The fluid-phase binding of human C4 and its genetic variants, C4A3 and C4B1, to immunoglobulins.
Covalent binding of the fourth complement protein, C4, to immune complexes is an important first step in the complement mediated processing of the complexes. Many of the initial encounters between the proteins of the complement system and antigen and antibody occur in solution, and prior to this report, studies of the interactions between them have focused on complement binding to preformed immune precipitates that most likely are not found in vivo. We have characterized the covalent binding of C4b to immunoglobulin molecules in a fluid-phase system consisting only of antibody in solution and purified C4 and C1s. We demonstrate that human C4b binds to IgG in the fluid phase, that its covalent binding is predominantly to the heavy chain of IgG, and that the covalent linkage is by either amide or acyl ester bonds. In addition, we compare the covalent binding efficiencies of two genetic variants of C4, C4A3 and C4B1, to IgG. C4A3 binds 3-4 times more IgG than C4B1 over a range of C4 concentrations, and C4A3 has a higher binding efficiency than C4B1 for IgM, IgA, IgG2a and F(ab')2 as well as for a protein antigen, BSA. Furthermore, we found that whereas C4A3 is bound to immunoglobulins in the fluid-phase predominantly by amide linkage, C4B1 is bound by either amide or acyl ester bonds. The results presented here suggest that the covalent binding efficiency of C4A3 and C4B1 to IgG is similar to that reported for their covalent binding to small molecules.


Protein glycosylation and glycoinformatics for novel biomarker discovery in neurodegenerative diseases.
Glycosylation is a common post-translational modification of brain proteins including cell surface adhesion molecules, synaptic proteins, receptors and channels, as well as intracellular proteins, with implications in brain development and functions. Using advanced state-of-the-art glycomics and glycoproteomics technologies in conjunction with glycoinformatics resources, characteristic glycosylation profiles in brain tissues are increasingly reported in the literature and growing evidence shows deregulation of glycosylation in central nervous system disorders, including aging associated neurodegenerative diseases. Glycan signatures characteristic of brain tissue are also frequently described in cerebrospinal fluid due to its enrichment in brain-derived molecules. A detailed structural analysis of brain and cerebrospinal fluid glycans collected in publications in healthy and neurodegenerative conditions was undertaken and data was compiled to create a browsable dedicated set in the GlyConnect database of glycoproteins (https://glyconnect.expasy.org/brain). The shared molecular composition of cerebrospinal fluid with brain enhances the likelihood of novel glycobiomarker discovery for neurodegeneration, which may aid in unveiling disease mechanisms, therefore, providing with novel therapeutic targets as well as diagnostic and progression monitoring tools.


The Effect of Irreducible Dislocation on Functional Outcomes in Knees With Multiligament Injuries: A Matched-Cohort Analysis.
Most cases of bicruciate knee dislocation (KD) with associated posteromedial disruption (KD-IIIM) are reducible, but some cannot be reduced by closed reduction because of soft tissue incarceration. To compare the clinical characteristics and functional outcomes of KD-IIIM injuries in patients with or without incarceration of soft tissue requiring open or arthroscopic reduction. Cohort study; Level of evidence, 3. This retrospective cohort study of patients with KD was conducted between January 2013 and December 2017 at a single large institution. We applied a 1:2 matching ratio between patients with irreducible KD-IIIM injuries (irreducible group; n = 14) and those with reducible KD-IIIM injuries (control group; n = 28). There were 13 patients in the irreducible group and 25 in the control group who completed follow-up (≥2 years) and were included in our analysis. The efficacy of treatment in patients with KD was evaluated based on range of motion, the Tegner score, the Lysholm score, and the International Knee Documentation Committee (IKDC) score. At the end of follow-up, the mean Tegner score was 4.5 (range, 4-6), the mean Lysholm score was 79.2 (range, 60-95), and the mean IKDC score was 78.6 (range, 60.9-95.4) in the irreducible group. The respective results in the control group were 4.6 (range, 3-8), 83.1 (range, 39-100), and 80.6 (range, 42.5-96.6). These scores did not differ significantly between the 2 groups. Similarly, mean range of motion was similar between groups (irreducible, 118.1°; control, 124.8°). In the irreducible group, the acute subgroup showed significantly higher Lysholm and IKDC scores than the chronic subgroup, while the acute and chronic subgroups in the control group showed no significant differences in these respective outcome scores. In the present study, the treatment of irreducible KD led to similar functional outcomes compared with reducible KD. However, the treatment of chronic irreducible KD led to worse outcomes compared with acute irreducible KD, and therefore, urgent reduction is recommended in these patients.


Ethnic and gender differences in normative perceptions of substance use and actual use among college students.
The primary objective of this study was to examine whether perceived norms about cigarette, alcohol, and marijuana use differed from actual use by ethnicity using data from the 2011 College Health Survey (N = 974). Analyses of covariance controlling for year in college and sorority or fraternity membership indicated a higher mean discrepancy scores for all substances for minority students compared with White students. Results suggest that minorities may be at an increased risk for substance use due to their perception that the typical student is using more than they actually are. An implication is that social marketing messages may need to be tailored to recognize these discrepancies.


High expression of peptide receptors as a novel target in gastrointestinal stromal tumours.
Recent significant advances in understanding the biology of gastrointestinal stromal tumours (GIST) have led to the introduction of a new targeted therapy (imatinib mesylate, Glivec). Hopes of a new era of a specific cancer therapy, however, have been tempered by the recognition that a significant proportion of patients who initially respond to the drug eventually become resistant to it. Given the successful development of peptide receptor scintigraphy and radiotherapy for neuroendocrine tumours, we postulated that a similar approach could offer a valid alternative in the diagnosis and therapy of GIST. Using in vitro receptor autoradiography to measure peptide receptors, we found that 16/19 GIST expressed bombesin subtype 2 receptors, 16/19 expressed vasoactive intestinal peptide subtype 2 receptors (VPAC(2)) and 12/19 expressed cholecystokinin subtype 2 receptors, in most cases in extremely high densities. All GIST metastases were shown to express two or more of these peptide receptors in very high density. Receptors were also expressed in non-responders to Glivec or after chemo-embolisation. Conversely, somatostatin subtype 2, cholecystokinin subtype 1, bombesin subtype 1 and 3, and neuropeptide Y subtype Y(1) and Y(2) receptors were not or only rarely expressed. These data represent a strong molecular basis for the use of radiolabelled bombesin, vasoactive intestinal peptide and/or cholecystokinin analogues as targeting agents to localise GIST tumours in patients by in vivo scintigraphy and/or to perform targeted radiotherapy to destroy GIST primaries, metastases and recurrences, including those resistant to Glivec.


Novel mutations in EPO-R and oxygen-dependent degradation (ODD) domain of EPAS1 genes-a causative reason for Congenital Erythrocytosis.
Congenital Erythrocytosis (CE) can be primary or secondary due to the mutations in genes involved in the erythropoietin receptor and oxygen sensing pathway. In this study, 42 patients with 38 unrelated patients and one family (4 patients) who were JAK-2 mutation (both exon 12 and exon 14) negative with high haematocrit values were investigated. The Endogenous Erythroid colony (EEC) assay was performed in all patients, interestingly EEC colonies were high in EPAS1 and EPOR mutated patients compared to non-mutated patients. The sequence analysis of EPAS1 (exon 12), EPO-R (exon-8), VHL (exon-3), and EGLN1 (exon-1) genes in all these patients showed 19% of patients (8/42) had mutations, in exon12 of EPAS1 and exon 8 of EPO-R genes. Two novel missense mutations MW_600850:c.1183G>C, MW_600851:c.1028A>C in EPO-R gene were observed in the study group. One new MW_600849:c.1969C>T nonsense mutation and five MW_619914:c.1715A>G, MW_619915:c.1694G>T, MW_619916:c.1634T>C, MW_600852:c.1771C>G, MW_600848:c.1859G>A novel missense mutations were observed in the EPAS1 gene. Among them, 4 mutations p. (Gln572Arg), p. (Ser565Ile), p. (Ile545Thr), p. (Gln591Glu) in the ODD (Oxygen-dependent degradation) domain of HIF2α, all these variations contributed to the formation of non-functional HIF2α. No mutations were observed in VHL and EGLN1 genes. Using in silico analysis we observed that these mutations contributed to major conformational changes in the HIF2α protein making it non-functional. The mutations in the EPAS1 gene were heterozygous and show autosomal dominant inheritance patterns and we observed in one family. These novel mutations in the EPAS1 (75% (6/8)) and 25% (2/8) EPO-R genes correlating with EEC positivity were observed for the first time in India in CE patients.


Empirical correlates of the MMPI-2 Restructured Clinical (RC) Scales in a nonclinical setting.
We examined the empirical correlates of the MMPI-2 Restructured Clinical (RC; Tellegen et al., 2003) scales in a nonclinical setting. We administered 12 criterion measures assessing variables expected to be associated differentially with the RC Scales along with the MMPI-2 to a sample of 1,038 college students (Men, N = 407; Women, N = 631). Criteria included measures of somatization, depression, Machiavellian negativism, drug and alcohol abuse, anger, anxiety, social phobias, obsessive-compulsive tendencies, magical ideation, perceptual aberration, lability, and impulsivity. Results demonstrate good convergent and discriminant validity for the RC scales and add to a growing body of empirical correlates of these scales.


Acoustic trauma effects from doubling the exposure time.
Guinea pigs were used to test acoustic trauma effects from doubling the exposure time. Previously, two frequencies (20 kHz and 4 kHz) were used in conjunction with each other (ie double exposure) to see whether a prior exposure of the cochlea to one frequency would alter the extent of damage caused by a secondary frequency, when compared with damage caused by either frequency alone. A reduced area of damage was attained after double exposures. To complete the series, the same two frequencies were used separately, but the exposure time was doubled. The results from the 20 kHz series surprisingly indicated that a reduced area of damage was obtained after doubling the exposure time. No significant differences were found in the 4 kHz series.


Management of thoracic outlet syndrome.
The experience with transaxillary first-rib resection and scalenotomy reported herein shows these to be safe and effective treatments for patients with thoracic outlet syndrome (TOS). The former operation usually offers the best possibility for complete resection of the first rib and all anomalous congenital bands, and is curative in most cases, regardless of the mechanism of the compression. Scalenotomy, or Powers' operation, is also helpful, in particular for cases of TOS with a vertebral arterial insufficiency. Accurate diagnosis of TOS and selection for surgery after a detailed history and proper physical examination will result in gratifying relief of symptoms in almost all patients with TOS.


Mechanisms for incorporation of glycerol-derived precursors into polyketide metabolites.
Several polyketide secondary metabolites are shown by feeding experiments to incorporate glycerol-derived 3-carbon starter units, 2-carbon extender units, or 3-carbon branches into their hydrocarbon chains. In recent years, genetic studies have begun to elucidate the mechanisms by which this occurs. In this article we review the incorporation of glycerol-derived precursors into polyketides and propose new mechanisms for the incorporation processes.


Selective, colorimetric assay of glucose in urine using G-quadruplex-based DNAzymes and 10-acetyl-3,7-dihydroxy phenoxazine.
A selective, colorimetric assay for detection of glucose in urine was developed by transducing oxidation of glucose into the color change of 10-acetyl-3,7-dihydroxy phenoxazine (ADHP) using hemin-G quadruplex DNAzyme. Oligonucleotide 5'-ATTGGGAGGGATTGGGTGGGCAC-3' was used to form a stable G-quadruplex structure. After binding with hemin, the complex of G-quadruplex and hemin acted as a horseradish peroxidase mimicking DNAzyme and catalyzed the oxidation of colorless ADHP to red resorufin by H2O2 produced by the reaction of glucose and oxygen catalyzed by glucose oxidase. Therefore, the oxidation of glucose could be transduced into the color change of ADHP by combining these two reactions. Under the optimum conditions, the absorbance of resorufin at 570 nm was proportional to the concentration of glucose over the range of 3.0-100 μM, with a linear regression equation of A=0.017+0.0035 C (C: μM, R=0.988) and a detection limit of 1.0 μM (signal/noise 3). Some interfering compounds, such as acetaminophen, uric acid, and ascorbic acid exhibited no response under the same conditions. Therefore, the assay can be used in the selective detection of glucose in human serum and urine samples.


Scoping review on Physical Health Conditions in Irish Travellers (Mincéiri).
The objective of this scoping review was to collate physical health conditions in Mincéiri-Irish Travellers. Scoping review. MEDLINE/PubMed, EMBASE, PEDro, AMED, CINAHL, PsycINFO, SCOPUS as well as reports and grey literature were searched for primary data reporting physical health conditions of Irish Travellers up to 4 April 2023. Data was extracted, described and organised meaningfully into tables according to reported physical health conditions. The population was Travellers. The concept referred to physical health conditions. The context was Irish Travellers based in any location or setting. Exclusion criteria was data/research other than primary data relating to physical health conditions of Irish Travellers. From 198 citations generated from the database search, 11 unique studies (20 reports) were included in this scoping review, including n=7397 participants. Driven by the data, physical health conditions were categorised into cardiovascular diseases, respiratory diseases, injuries/musculoskeletal/arthritic disorders, genetic disorders and gut/bowel conditions. This review showed that the metabolic syndrome, asthma, bronchitis, tuberculosis and intentional injuries were 2-3 times more prevalent in Irish Travellers compared with the background population. Genetic conditions were also described in a proportion of Travellers. Overall, Irish Travellers experience a disproportionate burden of physical health conditions compared with background populations. Healthcare providers need to be aware of the unique physical health burden experienced by many Irish Travellers. Multifaceted strategies are needed to improve the health profile of this vulnerable and marginalised group.


The emerging field of oncolytic virus-based cancer immunotherapy.
Oncolytic viruses (OVs) provide novel and promising therapeutic options for patients with cancers resistant to traditional therapies. Natural or genetically modified OVs are multifaceted tumor killers. They directly lyse tumor cells while sparing normal cells, and indirectly potentiate antitumor immunity by releasing antigens and activating inflammatory responses in the tumor microenvironment. However, some limitations, such as limited penetration of OVs into tumors, short persistence, and the host antiviral immune response, are impeding the broad translation of oncolytic virotherapy into the clinic. If these challenges can be overcome, combination therapies, such as OVs plus immune checkpoint blockade (ICB), chimeric antigen receptor (CAR) T cells, or CAR natural killer (NK) cells, may provide powerful therapeutic platforms in the clinic.


TNFAIP8 overexpression: clinical relevance to esophageal squamous cell carcinoma.
Tumor necrosis factor alpha-induced protein 8 (TNFAIP8) is a suppressor of TNF-α mediated apoptosis, and its expression is induced by NF-κB activation. TNFAIP8 expression is significantly increased in various cancer cell lines. A correlation between TNFAIP8 overexpression, cancer progression, and poor prognosis has been described in many reports of human solid cancers. To clarify the functional and clinical significance of the cancer progression-related gene, TNFAIP8, in esophageal squamous cell carcinoma (ESCC), we used immunohistochemistry to demonstrate TNFAIP8 expression in ESCC. Next, TNFAIP8 expression was depleted by using siRNA to examine the function of TNFAIP8 in the proliferation and apoptosis induction of ESCC cell lines. We detected correlations between TNFAIP8 expression and TNM stage (P < 0.001), tumor depth (P = 0.002), lymph node metastasis (P = 0.013), distant metastasis (P = 0.001), lymphatic invasion (P < 0.001), and venous invasion (P < 0.001) among the clinicopathological characteristics of ESCC patients, and high TNFAIP8 expression was found in poor survival. TNFAIP8 depletion was significantly associated with apoptosis induction after cisplatin administration and reduced proliferation. Our results suggest that TNFAIP8 might be an effective therapeutic target for ESCC in the future.


Liver stiffness assessed by magnetic resonance elastography predicts clinical outcomes in patients with heart failure and without chronic liver disease.
Evaluation of liver stiffness (LS) by magnetic resonance elastography (MRE) is useful for estimating right atrial pressure (RAP) in patients with heart failure (HF). However, its prognostic implications are unclear. We sought to investigate whether LS measured by MRE (LS-MRE) could predict clinical outcomes in patients with HF. We prospectively examined 207 consecutive HF patients between April 2018 and May 2021 after excluding those with organic liver disease. All patients underwent 3.0-T MRE. The primary outcome of interest was the composite of all-cause death and hospitalisation for HF. During a median follow-up period of 720 (interquartile range [IQR] 434-1013) days, the primary outcome occurred in 44 patients (21%), including 15 (7%) all-cause deaths and 29 (14%) hospitalisations for HF. The patients were divided into two groups according to median LS-MRE of 2.54 (IQR 2.34-2.82) kPa. Patients with higher LS-MRE showed a higher incidence of the primary outcome compared to those with lower LS-MRE (p < 0.001). Multivariable Cox regression analyses revealed that LS-MRE value was independently associated with the risk of adverse events (hazard ratio 2.49, 95% confidence interval 1.46-4.24). In multivariable linear regression, RAP showed a stronger correlation with LS-MRE (β coefficient = 0.31, p < 0.001) compared to markers related to liver fibrosis. In patients without chronic liver disease and presenting with HF, elevated LS-MRE was independently associated with worse clinical outcomes. Elevated LS-MRE may be useful for risk stratification in patients with HF and without chronic liver disease. • Magnetic resonance elastography (MRE) is an emerging non-invasive imaging technique for evaluating liver stiffness (LS) which can estimate right atrial pressure. • Elevated LS-MRE, which mainly reflects liver congestion, was independently associated with worse clinical outcomes in patients with heart failure. • The assessment of LS-MRE would be useful for stratifying the risk of adverse events in heart failure patients without chronic liver disease.


Studies on the intramolecular C[bond]H...X (X = O, S) interactions in (S)-N-acyl- 4-isopropyl-1,3-thiazolidine-2-thiones and related 1,3-oxazolidin-2-ones.
[reaction: see text] Two intramolecular C[bond]H...X (X = O, S) interactions in (S)-N-acyl-4-isopropyl-1,3-thiazolidine-2-thiones are documented through crystallographic and spectroscopic evidence and high-level theoretical calculations. The key role played by the sulfur atoms has been made clear by comparison with structurally related (S)-N-acyl-4-isopropyl-1,3-oxazolidin-2-ones.


Venous skin flaps: an experimental study and report of two clinical distal island flaps.
An experimental study of saphenous flaps in 26 dogs is reported, which confirmed the work of Baek et al. (1985) that venous flaps can survive. In addition, it showed that venous island flaps could survive after division of the venous pedicle proximally or distally, or as free flaps, providing through flow was re-established by venous anastomoses. In this study no flaps survived on a single venous pedicle without through flow. Two successful clinical cases of venous flaps are also reported, in which through flow was re-established by a simple venous anastomosis. One of these flaps threatened to become necrotic until the thrombosed anastomosis was successfully redone.


Cytotoxicity on Allium cepa of the two main sulcotrione photoproducts, xanthene-1,9-dione-3,4-dihydro-6-methylsulphonyl and 2-chloro-4-mesylbenzoic acid.
The cytotoxic effects of 2-chloro-4-mesylbenzoic acid (CMBA) and xanthene-1,9-dione-3,4-dihydro-6-methylsulphonyl (XDD), the two main photoproducts of sulcotrione, were investigated on Allium root meristematic cells at different concentrations. Degradation of sulcotrione was correlated to mitotic index decrease, together with increasing anomaly and c-mitosis frequencies. Mitotic index significantly decreased with increasing XDD and CMBA concentrations. Cell frequency with abnormal chromosomes increased with CMBA or XDD application rates. In contrast, CMBA induced a low micronucleus rate even for high concentrations while XDD increased the micronucleus ratio. C-mitoses, chromosomal aberrations due to an inactivation of the spindle, were enhanced by CMBA treatments but not by XDD. The photochemical degradation process of the pesticide can change the risk for the environment.


The "Penumbra Sign" on Magnetic Resonance Images of Brodie's Abscess: A Case Report.
This report presents the "penumbra sign" of a Brodie's abscess in a 69-year-old male patient. The lesion was located in the proximal metaphysis of the left tibia. Histopathology confirmed the diagnosis of subacute osteomyelitis. The penumbra sign on magnetic resonance (MR) images is a helpful sign for the diagnosis of Brodie's abscess.


Synthesis of a thymine glycol building block and its incorporation into oligonucleotides.
A phosphoramidite building block of thymine glycol, a major oxidative base damage in DNA, was synthesized in four steps from protected thymidine. The two hydroxyl functions of the oxidized base were protected with the tert-butyldimethylsilyl group. Using this building block, oligonucleotides containing this damage were synthesized.


Ginsenoside Rb₁ inhibits the carotid neointimal hyperplasia induced by balloon injury in rats via suppressing the phenotype modulation of vascular smooth muscle cells.
This study aims to investigate the effects of ginsenoside Rb(1) on vascular intimal hyperplasia in rats and explore the mechanisms. The rat vascular neointimal hyperplasia model was made by rubbing the endothelia of carotid artery with a balloon and Rb(1) (10 and 30 mg/kg/day) was given the day after surgery for 14 consecutive days. The neointimal hyperplasia level and the degree of vascular smooth muscle cells (VSMCs) proliferation were evaluated by histopathology and by calculating the proliferating cell nuclear antigen (PCNA) positive expression percentage; protein expressions of PCNA, phosphorylation extracellular signal-regulated kinase 1/2 (pERK1/2), smooth muscle α-actin (SM α-actin), and the mRNA expressions of proto-oncogene c-myc, SM α-actin, SM-emb (embryonic smooth muscle myosin heavy chain) and p38 MAPK were detected by immunohistochemistry and Real Time RT-PCR, respectively. Compared with the endothelia rubbing model group, Rb(1) 10 and 30 mg/kg/day medication significantly ameliorated the neointimal hyperplasia (P<0.05), and decreased the positive expression percentage of PCNA(P<0.05). Rb(1) medication also significantly decreased the elevated protein expression of pERK1/2 and the mRNA expression of c-myc(P<0.05), and tended to reduce the expression of p38 MAPK mRNA. Endothelial rubbing increased the SM-emb mRNA expression, but decreased the expression of SM α-actin mRNA which was reversed by Rb(1) (P<0.05). The results indicate that Rb(1) inhibits the vascular neointimal hyperplasia induced by balloon-injury in rats via suppressing the VSMC proliferation, which may be involved in part the inhibition of pERK1/2 protein and related to its inhibition on VSMC phenotype modulation.


The impact of action plans on habit and intention strength for physical activity in a web-based intervention: is it the thought that counts?
Action planning is a common approach used in physical activity interventions. The aim of this study was to assess the association of frequency, consistency and content of action planning with physical activity behaviour, intention strength and habit strength. Within a 3-month web-based, computer-tailored physical activity intervention, participants (N = 115; 68.7% female, M age =43.9; range = 22-73 years) could create 6 rounds of action plans for 4 activities each (24 total). Consistency of action planning during the intervention was associated with change in physical activity at 9-months, and intention and habit strength at 3-months and 9-months. Frequency of action planning was negatively associated with intention at 3-months and 9-months. The effect of action planning consistency on physical activity behaviour was no longer significant when accounting for change in intention and habit strength. Consistency of how, where, when and with whom people plan their physical activity may translate into stronger physical activity habits. Interventions should avoid encouraging making many distinct action plans, but rather encourage stable contexts through consistent action planning.


Cued uncertainty modulates later recognition of emotional pictures: An ERP study.
Previous studies have shown that uncertainty about the emotional content of an upcoming event modulates event-related potentials (ERPs) during the encoding of the event, and this modulation is affected by whether there are cues (i.e., cued uncertainty) or not (i.e., uncued uncertainty) prior to the encoding of the uncertain event. Recently, we showed that uncued uncertainty affected ERPs in later recognition of the emotional event. However, it is as yet unknown how the ERP effects of recognition are modulated by cued uncertainty. To address this issue, participants were asked to view emotional (negative and neutral) pictures that were presented after cues. The cues either indicated the emotional content of the pictures (the certain condition) or not (the cued uncertain condition). Subsequently, participants had to perform an unexpected old/new task in which old and novel pictures were shown without any cues. ERP data in the old/new task showed smaller P2 amplitudes for neutral pictures in the cued uncertain condition compared to the certain condition, but this uncertainty effect was not observed for negative pictures. Additionally, P3 amplitudes were generally enlarged for pictures in the cued uncertain condition. Taken together, the present findings indicate that cued uncertainty alters later recognition of emotional events in relevance to feature processing and attention allocation.


Glycomics: revealing the dynamic ecology and evolution of sugar molecules.
Sugars are the most functionally and structurally diverse molecules in the biological world. Glycan structures range from tiny single monosaccharide units to giant chains thousands of units long. Some glycans are branched, their monosaccharides linked together in many different combinations and orientations. Some exist as solitary molecules; others are conjugated to proteins and lipids and alter their collective functional properties. In addition to structural and storage roles, glycan molecules participate in and actively regulate physiological and developmental processes. Glycans also mediate cellular interactions within and between individuals. Their roles in ecology and evolution are pivotal, but not well studied because glycan biochemistry requires different methods than standard molecular biology practice. The properties of glycans are in some ways convenient, and in others challenging. Glycans vary on organismal timescales, and in direct response to physiological and ecological conditions. Their mature structures are physical records of both genetic and environmental influences during maturation. We describe the scope of natural glycan variation and discuss how studying glycans will allow researchers to further integrate the fields of ecology and evolution.


Transgenic animal bioreactors in biotechnology and production of blood proteins.
The regulatory elements of genes used to target the tissue-specific expression of heterologous human proteins have been studied in vitro and in transgenic mice. Hybrid genes exhibiting the desired performance have been introduced into large animals. Complex proteins like protein C, factor IX, factor VIII, fibrinogen and hemoglobin, in addition to simpler proteins like alpha 1-antitrypsin, antithrombin III, albumin and tissue plasminogen activator have been produced in transgenic livestock. The amount of functional protein secreted when the transgene is expressed at high levels may be limited by the required posttranslational modifications in host tissues. This can be overcome by engineering the transgenic bioreactor to express the appropriate modifying enzymes. Genetically engineered livestock are thus rapidly becoming a choice for the production of recombinant human blood proteins.


Transdermal delivery of brucine-encapsulated liposomes significantly enhances anti-tumor outcomes in treating triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is always the most challenging breast cancer subtype. Herein, brucine, encapsulated in peptide-modified liposomes, was proposed for treating TNBC by transdermal delivery. For the TD peptide-modified brucine-loaded liposome (Bru-TD-Lip) we developed, it presents high encapsulation efficiency of brucine and stability. In vitro, Bru-TD-Lip shows the enhanced percutaneous permeability of brucine, is able to readily enter TNBC cells, and significantly inhibits the proliferation, migration, and invasion of these cells. In vivo, through transdermal delivery, Bru-TD-Lip presents good biosafety and anti-tumor efficacy. The transdermal delivery of Bru-TD-Lip effectively targets and inhibits subcutaneous mammary carcinogenesis in female nude mice. Compared with oral administration, the transdermal delivery significantly reduces the damage of brucine to major organs and enhances the antitumor outcomes of brucine in treating TNBC. This study provides a new therapeutic strategy for treating triple-negative breast cancer by brucine.


The political ecology of seed security in the Northern Ghanaian Savannahs.
Seed security is being promoted as a means of achieving productivity, food security, and resilience among smallholders. This has resulted in notions that vulnerabilities among smallholders in Africa are the outcomes of inadequate adoption of improved seeds. What these perspectives have neglected is: How politics mediate access to seeds? and Whether and how politics influence farmers' perception of seed security? This study draws upon a case study of Northern Ghanaian Savannahs to examine politics and seed security among smallholders. The logistic analysis shows that the presence of recurring conflicts significantly determines how farmers perceived vulnerability to seed insecurity. Thus, farmers from relatively peaceful villages were 4.705 times more likely to rate themselves as not vulnerable to seed insecurity compared to their counterparts experiencing recurring conflicts. Analysis further shows that smallholder vulnerabilities to seed insecurity are constructed at the intersection of historical ethnic conflicts and neoliberal policies in ways that contest the dominant narratives. Key for achieving seed security is a better understanding of how local and macro politics influence perceptions and mediate access to healthy and desirable seeds.


Nurse case management program of chronic pain patients treated with methadone.
Methadone treatment in chronic pain patients is still limited owing to misconceptions about addiction, safety, and its unique pharmacokinetic and pharmacodynamic properties. Nevertheless, patients with chronic noncancer pain are frequently treated with methadone at our Pain Centre either as the first opioid of choice, for specific pain conditions, or as a second-line opioid in patients developing tolerance or intractable side effects with other opioids. The aim of this study was to examine whether a nurse case management program of chronic pain patients treated with methadone is feasible and safe in trying to improve patients' care in an ambulatory setting. This program consisted of three phases: initial primary education session, telephone follow-up during methadone titration, and a subsequent maintenance period. The nurse case manager functioned autonomously and when required reported to and consulted the physician. The study included 75 subjects and was done over a nine-month period by completing follow-up questionnaires for every call. Of a total of 194 recorded calls, 41% were unscheduled. Forty-four percent of phone calls resulted in a methadone increase and 11% led to a decrease or cessation of methadone. No patients developed serious morbidity or mortality. Fifty-seven percent of patients were either satisfied or very satisfied with their treatment. A nurse-led case management program of methadone in chronic pain patients can improve patient care in an ambulatory setting.


Deletion of ferritin H in neurons counteracts the protective effect of melatonin against traumatic brain injury-induced ferroptosis.
Accumulating evidence demonstrates that ferroptosis may be important in the pathophysiological process of traumatic brain injury (TBI). As a major hormone of the pineal gland, melatonin exerts many beneficial effects on TBI, but there is no information regarding the effects of melatonin on ferroptosis after TBI. As expected, TBI resulted in the time-course changes of ferroptosis-related molecules expression and iron accumulation in the ipsilateral cortex. Importantly, we found that treating with melatonin potently rescued TBI induced the changes mentioned above and improved functional deficits versus vehicle. Similar results were obtained with a ferroptosis inhibitor, liproxstatin-1. Moreover, the protective effect of melatonin is likely dependent on melatonin receptor 1B (MT2). Although ferritin plays a vital role in iron metabolism by storing excess cellular iron, its precise function in the brain, and whether it involves melatonin's neuroprotection remain unexplored. Considering ferritin H (Fth) is expressed predominantly in the neurons and global loss of Fth in mice induces early embryonic lethality, we then generated neuron-specific Fth conditional knockout (Fth-KO) mice, which are viable and fertile but have altered iron metabolism. In addition, Fth-KO mice were more susceptible to ferroptosis after TBI, and the neuroprotection by melatonin was largely abolished in Fth-KO mice. In vitro siFth experiments further confirmed the results mentioned above. Taken together, these data indicate that melatonin produces cerebroprotection, at least partly by inhibiting neuronal Fth-mediated ferroptosis following TBI, supporting the notion that melatonin is an excellent ferroptosis inhibitor and its anti-ferroptosis provides a potential therapeutic target for treating TBI.


Participants' barriers to diagnostic resolution and factors associated with needing patient navigation.
Patient navigation (PN) may improve cancer care by identifying and removing patient-reported barriers to care. In 2012, the American College of Surgeons Commission on Cancer (CoC) announced that health care facilities seeking CoC accreditation must have PN processes in place by January 1, 2015. Given these unfunded mandates, hospitals are looking for cost-effective ways to implement PN. This study examined demographic and psychosocial predictors of barriers to diagnostic resolution among individuals with a cancer screening abnormality enrolled in the Ohio Patient Navigation Research Project. Data were obtained from patients who received care at 1 of 9 Ohio Patient Navigation Research Project intervention clinics. Descriptive statistics and logistic regression models were used. There were 424 participants, and 151 (35.6%) reported a barrier to diagnostic resolution within 90 days of study consent. The most commonly reported barriers were misconceptions about a test or treatment (16.4%), difficulty in communicating with the provider (15.0%), and scheduling problems (11.5%). Univariate analyses indicated that race, education, employment, income, insurance, clinic type, friend support, and physical and psychological functioning were significantly associated with reporting a barrier to diagnostic resolution. Multivariate analyses found that comorbidities (odds ratio, 1.65; 95% confidence interval, 1.04-2.61) and higher intrusive thoughts and feelings (odds ratio, 1.25; 95% confidence interval, 1.10-1.41) were significantly associated with reporting a barrier to diagnostic resolution. The results suggest that demographic and psychosocial factors are associated with barriers to diagnostic resolution. To ensure compliance with the CoC mandate and provide timely care to all patients, CoC-accredited facilities can systematically identify the patients most likely to have barriers to care and assign them to PN.


Multiserotype enzyme-linked immunosorbent assay as a diagnostic aid for periodontitis in large-scale studies.
Periodontitis is a common chronic oral infection caused by gram-negative bacteria, including Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Periodontitis evokes inflammatory host response locally in the periodontium but also systemically. The systemic humoral antibody response against oral pathogens can conveniently be measured by an immunoassay. The aim of the study was to measure serum immunoglobulin G class antibodies against A. actinomycetemcomitans and P. gingivalis by an enzyme-linked immunosorbent assay (ELISA) in which mixtures of several serotypes of the pathogens were used as antigens to avoid biasing of the results in favor of a particular strain. For A. actinomycetemcomitans the antigen consisted of six strains representing serotypes a, b, c, d, and e and one nonserotypeable strain. In the P. gingivalis ELISA, antigens representing serotypes a, b, and c were used. Serum samples from 90 subjects, including 35 samples from patients with diagnosed periodontitis, 10 samples from periodontally healthy controls, and 45 samples from randomly selected apparently healthy volunteers (referred to as "healthy subjects"), were tested. For both pathogens the antibody levels (means +/- standard deviations) of the patients--xpressed as area under the dilution curve--were significantly higher than those for healthy controls or healthy subjects, with values for A. actinomycetemcomitans and P. gingivalis, respectively, as follows: patients, 22.60 +/- 9.94 mm(2) and 26.72 +/- 11.13 mm(2); healthy controls, 9.99 +/- 3.92 mm(2) and 6.90 +/- 3.38 mm(2); and healthy subjects, 16.85 +/- 6.67 mm(2) and 8.51 +/- 4.23 mm(2). The serotype mixture ELISA is suitable for measuring antibodies against periodontal pathogens in large epidemiological studies in order to evaluate the role of periodontitis as a risk factor for other diseases.


Intertemporal trade-off between population growth rate and carrying capacity during public good production.
Public goods are biomolecules that benefit cellular populations, such as by providing access to previously unutilized resources. Public good production is energetically costly. To reduce this cost, populations control public good biosynthesis, for example using density-dependent regulation accomplished by quorum sensing. Fitness costs and benefits of public good production must be balanced, similar to optimal investment decisions used in economics. We explore the regulation of a public good that increases the carrying capacity, through experimental measurements of growth in Escherichia coli and analysis using a modified logistic growth model. The timing of public good production showed a sharply peaked optimum in population fitness. The cell density associated with maximum public good benefits was determined by the trade-off between the cost of public good production, in terms of reduced growth rate, and benefits received from public goods, in the form of increased carrying capacity.


Transcription associated cyclin-dependent kinases as therapeutic targets for prostate cancer.
Transcriptional deregulation has emerged as a hallmark of several cancer types. In metastatic castration-resistant prostate cancer, a stage in which systemic androgen deprivation therapies fail to show clinical benefit, transcriptional addiction to the androgen receptor is maintained in most patients. This has led to increased efforts to find novel therapies that prevent oncogenic transactivation of the androgen receptor. In this context, a group of druggable protein kinases, known as transcription associated cyclin-dependent kinases (tCDKs), show great potential as therapeutic targets. Despite initial reservations about targeting tCDKs due to their ubiquitous and prerequisite nature, preclinical studies showed that selectively inhibiting such kinases could provide sufficient therapeutic window to exert antitumour effects in the absence of systemic toxicity. As a result, several highly specific inhibitors are currently being trialled in solid tumours, including prostate cancer. This article summarises the roles of tCDKs in regulating gene transcription and highlights rationales for their targeting in prostate cancer. It provides an overview of the most recent developments in this therapeutic area, including the most recent clinical advances, and discusses the utility of tCDK inhibitors in combination with established cancer agents.


Capillaria hepatica, a parasite of zoonotic importance--a brief overview.
This review briefly elucidates the biology and mode of transmission of the parasite capillaria hepatica, an cuimial parasite. Occasional transmitted to man.


Antioxidation improves in puberty in normal weight and obese boys, in positive association with exercise-stimulated growth hormone secretion.
Oxidative stress is associated with obesity while the evidence for the role of GH in pro- and antioxidation is inconclusive. This study investigates the relationships between growth hormone (GH), pro- and antioxidation in relation to obesity and puberty before and after an acute bout of exercise. In this case-control study, 76 healthy normal-weight and obese, prepubertal and pubertal boys underwent a blood sampling before and immediately after an aerobic exercise bout until exhaustion at 70% maximal oxygen consumption. Markers of prooxidation (thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PCs)) and antioxidation (glutathione (GSH), oxidized glutathione disulfide (GSSG), GSH/GSSG ratio, glutathione peroxidase (GPX), catalase, and total antioxidant capacity (TAC)) and hormones (GH, insulin-like growth factor (IGF)-1, IGF-BP-3, luteinizing hormone, follicle-stimulating hormone, and testosterone) were measured. Baseline and postexercise TBARS and PCs were greater, while baseline GSH, GSH/GSSG ratio, GPX, and TAC were lower in obese than that in normal-weight participants. In all participants, waist was the best negative and positive predictor for postexercise GPX and TBARS, respectively. Baseline TAC was greater in pubertal than that in pre-pubertal participants. In all participants, baseline GH was the best negative predictor for postexercise PCs. Significant positive linear correlation exists between the exercise-associated GH, and GSSG increases in pubertal normal-weight boys. Higher prooxidation and lower antioxidation were observed in obese boys, while antioxidation improves with puberty and postexercise, paralleling GH accentuated secretion.


Mechanisms of resistance to cis-diamminedichloroplatinum (II) in a rat ovarian carcinoma cell line.
A cis-diamminedichloroplatinum (II) (cisplatin)-resistant subline (Cis-Ptr) demonstrated 20-fold greater resistance to the cytotoxic effects of cisplatin, compared with the parental cloned rat ovarian carcinoma cell line (ROT 68/C1). The uptake of cisplatin into the Cis-Ptr cells was identical to that into the ROT68/C1 cells in vitro and in vivo. Glutathione activity in a cytoplasmic extract was 1.4-fold and 1.8-fold greater in the Cis-Ptr cells than in the ROT68/C1 cells in vitro and in vivo, respectively. There was no difference between the ROT68/C1 and Cis-PTr cells in 195m cisplatin binding per micrograms DNA. DNA repair of cisplatin DNA damage was increased in the Cis-PTr cells but not in the ROT68/C1 cells. These results suggest that the mechanisms of resistance to cisplatin in rat ovarian carcinoma cells involve increased activity of the DNA repair system and increased cytosolic binding to thiols may also be involved.


Gambling problems in treatment for affective disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).
Gambling problems co-occur frequently with other psychiatric difficulties and may complicate treatment for affective disorders. This study evaluated the prevalence and correlates of gambling problems in a U. S. representative sample reporting treatment for mood problems or anxiety. n=3007 respondents indicating past-year treatment for affective disorders were derived from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Weighted prevalence estimates were produced and regression analyses examined correlates of gambling problems. Rates of lifetime and past-year problem gambling (3+DSM-IV symptoms) were 3.1% (95% CI=2.4-4.0%) and 1.4% (95% CI=0.9-2.1%), respectively, in treatment for any disorder. Rates of lifetime problem gambling ranged from 3.1% (95% CI=2.3-4.3%) for depression to 5.4% (95% CI=3.2-9.0%) for social phobia. Past-year conditions ranged from 0.9% (95% CI=0.4-2.1%) in dysthymia to 2.4% (95% CI=1.1-5.3%) in social phobia. Higher levels were observed when considering a spectrum of severity (including 'at-risk' gambling), with 8.9% (95% CI=7.7-10.2%) of respondents indicating a history of any gambling problems (1+ DSM-IV symptoms). Lifetime gambling problems predicted interpersonal problems and financial difficulties, and marijuana use, but not alcohol use, mental or physical health, and healthcare utilisation. Data were collected in 2001-02 and were cross-sectional. Gambling problems occur at non-trivial rates in treatment for affective disorders and have mainly psychosocial implications. The findings indicate scope for initiatives to identify and respond to gambling problems across a continuum of severity in treatment for affective disorders.


Clinical mapping approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation.
The perpetuating mechanisms for human atrial fibrillation (AF) remain undefined. Localized rotors and focal beat sources may sustain AF in elegant animal models, but there has been no direct evidence for localized sources in human AF using traditional methods. We developed a clinical computational mapping approach, guided by human atrial tissue physiology, to reveal sources of human AF. In 49 AF patients referred for ablation (62 ± 9 years; 30 persistent), we defined repolarization dynamics using monophasic action potentials (MAPs) and recorded AF activation from 64-pole basket catheters in left atrium and, in n = 20 patients, in both atria. Careful positioning of basket catheters was required for optimal mapping. AF electrograms at 64-128 electrodes were combined with repolarization and conduction dynamics to construct spatiotemporal AF maps. We observed sustained sources in 47/49 patients, in the form of electrical rotors (n = 57) and focal beats (n = 11) that controlled local atrial activation with peripheral wavebreak (fibrillatory conduction). Patients with persistent AF had more sources than those with paroxysmal AF (2.1 ± 1.0 vs 1.5 ± 0.8, P = 0.02), related to shorter cycle length (163 ± 19 milliseconds vs 187 ± 25 milliseconds, P < 0.001). Approximately one-quarter of sources lay in the right atrium. Physiologically guided computational mapping revealed sustained electrical rotors and repetitive focal beats during human AF for the first time. These localized sources were present in 96% of AF patients, and controlled AF activity. These results provide novel mechanistic insights into human AF and lay the foundation for mechanistically tailored approaches to AF ablation.


Comparative in vitro activity of the new fluoroquinolone BMY-40062.
The results are presented of comparative in vitro susceptibility testing of BMY-40062, a new fluorinated quinolone which contains a tetrabutyl moiety at N-1 and a piperazinyl group at C-7. BMY-40062 inhibited 90% of Enterobacteriaceae strains at less than 0.5 microgram/ml, being either equal in activity to ciprofloxacin or two- to four-fold less active, depending upon the species. BMY-40062 was as active as ciprofloxacin against Pseudomonas aeruginosa (MIC90 0.5 micrograms/ml) and inhibited most other strains of Pseudomonas species at less than 1 microgram/ml. It was more active than ciprofloxacin or ofloxacin against hemolytic streptococci and Streptococcus pneumoniae, 90% of strains being inhibited at less than 0.5 micrograms/ml. MICs increased in the presence of 9 mM Mg2+ and at pH 5.5. The frequency of spontaneous mutation was low for Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus (10(-10), but repeated exposure to BMY-40062 caused selection of resistant isolates. Clinical isolates of Pseudomonas aeruginosa resistant to ciprofloxacin and ofloxacin were resistant to BMY-40062.


Arterial Baroreceptors Sense Blood Pressure through Decorated Aortic Claws.
Mechanosensory neurons across physiological systems sense force using diverse terminal morphologies. Arterial baroreceptors are sensory neurons that monitor blood pressure for real-time stabilization of cardiovascular output. Various aortic sensory terminals have been described, but those that sense blood pressure are unclear because of a lack of selective genetic tools. Here, we find that all baroreceptor neurons are marked in Piezo2-ires-Cre mice and then use genetic approaches to visualize the architecture of mechanosensory endings. Cre-guided ablation of vagal and glossopharyngeal PIEZO2 neurons eliminates the baroreceptor reflex and aortic depressor nerve effects on blood pressure and heart rate. Genetic mapping reveals that PIEZO2 neurons form a distinctive mechanosensory structure: macroscopic claws that surround the aortic arch and exude fine end-net endings. Other arterial sensory neurons that form flower-spray terminals are dispensable for baroreception. Together, these findings provide structural insights into how blood pressure is sensed in the aortic vessel wall.


Application of statistical design for the optimization of dextranase production by a novel fungus isolated from Red Sea sponge.
Marine endophytic fungi isolated from Red Sea organisms were screened for the production of dextranase enzyme. The most potent isolate was from the Red Sea sponge Callyspongia spp. and was selected for identification. The18S rRNA amplification for phylogenetic study revealed that the isolate was highly related to Aspergillus flocculosus strain NRRL 5224 by 99 %. Medium composition and culture conditions for dextranase production were optimized by response surface methodology. A significant influence of dextran, yeast extract, K2HPO4, NaNO3, NaCl, MgSO4.7H2O and culture requirements such as incubation time, inoculum size, medium volume and inoculum age on dextranase production was evaluated by Plackett-Burman design. The most significant factors were further optimized using Box-Behnken design. The model predicted a dextranase activity of 438.15 U/ml when dextran concentration, medium volume and incubation time were 2.1 g/l, 52.47/250 ml flask and 80.48 h, respectively. Verification of the model showed that dextranase production of 440 U/ml was observed under the optimal condition confirming the validity of the model.


NMDA Receptors Multiplicatively Scale Visual Signals and Enhance Directional Motion Discrimination in Retinal Ganglion Cells.
Postsynaptic responses in many CNS neurons are typically small and variable, often making it difficult to distinguish physiologically relevant signals from background noise. To extract salient information, neurons are thought to integrate multiple synaptic inputs and/or selectively amplify specific synaptic activation patterns. Here, we present evidence for a third strategy: directionally selective ganglion cells (DSGCs) in the mouse retina multiplicatively scale visual signals via a mechanism that requires both nonlinear NMDA receptor (NMDAR) conductances in DSGC dendrites and directionally tuned inhibition provided by the upstream retinal circuitry. Postsynaptic multiplication enables DSGCs to discriminate visual motion more accurately in noisy visual conditions without compromising directional tuning. These findings demonstrate a novel role for NMDARs in synaptic processing and provide new insights into how synaptic and network features interact to accomplish physiologically relevant neural computations.


Delayed termination of re-entrant atrioventricular nodal tachycardia.
Termination of atrioventricular nodal (AVN) re-entrant tachycardia by one or two induced premature beats generally occurs within one tachycardia cycle from the last premature beat. Two cases are described in which programmed stimulation during sustained re-entrant AVN tachycardia caused delayed termination in the second or third tachycardia cycle following the extrastimuli. The site of block was the antegrade pathway in one case and the retrograde pathway in the other. The most likely mechanism was induced second degree block in one limb of the tachycardia circuit. Delayed termination provided evidence for concealed penetration of the tachycardia circuit in one case. We conclude that delayed termination of tachycardia is not an indicator of the underlying mechanism of tachycardia. Delayed termination may reveal concealed penetration of the tachycardia circuit. Lastly, in unusual cases programmed stimulation may fail to cause immediate termination of re-entrant tachycardia but may perturb the tachycardia circuit enough to cause termination in subsequent tachycardia cycles.


Pd(II)-catalyzed coupling cyclization of 2,3-allenoic acids with allylic halides. An efficient methodology for the synthesis of beta-allylic butenolides.
An effective method for the synthesis of beta-allyl polysubstituted butenolides from the easily available allylic halides and 2,3-allenoic acids is described. By using this method optically active butenolides can be obtained. According to the results presented in this paper, the reaction may proceed via three consecutive steps: cyclic oxypalladation of the allene, insertion of the C=C bond in allylic halides, and beta-dehalopalladation.


Explaining nurses' experiences of caring for brain dead patients: a content analysis.
Caring for patients with brain death diagnosis is the heaviest of duties for nurses, and, due to the complexities and stressors, it is the biggest challenge of nursing in an intensive care unit. This qualitative research aimed to disclose the nurses' experience of caring for brain-dead patients. The present study was a qualitative research using a content analysis, where the data collection process included 21 semi-structured and in-depth interviews with intensive care nurses, physicians, head nurses, a transplantation committee coordinator, and the authority of the organ procurement unit. Adequate data were collected from March 2014 until the saturation point was reached in June 2016. Data were analyzed simultaneously with data collection using qualitative content analysis with a conventional approach. Qualitative content analysis of data resulted in two themes and eight subthemes, reflecting the analysis of nurses' experiences of caring for brain-dead patients. The themes included "Challenges of right and duty requirement," and "turbulent confrontation with successive chains of tension". Finally, the main themes of "resonance of stress and internal conflict in care" were abstracted. The findings deepened our understanding and knowledge of the issue. Despite all the stress, nurses care for potential organ donors, and this results in preserving the organs' viability for donation. Nurses' problems and challenges in this caring process should be considered by policymakers of health and treatment systems and a supportive model be designed for nurses in the intensive care unit.


The iron-sulfur cluster assembly network component NARFL is a key element in the cellular defense against oxidative stress.
Aim of this study was to explore cellular changes associated with increased resistance to atmospheric oxygen using high-resolution DNA and RNA profiling combined with functional studies. Two independently selected oxygen-resistant substrains of HeLa cells (capable of proliferating at >80% O2, i.e. hyperoxia) were compared with their parental cells (adapted to growth at 20% O2, but unable to grow at >80% O2). A striking consistent alteration found to be associated with the oxygen-resistant state appeared to be an amplified and overexpressed region on chromosome 16p13.3 harboring 21 genes. The driver gene of this amplification was identified by functional studies as NARFL, which encodes a component of the cytosolic iron-sulfur cluster assembly system. In line with this result we found the cytosolic c-aconitase activity as well as the nuclear protein RTEL1, both Fe-S dependent proteins, to be protected by NARFL overexpression under hyperoxia. In addition, we observed a protective effect of NARFL against hyperoxia-induced loss of sister-chromatid cohesion. NARFL thus appeared to be a key factor in the cellular defense against hyperoxia-induced oxidative stress in human cells. Our findings suggest that new insight into age-related degenerative processes may come from studies that specifically address the involvement of iron-sulfur proteins.


Virus-assisted directed evolution of biomolecules.
Directed evolution is a powerful technique that uses principles of natural evolution to enable the development of biomolecules with novel functions. However, the slow pace of natural evolution does not support the demand for rapidly generating new biomolecular functions in the laboratory. Viruses offer a unique path to design fast laboratory evolution experiments, owing to their innate ability to evolve much more rapidly than most living organisms, facilitated by a smaller genome size that tolerate a high frequency of mutations, as well as a fast rate of replication. These attributes offer a great opportunity to evolve various biomolecules by linking their activity to the replication of a suitable virus. This review highlights the recent advances in the application of virus-assisted directed evolution of designer biomolecules in both prokaryotic and eukaryotic cells.


Control of fatty acid metabolism in ischemic and hypoxic hearts.
The effects of whole heart ischemia on fatty acid metabolism were studied in the isolated, perfused rat heart. A reduction in coronary flow and oxygen consumption resulted in lower rates of palmitate uptake and oxidation to CO2. This decrease in metabolic rate was associated with increased tissue levels of long chain acyl coenzyme A and long chain acylcarnitine. Cellular levels of acetyl-CoA, acetylcarnitine, free CoA, and free carnitine decreased. These changes in CoA and its acyl derivatives indicate that beta oxidation became the limiting step in fatty acid metabolism. The rate of beta oxidation was probably limited by high levels of NADH and FADH2 secondary to a reduced supply of oxygen. Tissue levels of neutral lipids showed a slight increase durning ischemia, but incorporation of [U-14C]palmitate into lipid was not altered significantly. Although both substrates for lipid synthesis were present in higher concentrations during ischemia, compartmentalization of long chain acyl-CoA in the mitochondrial matrix and alpha-glycerol phosphate in the cytosol may have accounted for the relatively low rate of lipid synthesis.


Patient identification errors: the detective in the laboratory.
The eradication of errors regarding patients' identification is one of the main goals for safety improvement. As clinical laboratory intervenes in 70% of clinical decisions, laboratory safety is crucial in patient safety. We studied the number of Laboratory Information System (LIS) demographic data errors registered in our laboratory during one year. The laboratory attends a variety of inpatients and outpatients. The demographic data of outpatients is registered in the LIS, when they present to the laboratory front desk. The requests from the primary care centers (PCC) are made electronically by the general practitioner. A manual step is always done at the PCC to conciliate the patient identification number in the electronic request with the one in the LIS. Manual registration is done through hospital information system demographic data capture when patient's medical record number is registered in LIS. Laboratory report is always sent out electronically to the patient's electronic medical record. Daily, every demographic data in LIS is manually compared to the request form to detect potential errors. Fewer errors were committed when electronic order was used. There was great error variability between PCC when using the electronic order. LIS demographic data manual registration errors depended on patient origin and test requesting method. Even when using the electronic approach, errors were detected. There was a great variability between PCC even when using this electronic modality; this suggests that the number of errors is still dependent on the personnel in charge of the technology.


Abnormal seasonality of schizophrenic births. A specific finding?
The unusual finding of an abnormal seasonal distribution of schizophrenic births, showing an excess of 10% in the winter or spring months and an equal deficit in the summer or autumn months, cannot be explained by artefacts. It has not yet been established whether the finding is specific to schizophrenia. We observed an excess of schizophrenic births of some 10% in March to May, significant at the 5% level, and a deficit of approximately the same size in June to August on the birth data of first-admission patients with the clinical diagnosis of schizophrenia. The data, obtained from the Mannheim Psychiatric Case Register, were compared with those of the Mannheim population and a control group matched by birth year and sex. The total population of mentally retarded children aged 7 to 16 years from the Mannheim population showed an excess of some 20% in April to June and an equal deficit in the last two quarters of the year, compared with the Mannheim population of the same birth years. The finding was not significant, but allowance must be made for the low case number of 415. We also compared 3409 first-admission patients with depressive syndromes (ICD 296 and 300.4) and 5615 first-admission patients with the diagnosis of "neurosis and personality disorders" (ICD 300-302, except 300.4, and 305-309) from the Mannheim Case Register with a control population and a parallel control group. Depressed males showed an excess of births in March to May, which was significant at the 1% level; the birth peak for females was smaller and not significant. The same findings were obtained for the category of neurosis and personality disorders, i.e. an excess of about 10% in March to May for males, significant at the 1% level, and a non-significant excess for females. Our findings are awaiting replication. Causal explanations will be discussed with great reservation. The procreational hypothesis, assuming those factors that lead to an equidirectional seasonal pattern of births with a slight deviation from the average of a year in the general population, to be reinforced in the disease categories mentioned, is regarded as the most simple and plausible explanation. It is based on the assumption that some of the parents of individuals suffering from schizophrenia, mental retardation or probably also some other mental disorders running from generation to generation, have a higher threshold in partner-seeking behaviour, which is overcome more easily in the summer months with the consequence of increased pregnancies.


The clinical manifestation and outcome of COVID-19 in patients with a history of ischemic heart disease; a retrospective case-control study.
Coronary artery disease (CAD) is considered an independent risk factor for COVID-19. However, no study has specifically examined the clinical manifestations and outcomes of COVID-19 in patients with ischemic heart disease (IHD). In a retrospective case-control study between 20 March 2020 to 20 May 2020, the medical record of 1611 patients with laboratory-confirmed SARS-CoV-2 infection was reviewed. IHD was defined as a history of an abnormal coronary angiography, coronary angioplasty, coronary artery bypass graft (CABG), or chronic stable angina. Demographic data, past medical history, drug history, symptoms, vital signs, laboratory findings, outcome, and death were investigated from medical records. 1518 Patients (882 men (58.1%)) with a mean age of 59.3 ± 15.5 years were included in the study. Patients with IHD (n = 300) were significantly less likely to have fever (OR: 0.170, 95% CI: 0.34-0.81, P < 0.001), and chills (OR: 0.74, 95% CI: 0.45-0.91, P < 0.001). Patients with IHD were 1.57 times more likely to have hypoxia (83.3% vs. 76%, OR: 1.57, 95% CI: 1.13-2.19, P = 0.007). There was no significant difference in terms of WBC, platelets, lymphocytes, LDH, AST, ALT, and CRP between the two groups (P > 0.05). After adjusting for demographic characteristics, comorbidities and vital signs, the risk factors for mortality of these patients were older age (OR: 1.04 and 1.07) and cancer (OR: 1.03, and 1.11) in both groups. In addition, in the patients without IHD, diabetes mellitus (OR: 1.50), CKD (OR: 1.21) and chronic respiratory diseases (OR: 1.48) have increased the odds of mortality. In addition, the use of anticoagulants (OR: 2.77) and calcium channel blockers (OR: 2.00) has increased the odds of mortality in two groups. In comparison with non-IHD, the symptoms of SARS-CoV-2 infection such as fever, chills and diarrhea were less common among patients with a history of IHD. Also, older age, and comorbidities (including cancer, diabetes mellitus, CKD and chronic obstructive respiratory diseases) have been associated with a higher risk of mortality in patients with IHD. In addition, the use of anticoagulants and calcium channel blockers has increased the chance of death in two groups without and with IHD.


A spectrophotometric method for the standardization of thromboplastin clot-promoting activity.
A simple spectrophotometric method for the quantitating of the clot promoting activity of thromboplastin in commercial preparations was developed. Thromboplastin activities were proportional to the maximum rate of clot formation. This was calculated from curves of absorption change during the coagulation of plasma coagulation control. The clot-promoting effects of thromboplastin in commercial preparations varied widely when assayed by this method.


Elimination of cellular active adhesion on microdomain-structured surface of graft-polyamine copolymers.
To investigate the mechanisms involved in lymphocyte adsorption on poly(2-hydroxyethyl methacrylate)-graft-polyamine copolymer, which is utilized as an adsorbent for cell separation, the role of cellular metabolism in lymphocyte adsorption on these copolymers was evaluated. We examined the effect of lowering environmental temperature and of the drug cytochalasin B that inhibits reorganization of microfilaments in cellular cytoskeletons on lymphocyte adsorption. Although the adsorption of lymphocytes on poly(2-hydroxyethyl methacrylate) was considerably reduced in the presence of cytochalasin B or by lowering temperature, no marked influence of these factors was observed for lymphocyte adsorption on poly(2-hydroxyethyl methacrylate)-graft-polyamine copolymers. These results suggest that, in contrast to common plastics surfaces including poly(2-hydroxyethyl methacrylate), the surface of poly(2-hydroxyethyl methacrylate)-graft-polyamine copolymers does not stimulate or activate adsorbed lymphocytes.


Radiosurgery of cerebral arteriovenous malformations with the dynamic stereotactic irradiation.
From December 1986 through December 1988, 33 patients with inoperable arteriovenous malformation (AVM) were treated in our center with the dynamic stereotactic radiosurgery, which uses a standard 10 MV isocentric linear accelerator. There were 18 females and 15 males with a median age of 26 years (range: 9-69) and a median follow-up time of 16 months (range: 7-32). The arteriovenous malformation volumes treated ranged from 0.2 to 42 cm3. The prescribed doses at the isocenter varied from 50 to 55 Gy and were given as a single fraction in the majority of the patients (31/33). Late complications consisting of intracranial bleeding and/or hemiparesis were observed in three patients. To date, 21 patients underwent repeat angiographic studies at 1 year post-treatment. A complete obliteration of the lesion was achieved in 38% of these patients. For the patients whose arteriovenous malformation nidus was covered by a minimum dose of 25 Gy, the total obliteration rate was 61.5% (8/13), whereas none of the patients who had received less than 25 Gy at the edge of the nidus obtained a total obliteration. Our preliminary analysis at 1 year post-radiosurgery reveals results comparable to those previously reported for other radiosurgical techniques for the same follow-up period.


High prevalence of HPV59 in cytologically abnormal cervical samples.
Cervical cancer is the second most common form of cancer among women. There are over 100 different types of human papillomavirus (HPV), 40 of which are frequently detected in anogenital mucosa. HPV is the primary etiological agent of cervical cancer and is present predominantly in cervical cancers. Thirteen commonly recognized high-risk genotypes have oncogenic potential. The most common high-risk HPV (hrHPV) genotypes in cervical cancer are HPV16 and HPV18, which have the greatest malignancies. The objective of this study was to determine the distribution of hrHPV types in patient samples received at the Mount Sinai Medical Center for routine cytology and HPV testing. In addition, the study compared the sensitivity of the Hybrid Capture 2 (HC2) and Roche Linear Array HPV Genotyping assays. Cytology specimens with abnormal diagnoses were tested for HPV by the Roche Linear Array HPV Genotyping and Digene Hybrid Capture 2 molecular systems. The Roche Linear Array HPV Genotyping Assay was more sensitive than HC2. Additionally, specimens exhibited higher rates of HPV16, HPV51, and HPV59 infections than HPV16 and HPV18 infections. The results demonstrate that geographical distribution of HPV genotypes may play an important role in clinical management of HPV infection, particularly when treating cervical dysplasia and recommending HPV vaccination.


Analysis of serum genome-wide microRNAs for breast cancer detection.
Among methods for profiling levels of miRNAs, next-generation sequencing (NGS) has an effective one for genome-wide profiles, which not only can accurately quantify known miRNAs expression, but also discovery novel miRNAs. In this paper, we investigated that whether specific miRNAs were co-expressed in the serum and tissue of breast cancer (BC) patients as novel biomarkers by SOLiD sequencing. Different miRNA expression profiles of serum and tissue in breast cancer patients and control subjects were obtained by NGS -SOLiD sequencing. Real-time PCR was used to selected and validated candidate miRNA-biomarkers. Novel miRNAs were predicted by computational pipeline, and validated by Northern blot analysis. Of genome-wide miRNA analysis using SOLiD sequencing, 7 miRNAs were found to be co-upregulated (i.e., miR-103, miR-23a, miR-29a, miR-222, miR-23b, miR-24 and miR-25). miR-222 was significantly increased in the serum of BC patients by further validation(P<0.05), which may be a useful biomarker for differentiating BC patients from controls with receiver operating characteristic (ROC) curve area 0.67 of (95% CI=0.5649 to 0.7775). A novel miRNA, named miR-BS1 was preliminarily identified and validated. Pre-miR-BS1 has a characteristic secondary structure. Mature miR-BS1 expression was detected in MCF-7 and MDA-MB-231 cells. Through gene ontology analysis, predicted target genes of miR-BS1, such as FOXO3 and KRAS, were involved in cancer-related signaling pathway. This study presented a connection between serum- and tissue- based miRNA of breast cancer which suggested that serum-miRNAs may be potential biomarkers for BC detection. And next-generation sequencing will provide a robust platform for miRNA profilings.


Association between a novel polymorphism (rs2046210) of the 6q25.1 locus and breast cancer risk.
The novel single nucleotide polymorphism (SNP), rs2046210, was identified in a breast cancer genome-wide association study of Chinese women. The SNP is located on 6q25.1 in proximity to the C6orf97 and estrogen receptor 1 (ESR1) genes. To replicate this susceptibility, a number of case-control studies have been conducted in various populations. However, some results were inconclusive due to the restriction of sample size or ethnic diversity. To derive a more precise estimation of the relationship between rs2046210 and genetic risk of breast cancer, we performed the first comprehensive meta-analysis which included 121,494 cases and 119,295 controls from 14 published studies. Overall, significant increased risk between the A allele of rs2046210 and breast cancer was found in the total population (allelic model: OR = 1.16, 95 %CI = 1.11-1.21, P heterogeneity < 0.0001; dominant model: OR = 1.22, 95 %CI = 1.14-1.29, P heterogeneity < 0.0001; recessive model: OR = 1.21, 95 %CI = 1.13-1.29, P heterogeneity < 0.0001). When stratified by ethnicity, significant elevated risk was found among Europeans and Asians. However, no significant association was detected in African descent population. In the subgroup analyses according to estrogen receptor (ER) positive/negative status, our results suggested that this polymorphism tended to increase breast cancer risk in ER negative tumors by a greater magnitude compared to ER positive tumors. In addition, our subgroup analysis also indicated that this SNP was significantly associated with the risk of breast cancer for BRCA1 mutation carriers and exhibited weaker association with the risk for BRCA2 mutation carriers. Substantial heterogeneity was present in the overall analysis, but largely disappeared after stratification by ethnicity. Despite some limitations, this meta-analysis demonstrates that the rs2046210 polymorphism may be a risk factor associated with increased breast cancer risk. However, the association varies in different ethnicities.


Overexpression of Trps1 contributes to tumor angiogenesis and poor prognosis of human osteosarcoma.
Trichorhinophalangeal syndrome 1 (Trps1) gene is a member of GATA transcription factor family and has an important function in tumorigenesis and progression. However, there are rare studies on its roles in carcinogenesis and prognostic significance in human osteosarcoma. The expression of Trps1 was detected by immunohistochemistry, and MVD was evaluated to determine the amounts of microvessels by counting CD31-positive endothelial cells. Of the 74 cases that underwent study, Trps1-positive cases were 24. And it was associated with MVD significantly (P = 0.008). The data also exhibited more cases of remote metastasis (P = 0.013) and higher Enneking stage (P = 0.017) in Trps1-positive group compared to Trps1-negative group. Univariate analysis revealed that distant metastasis, MVD and Trps1 expression were associated with a lower 3-year overall survival rate and disease-free survival rate (P = 0.003, and P = 0.012 respectively). Furthermore, Trps1 and distant metastasis retained their significant prognostic effects on patients survival rate by multivariate analysis (P < 0.05). Trps1 plays a crucial role in osteosarcoma angiogenesis, metastasis and clinical surgical stage. Trps1 can be a novel promising prognostic marker and therapeutic target, and antiangiogenic therapy which targets Trps1 molecule in patients with osteosarcoma may lead to improved prognosis and longer-term survival.


The role of adjuvants in vaccines for seasonal and pandemic influenza.
Current seasonal influenza vaccines aim to induce high-titred virus-neutralizing antibody to the viral hemagglutinin (HA), which is the best form of protection against infection, but these vaccines can be poorly efficacious in the elderly and other target groups that rely on them most. Furthermore, little cross-protection is provided against significantly drifted strains and even less against different subtypes of virus with pandemic potential. Adjuvants could theoretically have two different roles in improving control of influenza through vaccination. Firstly, a role in enhancing the antibody response in situations where the split virus preparation is poorly immunogenic or if there is an imperative to provide "dose sparing" in the context mass vaccination with a virus to which the population is immunologically naïve. Secondly, adjuvants could be used to allow induction of additional arms of the immune response that are not stimulated by current split virus vaccines. Briefly reviewed here are our efforts to investigate the role of adjuvants in both these contexts.


Cortisol modulates glucose metabolism and oxidative response after acute high temperature stress in Pacific oyster Crassostrea gigas.
Cortisol is the main stress hormone that plays crucial roles in energy metabolism and immune response in vertebrates. In the present study, the homologues of 11β-hydroxysteroid dehydrogenase type 1 (designated Cg11β-HSD1) and 5α-reductase 1 (designated Cg5αR1), the key enzymes related to cortisol metabolism, were identified from Pacific oyster Crassostrea gigas. The Cg11β-HSD1 harbored a conserved SDR domain, and Cg5αR1 contained a Steroid_dh domain and three transmembrane domains. The mRNA transcripts of Cg11β-HSD1 and Cg5αR1 were constitutively expressed in all the examined tissues of oysters, with the highest expression level in haemocytes and labial palp, respectively. After acute high temperature stress (28 °C), the mRNA expression level of Cg11β-HSD1 in hepatopancreas significantly up-regulated at 6 h and 12 h, and that of Cg5αR1 significantly up-regulated at 6 h, compared with the Blank group (11 °C). The concentration of cortisol and glucose, as well as the activities of superoxide dismutase (SOD) and catalase (CAT) in hepatopancreas all significantly up-regulated after acute high temperature stress, while the glycogen concentration in adductor muscle decreased significantly at 6 h and 12 h. After the blockage of Cg11β-HSD1 with metyrapone, the cortisol concentration and the activities of SOD and CAT significantly decreased after acute high temperature stress, the glucose concentration in hepatopancreas significantly increased at 24 h, and the glycogen concentration in adductor muscle significantly increased at 6 h. These results collectively suggested that cortisol played a crucial role in regulating glucose metabolism and oxidative response in oysters upon acute high temperature stress.


Amiodarone-associated hemoptysis.
Amiodarone is a benzofuran derivative with a chemical structure similar to thyroxine. Originally introduced to treat angina pectoris, amiodarone was found to have antiarrhythmic properties, and in 1985, was approved in the United States for treatment of life-threatening ventricular arrhythmias. It is now used for various ventricular and supraventricular arrhythmias refractory to conventional first-line medications, and as a result, side effects have been observed with increased frequency. The most severe and potentially life-threatening of these side effects is the development of pulmonary toxicity. Typically, amiodarone pulmonary toxicity (APT) is manifested by acute pneumonitis and chronic fibrosis. Amiodarone-associated hemoptysis (AAH) is a rare occurrence. The authors describe a case of AAH successfully treated with cessation of drug and steroid therapy.


The role of antenatal corticosteroids in twin pregnancies complicated by preterm birth.
Data regarding the effects of antenatal corticosteroids in twin pregnancies are limited because of the insufficient number of women with twins enrolled in randomized controlled trials on antenatal corticosteroids. Furthermore, the interpretation of available data is limited by the fact that the interval from the administration of antenatal corticosteroids to delivery is greater than 7 days in a large proportion of twins, a factor that has been shown to affect the efficacy of antenatal corticosteroids and has not been controlled for in previous studies. The objective of the study was to compare neonatal mortality and morbidity in preterm twins receiving a complete course of antenatal corticosteroids 1-7 days before birth to those who did not receive antenatal corticosteroids and to compare these outcome effects with those observed in singletons. We performed a retrospective cohort study using data collected on singleton and twin neonates born between 24(0/7) and 33(6/7) weeks' gestational age and were admitted to tertiary neonatal units in Canada between 2010 and 2014. A comparison of neonatal outcomes between twin neonates who received a complete course of antenatal corticosteroids 1-7 days before birth (n = 1758) and those who did not receive antenatal corticosteroids (n = 758) and between singleton neonates who received a complete course of antenatal corticosteroids 1-7 days before birth (n = 4638) and those did not receive antenatal corticosteroids (n = 2312) was conducted after adjusting for gestational age, sex, hypertension, outborn status, small for gestational age, parity, and cesarean birth. Adjusted odds ratios and 95% confidence intervals for various neonatal outcomes were calculated. Administration of a complete course of antenatal corticosteroids within 1-7 days before birth in both twins and singletons was associated with similar reduced odds of neonatal death (for twins adjusted odds ratio 0.42 [95% confidence interval, 0.24-0.76] and for singletons adjusted odds ratios, 0.38 [95% confidence interval, 0.28-0.50]; P = .7 for comparison of twins vs singletons), mechanical ventilation (for twins adjusted odds ratio, 0.47 [95% confidence interval, 0.35-0.63] and for singletons adjusted odds ratio, 0.47 [95% confidence interval, 0.41-0.55]; P = .9), respiratory distress syndrome (for twins adjusted odds ratio, 0.53 [95% confidence interval, 0.40-0.69], and for singletons adjusted odds ratio, 0.54 [95% confidence interval, 0.47-0.62]; P = .9) and severe neurological injury (for twins adjusted odds ratio, 0.50 [95% confidence interval, 0.30-0.83] and for singletons adjusted odds ratio, 0.45 [95% confidence interval, 0.34-0.59]; P = .7). Administration of a complete course of antenatal corticosteroids was not associated with a reduced odds of bronchopulmonary dysplasia, severe retinopathy of prematurity, or necrotizing enterocolitis in both twins and singletons. Administration of a complete course of antenatal corticosteroids 1-7 days before birth in twin pregnancies is associated with a clinically significant decrease in neonatal mortality, short-term respiratory morbidity, and severe neurological injury that is similar in magnitude to that observed among singletons.


Delineation of the phenotype associated with 7q36.1q36.2 deletion: long QT syndrome, renal hypoplasia and mental retardation.
Terminal deletions of the long arm of chromosome 7 are well known and are frequently associated with hypotelorism or holoprosencephaly due to the involvement of the SHH gene located in 7q36.3. These deletions are easily detectable with routine subtelomeric MLPA analysis. Deletions affecting a more proximal part of 7q36, namely bands 7q36.1q36.2 are less common, and may be missed by subtelomeric MLPA analysis. We report a 9-year-old girl with a 5.27 Mb deletion in 7q36.1q36.2, and compare her to literature patients proposing a phenotype characterized by mental retardation, unusual facial features, renal hypoplasia and long QT syndrome due to loss of the KCNH2 gene. These characteristics are sufficiently distinct that the syndrome may be diagnosed on clinical grounds.


Drivers of the rapid rise and daily-based accumulation in PM1.
Submicron particle matter (PM1) that rapidly reaches exceedingly high levels in several or more hours in the North China Plain (NCP) has been threating~400 million individuals' health for decades. The precise cause of the rapid rise in PM1 remains uncertain. Based on sophisticated measurements in PM1 characterizations and corresponding boundary-layer (BL) meteorology in the NCP, it demonstrates that this rising is mainly driven by BL meteorological variability. Large increases in near-ground inversions and decreases in vertical heat/momentum fluxes during the day-night transition result in a significant reduction in mixing space. The PM1 that is vertically distributed before accumulates at the near-ground and then experiences a rapid rise. Besides meteorological variability, a part of the rise in organics is ascribed to an increase of coal combustion at midnight. The daily-based accumulation of PM1 is attributed to day-to-day vertical meteorological variability, particularly diminishing mixing layer height exacerbated by aerosol-radiation feedback. Resolved by a multiple linear regression model, BL meteorological variability can explain 71% variances of PM1. In contrast, secondary chemical reactions facilitate the daily-based accumulation of PM1 rather than the rapid rise. Our results show that BL meteorological variability plays a dominant role in PM1 rising and day-to-day accumulation, which is crucial for understanding the mechanism of heavy pollution formation.


Glucagon-like Peptide-1 Receptor Agonist Use in Patients With Liver Cirrhosis and Type 2 Diabetes.
Liver cirrhosis is often associated with type 2 diabetes (T2D), but research on treatment of T2D in cirrhotic patients is scarce. We investigated the long-term outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with T2D and cirrhosis. Using propensity score matching, we selected 467 matched pairs of GLP-1 RA users and nonusers from the National Health Insurance Research Database of Taiwan from January 1, 2008, to December 31, 2019. Multivariable-adjusted Cox proportional hazards models were used to compare the outcomes between GLP-1 RA users and nonusers. The mean follow-up time was 3.28 and 3.06 years for GLP-1 RA users and nonusers, respectively. The rates of death were 27.46 and 55.90 per 1000 person-years for GLP-1 RA users and nonusers, respectively. The multivariable-adjusted models showed that GLP-1 RA users had lower risks of mortality (adjusted hazard ratio [aHR], 0.47; 95% confidence interval [CI], 0.32-0.69), cardiovascular events (aHR, 0.6; 95% CI, 0.41-0.87), decompensated cirrhosis (aHR, 0.7; 95% CI, 0.49-0.99), hepatic encephalopathy (aHR, 0.59; 95% CI, 0.36-0.97), and liver failure (aHR, 0.54; 95% CI, 0.34-0.85) than nonusers. A longer cumulative duration of GLP-1 RA use had a lower risk of these outcomes than GLP-1 RA nonuse. This population-based cohort study showed that GLP-1 RA users exhibited a significantly lower risk of death, cardiovascular events, decompensated cirrhosis, hepatic encephalopathy, and liver failure in patients with T2D and compensated liver cirrhosis. Additional studies are needed to confirm our results.


Defining the functions of trans-SNARE pairs.
The homotypic fusion of yeast vacuoles includes a 'docking' step, which we show here to consist of two sequential reactions: a reversible 'tethering' mediated by the GTPase Ypt7, and 'SNARE pairing', in which SNARE proteins from opposite membranes form a complex in trans. The function of this trans-SNARE complex must be transient, as the complex can be disassembled by excess Sec18 in the presence of Sec17 and ATP without influencing the fusion rate. These data indicate that SNARE pairing may transiently signal to downstream factors, leading to fusion.


The nasal tent: an adjuvant for performing endoscopic endonasal surgery in the Covid era and beyond.
To propose a cost-effective reproducible barrier method to safely perform endoscopic endonasal surgery during the Covid-19 pandemic. This manuscript highlights the use of a clear, cost-effective disposable plastic sheet that is draped as a tent over the operating area to contain aerolization of particles. This is then connected to a suction to remove airborne particles and thus reduce transmission of the virus. The use of a nasal tent is a simple and affordable method to limit particle spread during high-risk aerolisation procedures during the Covid era and beyond.


Clinical and epidemiological features of leishmaniasis in northwestern-Argentina through a retrospective analysis of recent cases.
Leishmaniasis is a parasitic disease caused by hemoflagellates of the genus Leishmania and is transmitted to humans by the bite of infected phlebotomine sandflies. Depending on the Leishmania species, the disease has different clinical forms including cutaneous, mucocutaneous, and visceral manifestations. Previous studies performed in endemic zones of northwestern-Argentina, during epidemic outbreaks, have been important for detecting patients suffering from the acute phase of the disease, but have not given a complete representation of the clinical and epidemiological features in the region. Furthermore, due to the resurgence of leishmaniasis worldwide and in particular the large increase of international tourism to the region, it seems pertinent to update the current epidemiological and clinical profile of leishmaniasis in northwestern-Argentina. Here we present a retrospective analysis of 95 Leishmania positive cases, presenting between 2000 and 2014. Patients were derived from hospitals and diagnosed in our lab at the University of Salta, located in a non-endemic area in Salta, Argentina. We detected numerous extensive mucocutaneous cases (34/95, 35.8%) distinct from mucosal affected patients, some instances originating in locations with no previously reported human cases. Additionally patients suffering from concomitant diseases, besides leishmaniasis, were assessed. These included Chagas disease, syphilis, deep mycoses, tuberculosis, toxoplasmosis and intestinal parasitosis. This study updates the clinical and epidemiological features of leishmaniasis in northwestern-Argentina, and discusses the implications and management strategy for patients who acquire the disease in this region.


Visceral leishmaniasis in organ transplant recipients: 11 new cases and a review of the literature.
Eleven new cases of visceral leishmaniasis (VL) are reported in organ transplant patients in France. The epidemiological, clinical, biological, diagnostic and therapeutic features are reviewed, based on these cases and 46 cases reported in the literature. VL was most commonly associated with renal transplantation (77% of the cases). Most patients were from Southern European countries. The main clinical symptom was fever. Leucopoenia and anaemia were the most frequent haematological disorders. Diagnosis was by direct finding of the parasite in smears of bone marrow (85.2%) or, by positive serology (90.9%). Without antileishmanial treatment, VL in transplant recipients was fatal. Treatment using either antimonials or amphotericine B gave similar cure rates of around 80% of the cases. But toxicity was higher for antimonials. Relapses occurred in 14.3%.


A novel tissue inhibitor of metalloproteinase-1 (TIMP-1) polymorphism associated with asthma in Australian women.
Airway remodelling is a characteristic feature of chronic asthma and there is evidence that an airway imbalance between levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) is associated with airway remodelling. On this basis, we hypothesised that polymorphisms in the MMP-9 and TIMP-1 genes were associated with the disease process. A number of MMP-9 and TIMP-1 gene polymorphisms were examined in an adult white Australian population of mild (n = 259), moderate (n = 213) and severe (n = 71) asthmatics and non-asthmatic controls (n = 406) using PCR-RFLP and PCR-SSCP analyses. MMP-9 -1562C>T and 836G>A (Arg279Gln) were not associated with asthma (p> or =0.15) or asthma severity (p> or =0.13), and TIMP-1 434T>C (Phe124Phe) was not associated with asthma in women (p = 0.094) or men (p = 0.207). In this population, MMP-9 -861C>T and TIMP-1 323C>T (Pro87Pro) were not informative (with minor allele frequencies of <1%), and MMP-9 -1702T>A and TIMP-1 595C>T (Ser178Phe) were not detectable. However, a novel polymorphism was detected in the TIMP-1 gene 536C>T (Ile158Ile) which was significantly associated with asthma in women (p = 0.011; OR = 5.54, 95% CI 1.66 to 34.4) but not in men (p = 1.0). 536C>T was found to be in linkage disequilibrium with 434T>C, and haplotype analysis supported an association with asthma (p = 0.014). This is the first reported association between a polymorphism in the TIMP-1 gene and asthma, and supports the hypothesis that the protease/antiprotease balance has an important role in this common disease.


Anorectal functional abnormalities in Egyptian children with chronic functional constipation.
Chronic functional constipation represents 95% of the cases of paediatric constipation. Epidemiologic data, pathophysiology and anorectal functional abnormalities vary greatly among different reports across different populations. The aim of this study was to evaluate these data in Egyptian children with chronic functional constipation. This study included 150 children with chronic functional constipation (101 males, 49 females; mean age 6 ± 3.1 years); a control group of 50 age- and sex-matched healthy children were enrolled for standardisation of the manometry technique. A structured symptom questionnaire and clinical examination including digital rectal examination in addition to anorectal manometry were done for all included children. Defaecation dynamics were assessed in all children 5 years or older using anorectal manometry with integrated electromyogram of the external anal sphincter and the puborectalis muscle. The maximal tolerable volume was significantly higher in the constipated children than in the control group (p=0.03). No significant differences existed between constipated and control children regarding other anorectal manometric parameters. Abnormal defaecation dynamics were detected in 35 out of 95 tested patients (36.8%). Increased maximal tolerable volume is the most striking manometric feature in Egyptian children with chronic functional constipation. Abnormal defaecation dynamics were detected in about one-third of the tested patients. Standardisation of the measurement techniques and obtaining normal ranges for anorectal manometric parameters for each laboratory are recommended.


Minimum concentration of levobunolol required to control intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension.
In a double-masked, randomized, comparison titration study to determine the effective dose of topically applied levobunolol, three concentrations of levobunolol (0.25%, 0.5%, and 1%) and of timolol (0.125%, 0.25%, and 0.5%) were evaluated in patients with mild open-angle glaucoma or ocular hypertension. Following a washout of ocular hypotensive medication, twice-daily treatment in both eyes was initiated with the lowest of the three doses of either drug. The concentration was increased if intraocular pressure remained uncontrolled. Intraocular pressure was controlled in 63% (15 of 24) of the patients tested with the lowest concentration of levobunolol and 69% (18 of 26) with the lowest concentration of timolol. Overall, 75% (18 of 24) of the patients in the levobunolol group and 73% (19 of 26) of the patients in the timolol group had adequately controlled intraocular pressure. At the lowest concentrations tested, mean decreases from baseline in intraocular pressure ranged from 6 to 8 mm Hg in both treatment groups.


Thoracic perfusion of matrine as an adjuvant treatment improves the control of the malignant pleural effusions.
Many studies have investigated the efficacy and safety of matrine in treating malignant pleural effusion by thoracic perfusion. This study is an analytic value of available evidence. Twelve studies were analyzed in this study. Pooled odds ratios and hazard ratio with 95 % confidence intervals were calculated using the fixed effects model. Overall response rate of matrine combined with other medications in treating malignant pleural effusion (MPE) was significantly higher than those of other medications alone (p < 0.05). Time to pleural effusion relief and quality of life were improved after the treatment of matrine combined with other medications (p < 0.05). Moreover, matrine combined with other medications had a lower incidence of adverse reactions (p < 0.05). Matrine combined with other medications improves the control of the malignant pleural effusions and decreases the incidence of adverse reactions.