Pelvic injury prognosis is more closely related to vascular injury severity than anatomical fracture complexity: the WSES classification for pelvic trauma makes sense.
The most common cause of death in cases of pelvic trauma is exsanguination caused by associated injuries, not the pelvic injury itself. For patients with relatively isolated pelvic trauma, the impact of vascular injury severity on outcome remains unclear. We hypothesized that the severity of the pelvic vascular injury plays a more decisive role in outcome than fracture pattern complexity. Medical records of patients with pelvic fracture at a single center between January 2016 and December 2017 were retrospectively reviewed. Those with an abbreviated injury scale (AIS) score ≥ 3 in areas other than the pelvis were excluded. Lateral compression (LC) type 1 fractures and anteroposterior compression (APC) type 1 fractures according to the Young-Burgess classification and ischial fractures were defined as simple pelvic fractures, while other fracture types were considered complicated pelvic fractures. Based on CT, vascular injury severity was defined as minor (fracture with or without hematoma) or severe (hematoma with contrast pooling/extravasation). Patient demographics, clinical parameters, and outcome measures were compared between the groups. Severe vascular injuries occurred in 26 of the 155 patients and were associated with poorer hemodynamics, a higher injury severity score (ISS), more blood transfusions, and a longer ICU stay (3.81 vs. 0.86 days, p = 0.000) and total hospital stay (20.7 vs. 10.1 days, p = 0.002) compared with minor vascular injuries. By contrast, those with complicated pelvic fractures (LC II/III, APC II/III, vertical shear, and combined type fracture) required a similar number of transfusions and had a similar length of ICU stay as those with simple pelvic fractures (LC I, APC I, and ischium fracture) but had a longer total hospital stay (13.6 vs. 10.3 days, p = 0.034). These findings were similar even if only patients with ISS ≥ 16 were considered. Our results indicate that even in patients with relatively isolated pelvic injuries, vascular injury severity is more closely correlated to the outcome than the type of anatomical fracture. Therefore, a more balanced classification of pelvic injury that takes both the fracture pattern and hemodynamic status into consideration, such as the WSES classification, seems to have better utility for clinical practice.


Back-to-BACs in Huntington's disease modeling.
In this issue of Neuron, Gu et al. (2022) describe a new BAC mouse model that faithfully recapitulates various aspects of Huntington's disease pathobiology and reveals important insights into the relative toxicities of mHTT-derived products.


Levator syndrome. A treatment that works.
Forty-five patients with levator syndrome were treated by high voltage electrogalvanic stimulation of the levator ani by means of an intra-anal probe. Voltage varied from 150 to 400 volts, depending on patient tolerance. Negative electrodes and 80 cycles per second were used for 20 minutes every other day. An average of five treatments was needed for complete pain relief. Excellent results (total pain relief) were obtained in 36 patients, good results in five, fair results in two, and poor results (no relief) in two. High voltage electrogalvanic stimulation is the treatment of choice for levator syndrome because it can be standardized, is well tolerated, and is over 90 percent effective.


Prospective study of breakfast frequency and timing and the risk of incident type 2 diabetes in community-dwelling older adults: the Cardiovascular Health Study.
No evidence-based recommendations regarding optimal breakfast frequency and timing and type 2 diabetes mellitus (T2DM) exist for older adults because of limited studies. We sought to prospectively assess relations between breakfast frequency and timing and T2DM risk among older adults and determine whether these depended on sex or cardiometabolic risk factors. Weekly breakfast frequency and usual daily breakfast time were assessed by questionnaire at baseline in 3747 older adults (aged ≥ 65 y) from the Cardiovascular Health Study (CHS) who were free of cancer and T2DM and followed for 17.6 y. Multivariable-adjusted hazard ratios (aHRs) with 95% CIs estimated from Cox proportional hazards models were used to quantify associations with T2DM. Most CHS participants (median age: 74 y; IQR: 71-78 y) consumed breakfast daily (85.5%), and 73% had their first daily eating occasion between 07:00 and 09:00, both of which were associated with higher socioeconomic status, factors that are indicative of a healthier lifestyle, and lower levels of cardiometabolic risk indicators at baseline. During follow-up, 547 T2DM cases were documented. No strong evidence was observed linking breakfast frequency and risk of T2DM. Compared with participants whose breakfast timing (first eating occasion of the day) was 07:00-09:00, those who broke fast after 09:00 had an aHR for T2DM of 0.71 (95% CI: 0.51, 0.99). This association was present in participants with impaired fasting glucose at baseline (aHR: 0.61; 95% CI: 0.39, 0.95) but not in those without (aHR: 0.83; 95% CI: 0.50, 1.38). No associations between eating frequency or timing and T2DM were observed within other prespecified subgroups. Eating breakfast daily was not associated with either higher or lower risk of T2DM in this cohort of older adults, whereas a later (after 09:00) daily first eating occasion time was associated with lower T2DM risk in participants with impaired fasting glucose at baseline.This trial was registered at clinicaltrials.gov as NCT00005133.


Seven undescribed compounds from the flower heads of Helianthus annuus L.
Seven undescribed compounds, namely, 4-hydroxy-3-(2'-hydroxy-3'-methyl-1'-butenyl) acetophenone-1'-O-β-D-glucopyranoside (1), 4-hydroxy-3-((Z)-3'-hydroxy-3'-methyl-1'-butenyl) acetophenone-8-O-β-D-glucopyranoside (2), 4,6-hydroxy-3-((Z)-3'-hydroxy-3'-methyl-1'-butenyl) acetophenone-8-O-β-D-glucopyranoside (3), 4-hydroxy-3-((Z)-3'-hydroxy-3'-methyl-1'-butenyl) acetophenone-6-O-β-D-glucopyranoside (4), 2-hydroxymethylimino-3,4-dimethyl-7-hydroxy-6-methyl ketone-2H-chromon (5), annuolide A-15-O-β-D-glucopyranoside (6) and heliannuoside A (7), together with eighteen known compounds, were obtained from water extract of the flower heads of Helianthus annuus L. (Asteraceae). The structures of these compounds were elucidated based on spectroscopic analyses. Upon evaluation of the anti-inflammatory activity of compounds 1-9, 15-18, 21 and 24-25 by their effects on the release of NO in MH-S cells, compound 6 showed significant inhibition of NO secretion at 12.5 μM (P < 0.05) and 25 μM (P < 0.01) in a dose-dependent manner, and compound 18 showed inhibition of NO secretion at 25 μM (P < 0.05).


Renal scarring following reflux and nonreflux pyelonephritis in children: evaluation with 99mtechnetium-dimercaptosuccinic acid scintigraphy.
99mTechnetium dimercaptosuccinic acid (DMSA) scintigraphy is the imaging modality of choice for the detection of acute pyelonephritis and chronic renal scarring in children. Using the DMSA scan we prospectively evaluated renal scarring after reflux and nonreflux pyelonephritis in children. The study population consisted of 33 patients with acute pyelonephritis documented by a DMSA renal scan at infection. The children were evaluated for renal scarring with a followup DMSA scan 4 to 42 months (mean 10.7 months) after the acute infection. All new scarring on followup DMSA scans occurred at sites corresponding exactly to areas of acute inflammation on the initial DMSA scan. Therefore, only those kidneys with acute changes on the initial scan were subsequently analyzed. Of 38 kidneys new or progressive scarring developed in 16 (42%), including 6 of 15 (40%) with associated vesicoureteral reflux and 10 of 23 (43%) without demonstrable reflux. New renal scarring developed in 6 of the 7 kidneys (86%) associated with a neuropathic bladder or posterior urethral valves. In contrast, new scarring developed in only 10 of 31 kidneys (32%) associated with a normal bladder (p = 0.028). Excluding the kidneys associated with a neuropathic bladder or posterior urethral valves, new renal scarring developed in 3 of 12 (25%) with primary reflux, compared with 7 of 19 (37%) without vesicoureteral reflux. Except for the white blood count and the species of infecting bacteria, no other statistically significant differences could be found between those cases in which scars did or did not develop. We conclude that acquired renal scarring only occurs at sites corresponding to previous areas of acute pyelonephritis, the acute parenchymal inflammatory changes of acute pyelonephritis are reversible and do not lead to new renal scarring in the majority of cases, and once acute pyelonephritis has occurred ultimate renal scarring is independent of the presence or absence of vesicoureteral reflux.


Paediatric neuroimaging.
An increasing number of advanced magnetic resonance (MR) techniques are routinely performed in paediatric neuroradiology departments. The most diffuse technique, standard diffusion weighted imaging, is very fast and is becoming increasingly common in routine practice. The usefulness of calculating apparent diffusion coefficient (ADC) is also well known and frequently used, together with voxel proton spectroscopy. Others techniques such as perfusion or BOLD still have a limited use. The most frequent applications of these techniques are discussed in some of the most representative fields of paediatric neuroradiology.


Monoclonal antibodies for the identification of herpesvirus simiae (B virus).
To differentiate between B virus and HSV isolates from monkeys and man monoclonal antibodies (mabs) were produced to herpesvirus simiae (B virus) and herpes simplex type 1 and 2 (HSV-1 and HSV-2). Mabs were tested by indirect immunofluorescence (IFAT) for reactivity against herpesviruses from Asiatic monkeys (B virus), African monkeys (SA 8 virus), and man (HSV-1, HSV-2, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus). Mabs could be divided into groups A-E displaying specific reactivity for B virus (A); reactivity with both B virus and SA 8 but not HSV (B); reactivity with B virus, SA 8 virus and HSV strains (C); specific reactivity with HSV-1 (D); and specific reactivity with HSV-2 (E). Two of the B virus specific mabs were able to differentiate between cynomolgus and rhesus strains of B virus. None of the mabs reacted with human varicella-zoster virus, cytomegalovirus, or Epstein-Barr virus. A panel of mabs for the unequivocal identification of B virus isolates from monkey or man is proposed.


The Friedrich-Lively Instrument to Assess the Impact of Schizophrenia on Siblings (FLIISS): Part II--reliability and validity assessment.
Siblings of persons with schizophrenia who provide primary or secondary care for their sibling and support to parents may experience stress, decreased quality of life, grief, chronic illness, depression, and anxiety. The effects on siblings have not been widely studied and there have not been appropriate instruments to measure the types and degree of stress and associated mental, emotional, and physical distress. The Friedrich-Lively Instrument to Assess the Impact of Schizophrenia on Siblings (FLIISS) is a comprehensive instrument based on extensive research and work with siblings of persons with schizophrenia. Construction of the FLIISS and its relationship to a conceptual model of stress is presented in an article (Part I) elsewhere in this issue. In this article (Part II), reliability results and construct validity are reported for the FLIISS. The FLIISS demonstrates appropriate usefulness and content, acceptable internal consistency, and strong construct validity. Health professionals can use the instrument for collecting information that will increase their ability to identify sources of stress faced by siblings of persons with schizophrenia and develop interventions to help these siblings.


Cooperative modelling and design on the computing grid: data, flux and knowledge interoperability.
The fast interconnections of the presently available distributed platforms allow scientists to target highly complex problems by chaining software developed and maintained by experts of the relevant fields. A pillar of such cooperative endeavor in molecular and materials science and technologies is the so-called grid empowered molecular simulator that combines the expertise of molecular science theorists (electronic structure and nuclei dynamics) and experimentalists in order to build and validate ab initio models. This line has prompted an unprecedented level of data format standardization procedures, the bridging of high throughput and high performance platforms, the assemblage of ad hoc designed virtual experiments. In addition this approach has prompted the design and development of tools allowing the evaluation of the quality of the cooperative effort produced by the members of a given research community as well as its rewards to such effort through a credit economy is reported.


Proton production, regulation and pathophysiological roles in the mammalian brain.
The recent demonstration of proton signaling in C. elegans muscle contraction suggests a novel mechanism for proton-based intercellular communication and has stimulated enthusiasm for exploring proton signaling in higher organisms. Emerging evidence indicates that protons are produced and regulated in localized space and time. Furthermore, identification of proton regulators and sensors in the brain leads to the speculation that proton production and regulation may be of major importance for both physiological and pathological functions ranging from nociception to learning and memory. Extracellular protons may play a role in signal transmission by not only acting on adjacent cells but also affecting the cell from which they were released. In this review, we summarize the upstream and downstream pathways of proton production and regulation in the mammalian brain, with special emphasis on the proton extruders and sensors that are critical in the homeostatic regulation of pH, and discuss their potential roles in proton signaling under normal and pathophysiological conditions.


Recurrent endometrial polyps in postmenopausal breast cancer patients on tamoxifen.
Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure, with an incidence of up to 10.7% of malignancy. Some women tend to develop recurrent polyps. However, no one has yet described any risk factors for the development of recurrent endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients. We compared various clinical features of 64 postmenopausal breast cancer tamoxifen-treated patients with a primary endometrial polyp (Group I), with those of 27 similar patients with recurrent polyps (Group 2). Previous exposure to hormone replacement therapy was significantly more common and duration of tamoxifen treatment, up to the diagnosis of primary endometrial polyp, was significantly shorter in Group II patients (P = 0.0217 and P = 0.0148, respectively). Logistic regression analysis revealed that the combination of shorter tamoxifen exposure before the diagnosis of primary polyp, lower parity, lower menopausal age at the diagnosis of primary polyp, and higher years of tamoxifen treatment was found to increase significantly the risk of developing recurrent endometrial polyps. Any additional year of tamoxifen treatment may increase by fivefold the risk of developing recurrent polyps. There was no significant difference in ultrasonographic endometrial thickness measured before resection of the primary polyps in both groups and before the resection of recurrent polyps in Group II. Previous use of HRT, shorter duration of tamoxifen exposure, and additional years of tamoxifen treatment may significantly increase the risk of developing recurrent endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients.


An integrated metabonomics and transcriptomics approach to understanding metabolic pathway disturbance induced by perfluorooctanoic acid.
Perfluorooctanoic acid (PFOA) is one of the most representative perfluorinated compounds and liver is the major organ where PFOA is accumulated. Although the multiple toxicities had been reported, its toxicological profile remained unclear. In this study, a systems toxicology strategy integrating liquid chromatography/mass spectrometry-based metabonomics and transcriptomics analyses was applied for the first time to investigate the effects of PFOA on a representative Chinese normal human liver cell line L-02, with focusing on the metabolic disturbance. Fifteen potential biomarkers were identified on metabolic level and most observations were consistent with the altered levels of gene expression. Our results showed that PFOA induced the perturbations in various metabolic processes in L-02 cells, especially lipid metabolism-related pathways. The up-stream mitochondrial carnitine metabolism was proved to be influenced by PFOA treatment. The specific transformation from carnitine to acylcarnitines, which showed a dose-dependent effect, and the expression level of key genes involved in this pathway were observed to be altered correspondingly. Furthermore, the down-stream cholesterol biosynthesis was directly confirmed to be up-regulated by both increased cholesterol content and elevated expression level of key genes. The PFOA-induced lipid metabolism-related effects in L-02 cells started from the fatty acid catabolism in cytosol, fluctuated to the processes in mitochondria, extended to the cholesterol biosynthesis. Many other metabolic pathways like amino acid metabolism and tricarboxylic acid cycle might also be disturbed. The findings obtained from the systems biological research provide more details about metabolic disorders induced by PFOA in human liver.


Engineering chimeric thermostable GH7 cellobiohydrolases in Saccharomyces cerevisiae.
We report here the effect of adding different types of carbohydrate-binding modules (CBM) to a single-module GH7 family cellobiohydrolase Cel7A from a thermophilic fungus Talaromyces emersonii (TeCel7A). Both bacterial and fungal CBMs derived from families 1, 2 and 3, all reported to bind to crystalline cellulose, were used. Chimeric cellobiohydrolases with an additional S-S bridge in the catalytic module of TeCel7A were also made. All the fusion proteins were secreted in active form and in good yields by Saccharomyces cerevisiae. The purified chimeric enzymes bound to cellulose clearly better than the catalytic module alone and demonstrated high thermal stability, having unfolding temperatures (T m) ranging from 72 °C to 77 °C. The highest activity enhancement on microcrystalline cellulose could be gained by a fusion with a bacterial CBM3 derived from Clostridium thermocellum cellulosomal-scaffolding protein CipA. The two CBM3 fusion enzymes tested were more active than the reference enzyme Trichoderma reesei Cel7A both at moderate (45 °C and 55 °C) and at high temperatures (60 °C and 65 °C), the hydrolysis yields being two- to three-fold better at 60 °C, and six- to seven-fold better at 65 °C. The best enzyme variant was also tested on a lignocellulosic feedstock hydrolysis, which demonstrated its potency in biomass hydrolysis even at 70 °C.


Characterization of the novel HLA-B*27:05:57 allele detected in a potential hematopoietic stem cell donor.
The novel HLA-B*27:05:57 allele differs by two nucleotide changes from HLA-B*27:05:02:01.


The three-dimensional structure of trichocyte (hard alpha-) keratin intermediate filaments: features of the molecular packing deduced from the sites of induced crosslinks.
The spatial distribution of the crosslinks that can be induced between lysine residues in trichocyte (alpha-) keratin intermediate filaments (IF) using disulfosuccinimidyl tartrate has been analyzed in detail and the results used to provide information about the three-dimensional (3-D) structure. The pattern of inter-molecular interactions derived from earlier studies is essentially two-dimensional in that it involves projection on to a cylinder followed by unwrapping to give a sheet. Crosslinks are observed between molecular strands four apart and it is shown that this can only occur if the paths of the molecular strands through the IF are systematically distorted. These crosslinks are clustered axially at intervals of around 15 nm, a value closely related to the pitch length of the constituent coiled-coil molecules in the rod domains. The number of crosslinks between adjacent molecular strands shows a striking difference depending on lateral direction and provides support for the concept of a head-to-tail stacking of tetramers defined by the A(CN) mode of packing to form protofilament substructures in the fully formed IF. Each protofilament would consist of a pair of oppositely directed molecular strands stabilized by A(11) and A(22) interactions identified in earlier work. A detailed model for the IF in the reduced state comprising a ring of eight protofilaments is suggested. When combined with earlier studies of crosslink formation in the oxidized state, the present findings lead to the conclusion that there is a major reorganization of the molecular packing within the protofilaments during keratinization in vivo. Taken in conjunction with existing X-ray data on the fully keratinized structures, the new evidence for a protofilament substructure also enables a detailed 3-D model for the mature IF to be suggested.


Development of an ELISA-array for simultaneous detection of five encephalitis viruses.
Japanese encephalitis virus(JEV), tick-borne encephalitis virus(TBEV), and eastern equine encephalitis virus (EEEV) can cause symptoms of encephalitis. Establishment of accurate and easy methods by which to detect these viruses is essential for the prevention and treatment of associated infectious diseases. Currently, there are still no multiple antigen detection methods available clinically. An ELISA-array, which detects multiple antigens, is easy to handle, and inexpensive, has enormous potential in pathogen detection. An ELISA-array method for the simultaneous detection of five encephalitis viruses was developed in this study. Seven monoclonal antibodies against five encephalitis-associated viruses were prepared and used for development of the ELISA-array. The ELISA-array assay is based on a "sandwich" ELISA format and consists of viral antibodies printed directly on 96-well microtiter plates, allowing for direct detection of 5 viruses. The developed ELISA-array proved to have similar specificity and higher sensitivity compared with the conventional ELISAs. This method was validated by different viral cultures and three chicken eggs inoculated with infected patient serum. The results demonstrated that the developed ELISA-array is sensitive and easy to use, which would have potential for clinical use.


Analysis of ergot alkaloids - a review.
Methods for detection and determination of ergot alkaloids in grains, grasses, feeds and grain foods are reviewed. They incorporate simple detection procedures - colorimetry, thin layer chromatography and enzyme-linked immunosorbent assay - or instrumental procedures such as liquid chromatography with fluorescence, mass spectrometric (MS) or MS/MS detection, capillary zone electrophoresis, and direct MS/MS.


Restoration of miR-650 leads to down-regulation of KISS1, a possible route involved in overcoming 5-FU resistance and induction of apoptosis in CRC cells in-vitro.
Colorectal cancer (CRC) is one of the most common cancers and the fourth leading cause of cancer-related deaths worldwide. We aimed to determine the role of miR-650 in CRC pathogenesis. In this study, we examined the expression of miR-650 and KISS1 in 80 CRC patients who either received or did not receive chemo agents. For this aim, we assessed the miR-650 and KISS1 expression levels in 80 CRC tissues, 30 of which had no history of chemotherapy. The effect of miR-650 and 5-FU on KISS1 expression was measured using qPCR and Western blotting. Also, the 5- FU effect on miR-650 expression in the CRC cell lines was measured by qRT-PCR. Next, MTT assay and Flowcytometry assays were conducted to determine the role of miR-650 in cell viability and apoptosis. The results showed that miR-650 was down-regulated in CRC tissues. However, patients who received 5-FU before surgery showed increased expression of miR-650. The results for KISS1 were insignificant while administering 5-FU to patients preoperatively increased its expression. In-vitro studies showed that 5-FU led to the up-regulation of miR-650 in the SW480 CRC cell line. Furthermore, the administration of miR-650 and 5-FU downregulated KISS1, especially when combined. Moreover, miR-650 with 5-FU significantly reduced cell viability in CRC cell lines by inducing apoptosis. These results indicate that miR-650 has a tumor suppressive function, overcoming 5-FU chemoresistance in CRC, and induces apoptosis probably by alleviating KISS1. These results suggest that miR-650 is a potential contributor to CRC pathogenesis.


A funny thing happened on the way to articulation: N400 attenuation despite behavioral interference in picture naming.
We measured Event-Related Potentials (ERPs) and naming times to picture targets preceded by masked words (stimulus onset asynchrony: 80 ms) that shared one of three different types of relationship with the names of the pictures: (1) Identity related, in which the prime was the name of the picture ("socks" - <picture of socks>), (2) Phonemic Onset related, in which the initial segment of the prime was the same as the name of the picture ("log" - <picture of a leaf>), and (3) Semantically related in which the prime was a co-category exemplar and associated with the name of the picture ("cake" - <picture of a pie>). Each type of related picture target was contrasted with an Unrelated picture target, resulting in a 3×2 design that crossed Relationship Type between the word and the target picture (Identity, Phonemic Onset and Semantic) with Relatedness (Related and Unrelated). Modulation of the N400 component to related (versus unrelated) pictures was taken to reflect semantic processing at the interface between the picture's conceptual features and its lemma, while naming times reflected the end product of all stages of processing. Both attenuation of the N400 and shorter naming times were observed to pictures preceded by Identity related (versus Unrelated) words. No ERP effects within 600 ms, but shorter naming times, were observed to pictures preceded by Phonemic Onset related (versus Unrelated) words. An attenuated N400 (electrophysiological semantic priming) but longer naming times (behavioral semantic interference) were observed to pictures preceded by Semantically related (versus Unrelated) words. These dissociations between ERP modulation and naming times suggest that (a) phonemic onset priming occurred late, during encoding of the articulatory response, and (b) semantic behavioral interference was not driven by competition at the lemma level of representation, but rather occurred at a later stage of production.


Pharmacokinetic and pharmacodynamic studies with 4'-epi-doxorubicin in nasopharyngeal carcinoma patients.
The plasma pharmacokinetic profile of 4'-epidoxorubicin (epirubicin) was investigated in 28 patients with nasopharyngeal carcinoma (NPC) after single i.v. rapid infusions. All patients had normal liver and renal functions. Plasma concentrations of the parent compound were specifically determined by a high-performance liquid chromatographic (HPLC) method, with UV detection at 254 nm. Plasma levels of the compound were fitted to a three-compartment open model; a triexponential decrease in plasma concentrations with a long terminal plasma half-life (44.8 +/- 21.2 h) was observed in 27 patients. The respective mean (+/- SD) serum concentration at 72 h and the AUC, plasma clearance, and terminal elimination rate constant in complete responders were 7.67 +/- 1.98 ng/ml, 4,002 +/- 3,080 ng.h/ml, 26.6 +/- 12.9 l/h.m2, and 0.009 +/- 0.007 l/h, whereas those in nonresponders were 4.96 +/- 1.8 ng/ml, 1.88 +/- 652.8 ng.h/ml, 44.4 +/- 15 l/h.m2, and 0.017 +/- 0.006 l/h, respectively; these differences were significant (P less than 0.05). Epirubicin produced a 52% response rate, including 6 patients with a complete response, 8 with a partial response, 11 with no change, and 2 with progressive disease. No relationship could be found between the various pharmacokinetic parameters and either leukopenia, age, or sex. These observations strongly suggest that plasma clearance may be one of the determining factors affecting the response or nonresponse of NPC patients to epirubicin, and a dose adjustment according to plasma clearance would probably increase the response rate.


Synthesis, characterization and antibacterial activity of cobalt(III) complexes with pyridine-amide ligands.
The ligands 2-(N-(X-pyridyl)carbamoyl)pyridine (X=2, 3 or 4 for HL1-HL3, respectively) and 2,6-bis(N-(Y-pyridyl)carbamoyl)pyridine (Y=2, 3 or 4 for H2L4-H2L6, respectively) in their mono- and di-deprotonated forms have been used to synthesize kinetically stable cobalt(III) compounds [Co(L1-3)3] (1-3) and Na[Co(L4-6)2] (4-6), respectively. The Co(III) ion is in octahedral environment and is surrounded by three bidentate ligands in complexes 1-3 and two tridentate ligands in complexes 4-6. Ligands coordinate the cobalt center via amidic-N and pyridine-N centers forming a 5-membered chelate ring. Complexes 1-6 have thoroughly been characterized by the various spectroscopic analyses (1H NMR, 13C NMR, UV-vis, IR, mass), elemental analysis, and conductivity measurement. All complexes have been assayed for in vitro antimicrobial activity against clinically isolated resistant strains of Pseudomonas, Proteus, Escherichia coli and standard strains of Pseudomonas aeruginosa (MTCC 1688), Shigella flexneri (MTCC 1457), Klebsiella planticola (MTCC 2272). All cobalt compounds show mild to moderate activity. However, complexes [Co(L1)3] (1) and Na[Co(L4)2] (4) were found to have potent activity against standard and pathogenic resistant bacteria used in the study. Their MIC ranged from 2.7 to 187 microg/ml. In vitro toxicity tests demonstrated that all complexes were less cytotoxic than that of gentamycin on HEK cell lines and the results reveal that these complexes can act as potent antimicrobial agents.


Lichen planus and other cutaneous manifestations in chronic hepatitis C: pre- and post-interferon-based treatment prevalence vary in a cohort of patients from low hepatitis C virus endemic area.
Several controversies exist regarding the relationship between hepatitis C virus (HCV) infection and some cutaneous manifestations, lichen planus (LP) in particular. To determine the prevalence of LP and other cutaneous manifestations in a cohort of patients infected with HCV from low HCV endemic area of Slovenia, to correlate findings with chosen biological variables and to assess the role of interferon (IFN)-based treatment of HCV infection in cutaneous manifestations. Methods A total of 171 consecutive HCV-seropositive patients and 171 HCV-seronegative age- and gender-matched controls were studied prospectively. Prevalence of cutaneous manifestations, comparison between study patients and controls and correlation of skin findings with demographic, biochemical, virological and liver histologic findings as well as IFN-based therapy were assessed. Overall presence of LP in HCV-seropositives was 2.3%; although LP was not found in controls, the difference was not statistically significant (P = 0.123). Significantly higher than in controls was the prevalence of pruritus (31.0%, P < 0.001), dry skin (16.4%, P < 0.001) and hair loss (9.9%, P < 0.001). In IFN-based treatment naïves, skin findings were more frequent compared with controls, but not significantly, with no correlation to chosen biological variables. Current IFN-based treatment was significantly connected to pruritus (P < 0.001) and dry skin (P < 0.001). Compared with treatment naïves, in post-treated patients pruritus (odds ratio, 19.13; 95% confidence interval, 6.85-53.42; P < 0.001), dry skin (odds ratio, 4.21; 95% confidence interval, 1.44-12.31; P < 0.001) and hair loss (P < 0.001) were significantly more common. LP was not significantly related to HCV infection. Prevalence of pruritus, dry skin and hair loss was significantly higher in post-compared with pre-treated patients. The role of IFN in post-treatment persistence of skin manifestations needs to be assessed.


Influence of culture media composition on the rheology of microalgae concentrates on a large scale.
The role of microalgae in the production of bioproducts and biofuels, along with their ability to provide a sustainable pathway for wastewater treatment, makes them promising alternatives to conventional processes. Nevertheless, large-scale downstream processing requires an understanding of biomass rheology that needs to be addressed further. This study aimed to characterize microalgal concentrates rheologically in different culture media. The presence of bacteria was quantified by photorespirometry and plate counting techniques. The culture medium was found to significantly influence viscosity, with primary wastewater exhibiting the highest viscosity and seawater plus pig slurry the lowest. The concentration of heterotrophic bacteria was directly related to the viscosity. Extracellular polysaccharides (EPS) in supernatant exhibited an inverse viscosity trend compared to biomass concentrates, with pig slurry cultures having higher concentrations. These findings emphasize the profound influence of culture medium and EPS on the rheology of microalgal biomass, underscoring the need for continued research aimed at facilitating and optimizing large-scale downstream processes within the framework of a circular economy and the attainment of the Sustainable Development Goals (6,8, and 12).


Regional impacts of COVID-19 on carbon dioxide detected worldwide from space.
Activity reductions in early 2020 due to the coronavirus disease 2019 pandemic led to unprecedented decreases in carbon dioxide (CO2) emissions. Despite their record size, the resulting atmospheric signals are smaller than and obscured by climate variability in atmospheric transport and biospheric fluxes, notably that related to the 2019–2020 Indian Ocean Dipole. Monitoring CO2 anomalies and distinguishing human and climatic causes thus remain a new frontier in Earth system science. We show that the impact of short-term regional changes in fossil fuel emissions on CO2 concentrations was observable from space. Starting in February and continuing through May, column CO2 over many of the world's largest emitting regions was 0.14 to 0.62 parts per million less than expected in a pandemic-free scenario, consistent with reductions of 3 to 13% in annual global emissions. Current spaceborne technologies are therefore approaching levels of accuracy and precision needed to support climate mitigation strategies with future missions expected to meet those needs.


T cell differentiation in the thymus.
T lymphocytes arise in the thymus and seed to peripheral lymphoid organs as fully functional cells at the time of exit. In humans, the thymus begins to function very early in ontogeny and releases large numbers of T cells before the time of birth. However, the vast majority of developing thymocytes (>95%) die within the thymus as a result of stringent selection processes. Positive selection imposes self-MHC-restriction on thymocytes and dictates the MHC-restricted repertoire of post-thymic T cells. Negative selection results in deletion of autoreactive cells. Both types of selection depend on cell to cell contracts and on the presence of appropriate growth factors which are still largely undetermined. Cell to cell contacts occur between developing thymocytes and cells of the thymic microenvironment (accessory cells), and are mediated by several receptor/ligand interactions which subserve the function of establishing and stabilizing these contacts. Besides MHC-TCR interactions, adhesion molecules are important for thymocyte maturation, selection and activation, and for the export and peripheral homing of mature T cells produced in the thymus. Here we describe a novel integrin involved in thymocyte-thymic epithelial cell interactions.


Evidence on the causes of the rising levels of CODMn along the middle route of the South-to-North Diversion Project in China: The role of algal dissolved organic matter.
As the biggest inter-basin water transfer scheme in the world, the South-to-North Water Diversion Project (SNWD) was designed to alleviate the water crisis in North China. The main channel of the middle route of the SNWD is of great concern in terms of the drinking water quality. In this study, we tested the hypothesis that the dissolved organic matter (DOM) derived from the planktonic algae causes the rising levels of CODMn along the middle route by monitoring data on water quality (2015-2019, monthly resolution). The results showed that algal density in the main channel increased along the channel and was significantly correlated with CODMn (p < 0.01). Five fluorescent components of DOM, including tyrosine-like (14.85%), tryptophan-like (22.48%), microbial byproduct-like (26.34%), fulvic acid-like (11.41%), and humic acid-like (24.92%) components, were detected. The level of tyrosine-like components increased along the channel and was significantly correlated with algal density (p<0.01), indicating that algae significantly changed the level of DOM in the channel. Algal decomposition and metabolism were found to be the main mechanisms that drive the changes in CODMn. Therefore, controlling algal density would be an important measure to prevent further increase in CODMn and for the guarantee of excellent water quality.


High prevalence of amblyopia risk factors in preverbal children with nasolacrimal duct obstruction.
To report the percentage of children under the age of 3 with nasolacrimal duct obstruction (NLDO) and amblyopia risk factors who develop clinical evidence of amblyopia over time. Records of children under 3 years of age presenting to a pediatric oculoplastic specialist with NLDO between January 1, 2001, and August 8, 2009, were retrospectively reviewed to identify those who also had amblyopia risk factors. Amblyopia was diagnosed based on visual acuity and treatment history. A total of 375 children under the age of 3 had NLDO. Of these, 82 (22%) had amblyopia risk factors, and 70 received a follow-up examination. Average age at first visit was 12 months (1-27 months). In all patients with anisometropia and unilateral NLDO, the side with the NLDO had higher hyperopia. Of the 70 with risk factors, 44 (63%) were later treated for amblyopia: 29 with spectacles alone, 2 with occlusion therapy, 13 with spectacles and occlusion therapy. Six patients required strabismus surgery. In all patients with anisometropia and unilateral NLDO, the side with the NLDO had higher hyperopia. The percentage of children identified with amblyopia risk factors who later develop clinical amblyopia was much higher than the 1.6% to 3.6% expected in a cohort of normal children.


Abdominal ultrasonogram of autoimmune pancreatitis: Five cases of pancreatic lesions accompanied by Sjögren syndrome.
The concept of autoimmune pancreatitis has recently been established, and ultrasonographic findings we obtained from five cases consistent with autoimmune pancreatitis are reported here. Case 1, a 77-year-old man, was admitted complaining of loss of body weight. Serum hepatobiliary enzymes and γ-globulin levels were elevated, and antinuclear antibody was positive, Abdominal ultrasonography showed dilatation of the intrahepatic bile duct, wall thickening of the common bile duct and hypoechoic swelling of the pancreatic head and body. ERCP revealed multiple stenosis of the intra-and extra-hepatic bile ducts, and diffuse irregular narrowing of the main pancreatic duct. The patient complained of thirst, and the minor salivary gland was examined histologically. Our diagnosis was Sjögren syndrome accompanied by sclerosing cholangitis and a pancreatic lesion. Obstructive jaundice also developed, and PTCD was therefore performed. Both the pancreatic swelling and multiple stenosis of the bile duct improved after steroids were administered. Case 2, a 71-year-old man, was admitted with jaundice. Abdominal ultrasonography showed hypoechoic swelling of the pancreas. ERCP showed stenosis of the common bile duct in the pancreatic head region and diffuse irregular narrowing of the main pancreatic duct. Histological examination of the minor salivary gland suggested Sjögren syndrome. Steroids were therefore administered because the presence of both hyper-γ-globulinemia and positive antinuclear antibody suggested involvement of the autoimmune mechanism. Steroid therapy improved the jaundice as well as the findings from the cholangiograms and pancreatograms. We also encountered three similar cases, all consistent with the concept of autoimmune pancreatitis. The ultrasonographic findings of the pancreatic lesion (1) showed them as homogeneous and markedly hypoechoic areas and, (2) visualized the main pancreatic duct in the lesion, which facilitated a differential diagnosis of the neoplastic lesions. (3) Steroid therapy effectively decreased the hypoechoic area; in some cases, however, a hypoechoic area remained around the main pancreatic duct.


The role of cyclic AMP in the regulation of ecdysone synthesis.
The involvement of cAMP in the steroidogenic action of the cerebral neuropeptide, prothoracicotropic hormone (PTTH), was examined in the tobacco hornworm, Manduca sexta. PTTH stimulates ecdysone synthesis by paired organs in the thorax, the prothoracic glands. The steroidogenic effect of PTTH on prothoracic glands of day 3 fifth instar larvae and day 0 pupae is mimicked in vitro by agents that act by increasing the intracellular levels of cAMP (1-methyl-3-isobutylxanthine, cAMP analogs and forskolin). In addition, partially purified big PTTH (Mr 28500 daltons) stimulates the formation of cAMP in both stages of glands in a rapid, dose-dependent manner. However, a significant accumulation of cAMP in response to PTTH occurs only in larval prothoracic glands. In pupal glands, effects of the neuropeptide on cAMP synthesis are seen only in the presence of a phosphodiesterase inhibitor. The results indicate that cAMP is involved as a second messenger in PTTH action, but that the developmental status of the prothoracic glands influences the degree to which cAMP accumulates in response to the neurohormone.


Inhibition of PDGF-stimulated and matrix-mediated proliferation of human vascular smooth muscle cells by SPARC is independent of changes in cell shape or cyclin-dependent kinase inhibitors.
Interactions among growth factors, cells, and extracellular matrix regulate proliferation during normal development and in pathologies such as atherosclerosis. SPARC (secreted protein, acidic, and rich in cysteine) is a matrix-associated glycoprotein that modulates the adhesion and proliferation of vascular cells. In this study, we demonstrate that SPARC inhibits human arterial smooth muscle cell proliferation stimulated by platelet-derived growth factor or by adhesion to monomeric type I collagen. Binding studies with SPARC and SPARC peptides indicate specific and saturable interaction with smooth muscle cells that involves the C-terminal Ca2+-binding region of the protein. We also report that SPARC arrests monomeric collagen-supported smooth muscle cell proliferation in the late G1-phase of the cell cycle in the absence of an effect on cell shape or on levels of cyclin-dependent kinase inhibitors. Cyclin-dependent kinase-2 activity, p107 and cyclin A levels, and retinoblastoma protein phosphorylation are markedly reduced in response to the addition of exogenous SPARC and/or peptides derived from specific domains of SPARC. Thus, SPARC, previously characterized as an inhibitor of platelet-derived growth factor binding to its receptor, also antagonizes smooth muscle cell proliferation mediated by monomeric collagen at the level of cyclin-dependent kinase-2 activity.


Investigation of structural, electronic, mechanical, & optical characteristics of Ra based-cubic hydrides RbRaX3 (X= F and cl) perovskite materials for solar cell applications: First principle study.
Perovskite materials are considered the gateway of various physical applications to meet the production and consumption of energy and medical fields. Density Functional Theory (DFT) becomes the most important field in the modern era to investigate perovskite materials for various physical properties. DFT nowadays is used to explore the perovskite materials for a lot of applications like photocatalytic, optoelectronic, and photovoltaics. We discussed radium based cubic hydrides RbRaX3 (while X = F & Cl) perovskite material's electrical, optical, elastic, & physical characteristics with the help of DFT-based CASTEP code with PBE exchange-correlation efficient of GGA. The RbRaF3 & RbRaCl3 have three-dimensional nature by means of space group 221 (Pm3 m). According to electronic characteristics, the direct bandgap of RbRaF3 RbRaCl3 are 3.18eV and 2.209eV, respectively. Both compounds are brittle in nature via Poisson's ratio & Pugh's criteria. Thus, our novel RbRaX3 (X = F and Cl) compounds have excellent applications for solar cell and medical areas.


Echocardiography diagnosis of ruptured congenital right coronary sinus of Valsalva aneurysm into right ventricle.
We describe a case of ruptured aneurysm of the right coronary sinus of Valsalva (ASV) diagnosed by transthoracic two-dimensional echocardiography which allowed to quickly establish a correct diagnosis in a patient with a recent onset of continuous murmur and acute right congestive heart failure.


Combined genome-wide allelotyping and copy number analysis identify frequent genetic losses without copy number reduction in medulloblastoma.
Detailed analysis of mechanisms of genetic loss for specific tumor suppressor genes (TSGs; e.g., RB1, APC and NF1) indicates that TSG inactivation can occur by allelic loss of heterozygosity (LOH), without any alteration in DNA copy number. However, the role and prevalence of such events in the pathogenesis of specific malignancies remains to be established on a genome-wide basis. We undertook a detailed molecular assessment of chromosomal defects in a panel of nine cell lines derived from primary medulloblastomas, the most common malignant brain tumors of childhood, by parallel genome-wide assessment of LOH (allelotyping) and copy number aberrations (comparative genomic hybridization and fluorescence in situ hybridization). The majority of genetic losses observed were detected by both copy number and LOH methods, indicating they arise through the physical deletion of chromosomal material. However, a significant proportion of losses (17/42, 40%) represented regions of allelic LOH without any associated copy number reduction; these events involved both whole chromosomes (10/17) and sub-chromosomal regions (7/17). Using this approach, we identified medulloblastoma-characteristic alterations, e.g., isochromosome for 17q, MYC amplification and losses on chromosomes 10, 11, and 16, alongside novel regions of genetic loss (e.g., 10q21.1-26.3, 11q24.1-qter). This detailed genetic characterization of the majority of medulloblastoma cell lines provides important precedent for the widespread involvement of copy number-neutral genetic losses in medulloblastoma and demonstrates that combined assessment of copy number aberrations and LOH will be necessary to accurately determine the contribution of chromosomal defects to tumor development.


Malignant solitary fibrous tumor of the tongue.
Solitary fibrous tumor is a generally benign spindle-cell neoplasm that has been predominantly described in the visceral pleura and other serosal sites and is extremely rare in the head and neck area. We report the first known case of malignant solitary fibrous tumor of the tongue in a 57-year-old female patient who experienced rapid growth of a longstanding right anterior tongue mass, with associated dysphagia and dysarthria. Magnetic resonance imaging was suggestive of a low-flow vascular malformation not requiring preoperative embolization. The patient underwent partial peroral glossectomy for the excision of the tumor. Final pathology, however, was consistent with solitary fibrous tumor, characterized as malignant by histopathologic criteria, and the patient was returned for re-excision of the close surgical margins. The patient has experienced symptomatic improvement, and she remains free of recurrence 12 months later. All reports of solitary fibrous tumors of the oral cavity and 3 reports of the tongue tumors described in the literature to date represent benign lesions. To our knowledge, this is the first report of a malignant solitary fibrous tumor of the tongue. Presentation, differential diagnosis, criteria for malignancy, treatment, and possible prognostic implications of this rare entity are discussed.


Serum-induced changes in electrophoretic mobility of creatine phosphokinase isoenzymes?
BB isoenzyme of creatine phosphokinase (CK-BB) obtained from human brain-extract changes its electrophoretic mobility after incubation in human serum at 37 degrees C. No change of electrophoretic mobility of CK-BB is observed after incubation in isotonic saline. We have shown by means of immunoprecipitation with specific antibodies that the structure of CK-BB is not changed. These findings are supported by other authors and make the diagnostic value of electrophoretic separation of CK isoenzymes doubtful as after a 3-h incubation CK-BB migrates similarly to CK-BB and consequently may be misinterpreted.


School-based universal screening for hypercholesterolemia in children.
In 2011, the American Academy of Pediatrics recommended universal lipid screening during childhood and adolescence. However, this approach was shown to be lacking in adherence. Only 6% of non-high-risk children received lipid screening by age 12. Our study designed a school-based universal screening for hypercholesterolemia in children. The goal was to investigate a feasible strategy for lipid screening of children. The study enrolled all the fourth-grade students of 30 elementary schools from 2020 to 2021. Non-fasting non-HDL was used as a screening tool. These students were classified into three groups: acceptable group (non-HDL < 120 mg/dL), borderline group (120-144 mg/dL), and abnormal group (≥145 mg/dL). The abnormal group was referred to our hospital for confirmatory fasting lipid studies. The complete rate and timing were calculated. Six hundred students were enrolled in this study. In the abnormal group (95 children), a total of 92 students received confirmatory fasting lipid studies. These confirmatory studies were completed within three months after the family received their reports. The study had a rate of coverage of 62% and the referred percentage of the abnormal group was 97%. BMI had poor association with fasting LDL (CORR = 0.06752, p = 0.444). In the abnormal group, only 29.5% children had family history of early CVD or dyslipidemia. School-based universal screening for hypercholesterolemia in children is a feasible and effective way to identify patients at high-risk for early CVD. Neither BMI nor family history was a good indicator for the screening of dyslipidemia.


The effect of intravenous N-acetylcysteine on prevention of atrial fibrillation after coronary artery bypass graft surgery: a double-blind, randomised, placebo-controlled trial.
Atrial fibrillation (AF) is one of the most frequently occurring dysrhythmias after coronary artery bypass graft (CABG) surgery. The aim of this study was to evaluate the effect of intravenous N-acetylcysteine (NAC) on the prevention of AF after CABG surgery. In a double-blind, randomised controlled trial, a total of 150 patients who were scheduled for on-pump CABG surgery were randomly assigned into two groups. In group A, patients received an intravenous NAC infusion (50 mg/kg) after induction of anaesthesia. These patients additionally received two intravenous doses of NAC on postoperative days 1 and 2. Patients in group B received normal saline (as a placebo) with the same volume, during the same time interval. During the first three days after surgery, postoperative AF (POAF) was assessed by continuous electrocardiogram monitoring; serum high-sensitivity C-reactive protein (hsCRP) level was also assessed before and three days after surgery. During follow-up, 17 patients (17/141, 12.1%) developed POAF. POAF occurred in four (5.6%) patients in the NAC group and 13 (18.8%) patients in the placebo group (OR 0.23; 95% CI 0.08-0.82; p = 0.02). In the multivariable logistic regression analysis, the only predictor of AF after CABG surgery was the use of NAC (OR 0.21; 95% CI 0.06-0.73; p = 0.01). Also, the hsCRP level trend in the NAC group was different from the trend in the control group (group time interaction or interaction effect) (p < 0.001). It seems that perioperative intravenous NAC therapy can be effectively used to reduce inflammation and the incidence of POAF after CABG surgery. The clinical trial registration number: IRCT2015040921669N1.


Biliary peritonitis after percutaneous nephrolithotomy: case studies and management concerns.
To evaluate cases of gallbladder injury, a rare and potentially serious complication, in the setting of percutaneous nephrolithotomy. We report two cases of gallbladder injury after percutaneous nephrolithotomy and review the literature on this rare complication. Both cases of gallbladder injury at our institution along with the four other case reports in the literature all necessitated cholecystectomy. Medial right-sided collecting system access during percutaneous nephrolithotomy may increase the risk for biliary injury. Both recognized and unrecognized gallbladder injury may lead to biliary peritonitis necessitating subsequent cholecystectomy.


Autoantibodies--a mechanism of microdebridement.
Antibodies to foreign debris are generally beneficial because they speed inflammation and debridement of tissue. Intracellular components are debris if they reach extracellular space. If not rapidly debrided from extracellular space, intracellular components stimulate autoantibody production. If not debrided, cellular constituents like other foreign material can initiate a chronic tissue response. Antibodies will speed removal of debris if an effective microdebridement mechanism is present. This is their general biologic significance. If the patient has a defective microdebridement system as in lupus erythematosus or rheumatoid arthritis, the autoantibodies occur to large numbers of intracellular substances and accumulate and contribute to tissue damage. Tissue damage occurs and autoantibodies accumulate in lupus erythematosus and rheumatoid arthritis because of inadequate microdebridement. This should not detract from the fact that autoantibodies are a common secondary phenomenon which plays an important part in maintaining tissue microdebridement.


Predicting glioblastoma prognosis networks using weighted gene co-expression network analysis on TCGA data.
Using gene co-expression analysis, researchers were able to predict clusters of genes with consistent functions that are relevant to cancer development and prognosis. We applied a weighted gene co-expression network (WGCN) analysis algorithm on glioblastoma multiforme (GBM) data obtained from the TCGA project and predicted a set of gene co-expression networks which are related to GBM prognosis. We modified the Quasi-Clique Merger algorithm (QCM algorithm) into edge-covering Quasi-Clique Merger algorithm (eQCM) for mining weighted sub-network in WGCN. Each sub-network is considered a set of features to separate patients into two groups using K-means algorithm. Survival times of the two groups are compared using log-rank test and Kaplan-Meier curves. Simulations using random sets of genes are carried out to determine the thresholds for log-rank test p-values for network selection. Sub-networks with p-values less than their corresponding thresholds were further merged into clusters based on overlap ratios (>50%). The functions for each cluster are analyzed using gene ontology enrichment analysis. Using the eQCM algorithm, we identified 8,124 sub-networks in the WGCN, out of which 170 sub-networks show p-values less than their corresponding thresholds. They were then merged into 16 clusters. We identified 16 gene clusters associated with GBM prognosis using the eQCM algorithm. Our results not only confirmed previous findings including the importance of cell cycle and immune response in GBM, but also suggested important epigenetic events in GBM development and prognosis.


A phase 1, randomized, observer blind, antigen and adjuvant dosage finding clinical trial to evaluate the safety and immunogenicity of an adjuvanted, trivalent subunit influenza vaccine in adults ≥ 65 years of age.
To assess the safety and immunogenicity of the MF59®-adjuvanted trivalent influenza vaccine (aTIV; Fluad®) compared with modified aTIV formulations. A total of 196 subjects ≥ 65 years were randomized to receive7different formulations of vaccine containing a range of adjuvant and antigen dosesby single injection, or divided into two injections at a single time point. The primary study objective was to compare the serologic response of different formulations of aTIV containing increased amounts of adjuvant and antigen21 days after vaccination. Subjects were followed for immunogenicity and safety for one year. The highest immune response, as measured by hemagglutination inhibition (HI) assay, 3 weeks after vaccination was observed in subjects in Group 6 with GMT 382.2 (95% confidence interval [CI] 237.5 to 615.0), 552.3 (364.8 to 836.1), and 54.1 (36.9 to 79.4) against A/H1N1, A/H3N2, and B respectively. Rates of seroconversion were also generally highest in this treatment group: 75% (95% CI 55.1 to 89.3), 75% (55.1 to 89.3), and 42.9% (24.5 to 62.8), respectively, against A/H1N1, A/H3N2, and B strains. The highest incidence of solicited adverse events (AEs) was reported by subjects who received both the highest dosage of antigen in combination with the highest dosage of adjuvant at the same site: 67.9% and 57.1% in Groups 4 and 6, respectively. The majority of solicited AEs were mild to moderate in severity. The number of unsolicited AEs was similar across the different dosages. In this phase I trial of adults ≥ 65 years of age who received increased adjuvant and antigen dosages relative to the licensed aTIV, increased dosage of MF59 resulted in increased immunogenicity against all 3 components of seasonal influenza vaccine. The increase in immunogenicity was accompanied by an increase in the incidence of local reactogenicity.


Venous Thromboembolic Complications of Lung Transplantation: A Contemporary Single-Institution Review.
The incidence and consequences of deep venous thrombosis (DVT) and pulmonary embolism (PE) have not been described recently in lung transplant recipients. We sought to characterize DVT and PE in a contemporary series of lung transplant recipients and describe their association with clinical outcomes. The records of all lung transplant recipients from July 1, 2008, to June 30, 2013, were reviewed and analyzed. DVT was diagnosed by venous duplex ultrasonography. PE was diagnosed by computed tomography angiography, nuclear ventilation/perfusion scanning, or pulmonary angiography. The study comprised 117 patients who underwent 123 transplants. The median age was 63 years (range, 17 to 77 years). Forty-five patients (39%) had evidence of lower extremity DVT, 53 (45%) had no evidence of lower extremity DVT, and 19 (16%) were not tested. Fifty-three (45%) had evidence of upper extremity DVT, 30 (26%) had no evidence of upper extremity DVT, and 34 (29%) were not tested. Eighteen (15%) had evidence of PE, 82 (70%) had no evidence of PE, and 17 (15%) were not tested. A multivariable, stepwise Cox proportional hazards model revealed that the presence of lower extremity DVT (hazard ratio, 2.43; 95% confidence interval, 1.29 to 4.64), use of cardiopulmonary bypass (hazard ratio, 2.21; 95% confidence interval, 1.04 to 4.68), and unilateral lung transplantation (hazard ratio, 2.13; 95% confidence interval, 1.07 to 4.25) were associated with diminished survival. The incidence of DVT and PE in lung transplant recipients is high. Posttransplant surveillance and treatment based on findings are warranted.


Ovarian teratomas: a comparison of the sonographic appearance in prepubertal and postpubertal girls.
Sonography was performed in 17 pediatric patients with 18 benign cystic teratomas of the ovary in order to compare the appearance of this entity in prepubertal and postpubertal girls. Particular attention was paid to the frequency of the characteristic features of this lesion, particularly mural nodules and acoustic shadowing. Of the eight lesions in children less than 13 years old, five were complex lesions and three were cystic. Mural nodules were found in three (38%) of eight lesions and acoustic shadowing in one (13%). Of the 10 lesions in the patients 13 years old or more, seven were complex and three were solid. Seven (70%) of 10 lesions contained a mural nodule, seven (70%) had acoustic shadowing, and one (10%) had a fluid/fluid level. Our experience suggests that typical sonographic features of ovarian teratomas occur more frequently in postpubertal than prepubertal girls.


Gephyrin antisense oligonucleotides prevent glycine receptor clustering in spinal neurons.
Each neuron in the mammalian brain carries many postsynaptic membrane specializations containing high densities of receptors that mediate signal transduction upon neurotransmitter release from the apposed nerve terminal. Little is known about the mechanisms by which receptors are transported to and anchored at postsynaptic sites, but extracellular as well as intracellular components may be involved. Ultrastructural studies have shown that the peripheral membrane protein gephyrin, which co-purifies with the postsynaptic inhibitory glycine receptor (GlyR) upon affinity chromatography, is situated on the cytoplasmic face of glycinergic postsynaptic membranes. Moreover, gephyrin binds with high affinity to polymerized tubulin and has been postulated to link the GlyR to the subsynaptic cytoskeleton. Here we report that treatment of rat spinal neurons in culture with gephyrin antisense oligonucleotides prevents the formation of GlyR clusters in the dendritic plasma membrane. Thus, gephyrin is essential for localizing the GlyR to presumptive postsynaptic plasma membrane specializations.


Deconvoluting the biology and druggability of protein lipidation using chemical proteomics.
Lipids are indispensable cellular building blocks, and their post-translational attachment to proteins makes them important regulators of many biological processes. Dysfunction of protein lipidation is also implicated in many pathological states, yet its systematic analysis presents significant challenges. Thanks to innovations in chemical proteomics, lipidation can now be readily studied by metabolic tagging using functionalized lipid analogs, enabling global profiling of lipidated substrates using mass spectrometry. This has spearheaded the first deconvolution of their full scope in a range of contexts, from cells to pathogens and multicellular organisms. Protein N-myristoylation, S-acylation, and S-prenylation are the most well-studied lipid post-translational modifications because of their extensive contribution to the regulation of diverse cellular processes. In this review, we focus on recent advances in the study of these post-translational modifications, with an emphasis on how novel mass spectrometry methods have elucidated their roles in fundamental biological processes.


Prioritizing risk analysis quality control plans based on Sigma-metrics.
Six Sigma provides data-driven techniques that can enhance and improve the EP23 risk management approach for formulating quality control (QC) Plans. Risk analysis has significant drawbacks in its ability to identify and appropriately prioritize hazards and failure modes for mitigation of risks. Six Sigma quality management is inherently risk oriented on the basis of the required tolerance limits that define defective products. Six Sigma QC tools provide a quantitative assessment of method performance and an objective selection/design of statistical QC procedures. Furthermore, the observed sigma performance of a method is useful for prioritizing the need for development of QC plans.


Energy requirement for symbiotic nitrogen fixation.
Comparing the energy required by legumes for symbiotic nitrogen fixation with that of assimilation of nitrate, Gibson concluded the costs to be about the same. About 15% of net photosynthetic production by the plant may be used in meeting its nitrogen requirements. If energy for the fixation of nitrogen symbiotically and that for the assimilation of NH4+ or NO3- from the soil solution are both provided by the chemical products of photosynthesis, then the CO2 respired in supplying that energy must contribute to the total efflux of CO2 from the plant in the dark. McCree and Thornley have discussed methods of partitioning the dark CO2 efflux into a growth (synthesis) and a maintenance component. Both nitrogen fixation and nitrogen assimilation can be expected to contribute to the CO2 flux associated with synthesis. If Gibson is correct, nodulated plants using only symbiotically fixed nitrogen should have the same growth coefficient as non-nodulated plants supplied with exogenous mineral nitrogen when grown in the same conditions. I have examined this hypothesis using a modification of the method used by McCree with Trifolium subterraneum L. cultivar Woogenellup as test material.


Purinergic receptor-induced changes in paracellular resistance across cultures of human cervical cells are mediated by two distinct cytosolic calcium-related mechanisms.
In human cervical (CaSki) cells, extracellular adenosine triphosphate (ATP) induces an acute decrease in the resistance of the lateral intercellular space (RLIS), phase I response, followed by an increase in tight junctional resistance (RTJ), phase II response. ATP also stimulates release of calcium from intracellular stores, followed by augmented calcium influx, and both effects have similar sensitivities to ATP (EC50 of 6 microM). The objective of the study was to determine the degree to which the changes in [Ca2+]i mediate the responses to ATP. 1,2-bis (2-aminophenoxy) ethane-N,N,N1,N1-tetraacetic acid (BAPTA) abrogated calcium mobilization and phase I response; in contrast, nifedipine and verapamil inhibited calcium influx and attenuated phase II response. Barium, La3+, and Mn2+ attenuated phase I response and attenuated and shortened the ionomycin-induced phase I-like decrease in RLIS, suggesting that store depletion-activated calcium entry was inhibited. Barium and La3+ also inhibited the ATP-induced phase II response, but Mn2+ had no effect on phase II response, and in the presence of low extracellular calcium it partly restored the increase in RTJ. KCl-induced membrane depolarization stimulated an acute decrease in RLIS and a late increase in RTJ similar to ATP, but only the latter was inhibited by nifedipine. KCl also induced a nifedipine-sensitive calcium influx, suggesting that acute increases in [Ca2+]i, regardless of mobilization or influx, mediate phase I response. Phase II-like increases in RTJ could be induced by treatment with diC8, and were not affected by nifedipine. Biphasic, ATP-like changes in RTE could be induced by treating the cells with ionomycin plus diC8. We conclude that calcium mobilization mediates the early decrease in RLIS, and calcium influx via calcium channels activates protein kinase C and mediates the late increase in RTJ.


Detection and prognosis of the asymptomatic patient with silent myocardial ischemia.
Detection of asymptomatic silent ischemia relies mainly on exercise screening procedures in (1) selected patient subgroups with increased likelihood of having latent coronary artery disease and (2) patients after infarction with uncomplicated courses. Prognosis in these patients varies, depending on the extent of disease and left ventricular dysfunction. The worst prognosis is found in patients with prior infarctions, 3-vessel disease and poor exercise tolerance. Prognosis is excellent in totally asymptomatic patients with only 1-vessel disease and good ventricular function.


Decoding Immune Signature to Detect the Risk for Early-Stage HCC Recurrence.
Hepatocellular carcinoma (HCC) is often recognized as an inflammation-linked cancer, which possesses an immunosuppressive tumor microenvironment. Curative treatments such as surgical resection, liver transplantation, and percutaneous ablation are mainly applicable in the early stage and demonstrate significant improvement of survival rate in most patients. However, 70-80% of patients report HCC recurrence within 5 years of curative treatment, representing an important clinical issue. However, there is no effective recurrence marker after surgical and locoregional therapies, thus, tumor size, number, and histological features such as cancer cell differentiation are often considered as risk factors for HCC recurrence. Host immunity plays a critical role in regulating carcinogenesis, and the immune microenvironment characterized by its composition, functional status, and density undergoes significant alterations in each stage of cancer progression. Recent studies reported that analysis of immune contexture could yield valuable information regarding the treatment response, prognosis and recurrence. This review emphasizes the prognostic value of tumors associated with immune factors in HCC recurrence after curative treatment. In particular, we review the immune landscape and immunological factors contributing to early-stage HCC recurrence, and discuss the immunotherapeutic interventions to prevent tumor recurrence following curative treatments.


Expression of genes for platelet-derived growth factor in adult human venous endothelium. A possible non-platelet-dependent cause of intimal hyperplasia in vein grafts and perianastomotic areas of vascular prostheses.
Neointimal fibromuscular hyperplasia (NFH) in vein grafts and perianastomotic zones of vascular prostheses has been attributed to the effects of platelet-derived growth factor (PDGF) released by platelets interacting with bypass conduits. But inhibition of platelet aggregation often fails to prevent NFH, and recurrent growth of intact, platelet-free endothelium over perianastomotic areas where NFH occurs is inconsistent with the concept of sustained PDGF release from platelets causing NFH progression at late times after surgical procedures. Cultured bovine aortic endothelial cells (ECs) and human umbilical vein ECs have been shown to release a PDGF-like molecule. We report that confluent cultured fourth passage adult human saphenous vein ECs (AHSVECs) grown in the presence of heparin (100 micrograms/ml) and retina-derived growth factor (RDGF) studied by Northern blotting transcribed a messenger ribonucleic acid (mRNA) of 3.9 kb, strongly hybridizing to PDGF B chain probes, and two species of 2.0 and 2.6 kb hybridizing to PDGF A chain probes. Withdrawal of RDGF and heparin from these cultures for 48 hours before mRNA extraction amplified the scanning densitometric mRNA signal per cell by 8.0 +/- 7.6 fold (mean +/- SD) (N = 4 cultures) for B chain mRNA and 5.2 +/- 3.6 fold (N = 3 cultures) for A chain mRNA. In addition, AHSVEC cultures released a PDGF-like substance, because 50% vol/vol AHSVEC-conditioned serum-free medium increased tritiated thymidine uptake elevenfold in PDGF receptor-bearing 3T3 cells whereas an excess (50 micrograms/ml) of nonspecific goat anti-human-PDGF antibody significantly reduced this increase by a mean of 30% to 7.0 +/- 3.4 fold (N = 6 trials, p less than 0.001). Flow cytometry determined AHSVEC cultures to be proliferating with a mean of 6.2% +/- 1.9% (N = 3 culture lines) of ECs in S phase even at confluence when deprived of EC mitogens for 48 hours. Adult human ECs, which proliferate on bypass conduits and host vessels after perioperative injury, may play a role in causing NFH by stimulating proliferation of adjacent smooth muscle cells. Prevention of NFH may require not only antiplatelet agents but also ways to prevent EC release of smooth muscle cell mitogens in response to perioperative EC injury.


A computational model of stem cells' decision-making mechanism to maintain tissue homeostasis and organization in the presence of stochasticity.
The maintenance of multi-cellular developed tissue depends on the proper cell production rate to replace the cells destroyed by the programmed process of cell death. The stem cell is the main source of producing cells in a developed normal tissue. It makes the stem cell the lead role in the scene of a fully formed developed tissue to fulfill its proper functionality. By focusing on the impact of stochasticity, here, we propose a computational model to reveal the internal mechanism of a stem cell, which generates the right proportion of different types of specialized cells, distribute them into their right position, and in the presence of intercellular reactions, maintain the organized structure in a homeostatic state. The result demonstrates that the spatial pattern could be harassed by the population geometries. Besides, it clearly shows that our model with progenitor cells able to recover the stem cell presence could retrieve the initial pattern appropriately in the case of injury. One of the fascinating outcomes of this project is demonstrating the contradictory roles of stochasticity. It breaks the proper boundaries of the initial spatial pattern in the population. While, on the flip side of the coin, it is the exact factor that provides the demanded non-genetic diversity in the tissue. The remarkable characteristic of the introduced model as the stem cells' internal mechanism is that it could control the overall behavior of the population without need for any external factors.


Emergency nurse practitioner management of tetanus status and tetanus-prone wounds.
The aim of this paper is to address the management of tetanus-prone wounds and the use of tetanus prophylaxis within the remit of the emergency nurse practitioner (ENP) to ensure safe and effective management of patients who present to the Emergency Department (ED) with tetanus-prone wounds. The paper will also provide the reader with an overview of the epidemiology of tetanus along with the signs and symptoms of tetanus. Practicalities of tetanus vaccine storage and injection will also be discussed. The paper will also discuss Protetanus which is a single step immunoassay for the determination of anti-tetanus immune status; this product has the potential to reduce over immunisation with tetanus and can provide the clinician with a tetanus antibody status in patients who are unaware of their own immunisation status.


Recruitment and retention of volunteer multiple mini interview interviewers: Understanding their motivations.
Without volunteer interviewers, many universities would not be able to run multiple mini interviews (MMIs) due to the prohibitive cost of paying interviewers. Despite the opportunity cost borne by volunteers, many interviewers participate in multiple MMI sessions per year and volunteer year after year. There is surprisingly little research into what motivates interviewers to volunteer as MMI interviewers. This research aims to explore both what motivates individuals to volunteer to interview in MMIs for undergraduate medical selection and what adds and detracts value from their participation. We applied a qualitative sequential two-phase design consisting of open-ended survey questions, followed by semi-structured interviews to explore interviewers' motivators in more depth. The survey data on motivators and the six functions from the volunteer functions inventory (VFI) informed interview data collection and provided a lens through which to examine MMI interviewer motivations. Content analysis was used to analyse the survey data. Framework analysis was used to analyse the interview data. The survey was completed by 108 interviewers (50% response rate), and 19 semi-structured interviews were conducted (54% response rate). From the content analysis, the time commitment of involvement was the biggest detractor identified by participants. Through the framework analysis, five overarching motivators were developed: (i) acting on values, (ii) gaining understanding, (iii) gaining personal satisfaction and gratification, (iv) shaping the future workforce and (v) having social interaction. These mirrored five of the six functions proposed in the VFI. There are a range of motivating factors that influenced the participants' decision to volunteer as an interviewer for MMIs. Some motivations were for the benefit of others, some were self-serving, and some a combination of both. Universities should utilise these motivating factors to aid in targeted recruitment of volunteer interviewers.


Changes in Membrane Protein Structural Biology.
Membrane proteins are essential components of many biochemical processes and are important pharmaceutical targets. Membrane protein structural biology provides the molecular rationale for these biochemical process as well as being a highly useful tool for drug discovery. Unfortunately, membrane protein structural biology is a difficult area of study due to low protein yields and high levels of instability especially when membrane proteins are removed from their native environments. Despite this instability, membrane protein structural biology has made great leaps over the last fifteen years. Today, the landscape is almost unrecognisable. The numbers of available atomic resolution structures have increased 10-fold though advances in crystallography and more recently by cryo-electron microscopy. These advances in structural biology were achieved through the efforts of many researchers around the world as well as initiatives such as the Membrane Protein Laboratory (MPL) at Diamond Light Source. The MPL has helped, provided access to and contributed to advances in protein production, sample preparation and data collection. Together, these advances have enabled higher resolution structures, from less material, at a greater rate, from a more diverse range of membrane protein targets. Despite this success, significant challenges remain. Here, we review the progress made and highlight current and future challenges that will be overcome.


Mass Spectrometric Analysis of Cerebrospinal Fluid Ubiquitin in Alzheimer's Disease and Parkinsonian Disorders.
Dysfunctional proteostasis, with decreased protein degradation and an accumulation of ubiquitin into aggregated protein inclusions, is a feature of neurodegenerative diseases. Identifying new potential biomarkers in cerebrospinal fluid (CSF) reflecting this process could contribute important information on pathophysiology. A developed method combining SPE and PRM-MS is employed to monitor the concentration of ubiquitin in CSF from subjects with Alzheimer's disease (AD), Parkinson's disease (PD), and progressive supranuclear palsy (PSP). Four independent cross-sectional studies are conducted, studies 1-4, including controls (n = 86) and participants with AD (n = 60), PD (n = 15), and PSP (n = 11). The method shows a repeatability and intermediate precision not exceeding 6.1 and 7.9%, respectively. The determined LOD is 0.1 nm and the LOQ range between 0.625 and 80 nm. The CSF ubiquitin concentration is 1.2-1.5-fold higher in AD patients compared with controls in the three independent AD-control studies (Study 1, p < 0.001; Study 2, p < 0.001; and Study 3, p = 0.003). In the fourth study, there is no difference in PD or PSP, compared to controls. CSF ubiquitin may reflect dysfunctional proteostasis in AD. The described method can be used for further exploration of ubiquitin as a potential biomarker in neurodegenerative diseases.


Fully automated computational measurement of noise in positron emission tomography.
To introduce an automated computational algorithm that estimates the global noise level across the whole imaging volume of PET datasets. [18F]FDG PET images of 38 patients were reconstructed with simulated decreasing acquisition times (15-120 s) resulting in increasing noise levels, and with block sequential regularized expectation maximization with beta values of 450 and 600 (Q.Clear 450 and 600). One reader performed manual volume-of-interest (VOI) based noise measurements in liver and lung parenchyma and two readers graded subjective image quality as sufficient or insufficient. An automated computational noise measurement algorithm was developed and deployed on the whole imaging volume of each reconstruction, delivering a single value representing the global image noise (Global Noise Index, GNI). Manual noise measurement values and subjective image quality gradings were compared with the GNI. Irrespective of the absolute noise values, there was no significant difference between the GNI and manual liver measurements in terms of the distribution of noise values (p = 0.84 for Q.Clear 450, and p = 0.51 for Q.Clear 600). The GNI showed a fair to moderately strong correlation with manual noise measurements in liver parenchyma (r = 0.6 in Q.Clear 450, r = 0.54 in Q.Clear 600, all p < 0.001), and a fair correlation with manual noise measurements in lung parenchyma (r = 0.52 in Q.Clear 450, r = 0.33 in Q.Clear 600, all p < 0.001). Classification performance of the GNI for subjective image quality was AUC 0.898 for Q.Clear 450 and 0.919 for Q.Clear 600. An algorithm provides an accurate and meaningful estimation of the global noise level encountered in clinical PET imaging datasets. An automated computational approach that measures the global noise level of PET imaging datasets may facilitate quality standardization and benchmarking of clinical PET imaging within and across institutions. • Noise is an important quantitative marker that strongly impacts image quality of PET images. • An automated computational noise measurement algorithm provides an accurate and meaningful estimation of the global noise level encountered in clinical PET imaging datasets. • An automated computational approach that measures the global noise level of PET imaging datasets may facilitate quality standardization and benchmarking as well as protocol harmonization.


Pathophysiology of Tourette's syndrome: striatal pathways revisited.
Stereotypic behaviors and thoughts are manifested in a range of neuropsychiatric disorders including Tourette's syndrome. To understand and to treat these pathologic stereotypies it is important to establish the molecular, pharmacological and systems-level alterations in brain circuits that accompany such behaviors. We review here experiments performed in rodents and primates that focus on neural concomitants of stereotypies induced by dopaminergic treatments. These studies emphasize the functional importance of the compartmental organization of the striatum and raise the possibility that differential activation of striosomes is related to the severity of the expressed stereotypies and sensitized responses.


A managed case of rare intraosseous lipoma of femoral neck.
43 year-old female presented with anterior hip pain not responding to conservative treatments. Plain radiograph showed radio-lucent area with sclerotic margin in the femoral neck region. On MRI scan the diagnosis of intraosseous lipoma was confirmed. Due to persistent pain and risk of fracture, decision of operative treatment was made. She underwent curettage of the lesion under image-intensifier and reinforcement of femoral neck with non-vascularised fibular grafting. Post-operative x-rays showed incorporation of the fibular graft with good clinical and functional outcome. Intraosseous lipoma in the femoral neck is a rare presentation and in cases with persistent symptoms or risk of impending fracture, operative treatment gives a good functional outcome.


Photochemical properties of a riboflavins/cytochrome P450 2B4 complex.
The present study demonstrates the possible use of a non-covalent complex of riboflavins with cytochrome P450 2B4 (artificial flavocytochrome P450 2B4) for photo-induced intermolecular electron transfer between the isoalloxazine cycle of flavins and the ferric heme group of cytochrome P450 2B4. Riboflavin was used as a light-induced electron donor for the transfer of electrons to cytochrome P450. The quantitative measurement of the photocurrent, generated by photoreduction of non-covalent flavocytochrome P450 2B4, was carried out. In the presence of typical substrates for cytochrome P450 2B4 the decrease of cathodic photocurrent occurred, generated not only by riboflavin itself but also by a riboflavin/cytochrome P450 complex. It was demonstrated that flavocytochromes might serve as molecular amplifiers of a photocurrent, generated upon flavins' reduction. Introduction of flavin residues into the cytochrome P450 molecule transformed this haemoprotein into a photoreceptor and a photodiode and, in addition, into a photosensitive and photo-activated enzyme.


Organization of a Latent Space structure in VAE/GAN trained by navigation data.
We present a novel artificial cognitive mapping system using generative deep neural networks, called variational autoencoder/generative adversarial network (VAE/GAN), which can map input images to latent vectors and generate temporal sequences internally. The results show that the distance of the predicted image is reflected in the distance of the corresponding latent vector after training. This indicates that the latent space is self-organized to reflect the proximity structure of the dataset and may provide a mechanism through which many aspects of cognition are spatially represented. The present study allows the network to internally generate temporal sequences that are analogous to the hippocampal replay/pre-play ability, where VAE produces only near-accurate replays of past experiences, but by introducing GANs, the generated sequences are coupled with instability and novelty.


Management of bipseudophakia with implantation of an iris claw lens.
We discuss a case of bipseudophakia with secondary dislocation of a posterior chamber intraocular lens (IOL) into the anterior chamber that was managed by explantation of the anterior and posterior chamber IOLs and implantation of an iris claw IOL.


'Dedicated district nursing team gave the best care in the world'.
Nothing has ever been too much trouble for the district nurse team operating out of Tennant Street Medical Practice in Stockton-on-Tees, who cared for my wife Maureen for nearly four years.


Blood carbon dioxide tension changes during hysteroscopy.
During hysteroscopy the uterus may be distended with carbon dioxide (CO2), nitrous oxide (N2O), or Hyskon (a high molecular weight dextran). An initial study in 27 patients (group 1) using arterialized venous blood samples demonstrated rises in carbon dioxide tension (PCO2) when N2O was insufflated by using a laparoscopy insufflating device--a constant-pressure, variable-volume gas source. Cardiovascular collapse occurred in one patient in this group, most probably as a result of macropulmonary emboli of N2O. The rise in PCO2 is accounted for by an increase in physiologic dead space. In another 24 patients (group 2) the gaseous media were introduced by using a constant-volume, variable-pressure gas source; this resulted in minimal changes in arterial PCO2. The choice of whether a gaseous or liquid distending medium is used for hysteroscopy is governed by the state of the endometrium. If a gaseous medium is indicated, then CO2 is preferable to N2O and should be introduced with a constant-volume, variable-pressure gas source.


Development of certified reference materials for four polyunsaturated fatty acid esters.
Certified reference materials (CRMs) with high accuracy and traceability are essential tools for the validation of analytical methods and calibration of equipment. In this study, purity CRMs for four polyunsaturated fatty acids (PUFAs) esters, namely, cis-(4,7,10,13,16,19)- Docosahexaenoic acid methyl ester (DHA-ME), cis-4,7,10,13,16,19- Docosahexaenoic acid ethyl ester (DHA-EE), cis-(5,8,11,14,17)- Eicosapentaenoic acid methyl ester (EPA-ME) and cis-(5,8,11,14,17)- Eicosapentaenoic acid ethyl ester (EPA-EE), were first developed according to the ISO Guide. The CRMs' purity values were assigned based on the average of quantitative nuclear magnetic resonance and mass balance approaches. The certified value with expanded uncertainties (k = 2, 95% confidence interval) were determined to be (98.8 ± 0.4) %, (99.0 ± 0.3) %, (98.9 ± 0.4) % and (98.9 ± 0.4) % for DHA-ME, DHA-EE, EPA-ME and EPA-EE, respectively. The four PUFAs esters were homogeneous and stable for 12 months at -4 °C and 7 days at 50 °C.


Pathoetiology and pathophysiology of borderline personality: Role of prenatal factors, gut microbiome, mu- and kappa-opioid receptors in amygdala-PFC interactions.
The pathoetiology and pathophysiology of borderline personality disorder (BPD) have been relatively under-explored. Consequently, no targetted pharmaceutical treatments or preventative interventions are available. The current article reviews the available data on the biological underpinnings of BPD, highlighting a role for early developmental processes, including prenatal stress and maternal dysbiosis, in BPD pathoetiology. Such factors are proposed to drive alterations in the infant's gut microbiome, in turn modulating amygdala development and the amygdala's two-way interactions with other brain regions. Alterations in opioidergic activity, including variations in the ratio of the mu-and kappa-opioid receptors seem a significant aspect of BPD pathophysiology, contributing to its comorbidities with depression, anxiety, impulsivity and addiction. Stress and dysphoria are commonly experienced in people classed with BPD. A growing body of data, across a host of medical conditions, indicate that stress and mood dysregulation may be intimately associated with gut dysbiosis and increased gut permeability, coupled to heightened levels of oxidative stress and immune-inflammatory activity. It urgently requires investigation as to the relevance of such gut changes in the course of BPD symptomatology. Accumulating data indicates that BPD symptom exacerbations may be linked to cyclical variations in estrogen, in turn decreasing serotonin and local melatonin synthesis, and thereby overlapping with the pathophysiology of migraine and endometriosis, which also have a heightened association with BPD. Future research directions and treatment implications are indicated.


Synthesis of a New Titanate Coupling Agent for the Modification of Calcium Sulfate Whisker in Poly(Vinyl Chloride) Composite.
A new titanate coupling agent synthesized from polyethylene glycol (PEG), isooctyl alcohol, and phosphorus pentoxide (P₂O₅) was used for the modification of calcium sulfate whiskers (CSWs) and the preparation of high-performance CSW/poly(vinyl chloride) (PVC) composites. The titanate coupling agent (sTi) and the modified CSWs (sTi-CSW) were characterized by Fourier transform infrared (FTIR) spectroscopy, and the mechanical, dynamic mechanical, and heat resistant properties and thermostability of sTi-CSW/PVC and CSW/PVC composites were compared. The results show that sTi-CSW/PVC composite with 10 wt. % whisker content has the best performance, and its tensile strength, Young's modulus, elongation at break, break strength, and impact strength are 67.2 MPa, 1926 MPa, 233%, 51.1 MPa, and 12.75 KJ·m-2, with an increase of 20.9%, 11.5%, 145.3%, 24.6%, and 65.4% compared to that of CSW/PVC composite at the same whisker content. As the whisker content increases, the storage modulus increases, the Vicat softening temperature decreases slightly, and the glass transition temperature increases at first and then decreases.


Isolation and characterization of a novel Escherichia coli Kayfunavirus phage DY1.
Phage therapy has been revitalized since antibiotic resistance in bacteria is increasing. Compared with antibiotics, phages can target specific bacteria precisely, which requires more understanding of phage-host interactions by investigating different phages. Escherichia coli is a common pathogen with very high diversity. Based on the O antigens, E. coli can be classified into at least 183 serotypes and existing phages are far from being able to lyse all E. coli. Therefore, a novel phage specific to E. coli, named DY1, was identified and characterized to enhance our understanding of the phages of E. coli and expand the phage library. Phage DY1 belongs to the family Autographiviridae which is derived from Podoviridae. The genome of DY1 was determined to be 39,817 bp and comprises 54 putative open reading frames. Comparative genome and phylogenetic analysis demonstrated that DY1 was highly similar to phages belonging to the genus Kayfunavirus; however, the highest average nucleotide identity (ANI) values of DY1 with known phages was 0.82 suggesting that DY1 was a novel phage. Through stability tests, DY1 was very stable at temperatures ranging from 20 to 50 °C and pH levels from 5 to 11. Taken together, we report that phage DY1 is a novel Kayfunavirus phage with the potential for phage therapy.


VO2max as an exercise tolerance endpoint in people with cystic fibrosis: Lessons from a lumacaftor/ivacaftor trial.
The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied. We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants ≥ 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VO2max) during cardiopulmonary exercise testing (CPET) at Week 24. The key secondary endpoint was relative change from baseline in exercise duration during CPET at Week 24. Other secondary endpoints included changes in other indices of exercise tolerance and changes in CF assessments; safety and tolerability were assessed as an endpoint. Seventy participants were randomized to receive lumacaftor/ivacaftor (n = 34) or placebo (n = 36). The least-squares mean difference for lumacaftor/ivacaftor versus placebo in relative change in VO2max from baseline at Week 24 was -3.2% (95% CI: -9.2, 2.9; P=0.3021); the least-squares mean difference in relative change from baseline in exercise duration at Week 24 was -3.2% (95% CI: -8.0, 1.6). Safety results were consistent with the known lumacaftor/ivacaftor safety profile. Definitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results; however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. NCT02875366.


Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension.
Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis-pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH.


The validity of health assessments: resolving some recent differences.
The purpose of this paper is to examine what is meant by a valid measure of health. Guyatt, Kirshner and Jaeschke propose that health tests should be designed so as to have one of several kinds of validity: "longitudinal construct validity" for those which are used for longitudinal research designs, and "cross-sectional construct validity" for those which are used for cross-sectional designs. Williams and Naylor argue that this approach to test classification and validation confuses what a test purports to measure with the purpose for which it is used, and that some tests have multiple uses. A review of the meanings of validity in the psychological test literature shows that both sets of authors use the term validity in an idiosyncratic way. Although the use of a test (evaluated by content validity) should not be conflated with whether the test actually measures a specified construct (evaluated by construct validity), if health is actually made up of several constructs (as suggested in Hyland's interactional model) then there may be an association between types of construct and types of purpose. Evidence is reviewed that people make several, independent judgements about their health: cognitive perceptions of health problems are likely to be more sensitive to change in a longitudinal research design, whereas emotional evaluations of health provide less bias in cross-sectional designs. Thus, a classification of health measures in terms of the purpose of the test may parallel a classification in terms of what tests purport to measure.