Successful laparoscope-assisted orchiectomy in three cryptorchid sheep.
Three adult Corriedale cryptorchid sheep were subjected to laparoscope-assisted orchiectomy of the retained testicles. One (n = 2) or both (n = 1) the testicles were missing in their scrotal sac and inguinal regions. Ultrasonography was used to locate the retained testicles and their distance from the abdominal surface. The animals were restrained in dorsal recumbency and Trendlenburg posture under lumbosacral epidural anaesthesia using 2% lignocaine hydrochloride. Two laparoscopic ports were created in the caudal abdomen adjacent to the retained testicles. They were identified by their ovoid shape, white glistening surface (Tunica albuginea) and typical vasculature. Laparoscope-assisted exteriorization of the testicles after enlarging the ports, ligation of their blood supply and resection of the spermatic cord was performed successfully. The scrotal testes in two rams were then subjected to routine Burdizzoo castration. The laparoscopic port sites healed without complications and all the animals continued to do well subsequently. From this case report, it is concluded that in sheep the laparoscopy; a minimally invasive procedure can confirm abdominal retention of testicle/s and may also be used for their retrieval in a single sitting. Although total laparoscopic procedure is expected to reduce the incision size further but requires advanced laparoscopic instruments and expertise.


Wheat-associated microbiota and their correlation with stripe rust reaction.
This study was aimed at revealing the composition of microbiota in leaves, roots and rhizosphere soil of wheat plants that are resistant or susceptible to stripe rust, one of the most widely destructive leaf diseases in wheat production. A total of 36 wheat plants that showed resistant or susceptible reactions to stripe rust were sampled. Three compartments of each plant including leaves, roots and rhizosphere soil were used for whole-genomic DNA extraction and the DNA samples were subjected to high-throughput 16S rRNA gene sequencing. A total of 2885 operational taxonomic units (OTUs) were revealed from the sequencing, and they mainly distributed in the phylum of Proteobacteria. Twenty-nine OTUs formed the core microbiota of wheat plants. The differences between above- and below-ground environments could explain most of the dissimilarity of wheat-associated microbial communities. Therefore, those microbes that were able to adapt to the above-ground (leaf) environment might be more important resources for biocontrol agents against stripe rust, and they could be from genera Hymenobacter, Flavobacterium, Chitinophage, Flavisolibacter, Niastella, Mucilaginibacter, Pedobacter, Aquincola, Massilia, Citrobacter, Cronobacter, Ewingella, Acinetobacter and Pseudomonas. No matter the microbial taxa were significantly selected by the resistant or susceptible wheat plants, they contained the members with plant growth promoting (PGP) features and could be used as potential biocontrol agents to reduce stripe rust damage. The core microbiota associated with wheat plants and microbial taxa that were significantly correlated with reactions to stripe rust were identified in this study. Few studies had been done on the microbiota associated with wheat so far. Our study will not only provide fundamental knowledge about the composition of wheat-associated microbiota but also reveal the microbial taxa that have the potential to be integrated into the strategy of stripe rust management.


Extensive pneumothorax, pneumomediastinum and surgical emphysema as a complication of bleomycin therapy.
Bleomycin is a commonly used chemotherapeutic agent and one of the commonest cytotoxic drugs leading to pulmonary parenchymal damage. It generally leads to interstitial pneumonitis and fibrosis, hypersensitivity reactions and acute respiratory distress syndrome. We describe an 8-year-old boy who, following prolonged bleomycin therapy, demonstrated extensive air dissection and extrapulmonary air, an unusual and fatal complication.


Complex patterns of immediate early gene induction in rat brain following brightness discrimination training and pseudotraining.
Following training of rats on a footshock-motivated brightness discrimination task in a Y-maze, different sets of transcription factor encoding immediate early genes (IEGs) were induced in anatomically distinct brain regions. As revealed by Northern analysis, mRNA levels of c-fos, jun-B and zif/268 increased in the hippocampus, while the expression of c-jun remained unchanged over a period of 7 h. In the cerebral cortex, c-jun was induced in addition to the other genes examined. In contrast, only c-fos, but not c-jun or zif/268 mRNAs were increased in the cerebellum. The induction of IEGs was rapid and transient, reaching maximal levels immediately after training and returning to basal levels within 2 h. Similar spatiotemporal expression patterns were observed in rats that received identical, but unpaired, stimuli in a pseudotraining procedure. Our results suggest that the initial prerequisites of learning, such as stimulus novelty, lead to an increased expression of IEG mRNAs after training and pseudotraining as an early necessary but not sufficient precondition for memory consolidation. Additional converging inputs might control at the transcriptional, translational or post-translational level the synthesis and biological effectiveness of proteins necessary to complete the formation of the memory trace in trained animals.


Multiplex PCR using real time DNA amplification for the rapid detection and quantitation of HTLV I or II.
A multiplex 'real-time' polymerase chain reaction (PCR) has been established as a general technique for the quantitation of proviral human T-lymphotrophic virus types 1 and 2 (HTLV-I/II). The technology utilizes fluorescence to measure amplification products from the tax gene of Human T-cell lymphotropic virus type 1 or the 5' long terminal repeat of Human T-cell lymphotropic virus type 2. The quantitative amplification of the standard was linear across four orders of magnitude with nearly identical amplification efficiencies for monoplex or the biplex format from 1.4 copes/assay (60 copies proviral DNA/0.5 micrograms human DNA) to 6000 copies/assay (240000 proviral copies/0.5 micrograms human DNA). The human beta-globin gene was used to normalize for human DNA input to determine the proviral DNA load. Three hundred fifty-six specimens received by Specialty Laboratories for HTLV I/II detection provided identical results in the detection of HTLV I/II proviral DNA. No additional positive specimens were identified with the biplex assay format. The coefficient of variation for the proviral DNA load was less than 30% for HTLV I or II quantitation (n=5). For spiked specimens, two groups of five separate 0.25 ml blood specimens (20 total) were spiked, respectively, with 0, 9.6, 48, 240 and 1200 copies of HTLV I or HTLV II DNA standards. The specimens were amplified with the HTLV I/II multiplex format. Twenty of twenty expected negative HTLV I or HTLV II specimens were negative (100% specificity) and 14/16 specimens spiked with 48 copies or more HTLV I were detected (87.5% sensitivity). Thirteen of sixteen HTLV II spiked specimens (>48 copies of HTLV II standard per 10 assays) were detected (81.2%). The real-time detection provides accurate and reliable results in a single amplification for both HTLV (I or II) targets with a more rapid turnaround time and a decrease in material required for results.


The stability of surgically assisted rapid maxillary expansion (SARME): A systematic review.
This systematic review was conducted to determine the stability of surgically assisted rapid maxillary expansion (SARME) for correction of transverse maxillary deficiency, the effect of distractor type (tooth-borne vs. bone-borne) and the influence of a retainer on post-expansion stability. The review was conducted applying the PICO criteria. Electronic database searches of published literature (MEDLINE via PubMed), Ovid via MEDLINE, the Cochrane Oral Health Group's Trial Register, Cochrane Central Register of Controlled Trials, (CENTRAL) and unpublished literature were accessed until January 2019. Search terms included SARME, 'stability', 'relapse', 'surgery', 'expansion' and 'maxillary expansion'. Five hundred and ten studies were identified overall and 15 studies were included (3 RCTs, 2 prospective & 10 retrospective) following initial screening and data extraction of full texts. The quality of evidence was assessed using the Cochrane Risk of Bias tool for RCTs and the Newcastle-Ottawa Scale for prospective & retrospective studies. The heterogeneity of the retrieved articles prohibited quantitative analysis. Overall, the studies were either of high risk of bias or low quality. Qualitative analysis reveals SARPE to achieve expansion at the inter-canine region of 4-for inter 6 mm, inter-molar region of 6-8.9 mm, and skeletal level of 2.3-3.1 mm with relapse rates in the region of 0.1-2.3 mm (inter-canine), 0.2-3 mm (inter-molar) and 0-1.8 mm (skeletal) reported. Qualitative evaluation suggests SARPE results in significant expansion at the dental and skeletal level and that this appears to be stable. Existing literature is equivocal on the clinical benefits of a retention device or distractor type (bone-borne vs. tooth borne) on stability. This review has unearthed the need for high quality prospective RCTs to fully understand the stability of SARME, particularly with relation to varying distractor types and use of retention devices. As such, the inferences drawn should be considered with some discretion based on the quality of the available evidence.


Juvenile hormone in spiders. Is this the solution to a mystery?
The juvenile hormone (JH) plays a crucial role in arthropod physiological processes, e.g., the regulation of metamorphosis, development, and reproduction (the vitellogenesis, the development of gonads, egg production). Still, data about this sesquiterpenoid hormone in spiders (Araneae) are rudimentary and equivocal. The presence of the JH or its precursors (e.g. methyl farnesoate) is not confirmed in spiders. The site of synthesis of its is still undetermined. No receptors of the JH are identified in spiders and thus, the molecular mechanism of action of this group of hormones is still unknown. Here we show by using the phylogenetic analysis and qPCR method the presence of the transcript of the enzyme catalyzing the last phase of the JH biosynthesis pathway (epox CYP15A1), the JH receptor (Met), and a possible candidate to the methyl farnesoate receptor (USP) in the various tissues and stages of ontogenesis in both sexes of spider Parasteatoda tepidariorum. Our results indicate that the juvenile hormone and/or methyl farnesoate presence is possible in the species of spider P. tepidariorum. The presence of the Ptepox CYP15A1 gene suggests that the main site of the juvenile hormone synthesis can be the integument and not the Schneider organ 2. It also seems that the juvenile hormone and/or methyl farnesoate can be hormones with biological activity due to the presence of the transcript of insect and crustacean JH/MG receptor - Met. The Ptepox CYP15A1, PtMet, and Ptusp expression are sex-, tissue-and time-specific. This study is the first report about the presence of the Ptepox CYP15A1 and PtMet transcripts in the Arachnida, which may indicate the presence of the juvenile hormone and/or methyl farnesoate in spiders.


Duration of palliative care involvement and immunotherapy treatment near the end of life among patients with cancer who died in-hospital.
Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment, but their use near the end of life in patients with advanced cancer is poorly documented. This study investigated the association between administration of ICI therapy in the last month of life and the duration of involvement of the palliative care (PC) team, among patients with advanced cancer who died in-hospital. In a retrospective, multicentre study, we included all patients who died in 2018 of melanoma, head and neck carcinoma, non-small cell lung cancer or urothelial or renal cancer, in 2 teaching hospitals and one community hospital in France. The primary outcome was the association between ICI therapy in the last month of life and duration of involvement of the PC team in patient management. Among 350 patients included, 133 (38%) received anti-cancer treatment in the last month of life, including 71/133 (53%) who received ICIs. A total of 207 patients (59%) received palliative care, only 127 (36%) 30 days before death. There was a significant association between ongoing ICI therapy in the last month of life and shorter duration of PC management (p = 0.04). Receiving ICI therapy in the last month of life was associated with an increased risk of late PC initiation by multivariate regression analysis (hazard ratio 1.668; 95% CI 1.022-2.722). ICI therapy is frequently used close to the end of life in patients with advanced cancer. Innovative new anti-cancer treatments should not delay PC referral. Improved collaboration between PC and oncological teams is needed to address this issue.


Generic and specific recurrent neural network models: Applications for large and small scale biopharmaceutical upstream processes.
The calculation of temporally varying upstream process outcomes is a challenging task. Over the last years, several parametric, semi-parametric as well as non-parametric approaches were developed to provide reliable estimates for key process parameters. We present generic and product-specific recurrent neural network (RNN) models for the computation and study of growth and metabolite-related upstream process parameters as well as their temporal evolution. Our approach can be used for the control and study of single product-specific large-scale manufacturing runs as well as generic small-scale evaluations for combined processes and products at development stage. The computational results for the product titer as well as various major upstream outcomes in addition to relevant process parameters show a high degree of accuracy when compared to experimental data and, accordingly, a reasonable predictive capability of the RNN models. The calculated values for the root-mean squared errors of prediction are significantly smaller than the experimental standard deviation for the considered process run ensembles, which highlights the broad applicability of our approach. As a specific benefit for platform processes, the generic RNN model is also used to simulate process outcomes for different temperatures in good agreement with experimental results. The high level of accuracy and the straightforward usage of the approach without sophisticated parameterization and recalibration procedures highlight the benefits of the RNN models, which can be regarded as promising alternatives to existing parametric and semi-parametric methods.


Age related rejoining of broken chromosomes in human leukocytes following X-irradiation.
One theory of aging is that the ability to repair DNA or chromosome damage decreases with age. This study made use of a method which allows the measurement of chromatid repair in interphase nuclei, the technique of premature chromosome condensation. The number of excess chromosome fragments per cell remaining after 24 h of incubation at 37 degrees C was determined and used as a measure of the ability of leukocytes to repair. The leukocytes from male donors of several ages were used and the cells from older donors showed greater residual damage and, therefore, less repair.


Etomidate and its Analogs: A Review of Pharmacokinetics and Pharmacodynamics.
Etomidate is a hypnotic agent that is used for the induction of anesthesia. It produces its effect by acting as a positive allosteric modulator on the γ-aminobutyric acid type A receptor and thus enhancing the effect of the inhibitory neurotransmitter γ-aminobutyric acid. Etomidate stands out among other anesthetic agents by having a remarkably stable cardiorespiratory profile, producing no cardiovascular or respiratory depression. However, etomidate suppresses the adrenocortical axis by the inhibition of the enzyme 11β-hydroxylase. This makes the drug unsuitable for administration by a prolonged infusion. It also makes the drug unsuitable for administration to critically ill patients. Etomidate has relatively large volumes of distributions and is rapidly metabolized by hepatic esterases into an inactive carboxylic acid through hydrolyzation. Because of the decrease in popularity of etomidate, few modern extensive pharmacokinetic or pharmacodynamic studies exist. Over the last decade, several analogs of etomidate have been developed, with the aim of retaining its stable cardiorespiratory profile, whilst eliminating its suppressive effect on the adrenocortical axis. One of these molecules, ABP-700, was studied in extensive phase I clinical trials. These found that ABP-700 is characterized by small volumes of distribution and rapid clearance. ABP-700 is metabolized similarly to etomidate, by hydrolyzation into an inactive carboxylic acid. Furthermore, ABP-700 showed a rapid onset and offset of clinical effect. One side effect observed with both etomidate and ABP-700 is the occurrence of involuntary muscle movements. The origin of these movements is unclear and warrants further research.


Early-onset multiple myeloma: an illustrative case report.
This case study describes a patient diagnosed with early manifestations of multiple myeloma and illustrates relevant aspects of differential diagnosis and the use of laboratory, radiologic, and advanced imaging techniques to aid in establishing the diagnosis and issues of management. A 36-year-old male student experienced midback pain that occurred primarily at night in conjunction with fever and unexplained weight loss. Minor trauma induced a significant fracture and an occult fracture in the upper extremity. Physical examination revealed an elevated temperature indicating a fever of undetermined etiology. Plain radiographs revealed diffuse osteoporosis of the thoracic spine. Laboratory tests revealed anemia, hypercalcemia, and abnormal monoclonal paraprotein. Magnetic resonance imaging revealed a fracture with poor healing and an occult fracture in the upper extremity. The patient was initially assessed for fever of undetermined etiology in association with nocturnal midback pain. Although considered a disease of the geriatric population, subsequent laboratory and radiologic evaluations established a diagnosis of early-onset multiple myeloma. Early recognition and referral with comanagement by an oncologist provided optimum care. Early-onset cases of multiple myeloma tend to have a more favorable response to treatment as compared with cases diagnosed in the geriatric population. Multiple myeloma should be a consideration when a patient presents with nocturnal back pain and fever of undetermined etiology. Differentiating multiple myeloma from other causes of back pain is especially important in making management decisions. With a precise history and physical diagnosis, the diagnosis may be suspected, but confirmation must rely on ancillary investigations. Multiple myeloma is frequently accompanied by a poor prognosis, but early-onset cases generally respond more favorably to interventions.


Reduction Mechanisms of Anticancer Osmium(VI) Complexes Revealed by Atomic Telemetry and Theoretical Calculations.
Resonant X-ray emission spectroscopy (RXES) has developed in the past decade as a powerful tool to probe the chemical state of a metal center and in situ study chemical reactions. We have used it to monitor spectral changes associated with the reduction of osmium(VI) nitrido complexes to the osmium(III) ammine state by the biologically relevant reducing agent, glutathione. RXES difference maps are consistent with the proposed DFT mechanism and the formation of two stable osmium(IV) intermediates, thereby supporting the overall pathway for the reduction of these high-valent anticancer metal complexes for which reduction by thiols within cells may be essential to the antiproliferative activity.


The topographical anatomy of the brachial plexus.
The anatomy of the shoulder region is discussed focusing on the course of the brachial plexus. Magnetic resonance imaging enables one to visualize the topographical anatomy of this area.


Microbiota-dependent presence of murine enteric glial cells requires myeloid differentiation primary response protein 88 signaling.
Enteric glial cells (EGCs) were shown to maintain the barrier integrity and immune homeostasis of the bowel. Postnatally, EGCs develop from progenitor cells located in the myenteric plexus and are continuously replenished through adulthood. Both, murine EGC development and replenishment were shown to depend on the microbiome. The underlying mechanisms are still unknown, and we hypothesized that the myeloid differentiation primary response protein 88 (Myd88) or toll-like receptor signaling pathways may be involved. Adult and neonatal C57BL/6 wild-type (wt) and Myd88-/- mice were housed under specific pathogen-free (SPF) or germ-free (GF) conditions. GF mice were further conventionalized by gavaging stools from, and cohousing with, SPF mice having intact microbiomes. The small bowels were harvested at various time points, and immunohistochemistry and qPCR analysis of EGC markers in the muscularis externa and mucosa were performed. In wt mice, after conventionalization, the glial cell-specific markers, glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein β (S100β), were upregulated in the mucosa and muscularis externa. In Myd88-/- mice, this upregulation did not occur. Importantly, GFAP (only in the mucosa) and S100β (in both the mucosa and muscularis externa) were significantly reduced in conventionalized Myd88-/- mice compared with the conventionalized wt mice. In neonatal mice, the gene expressions of GFAP and S100β increased between the day of birth (P0) and postnatal day 15 (P15) in the mucosa and muscularis externa of both wt and Myd88-/- mice. Notably, in the mucosa but not the muscularis externa, at P15, the gene expressions of GFAP and S100β were significantly reduced in Myd88-/-. Our data demonstrated that postnatal development and replenishment of EGCs require intestinal microbiota and depend on Myd88. The specific upstream mechanisms may involve toll-like-receptor recognition of the microbiota and will be the subject of further research.


Tuberous sclerosis.
The strong relationship between tuberous sclerosis, cardiac rhabdomyoma, and angiomyolipoma of the kidney is well illustrated in this family case study.


Impact of Intimate Partner Forced Sex on HIV Risk Factors in Physically Abused African American and African Caribbean Women.
We examined associations between intimate partner forced sex (IPFS) and HIV sexual risk behaviors among physically abused Black women. Women aged 18-55 in intimate relationships were interviewed in health clinics in Baltimore, MD and St. Thomas and St. Croix, US Virgin Islands (USVI). Of 426 physically abused women, 38% experienced IPFS; (Baltimore = 44 and USVI = 116). USVI women experiencing IPFS were more likely to have 3+ past-year sex partners (AOR 2.06, 95% CI 1.03-4.14), casual sex partners (AOR 2.71, 95% CI 1.42-5.17), and concurrent sex partners (AOR 1.94, 95% CI 1.01-3.73) compared to their counterparts. Baltimore women reporting IPFS were more likely to have exchanged sex (AOR 3.57, 95% CI 1.19-10.75). Women experiencing IPFS were more likely to report their abuser having other sexual partners in Baltimore (AOR 3.30, 95% CI 1.22-8.88) and USVI (AOR 2.03, 95% CI 1.20-3.44). Clinicians should consider the influence of IPFS on individual and partnership HIV sexual risk behaviors.


The cattle tick antigen, Bm95, expressed in Pichia pastoris contains short chains of N- and O-glycans.
Bm95 is an antigen isolated from Boophilus microplus strains with low susceptibility to antibodies developed in cattle vaccinated with the recombinant Bm86 antigen (Gavac, HeberBiotec S.A., Cuba). It is a Bm86-like surface protein, which by similarity contains seven EGF-like domains and a lipid-binding GPI-anchor site at the C-terminal region. The primary structure of the recombinant (rBm95) protein expressed in Pichia pastoris was completely verified by LC/MS. The four potential glycosylation sites (Asn 122, 163, 329, and 363) are glycosylated partially with short N-glycans, from Man(5)GlcNAc(2) to Man(9)GlcNAc(2) of which, Man(8-9)GlcNAc(2) were the most abundant. O-Glycopeptides are distributed mostly towards the protein N-terminus. While the first N-glycosylated site (Asn(122)) is located between EGF-like domains 2 and 3, where the O-glycopeptides were found, two other N-glycosylated sites (Asn(329) and Asn(363)) are located between EGF-like domains 5 and 6, a region devoid of O-glycosylated Ser or Thr.


Histone demethylase KDM4A regulates adipogenic and osteogenic differentiation via epigenetic regulation of C/EBPα and canonical Wnt signaling.
Epigenetic modifications play a central role in cell differentiation and development. In the current study, we have recognized lysine demethylase 4A (KDM4A) as a novel epigenetic regulator of osteoblast and adipocyte differentiation. Kdm4a expression was upregulated during osteogenesis and adipogenesis of primary marrow stromal cells and established stromal ST2 line. Overexpression of wild-type Kdm4a promoted adipogenic differentiation and blocked osteogenic differentiation of the progenitor cells. This effect was largely alleviated when the catalytically dead mutation was made. Conversely, depletion or inactivation of Kdm4a in undifferentiated progenitor cells inhibited the formation of adipocytes and promoted the differentiation of osteoblasts. Mechanism explorations showed that overexpression of Kdm4a upregulated the expression of secreted frizzled-related protein 4 (Sfrp4) and CCAAT/enhancer-binding protein α (C/ebpα). Chromatin immunoprecipitation assay demonstrated that KDM4A directly bound the promoters of Sfrp4 and C/ebpα, removed the histone methylation mark H3K9me3, and reduced DNA methylation levels of CpG in promoter regions of C/ebpα and Sfrp4. Furthermore, overexpression of Kdm4a inactivated canonical Wnt signaling. Moreover, activation of canonical Wnt signaling through silencing of Sfrp4 in ST2 attenuated the inhibition of osteogenic differentiation and the enhancement of adipogenic differentiation by KDM4A. These data have identified KDM4A as a novel regulator of osteoblast and adipocyte differentiation and suggest KDM4A inhibition as a potential therapeutic target for treating metabolic disorders such as osteoporosis.


A γ-PGA/KGM-based injectable hydrogel as immunoactive and antibacterial wound dressing for skin wound repair.
Injectable hydrogels, of which the cover area and volume can be flexibly adjusted according to the shape and depth of the wound, are considered to be an ideal material for wound dressing. Konjac glucomannan (KGM) is a natural polysaccharide with immunomodulatory capability, while γ-polyglutamic acid (γ-PGA) is a single chain polyamino acid with moisturizing, water-retention and antibacterial properties. This work intended to combine the advantages of the two materials to prepare an injectable hydrogel (P-OK) by mixing the adipic acid dihydrazide (ADH) modified γ-PGA with oxidized KGM. The chemical structures, the physical and chemical properties, and the biological properties of the P-OK hydrogel were evaluated. The optimal conditions to form the P-OK hydrogel were fixed, and the cytotoxicity, qPCR, antibacterial and animal experiments were performed. Results showed that the P-OK hydrogel had a fast gelation time, good water-retention rate, little cytotoxicity, good immunomodulating and antibacterial capabilities, and could shorten the healing period in the rat full-thickness defect model, which makes it a potential candidate for wound repair dressing.


Unravelling the potential of seaweeds from the Black Sea coast of Romania as bioactive compounds sources. Part I: Cystoseira barbata (Stackhouse) C. Agardh.
The Romanian coastlines of the Black Sea have abundant seaweed resources, but little effort has been done to investigate their biological potential. The aim of the present study was to assess the in vitro antioxidant and anti-proliferative effects of Cystoseira barbata (Stackhouse) C. Agardh (Sargassaceae), a brown alga inhabiting the Black Sea coast of Romania. The 70% acetone, methanol and water extracts of C. barbata were evaluated for their total phenolic content, antioxidant activity and anti-proliferative potential against human tumor cell lines (pulmonary A549, colon HT-29, mammary MCF-7) and the non-tumor mammary epithelial MCF-10A cell line. C. barbata 70% acetone extract (CBAE) displayed the highest antioxidant and cytotoxic activities. The mechanism of CBAE anti-proliferative activity involved initially increased intracellular ROS accumulation, followed by increased DNA content in the subG1 phase and DNA fragmentation leading to excessive apoptosis. Thus, our study provides a theoretical basis for the use of CBAE as a tumor preventive agent. Furthermore, UHPLC-DAD-QTOF-MS analysis of CBAE tentatively identified 18 phlorotannins as fucophlorethol and eckol derivatives, containing three up to seven phloroglucinol units. In conclusion, C. barbata represents a valuable source for the development of macroalgal-based products with putative use as nutraceuticals and pharmaceuticals.


Pharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated Review.
Flavonoids are phytochemicals that are well known for their beneficial pharmacological properties. Diosmin is a flavone glycoside derived from hesperidin, a flavanone abundantly found in citrus fruits. Daflon is an oral phlebotonic flavonoid combination containing diosmin and hesperidin (9:1) that is commonly used for the management of blood vessel disorders. After oral administration, diosmin is converted to diosmetin, which is subsequently absorbed and esterified into glucuronide conjugates that are excreted in the urine. Pharmacological effects of diosmin have been investigated in several in vitro and in vivo studies, and it was found to possess anti-inflammatory, antioxidant, antidiabetic, antihyperlipidemic, and antifibrotic effects in different disease models. Diosmin also demonstrated multiple desirable properties in several clinical studies. Moreover, toxicological studies showed that diosmin has a favorable safety profile. Accordingly, diosmin is a potential effective and safe treatment for many diseases. However, diosmin exhibits inhibitory effects on different metabolic enzymes. This encourages the investigation of its potential therapeutic effect and safety in different diseases in clinical trials, while taking potential interactions into consideration.


Catalytic micromotors as self-stirring microreactors for efficient dual-mode colorimetric detection.
A catalytic micromotor-based (MIL-88B@Fe3O4) colorimetric detection system which exhibit rapid color reaction for quantitative colorimetry and high-throughput testing for qualitative colorimetry have been successfully developed. Taking the advantages of the micromotor with dual roles (micro-rotor and micro-catalyst), under rotating magnetic field, each micromotor represents a microreactor which have micro-rotor for microenvironment stirring and micro-catalyst for the color reaction. Numerous self-string micro-reactions rapidly catalyze the substance and show the corresponding color for the spectroscopy testing and analysis. Additionally, owing to the tiny motor can rotate and catalyze within microdroplet, a high-throughput visual colorimetric detection system with 48 micro-wells has been innovatively conducted. The system enables up to 48 microdroplet reactions based on micromotors run simultaneously under the rotating magnetic field. Multi-substance, including their species difference and concentration strength, can be easily and efficiently identified by observing the color difference of the droplet with naked eye after just one test. This novel catalytic MOF-based micromotor with attractive rotational motion and excellent catalytic performance not only endowed a new nanotechnology to colorimetry, but also shows hold great potentials in other fields, such as refined production, biomedical analysis, environmental governance etc., since such micromotor-based microreactor can be easily applied to other chemical microreactions.


Effects of repetitive practice of motor tasks on somatosensory gating.
During voluntary muscle contraction, the amplitude of the somatosensory evoked potential (SEP) is reduced by inhibiting sensory information from a peripheral nerve supplying the contracted muscle. This phenomenon is called "gating." We reported that participants with good motor skills indicated strong suppression of somatosensory information. The present study investigated the effects of motor performance improvement following repetitive practice on the SEP amplitude. The ball rotation task (BR task) was practiced by 15 healthy participants repetitively. SEPs were recorded before (pre) and after (post) repetitive practice. The BR task performance was significantly improved and the required muscle activation to perform the task was significantly reduced after the repetitive practice. The degree of gating was not significant between pre and post- for the SEP amplitude. A significant correlation was found between changes in SEP amplitude from pre to post and performance improvement. After repetitive practice, the degree of gating did not change, but the performance of the BR task improved, and the muscle activity required for the BR task decreased. These results suggest that repetitive practice does not change the degree of gating but changes the mechanism of gating. Furthermore, they indicate that suppression of the somatosensory area may play a role in improving task performance.


Using rare earth element tracers and neutron activation analysis to study rill erosion process.
Spatially averaged soil erosion data provide little information on the process of rill erosion. The dynamically varied data on the temporal and spatial distributions in the rill erosion process are needed to better understand the erosion process and reveal its innate characteristics. The objectives of this study were to examine the feasibility and effectiveness of rare earth element (REE) tracers and the neutron activation analysis (NAA) method on the study of the rill erosion process and to reveal quantitatively the relationships and characteristics of temporal and spatial distributions of sediment yield in rill erosion. Four REEs were used to study the changeable process of rill erosion at 4 slope positions. Four water inflow rates were applied to a 0.3 x 5 m soil bed at 3 slopes of 10.5%, 15.8% and 21.2% in scouring experiments. All of the runoff was collected in the experiment. Each sample was air-dried and well mixed. Then 20 g of each sample was sieved through 100-mesh and about a 50 mg sample was weighed for analysis of the four elemental compositions by NAA. Results indicate that the REE tracers and NAA method can be used to not only quantitatively determine soil erosion amounts on different slope segments, but also to reveal the changeable process of rill erosion amount. All of the relative errors of the experimental results were less than 25%, which is considered satisfactory on the study of rill erosion process.


Ustilaginoidin D induces hepatotoxicity and behaviour aberrations in zebrafish larvae.
Ustilaginoidins, a group of bis-naphtho-γ-pyrones, are one of the major mycotoxins produced by Ustilaginoidea virens. This group of bis-naphtho-γ-pyrone mycotoxins has been demonstrated to have antibacterial and immunological inhibitory activities and strong cytotoxicity to human oral epidermoid carcinoma. However, little is yet known about the toxicity of ustilaginoidins to animals or toxicity mechanisms. In this study, toxicity assays to zebrafish larvae show that ustilaginoidin D is highly toxic to zebrafish with an LC50 of ∼7.50 μM. Ustilaginoidin D causes an obvious yolk sac absorption delay and liver damage in zebrafish, which is indicated by liver atrophy and the increased alanine and aspartate transaminase activities. Interestingly, different doses of ustilaginoidin D can alter zebrafish movement behavior in a distinct manner. Transcriptome analyses show that global gene expression profiling in zebrafish is significantly changed in response to ustilaginoidin D exposure. KEGG pathway analyses reveal that differentially expressed genes are enriched in the pathways related to lipid metabolism and hyperbilirubinemia, which are indicators of severe liver injury. Consistently, the expression of the marker genes for hepatotoxic responses is significantly induced by ustilaginoidin D. The findings indicate that ustilaginoidin D induces lipid metabolism disorders and hepatotoxicity in zebrafish larvae and poses a potential risk to food safety.


[Registries for rare diseases : OSSE - An open-source framework for technical implementation].
Meager amounts of data stored locally, a small number of experts, and a broad spectrum of technological solutions incompatible with each other characterize the landscape of registries for rare diseases in Germany. Hence, the free software Open Source Registry for Rare Diseases (OSSE) was created to unify and streamline the process of establishing specific rare disease patient registries. The data to be collected is specified based on metadata descriptions within the registry framework's so-called metadata repository (MDR), which was developed according to the ISO/IEC 11179 standard. The use of a central MDR allows for sharing the same data elements across any number of registries, thus providing a technical prerequisite for making data comparable and mergeable between registries and promoting interoperability.With OSSE, the foundation is laid to operate linked patient registries while respecting strong data protection regulations. Using the federated search feature, data for clinical studies can be identified across registries. Data integrity, however, remains intact since no actual data leaves the premises without the owner's consent. Additionally, registry solutions other than OSSE can participate via the OSSE bridgehead, which acts as a translator between OSSE registry networks and non-OSSE registries. The pseudonymization service Mainzelliste adds further data protection.Currently, more than 10 installations are under construction in clinical environments (including university hospitals in Frankfurt, Hamburg, Freiburg and Münster). The feedback given by the users will influence further development of OSSE. As an example, the installation process of the registry for undiagnosed patients at University Hospital Frankfurt is described in more detail.


A pediatric colorectal and pelvic reconstruction course improves content exposure for pediatric surgery fellows: A three-year consecutive study.
Interactive courses play an important role in meeting the educational needs of pediatric surgical trainees. We investigated the impact of a multimodal pediatric colorectal and pelvic reconstruction course on pediatric surgery trainees. A retrospective evaluation was performed of pre- and post-course surveys for an annual colorectal and pelvic reconstruction course over 3 consecutive years (2017-2019). The course included didactic and case-based content, interactive questions, video, and live case demonstration, and a hands-on lab. Pre- and post-course surveys were distributed to participants. Comfort with operative/case procedures was scored on a 5-point Likert scale (1 uncomfortable, 5 very comfortable). The primary outcome was improved confidence and content knowledge for pediatric colorectal surgical conditions. 165 pediatric surgical fellow participants with a 70 responses (42.4% response rate) comprised the cohort. Participants had limited advanced pediatric colorectal experience. At the time of the course, participants reported a median of 5 [3,10] Hirschsprung pull-throughs, 6 [3,10] anorectal malformation, and 1 [0,1] cloaca cases. Participants transitioned from discomfort to feeling comfortable with pediatric colorectal operative set-up and case management (pre-course 2 [2,3] and post-course 4 [4,5] p<0.001). Pediatric surgery trainees report limited exposure to advanced pediatric colorectal and pelvic reconstruction cases and management during their pediatric surgical fellowship training but report improved content knowledge- and technical understanding of complex pediatric disorders upon completion of a dedicated course. The course is an important adjunct to the experience gained in pediatric surgery fellowship for achieving competency in managing patients with Hirschsprung disease, anorectal malformation, and cloacal reconstructions.


Age-dependent changes of biochemical parameters during the perfusion of the isolated rat liver.
The livers were isolated from Sprague-Dawley rats in 5 groups aged from 4 to 5, 10 to 12, 24 to 26, 30 to 32 and 35 to 37 months and perfused for 5 h to study the activities of GOT and GPT, the K+ level and to form the quotient of lactate/pyruvate and beta-hydroxybutyrate/acetoacetate in the perfusion medium. The K+ level showed no age related changes, which eliminates, by use of the method described in this paper, the K+ level as sensitive parameter of cell membrane function. Both redox quotients indicate a metabolic breakdown after 240 min perfusion in the oldest group, which points to a reduced adaptability in senescent animals to changed metabolical conditions during the perfusion of the isolated livers. The transaminases GOT and GPT proved to be the most sensitive parameters of cell membrane function, allowing the finest discriminations between the various age groups. Here also the senescent group showed the first signs of membrane damages.


Demonstration of sex hormone binding globulin in human cerebrospinal fluid.
This study demonstrates the existence of sex hormone binding globulin (SHBG) in human cerebrospinal fluid (CSF) by means of a highly sensitive radioligand saturation assay that has been recently described by us for measurement of SHBG in human plasma. The molecular similarity of this 5 alpha-dihydrotestosterone binding protein with plasma-SHBG was substantiated by a number of experiments in which the CSF-protein displayed the same properties as plasma-SHBG with respect to thermolability, affinity, specificity and sedimentation rate. SHBG levels in the CSF of normal women were found to be 0.139 +/- 0.04 nmol/l (mean +/- standard deviation), and in normal men to be 0.083 +/- 0.03 nmol/l respectively. CSF-SHBG in patients with a variety of neurological diseases associated with different degrees of a blood-CSF barrier disturbance, showed a good correlation with commonly determined parameters such as CSF-albumin and CSF-IgG that are known to be of plasma origin. The concept of CSF-SHBG originating from plasma by restricted diffusion is strongly supported by the finding that the CSF/plasma ratio of SHBG is independent of the plasma-SHBG concentration in the entire physiological range. Possible diagnostic and pathophysiological implications of this so far undetected CSF-constituent are discussed with regard to neurological and endocrine abnormalities.


[4 methods for primary impressions in complete removable dentures].
First necessary step to realize full denture prosthesis, primary impression can be made by different ways. Plaster and alginate, easy to use and often employed remain references technics. Several viscosities silicones allow real prefunctional registrations. Delayed setting resins give precise physiological limits to first impressions.


HILPDA promotes NASH-driven HCC development by restraining intracellular fatty acid flux in hypoxia.
The prevalence of non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) is rising rapidly, yet its underlying mechanisms remain unclear. Herein, we aim to determine the role of hypoxia-inducible lipid droplet associated protein (HILPDA)/hypoxia-inducible gene 2 (HIG2), a selective inhibitor of intracellular lipolysis, in NASH-driven HCC. The clinical significance of HILPDA was assessed in human NASH-driven HCC specimens by immunohistochemistry and transcriptomics analyses. The oncogenic effect of HILPDA was assessed in human HCC cells and in 3D epithelial spheroids upon exposure to free fatty acids and either normoxia or hypoxia. Lipidomics profiling of wild-type and HILPDA knockout HCC cells was assessed via shotgun and targeted approaches. Wild-type (Hilpdafl/fl) and hepatocyte-specific Hilpda knockout (HilpdaΔHep) mice were fed a Western diet and high sugar in drinking water while receiving carbon tetrachloride to induce NASH-driven HCC. In patients with NASH-driven HCC, upregulated HILPDA expression is strongly associated with poor survival. In oxygen-deprived and lipid-loaded culture conditions, HILPDA promotes viability of human hepatoma cells and growth of 3D epithelial spheroids. Lack of HILPDA triggered flux of polyunsaturated fatty acids to membrane phospholipids and of saturated fatty acids to ceramide synthesis, exacerbating lipid peroxidation and apoptosis in hypoxia. The apoptosis induced by HILPDA deficiency was reversed by pharmacological inhibition of ceramide synthesis. In our experimental mouse model of NASH-driven HCC, HilpdaΔHep exhibited reduced hepatic steatosis and tumorigenesis but increased oxidative stress in the liver. Single-cell analysis supports a dual role of hepatic HILPDA in protecting HCC cells and facilitating the establishment of a pro-tumorigenic immune microenvironment in NASH. Hepatic HILPDA is a pivotal oncometabolic factor in the NASH liver microenvironment and represents a potential novel therapeutic target. Non-alcoholic steatohepatitis (NASH, chronic metabolic liver disease caused by buildup of fat, inflammation and damage in the liver) is emerging as the leading risk factor and the fastest growing cause of hepatocellular carcinoma (HCC), the most common form of liver cancer. While curative therapeutic options exist for HCC, it frequently presents at a late stage when such options are no longer effective and only systemic therapies are available. However, systemic therapies are still associated with poor efficacy and some side effects. In addition, no approved drugs are available for NASH. Therefore, understanding the underlying metabolic alterations occurring during NASH-driven HCC is key to identifying new cancer treatments that target the unique metabolic needs of cancer cells.


The Rate of Heterotopic Ossification Following Cervical Disc Arthroplasty: A Systematic Review and Comparison of Data.
Systematic review. The purpose of the current study is to determine the overall incidence of Heterotopic Ossification (HO) following cervical disc arthroplasty (CDA) as well as per annum rates. CDA is a well-established surgical modality for treatment of one- and two-level degenerative disc disease that has failed conservative treatment. Despite its proven mid-term clinical success, the potential for accelerated HO following CDA remains an area of clinical concern. A MEDLINE literature search was performed using PubMed, the Cochrane Database of Systematic Reviews, and Embase from January 1980 to February 2018. We included studies involving adult patients, who underwent CDA, documentation of HO, with >12 month follow-up. The pooled results were obtained by calculating the effect size based on the logit event rate. Per annum rates were determined based on weighted averages according to average follow-up period. The initial database review resulted in 230 articles, with 19 articles that met inclusion and exclusion criteria. These pooled results included 2151-disc levels and 1732 patients (50% men and 50% women) who underwent CDA and were evaluated for postoperative HO. The mean age was 45 years with a mean follow-up of 60 months. Sixteen studies reported the occurrence of severe HO resulting in 22.8% of disc levels developing severe HO. When stratifying these studies based on funding type, severe HO was reported at a rate of 21.6% by IDE studies and 27.9% by independent studies. The findings of the pooled data show the incidence of severe HO following CDA to be 22.8%. However, there is a significant difference in reported rates of mild and severe HO between IDE and independent data. This alludes to possible underreporting of HO and severity of HO in the industry sponsored IDE studies when compared with independent studies. 2.


Atmospheric silicon wet deposition and its influencing factors in China.
Silicon (Si) is considered a "quasi-essential" nutrient element for plants and is also an essential nutrient for some phytoplankton. Except for the silicate provided by weathering, atmospheric deposition has gradually become an important supplementary method for Si nutrients to enter the ecosystem. However, national observational studies on atmospheric silicon deposition have not yet been reported. Herein, based on the China Wet Deposition Observation Network, we continuously collected monthly wet deposition samples from 43 typical ecosystems from 2013 to 2020 and measured the content of dissolved silica (dSi) in precipitation to quantify the spatiotemporal patterns of Si wet deposition in China. The results showed that the mean annual dSi wet deposition in China during 2013-2020 was approximately 2.07 ± 0.27 kg ha-1 yr-1. Atmospheric dSi deposition was higher in Southwest, North, and South China but lower in the Northwest and Northeast China, which was mainly regulated by precipitation and soil available Si content. There was no significant annual variation trend in dSi deposition during 2013-2020 in China, which showed disorderly fluctuations from year to year. This study revealed the spatiotemporal patterns of atmospheric dSi deposition in China for the first time, which can provide unique scientific data to explore the potential effect of dSi deposition on carbon sequestration in aquatic ecosystems. A comprehensive evaluation of the nutrient balance of aquatic ecosystems from the perspective of nitrogen, phosphorus, and silicon stoichiometry is required in the future.


Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile.
We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).


Long-term prognosis of asymptomatic individuals with spontaneous or drug-induced type 1 electrocardiographic phenotype of Brugada syndrome.
Risk stratification of asymptomatic individuals with type 1 electrocardiogram (ECG) phenotype of Brugada syndrome (BS) still remains controversial. This study investigated the long-term prognosis of asymptomatic subjects with spontaneous or drug-induced type 1 ECG pattern of BS. Data from 33 apparently healthy individuals (30 males; age, 43.6 ± 13.4 years) with spontaneous (n = 12) or drug-induced (n = 21) type 1 ECG pattern of BS were retrospectively analyzed. Thirteen subjects (39.4%) displayed a positive family history of BS and/or sudden cardiac death. Electrophysiologic study was performed in 16 subjects, and programed right ventricular stimulation induced polymorphic ventricular tachycardia in 9 (56.3%) of them. A cardioverter defibrillator was implanted in 6 cases. During a mean follow-up period of 5.3 ± 2.8 years, all subjects remained asymptomatic. None of them had syncope or cardioverter defibrillator discharges due to ventricular arrhythmias. Asymptomatic individuals with spontaneous or drug-induced type 1 ECG phenotype of BS display a benign clinical course during long-term follow-up.


Editorial for the Special Issue on Micro/Nano Devices for Blood Analysis, Volume II.
The development of micro- and nanodevices for blood analysis continues to be a growing interdisciplinary subject that demands the careful integration of different research fields [...].


Communicating hydrocephalus after radiosurgery for vestibular schwannomas: does technique matter? A systematic review and meta-analysis.
Communicating hydrocephalus (cHCP) after radiosurgery (RS) for vestibular schwannomas (VS) has been reported. Many hypothetical mechanisms for this pathology have been proposed without consensus. The aim of this study is to determine if the platform used to treat the disease, Gamma Knife (GK) versus linear accelerator (LINAC)-based RS, makes a difference in outcome. We conducted a meta-analysis of databases PubMed and Cochrane to identify all articles for the period January 2000-August 2018 with the following inclusion criteria: (1) VS treated with single fraction SRS (2) > 10 patients (3) original reports only (4) hydrocephalus reported as complication (5) human study. A total of 7039 and 988 VS patients reported in 35 and 10 papers were treated with GK or LINAC RS, respectively. Demographic baseline characteristics not reported in aggregate did not differ between the two groups. The incidence of cHCP was 3% [95% CI 2-4] and 2% [95% CI 1-3] for GK and LINAC RS patients, respectively. Surgical CSF diversion was performed in 88% and 68% of patients evaluated for cHPC in the GK and LINAC group, respectively. Follow-up range was 30-150 and 29-92 months for GK and LINAC, respectively. The incidence of cHCP following RS for VS is very low in both GK and LINAC treated patients, albeit not identical. The higher reported surgical intervention rate for VS patients treated with GK RS might be multi-factorial, including longer follow-up in the GK group.


Preliminary study of ultrasonographic tissue quantification of the breast using the acoustic radiation force impulse (ARFI) technology.
To investigate the shear wave velocity of normal breast tissue and breast lesion using acoustic radiation force impulse (ARFI) technology. This retrospective study was conducted with the approval of the institutional review board. Shear wave velocity was measured using a linear array transducer with a bandwidth of 4-9 MHz and Virtual Touch tissue quantification (Siemens Medical Solutions, Mountain View, CA, USA) in 50 patients. First, the values of the shear wave velocity were determined in the normal tissues. Then, the changes in the shear wave velocity while applying external compression on the breast were determined. For the differential diagnosis of breast lesions, the shear wave velocities of 30 mass lesions (13 benign and 17 malignant lesions) classified as BI-RADS category 4 were measured. The mean shear wave velocities in the subcutaneous fat and the mammary gland parenchyma were 2.66 m/s and 3.03 m/s, respectively (p=0.0006). The mean shear wave velocity measured while applying external compression was 3.33 m/s for subcutaneous fat (p<0.0001), and 3.84 m/s for the mammary gland parenchyma (p<0.0001). In 4 of malignant cases, the shear wave velocity was not indicated (displayed as X.XX; unmeasurable state). The mean shear wave velocity of the 13 malignant lesions (4.49 m/s) was higher than that of benign lesions (2.68 m/s) (p<0.01). ARFI tissue quantification is thought to be a potentially promising ultrasound technique for the diagnosis of breast lesions, but further investigation is required to identify the most appropriate method of measurement.


Statin post-treatment provides protection against simulated ischemia in bovine pulmonary arterial endothelial cells.
Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, can have protective effects in various organs. We determined whether application of statins after a detrimental insult protected endothelial cells. Bovine pulmonary arterial endothelial cells (BPAEC) were subjected to a 5-h oxygen-glucose deprivation (OGD) and a 1-h simulated reperfusion. Simvastatin or atorvastatin alone or plus mevalonate (the immediate product of the reaction mediated by HMG-CoA reductase), geranylgeranyl pyrophosphate (GGPP, a product downstream of mevalonate), Ly294002 (a protein kinase B/Akt inhibitor), U0126 [an extracellular signal-regulated kinase (ERK) pathway inhibitor] or diphenyleneiodonium [a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor] were added to cells immediately after the OGD for 1h. Simvastatin and atorvastatin dose-dependently reduced the OGD and simulated reperfusion-induced lactate dehydrogenase (LDH) release from primary BPAEC and BPAEC between passage 4 and 15. This effect was inhibited by mevalonate, GGPP and Ly294002 and was not affected by U0126. Consistent with those results, simvastatin and atorvastatin increased the expression of phospho-Akt/activated Akt, and did not change the expression of phospho-ERK/activated ERK after the OGD and simulated reperfusion. The OGD and simulated reperfusion-induced LDH release and superoxide production, as measured by the dihydroethidium fluorescent intensity, were inhibited by diphenyleneiodonium. These results suggest that statin post-treatment reduces OGD and simulated reperfusion-induced cell injury. This effect may be mediated by inhibiting HMG-CoA reductase and the subsequent inhibition of small GTPases. GTPase activation depends on GGPP generation and contributes to the formation of NADPH oxidase complex that produces superoxide. The statin post-treatment-induced protection may also involve activated Akt.


Maximal Medical Improvement Following Shoulder Stabilization Surgery May Require up to 1 Year: A Systematic Review.
There is increased emphasis on properly allocating healthcare resources to optimize value within orthopedic surgery. Establishing time to maximal medical improvement (MMI) can inform clinical decision-making and practice guidelines. We sought (1) to evaluate the time to MMI as predicted by commonly used patient-reported outcome measures (PROMs) for evaluation of shoulder stabilization and (2) to evaluate typical time to return to sports and employment following surgery. A systematic review of the Medline database was conducted to identify outcome studies reporting sequential follow-up at multiple time points, up to a minimum of 2 years after shoulder stabilization surgery. The included studies examined the outcomes of arthroscopic or open surgical techniques on anterior instability. Clinically significant improvements were evaluated utilizing the minimal clinically important difference specific to each PROM. Secondary outcomes included range of motion, return to sport/work, and recurrent instability. Ten studies comprising 590 surgically managed cases of anterior shoulder instability were included (78% arthroscopic, 22% open). Clinically significant improvements in PROMs were achieved up to 1 year post-operatively for Rowe, Western Ontario Instability Index (WOSI), American Shoulder and Elbow Surgeons (ASES), and Simple Shoulder Test (SST) scores. For the three most utilized tools (Rowe, WOSI, ASES), the majority of improvement occurred in the first 6 post-operative months. Clinically significant improvements in Constant Score and Oxford Shoulder Instability Score (OSIS) were achieved up to 6 months and 2 years after surgery, respectively. No clinically significant improvements were achieved on the Disabilities of the Arm, Shoulder, and Hand (DASH) tool. Maximal medical improvement as determined by commonly utilized PROMs occurs by 1 year after operative management of anterior shoulder instability. The DASH tool does not appear to demonstrate a reliable time frame for clinically significant outcome improvement.


Association between exposure to the Chinese famine during infancy and the risk of self-reported chronic lung diseases in adulthood: a cross-sectional study.
To examine the association between early-life exposure to the Chinese famine and the risk of chronic lung diseases in adulthood. Data analysis from a cross-sectional survey. 4135 subjects were enrolled into the study from the China Health and Retirement Longitudinal Study (CHARLS) 2011-2012 baseline survey to analyse the associations between prenatal and early postnatal famine exposure and the risk of chronic lung diseases in adulthood. Chronic lung diseases were defined based on self-reported information. The prevalence of self-reported chronic lung diseases in fetus-exposed, infant-exposed, preschool-exposed, and non-exposed groups was 6.5%, 7.9%, 6.8%, and 6.1%, respectively. The risk of chronic lung diseases in the infant-exposed group was significantly higher (OR 1.95, 95% CI 1.10 to 3.44) than the non-exposed group in severely affected areas, even after adjusting for gender, smoking, and drinking, family economic status, and the highest educational attainment of the parents (OR 2.57, 95% CI 1.26 to 5.25). In addition, after stratification by gender and famine severity, we found that only infant exposure to the severe famine was associated with the elevated risk of chronic lung diseases among male adults (OR 3.16, 95% CI 1.17 to 8.51). Severe famine exposure during the period of infancy might increase the risk of chronic lung diseases in male adults.


Characterization of bacteriophage T7 RNA polymerase by linker insertion mutagenesis.
Thirty-four mutants of phage T7 RNA polymerase (RNAP) were generated by linker-insertion mutagenesis and characterized with respect to their ability to carry out various steps in the transcription cycle. A number of mutants with interesting biochemical properties were identified. These include: (1) Mutant RNAPs that are catalytically active but that bind weakly to a T7 promoter; one of these mutants is affected in a region of the RNAP that exhibits homology with the sigma subunit of Escherichia coli RNAP. Another is affected in a region that has been previously implicated in the discrimination of T7 versus T3 promoters (Joho, et al., 1990). (2) Mutant RNAPs that can bind to the promoter but are transcriptionally inactive; some of these RNAPs lack catalytic activity, others are catalytically active but are unable to initiate productive transcription at a T7 promoter. Among the latter class of mutants are enzymes that appear to be weakened in their ability to melt open (or to remain associated with) double-stranded DNA; these RNAPs make only abortive initiation products and are unable to proceed to the formation of a productive elongation complex. The mutations causing this phenotype affect regions of the RNAP that exhibit homology with the catalytic site of DNA polymerase I (Delarue et al., 1990). (3) A C-terminal insertion mutant with properties similar to a previously characterized "foot" mutant (Mookhtiar et al., 1991). This RNAP appears to be defective in the very early steps of transcription and may be unable to translocate and/or empty the active site. (4) A mutant that is transcriptionally active, but is unable to complement the growth of T7 gene 1- phage. This phenotype may result from disruption of a function of the RNAP that is distinct from its role in RNA synthesis.


Expression of activated VEGFR2 by R1051Q mutation alters the energy metabolism of Sk-Mel-31 melanoma cells by increasing glutamine dependence.
Vascular endothelial growth factor receptor 2 (VEGFR2) activating mutations are emerging as important oncogenic driver events. Understanding the biological implications of such mutations may help to pinpoint novel therapeutic targets. Here we show that activated VEGFR2 via the pro-oncogenic R1051Q mutation induces relevant metabolic changes in melanoma cells. The expression of VEGFR2R1051Q leads to higher energy metabolism and ATP production compared to control cells expressing VEGFR2WT. Furthermore, activated VEGFR2R1051Q augments the dependence on glutamine (Gln) of melanoma cells, thus increasing Gln uptake and their sensitivity to Gln deprivation and to inhibitors of glutaminase, the enzyme initiating Gln metabolism by cells. Overall, these results highlight Gln addiction as a metabolic vulnerability of tumors harboring the activating VEGFR2R1051Q mutation and suggest novel therapeutic approaches for those patients harboring activating mutations of VEGFR2.


Validity and reliability of the health-related questionnaire IBDQ-32 in Mexican patients with inflammatory bowel disease.
Inflammatory bowel disease comprises two conditions: ulcerative colitis and Crohn's disease. Inflammatory Bowel Disease Questionnaire 32 (IBDQ-32) is a specific questionnaire which has been translated from English into Spanish and validated. In the Spanish-speaking countries of America it has not been validated. The aim was to determine the psychometric properties, validity and reliability of the Mexican version of the IBDQ-32 questionnaire. A total of 316 patients with inflammatory bowel disease and 100 healthy controls participated in the study. The questionnaires IBDQ-32 and SF-36 were issued on two occasions (separated by 15 days). The psychometric properties of the Mexican version of the IBDQ-32 questionnaire were determined. Patients with inflammatory bowel disease had an impaired quality of life compared to healthy controls. There were no differences between ulcerative colitis and Crohn's disease in the total scores of IBDQ-32 and its domains. The internal consistency reliability was good. The intraclass coefficient showed good reliability (repeated measurement) for total scale and all four subscales. Factor analysis explained variance is higher than 50% therefore is considered adequate/acceptable. The correlation between IBDQ-32 and SF-36 showed a satisfactory association. The social domain is the only one that presented a ceiling effect. The Mexican version of the IBDQ-32 quality of life questionnaire is valid and reliable. This sample included the entire spectrum of inflammatory disease (remission and activity) and was comparable when assessing quality of life with the SF-36 generic questionnaire.


Zombie intuitions.
In philosophical thought experiments, as in ordinary discourse, our understanding of verbal case descriptions is enriched by automatic comprehension inferences. Such inferences have us routinely infer what else is also true of the cases described. We consider how such routine inferences from polysemous words can generate zombie intuitions: intuitions that are 'killed' (defeated) by contextual information but kept cognitively alive by the psycholinguistic phenomenon of linguistic salience bias. Extending 'evidentiary' experimental philosophy, this paper examines whether the 'zombie argument' against materialism is built on zombie intuitions. We examine the hypothesis that contextually defeated stereotypical inferences from the noun 'zombie' influence intuitions about 'philosophical zombies'. We document framing effects ('zombie' vs 'duplicate') predicted by the hypothesis. Findings undermine intuitions about the conceivability of 'philosophical zombies' and address the philosophical 'hard problem of consciousness'. Findings support a deflationary response: The impression that principled obstacles prevent scientific explanation of how physical processes give rise to conscious experience is generated by philosophical arguments that rely on epistemically deficient intuitions.


Hepatic uptake of sex steroids in men with alcoholic cirrhosis.
We attempted to determine to what extent the degree of liver function impairment might affect the hepatic uptake and, as a consequence, alter the systemic plasma levels of endogenous sex steroids in male patients with alcoholic cirrhosis. The plasma levels and hepatic uptake of the steroids dehydroepiandrosterone, androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, progesterone, and 17-hydroxyprogesterone were assessed. Systemic plasma levels of testosterone and dehydroepiandrosterone were significantly (p less than 0.05) reduced, whereas those of androstenedione, estrone, and estradiol were significantly (p less than 0.05) elevated in men with alcoholic cirrhosis when compared to controls. Sex hormone binding globulin levels were also significantly elevated (p less than 0.01). The hepatic uptake of sex steroids depended on the degree of liver function impairment as shown by the linear significant relationship between their hepatic extractions and that of indocyanine green (r = 0.74-0.92, p less than 0.05; except for dihydrotestosterone, r = 0.17, not significant). In addition, the hepatic uptake of sex steroids depended on the binding affinity to sex hormone binding globulin. The higher the affinity for sex hormone binding globulin, the lower the hepatic uptake influenced by liver function impairment. It was estimated that hepatic clearances accounted for only 20%-50% of the metabolic clearance of sex steroids. No significant relationship between plasma levels of sex steroids and their hepatic clearance was found. We show here that in alcoholic cirrhosis the extent of hepatic uptake of sex steroids depends partly on the degree of liver function impairment and partly on the degree to which they are bound to sex hormone binding globulin. Production rate or peripheral metabolism, or both, rather than hepatic uptake alone may account for the altered circulating levels of sex steroids.


Disposable diapers biodegradation by the fungus Pleurotus ostreatus.
This research assesses the feasibility of degrading used disposable diapers, an important component (5-15% in weight) of urban solid waste in Mexico, by the activity of the fungus Pleurotus ostreatus, also known as oyster mushroom. Disposable diapers contain polyethylene, polypropylene and a super absorbent polymer. Nevertheless, its main component is cellulose, which degrades slowly. P. ostreatus has been utilized extensively to degrade cellulosic materials of agroindustrial sources, using in situ techniques. The practice has been extended to the commercial farming of the mushroom. This degradation capacity was assayed to reduce mass and volume of used disposable diapers. Pilot laboratory assays were performed to estimate the usefulness of the following variables on conditioning of used diapers before they act as substrate for P. ostreatus: (1) permanence vs removal of plastic cover; (2) shredding vs grinding; (3) addition of grape wastes to improve structure, nitrogen and trace elements content. Wheat straw was used as a positive control. After 68 days, decrease of the mass of diapers and productivity of fungus was measured. Weight and volume of degradable materials was reduced up to 90%. Cellulose content was diminished in 50% and lignine content in 47%. The highest efficiency for degradation of cellulosic materials corresponded to the substrates that showed highest biological efficiency, which varied from 0% to 34%. Harvested mushrooms had good appearance and protein content and were free of human disease pathogens. This research indicates that growing P. ostreatus on disposable diapers could be a good alternative for two current problems: reduction of urban solid waste and availability of high protein food sources.


4-Amino-1-(2-benzoyl-1-phenyl-eth-yl)-3-phenyl-1H-1,2,4-triazol-5(4H)-thione.
In the title compound, C(23)H(20)N(4)OS, the two phenyl rings of the diphenyl-propanone fragment form a dihedral angle of 86.8 (1)°, and the third phenyl ring attached to the triazole ring is twisted from the latter at 40.1 (1)°. In the crystal, mol-ecules are paired into centrosymmetric dimers via pairs of inter-molecular N-H⋯O and N-H⋯S hydrogen bonds.


Effect of acupuncture in prevention and treatment of chemotherapy-induced nausea and vomiting in patients with advanced cancer: study protocol for a randomized controlled trial.
Chemotherapy-induced nausea and vomiting (CINV) is one of the most common and distressing side effects in patients with cancer. The introduction and development of antiemetic drugs have significantly improved the ability of clinicians to control CINV, but it is not easy to translate to practical application, owing to financial issues, provider-related barriers, and patient factors. Nondrug therapies are needed to alleviate the symptoms of CINV. Acupuncture is an appropriate adjunctive treatment for CINV, but additional evidence is needed. This study is a multicenter, randomized, sham-controlled prospective clinical trial. A total of 136 participants will be randomly allocated into the intervention group (verum acupuncture) or the control group (sham acupuncture) in a 1:1 ratio. All treatment will be given for 5 days. Participants in both groups will receive acupuncture sessions twice on the first day of chemotherapy and once consecutively on the following 4 days. Each session takes approximately 30 minutes. The primary outcome measure will be the Common Terminology Criteria for Adverse Events to assess CINV. The secondary outcome measures will be the Eastern Cooperative Oncology Group score, Simplified Nutritional Appetite Questionnaire, and Hospital Anxiety and Depression scale. Safety will be assessed at each visit. The results of this trial will provide clinical evidence for the effect and safety of acupuncture for CINV. ISRCTN Registry identifier: ISRCTN13287728 ). Registered on 28 February 2015. ClinicalTrials.gov identifier: NCT02369107 . Registered on 17 February 2015.


Radioimmunoassay of arginine-rich apolipoprotein of rat serum.
A double-antibody radioimmunoassay was developed for quantification of rat arginine-rich apolipoprotein in sodium decyl sulfate. Arginine-rich protein, labeled with 125I by the chloramine-T method, had the same chromatographic characteristics on Sephadex G-200 as unlabeled arginine-rich protein and up to 70% of 125I-labeled arginine-rich protein was precipitated by antisera to arginine-rich protein in rabbits. The assay is sensitive at the level of 1-10 ng and has intraassay and interassay coefficients of variation of 5.4 and 6.8%, respectively. The specificity of the assay was established by competitive displacement of 125I-labeled arginine-rich protein from its antiserum by arginine-rich protein and lipoproteins containing this protein, but not by rat albumin or other purified apolipoproteins. Immunoreactivity of rat serum and lipoproteins was complete as demonstrated by comparison with their delipidated form. The accuracy of the immunoassay was further substantiated by comparison with the amount of arginine-rich protein in chromatographic fractions of total apoprotein of very low and high density lipoproteins, and by recovery experiments in ultracentrifugally separated fractions of serum. In contrast to an immunoassay reported previously for rat apo A-I, sodium decyl sulfate was not required for complete immunoreactivity of serum and lipoproteins. The inclusion of sodium decyl sulfate (9 mM final concentration) was necessary, however, for stability of labeled and unlabeled preparations of arginine-rich protein. Content (weight %, means values +/- S.D.), of immunoassayable arginine-rich protein in isolated lipoproteins was 15 +/- 1.5% in very density lipoproteins; 6.8% in low density lipoproteins (1.02 less than d less than 1.04 g/m); 7.1 +/- 0.3% in high density lipoproteins; and 4.8 +/- 0.5% in lymph chylomicrons. Concentration in whole serum was 18.1 +/- 1.4 and 20.4 +/- 2.3 mg/dl for male and female rats, respectively. Only about 55% of arginine-rich protein was recovered in the major lipoprotein classes and about 40% was in "lipoprotein-free" serum (d greater than 1.25 g/ml). Among the lipoproteins, the high density lipoprotein fraction contained twice the amount of arginine-rich protein recovered in very low or low density lipoproteins (26.6 vs. 13.5 and 13.4%, respectively). The significance of the large amount of arginine-rich protein in the 1.25 g/ml infranatant fraction is not apparent. Although repetitive centrifugation did not alter the amount recovered in this fraction, the possibility of an artifact induced by centrifugation and high salt concentration cannot be excluded.


Association of Nutritional Status with New-Onset Delirium in Elderly, Acute Care, Orthopaedic Trauma Patients: A Single-Center Observational Study.
To determine whether nutritional status at hospital admission is independently associated with new-onset delirium (NOD) in elderly, orthopaedic trauma patients. Single-center, retrospective, cross-sectional study. Data from patients at a large teaching hospital in Boston, MA, were analyzed. All patients were ≥65 years and hospitalized for acute surgical management of their major fractures after trauma. None. Nutritional status was assessed at admission using the Mini Nutritional Assessment-Short Form (MNA-SF). Delirium was assessed using the Confusion Assessment Method within 24 hours of admission and daily throughout hospitalization. The incidence of delirium was 20% (94/471). Each unit decrement in MNA-SF was associated with a 14% higher risk of NOD (adjusted OR 1.14; 95% CI 1.05-1.28). Moreover, malnourished patients (MNA-SF score 0-7) were twice as likely to develop NOD (adjusted OR 2.07; 95% CI 1.01-4.35) compared with patients who were not malnourished (MNA-SF score 8-14). In hospitalized, elderly, orthopaedic trauma patients, poor nutritional status may be a modifiable risk factor for NOD. Future studies are needed to determine whether aggressive nutritional interventions can reduce the incidence of NOD and improve outcomes in this cohort of patients. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Differences in eating pattern labels between maintainers and nonmaintainers in the Women's Health Initiative.
To describe how a sample of women in the Women's Health Initiative Dietary Modification Trial (WHIDM) labeled a healthy eating pattern and to compare these labels to their dietary maintenance. Participants completed a food frequency questionnaire and were divided into two maintenance groups, based on the percentage of energy derived from fat in their diets. Individual, semistructured interviews with the same subjects elicited information on labels they use to describe a healthy eating pattern. Subjects were 100 postmenopausal women, 50 to 79 years of age, free of breast and colorectal cancer, and participating in a dietary intervention that consisted of 20% or less energy from fat. Percentage of energy from fat in the diet and labels used to define a healthy eating pattern. Multivariate analysis. The label "consistent/patterned" was a predictor of dietary nonmaintenance (p <.05). Future studies should use this information to re-educate nonmaintainers on compliance issues.


A Novel Model and Infrastructure for Clinical Outcomes Data Collection and Their Systematic Evaluation for UK Patients Receiving Proton Beam Therapy.
To establish an infrastructure for sustainable, comprehensive data collection and systematic outcomes evaluation for UK patients receiving proton beam therapy (PBT). A Proton Outcomes Working Group was formed in 2014 to develop a national minimum dataset for PBT patients and to define a clinically integrated informatics solution for data collection. The Christie Proton Beam Therapy Centre formed its Proton Clinical Outcomes Unit in 2018 to collect, curate and analyse outcomes data prospectively for UK-treated patients and retrospectively for UK patients referred abroad for PBT since 2008 via the Proton Overseas Programme (POP). A single electronic form (eForm) was developed to capture the agreed data, using a data tree approach including conditional logic: data items are requested once, further questions depend on previous answers and are sensitive to tumour site and patient pathway time point. Relevant data automatically populate other forms, saving time, prompting completeness of clinical assessments and ensuring data consistency. Completed eForm data populate the electronic patient record and generate individualised outputs, including consultation letters, treatment summary and surveillance plans, based on organs at risk irradiated, age and sex. All data regarding POP-treated patients are verified and migrated into the system, ensuring that patient data, whether overseas or UK treated, are consistently recorded. The eForm utilises a 'user friendly' web portal interface, the Clinical Web Portal, including clickable tables and infographics. Data items are coded to a universally recognised standard comparable with other data systems. Patient-reported outcomes are also integrated, highlighting significant toxicities and prompting a response. Outcomes data can be correlated with dosimetric DICOM data to support radiation dose modelling. Outcomes data from both POP-treated and The Christie-treated patients support long-term care, allow evaluation of PBT efficacy and safety, assist future selection of PBT patients and support hypothesis generation for future clinical trials.


The utility of magnetic resonance imaging in the detection of brain metastases in the staging of cutaneous melanoma.
To retrospectively evaluate the use of brain magnetic resonance imaging (MRI) in the initial staging of patients with cutaneous melanoma in our melanoma unit. The radiology request forms for brain MRI for melanoma staging for 193 consecutive patients were reviewed. Patient hospital records were also retrospectively reviewed. Patients with no histological confirmation of a cutaneous primary or patients whose scan was to primarily investigate their neurological symptoms were excluded. Records were also searched for incidental symptoms that may have been associated with brain metastases. One hundred patients were eligible. No patients were upstaged by MRI. Of a total of 33 patients already graded as stage IV by prior staging, 11 (33%) were found to have brain metastases. No patients graded less than stage IV were found to have brain metastases on MRI. Six out of 12 patients with incidental symptoms had metastases. Five patients graded as stage IV had asymptomatic brain metastases. We recommend brain MRI only for patients with stage IV disease and for other patients with melanoma contemplating further adjuvant therapy where brain metastases would change management.


Measuring the palpable pulsatility length as a physical examination test in defining the severity of inflow stenosis for hemodialysis fistulas.
Pulsatility is an important property of hemodialysis arteriovenous fistulas (AVF) and can be perceived by the fingers as a gradual decrease in strength downstream from the anastomosis along the main trunk of the fistula. The distance from the point at which the pulse becomes imperceptible to the anastomosis is termed the palpable pulsatility length (PPL); we considered this length may play a role in assessing the severity of inflow stenosis for hemodialysis fistulas. This study was performed by retrospective analysis of routinely collected data. Physical examinations and fistula measurements were performed in a selected population of 76 hemodialysis patients with mature fistulas during half a year. Fistula measurements included the PPL before and after treatment and the distance between the anastomosis and the arterial cannulation site (aPump length). The aPump index (API) was calculated by dividing the PPL by the aPump length. Angiograms were reviewed to determine the location and severity of stenosis. PPL and API were used to detect the critical inflow stenosis, which indicates severe inflow stenosis of an AVF. Receiver operating characteristic analysis showed that the area under the curve was 0.895 for API and 0.878 for PPL. A cutoff value of API < 1.29 and PPL < 11.0 cm were selected to detect the critical inflow stenosis. The sensitivity was 96.0% versus 80.0% and specificity was 84.31% versus 84.31% for API and PPL, respectively. PPL and API are useful tools in defining the severity of pure inflow stenosis for mature AVFs in the hands of trained examiners with high sensitivity and specificity.


Applying locally optimal criterion for classifying highly-reliable products with a control.
At the research and development stage, decision-makers may wish to classify several competing designs with respect to a control (or standard) one. The classification problem may become very difficult when the products are highly reliable, since only a few (or even no) failures may be observed under normal use condition. The accelerated life test model resolves this difficulty by shortening the time of life testing and quickly provides life data of products. For highly-reliable products with a Weibull log-linear model, we propose a classification rule based on a locally optimal criterion. A suitable sampling plan based on this rule is also developed. The performance of this rule is compared with a pairwise comparison classification rule. It is shown that the sample sizes needed for the new rule are considerably lower than those needed for the pairwise comparison rule.


Tuberculosis control in crisis-causes and solutions.
Tuberculosis (TB) incidence is projected to decline at too slow a rate to meet the targets set at the UN high level meeting on ending TB, convened in New York in 2018. To understand the causes of the slow progress in TB control, the Bill and Melinda Gates Foundation supported a patient-pathway analysis that identified significant gaps with patients being "lost" at all points along the care cascade. Although each country differed in the reasons for failure, some commonalities were identified. Most striking was the failure to diagnose and report TB patients to a national registry making finding the missing patients a priority for TB control globally. The analysis also found that optimal use of existing tools will not accelerate the rate of decline in TB incidence sufficiently, necessitating the development of new and improved tools for TB control. Finally, it was recognized that gaps in our understanding of TB pathogenesis and protective immunity as well as limited knowledge about the host pathogen interactions in granulomas of infected tissues, hinder the progress needed to develop the new tools for improved TB control. A commitment of all governments to support research, develop new tools such as new diagnostics, better drug regimens and efficacious vaccines, and improving service delivery by TB control programs will be needed to accelerate the reduction in incidence and reduce disease burden globally.


Late results of combined carotid and coronary surgery using actual versus actuarial methodology.
Controversy exists over the short-term results and long-term efficacy of concomitant coronary artery bypass grafting and carotid endarterectomy. Additionally, in this population actual versus actuarial assessment of nonfatal late events has not been previously reported. Hospital records of 500 consecutive patients having concomitant carotid endarterectomy and coronary artery bypass grafting between 1979 and 2001 were reviewed, allowing at least 1 year of follow-up on all patients. Long-term nonfatal complications were assessed by actual and actuarial methods. Patient demographics revealed a mean age of 69 years; 74% (370 patients) were male; 75% (377 patients) presented with unstable coronary syndromes; 10% (50 patients) had an intraaortic balloon pump; and 66% (329 patients) were neurologically asymptomatic. Hospital mortality was 3.6% (18 patients). Significant multivariable predictors of hospital death were preoperative transient ischemic attack or myocardial infarction, and nonelective operation. Perioperative strokes were 4.6% (23 patients), of which 2.4% (12 patients) were ipsilateral and 2.2% (11 patients) were contralateral. Significant multivariable predictors of stroke were peripheral vascular disease and use of the right internal mammary artery. Ten-year actuarial survival was 43%. Ten-year actual versus Kaplan-Meier actuarial freedoms with 95% confidence limits from late events were myocardial infarction 87% (78% and 92%) versus 81% (75% and 87%); percutaneous coronary intervention 92% (85% and 96%) versus 89% (84% and 94%); reoperative coronary grafting 96% (89% and 99%) versus 94% (90% and 98%); total stroke 85% (77% and 91%) versus 82% (76% and 87%); ipsilateral stroke 90% (83% and 94%) versus 87% (82% and 92%); carotid endarterectomy 82% (73% and 88%) versus 75% (69% and 82%). Concomitant carotid and coronary artery surgery is safe and effective, particularly in preventing ipsilateral stroke, and neutralizes the impact of unilateral carotid stenosis on early and late stroke. Actual, not actuarial, methods more accurately represent the true risk of nonfatal late events.


Shear stress activation of nitric oxide synthase and increased nitric oxide levels in human red blood cells.
Red blood cells (RBC) play an important role in the balance between generation and scavenging of nitric oxide (NO) and hence its local bioavailability and influence on vasomotor control. Previous studies have reported increased NO levels in RBC suspensions subsequent to exposure to shear forces; the present study was designed to further investigate changes in intracellular NO concentration and possible mechanisms involved for RBC exposed to well-controlled shear forces. Attached human RBC were subjected to shear stresses up to 0.1Pa in a parallel-plate flow channel; fluorescent methods were used to monitor changes in intracellular NO and calcium concentrations. Intracellular NO concentration, estimated by the fluorescence level of 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM), increased sharply within 30s following the application of shear stress between 0.013 and 0.1Pa. This increase was only partially prevented by the absence of l-arginine and by the presence of l-N-acetyl-methyl-arginine (L-NAME), strongly suggesting that this response was in part related to the activation of NO-synthase (NOS) enzyme. The increase in intracellular NO concentration under shear stress was also inhibited by calcium chelation in the suspending medium, indicating the role of calcium entry for NOS activation. Increases of intracellular calcium concentrations under the same shearing conditions were demonstrated by monitoring Fluo-3/AM fluorescence in RBC exposed to shear stress. Serine 1177 phosphorylated NOS protein, the activated form of the enzyme determined by immunohistochemistry, was found to be significantly increased following the exposure of RBC to 0.1Pa shear stress for 1min. These data confirm that RBC possess a NOS enzyme that is actively synthesizing NO and activated by effective shear forces. The data also suggest that there may be additional (e.g., non-enzymatic) NO generating mechanisms in RBC that are also enhanced under shear stress.


Enzymatic hydrolysis of soy and chickpea protein with Alcalase and Flavourzyme and formation of hydrogen bond mediated insoluble aggregates.
Food applications involving plant proteins require modification of their functionality to mimic the unique properties of animal proteins. Enzymatic hydrolysis is commonly used to alter the functionality of plant proteins, particularly to improve their solubility near the isoelectric point. Current methodological approaches mostly indicate improved solubility upon hydrolysis. However, published methods include the removal of insoluble material before analysis, and calculations are based on only the solubilized material as a percentage of the filtered protein. This approach artificially increases solubility estimation and gives an incorrect assessment of the efficacy of hydrolysis. By using the total amount of protein, this study aims to determine the effect of two microbial proteases, Flavourzyme and Alcalase, on the solubility and structural and thermal properties of soy and chickpea proteins. Protein isolates were first extracted from soy and chickpea flour and hydrolyzed from 0 to 3 h. Then, their degree of hydrolysis and solubility at a range of pHs were determined using the o-phthaldialdehyde (OPA) and Lowry methods, respectively. Proteins' electrophoretic mobility, protein-protein interactions, thermal properties, and protein secondary structures were also determined. Solubility decreased over time though the solubility of the hydrolysate improved near the isoelectric point. Soy Flavourzyme hydrolysates remained the most soluble and chickpea Flavourzyme hydrolysates showed the least solubility. Thermal data suggested that Alcalase reduced the protein denaturation temperature, leading to a loss of solubility upon thermal enzyme inactivation. The loss of solubility of hydrolysates was strongly associated with hydrogen bonding, which may result from the formation of polar peptide termini. These results challenge commonly accepted beliefs that hydrolysis inevitably improves solubility of plant proteins. Instead, it is shown that hydrolysis causes structural changes that result in aggregation, thus potentially limiting the application of enzymatic hydrolysis without the addition of further processing methods.


Endoscopic hemoclips in postoperative bleeding.
The field of application for endoscopic hemoclips has been increasingly extended, especially thanks to improvements in clips and additional clinical indications. Hemoclips are used more frequently for upper gastrointestinal (GI) bleeding and sometimes after therapeutic endoscopy. We report the successful use of endoscopic hemoclips in the management of two cases of postoperative colonic haemorrhage.


Changes in cardiac output during swimming and aquatic hypoxia in the air-breathing Pacific tarpon.
Pacific tarpon (Megalops cyprinoides) use a modified gas bladder as an air-breathing organ (ABO). We examined changes in cardiac output (V(b)) associated with increases in air-breathing that accompany exercise and aquatic hypoxia. Juvenile (0.49 kg) and adult (1.21 kg) tarpon were allowed to recover in a swim flume at 27 degrees C after being instrumented with a Doppler flow probe around the ventral aorta to monitor V(b) and with a fibre-optic oxygen sensor in the ABO to monitor air-breathing frequency. Under normoxic conditions and in both juveniles and adults, routine air-breathing frequency was 0.03 breaths min(-1) and V(b) was about 15 mL min(-1) kg(-1). Normoxic exercise (swimming at about 1.1 body lengths s(-1)) increased air-breathing frequency by 8-fold in both groups (reaching 0.23 breaths min(-1)) and increased V(b) by 3-fold for juveniles and 2-fold for adults. Hypoxic exposure (2 kPa O2) at rest increased air-breathing frequency 19-fold (to around 0.53 breaths min(-1)) in both groups, and while V(b) again increased 3-fold in resting juvenile fish, V(b) was unchanged in resting adult fish. Exercise in hypoxia increased air-breathing frequency 35-fold (to 0.95 breaths min(-1)) in comparison with resting normoxic fish. While juvenile fish increased V(b) nearly 2-fold with exercise in hypoxia, adult fish maintained the same V(b) irrespective of exercise state and became agitated in comparison. These results imply that air-breathing during exercise and hypoxia can benefit oxygen delivery, but to differing degrees in juvenile and adult tarpon. We discuss this difference in the context of myocardial oxygen supply.


ZmPRD1 is essential for double-strand break formation, but is not required for bipolar spindle assembly during maize meiosis.
Homologs of PUTATIVE RECOMBINATION INITIATION DEFECT 1 (PRD1) are known to be essential for meiotic double-strand break (DSB) formation in mouse (Mus musculus), Arabidopsis, and rice (Oryza sativa). Recent research has shown that rice PRD1 also plays an unanticipated role in meiotic bipolar spindle assembly, revealing that PRD1 has multiple functions in plant meiosis. In this study, we characterize the meiotic function of PRD1 in maize (Zea mays; ZmPRD1). Our results show that Zmprd1 mutant plants display normal vegetative growth but have complete male and female sterility. Meiotic DSB formation is fully abolished in mutant meiocytes, leading to failure in homologous pairing, synapsis, and recombination. ZmPRD1 exhibits a different pattern of chromosome localization compared to its rice homologs. The ZmPRD1 protein interacts with several DSB-forming proteins, but does not directly interact with the kinetochore proteins REC8 and SGO1. Possibly as a result of this, there are no significant abnormalities of bipolar spindle assembly in Zmprd1 meiocytes. Overall, our results demonstrate that ZmPRD1 is essential for DSB formation and homologous recombination in maize meiosis. However, the recently-identified function of PRD1 in bipolar spindle assembly during rice meiosis is not conserved in maize.


Impact modelling studies for a three-wheeled scooter taxi.
Three-wheeled scooter taxis (TSTs) are being used in many Asian countries and along with buses are the main mode of public transport for the urban middle class population. The TST chassis is made by the manufacturer and the body is fabricated by local body-makers. The vehicle is not subject to any crash safety specifications. This work is the first attempt to study the crash characteristics of TSTs using a crash simulation computer software (MADYMO) with the objective of developing practical guidelines to make the vehicle safer in collisions with other motorized road users and pedestrians. Impact modelling was done for the standard and modified TST occupied by a driver and one passenger at impact velocities of 10-30 km/h crashing with a pedestrian and a bus front. The results show that the passenger and the driver of the standard TST can sustain high HICs, face/head contact forces and tibia/knee contact forces in crashes with buses at velocities 20 km/h and greater. The magnitude of these parameters can be reduced slightly by small changes in the design of the interior and padding of critical surfaces. To increase the safety of the TST significantly major modifications need to be incorporated in the design of TSTs and bus fronts. Pedestrian impact simulations indicate that it may be possible to reduce the impact forces by changing the shape of the front of the TST. The results indicate that it should be possible to improve the crash safety properties of vehicles indigenously designed in Asian and African countries by the use of crash simulation models like MADYMO. This procedure is relatively inexpensive and can provide the first approximations for design of safer vehicles.