Cooperative pathway induction of T lymphocyte mitogen stimulation.
Isolated peritoneal mouse macrophages pretreated with the mitogenic enzyme combination neuraminidase (EC 220.127.116.11) plus galactose oxidase (EC 220.127.116.11.) (NAGO), or with NaIO4, stimulate macrophage-depleted lymphocytes mitogenically by a macrophage-derived signal, different from the originally used mitogen. Polyethylene glycol (PEG) treatment of the cultures, although itself nonmitogenic, strongly enhances the mitogenic response of the lymphocytes. Under culture conditions the macrophage-derived signal is transmitted to lymphocytes by direct cell contact, a finding which explains the need of a critical cell density for T lymphocyte stimulation. In the absence of macrophages, lysates from mitogen-preteated macrophages stimulate column-purified lymphocytes in the presence of PEG. Our results indicate that mitogenic activation of lymphocytes is mediated through two sequential triggering events, induction (by mitogen treatment) of a macrophage-derived signal and commitment (by nonmitogenic PEG treatment) of lymphocytes to react to the signal. Reconstitution of the mitogenic response can be achieved by a sequential induction of both these events.


Unexpected mild C-N bond cleavage mediated by guanidine coordination to a niobium iminocarbamoyl complex.
The complex [Nb(NMe2)2{(NMe2)C=N(t)Bu}{N(2,6-(i)Pr2C6H3)}] reacts with trialkylguanidines and undergoes a room temperature C-N bond cleavage of the iminocarbamoyl moiety. This reaction affords the guanidinate complexes [Nb(NMe2)2{N(2,6-(i)Pr2C6H3)}{(N(i)Pr)2C(NH(i)Pr)}] or [Nb(NMe2)2{N(2,6-(i)Pr2C6H3)}{(N(i)Pr)2C(NH(n)Bu)}] and free isocyanide. The first crystal structure of a niobium iminocarbamoyl complex is reported.


The ADAMs family of proteases: new biomarkers and therapeutic targets for cancer?
The ADAMs are transmembrane proteins implicated in proteolysis and cell adhesion. Forty gene members of the family have been identified, of which 21 are believed to be functional in humans. As proteases, their main substrates are the ectodomains of other transmembrane proteins. These substrates include precursor forms of growth factors, cytokines, growth factor receptors, cytokine receptors and several different types of adhesion molecules. Although altered expression of specific ADAMs has been implicated in different diseases, their best-documented role is in cancer formation and progression. ADAMs shown to play a role in cancer include ADAM9, ADAM10, ADAM12, ADAM15 and ADAM17. Two of the ADAMs, i.e., ADAM10 and 17 appear to promote cancer progression by releasing HER/EGFR ligands. The released ligands activate HER/EGFR signalling that culminates in increased cell proliferation, migration and survival. Consistent with a causative role in cancer, several ADAMs are emerging as potential cancer biomarkers for aiding cancer diagnosis and predicting patient outcome. Furthermore, a number of selective ADAM inhibitors, especially against ADAM10 and ADAM17, have been shown to have anti-cancer effects. At least one of these inhibitors is now undergoing clinical trials in patients with breast cancer.


Patterns of protein synthesis in a growth delay mutant (nuv) of Escherichia coli after treatment by near-UV radiation or hydrogen peroxide.
When Escherichia coli cells are stressed by hydrogen peroxide (H2O2), synthesis of a large number of proteins is repressed, while several other proteins are induced. Since there is evidence that some lethal effects of near-UV (NUV) radiation may be directly or indirectly due to hydrogen peroxide generated by NUV light, treatment of cells with NUV radiation or H2O2 might be expected to repress and induce the same set of proteins. In this study, we compared the effects of H2O2 and NUV irradiation on patterns of protein induction and/or repression which were separate from the 4-thiouridine-dependent response using growth delay mutants (nuv). Concentrating initially on the proteins that ceased synthesis following NUV irradiation in an nuv mutant, we observed that these were not the same as those that ceased synthesis following H2O2 treatment. Inspection of two-dimensional polyacrylamide gel electrophoresis proteins indicated that NUV irradiation repressed synthesis of a different set of proteins, although there was some overlap between the two (45%). It was also observed that the new proteins which appeared after each of the two treatments were different. This suggests that the induction and/or repression of new proteins following NUV irradiation is not triggered solely via oxidative stress, although there is some overlap between the proteins that are induced or repressed following the two treatments.


Effects of imatinib mesylate on cutaneous neurofibromas associated with neurofibromatosis type 1.
Imatinib mesylate seemed to inhibit development of cutaneous neurofibromas (c-NFs) and promote growth of pre-existing c-NFs in our neurofibromatosis type 1 case. This report potentially provides new findings in the effects of imatinib mesylate.


Analysis of cerebrospinal fluid in healthy rabbits and rabbits with clinically suspected encephalitozoonosis.
Samples of uncontaminated cerebrospinal fluid (csf) were collected from the cisterna magna of 20 healthy laboratory rabbits and 21 pet rabbits with vestibular disease and/or paresis due to clinically suspected encephalitozoonosis. In the healthy rabbits' csf the leucocyte count was <or=4 leucocytes/microl (median 1.5 microl) and the concentration of protein ranged from 0.13 to 0.31 g/l (median 0.24 g/l). In the diseased rabbits, the number of leucocytes ranged from 1 to 87/microl (median 15/microl; P<0.001), and the concentration of protein ranged from 0.31 to 1.54 g/l (median 0.79 g/l; P<0.001); a cytological evaluation showed that they had greater numbers of lymphocytes and monocytes. It was concluded that encephalitozoonosis in rabbits is characterised by lymphomonocytic pleocytosis in CSF.


Lymphocytic lymphoma and acquired C1 esterase inhibitor deficiency.
We report a 59-year-old woman who had progressive symptoms of angioedema for 3 years, culminating in an attack of laryngeal stridor. C1 esterase inhibitor deficiency was confirmed and treatment with tranexamic acid produced considerable clinical benefit and improvement in complement levels. Two years later she developed clinical evidence of lymphocytic lymphoma. Splenectomy resulted in rapid correction of complement abnormalities. The patient received 6 months of chemotherapy after surgery and remained asymptomatic with normal complement levels 4 years later.


How I approach the prevention and treatment of thrombotic complications in hospitalized patients.
This article uses case-based discussion to review prevention and management of thrombotic problems in hospitalized patients that involve a clinical hematologist. There is variation in the clinical hematologist's role in thrombosis practice throughout the world, and we discuss this where indicated. Hospital-associated venous thromboembolism (VTE), or hospital-associated thrombosis (HAT), is the term to cover VTE occurring during admission and for 90 days postdischarge and is a common patient safety problem. HATs are the most common cause of VTE accounting for 55% to 60% of all VTE, with an estimated 10 million occurring globally. VTE risk assessment alongside evidence-based thromboprophylaxis reduces this risk significantly. Many hospitalized patients, especially older patients, use direct oral anticoagulants (DOACs), mainly to prevent stroke in atrial fibrillation. DOACs require perioperative management and may need urgent reversal. Other complex interventions such as extracorporeal membrane oxygenation which require anticoagulation are also discussed. Lastly, those with uncommon high-risk thrombophilias, especially those with antithrombin deficiency, produce unique challenges when hospitalized.


Recognition of walking directional intention employed ground reaction forces and center of pressure during gait initiation.
Movement intentions are generally classified by Electroencephalogram (EEG) and have been used in gait initiation prediction. However, it is not easy to collect EEG data and practical in reality. Alternatively, ground reaction force (GRF) and the center of pressure (COP) is produced by the contact between the foot and the ground during a specific period of walking, which are the characteristics of evaluating gait performance RESEARCH QUESTION: The study aims to use a deep learning technique to recognize the data of the COP and GRF to classify straight walking and right turn. Second, the study aims to reveal gait characteristics that could replace EEG to predict walking directional intentions METHODS: Ten healthy male adults were instructed to stand on the force platform and self-selected to perform three conditions: standstill, straight walking, and right turn. The onset of gait initiation was evaluated by muscle activation of the right tibialis anterior, and EEG and the COP displacement evaluated the onset of gait intention. Subsequently, GRF and COP would be treated as features to classify the gait intention in the Long Short-Term Memory (LSTM) model. The results revealed that the onset of EEG and the COP displacement initiation were statistically significant differences between straight walking and right turn. For the classification, the average accuracy of the LSTM model with GRF and COP as features reached the highest one, 94.79 %, depending on the heel- or toe-off of the swing leg. The results indicated that gait intentions could be classified based on the GRF and COP. The machine learning technique of LSTM with gait parameters can recognize the gait intention of changing walking orientation. Our model and approach would be expected to provide advanced predictions, such as exoskeleton control or pedestrian traffic flow.


LEM domain containing 1 promotes oral squamous cell carcinoma invasion and endothelial transmigration.
Oral squamous cell carcinomas have high potential for locoregional invasion and nodal metastasis. Thus, early detection and elucidation of detailed molecular mechanisms of OSCCs are important. Roles of LEM domain containing 1 (LEMD1), a novel cancer-testis antigen, in OSCCs are unclear. We performed immunohistochemical analysis of LEMD1 in 289 OSCC patients and examined functions of LEMD1 in these carcinomas. Immunohistochemical analysis showed that 101 patients were positive for LEMD1. LEM domain containing 1 expression levels in OSCCs significantly correlated with tumour progression (T factor and clinical stage), nodal metastasis, and poor prognosis. LEM domain containing 1 expression was an independent predictor of disease-free survival in OSCC patients. In OSCCs, LEMD1 knockdown suppressed cancer cell invasion. Moreover, downregulation of LEMD1 expression inhibited adhesion and transmigration of OSCCs and vascular or lymphatic vascular endothelial cells. Our findings suggest that LEMD1 is a novel tumour progressive factor and may be a useful diagnostic and therapeutic target in OSCCs.


Probiotics-A complete oral healthcare package.
Probiotics are living bacterial cells that have significant therapeutic potential for treating human infectious diseases. There is a huge market for probiotics in the pharmaceutical sector. They have been frequently used to treat the gastrointestinal diseases and improve gut immunity. In this review, the strains currently in use for manufacturing oral probiotic formulations are discussed. The review further recommends the use of probiotics for the control of various oral health disorders, like dental caries, periodontitis, gingivitis, halitosis, burning mouth syndrome, and oral cancer. Finally, this review also explores the use of various commercial probiotic products in maintaining oral health, their market values, and government acts and regulations that are relevant to the production and marketing of probiotics. Probiotics have tremendous therapeutic potential and more in-depth research must be done on these beneficial bacteria to make them one of the leading drugs in treating oral disorders.


MRI of the knee after locked unreamed intramedullary nailing of tibia.
We analysed the reason for knee pain after intramedullary (IM) nailing with standard MRI sequences at a mean of 27 months (range 2-45) after nail removal in eleven patients with a mean age of 30 years (range 15-52). Knee pain was assessed in four grades. All our patients had signal changes of fluid in the nail channel, areas of low signal intensity in Hoffa's fat pad and subcutaneous low signal nodes in front of a thickened patellar ligament. Ten patients had low signal adhesions from the nail insertion towards the patellar ligament. Six patients had severe knee pain and even marked adhesions. Two patients had no knee pain; one of these two had minimal adhesions and the other one no adhesions. Five of the patients had a meniscal tear and/or local cartilage reduction. The degree of adhesions from the nail insertion in the tibia towards the patellar ligament was proportional to the degree of knee pain. No sign of acute inflammation was found.


State policy affecting pain management: recent improvements and the positive impact of regulatory health policies.
Criteria-driven policy analysis resources from the University of Wisconsin Pain and Policy Studies Group (PPSG) evaluated drug control and professional practice policies that can influence use of controlled substances for pain management, and documented changes over a 3-year period. Additional research was needed to determine the extent of change, the types of messages contained in the policies, and what has contributed to changing policy content. Four research aims guided this study: (1) evaluate change between 2000 and 2003 of state policy that can affect pain relief, (2) describe content differences for statutes, regulations, guidelines, and policy statements, (3) evaluate differences between policies specific to pain management and policies governing general healthcare practice, and (4) compare content of policies specific to pain management created by healthcare regulatory boards to those created by state legislatures. Results showed that more current policies, especially policies regulating health professionals, tend to encourage pain management and avoid language that restricts professional decision-making and patient treatment. In addition, pain policies from healthcare regulatory boards were generally less restrictive than statutes or policies that govern general healthcare practice. These findings suggest that the positive policy change results primarily from state medical, pharmacy, and nursing boards adopting policies promoting pain management and the use of opioids, while containing few if any restrictions. Despite this improvement, further progress can be made when states continue to abrogate additional restrictions or clinically obsolete provisions from policies. PPSG policy evaluations provide guidance to lawmakers, healthcare regulators, and clinicians who are striving to achieve balanced policy, an attainable but redoubtable goal, to benefit patient care.


Redo heart transplantation in a high-risk patient due to severe aortic regurgitation and accompanying right ventricular failure after LVAD implantation and temporary RVAD support.
We report a 62-year-old patient who received redo-orthotopic heart transplantation due to worsening severe aortic regurgitation after 19 months of continuous flow left ventricular assist device (LVAD) (cf-LVAD) and temporary right ventricular assist device (RVAD) support for 1 month. The patient received a heartware LVAD (heartware ventricular assist device) and annuloplasty of the tricuspid valve due to end-stage heart failure (as a consequence of dilated cardiomyopathy) and severe tricuspid regurgitation in addition to right-sided extracorporeal membrane oxygenation (ECMO) implantation. Postoperatively due to the inability to wean the implanted ECMO, a temporary RVAD was implanted after which the patient's condition improved so that it had been explanted later and the patient was discharged after 9 months. In immediate postoperative echo, minimal aortic regurgitation was noted but in the follow-up transthoracic echocardiograms, there was a gradual increase in the severity of aortic regurgitation with worsening both right and left ventricular functions. Transcatheter aortic valve implantation was not an option due to unfavorable anatomical issues. That's why the patient was listed for urgent heart transplantation, performed 19 months after the LVAD implantation. The postoperative course was complicated due to acute renal failure. After recompensation, dialysis, and intensive physiotherapy, the patient could be discharged home after 3 months. Severe aortic regurgitation is a recognizable complication after cf-LVAD implantation which in our case was managed successfully with orthotopic heart transplantation in this high-risk patient.


Ultrasensitive, label-free voltammetric determination of norfloxacin based on molecularly imprinted polymers and Au nanoparticle-functionalized black phosphorus nanosheet nanocomposite.
Norfloxacin (NOR) is an antibiotic commonly used to treat humans and food-producing animals. Owing to NOR abuse, its residues are frequently found in animal-derived food products and the surrounding environment. Therefore, development of an efficient analytical technique for the selective determination of trace NOR is greatly significant for food safety and environmental protection. Here, we fabricated an ultrasensitive, label-free molecularly imprinted polymer (MIP) voltammetric sensor for the selective determination of NOR, based on an Au nanoparticle-functionalized black phosphorus nanosheet nanocomposite (BPNS-AuNP) covered by a polypyrrole-imprinted film. BPNS-AuNP nanocomposites were prepared via an in-situ one-step method without the use of reducing agents. The imprinted polypyrrole film was formed on the surface of the BPNS-AuNPs in the presence of NOR. The physical properties and electrochemical behavior of the MIP/BPNS-AuNPs were investigated using various characterization techniques, and the analytical parameters were optimized. We found that BPNS-AuNPs improve the ambient stability and electrocatalytic activity, providing a large surface area for locating a higher number of specific recognition sites. Consequently, the MIP/BPNS-AuNP/GCE showed excellent sensing performance toward NOR, with a wide linear response range (0.1 nM - 10 μM), an extremely low limit of detection (0.012 nM), and extraordinary selectivity. Moreover, the MIP/BPNS-AuNP/GCE was used to determine NOR in various experimental samples with satisfactory results.


Oscillatory entrainment to our early social or physical environment and the emergence of volitional control.
An individual's early interactions with their environment are thought to be largely passive; through the early years, the capacity for volitional control develops. Here, we consider: how is the emergence of volitional control characterised by changes in the entrainment observed between internal activity (behaviour, physiology and brain activity) and the sights and sounds in our everyday environment (physical and social)? We differentiate between contingent responsiveness (entrainment driven by evoked responses to external events) and oscillatory entrainment (driven by internal oscillators becoming temporally aligned with external oscillators). We conclude that ample evidence suggests that children show behavioural, physiological and neural entrainment to their physical and social environment, irrespective of volitional attention control; however, evidence for oscillatory entrainment beyond contingent responsiveness is currently lacking. Evidence for how oscillatory entrainment changes over developmental time is also lacking. Finally, we suggest a mechanism through which periodic environmental rhythms might facilitate both sensory processing and the development of volitional control even in the absence of oscillatory entrainment.


Biological characteristics of intratumoral [F-18]‑fluoromisonidazole distribution in a rodent model of glioma.
Accurate imaging to identify hypoxic regions in tumors is key for radiotherapy planning. [F-18]‑fluoro-misonidazole ([F-18]-FMISO) is widely used for tumor hypoxia imaging and has the potential to optimize radiotherapy planning. However, the biological characteristics of intratumoral [F-18]-FMISO distribution have not yet been fully investigated. In hypoxic cells, the hypoxia-inducible factor-1 (HIF-1) target proteins that induce cellular proliferation and glucose metabolism, glucose transporter-1 (Glut-1) and hexokinase-II (HK-II), are upregulated. In this study, we determined the intratumoral distribution of [F-18]-FMISO by autoradiography (ARG) and compared it with pimonidazole uptake, expression of Glut-1, tumor proliferative activity (Ki-67 index) and glucose metabolism ([C-14]2-fluoro-2-deoxy-D-glucose uptake; [C-14]-FDG) in a glioma rat model. Five C6 glioma‑bearing rats were injected with [F-18]-FMISO and [C-14]-FDG. After 90 min, the rats were injected with pimonidazole and 60 min later, the rats were sacrificed and tumor tissues were sectioned into slices. The adjacent slices were used for ARG and immunohistochemical (IHC) analyses of pimonidazole, Glut-1 and Ki-67. [F-18]-FMISO ARG images were divided into regions of high [F-18]-FMISO uptake (FMISO+) and low [F-18]-FMISO uptake (FMISO-). Pimonidazole and Glut-1 expression levels, Ki-67 index and [C-14]-FDG distribution were evaluated in the regions of interest (ROIs) placed on FMISO+ and FMISO-. [F-18]-FMISO distribution was generally consistent with pimonidazole distribution. The percentage of positively stained areas (% positive) of Glut-1 in FMISO+ was significantly higher compared to FMISO- (24 ± 8% in FMISO+ and 9 ± 4% in FMISO-; P<0.05). There were no significant differences in Ki-67 index and [C-14]-FDG uptake between FMISO+ and FMISO- (for Ki-67, 10 ± 5% in FMISO+ and 12 ± 5% in FMISO-, P=ns; for [C-14]-FDG, 1.4 ± 0.3% ID/g/kg in FMISO+ and 1.3 ± 0.3% ID/g/kg in FMISO-, P = ns). Intratumoral [F-18]-FMISO distribution reflected tumor hypoxia and expression of the hypoxia‑related gene product Glut-1; it did not, however, reflect tumor proliferation or glucose metabolism. Our findings help elucidate the biological characteristics of intratumoral [F-18]-FMISO distribution that are relevant to radiotherapy planning.


Laparoscopic surgery combined with preservation of the spleen for distal pancreatic tumors.
Laparoscopic distal pancreatectomy combined with spleen salvage by preservation of the splenic vessels has been described in selected patients with islet cell tumors. Laparoscopic resection of the left side of the pancreas with spleen preservation on the vasa brevia was attempted in six consecutive patients. Four distal pancreatectomies with spleen preservation were completed laparoscopically. There were two conversions to laparotomy. The median operating time was 300 min (range, 240-360). There was no mortality, but two patients developed a pancreatic fistula. The median postoperative hospital stay was 34.5 days (range, 5-60). All the patients remain well at a median follow-up of 30 months (range, 22-41). Minimally invasive surgery for distal pancreatic tumors is feasible and appropriate for most benign tumors. The spleen can be safely preserved laparoscopically on its blood supply from the short gastric vessels. The operative technique and especially the closure of the pancreatic stump need further study.


Comparison of the safety and efficacy of fingolimod and tofacitinib in the zebrafish model of colitis.
Oral targeted small molecules, including sphingosine 1 phosphate receptor (S1PR) modulators and tyrosine kinase inhibitors (TKIs), seem to revolutionize the management of inflammatory bowel disease (IBD). To select the most effective treatment, there is an unmet need to comparatively study their mechanism of action, efficacy, and toxicity in the preclinical stage and further translate it into clinical practice. Using 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced adult zebrafish colitis model, LC50 of fingolimod and tofacitinib were determined based on the acute toxicity test to compare aquatic toxicity potential. Subsequently, the efficacy of different concentrations of tofacitinib and fingolimod was compared using flow cytometry, qPCR, and histopathology analyses. TNBS significantly reduced the length of villi, and the number of goblet cells increased the level of TNF-α, MyD88, and NF-κB2, the thickness of villi and necrosis, and induced histopathological changes. All of these parameters were reversed almost dose-dependently with both medications, with the highest concentration of fingolimod being superior to other groups. Additionally, results from qPCR analysis suggested that these medications might suppress canonical and non-canonical NF-κB pathways by targeting toll-like receptors and MyD88. LC50 of tofacitinib and fingolimod was 0.9014 and 0.36 mg/L, respectively. Hence, both are in the cory 1 of the Global Harmonization System (GHS) aquatic toxicity and are toxic to adult zebrafish life. Given the better efficacy of fingolimod, it is worth translating the effectiveness and safety of S1PR modulators into IBD patients and comparing them with TKIs in head-to-head studies; albeit, their toxicity should not be overlooked.


Radiographic definition of the dorsal and palmar edges of the distal radius.
The dorsal and palmar edges of the distal radius, as well as the concavity of the articular surface were labeled with wire and radiographs taken from neutral to 30 degrees of added dorsal tilt. The dorsal edge was identified as the structure that protrudes distally in neutral. The palmar edge was found to overlap with the sclerotic subchondral bone of the radius in neutral. With increasing dorsal tilt the profile of the palmar edge appeared as it protruded distal to the sclerotic subchondral line of the radius. The profile of the palmar edge could be distinguished from that of the dorsal edge on the anteroposterior view. The wire, which was placed midway between the dorsal and palmar edges and the concavity of the articular surface corresponded to the prominent sclerotic subchondral bone line of the distal radius. This did not change in position with increasing dorsal tilt. This clarification of the radiologic anatomy is helpful in extending the use of the anteroposterior radiograph for the interpretation of fractures and malunions of the distal radius.


Recombinant H-chain ferritins: effects of changes in the 3-fold channels.
Human H-chain ferritins bearing sequence changes in the 3-fold channels have been expressed in E. coli to investigate the role of these channels in iron-storage processes. The proteins assemble into shells resembling those of native ferritins. Iron uptake measurements indicate that residues in the 3-fold channels are involved neither in initial Fe(II)-oxidation nor in iron-core nucleation.


Mice lacking the p53-effector gene Gadd45a develop a lupus-like syndrome.
This study addresses the biological function of the p53-effector genes Gadd45a and p21 in the immune system. We find that Gadd45a is a negative regulator of T cell proliferation because, compared to wild-type cells, Gadd45a(-/-) T cells have a lower threshold of activation and proliferate to a greater extent following primary T cell receptor stimulation. Gadd45a(-/-) mice develop an autoimmune disease, similar to human systemic lupus erythematosus (SLE), characterized by high titers of anti-dsDNA, anti-ssDNA, and anti-histone autoantibodies, severe hematological disorders, autoimmune glomerulonephritis, and premature death. Here we show that the lack of both Gadd45a and p21 dramatically accelerates the development of autoimmunity observed in each individual single-gene disruption mutant, demonstrating that these genes play nonredundant roles in the immune response.


Metal homeostasis in dementia.
The molecular determinants of dementia of Alzheimer's tipe (DAT) are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor is represented by the unbalanced homeostasis of two cations: calcium (Ca(2) ) and zinc (Zn(2)). The two ions serve a critical role in the physiological signalling of the central nervous system. However, Alzheimer's disease-related neurodegeneration, deregulation of brain levels of Ca(2) and Zn(2) is instrumental in promoting amyloid-β (Aβ) dysmetabolism and tau phosphorylation as well as interference with additional pathogenic factors like energy production failure, hyperexcitabilty, excitotoxicity, and oxidative stress. Hyperexcitabilty and excitotoxicity are key mechanisms in the disease development and progression as an altered glutamatergic activation can further promote both Ca(2) and Zn(2) dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further increase intracellular Ca(2) and Zn(2) rises and set the stage for a self-perpetuating injurious loop. In the talk, we will review mechanisms of AD-related Ca(2) and Zn(2) dyshomeostasis in a preclinical model of DAT and discuss opportunity for disease-modifying strategies based on interventions aimed at restoring brain metal homeostasis.


Short- and long-term outcomes of percutaneous coronary intervention in patients with low, intermediate and high ejection fraction.
Reduced ejection fraction (EF) has previously been shown to be a risk factor for adverse outcomes in patients undergoing percutaneous coronary intervention (PCI). However, with the advent of stents, procedural complications and restenosis rates have reduced dramatically. The aim of this study was to assess the association between left ventricular (LV ) ejection fraction and in-hospital and longterm outcomes using a prospective registry. After exclusion of patients with acute myocardial infarction (MI) and those with missing data on left ventricular ejection fraction, 2 030 patients undergoing PCI between March 2002 and 2004 remained in our prospective registry. Patients were divided into three categories: group 1: EF <or= 40% (n = 293), group 2: EF = 41-49% (n = 268) and group 3: EF >or= 50% (n = 1 469). The frequency of in-hospital and follow-up outcomes between groups was compared using appropriate statistical methods. Stents were used for over 85% of the patients in each group. The mean EF +/- SD in the lowest to highest EF groups was 35.8 +/- 5.4%, 45.5 +/- 1.6% and 57 +/- 5.7%, respectively. The angiographic and procedural success rates were 91.8, 92.1 and 94.1%, (p = 0.16); and 91.1, 90.3 and 92.9%, (p = 0.09), respectively. The respective cumulative major adverse cardiac events (MACE) and cardiac death rates at follow-up were 5.8, 2.2 and 3.3% (p = 0.04) and 2, 0.4 and 0.3% (p = 0.02), respectively. The hazards ratio (95% CI) for MACE and cardiac death in the lowest versus highest EF groups were 2.07 (1.03-4.16) and 5.49 (1.29-23.3). Patients with significant left ventricular dysfunction had higher long-term major adverse cardiac events and cardiac death rates. Even the use of newer techniques such as stenting did not compensate for this.


Changes of activity of daunorubicin, adriamycin and stereoisomers following the introduction or removal of hydroxyl groups in the amino sugar moiety.
The results of a study of the effects of hydroxyl groups at positions, 2, 4 and 6 of the amino sugar on the activity of daunorubicin, adriamycin, and stereoisomers are presented. While the 4'-deoxy derivatives showed a slightly increased biological activity as compared with the parent compounds, the derivatives containing an additional hydroxyl group were less active. It is suggested that the changes in the polarity and in the DNA binding ability of these derivatives are the main factors accounting for the difference in the in vivo activity. The possible relations among the pKa values, the DNA binding properties, and the cellular uptake of the compounds are discussed with particular reference to their therapeutic effectiveness.


The prognostic value of exercise testing in elderly men.
Our purposes were to compare the responses to exercise testing in elderly (> or =65 years of age) and younger men, and to investigate whether exercise testing has similar prognostic value in the two age groups. We included all elderly (n = 1185) and younger (n = 2789) male veterans without established coronary heart disease who underwent routine clinical exercise testing between 1987 and 2000 at two academically affiliated Veteran's Affairs medical center laboratories. Measurements included a standardized medical history, exercise testing, and all-cause mortality. Compared with younger patients, elderly patients achieved a lower workload (a mean [+/- SD] of 7 +/- 3 vs. 10 +/- 4 metabolic equivalents [METs], P <0.001) and were more likely to have abnormal ST depression (27% [n = 324] vs. 16% [n = 436], P <0.001). During the mean follow-up of 6 years, annual mortality was twice as high among elderly patients as among younger patients (4% vs. 2%, P <0.001). The only exercise test variable that was associated significantly with time to death in both age groups was maximal METs achieved: each 1 MET increase in exercise capacity was associated with an 11% reduction in annual mortality. Exercise-induced ST depression was more common in those who subsequently died, but was not an independent predictor of mortality. In elderly men, exercise testing provided prognostic information incremental to clinical data. Achieved workload (in METs) was the major exercise testing variable associated with all-cause mortality. Its prognostic importance was the same in elderly as in younger men.


[Study on applying principle component analysis to data processing on chromatographic fingerprints for Pinellia Cum Bile].
To explore the utility of principle component analysis (PCA) on chromatographic data for quality control to Dannanxing (Pinellia Cum Bile). Chromatographic fingerprints of sample were determined by TLC, PCA and multivariat analysis were used for data processing. The quantitative differences among samples procesed with different biles and heating time were found with the method. PCA could be used in data processing for chromato-gramphic fingerprints of Dannanxing.


How reliable is the high-volume definition in prostate cancer patients: the potential game-changing role of PSMA.
To evaluate whether metabolic and volumetric data from 68 Ga-PSMA PET/CT performed during staging of de-novo high-volume mCSPC patients who received docetaxel could be used to predict survival. Forty-two de-novo high-volume mCSPC patients, who received ADT + Docetaxel and underwent 68 Ga-PSMA PET/CT for staging, were included in the study. The association between patients' pathological data, all PSA measurements, treatments they received, the data obtained from 68 Ga-PSMA PET/CT and progression-free and overall survival were examined. In the multivariate analysis, PSMA-TV (primary) and PSMA-TV (WB) variables were shown to be independent negative predictors of overall survival. For the threshold value of 19.91 cm 3 obtained for PSMA-TV (primary), HR was calculated as 6.31, the 95% confidence interval (CI): 1.01-39.18, P = 0.048. For the threshold value of 1226.5 cm 3 obtained for PSMA-TV (WB) variable, HR was calculated as 58.62, the 95% CI: 2.55-1344.43, P = 0.011. In our study, SUVmax (WB) variable was found to be an independent and negative predictor of progression-free survival. For the determined threshold value of 17.74, HR was calculated as 16.24, 95% CI: 1.18-22.76, P = 0.037. Metabolic and volumetric data obtained from 68 Ga-PSMA PET/CT can be used to predict survival in de-novo high-volume mCSPC. Our results show that in ADT + Docetaxel receiving patients, a subgroup with higher PSMA-TV (WB) values have a significantly worse prognosis. This situation suggests that the high-volume disease definition in the literature may be insufficient for this group, and that 68 Ga-PSMA PET/CT can play an essential role in demonstrating the heterogeneity within the group.


The thyroid gland: physiology and pathophysiology.
The thyroid gland contains many follicular cells that store the thyroid hormones within the thyroglobulin molecule until they are needed by the body. The thyroid hormones, often referred to as the major metabolic hormones, affect virtually every cell in the body. Synthesis and secretion of the thyroid hormones depend on the presence of iodine and tyrosine as well as maturation of the hypothalamic-pituitary-thyroid system. Interruption of this development, as occurs with premature delivery, results in inadequate production of thyroid-stimulating hormone and thyroxine, leading to a variety of physiologic conditions. Pathologic conditions occur in the presence of insufficient thyroid production or a defect in the thyroid gland. Laboratory tests are important in diagnosing conditions of the thyroid gland. A thorough history in combination with clinical manifestations and radiologic findings are also useful in diagnosing specific thyroid conditions. Nurses play an important role in identifying and managing thyroid disorders and in providing supportive care to infants and their families.


When is prostate cancer really cancer?
Several investigators have challenged the idea that low-grade cancers are a cause for concern, suggesting that the term cancer should not be applied to these tumors. This article reviews the defining features of cancer, and the diagnostic and prognostic classification systems currently used for prostate cancer. Logical, morphologic, and molecular evidence is presented to show that low-grade prostate cancers are correctly classified as cancer. The authors suggest, however, that 6 out of 10 on an aggressiveness scale is inappropriate for indolent cancer, and that a proposed reinterpretation of Gleason grading categories is a more logical way to address overtreatment.


Phencyclidine-like discriminative stimulus properties of MK-801 in rats.
The discriminative stimulus properties of the N-methyl-D-aspartate (NMDA) antagonist MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine) were investigated in rats trained to discriminate phencyclidine (PCP; 1.25 mg/kg i.p.) from saline on a standard two-lever fixed ratio 32 schedule of food reinforcement. MK-801 was generalized from PCP in a dose-dependent manner, with an ED50 of 0.10 mg/kg i.p. The ED50 for PCP was 0.7 mg/kg io.p. MK-801 is, therefore, a very potent PCP-like drug which may share cellular mechanisms and other effects with PCP, including the antagonism of NMDA.


Leaves, seeds and exocarp of Ginkgo biloba L. (Ginkgoaceae): A Comprehensive Review of Traditional Uses, phytochemistry, pharmacology, resource utilization and toxicity.
Ginkgo biloba L. (Ginkgoaceae) is a treasure species with high medicinal value. The Ming Dynasty "Compendium of Materia Medica" and Qing Dynasty "Bencao Fengyuan" in China recorded this herbal medicine can reduce phlegm, clear poison, treat diarrhea and frequent urination, etc. AIM OF THE STUDY: Until now, there is no painstakingly summarized review on leaves, seeds and exocarp of G. biloba simultaneously. This review will systematically summarize and compare current knowledge of G. biloba. Ample original publications related to traditional uses, phytochemistry, pharmacology, resource utilization and toxicity of G. biloba leaves, seeds and exocarp till the end of 2021 were searched and collected by using various literature databases, including China National Knowledge Infrastructure, PubMed, Elsevier, Springer, Google Scholar and Web of Science database. According to classical Chinese herbal books and Chinese Pharmacopoeia, relieving cough, reducing phlegm, clearing poison and relieving diarrhea are the main pharmacological effects of G. biloba. The common chemical ingredients in different parts of G. biloba are flavonoids, terpenoids, phenolic acids, polysaccharides and endotoxin, etc. Among them, flavonoids and terpenoids are the main bioactive compounds in G. biloba leaves. Phenolic acids are the main bioactive compounds in G. biloba exocarp. G. biloba seeds are rich in nutritional ingredients, such as starch, adipose, protein, etc. Modern pharmacological studies showed that the crude extracts or compounds of G. biloba leaves, seeds and exocarp can be used for treating cardiovascular and cerebrovascular diseases, Alzheimer's disease, atherosclerosis, cancer, asthma, non-alcoholic fatty liver, diabetic complications and other diseases. In daily life, G. biloba seeds were usually used as raw material or additives for commodities, healthy food, drinks, even insecticides and antibacterial agents, etc. G. biloba leaves and seeds have been mainly applied for treating cardiovascular and cerebrovascular diseases, cough and asthma in clinical. However, endotoxins and ginkgolic acids have been identified as the dominating toxic ingredients in different parts of G. biloba. Besides, flavonoids and ginkgolides also have been proved to have toxicity recently. This review systematically sums up and compares the traditional uses, phytochemistry, pharmacology, resource utilization and toxicity research progress of G. biloba leaves, seeds and exocarp for the first time. It will provide some comprehensive reference data and suggestions for future research on this herbal medicine.


ELIXIR biovalidator for semantic validation of life science metadata.
To advance biomedical research, increasingly large amounts of complex data need to be discovered and integrated. This requires syntactic and semantic validation to ensure shared understanding of relevant entities. This article describes the ELIXIR biovalidator, which extends the syntactic validation of the widely used AJV library with ontology-based validation of JSON documents. Source code: https://github.com/elixir-europe/biovalidator, Release: v1.9.1, License: Apache License 2.0, Deployed at: https://www.ebi.ac.uk/biosamples/schema/validator/validate. Supplementary data are available at Bioinformatics online.


Thr308 determines Akt1 nuclear localization in insulin-stimulated keratinocytes.
Here, we determined the localization and activation of protein kinase B (Akt) in acute cutaneous wound tissue in mice. Akt1 represented the major Akt isoform that was expressed and activated in wound margin keratinocytes and also in the cultured human keratinocyte line HaCaT. Mutation of Akt1 protein, exchanging the activation-essential Ser473 and Thr308 residues for inactive Ala or phosphorylation-mimicking Asp and Glu residues, revealed that phosphorylation of Ser473 represented an essential prerequisite for auto-phosphorylation of Thr308 within the Akt1 protein in keratinocytes. Moreover, cell culture experiments and transfection studies using Thr308 mutated Akt1 proteins demonstrated that phosphorylation of Akt1 at Thr308 appeared to selectively exclude the active kinase from the nucleus and direct the kinase to the cytoplasmic compartment in keratinocytes upon insulin stimulation. In summary, our data show that phosphorylation of Thr308 during insulin-mediated Akt1 activation is an essential prerequisite to exclude Akt1 from the nuclear compartment.


Radiograph assessment of the basal thumb joint.
Evaluation and treatment of basal thumb joint problems require a careful history, physical examination, and radiographs. The "true" AP and stress views provide useful information which supplements the standard plain radiographs. Additional maneuvers such as local injection and other imaging modalities are also sometimes employed, but their discussion is beyond the scope of this brief review.


Effectiveness of peer-learning assisted primary school students educating the rural community on insecticide-treated nets utilization in Jimma-zone Ethiopia.
Making insecticide-treated nets (ITNs) utilization a social norm would support the global goal of malaria eradication and Ethiopian national aim of its elimination by 2030. Jimma zone is one of the endemic settings in Ethiopia. This study aimed to report effects of malaria education, delivered by students, on community behaviours; particularly ITNs. In pre-posttest, cross-sectional household surveys conducted in rural villages of 5 districts in Jimma Zone, Ethiopia, 762 households were sampled. The intervention engaged students from primary schools in participatory peer education within small groups, followed by exposing parents with malaria messages aimed at influencing perceptions and practices. The data were analysed using SPSS version 20.0. Proportions/means differences were computed to compare changes in exposure, knowledge, perceptions, and practices using 95% CI at p < 0.05. Regression analyses were conducted to assess exposures to school-based education, content intensity, perception, and access related predictors of ITN utilization over the intervention periods. Over the intervention periods, the findings showed significant improvement in exposure to and content intensity of malaria messages delivered by students, effect size (ES) = 44.5% and 19.3%, p < 0.001, respectively. ITN utilization (ES = 25.8%), and the reported behaviour of giving ITN priority to children under 5 years old and pregnant women increased by ES = 16.3% and 24.8%, respectively. The exposure status or content intensity of malaria education, in turn, significantly improved comprehensive knowledge about malaria (β = +1.82), misconceptions about causes (β = - 11.46), awareness of caring for ITN (β = +24.79), identifying ITN as effective preventive methods (OR = 1.93), attitude towards ITN (β = +0.20), perceived efficacy of ITN (OR = 1.04), acceptance of ITN as a means to control the danger of malaria (β = +8.08%), and ITN utilization (OR = 1.85). Nonetheless, perceived threat (β = - 0.19) significantly negatively correlated with exposure to students' messages. Socio-demography, access, exposures to messages, and parental perception that students were good reminders predicted ITN utilization over the intervention periods with some changing patterns. Exposing the community to malaria education through students effectively supports behaviour change, particularly ITN usage, to be more positive towards desired malaria control practices. A school-based strategy is recommended to the national effort to combat malaria.


The origin and ultrastructural characteristics of corticotropin-releasing factor (CRF)-immunoreactive nerve fibers in the posterior pituitary of the rat.
A fine network of corticotropin-releasing factor (CRF)-immunopositive fibers was found in the posterior lobe of the pituitary of the rat. The intermediate and distal lobes were free of CRF-immunoreactivity. Varicose, terminal-like axons were frequently observed around capillary vessels. Surgical isolation of the paraventricular nuclei resulted in a complete disappearance of CRF-immunoreactive fibers from the posterior lobe. CRF-immunopositive fibers show the general characteristics of peptidergic axons. These ultrastructural observations support the idea that CRF is secreted into capillary vessels.


Dynamic effects of joint-leveling procedure on pressure at the distal radioulnar joint.
Wrist joint-leveling procedures for decompression of the radiocarpal and ulnocarpal joints are accompanied by the risk for subsequent disorders of the adjacent distal radioulnar joint (DRUJ). This study evaluated the dynamic change of the pressure pattern at the DRUJ after joint-leveling procedures. Thirteen fresh-frozen adult cadaveric upper extremities were used. A segment of the radius was excised at its midshaft to allow lengthening and shortening via a mini external fixator attachment. Dynamic pressure sensors were inserted into the DRUJ and the ulnocarpal joint. Axial loads were applied to the extensor carpi radialis brevis, extensor carpi radialis longus, extensor carpi ulnaris, flexor carpi radialis, and flexor carpi ulnaris for a total of 89 N with or without 30 N of radioulnar loading. The dynamic pressure distribution for full range of forearm rotation was recorded from 6 mm of radial shortening to 6 mm of radial lengthening in increments of 1 mm. The peak pressures at the DRUJ before the joint-leveling procedures averaged 3.3 MPa without radioulnar loading and 5.0 MPa with radioulnar loading. The peak pressures with axial and radioulnar loading increased 85% at 6 mm of lengthening and only 8% at 6 mm of shortening. The peak pressures at the DRUJ for radial lengthening of 4 mm or more were significantly greater than that of the original length. Pressure at the ulnocarpal joint increased in proportion to the amount of radial shortening and decreased with radial lengthening. Radial lengthening but not radial shortening significantly increases the peak pressure at the DRUJ.


Sensorimotor Incoordination in Musicians' Dystonia.
To acquire and maintain outstanding sensorimotor skills for playing musical instruments inevitably requires extensive training from childhood. However, on the way toward musical excellence, musicians sometimes develop serious disorders, such as tendinitis, carpal tunnel syndrome, and task-specific focal dystonia. Particularly, task-specific focal dystonia in musicians, which is referred to as musician's dystonia (MD), has no perfect cure and therefore often terminates professional careers of musicians. To better understand its pathological and pathophysiological mechanisms, the present article focuses on malfunctions of the sensorimotor system at the behavioral and neurophysiological levels. Based on emerging empirical evidence, we propose that the aberrant sensorimotor integration, possibly which occurs in both cortical and subcortical systems, underlies not only movement incoordination between the fingers (i.e., maladaptive synergy) but also failure of long-term retention of intervention effects in the patients with MD.


Kellgren-Lawrence grade of osteoarthritis is associated with change in certain morphological parameters.
To compare selected morphological parameters between normal and osteoarthritic (OA) knees, as well as to evaluate differences in these parameters between Kellgren-Lawrence (K-L) grades of OA. Knee joint morphology was evaluated using magnetic resonance (MR) images of 200 participants with knee OA (50 each of K-L grades 1-4) and 50 without knee OA, matched for age, body mass index, sex, and tibiofemoral angle. Knees with a coronal alignment within five degrees of neutral and no apparent bone loss on radiographs were included. Twenty-one morphologic parameters of the distal femur and proximal tibia were measured on MR images. Correlation between the K-L grade and measured parameters and differences in measured parameters across the K-L grades and between the OA and control groups were evaluated. The K-L grade was significantly correlated with multiple distal femur measurements including the posterior condylar angle (PCA), lateral epicondyle to posterior condylar cartilage (LEPC) length, medial epicondyle to posterior condylar cartilage (MEPC) length, medial epicondyle to distal cartilage (MEDC) length, medial tibial slope angle, femoral condylar cartilage height difference (FCHDc), and femoral condylar bone height difference (FCHDb) (P < 0.05). A significant difference was identified between the different K-L grades with regard to PCA, LEPC, MEPC, MEDC, and FCHDc (P < 0.05). There was no correlation between K-L grade and measured proximal tibial parameters. Among knees without significant angular deformity, progression of knee OA is associated with a change in the morphology of the femoral condyles but not of the proximal tibia.


Psychometric properties of a generic health measure in Chinese patients with low back pain in Hong Kong.
In Hong Kong, the measurement of perceived health status in patients with low back pain (LBP) can be facilitated by the availability of a health profile specifically designed for the Chinese culture. This prospective observational study investigated the psychometric properties of the generic Current Perceived Health 42 (CPH42) Profile in four separate samples (totalling 473) of Chinese patients with LBP in Hong Kong. The patients completed the CPH42 Profile and the Roland LBP Disability Scale at various points in the course of physiotherapy. Their pain intensity was measured using the 11-point pain numerical rating scale (NRS). The test-retest reliability and internal consistency of the CPH42 Profile demonstrated high intra-class correlation coefficient of 0.92 and Cronbach's alpha of 0.90. Validity was confirmed by a moderate correlation with the Chinese adaptations of the Roland LBP Disability Scale and the NRS at the commencement of physiotherapy (Spearman's correlation coefficients were 0.48 and 0.42, respectively). The responsiveness, measured from the commencement of physiotherapy to weeks 3 and 6 (standard response means of 0.33 and 0.58, respectively), were commensurate with the respective changes in pain intensity. The psychometric properties of the CPH42 Profile suggest its suitability for use as an outcome instrument in future efficacy studies on LBP intervention.


Cdon ablation in motor neurons causes age-related motor neuron degeneration and impaired sciatic nerve repair.
The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron diseases or aging-related muscle wasting in turn contribute to increased risk of adverse health outcomes in the elderly. Cdon (cell adhesion molecule-downregulated oncogene) belongs to the immunoglobulin superfamily of cell adhesion molecule and plays essential roles in multiple signalling pathways, including sonic hedgehog (Shh), netrin, and cadherin-mediated signalling. Cdon as a Shh coreceptor plays a critical role in motor neuron specification during embryonic development. However, its role in adult motor neuron function is unknown. Hb9-Cre recombinase-driven motor neuron-specific Cdon deficient mice (mnKO) and a compound mutant mice (mnKO::SOD1G93A ) were generated to investigate the role of Cdon in motor neuron degeneration. Motor neuron regeneration was examined by using a sciatic nerve crush injury model. To investigate the phenotype, physical activity, compound muscle action potential, immunostaining, and transmission electron microscopy were carried out. In the mechanism study, RNA sequencing and RNA/protein analyses were employed. Mice lacking Cdon in motor neurons exhibited middle age onset lethality and aging-related decline in motor function. In the sciatic nerve crush injury model, mnKO mice exhibited an impairment in motor function recovery evident by prolonged compound muscle action potential duration (4.63 ± 0.35 vs. 3.93 ± 0.22 s for f/f, P < 0.01) and physical activity. Consistently, neuromuscular junctions of mnKO muscles were incompletely occupied (49.79 ± 5.74 vs. 79.39 ± 3.77% fully occupied neuromuscular junctions for f/f, P < 0.0001), suggesting an impaired reinnervation. The transmission electron microscopy analysis revealed that mnKO sciatic nerves had smaller axon diameter (0.88 ± 0.13 vs. 1.43 ± 0.48 μm for f/f, P < 0.0001) and myelination defects. RNA sequencing of mnKO lumbar spinal cords showed alteration in genes related to neurogenesis, inflammation and cell death. Among the altered genes, ErbB4 and FgfR expressions were significantly altered in mnKO as well as in Cdon-depleted NSC34 motor neuron cells. Consistently, Cdon-depleted NSC34 cells exhibited elevated levels of cleaved Caspase3 and γH2AX proteins, as well as Bax transcription. Cdon-depleted NSC34 cells also exhibited impaired activation of Akt in response to neuregulin-1 (NRG1) treatment. Our current data demonstrate the functional importance of Cdon in motor neuron function and nerve repair. Cdon ablation causes alterations in neurotrophin signalling that leads to motor neuron degeneration.


Localized hand burns with or without concurrent blast injuries from fireworks.
This is a retrospective study of 32 cases with localized hand burns from fireworks. All cases occurred during two national festivals of our country. The majority (54%) were children between 5 and 14 years, and 94% were males. All patients had localized hand burns. Patients were divided into two groups. Group I (n=10) patients had isolated burn injuries and Group II (n=22) patients had other concurrent hand injuries from the 'blast' of the fireworks such as tendon avulsion, nerve injury, fracture, dislocations, and amputations. Primary management of concurrent injuries along with dressing to the burn injury in a "flamazine bag" was done. All burns healed within 3 weeks and all surgical wounds/fractures healed without infection. Three patients required secondary release of contractures and skin grafting. Eventually, all patients were able to use their injured hands in daily activities.


Preparation, characterization and antioxidant activity of cobalt polysaccharides from Qingzhuan Dark Tea.
The paradoxical effects of cobalt in biological processes have caused controversy regarding the application of cobalt-based biomaterials. Cobalt has recently been shown to be a trace element that promotes bone growth. Qingzhuan Dark Tea polysaccharides (TPS) has been shown to be a biomaterial with antioxidant and immunomodulatory effects. In order to develop a novel immunomodulatory biomaterial, we synthesized polysaccharide cobalt complex (TPS-Co) to prevent the paradoxical effects of cobalt while maintaining its beneficial effects, and evaluated its morphology, structure, and antioxidant activity. Fourier-transform infrared spectroscopy, X-ray diffraction and X-ray photoelectron spectroscopy demonstrated that cobalt complexed successfully with TPS. Scanning electron microscopy and atomic mechanical microscopy demonstrated that TPS-Co has a more homogeneous and concentrated morphological distribution compared to TPS. Thermal performance analysis demonstrated that TPS-Co has higher thermal stability. Atomic absorption spectroscopy showed a cobalt content of 3.8%. Ultraviolet spectroscopy indicated that TPS-Co does not contain nucleic acids and proteins. Antioxidant activity assays showed that TPS-Co has better antioxidant activity than TPS in the concentration range of 0.4-2 mg/mL. Proliferation assay of MC3T3-E1 cells demonstrated that TPS-Co has the best cell proliferation effect at a cobalt concentration of 2 ppm. Therefore, TPS-Co may have potential applications in bone regeneration.


Risk factors in miscarriage: a review.
Miscarriage is one of the most frequent problems in human pregnancy. The most widely accepted definition is that proposed by the World Health Organization (WHO) in 1977. The incidence among clinical pregnancies is about 12-15% but including early pregnancy losses it is 17-22%. The only two etiologic factors recognized by all authors are uterine malformations and parental balanced chromosomal rearrangements. There have been many other suggested risk factors. In this revision we discuss these.


Proteinuria as a risk factor for cardiovascular disease and mortality in older people: a prospective study.
The prognostic significance of proteinuria in older people is not well defined. We examined the associations between proteinuria and incident coronary heart disease, cardiovascular mortality, and all-cause mortality in older people. Casual dipstick proteinuria was determined in 1,045 men (mean [+/- SD] age 68 +/- 7 years) and 1,541 women (mean age 69 +/- 7 years) attending the 15th biennial examination of the Framingham Heart Study. Participants were divided by grade of proteinuria: none (85.3%), trace (10.2%), and greater-than-trace (4.5%). Cox proportional hazards analyses were used to determine the relations of baseline proteinuria to the specified outcomes, adjusting for other risk factors, including serum creatinine level. During 17 years of follow-up, there were 455 coronary heart disease events, 412 cardiovascular disease deaths, and 1,214 deaths. In men, baseline proteinuria was associated with all-cause mortality (hazards ratio [HR] = 1.3, 95% confidence interval [CI] 1.0 to 1.7 for trace proteinuria; HR = 1.3, 95% CI 1.0 to 1.8 for greater-than-trace proteinuria; P for trend = 0.02). In women, trace proteinuria was associated with cardiovascular disease death (HR = 1. 6, 95% CI 1.1 to 2.4), and all-cause mortality (HR = 1.4, 95% CI 1.1 to 1.7). Proteinuria is a significant, although relatively weak, risk factor for all-cause mortality in men and women, and for cardiovascular disease mortality in women.


Synthesis of 3,5-disubstituted isoxazoles via Cope-type hydroamination of 1,3-dialkynes.
An efficient method for the synthesis of 3,5-disubstituted isoxazoles is described. The reactions of 1,3-dialkynes with hydroxylamine proceeded smoothly in DMSO under mild reaction conditions to produce 3,5-disubstituted isoxazoles in satisfactory to excellent yields.


Cushing syndrome in pregnancy secondary to an adrenal cortical adenoma.
Cushing syndrome in pregnancy is rare. This is explained by the syndrome's association with amenorrhoea, oligomenorrhoea, infertility and abortions. Cushing syndrome commonly presents with hypertension, weight gain, diabetes, striae or truncal obesity, all of which can be consistent with pregnancy in women without Cushing syndrome. We describe a case of Cushing syndrome in pregnancy secondary to an adrenal cortical tumour which was discovered after an abnormal glucose tolerance test. The woman developed classical features of Cushing syndrome including gestational diabetes and hypertension and was managed successfully to term after a unilateral adrenalectomy at 23 weeks. The case is reported not only because of its rarity but also because the diagnosis was made after a routine screening test for gestational diabetes. Early diagnosis and treatment of adrenal adenoma causing Cushing syndrome in pregnancy reduces maternal and fetal morbidity and mortality.


Primary Prevention of Heart Failure in Women.
The incidence of heart failure (HF) is increasing, particularly among women, and constitutes a rapidly growing public health problem. The primary prevention of HF in women should involve targeted, sex-specific strategies to increase awareness, promote a heart healthy lifestyle, and improve treatments that optimally control the risk factors for HF with reduced ejection fraction and HF with preserved ejection fraction. Epidemiological and pathophysiological differences in both HF subtypes strongly suggest that sex-specific preventive strategies and risk factor reduction may be particularly beneficial. However, significant gaps in sex-specific knowledge exist and are impeding preventive efforts. To overcome these limitations, women need to be adequately represented in HF research, sex differences must be prospectively investigated, and effective sex-specific interventions should be incorporated into clinical practice guidelines. This review summarizes the existing evidence that supports the primary prevention of HF in women and identifies potential strategies that are most likely to be effective in reducing the burden of HF among women.


In-office needle arthroscopy is a cost-effective alternative for operating room diversion in medial meniscectomy: a financial analysis.
In-office needle arthroscopy (IONA) has been described as a diagnostic alternative to magnetic resonance imaging (MRI) for intra-articular pathology. However, few studies have analyzed its impact on cost and wait times when used as a therapeutic intervention. The purpose of this study was to investigate the impact on cost and wait times associated with offering IONA for partial medial meniscectomy as an alternative to traditional operating room (OR) arthroscopy for patients with irreparable medial meniscus tears on MRI. Two models were created comparing the existing care pathway (current state) to a proposed future state utilizing IONA. Data sources were accounting data from an academically affiliated hospital in Canada and supplemented with literature values. A Monte Carlo simulation combined with DuPont analysis running 10,000 simulations was conducted to calculate the revenue, expenses, profits, and effect on surgical waitlists (i.e., throughput) between the states. Sensitivity analyses examined the influence of patient preference and revision rates on profit and throughput. Two-sample Student's t test was performed (p < .05). An average of 198 (standard deviation (SD) 31) patients underwent arthroscopic meniscectomy or repair each year from 2016 to 2020. The IONA revision rate was calculated as 20.3%. Compared to the current state, annual expenses in the IONA pathway were significantly reduced ($266,912.68 versus $281,415.23, p < .0001), while improving throughput by 21.2% (3.54%). Sensitivity analysis revealed 10% of patients need to select IONA over traditional OR arthroscopy with the revision rate remaining below 40% for the proposed state profit to be higher than the current state. IONA is a cost-effective alternative to traditional OR arthroscopy in patients undergoing partial medial meniscectomy. The next steps are to assess patients' perceptions of IONA as an alternative to traditional OR arthroscopy, and to carry out clinical trials to determine the efficacy, patient-reported outcome metrics, and complications of IONA.


New insight into the relationship between Salmonella Typhimurium and the German cockroach suggests active mechanisms of vector-borne transmission.
Diarrheal diseases are among the most common illnesses in the world and the bacterium Salmonella enterica serovar Typhimurium is a leading cause of morbidity and mortality from diarrhea globally. The German cockroach (Blattella germanica) frequently harbors and has been linked to human outbreaks of Salmonella, but the mechanisms of vector-borne transmission are not fully clear. Transmission of S. Typhimurium by cockroaches has been previously described as mechanical. Mechanical transmission is a wholly passive process that involves physical transfer of a pathogen from one location or host to another but lacks bacterial replication in the vector and active bacterial processes that promote vector colonization or transmission. Towards the goal of obtaining novel insight into the mechanisms of S. Typhimurium transmission by cockroaches, here we orally provisioned wild type and mutant strains to adult B. germanica and examined several aspects of colonization and shedding. Our results provide evidence of three previously unappreciated phenomena with significant implications. First, we demonstrate that S. Typhimurium undergoes replication at multiple phases during colonization of the cockroach gut. Second, we show the formation of biofilm-like aggregates by S. Typhimurium in the cockroach foregut. Lastly, we identify two mutant strains of S. Typhimurium that are deficient in colonization and shedding relative to isogenic controls, implicating type III secretion and the formation of fimbriae as two processes that are necessary for interaction with the cockroach vector. Together, our data indicate that transmission of S. Typhimurium by cockroaches is not solely mechanical but may resemble biological transmission by other insect vectors that intake human pathogenic bacteria from infected hosts and are subsequently colonized, enabling active dissemination. Thus, these findings suggest that cockroaches and their control may be more important for infection prevention than is currently appreciated. Additional studies to better understand the cycle and biological mechanisms of vector-borne transmission are warranted.


Long-standing postsurgical lower cranial nerve palsy mimicking a pharyngolaryngeal submucosal mass in an elderly patient.
Changes that occur as a natural part of senescence in the complex action of deglutition predispose to dysphagia and aspiration. This dysfunction is worsened in patients with preexisting anatomic or functional alteration such as in case of a postsurgical lower cranial nerve palsy. We present the case of a 72-year-old woman who underwent surgical resection of a right jugulotympanic tumor 33 years ago, resulting in lower cranial nerve palsy, and came to our attention referring a 4 months' history of progressive dysphagia in which a pharyngolaryngeal submucosal mass was suspected.


Effects of microinjections of glutamate and glutamate receptor antagonists into A5 zone on generation of respiratory rhythm in ponto-bulbospinal preparations from newborn rats in vitro.
Activation of glutamate receptors in A5 neurons enhanced their tonic inhibitory influence on the respiratory rhythm generator in isolated newborn rat ponto-bulbospinal preparations. The stimulating effect of glutamate on A5 neurons is determined by its effect mainly on non-NMDA receptors and less so on NMDA receptors.


[Bilateral sclerosis of the submaxillary glands secondary to orthodontic treatment].
A hitherto unreported complication of orthodontic treatment secondary to the insertion of an inferior lingual arch: bilateral sclerosis of submandibular glands.


Unusual complication of central venous catheter in hemodialysis.
A case of a partial rupture of a cuffed central venous catheter (CVC) implanted in the femoral vein with the purpose of being used for chronic hemodialysis is described in a 74-year-old female patient. Of relevance is that the CVC described was from the same manufacturer as the previous one that had lasted 12 years.


Impact of CT in the neurosurgical management of intracranial tumors.
A total of 103 brain tumor patients examined with CT, radionuclide brain scan, and angiography or pneumoencephalography, and all surgically verified, were studied to evaluate the impact of CT on the neurosurgical handling of brain tumors. CT alone was usually sufficient for optimal handling of astrocytoma patients, angiography in most meningioma cases, and pneumoencephalography in cases with sellar, suprasellar, and some other midline tumors. Information obtained only through CT sometimes altered the therapy. Sometimes it led to biopsy instead of a meaningless attempt at a 'radical' excision: in other cases it permitted a 'radical' excision otherwise not possible.


Cardiovascular Magnetic Resonance in Valvular Heart Disease-Related Heart Failure.
Patients with valvular heart disease-related heart failure are unable to pump enough blood to meet the body's needs. Magnetic resonance imaging (MRI) can play an important role by identifying these patients and distinguishing them from patients whose valvular disease is not the cause of their heart failure. Heart failure is a major public health problem, with a prevalence of 5.8 million people in the United States and more than 223 million people worldwide. This article focuses on the diagnostic and prognostic value of MRI patients with valvular causes of heart failure.


Renal cell carcinoma in a horseshoe kidney presenting as an acute, left sided varicocele.
We present a rare case of renal cell carcinoma (RCC) in a horseshoe kidney presenting as an acute left sided varicocele. A left sided varicocele is a well-described presentation of RCC, usually caused by tumour thrombus extending along the renal vein with resultant testicular vein occlusion. However, in our case a tumour in the lower pole of a horseshoe kidney caused an acute varicocele by direct involvement and occlusion of the testicular vein.


Allopurinol blocks aortic aneurysm in a mouse model of Marfan syndrome via reducing aortic oxidative stress.
Increasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy. In aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1C1041G/+), aortic XOR mRNA transcripts and enzymatic activity of the oxidase form (XO) were augmented in the aorta of 3-month-old mice but not in older animals. The administration of the XOR inhibitor allopurinol (ALO) halted the progression of aortic root aneurysm in MFS mice. ALO administrated before the onset of the aneurysm prevented its subsequent development. ALO also inhibited MFS-associated endothelial dysfunction as well as elastic fiber fragmentation, nuclear translocation of pNRF2 and increased 3'-nitrotyrosine levels, and collagen maturation remodeling, all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2O2, and NOX4 and MMP2 transcriptional overexpression. Allopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients.


Mucopolysaccharidosis type II in females and response to enzyme replacement therapy.
Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked lysosomal storage disease caused by a deficiency of iduronate-2-sulfatase (IDS). Two affected girls with moderate and severe forms of MPS II with normal karyotypes and increased urinary dermatan sulphate and heparin sulphate excretion and marked deficiencies of IDS activity are reported. Molecular studies showed that case 1 has a heterozygous mutation c.1568A > G (p.Y523C) associated with almost totally skewed inactivation of the normal maternal X chromosome, and case 2 has a heterozygous deletion that includes exons 1-4 of IDS (minimal deletion range c.1-103_184del). The multi-exon deletion correlated with early onset of the disease and severe phenotype with intellectual disability, whereas the missense mutation was associated with moderate developmental delay. Although genotype-phenotype correlation in MPS II is difficult, gene deletions seem to correlate with more severe clinical manifestation of the disease. Enzyme replacement therapy (ERT) in these two females resulted in disease stabilization in both.


Hepatic proteomic analysis revealed altered metabolic pathways in insulin resistant Akt1(+/-)/Akt2(-/-) mice.
The aim of this study was to identify liver proteome changes in a mouse model of severe insulin resistance and markedly decreased leptin levels. Two-dimensional differential gel electrophoresis was utilized to identify liver proteome changes in AKT1(+/-)/AKT2(-/-) mice. Proteins with altered levels were identified with tandem mass spectrometry. Ingenuity Pathway Analysis was performed for the interpretation of the biological significance of the observed proteomic changes. 11 proteins were identified from 2 biological replicates to be differentially expressed by a ratio of at least 1.3 between age-matched insulin resistant (Akt1(+/-)/Akt2(-/-)) and wild type mice. Albumin and mitochondrial ornithine aminotransferase were detected from multiple spots, which suggest post-translational modifications. Enzymes of the urea cycle were common members of top regulated pathways. Our results help to unveil the regulation of the liver proteome underlying altered metabolism in an animal model of severe insulin resistance.


Temporal and spatial distribution of health, labor, and crop benefits of climate change mitigation in the United States.
Societal benefits from climate change mitigation accrue via multiple pathways. We examine the US impacts of emission changes on several factors that are affected by both climate and air quality responses. Nationwide benefits through midcentury stem primarily from air quality improvements, which are realized rapidly, and include human health, labor productivity, and crop yield benefits. Benefits from reduced heat exposure become large around 2060, thereafter often dominating over those from improved air quality. Monetized benefits are in the tens of trillions of dollars for avoided deaths and tens of billions for labor productivity and crop yield increases and reduced hospital expenditures. Total monetized benefits this century are dominated by health and are much larger than in previous analyses due to improved understanding of the human health impacts of exposure to both heat and air pollution. Benefit-cost ratios are therefore much larger than in prior studies, especially those that neglected clean air benefits. Specifically, benefits from clean air exceed costs in the first decade, whereas benefits from climate alone exceed costs in the latter half of the century. Furthermore, monetized US benefits largely stem from US emissions reductions. Increased emphasis on the localized, near-term air quality-related impacts would better align policies with societal benefits and, by reducing the mismatch between perception of climate as a risk distant in space and time and the need for rapid action to mitigate long-term climate change, might help increase acceptance of mitigation policies.


Effects of cataract surgery in Japanese patients with neovascular age-related macular degeneration.
To investigate the effects of cataract surgery in Japanese patients with neovascular age-related macular degeneration (nAMD). The primary endpoint in this prospective, observational study was patient satisfaction at 6 months after cataract surgery in patients with nAMD. Secondary endpoints comprised changes in best-corrected visual acuity (BCVA), M-chart score, central retinal thickness (CRT), AMD status, and number of AMD treatments. All examinations were performed before surgery, and at 1, 3, and 6 months postoperatively. Fifty patients (52 eyes) were included in this study (32 men; mean age, 76.1 ± 7.1 years). Thirty-nine patients (75.0%) reported satisfaction with cataract surgery. BCVA significantly improved at all postoperative timepoints (all p < 0.0001), whereas differences in M-chart scores were not statistically significant. The number of eyes with BCVA ≤ 0.3 logarithm of the minimum angle of resolution (logMAR) increased from 21 to 38; however, CRT did not change. The number of AMD treatments did not change during follow-up. All questionnaire scores showed postoperative improvement. Univariate and multivariate analyses revealed that final BCVA ≤ 0.3 logMAR was significantly associated with patient satisfaction. Cataract surgery significantly improved vision in Japanese patients with nAMD, without affecting AMD status. Patients were satisfied with cataract surgery, especially with respect to improvement of distance vision.


Early changes in ambulatory electrocardiography after transcatheter closure in patients with atrial septal defect and factors affecting heart rate variability.
Factors affecting heart rate variability (HRV) in patients with atrial septal defect (ASD) have not been clarified. This study sought to identify those factors and establish a preliminary risk model. A total of 154 patients with ASD who underwent transcatheter closure and met the study requirements were analyzed in this study. Moreover, 26 patients with patent foramen ovale (PFO) were enrolled in our study as a control group. All patients underwent echocardiography and ambulatory electrocardiography before and one day after the procedure. The standard deviation of all normal-to-normal (NN) intervals (SDNN) and the standard deviation of the averages of the NN intervals in all 5 min segments of the entire recording (SDANN) were significantly higher and the heart rate was lower after closure than before closure in patients with ASD (SDNN: 6.08, 95% CI 3.00 to 9.15, p < 0.001; SDANN: 7.57, 95% CI 4.50 to 10.64, p < 0.001; heart rate: -1.17, 95% CI - 2.86 to - 0.48, p = 0.006). Multiple regression analyses indicated that age, sex, defect diameter, heart rate and diabetes were significantly associated with HRV indices (SDNN: R2 = 0.415; P < 0.001). SDNN and SDANN had obvious correlations with right ventricular systolic pressure (SDNN: R = - 0.370, p < 0.001; SDANN: R = - 0.360, p < 0.001). Factors affecting HRV in patients with ASD include age, sex, heart rate, defect size and diabetes. Furthermore, right ventricular systolic pressure plays an important role in the change in HRV.


Comparative pharmacology, bioavailability, pharmacokinetics, and pharmacodynamics of inhaled glucocorticosteroids.
A comparison of the pharmacodynamics and pharmacokinetics of inhaled corticosteroids is necessary for their assessment. A good knowledge of these two aspects allows the optimization of efficacy and safety.The currently available inhaled corticosteroids already show some of the desired PK/PD parameters. The local adverse effects are decreased as soon as the inhaled corticosteroid is administered as an inactive prodrug or shows a bet-ter lung deposition. HFA-MDI beclomethasone dipropionate (BDP) and ciclesonide are two agents that illustrate this. Low oral bioavailability, rapid systemic clearance, and high plasma protein binding can minimize systemic adverse effects. Mometasone furoate, ciclesonide, and fluticasone propionate possess those characteristics. The pulmonary efficacy is maximized by high lung deposition and long pulmonary residence times. This effect can be achieved by slow dissolution in the lungs, as is the case for fluticasone propionate or lipid conjugation and has been shown for budesonide and ciclesonide. Furthermore, the lung deposition depends on the inhalation device, the particle size, and the inhalation technique. Therefore,improvement in the design of MDIs, DPIs, and nebulizers, and the development of more effective drug particles will lead to an optimized pulmonary targeting. Much progress has been made in the treatment of asthma. The available inhaled corticosteroids show a high safety profile and a good pulmonary selectivity. Development of newer compounds showed that improvement is possible as the result of a complete understanding of the PK/PD concepts. However,the introduction of further improved formulations with a better efficacy/safety profile will be difficult and protracted because the existing drugs are already highly efficient.


Missed Intrapulmonary Lymph Node Metastasis and Survival After Resection of Non-Small Cell Lung Cancer.
Pathologic nodal stage is a key prognostic factor for patients with surgically resected lung cancer. We previously described the extent of missed intrapulmonary nodal metastasis in a cohort of patients treated at institutions in metropolitan Memphis, TN. With long-term follow-up, we now quantify the survival impact of missed nodal metastasis. We conducted a prospective cohort study to evaluate inadvertently discarded lymph nodes in re-dissected remnant lung resection specimens from lung cancer patients. Retrieved material was histologically examined and classified as lymph nodes with and without metastasis. Survival information was obtained from hospital cancer registries. We plotted survival distributions with the use of the Kaplan-Meier method and evaluated them with proportional hazards models that controlled for important demographic and clinical factors. The study included 110 patients who were 54% women and 69% white. Discarded lymph nodes with metastasis were found in 25 patients (23%). Patients with missed lymph node metastasis had an increased risk of death with an unadjusted hazard ratio of 2.0 (p = 0.06) and an adjusted hazard ratio of 1.4 (p = 0.45) compared with patients without missed lymph node metastasis. Patients with more than 2 missed lymph nodes with metastasis had 4.8 times the hazard of death (p = 0.0005) compared with patients without missed lymph node metastasis (adjusted hazard ratio 6.5, p = 0.0001). Metastasis to inadvertently discarded intrapulmonary lymph nodes from lung cancer resection specimens was associated with reduced survival. A more rigorous gross dissection protocol for lung cancer resection specimens may provide prognostically useful information.


A contribution to the study of the Lower Volga center of scarab beetle diversity in Russia: checklist of the tribe Aphodiini (Coleoptera, Scarabaeidae) of Dosang environs.
The field sampling of the Aphodiini scarab beetles in Dosang environs (Astrakhan Province, European Russia) in 2006-2012 resulted in the collection of 44 species. All but one of them belong to Aphodius Hellwig (sensu lato). This is apparently the richest recorded local Aphodiini fauna in Russia. The high Aphodiini diversity in the area can be explained by the long vegetative season with high effective heat sum, large livestock providing abundant food resources throughout the year, and location in the transition belt between Volga-Akhtuba Floodplain and Desert floristic districts. The core fauna consists of mesophilous species widely distributed in the Palearctic region and confined to the intrazonal habitats. Other species have ranges mostly limited to the steppe, semidesert, and desert zones.


Solid-body trajectoids shaped to roll along desired pathways.
In everyday life, rolling motion is typically associated with cylindrical (for example, car wheels) or spherical (for example, billiard balls) bodies tracing linear paths. However, mathematicians have, for decades, been interested in more exotically shaped solids such as the famous oloids1, sphericons2, polycons3, platonicons4 and two-circle rollers5 that roll downhill in curvilinear paths (in contrast to cylinders or spheres) yet indefinitely (in contrast to cones, Supplementary Video 1). The trajectories traced by such bodies have been studied in detail6-9, and can be useful in the context of efficient mixing10,11 and robotics, for example, in magnetically actuated, millimetre-sized sphericon-shaped robots12,13, or larger sphericon- and oloid-shaped robots translocating by shifting their centre of mass14,15. However, the rolling paths of these shapes are all sinusoid-like and their diversity ends there. Accordingly, we were intrigued whether a more general problem is solvable: given an infinite periodic trajectory, find the shape that would trace this trajectory when rolling down a slope. Here, we develop an algorithm to design such bodies-which we call 'trajectoids'-and then validate these designs experimentally by three-dimensionally printing the computed shapes and tracking their rolling paths, including those that close onto themselves such that the body's centre of mass moves intermittently uphill (Supplementary Video 2). Our study is motivated largely by fundamental curiosity, but the existence of trajectoids for most paths has unexpected implications for quantum and classical optics, as the dynamics of qubits, spins and light polarization can be exactly mapped to trajectoids and their paths16.


Urinary Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) • Insulin-Like Growth Factor-Binding Protein 7 (IGFBP7) Predicts Adverse Outcome in Pediatric Acute Kidney Injury.
The G1 cell cycle inhibitors tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as promising biomarkers for the prediction of adverse outcomes including renal replacement therapy (RRT) and mortality in critically ill adult patients who develop acute kidney injury (AKI). However, the prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet. The product of the urinary concentration of TIMP-2 and IGFBP7 ([TIMP-2]•[IGFBP7]) was assessed by a commercially available immunoassay (NephroCheck™) in a prospective cohort study in 133 subjects aged 0-18 years including 46 patients with established AKI according to pRIFLE criteria, 27 patients without AKI (non-AKI group I) and 60 apparently healthy neonates and children (non-AKI group II). AKI etiologies were: dehydration/hypovolemia (n = 7), hemodynamic instability (n = 7), perinatal asphyxia (n = 9), septic shock (n = 7), typical hemolytic-uremic syndrome (HUS; n = 5), interstitial nephritis (n = 5), vasculitis (n = 4), nephrotoxic injury (n = 1) and renal vein thrombosis (n = 1). When AKI patients were classified into pRIFLE criteria, 6/46 (13%) patients fulfilled the criteria for the category "Risk", 13/46 (28%) for "Injury", 26/46 (57%) for "Failure" and 1/46 (2%) for "Loss". Patients in the "Failure" stage had a median 3.7-fold higher urinary [TIMP-2]•[IGFBP7] compared to non-AKI subjects (P<0.001). When analyzed for AKI etiology, highest [TIMP-2]•[IGFBP7] values were found in patients with septic shock (P<0.001 vs. non-AKI I+II). Receiver operating characteristic (ROC) curve analyses in the AKI group revealed good performance of [TIMP-2]•[IGFBP7] in predicting 30-day (area under the curve (AUC) 0.79; 95% CI, 0.61-0.97) and 3-month mortality (AUC 0.84; 95% CI, 0.67-0.99) and moderate performance in predicting RRT (AUC 0.67; 95% CI, 0.50-0.84). This study shows that urinary [TIMP-2]•[IGFBP7] has a good diagnostic performance in predicting adverse outcomes in neonatal and pediatric AKI of heterogeneous etiology.


Deficit of endogenous spatial orienting of attention in children with benign epilepsy with centrotemporal spikes (BECTS).
Attention difficulties have been reported in children with benign epilepsy with centrotemporal spikes (BECTS) but have not yet been fully specified. The aim of this study was to evaluate the functions of exogenous and endogenous spatial orienting of attention and alerting in these children. Two versions of the spatial cueing paradigm and an alerting task, including trials with and without warning signal, were performed by 25 children with BECTS aged 6-12 years and 25 controls matched for age, gender and IQ. In these three tasks, patients were slower and made more omissions than controls. The alert effect amplitude was comparable in both groups at the longer SOAs (450 ms and 800 ms) while, at the shortest SOA (100 ms), it was greater in controls than in the BECTS group. In the first version of the spatial cueing task (peripheral cues and no probability information), the validity effect amplitude, measured by longer response times (RTs) in invalid trials compared to valid trials, was comparable in both groups. In the second version (central cues and a 75% probability that the target would appear at the cued location), the validity effect was larger in the BECTS group compared to controls because of a higher cost of invalid trials compared to neutral trials. These results suggest the existence of impairments in the endogenous orienting of attention in children with BECTS, in particular an attention disengagement deficit, while exogenous orienting of attention appears to be preserved.


Integrating Differential Gene Expression Analysis with Perturbagen-Response Signatures May Identify Novel Therapies for Thyroid-Associated Orbitopathy.
To evaluate the efficacy of Library of Integrated Network-based Cellular Signatures (LINCS) perturbagen prediction software to identify small molecules that revert pathologic gene signature and alter disease phenotype in orbital adipose stem cells (OASCs) derived from patients with thyroid-associated orbitopathy (TAO). Differentially expressed genes identified via RNA sequencing were inputted into LINCS L1000 Characteristic Direction Signature Search Engine (L1000CDS2) to predict candidate small molecules to reverse pathologic gene expression. TAO OASC cell lines were treated in vitro with six identified small molecules (Torin-2, PX12, withaferin A, isoliquiritigenin, mitoxantrone, and MLN8054), and expression of key adipogenic and differentially expressed genes was measured with quantitative polymerase chain reaction after 7 days of treatment. OASCs were differentiated into adipocytes, treated for 15 days, and stained with Oil Red O (OD 490 nm) to evaluate adipogenic changes. The expression of key differentially expressed genes (IRX1, HOXB2, S100B, and KCNA4) and adipogenic genes (peroxisome proliferator activated receptor-γ, FABP4) was significantly decreased in TAO OASCs after treatment (P < .05). In treated TAO adipocytes (n = 3), all six tested small molecules yielded significant decrease (P < .05) in Oil Red O staining. In treated non-TAO adipocytes (n = 3), only three of the drugs yielded a significant decrease in Oil Red O staining. Combining disease expression signatures with LINCS small molecule prediction software can identify promising preclinical drug candidates for TAO. These findings may offer insight into future potential therapeutic options for TAO and demonstrate a streamlined model to predict drug candidates for other diseases.


Intrathecal analgesia and restrictive perioperative fluid management within enhanced recovery pathway: hemodynamic implications.
Intrathecal analgesia and avoidance of perioperative fluid overload are key items within enhanced recovery pathways. Potential side effects include hypotension and renal dysfunction. From January 2010 until May 2010, all patients undergoing colorectal surgery within enhanced recovery pathways were included in this retrospective cohort study and were analyzed by intrathecal analgesia (IT) vs none (noIT). Primary outcomes measures were systolic and diastolic blood pressure, mean arterial pressure, and heart rate for 48 hours after surgery. Renal function was assessed by urine output and creatinine values. One hundred and sixty-three consecutive colorectal patients (127 IT and 36 noIT) were included in the analysis. Both patient groups showed low blood pressure values within the first 4 to 12 hours and a steady increase thereafter before return to baseline values after about 24 hours. Systolic and diastolic blood pressure and mean arterial pressure were significantly lower until 16 hours after surgery in patients having IT compared with the noIT group. Low urine output (<0.5 mL/kg/h) was reported in 11% vs 29% (IT vs noIT; p = 0.010) intraoperatively, 20% vs 11% (p = 0.387), 33% vs 22% (p = 0.304), and 31% vs 21% (p = 0.478) for postanesthesia care unit and postoperative days 1 and 2, respectively. Only 3 of 127 (2.4%) IT and 1 of 36 (2.8%) noIT patients had a transitory creatinine increase >50%; no patients required dialysis. Postoperative hypotension affects approximately 10% of patients within an enhanced recovery pathway and is slightly more pronounced in patients with IT. Hemodynamic depression persists for <20 hours after surgery; it has no measurable negative impact and therefore cannot justify detrimental postoperative fluid overload.


Two-color in situ hybridization in the CNS of Aplysia californica.
Aplysia californica is an attractive model organism for cellular and systems neuroscience. Currently, there is a growing body of sequence data from Aplysia that includes many interesting genes. To fully exploit this molecular data it must be integrated with the large body of physiological data that are already available for identified neurons in Aplysia networks. In situ hybridization is a powerful technique that enables this to be done. Expression patterns of selected mRNA transcripts can be mapped to individual cells in the central nervous system (CNS). Here, we describe a detailed non-radioactive in situ hybridization protocol optimized for whole-mount preparations of Aplysia ganglia. The indirect alkaline phosphatase-based chromogenic detection method we employ may be used with one or two colors in order to detect one or two different transcripts in the same preparation. The procedure is also compatible with intracellular dye labeling, making it possible to couple localization of transcripts with electrophysiological studies in positively identified neurons. Double labeling was done for transcripts encoding the neuropeptides FMRFamide and sensorin. The sensitive detection of mRNA and great preservation of CNS morphology makes this method a useful tool for analyzing expression patterns of neuron specific genes in Aplysia.


Autoimmune optic neuropathy with anticardiolipin antibody mimicking multiple sclerosis in a child.
To demonstrate that autoimmune optic neuropathy (AON) may occur in the pediatric population. Interventional case report. A 4-year-old developed four episodes of bilateral optic neuritis with mild concurrent weakness, ataxia, or dizziness; one episode of unilateral optic neuritis; and one episode of weakness over a period of 4 years. Autoimmune optic neuropathy was diagnosed because of the presence of anticardiolipin antibody and an abnormal skin biopsy with thrombin and immunoreactant deposition. She was treated with corticosteroids, aspirin, and gammaglobulin. This diminished the frequency and intensity of her attacks. This case represents the diagnosis and treatment of AON in a child.


Correction: Zgura et al. Cytotoxicity, Antioxidant, Antibacterial, and Photocatalytic Activities of ZnO-CdS Powders. Materials 2020, 13, 182.
In the original publication [...].


6-Arylamino-5,8-quinazolinediones as potent inhibitors of endothelium-dependent vasorelaxation.
6-(Substituted-phenyl)amino-5,8-quinazolinediones (3) were synthesised by regioselective substitution of 5,8-quinazolinedione (5) with appropriate arylamines in the presence of Ce(III) ions. All synthesised 5,8-quinazolinediones 3 showed a potent and efficacious inhibitory effect on the acetylcholine (ACh)-induced vasorelaxation of rat aorta with the endothelium. The quinones 3, at a low concentration of 0.1 microM, reduced the maximal response with increase of EC(50) values for ACh. The results indicate that quinones 3 are potent inhibitors of endothelium-dependent vasorelaxation.


Epidemiology of spine trauma in an Irish regional trauma unit: a 4-year study.
Currently there is a lack of information on the full spectrum of spine trauma presenting to medical services in a defined geographic area. This study analyses the aetiology and demographics of a cohort of spine trauma in the West of Ireland. A regional trauma unit has been investigated for a 51-month period. Two hundred and eighty-five cases admitted with spine trauma were documented. The annual incidence of traumatic spinal injury was 19.54 cases/100,000 persons per year. Falls and low-energy trauma are shown to constitute a significant proportion of all cases (60.35%). Injury at greater than one level is frequently present. The highest peak of injury occurred in the 20-24-year-old age group (11.58%). A second peak occurred at 75-79 years of age (7.37%). The commonest cause of neurological injury was falls (n=9; 64.3%). This spine trauma register has provided valuable insights into the patterns of injury encountered in spine trauma patients in this region. It may act as a blueprint for a national spine trauma register and highlights the importance of patient education and injury prevention strategies.


Di-propyl-ammonium 4-amino-benzene-sulfonate.
In the title mol-ecular salt, NH2(C3H7)2 +·[NH2C6H4SO3]-, the cation displays an extended conformation. In the crystal, anion-to-anion N-H⋯O and N-H⋯(O,O) hydrogen bonds generate (101) layers. Cation-to-anion N-H⋯O hydrogen bonds connect the layers into a three-dimensional network.