BSP/CMC was further investigated using the dorsal skin burn model in Sprague-Dawley rats. The wound dressing had good antibacterial activity against Escherichia coli and Staphylococcus aureus through BA and ST, while the combination of BSP and CMC played an important role in promoting wound healing. The BA/ST/BSP/CMC porous sponge dressings were prepared using a freeze-drying method with the concentrations of BA and ST at 20 and 0.83 mg/mL, respectively, and the optimal ratio of 5% BSP to 4% CMC was 1:3. The average porosity, water absorption and air permeability of BA/ST/BSP/CMC porous sponge dressings were measured to be 90.43%, 746.1% and 66.60%, respectively. After treatment for 3 and 7 days, the healing rates of the BA/ST/BSP/CMC group and BA/BSP/CMC group were significantly higher than those of the normal saline (NS) group and silver sulfadiazine (SSD) group (P < 0.05). Interleukin-1β expression in the BA/ST/BSP/CMC group at 1 and 3 days was significantly lower than that in the other three groups (P < 0.05). After being treated for 3 days, vascular endothelial growth factor expression in the BA/BSP/CMC group and BA/ST/BSP/CMC group was significantly higher than that in the NS group and SSD group (P < 0.05). Inspection of histological sections showed that the BA/ST/BSP/CMC group and BA/BSP/CMC group began to develop scabbing and peeling of damaged skin after 3 days of treatment, indicating accelerated healing relative to the NS group and SSD group. The optimized concentration of BA/ST/BSP/CMC dressing was as follows: 6 mg BSP, 14.4 mg CMC, 0.5 mg ST and 12 mg BA. The BA/ST/BSP/CMC dressing, containing antibacterial constituents, was non-cytotoxic and effective in accelerating the healing of burn wounds, making it a promising candidate for wound healing. Please cite this article as: Gong YR, Zhang C, Xiang X, Wang ZB, Wang YQ, Su YH, Zhang HQ. Baicalin, silver titanate, Bletilla striata polysaccharide and carboxymethyl chitosan in a porous sponge dressing for burn wound healing. J Integr Med. 2023; 21(5): 487-495.


Differential effect of spironolactone in chronic constriction injury and vincristine-induced neuropathic pain in rats.
The present study was designed to investigate the ameliorative potential of spironolactone in chronic constriction injury and vincristine-induced neuropathic pain in rats. The chronic constriction injury was induced by placing four loose ligatures around the sciatic nerve, while vincristine (50 μg/kg) was administered for 10 days to induce chemotherapy-induced neuropathic pain. Acetone drop, pin-prick, hot plate and paint brush tests were performed to assess cold allodynia; mechanical and heat hyperalgesia; dynamic mechanical allodynia, respectively. The spontaneous pain and postural index in terms of foot deformity was also assessed. The levels of TNF-α were measured in the sciatic nerve as an index of inflammation. Chronic constriction injury led to significant development of cold allodynia; mechanical and heat hyperalgesia; dynamic mechanical allodynia; spontaneous pain and foot deformity along with rise in the levels of TNF-α. Administration of vincristine was associated with the development of allodynia and hyperalgesia without spontaneous pain, foot deformity and elevation in the levels of TNF-α. Administration of spironolactone (10 and 20 mg/kg) significantly attenuated chronic constriction injury-induced pain related behaviour and foot deformity along with attenuation of TNF-α levels, without modulating vincristine-induced neuropathic pain. The attenuating effect of spironolactone in chronic constriction injury may be due to its anti-inflammatory properties and ability to decrease pro-inflammatory cytokines, while involvement of non-inflammatory mechanisms in the pathogenesis of vincristine-induced pain may probably explain its lack of beneficial effect in chemotherapy associated pain.


Neuro-Behçet disease presented diplopia with hemiparesis following minor head trauma.
Behçet disease (BD) is rare in childhood. We report a 9-year-old boy with neuro-Behçet disease who presented diplopia and weakness on the left side after a cerebral concussion. Brain magnetic resonance imaging (MRI) revealed hyperintensity of the right mesodiencephalic junction on T2-weighted and fluid attenuated inversion recovery images. Prednisolone administration resulted in complete remission and normalization of abnormal MRI finding. Brain MRI is a useful diagnostic tool when the neurological sign is the first symptom of subclinical BD.


Construction of lncRNA/Pseudogene-miRNA Network Based on In Silico Approaches for Glycolysis Pathway to Identify Prostate Adenocarcinoma-Related Potential Biomarkers.
LncRNAs, pseudogenes, and miRNAs participate a fundamental function in tumorigenesis, metabolism, and invasion of cancer cells, although their regulation of tumor glycolysis in prostate adenocarcinoma (PRAD) is thoroughly not well studied. In this study, we applied transcriptomic, proteomic, and medical information to identify glycolysis-related key genes and modules associated with PRAD. Then, the glycolysis-related lncRNA/lncRNAs/pseudogenes-miRNA-mRNA network was constructed. Analysis of DNA methylation status and expression data determined a DNA methylation-dysregulated three-DE-mRNAs signature for predicting diagnosis, ANGPTL4, GNE, and HSPA in PRAD patients and healthy control. Several lncRNAs/pseudogenes, significantly correlated with the overall survival PVT1, CA5BP1, MIRLET7BHG, SNHG12, and ZNF37BP and disease-free survival status, MALAT1, GUSBP11, MIRLET7BHG, and SNHG1, of patients with PRAD were determined. The methylation profile of DE-lncRNA/pseudogenes was significantly proper for predicting PRAD prognostic model. The transcription level of 6 DE-mRNA ANGPTL4, QSOX1, BIK, CLDN3, DDIT4, and TFF3 was correlated with cancer-related fibroblast infiltration in PRAD. The mutated form of 7 mRNAs, COL5A1, IDH1, HK2, DDIT4, GNE, and QSOX1, was associated with PRAD. In addition to the glycolysis pathway, DE-RNAs play regulatory roles on several pathways, including DNA damage, RTK, cell cycle, RAS/MAPK, TSC/mTOR and PI3K/AKT, AR hormone, and EMT. Overall, our study improves our knowledge of the relation between lncRNAs/pseudogenes and miRNA related to glycolysis and PRAD pathogenesis. This schematics presents shows the websites and databases implemented in this research.


[1 of the pathways for normalization of populations of malignant cells].
The paper reports reasons for a possibility of tumour regression due to selection of low-malignant and differentiating clones. Experimental evidence is provided supporting this view.


Fatigue during chemoradiotherapy for nasopharyngeal cancer and its relationship to radiation dose distribution in the brain.
Fatigue during head and neck radiotherapy may be related to radiation dose to the central nervous system (CNS). The impact of patient, tumour, and dosimetric variables on acute fatigue was assessed in nasopharyngeal cancer patients undergoing chemoradiotherapy. Radiation dose to the following retrospectively-delineated CNS structures; brainstem, cerebellum, pituitary gland, pineal gland, hypothalamus, hippocampus and basal ganglia (BG) and clinical variables were related to incidence of ⩾ grade 2 fatigue in 40 patients. Sixty per cent of patients reported fatigue during and following radiotherapy. Dmean and D2 to the BG and Dmean to the pituitary gland were significantly associated with fatigue during radiation (P<0.01). Dmean to the cerebellum was associated with fatigue following radiotherapy and at any time (P < 0.01). After adjusting for clinical factors, an association remained between fatigue during radiotherapy and mean dose and D2 to the pituitary gland and BG (P = 0.012, 0.036, 0.009 and 0.018) and mean dose to the cerebellum following radiation and at any time (P = 0.042 and 0.029). Disruption of connections between BG, cerebellum, and higher cortical centres or disruption of pituitary-regulated hormonal balance may be implicated in the pathophysiology of radiation-related fatigue.


Hyperosmolality alters the ventilatory response to acute hypercapnia and hypoxia.
Acute hyperosmolality in the Pekin duck results in an extracellular acidosis and hypercarbia without any stimulation of ventilation. The development of the extracellular acidosis is accompanied by the concurrent development of an intracellular alkalosis systemically which has been hypothesized to depress ventilation (Kasserra et al., J. Appl. Physiol., 1993). In order to investigate this apparent suppression of ventilation, the ventilatory response to various respiratory challenges (CO2, O2, K+) was studied both before (normosmotic) and after (hyperosmotic) hypertonic sucrose infusion. Increased plasma osmolality caused a significant drop in arterial pH of 0.06 +/- 0.01 units and a 4 Torr increase in PaCO2, yet did not stimulate any significant increase in ventilation despite a significant increase in oxygen consumption. Acute hyperosmolality increased the PaCO2 associated with resting ventilation, and decreased the magnitude of the ventilatory response to a given increase in PaCO2, compared with the response to the same ventilatory challenge in normosmotic animals. Acute hyperosmolality increased the ventilatory response to hypoxia and K+ compared with normosmotic animals. The opposite effect of hyperosmolality on the ventilatory responses to hypercapnia compared with hypoxia suggests that the mechanisms of chemoreception for hypercapnia and hypoxia are different. The depressed ventilatory response curve to increased PaCO2 and decreased arterial pH during hyperosmolality, both alone and during the hypercapnic challenge, suggests that the peripheral chemoreceptor response to pH and CO2 is suppressed. It is hypothesized that the suppression results from the intracellular alkalosis occurring during acute hyperosmolality.


Efficacy and risk of cytotoxic chemotherapy in extensive disease-small cell lung cancer patients with interstitial pneumonia.
Small cell lung cancer (SCLC) is characterized by a high propensity for metastases and a poor prognosis irrespective of high sensitivity for initial chemotherapy. Although interstitial pneumonia (IP) is one of risk factors for lung cancer, efficacy of cytotoxic chemotherapy for patients with SCLC with IP remains unclear. Our study aims to evaluate the efficacy of systemic chemotherapy and assess risk of acute exacerbation (AE)-IP with cytotoxic drugs for extensive disease (ED)-SCLC patients with IP. We performed a retrospective study of 192 consecutive ED-SCLC patients with IP (n = 40) and without IP (n = 152) between 2008 and 2016. 31 of 40 ED-SCLC patients with IP and 130 of 152 patients without IP received systemic chemotherapy. The efficacy of chemotherapy in patients with IP was not inferior to that in patients without IP (overall survival [OS], 7.1 [95% confidence interval (CI): 0.2-14.0] vs. 10.0 [95% CI: 8.2-11.8] months, P = 0.57). Pretreatment serum levels of lactate dehydrogenase (LDH; 651.7 ± 481.0 vs. 301.4 ± 110.7 U/mL, P = 0.01) and C-reactive protein (CRP; 8.9 ± 9.6 vs. 1.8 ± 1.8 U/mL, P = 0.008) were correlated with developed AE-IP in the ED-SCLC patients with IP. Systemic chemotherapy was effective even in ED-SCLC patients with IP. However, the risk of developed AE-IP that was high in patients with IP and should be evaluated using serum LDH and CRP levels before initial chemotherapy.


Intraspecific variability in the alkaloid metabolism of Galanthus elwesii.
Alkaloid pattern of individuals from 16 Bulgarian Galanthus elwesii populations was investigated by GC/MS and TLC. Twenty-one Amaryllidaceae alkaloids were detected and 14 of them were identified. Crinane type alkaloids, haemanthamine or crinine, dominated alkaloid metabolism in most of the populations. With exception of one population, where the separate individuals showed variable alkaloid profiles (dominated by crinine or haemanthamine) the individuals of the rest of populations have identical and characteristic alkaloid profiles. Some populations showed remarkable differences in respect to their alkaloid pattern-type of biosynthesis, main alkaloids and number of alkaloids. Populations dominated by galanthamine type alkaloids were found as well. These data demonstrate that like the morphological features, the alkaloid metabolism of G. elwesii is also variable.


Intracranial arteriovenous fistula caused by endovascular stent-grafting and dilatation.
A 58-year-old man developed a self-occluding arteriovenous fistula following stent-grafting of the right internal carotid artery (ICA). Due to prolonged ischaemic neurological deficits carotid angiography had been performed 3 weeks previously. It revealed marked atherosclerotic lesions predominantly narrowing the distal right carotid siphon. MRI confirmed ischaemic lesions and massive deficits of perfusion in the right ICA cerebral territory. Stent-grafting was performed successfully, but subsequent angiography revealed a new arteriovenous fistula adjacent to the stent, between the right carotid siphon and the cavernous sinus. On angiography 10 days later, the fistula no longer was present, and flow MRI were normal; the patient was by then asymptomatic. Arteriovenous fistula can thus complicate following endovascular stenting.


Fleas and related disease.
This article considers the clinical signs of flea allergy dermatitis, and the diagnosis and general principles of flea control for the pet and its environment.


Investigating the need for therapeutic drug monitoring of imipenem in critically ill patients: Are we getting it right?
The drug levels and clearances of imipenem in critically ill patients are not comprehensively described in current literature, yet it is vital that adequate levels be achieved for therapeutic success. To determine the proportion of critically ill patients treated with imipenem/cilastatin with sub-therapeutic imipenem plasma levels, and to compare the clinical outcomes of those patients with therapeutic levels with those who had sub-therapeutic levels. Trough imipenem plasma levels of 68 critically ill patients from a surgical intensive care unit were measured using a validated high-performance liquid chromatography method. Imipenem trough levels were compared with the minimum inhibitory concentration (MIC) of the causative bacterial agents, based on a target value of 100% time above MIC (¦T >MIC). The proportion of participants with sub-therapeutic imipenem levels was 22% (95% confidence interval (CI) 13% - 34%). The 14- and 28-day mortality rates in the sub-therapeutic group were 33% and 40%, respectively, compared with 19% (p=0.293) and 26% (p=0.346), respectively, in the therapeutic group. Sub-therapeutic imipenem plasma levels are associated with adjusted hazard ratio of 1.47 (95% CI 0.55 - 3.91). The lower proportion of critically ill patients with sub-therapeutic imipenem plasma levels in this study compared with previous studies may be attributed to the practice of higher dosages and the administration method of extended infusions of imipenem/cilastatin in our setting. The results demonstrate a trend of higher mortality in patients with sub-therapeutic imipenem levels, although the results were not statistically significant at this sample size.


Screening and Evaluation of Sleep Disturbances and Sleep Disorders in Children and Adolescents.
Sleep disturbances and sleep disorders are prevalent in children/adolescents and have a bidirectional relationship with pediatric medical and mental health disorders. Screening tools and mechanisms for the evaluation and treatment of sleep disturbances and sleep disorders in the pediatric mental health clinic are less well-known; hence, sleep disturbances and disorders are under-recognized in the pediatric clinics. We present specific, validated screening and evaluation tools to identify sleep disturbances and sleep disorders in children/adolescents. We offer guidance related to the use of consumer wearables for sleep assessments and use of sleep telemedicine in pediatric mental health and primary care clinics.


Interventional uroradiology.
With advances in imaging capabilities and percutaneous instruments, many urologic diseases that were once managed surgically are now managed with minimally invasive image-guided techniques. Interventional uroradiology has evolved from simple renal biopsies for diagnostic confirmation, to percutaneous management of stones, to ablation of renal and adrenal tumors. Central to this evolution is the close cooperation with the urologist and nephrologist, each of whom provides specific skill sets and knowledge that can be used to successfully manage the patient. The purpose of this article is to detail the wide range of image-guided interventional techniques, including a discussion of indications, methods, success rates, and complications.


Nucleolin Overexpression Predicts Patient Prognosis While Providing a Framework for Targeted Therapeutic Intervention in Lung Cancer.
Notwithstanding the advances in the treatment of lung cancer with immune checkpoint inhibitors, the high percentage of non-responders supports the development of novel anticancer treatments. Herein, the expression of the onco-target nucleolin in patient-derived pulmonary carcinomas was characterized, along with the assessment of its potential as a therapeutic target. The clinical prognostic value of nucleolin for human pulmonary carcinomas was evaluated through data mining from the Cancer Genome Atlas project and immunohistochemical detection in human samples. Cell surface expression of nucleolin was evaluated by flow cytometry and subcellular fraction Western blotting in lung cancer cell lines. Nucleolin mRNA overexpression correlated with poor overall survival of lung adenocarcinoma cancer patients and further predicted the disease progression of both lung adenocarcinoma and squamous carcinoma. Furthermore, a third of the cases presented extra-nuclear expression, contrasting with the nucleolar pattern in non-malignant tissues. A two- to twelve-fold improvement in cytotoxicity, subsequent to internalization into the lung cancer cell lines of doxorubicin-loaded liposomes functionalized by the nucleolin-binding F3 peptide, was correlated with the nucleolin cell surface levels and the corresponding extent of cell binding. Overall, the results suggested nucleolin overexpression as a poor prognosis predictor and thus a target for therapeutic intervention in lung cancer.


Diagnostic and prognostic value of pretreatment PET/CT in extranodal natural killer/T-cell lymphoma: a retrospective multicenter study.
The objective of this research was to assess the utility of positron emission tomography combined with computed tomography (PET/CT) to detect bone marrow invasion (BMI) and the predictive value of PET/CT in extranodal natural killer/T-cell lymphoma (ENKTL) patients. This multicentre study enrolled ENKTL patients who underwent pretherapy PET/CT and bone marrow biopsy (BMB). The specificity, sensitivity, negative predictive value (NPV), and positive predictive value (PPV) of PET/CT and BMB for BMI were evaluated. Multivariate analysis was used to identify predictive parameters for constructing a nomogram. Seven hundred and forty-eight patients were identified from four hospitals, with eighty (10.7%) having focal skeletal lesions on PET/CT and fifty (6.7%) having positive BMB. When BMB is considered as the gold standard, the specificity, sensitivity, PPV, and NPV of PET/CT for diagnosing BMI were found to be 93.8%, 74.0%, 46.3%, and 98.1%, respectively. PET/CT-positive individuals showed significantly worse OS than PET/CT-negative patients in the subgroup of BMB-negative cases. The nomogram model created according to the significant risk factors from multivariate analysis performed well in predicting survival probability. PET/CT offers a superior degree of precision for determining BMI in ENKTL. A nomogram model including the parameters of PET/CT can predict survival probability and may help in applying appropriate personalized therapy.